Post on 26-Mar-2020
Current Topics in Medicinal Chemistry 2005 5 1393-1430 1393
1568-026605 $5000+00 copy 2005 Bentham Science Publishers Ltd
Recent Advances in the Synthesis of C-oligosaccharides
Xuejun Yuan and Robert J Linhardt
Department of Chemistry and Chemical Biology Rensselaer Polytechnic Institute Troy NY 12180 USA
Abstract This paper reviews the recent advances in the synthesis of catabolically stable sugar mimetics C-oligosaccharides These compounds are synthetic analogs of the naturally occurring O-oligosaccharides in which theinterglycosidic oxygen has been replaced by a methylene group This review is organized in terms of chemistry used toassemble C-oligosaccarides under the sub-headings anionic approaches cationic methods reductive glycosyl samariumchemistry cyclization methodology and free radical chemistry
1 INTRODUCTION
Oligosaccharides (oligo means few in Greek) arecomposed of 2 to 10 glycosidically-linked mono-saccharides[1] Oligosaccharides are hydrolyzed readily by aqueous acidto form an oligosaccharides constituent monosaccharidesOligosaccharides represent a unique class of glycosides inwhich the ldquoaglyconrdquo is also a carbohydrate residue instead ofa simple alcohol
Oligosaccharides and glycocojugates are involved in amultitude of biological processes including cell recognitioncell differentiation and cell adhesion In addition a numberof protein-carbohydrate interactions mediate critical biologicalprocess such as cell signaling in growth and differentiationand fertilization [2] While these above processes aregenerally beneficial carbohydrates also play major roles in anumber of detrimental processes including inflammationviral and bacterial infections and tumor metastasis Majorachievements in the development of carbohydrate basedtherapeutics include the synthesis of a heparin penta-saccharide which displays selective antithrombic activityand the design and synthesis of derivatives of sialyl Lewis Xantigen that are interest as potential anti-inflammatoryagents [3]
However the glycosidic bonds connecting individualsaccharides units within carbohydrate-based therapeutics areunstable to mild acid and to glycosidase enzymes in vivothus agents with enhanced stability need be developed [4]Considerable research has focused on the synthesis of C-glycosides stable mimics of the naturally occurring O-saccharides These molecules in which the interglycosidicoxygen has been replaced by a methylene group can beconsidered as chemically inert isosteres of natural O- and N-glycosides and are stable to mild acid in vitro andglycosidase enzymes in vivo [5]
C-Oligosaccharides are defined as compounds with twoor more sugar units linked by one carbon atom through(1rarr1) (1rarr2) (1rarr3) or (1rarr4) linkages or linked by twocarbon atoms for (1rarr1) or (1rarr6) linkages Syntheticallyprepared C-glycosides have so far proved useful for probing
Address correspondence to this author at Department of Chemistry andChemical Biology Rensselaer Polytechnic Institute Troy NY 12180 USAE-mail linharrpiedu
stereoelectronic effects which can control the conformationof oligosaccharides and can also prevent viral and bacterialattachment to lectins in adhesion assays to the same extentas O-glycosides [6] C-glycosides can inhibit some carbo-hydrate processing enzymes Oligosaccharides and glyco-conjugates are biosynthesized through complicated highlyefficient enzyme mediated routes The structure of the finalglycoconjugate is governed by the action of a series ofenzymes Alteration in the regulation of these enzymes isbelieved to be responsible for the biosynthesis ofcarbohydrates associated with disease processes Inhibitorsof glycosidase and glycosyltransferase enzymes are currentlyreceiving attention as new pharmaceutical agents Moreovera number of enzyme inhibitors have proven therapeuticefficacy for the treatment of diseases such as influenza andAIDS [7]
Biological studies have shown that the natural inhibitorshighlighted in Fig 1 exert their effects on a range ofglycosidases and are therefore of limited use as medicinalagents [8] Consequently more specific inhibitors arecurrently being sought that can be engineered to moreaccurately resemble the substrates that they are mimickingand thereby provide greater selectivity Early tests on C-glycosides have provided evidence for their potential to actas oligosaccharide processing inhibitors [7]
Fig (1) Natural inhibitors
The area of C-linked glycoside synthesis has beenextensively reviewed over the past 15 years [9] The
HON
HOOH
HONH
HO
OHOH
HONH
HOOH
OH
N
HOH
A
OH
Castanospermine(Glucosidase I and II)
Deoxynojrimycin (Glucosidase I)
Deoxymannojirimycin (Mannosidase)
Swainsonine(Mannosidase II)
1394 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
organization of this review is based on the type of chemistryused to assemble the target C-oligosaccharides The chemistryinvolved includes anionic and cationic chemistry reductivesamariation cyclization methodology and free radicalapproaches Methods that afford the C-oligosaccharides withhigh stereoselectivity at the anomeric center (α or β) areclearly desirable This selectivity can be controlled by eitherstarting with a stereochemically defined C-glycoside whichis then coupled with another sugar or by controlling thestereochemistry of the newly formed center
2 ANIONIC APPROACHES
21 Enolate Anions
Fraser-Reid and Jarosz coupled two monosaccharideunits through a directed aldol reaction [10] Aldehyde 1 wasdeprotonated with (Me3Si)2NLi (LiHMDS) to give thechelated enolate 2 which was condensed with aldehyde 3 togive 4a as the major product (Scheme 1)
The zinc-copper-mediated reaction between 5 and 6 givesrise to the generation of single product 7 in 78 yielddemonstrating a remarkable double stereoselectivity with astrong preference for α-C-glycosylation of the ulosyl bromide
together with the elaboration of the (R) configuration for theCHOH group linking the pyranoid moieties (Scheme 2) [11]
Vogel utilized a ldquonaked sugarrdquo approach for the synthesisof an aza-C-disaccharide Enolate derived from 8 wascoupled with aldehyde 9 to give the adduct 10 in 61 yieldThe ketone was reduced and the resulting diol wasacetylated This was followed by selenoxide elimination toafford olefin 11 which was converted to 12 as shown inScheme 3 [12]
Cross-aldol reaction of racemic aldehyde 14 with enan-tiomerically pure lithium enolate of (-)-(1R4R5R6R)- or (-)-(1S4S5S6S)-13 results in mixtures composed mostly ofenantiomerically pure (+)-15 and (-)-15 respectively in 37-48 (only one of the isomers is shown in Scheme 4) [13]
Vogel and co-workers use a novel approach to C-disaccharide synthesis that involves conjugate addition andenolate trapping [14] Levoglucosenone 16 was treated withMe2AlSPh to give the aluminium enolate 17 Condensationof 17 with aldehyde 18 gave the aldol product that wasreduced with DIBAL to 20 Treatment of 20 with acidicmethanol afforded the (1rarr3)-C-disaccharide 21 (Scheme 5)
Scheme (1)
Scheme (2)
OO
OOBn
CHO
LiHMDS
5R
OO
OOBn
OHC
O
OBn OMe
OBn
OBn
C
OH6R
OO
OBnO
CHOLi
5S
OO
OOBn
OHC
O
OBn OMe
OBn
OBn
C
OH
O
OBn OMe
OBn
OBn
CHO
6S
+
1 2 3
4a 4b
O
O
Br
OBz
BzO
BzO
OO
O
O
O
O
O
O
OBz
BzO
BzO
OH
O
O
O
OO
5
1 Zn-Cu THF -35degC
2 NaHCO3
6
7 78
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1395
Enone 22 was synthesized and condensation of trappingenolate with aldehyde 23 led to a mixture of aldols 24 and 25that were separated by column chromatography on silica geland isolated in 15 and 29 yield respectively Reductionof the major aldol 25 with NaBH4 in MeOHTHF was highlystereoselective and provided the C-disaccharide 26 in 77yield (Scheme 6) [15]
When reacted with PhMe2SiZnMe2Li in THF at -78 ordmCenone 27 afforded a single adduct 28 Treatment of ketone28 with dicyclohexylboron chloride and Et3N at -15 ordmCfollowed by addition of 29 the resulting aldol-borate wasoxidized with 35 H2O2 giving adduct 30 in 24 yieldStereoselective reduction of aldol 30 with Me4NBH(AcO)3
afforded diol 31 in 59 yield (Scheme 7) [15]
22 Nitro Stabilized Anions
Vasella and Martin pioneered the use of nitro-basedanions for C-saccharide synthesis Anomeric nitro derivative32 was treated with TBAF and exposed to aldehyde 33 togive the adduct 34 in 78 yield Acetylation of 34 followedby reductive denitration afforded 35 (Scheme 8) [16]
Martinrsquos work has also relied on the Henry reactionAldol condensation of nitro sugar 36 with aldehyde 33 gave37 Dehydration of 37 and conjugate reduction led to 38Removal of nitro group by radical-based reduction followedby the removal of protecting groups gave rise to the (1rarr6)-β-C-disaccharide 40 (Scheme 9) [17]
Scheme (3)
Scheme (4)
NCbz
BnO
O
O
O
Cl
OAc
OAc
NCbzBnO
OO
O
PhSe
Cl O
OH
NCbz
CHO
OBnO
O
HO
N
OBn
OAc
CO2Me
AcO
OMe
CbzOMe
OAc OAc
O
PhSe
Cl OTHF -95 o C
1 NaBH42 Ac2O Pyr3 mCPBA
1 SOCl2 MeOH2 Ac2O Pyr3 Me3NO OsO44 Ac2O Pyr5mCPBA
LiHMDS -78 oC
8
9
10
1112
O
BnO
TBSO
O
OBnO
BzO
OBz
Br
CHO
OTIPS
O
BnO
TBSO
O
OBnO
BzO
OBz
Br
OTIPS
OH1 LiHMDS
2
1315
14
1396 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (5)
Scheme (6)
OO
O
Me2AlSPh OAlMe2O
O
SPh
O
OH
O
O
OO
O
OH
SPh
OH
O
HO
HO
OMeOH
OMe
HO
O
O
SPhO
O
O
OO
H
HO
HO
OO
O
SPhO
O
OO
HOH
DIBAL
MeOHTsOH
50 o C
16 17
18
19
2021
OO
bull
OR
O
CHOOMe
OO
NaBH4
OOH
bull
OR
OOMe
OO
OH
OO
bull
OR
OOMe
OO
HO
OO
bull
OR
OOMe
OO
OH
Me2AlSPh -78 degC
R = (t-Bu)Me2Si
22
23
24 15
+
25 2926 77
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1397
Scheme (7)
Scheme (8)
An open chain sugar derived aldehyde was used to accessa C-trehalose derivative through the Henry reactionCondensation of 36 with aldehyde 41 in the presence of KFand crown ether 18-crown-6 gave adduct 42 which wasimmediately converted to 43 with a sequence of reactions in29 overall yield The intermediate was finally transformedto the C-linked-(1rarr1)-disaccharide 44 (C-ββ-trehalose)(Scheme 10) [17]
Martin and coworkers applied the same methodologyto prepare an OC-trisaccharide namely methyl O-β-D-glucopyranosyl-(1rarr4)-C-β-D-glucopyranosyl-(1rarr6)-D-
glucopyranoside 48 [18] The condensation of compound 45with 6-aldehydo-glucopyranoside 46 in the presence of KFin an aprotic medium afforded the desired pseudotri-saccharide 47 in 73 yield Application of the samechemistry to 47 gave the target compound 48 (Scheme 11)
Kobertz and coworkers utilized Martinrsquos methodology toprepare C-allolactose Nitro sugar 49 was condensed withaldehyde 50 afforded the adduct 51 as a mixture ofdiastereomers The hydroxyl group was converted to thecorresponding phenyl thiocarbonate ester 52 Treatment withtin hydride and a radical initiator effected elimination
OO
OR OR
O SiMePh
O
HO
PhMe2SiZnMe2 Li
O
TBSO
TBSO
OTBS
OTBS
H
O
O
OR
SiMePh
TBSO
OTBS
OTBS
OH
HOHO
TBSO
O
O
TBSO
TBSO
OTBS
OTBS
OH
H
O
OR
SiMePh
Me4NBH(OAc)3
R = (t-Bu)Me2Si
+
1 THF -78 oC
2 NH4Cl H2O
3 HCl H2O 20 oC
1 (c-hex) 2BCl Et3N
2
27
28
29
30 24 over 2 steps31 59
O
O
O
O O
NO2
TBAF
O
OH
OO
OO
O
O
OO O
NO2
OO
O
OO
OH
O
O
OO O
OO
O
OO
H
OAc
32
3334 78
1 Ac2O Pyr2 Bu3SnH AIBN
35 89
1398 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
reaction yielding only E-olefin 53 Finally the olefin wasreduced with dimide (generated in situ) and benzyl etherswere removed by dissolving metal reduction to afford thetarget disaccharide 54 (Scheme 12) [19]
Gurjar et al synthesized the first methyl α-C-D-araf-(1rarr5)-α-D-araf 60 the C-disaccharide segment of motif Cof Mycobacterium tuberculosis through nitro-aldol conden-
sation The coupling reaction between 55 and 56 gavediasteromeric mixture 57 which was subjected to threesubsequent steps ie dehydration selective reduction ofconjugated olefin and denitration to give the penta-O-benzylC-disaccharide 59 (Scheme 13) [20]
Witczak has used nitro anions for C-disaccharidesynthesis Michael addition of the nitro anion derived from
Scheme (9)
Scheme (10)
OAcO
AcOOAc
OAc
NO2O
OH
O
O
OO
OHO
HOOH
OH
O
HO
HOOH
OH
Bu3 SnH
OAcO
AcOOAc
OAc
NO2
OO
O
OO
OH
OAcO
AcOOAc
OAc
X
OO
O
OO
KF 18-C-6 MeCN
1 Ac2O Pyr2 NaBH4 EtOH
38 X = NO 2
39 X = H 57
1 NaOMe
2 H3O+
36
33
37
40 89 over 2 st eps
CHO
O
O
O
O
CH2OPiv
OAcO
AcOOAc
OAc
NO2
OHO
HOOH
OH
O OH
OH
HO
OH
OAcO
AcOOAc
OAc
NO2
PivO
OH
O
O
O
O
OAcO
AcOOAc
OAc
NO2
PivO
O
O
O
O
1 Ac2O Pyr2 80 AcOH3 Ac2O Pyr
1 AcOH
2 Ac2O-BF3 OEt
KF 18-C-6 MeCN
41 36
42
4344
3 Bu3SnH AIBN
4 NaOMe
5 H3O+
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1399
61 to levoglucosenone 62 gave adduct 63 in 43 yield Thesterics in 62 dictates the facial bias of the addition whichcan only occur from the α-face Reductive denitrationfollowed by reduction of lactol and ketone afforded 64 Ringopening deprotection and acetylation gave 65 (Scheme 14)[21]
23 Sulfur Stabilized Anions
The Taylor group employed the Meyers variant of theRamberg-Baumlcklund reaction to synthesize C-disaccharides[22] The penta-O-benzyl thioglucose 66 was coupled withiodide compound 67 followed by oxidation of the formedsulfide gave sulfone 68 Exposure of the sulfone to theMeyers variant of the Ramberg-Baumlcklund reaction affordedexo-glycal 69 as a mixture of isomers in 48 yieldHydrogenation of this mixture stereoselectively reduceddouble bond and cleaved the benzyl groups Peracetylated C-
trehalose 70 was furnished by acetylation of free sugar(Scheme 15)
This approach is well suited to analog synthesis simplyby varying the alkylating agent Thus the homologous(1rarr1rsquo)-C-disaccharide containing a two-carbon bridge(ldquohomoisotrehaloserdquo) was readily prepared (Scheme 16)[23] Lactol 71 was converted into sulfonate 74 by astraightforward three-step sequence involving Moffat-typeC-glycosylation to give ester 72 followed by reduction andmesylation Next 74 was coupled with thiol 75 in a similaralkylation-oxidation sequence to that above The resultingsulfone 77 underwent a halogenative Ramberg-Baumlcklundrearrangement (RBR) to give exo-glycal 78 as a 8812mixture of (Z)- and (E)-isomers in 57 yield Subsequentreductiondebenzylation followed by acetylation producedthe novel ethylene-bridged disaccahride 79
Scheme (11)
Scheme (12)
OBnO
OBnOMe
BnO
NO2
OBnO
OBn
BnO
OBn
CHO
OHO
OH
HO
OH
OHO
OHOMe
HO
OBnO
OBn
BnO
OBn
OBnO
OBnOMe
BnO
NO2R
OBnO
OBn
BnO
OBn
OBnO
OBnOMe
BnO
KF 18-C-6 MeCN+
1 n-BuLi2 PTC-Cl
51 R = OH
52 R = OC(S)OPh
Bu3 SnH AIBN
1 TsNHNH NaOAc
2 Na NH3
49
50
5354
OAcO
OAc
AcOO
OAcO
OAc
OAc
NO2OAc
OAc
AcO
OAcO
BnOOBn
OMe
BnO
OO
AcOOAc
OAc
OAcO
OMe
BnO O
BnOOBn
O
OO
AcOOAc
OAc
NO2
OAcO
OAc
AcO
OAcO
BnOOBn
OMe
BnO
OH
KF 18-C-6 MeCN
1 Ac2O Pyr2 NaBH4 EtOH3 Bu3SnH AIBN4 H2 Pd(OH)2
5 NaOMe MeOH
45
46
47
48
1400 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
This group also reported a rapid synthesis of a range ofC-disaccharides involving a tandem Horner-Wadsworth-Emmons (HWE)conjugate-addition C-glycosylation followedby a tandem halogenation-RBR sequence utilizing Meyersvariant of the RBR [24] The HWE reagent 81 proceeded theHWEconjugate-addition sequence with diisopropylidenemannofuranose 80 in 86 yield to produce the adductsulfone 82 (as a mixture of diastereomers) The keyhalogenation-RBR was carried out using the conditions
devised by Chan et al giving E-alkene 83 as the onlyisolable product Alkene hydrogenation and concomitantdebenzylation followed by acetylation for characterizationpurposes gave the novel disaccharide 84 in 69 yield overthe two reactions (Scheme 17)
A two-directional variant of this methodology can beused to prepare symmetrical C-disaccharides as shown inScheme 18 [24] The double HWE reaction on diisopro-pylidene mannofuranose 80 worked extremely well in the
Scheme (13)
Scheme (14)
BnO
OBn
O2N
OMe
O
CHO
OBnO
OBn
BnO
OMe
OHO
OH
OHO
OH
HO
OMe
OBnO
OBn
OBnO
OBn
BnO
HO
NO2
OMe
OBnO
OBn
OBnO
OBn
BnO
X
+
KF 18-C-6 MeCN
1 Ac2O Pyr2 NaBH4 EtOH
58 X = NO 2
59 X = H 44 over 3 st eps
Bu3SnH AIBN
Pd(OH)2 H2
rt 1 atm 24 h
40
60 74
55
56
57
O
BnOOBn
BnO
OBn
OH
O
OHNO2
O
O
BnOOBn
BnO
OBn
OH
O
ONO2
O
O
O
O
O
AcOOAc
AcO
OAc
O
OAc OAc
OAc
O
BnOOBn
BnO
OBn
NO2OH
Et3 N MeCN
1Bu3 SnH AIBN
2 BF OEt Et3SH
3 L-SelectrideTHF
64 61 in 3 steps
1 Pd(OH)2 C6 H10
2 Ac2O TESOTF
61 63 43
62
65
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1401
HWEconjugation-addition C-glycosydation sequence givingdiastereomeric sulfones 85 in a combined yield of 75RBR of the major stereoisomer (βα-79) using the Meyers-
Chan procedure gave alkene 86 in 66 unoptimized yieldand hydrogenation produced the novel C-linked bisfuranosedisaccharide 87 in 76 yield
Scheme (15)
Scheme (16)
OBnO
BnO
H
OBn
OH
OOBn
BnO
OBn
OBn
BnO
OBn
OBn
OBnO
BnO
OBn
OH
SO2
O
OBn
O O
AcO
AcO
AcO
OAc
OAc
OAc
OAc
OAc
OBnO
BnO
OBn
OH
I
O
HS
OBn
BnO
OBn
OBn
68 90 over 2 steps
KOH CCl4 t-BuOH H2O
1 H2 PdC
2 Ac2O Pyr
70 69 over 2 steps
+
1 K2CO3
2 mCPA66
67
69
O
BnOOBn
BnO
OBn
OH
(EtO)2P(O)CH2CO2Et
OBn
OBn
OBnO
OBn
OBnO
BnOOBn
OBn
X
O OBn
OBn
BnOOBn
OBnO
BnOOBn
OBn
OBnO
BnOOBn
OBn
R
OBnO
BnOOBn
OBn
SH
LiAlH4
OAc
AcOOAc
O OAcOAcOAcO
OAc
OAc
1 H2 Pd(OH)2C
2 Ac2 O Pyr
NaH THF
72 R = CO2Et
73 R = CH2OH
66 over 3 steps
K2CO3 acetone
76 X = S
77 X = SO2 79
Oxone THF MeOH H2 O
KOH CCl4 aq tBuOH
78 57ZE 8812
79
71
75
MsCl Et3N 74 R = CH2 OMs
1402 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Norris et al deprotonated 88 with n-BuLi and theresulting anion was coupled with an excess lactone 89 at lowtemperature to afford the adduct 90 in 77 yield SPhgroups were removed with Raney nickel and lactol 91 wasisolated as a syrup that contained two components in
approximately a 41 ratio The two compounds were thoughtto be α- and β-lactols with the latter being major It wasstraightforward to reduce the lactols with a high degree ofstereocontrol to afford the C-disaccharide 92 with a 51isolated yield (Scheme 19) [25]
Scheme (17)
Scheme (18)
O
O O
O
O OH
O OMe
OBnBnO
SO2
P
EtO
EtO
O
OBn
O
OMe
OAc
OAc
OAcO
O O
O
O
O
OO OMe
OBnBnO
SO2
OBn
O
O O
O
O O
O
O
O
OMe
OBn
OBn
OBn
83 50 E only
80
+
NaH THF -78 oC
82 86αβ 11
KOHAl2O3
CBr2F2 CH2Cl2
tBuOH 5 oC
2 h
1 H2PdC EtOAc RT 7h
2 Ac2 O Pyr RT
84 69 over 2 st eps
81
O
O O
O
O OH POEt
OEt
O
SO2
P
EtO
EtOO
O
O
O
OO
O
O
O
O O
O
O
O O
O
O
O
O SO2
O
O
O
O
O
O O
O
OO
O
O
85 75βαββ ca 31
86 66β αββ = 141 E only
H2PdC EtOAc
87 76βαβ β = 141
21 NaH THF -78 o C
80 (2 equiv)
KOHAl2O3CBr2F2 CH2Cl2tBuOH
on majorβα is omer
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1403
24 Phosphorous Stabilized Anions
The most common type of reaction discussed in thissection is Wittig approach to C-oligosaccharide synthesisThis methodology is particularly suited for synthesis of(1rarr6)-C-saccharides since one sugar can hold the aldehydewhile the other the ylid or phosphonate anion
Dondoni has utilized this approach to prepare a variety ofβ-D-(1rarr6)-C- disaccharides The general approach is shownin Scheme 20 Coupling of β-linked galactopyranosyl ormannofuranosyl derivative (93 94 95 or 96) with ylidefrom phosphonium iodide 97 or 98 gave alkene 99 Alkenewas reduced and removal of deprotecting groups gave thecorresponding β-D-(1rarr6)-C- disaccharide 100 [26]
α-D-(1rarr6)-C-disaccharide 103 was also synthesizedusing the approach (Scheme 21)
Dondoni applied this methodology in an iterative fashionto prepare the corresponding β-(1rarr6)-C-trigalactosides andβ-(1rarr6)-C-tetragalactosides [27] Starting with coupling ofylide 104 generated in situ with aldehyde 33 gave adduct105 (EZ 19) Removal of silyl protecting group followed byoxidation led to aldehyde 106 which was coupled with theylide from 104 to give C-trisaccharide 107 in 36 yield Thesame sequence was repeated with 107 afforded the protectedC-tetrasaccharide alkene 108 Compounds 108 wasdesilylated and exposed to hydrogen over Pd(OH)2 oncarbon followed to peracetylation gave protected C-tetrasaccharide 109 (Scheme 22)
Taking advantage of their experience on the stereo-selective synthesis of C-oligosaccharides by iterative Wittigolefination this group developed new building blocks and amodified protocol for the straightforward assembly of C-α-(1rarr5)-D-oligoarabinofuranosides [28] While the twomonofunctionalized sugar moieties 110 and 111 weresuitable precursors to the head and tail of the oligo-saccharidic chain the difunctionalized compound 114 was arepeating unit (Scheme 23) Building block 114 wasdesigned to allow after the Wittig coupling for regenerationof the formyl group in a single step under conditions that donot affect the chemical and stereochemical integrity of thegrowing saccharidic chain (Scheme 24)
Colinas et al reported a method for the synthesis of C-disaccharides by a sequence involving the Wittig reaction askey step and further glycosydation of these compounds toafford new C O-trisaccharides [29] The enol ether 122a-bwere prepared by the Wittig reaction of the α β mixture of2-deoxiglycosyl phosphonium salts 120a-b with aldehyde121 Hydrogenation of the exo-glycals afforded the β-C-disaccharides with good yields The O-glycosidationemploying the exo-glycals and the glycosyl acceptor 124 isillustrated in Scheme 25
25 C-1 Vinyl Anions
Schmidt was the first to explore the addition of sulfoxide-stabilized vinyl C-1-organolithiums to carbohydrate-basedcarbonyl compounds [30] The vinyl sulfoxide 126 was
Scheme (19)
OCH3
O O
OPhS
PhS
O O
OO
OCH3
O O
OO O
O H
OCH3
O O
OPhSPhS
O O
O OH
OCH3
O O
OO O
O OH
+
n-BuLi THF -78 oC
Raney Ni EtOH H2O rt
Et3SiH BF3 OEt2
90 77
92 51 over 2 steps 91 is omers rati o βα = 41
-78 oC
88
89
1404 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
deprotonated with LDA to give 127 Addition of 127 toaldehyde 128 gave a mixture of diastereoisomers of whichthe major 129 was formed in a 101 ratio Desulfurizationhydroboration and removal of benzyl groups gave the(1rarr5)- βminusC-disaccharide 130 (Scheme 26)
Schmidt and coworkers used this methodology for ahighly efficient synthesis of an analog of C-trehalose 134Scheme 27 [31] Anion 131 was converted to aldehyde 132
and condensation of this aldehyde with the same anion gaveadduct 133 which was then converted to the target C-disaccharide 134
26 Acetylide-Based Anions
Sinayuml was the first to prepare a C-disaccharide Hisapproach involved the coupling of a C-6 alkyne with ananomeric lactone followed by reduction of the formedhemiacetal [32] Aldehyde 135 was converted to the
Scheme (20)
Scheme (21)
OO O
O
O CHO
O
BnOOBn
BnO
OBn
CHO
OBn
CHO
BnO
O
BnOBnO
O
BnOOBn
BnO OBn
CHO
PPh3I-
OO
O
OO
O
OMeOBn
OBn
OBn
PPh3I-
OCHO
O
PPh3I-
ORRO
RO
OO
ORRHO
OO
OR
+ +
+
( 93 - 96 )
( 97 - 98 )
BuLi THF-HMPA
-30 iexclaelig
99
Reduction
100
+
93 9495
96 97 98
O
OBnBnO
BnO
OO
O
OO
HO
O
O
OO
PPh3I-
O
OHHO
HO
O
HOOH OH
HO
OBnBnO
CHO
BnO
O
+
BuLi THF-HMPA
-30 oC
1 p-MeC 6H4SO2-
NH2NH2 AcONa
2 H2 Pd(OH)2 3 bar
3 Amberli te H+
+
10197
102
103
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1405
dibromoalkene 136 which was treated with n-butyllithium togive an intermediate acetylide 137 The latter uponnucleophilic addition to lactone 138 gave a mixture of lactol139 in high yield Stereoselective reduction of lactol 139 wasfollowed by hydrogenation of benzyl groups and the triplebond affording the (1rarr6)-β-C-disaccharide 140 (Scheme28)
The lactone-addition methodology was later applied bySinayuml and co-workers in an iterative fashion for the
preparation of higher homologues [33] Hydroxylmethylenein compound 141 was converted to acetylide lithium incompound 142 by a sequence of reactions Condensation ofcompound 142 with the galacto lactone 143 gave 144 asmixture of anomers The lactol were stereoselectivelyreduced to and triple bond was hydrogenated to give 145Methyl glycoside 145 was hydrolyzed to the correspondinglactols which were oxidized to lactone 146 The samesequence was then repeated twice to give C-trisaccharide147 and C-tetrasaccharide 148 (Scheme 29)
Scheme (22)
O
BnOOBn
BnO OTBDPS
PPh3I-
BnO
H
O
BnOOBn
OTBDPS
OO
O
OO
O
CHOO
O
OO
O
BnO
O
BnOOBn
BnO
OO
O
OO
H
HOBn
BnO OTBDPS
O
BnOOBn
BnO O
OO
O
OO
H
OBn
BnO OTBDPS
PPh3I-
O
BnO
O
BnOOBn
BnO OTBDPS
PPh3I-
O
AcOOAc
AcO
O
AcOOAc
AcO
OO
O
OO
O
AcOOAc
AcO OAc
O
BnOOBn
BnO
O
BnOOBn
BnO
OO
O
OO
H
H
O
BnOOBn
BnO OTBDPS
H
1 TBAF2 PCC
+107 36
+
1 TBAF2 PCC3
+
1 TBAF2 H2 Pd(OH)2 C3 Ac2 O Pyr
104
33
105
106104
104
108109
BuLi THF-HMPA
-50 o C
70EZ 19
BuLi THF-HMPA
-50 o C
1406 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
The di- tri- and tetrasaccharide derivatives (145 147 and148) were all debenzylated and tested for their bindingaffinity to three different monoclonal immunoglobulins withspecificity for different O-β-(1rarr6)-D-galactopyranosyl deter-minants These C-saccharide analogs had similar bindingproperties to the corresponding O-saccharides
Schmidt has also used acetylide-lactone condensation toassemble C-disaccharides of ketoses [34] Lithium acetylide149 was condensed with ketone 150 to give a mixture ofalcohol 151 after removal of the pivoloyl group Attemptedcyclization under Lewis acid catalysis resulted only in theremoval of the acetonide Accordingly the diol was tiedback as the carbonate and the acetylene complex as thedicobalt species 152 The isomers were then separately
cyclized to give a 11 mixture of C-disaccharide 153 Thecobalt complex on α-C-disaccharide was removed understandard conditions to give 154 and deprotection of thecarbonate was followed by hydrogenation and peracetylationto give 155 (Scheme 30) Similar chemistry was also carriedout with the corresponding β-isomer
Van Boom and co-workers used lithiated alkynylderivative 156 in presence of ZnCl2 to selectively open ringof the 12-anhydrosugar 157 affording the α-C-(alkynyl)-glycoside 158 Hydrogenolysis of the benzyl groups wasfollowed by peracetylation to give the (1rarr6)-α-C-disaccharide 159 (Scheme 31) [35]
Normally attack of the nucleophile proceeds from anequatorial direction to give the β-isomer The unexpected
Scheme (23)
Scheme (24)
BnOO
OBnCHO
OBn
O
OBn
PPh3I-
OBn
OBn
O
OBn
BnOBnO
O
OBnOBn
OBnH
O
OH
HOHO
O
OHOH
OH+
BuLi
THF-HMPA
-20 oC+
1 TBAF2 H2 Pd(OH)2C
112 65 113 100
110
111
O
OBnCHO
OBnBnO
O
OBn
BnOBnO
O
OBnCH(OiPr)2
OBnH
O
OBnCH(OiPr)2
PPh3I-
OBn
O
OBn
BnOBnO
O
OBn
OBnH
O
OBnOBn
BnOH
O
OH
HOHO
O
OH
OH
O
OHOH
HO
++
BuLi
THF-HMPA
-20 oC
BuLi
THF-HMPA
-20 oC
TFA H2 O THF rt
115 49
116 R = CH(OiPr)2
117 R = CHO
118 45
H2 Pd(OH)2C
110
114
114
119
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1407
Scheme (25)
Scheme (26)
OBn
R1
R2
PPh3BF4-O
O
OOHC
O
O
O
O
O
O
O
O
HO
O
O
O
O
O O
OBn
R1
R2
O
O
O
O
O
O
H
O
OBn
R1
R2
O
O
O
O
O
O
O
O
OBn
R1
R2
O
O
O
+
BCl3 (005 equiv)
MS 4A CH2 Cl2 0 o C
+
BuLi THF -90 oC -90 o C
to rtH2 (1 atm) PdC Et3N MeOH
R1 R2 = OBn H
120a - b
121
122a - b
123a - b
124
125a - b
OTBDPS
BnO X
SO Ph
O
BnO
OHCO
BnO
OMeOBn
OBn
O
BnO
OTBDPS
BnO
SO Ph
O
BnO
OMeOBn
OBn
O
HO
OMeOH
OHO
HOHO
OH
OH
128
229 74
1 RaNi (74)
2 BH3 DMS
NaOH H 2O2 (74)
3 H2 PdC (70)
130 74
LDA THF
-100 oC
126 X = H
127 X = Li
1408 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (27)
Scheme (28)
stereochemical outcome is rationalized by the generation ofan initial zinc acetylide species which facilitates intra-molecular delivery to the α-face (Scheme 32)
Wightman synthesized C-disaccharide analogs of the α-D-arabinofuranosyl-(1rarr5)-α-D-arabinofuranosyl motif ofmycobacterial cell walls through alkynyl intermediates [36]The lactone 164 was treated with lithio(trimethylsilyl)ethyneat low temperature to give lactol in 66 yield of 165Treatment of this with triethylsilane and BF3
Et2O gavethe separable isomers 166α (60) and 166β (13)Desilylation of the major isomer 166α gave 167 in 97yield Treatment of 167 with n-BuLi followed by addition oflactone 164 gave 85 yield of the hemiacetal 168 which onreduction with Et3SiH and BF3
Et2O gave the disubstitutedalkyne 169 (83) as the major product Reduction-
hydrogenolysis of 169 then gave the C-disaccharide 170 innear-quantitative yield (Scheme 33)
3 REDUCTIVE GLYCOSYL SAMARIUM SPECIES
The introduction of SmI2 as reducing agent can becredited to Kagan and has since been utilized in numeroussynthetic schemes [37] Sinayuml and Beau introduced SmI2
chemistry into C-glycoside synthesis through intermolecularreactions with appropriate electrophiles and intramolecularreactions of silyl tethered substrates [38] Anomericsamarium species are highly stable and not likely to undergoβ-elimination Treatment of the aryl sulfone 171 with SmI2
affords the nucleophilic intermediate 172 through two singleelectron transfer processes Introduction of a suitableelectrophile (carbonyl compounds) affords the α-C-manno-
O
BnO
OTBDPS
BnO X
SO Ph
O
BnO
OBn
BnO Li
SO Ph
DMF
OHO
HOOH
OH
O OH
OH
HO
OHOH
O
BnO
OTBDPS
BnO
SO Ph
O
OBn
OBnOBnSO
Ph
OH
131 X = Li
132 X = CHO
THF -100 oC
1 Ra-Ni
2 BH3 DMS NaOH H2O2
3 H2 PdC
131
133
134
OBnO
OBnOMe
BnO
Li
OBnO
BnOOBn
OBn
OOBn
OBnOMeBnO
OH
OBnO
BnOOBn
OBn
O
n-BuLi
BnO
OMe
BnO
BrBr
O
OBn
OHO
OH
OH
HO
OHO
OH
HO
OMe
O
BnO
OMeOBn
O
BnO
139 92
1BF3 OEt2 EtOH
2 H2 PdC AcOH
140 52 over 2 steps
135 136 137
138
CBr4 PPh3
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1409
pyrannoside 173 in good yield and with excellent stereo-selectivity (Scheme 34) [38a]
Preparation of C-glycosides of ulosonic acids using SmI2
was pioneered by Linhardt and coworkers [39] Coupling ofpyridyl sulfone 174 with aldehyde 175 in the presence ofSmI2 gave an excellent yield of the N-acetylneuraminic acidC-disaccharide 176 as single isomer This stereochemicaloutcome was rationalized on the basis of the Felkin-Anhmodel for predicting the stereochemical outcome of akinetically controlled addition of a nucleophile to a chiraladehyde (Scheme 35 A)
Reductive samarium method was utilized to synthesizesialo-antigen C-analogs by the Linhardt group A fullyprotected C-analogue of the SialylTn antigen α-D-Neu5Ac-(2rarr6)α-D-GalNAc-(1rarrO)-Ser 182 was prepared [40] C-glycosylation of the neuraminic acid sulfone donor with
aldehyde acceptor in presence of excess SmI2 afforded the α-C-glycoside 180 as an RS mixture (11) The criticalintermediate aldehyde acceptor 178 was prepared in 13steps Chemoselective resolution to compound 180 wasundertaken by oxidation with DMSOAc2O to keto-bridgedcompound 181 followed by stereoselective reduction withZn(BH4)2 to regenerate the bridge hydroxyl function gave182 in gt90 de (Scheme 36)
A common versatile N-acetylneuraminic acid C-disaccharide precursor of the C-glycoside analogs ofgangliosides GM4 and GM3 has been synthesized [41]Samarium(II) iodide coupling of N-acetylneuraminic acidsulfone 179 with a 3-formyl galactopyranoside derivative183 afforded the corresponding C-disaccharide 184 as amixture of (R) and (S) isomers at the newly formedhydroxymethylene bridge This diastereoisomeric mixturewas resolved after debenzylation of the galactoside residue
Scheme (29)
O
BnO
BnOOBn
OBn
OOBn
OBnOMe
OBnOH
O
BnO
BnO
OBn
OBn
O
O
BnOOBn
OMe
BnO
Li
OBnO
OBn
OBn
OBnO
OBn
OBn
OMe
OBnO
OBn
OBnBnO
OBnO
OBn
OBn
OBnO
OBn
OBn
OMe
OBnO
OBn
OBnOBnO
OBn
OBnBnO
O
BnO
BnO
OBn
O
OBnO
OBn
OBnBnO
OBnO
OBn
OBnBnO
OBnO
OBn
OBn
OMe
OBnO
OBn
OBnBnO
OMe
1 PCC2 CBr4 Ph3P3 n-BuLi
144 overall yield 54
1 BF3 OEt2 Et3 OH
2 H2 PtO2 EtOAc
145 76
1 H2 SO4 AcOH
2 PCC
146 62
repeat steps
repeat st eps
141 142
143
147
148
1410 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (30)
Scheme (31)
O
BnOOBn
OMe
Li
BnO
OPivBnO
OBn
OBn
BnO
O OO
BF3 OEt2
OBnO
OBn
OBn
BnO
OO
O
OMe
BnOOBn
BnO
Co(CO)3
Co(CO)3
O
CAN
OBnO
OBn
OBn
BnO
OO
OO
BnOOBn
BnO
OMe
OHBnO
OBn
OBn
BnO
OHO
O
O
OMe
BnOOBn
BnO
Co(CO)3
Co(CO)3
O
OPivBnO
OBn
OBn
BnO
OH OO
O
OMe
BnOOBn
BnO
OAcO
OAc
OAc
AcO
OAcOAc
OAcO
OAc
AcO
OMe
1
2 NaOMe MeOH
1 Lewis acid2 ClCO2CCl3 Pyr3 Co2(CO)8
with a-isomer
1 Et3N Pyr H2O
2 H2 PdC H+
3 Ac2 O Pyr
149 151
152153
154 155
150
OBn
BnO
OBnO
OBn
BnO
OBnO
BnO
MeO
OBnO
OBn
BnO
O
OMe
AcO
OAcO
OAc
OAc
AcO
OAcO
OAc
O
BnOOBn
OMe
BnO
159 74 over 2 steps
+
BuLi ZnCl2 THF
1 H2 PdC2 Ac2O Pyr
156 157
158 59
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1411
Scheme (32)
Scheme (33)
and the chirality of each isomer assigned after acetylationConversion of the p-methoxyphenyl group in the peracety-lated (S) isomer 187 into the corresponding thiophenylglycoside 188 was accomplished affording the key inter-mediate for the synthesis of C-glycoside analogs of GM4GM3 and other related gangliosides (Scheme 37)
Ganglioside GM4 is a very important cell adhesionmolecule The C-disaccharide of GM4 is currently beingsynthesized in Linhardtrsquos lab using standard O-glycosylationof C-disaccharide with protected ceramide Once theceramide has been attached it can be oxidized to afford analdehyde group for coupling to keyhole limpet hemocyanin
OBnO
OBn
BnO
O
OBnO
ClZnO
OBn
BnOCl
R
OBnO
O
OBn
BnOCl
ZnR
O
ZnR
OBnO
OBn
BnO
160 161
162163
O
OBn
OBnBnO
O
O
OBn
OBnBnO H
TMS
O
OBn
OBnBnO H
O
OBn
BnO
OBnHO
O
OBn
OBnBnO OH
TMS
OBnBnO HO
OBn
TMS
O
OR
ORRO H
O
OR
RO
OR
OBn
OBnBnO
H
TMS
O+
K2CO3 MeOH
1 n-BuLi THF -78 oC
2 164
164165 66
166α 60 166β 13167 97
BF3 Et 2O Et 3SiH -78 oC
168 85
169 R = Bn 83
170 R = H near quantitative yield
H2 (1 atm)Pd(OH) 2C
TMS-acetyl ene
n-BuLi THF -78 oC BF3 Et2O Et3SiH
-78 o C
1412 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
O
OHCOBn
OBnBnO
OMe
O
CO2MeAcO
OAcAcHN
OAc
SO2
NAcO
OBnH
H
OBn
OBn
H
O
OMeH HH
A
O
CO2MeAcO
OAcAcHN
OAc
O
OBnOMe
OBnOBn
HO
AcO
+
Nu
174175
176
SmI2 THF
Scheme (34)
Scheme (35)
Scheme (36)
O
BnO
BnO
BnO
Si lylO
O2S N
O
BnO
HO R2R1
BnOBnO
SilylO
OBnO
BnO
BnO
SilylO
Sm(III)
R1COR2 SmI2 THF
171 172
173
NHBoc
OAcO
AcO
AcHN O
O
CO2BnO
OO
OO
OH
O
CO2MeAcO
OAcAcHN
OAc
AcO
SO2Ph
R2
O
CO2Me
AcHN
OAc
AcO
R1
AcO
AcO
AcHNO CO2Bn
NHBoc
AcO
OAc
O
Zn(BH4)2
180 R1 R2 = H OH ( RS 11)
181 R1 R2 = O
182 R1 = H R2 = OH de gt 90
DMSO Ac2O
177178
179
13 steps
22 equiv SmI2 THF
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1413
Scheme (37)
Fig (2)
(KLH) by reductive amination for use as carbohydrate-basedvaccine GM3 a related trisaccharide containg gangliosideplays an important role in cell growth and differentiationFig 2 The synthesis of C-oligosaccharide GM3 is currentlyunderway following a similar route to that of C-GM4synthesis [42]
Beau also reported a sialyl C-disaccharide synthesiswhich relied on the unprecedented use of a stable andcrystalline 2-pyridyl sulfide of the N-acetylneuraminic acidderivative 189 as the anomeric precursor in a samarium-Reformastky procedure [43] The coupling procedure withsulfide 189 and aldehyde 190 afforded the carbon-linkeddimer 191 in 93 yield as a 11 diastereomeric mixture
Alcohols 191 were converted into thiocarbonates anddeoxygenated by employing triphenyltin hydride catalyticAIBN and pentafluorophenol which yielded C-disaccharide192 as a single compound in 65 yield for the 2 stepsDesilylation hydrogenolysis acetylation and finalacetolysis of the methyl glycoside provided the carbon-linked mimic 193 of the disaccharidic component of thesialylTn tumor antigen (Scheme 38)
4 CATIONIC METHODS
This section is categorized according to reactions thatinvolve the generation of anomeric ions followed by thecapture with sugar-based nucleophiles
OAcAcHN
OAc
AcO
O
OBnBnO
OBnOMP
HO
O
MeO2CAcO
O
MeO2CAcO
OAcAcHN
OAc
AcO
O
OHHO
OHOMP
HO
O
OBnOHC
OBnBnO
OMP
O
MeO2CAcO
OAcAcHN
OAc
AcO
O
OHHO
OHOMP
HO
O
CO2MeAcO
OAcAcHN
OAc
AcO
SO2Ph
O
MeO2CAcO
OAcAcHN
OAc
AcO
O
OAcAcO
OAcX
AcO
H2 PdC EtOAc CH3OHH2O
+
Ac2O Pyr
187 X = OMP
188 X = SPh 73
184 85 R and S mixture
186 90 for two i somers
+
SmI2 THF183
179
185
O
HO2 CHO
OAcAcHN
OH
HO
O
OHHO
OH
OAcO
(CH2 )12 CH3
HN
OH
(CH2)14CH3
O
O
O
OHHO
OH
O
O
HO2 CHO
OAcAcHN
OH
HO
O
OHHO
OH
O(CH2)12CH3
HN
OH
(CH2)1 4CH3
GM4
GM3
1414 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
41 Exo-glycals as Nucleophiles
Nitotra et al have found that treatment of exo-glycal 194with BF 3
OEt2 followed by a water quench afforded the C-disaccharide 195 (Scheme 39) It is noteworthy tonoteworthy that the attack of the enol ether on the anomericoxonium ion occurs with high stereoselectivity on the α-face only 195 was obtained [44]
42 Silyl-based Nucleophiles
Isobe has designed and developed alkynylation as a keyreaction for the introduction of a carbon chain onto sugarsThose alkynylated compounds are called ldquosugar acetylenesrdquo[45] The mechanism includes eliminative formation ofcation to which silylacetylene can coordinate on the α-face(Scheme 40)
Double C-glycosylation between glycal 198 and bis(silylacetylene) gave C-disaccharide ldquolikerdquo compounds 199and 200 (Scheme 41)
Silylpropargyl-sugar 201 smoothly reacted with D-glucalto furnish exclusively the α-acetylene glycoside product 202in 88 (Scheme 42) [46]
5 CYCLIZATION METHODOLOGY
This approach to C-oligosaccharide synthesis relies onthe coupling of an open chain fragment with an intact
monosaccharide to give an intermediate that is then cyclizedto deliver the C-oligosaccharide target This section isdivided by the type of chemistry used to initially assemblethe two pre-cyclization fragments
51 Wittig Reaction-Cyclization
The Kishi group was the first to use Wittig-cyclizationapproach to synthesize C-disaccharides Starting with Wittigreaction between 203 and 204 the intermediate 205 wasafforded as a single stereoisomer in 82 yield Osmylationthen gave a mixture of diols with the major one formed in a61 ratio Selective protection of the diols gave 206a and206b The mono-para-methoxybenzyl ether 206a was thentransformed into the hemiketal 207 in 75 overall yield inthree steps ie (1) Swern oxidation (2) acetonide hydro-lysis (4 N HClTHFrt) and (3) benzoylation (3 equiv ofPhCOClpyCH2Cl2rt) Silane reduction of 207 in an acidicmedium should preferentially yield the equatorially substi-tuted β-C-glycoside which was deblocked and converted tothe methyl- βminusC-disaccharide 209 Exact parallel experi-ments applied to the minor isomer gave the correspondingC-disaccharide 210 (Scheme 43) [47]
Armstrong has employed Wittig-osmylation protocol forthe preparation of a small library of α-C-(1rarr6)-disaccha-rides [48] Readily available allyl C-glycoside 211 washomologated to diene ester 212 and subjected to osmylation
Scheme (38)
O
CO2MeAcO
OAcAcHN
OAc
AcO
S(2-Py)
O
TESO
AcHNOMe
O
HO
O
CO2MeAcO
OAcAcHN
OAc
AcO
O NHAcOAc
OAc
OAc
O
CO2MeAcO
OAcAcHN
OAc
AcO
O NHAcOBn
OTES
OMe
OAc
AcO
O NHAcOBn
OTES
OMeOH
O
CO2 MeAcO
OAcAcHN
+
192 65
1 MeOHHCl2 H2 PdC EtOH3 Ac2O Pyr4 Ac2OAcOHH2SO4
193 59 overall yield
25 equiv SmI2 THF
1 11-thiocarbonyldiimidazole DMAP2 Ph3SnH cat AIBN
191 93
189
190
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1415
Scheme (39)
Scheme (40)
Scheme (41)
OBnO
OBn
OBn
OBnO
OBn
OBn
OBnO
OBn
OBn
OBnO
OBnCH3
BnO
OH
CH2
OBnO
OBn
CH3
OBn
H2 O
BF3 OEt2 MeCN
194
195 96
OOAc
OAc
AcO
R SiMe3
SnCl4
O
OAc
AcO
R
O
OAc
AcO
O
OAc
AcO
Me3Si
R
SiMe3
196
197
Me3 Si SiMe3
O
AcO
OAc
OAc
SiMe3
SiMe3
O
AcO
OAc
O
OAc
OAc
O
AcO
AcOO
OAc
OAc
SnCl4 CH2Cl2
SnCl4 CH2Cl2198
199
200
1416 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (42)
Scheme (43)
AcO
OAc
OAc
Me3 Si
BnO
OBn
BnO
OBn
AcO
OAc
BnO
OBn
BnO
OBn
+ I2 CH2Cl2
202 88
198 201
O
OBn
OBn
O
O
O
OBn
OBn
O
O
OBn
OBn O
OBn
OBn
O
OPBH2M
OH
OBnO
BnO
BnO
O
OBn
OBn
O
OHOPMB
OHO
HO
HO
O
OH
OHOH
OH
HOOMe
O
OBnOBn
O
Ph3P
O
O
OBn
OBn O
OBn
OBn
O
OPBM
OH
O O
CHO
OBn
BnO
OO
OBn
OBn
O
OHOPMB
BnO
BnO
BnO
OHO
HO
HO
O
OH
OHOH
OH
HOOMe
+ THF -78 oC
1 OsO4 pyr THF
2 NaH PMBBr
206a 206b 206a206b 61
1 Swern [O]2 4N HCl3 PhCOCl pyr
1 Swern [O]2 4N HCl3 PhCOCl pyr
1 PrSiH BF3 OEt2
2 H2 Pd(OH)2C
3 HCl MeOH 90 oC
1 PrSiH BF3 OEt2
2 H2 Pd(OH)2C
3 HCl MeOH 90 o C
203
204
205
207
209
208
210
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1417
followed by reduction to afford a 51 mixture (213214215216) of lactols that were readily separable by chromato-graphy Following a deprotection of an equimolar mixture of213 and 214 217 and the DL hybrid C-disaccharide of D-glucose-O-(1rarr6)-L-galactose 218 were obtained The DDand DL derivatives 219 and 220 of glucose-α-(1rarr6)-idosewere also obtained as a near equimolar mixture afterdeprotection of 215 and 216 (Scheme 44)
52 Anion Addition-Cyclization
Kishi developed an approach for the synthesis of theCndashtrehalo sugars which relied on nucleophilic addition ofone intact sugar fragment to a fundamental aldehyde ieKishi-Nozaki reaction [49] Coupling of monosaccharide221 and aldehyde 222 gave 223 The triple bond waspartially reduced and osmylation was followed by selectiveprotection to afford 224 The acetonide was converted toepoxide 225 by standard methods and removal of the PMBgroup Acid-catalyzed cyclization followed by aglyconichydrolysis and protection of hydroxyl group with (p-methoxyphenyl)diphenylmethyl chloride (MMTrCl) gave226 Inversion of the C-2 hydroxyl and removal of protectinggroups delivered α α-C-trehalose 227 (Scheme 44)
Kishi and co-workers also employed aldol reactions as anefficient access to the C-trisaccharide related to the type IIABO(H) blood group determinant [50] Aldol condensationof the enolate of methyl ketone 228 with aldehyde 229 gavea 41 mixture of hydroxy ketones 230 and 231 The majorketol was cyclized desulfurized and oxidized to afford thedisaccharide ketone 233 The ketone in THF was treatedwith LiHMDS (3 equiv) and TMEDA followed by theaddition of MgBr2 Addition of the aldehyde 234 led toalmost exclusive formation of the equatorial products 235and 236 in a 12 ratio Mesylation of 235 and 236 followedby treatment with liquid ammonia gave enones 237a and237b which were reduced to yield exclusively the C-2rsquo-equatorial ketone 238 Sodium borohydride reduction of theC-3rsquo carbonyl proceeded with the desired stereoselectivity toyield the protected C-trisaccharide 239 which wasdeblocked to provide the polyol 240 (Scheme 46)
Sutherlin and Amstrong cleverly applied a recursivestereochemical deconvolution (RSD) combinatorial approachfor the synthesis of a small library of C-trisaccharides aspotential inhibitors for the cell surface proteins of bacteriumHelicobactor pylori [51] The workers chose to carry outvariations in galactose ring of these trisaccharides An
Scheme (44)
OBnO
BnOOBn
OBn
P O
OEtOEtO
EtO
R H
OH
OH
OH
OH
O
R H
OH
OH
OH
OH
O
OHO
HOOH
OH
O
HO
OHOH
OH
OHO
HOOH
OH
O
HO
OH
OH
OHO
HOOH
OH
O
HO
OH
OHOH
R H
OH
OH
OH
OH
O
R
OBnO
BnOOBn
OBn
O
OHO
HOOH
OH
OO
HOHO
OH
R H
OH
OH
OH
OH
O
1 OsO4 NMO 50
2 DIBAL -32 oC 40
++ +
213 214 215 216
217 218 219 220
1 9-BBN H2O22 Swern [O]
3 t-BuOK
4 I2 C6H6212
211
1418 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
efficient Nozaki-Kishi coupling of vinyl bromide 241 withaldehyde 242 in a diasteromeric ratio of 12 followed byprotection with TBSOTf led to 243 and 244 Hydroborationfollowed by oxidation gave aldehydes 245 and 246respectively Addition of allylmagnesium bromide toaldehyde 245 followed by removal of the silyl groupafforded 247 to 246 giving 248 and 249 Epoxidation gave a11 mixture of the corresponding epoxides which werecyclized to give the C-trisaccharide 250-255 after removalof the benzyl groups (Scheme 47)
Schmidt reported a stereoselective 6-exo-trig selectiveelectrophilic cylization approach for de novo synthesis of amethylene-bridged Neu5Ac-α-(23)-Gal C-disaccharide theC-analog of an important motif in glycosphingolipids [52]The open chain precusors 259ab (a 32-mixture ofdiaseteromeric alcohols) were formed by the addition oflithiated iodide 256 to open chain aldehyde 258 Subsequent
C1 incorporation using Tebbe-reagent formation of a cycliccarbonate and deprotection of the two isopropylidene ketalsafforded tetrol 264 which upon treatment with phenylselenyltrifilate was steroselectively cyclized in a 6-exo-trigselective manner affording a diasteromeric mixture of 251and 252 in a ratio of 71 A seleno-Pummerer rearrangementto afford aldehyde 267 in 5 steps in 90 overall yieldOxidation of the aldehyde and subsequent steps led to thedesired C-disaccharide 268 (Scheme 48)
53 Esterification-Cyclization
Work from the Postema group has focused on a ringclosing metathesis (RCM) approach for the synthesis of C-saccharides [53a] The chemistry is versatile and has beenused for the synthesis of a small library of differentiallylinked β-C-disaccharides through a radical allylation-RCMstrategy [53b] The synthesis of the β-(1rarr4)-glucopyranosyl
Scheme (45)
O
OBn
BnO
BnO
BnO
I
CrCl2-NiCl2O
OBn
OH
BnO
BnO
BnO
O
O
O
O
O
H
OBn
O
O
OBnBnO
BnO
BnO
OOBn
OBn
OAc
PMBOHOO
OBn
BnO
BnO
BnO
O
OBn
OBn
OAc
O
OH
HO
HO
HO
OH
OH
OH
O
OH
O
OBn
BnO
BnO
BnO
OBn
OBn
OAc
O
MMTr
+
1 p-TsOH2 K2CO3 MeOH3 MMTrCl pyr
1 Swern [O]2 BH3 THF
3 AcOH-H2 O4 H2 Pd(OH)2
221
222
223
1 Pd-Pb CaCO3 H22 NaH BnBr3 OsO44 Bu2 SnO5 CsF PMB-Cl6 Ac2 O 4-DMAP
1 AcOH2 TsCl pyr
3 NaH-imid4 DDQ
224225
226 227
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1419
Scheme (46)
OBnO O
OBn
OMe
OBn
XY
SMe
OBnBnO
O
OBn
OBn
OBn
OBn
O
BnO
YX
OBn
TBSO
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnOOBn
H
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnO
OBn
OHC OBn
OBn
OTBS
OMe
BnOOBn
CHO
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnOOBn
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnO
OBn
YX
OBnO O
OBn
OMe
OBn
OBn
O
BnO
O
OBn
OBn
OBn
OBn
O 1 LiHMDS
2
228
1 TBAF THF
2 MeSH BF3 OEt2
230 X = OH Y = H231 X = H Y = OH
230231 41
1 Bu3SnH AIBN2 Swern [O]
1 LiHMDS THF-TMEDA2 MgBr23
1 MsCl
2 liquid NH3
235 X = OH Y = H236 X = H Y = OH Bu3 SnH AIBN
237a and 237b
NaBH4 MeOH
238
239 X = OBn
240 X = OHH2 Pd(OH)2
229
232233
234
1420 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (47)
OH C
O
O BnAcHN
OO
O
OBn OBnOBn
Br
O
OBn OBnOBn
O
OBnA cHN
OO
O TBSO
OBn O BnO Bn
O
OBnAcHN
OO
OTBS
S2
S1
S2
OTBSS1
O H
S2
OT BSS1
O H
MgBrMgBr
S2
O TBSS1
O H
S2
OHS1
OH
S2
OTBSS1
OH
O
OHHO
O H
O
HO
H OO
OBnA cH N
HO
H O
O
O HHO
OH
O
HOHO
O
OBnA cH N
HO
H O
O
OHH O
OH
O
H O
HOO
OBnAcHN
HO
HO
O
O HH O
OH
O
H O
H O O
OBnA cHN
HO
HO
O
O HH O
O H
O
HO
H O O
OBnAcHN
HO
HO
O
OHHO
OH
O
H O
O
OBnA cHN
HO
HOHO
+
241 242
1 CrCl2-NiCl2 T HF-DMF 722 TBSOTf 2 6-lutidine 91
243 244
1 9-BBN 602 Dess-Mart in period inane 97
1 9 -BBN 552 D ess-Martin periodinane 98
245 246
1
2 T BAF 74
1
2 TBAF 88
247 248 249
250
251
250 251 1 1 252 253 1 1 254 255 1 1
252
253
254
255
1 MCPBA2 CSA CH 2Cl2 61 fo r 2 steps3 H 2 Pd (O H)2C 95
1 MCPBA2 CSA CH 2Cl2 63 fo r 2 s teps3 H 2 Pd (OH)2C 87
1 MCPBA2 CSA CH2Cl2 80 for 2 steps3 H2 Pd(O H)2C 95
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1421
Scheme (48)
O
OO
Se Ph
R
O
HO OHOH
O
OB n O B n
OB n
O B nO O
O O
R O OR
X
O
OO
R
Se Ph
O
HOOH
OH
O
OB nOB n
O Bn
OB n
O O
O O
R O O R
O H
O
O B n OB n
O B n
OB n
O
C HO
O
O O
R O OR
OAc HN
OAc
C O2NH 4HOOH
OH
O
OH O H
OH OH
O
OB n O B n
OB n
OB nO O
O O
R O OR
X
O
O
OAcOAc
C HOA cOOAc
OAc
O
OB n O B n
OB n
OB n
O
O Bn OB n
OB n
OB n
X
OH
OO
HOOH
OH
O
O
OMeOB n
OB nOB n
R
t-B uL i256 R = Li
257 R = L i
258
(R = t-B uMe 2Si )
(R = t-B uMe 2Si )
259ab (32) 79 com bine d yi eld
De ss-Ma rtin pe riodinane
260 X = O R = t-B uMe 2Si ) 95
261 X = O R = t -B uMe2S i) 62
T e bbe re age nt
TB A F THF262 X = O R = H 94
diphosge ne
C H2C l 2Pyr
263 95
T HFH2O T FAr t
264 quant it a ti ve yie ld
PhSe C l AgOT f
EtC N -80 oC
265
266
Quant it at i ve yi l ed 25 26 7 1
+
R =
1 Ac 2OPyr
2 mC PB A3 Ac 2ONa OAc
4 NaO HT HFMe OH
5 Ac2O P yr
267 90 overa ll yi e ld
ste ps
268
1422 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
glucopyranoside 280 represents an example of thischemistry The known triacetyl glucopyranoside 269 wasconverted to iodide 270 in good yield Radical allylation of271 proceeded to afford a mixture of equatorial and axialallylation products in a 61 ratio Oxidative cleavage of thedouble bond gave the corresponding aldehydes 273a and273b which were separable Pinnick oxidation of the majoraldehyde 273a then gave the C-4 equatorial acid 274 DCC-mediated coupling of alcohol 275 and acid 274 proceeded toafford ester 276 in good yield Methylenation of 276 gave277 and exposure to catalysist 278 gave a 41 yield of theC-disaccharide glycal which was exposed to an excess ofBH3
THF to give 64 yield of the β-C-disaccharide 279Removal of the benzyl groups and global peracetylation gavethe peracetylated (1rarr4)-β-C-disaccharide 281 in good yield(Scheme 49)
54 Ring Expansion-Cyclization
Nelson developed a new strategy for asymmetric andstereoselective synthesis of C-linked disaccharide mimeticsthe C58-C71 fragment of palytoxin [54] The diol (RR)-282was converted into the di-dihydropyran (DHP) template 283284 and 285 The di-DHPs were functionized in a twodirectional sense using dihydroxylation reactions The two-directional approach was often very efficient indeed forexample in the synthesis of 286 six new stereogenic centerswere introduced with almost complete stereocontrol using areduction and a dihydroxylation reaction The approach isnot restricted to the synthesis of C2-symmetricaldisaccharide mimetics Using the unsymmetrical template285 which has both a pseudo-axial and a pseudo-equatorialhydroxyl groups the unsymmetrical mimetics 289 and 290were prepared (Scheme 50)
6 RADICAL APPROACHES
The radical approach for C-C bond formation is a popularmethod within organic chemistry The use of radicalchemistry in carbohydrate synthesis has certain advantagesFirstly the reaction conditions are very mild and tolerant ofa range of functional and protecting groups Secondanomeric radicals are stable with respect to elimination andepimeration Most significantly the chemistry required toincorporate an appropriate substitute at C-1 employed in theinitial hemolytic cleavage step is common within carbo-hydrate chemistry [55] The use of such radical techniquecan be subdivided into two classes intermolecular andintramolecular approaches
61 Intermolecular Radical Approaches
Giese was the first to employ an intermolecular radical-based approach for synthesis of C-disaccharides [56]Addition of an alkene to an anomeric radical underappropriate conditions allowed exclusive entry to the α-linked C-glycoside a result which was mirrored by the workof Baldwin [57] The high α-selectivity of the reaction wasin contrast with other reports Thus radicals generated at theC-2 C-3 and C-4 centers all preferred to occupy equatorialpositions [58] When the anomeric bromide 291 was treatedwith tin hydride and AIBN resulting anomeric radical andreacted with lactone 292 in a Michael addition it afforded293 In this reaction hydrogen abstraction at the resulting
radical center occurs from axial face to selectively generatethe equatorial C-2rsquo substituent Reduction and acetylation of293 furnished C-disaccharide 294 (Scheme 51) [59]
Witczak used the facial bias of levoglucosene tostereoselectively add a carbohydrate-based radical in thepreparation of the 3-deoxy-(1rarr4)-β-C-disaccharide 299[60] Addition of the radical derived from iodide 295 to 296gave adduct 297 in 26 yield Removal of the anomerichydroxyl of 297 was achieved by treatment with triethylsilane borontrifluoride ether complex followed bystereoselective reduction of the keto function at C-2rsquo withthe formation of 298 in 89 yield Debenzylation followedby acetolysis of 16-anhydro ring produced the peracetylatedtarget C-disaccharide 299 in 19 overall yield from 295(Scheme 52)
Vogel has developed general methods to transformenantiomerically pure 7-oxabicyclo[221]heptyl derivatives(ldquonaked sugarsrdquo) into C-disaccharides Because of thesechiral bicyclic skeletons they undergo highly stereoselectivereactions with predictable diasteroselectivities An arsenal ofmethods is available that allow to substitute these ldquonakedrdquocarbon centers with a variety of functional groups with allpossible relative configurations The methods allowpreparation of both enantiomers of a given target with thesame ease Predictably high stereoselectivity of the reactionsof the bicyclic chirons adds to the flexibility of approachwhich can lead to high molecular diversity [61]
α-C-(1rarr3)-mannopyranoside of N-acetyl-galactosaminepotent β-galactosidase inhibitors was synthesized by thisapproach [61] Enone 302 was readily prepared from 300The addition of the radical derived from bromide 303 toenone 302 afforded the αminusisomer 304 The ketone was thenreduced and the selenide eliminated via the intermediacy ofthe selenoxide to give 305 Acid-promoted (CF3SO3H) 7-oxa ring opening of 305 in MeCN produced the amino-conduritol derivative 306 resulting from the quenching of theallylic cation intermediate by the solvent (Ritter reaction)Ozonolysis of the chloroalkene 306 generated an acylchloride-aldehyde intermediate that reacted with MeOH toproduce a mixture of methyl uronates The major compound307 was silylated and reduced The crude polyol obtainedwas acetylated to produce 308 Desilylated and ammonolysisafforded a mixture of α-β-pyranoses 309 and correspondingα-β-furanoses (Scheme 53)
Similar chemistry was carried out to synthesize non-protected α-C(1rarr2)-L-fucopyranoside of D-galactopyrano-side corresponding to a blood group mimetic [62] Giesersquosradical fucosidation of racemic enone 310 with α-L-bromoacetofucose 311 provided the mixture of diastereo-meric α-C-fucoside 312a and 312b in reproducible yield of78 Reduction of the mixture gave a 11 mixture of endo-alcohols 313 and 314 which were isolated pure in 40 and355 yield respectively Oxidative elimination of thebenzeneselenyl group of 313 followed by acetylation gaveendo acetate 315 in 85 yield Acid-promoted ring openingof 315 and ozonolysis of the resulted chloroalkene gavemethyl uronic ester 316 in modest yield (10) Treatment of316 with Cl3CCN and NaH followed with BF3
OEt2
furnished the totally protected C-disaccharide 317 in 79
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1423
Scheme (49)
Bu3SnO
HOAcO
OMeOAc
OAc
O
AcO
OMeOAc
OAcI
AIBN
O
AcO
OMeOBn
OBn
HO2C O
AcO
OMeOR
ORY
X
OHBnO
BnO
OBn
OBnO
BnO
OBn
O
AcO
OMeOBn
OBnX
i-Pr i-Pr
N
Mo C(Me2 Ph)((CF3)2 MeCO)2
O
RO
OMeOR
O
RO
OR
OR
RO
OR
278
I2 Ph3P
imidazole
269 270 93
271a X = CH2CH=CH2 Y = H R = Ac 64271b Y = CH2CH=CH2 X = H R = Ac 11272a X = CH2CH=CH2 Y = H R = Bn 75272b Y = CH2CH=CH2 X = H R = Bn 75273a X = CH2CHO Y = H R = Bn 79273a Y = CH2CHO X = H R = Bn 79
1 NaOMe MeOH2 NaOH BnBr DMF
OsO4 NaIO4
NaClO2 NaH2PO4
274 96
275
DCC 4-DMAP
276 X = O 82
277 X = CH2 51
TiCl4 Zn dust TMEDA CH2Br2PbCl2 (Cat )
1
2 BH3 THF H2O2 NaOH
H2 PdC EtOH
Ac2 O Pyr 4-DMAP
279 R = Bn R = H 64
280 R = R = H 99
281 R = R =Ac 97
1424 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (50)
Scheme (51)
O OOH
OH
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
286
1 VO(acac)2 t-BuOH 95
2 (MeO)3CH BF3 90
1 P-O2NC6H4 CO2H Ph3P DIAD2 K2CO3 MeOH 82 over 2 steps
1 PhCOCl Et3N DMAP 402 P-O2NC6H4 CO2H Ph3P DIAD3 KOH THF-H2O 75 over 2 steps
TMEDA OsO4
Cat OsO4 NMO 287
Cat OsO4 NMO288
TMEDA OsO4
Cat OsO4 NMO
290
289
(RR)-282283
284
285
OHO
AcO
BrOAc
OAc
BnO
O
OBn
OBnO
OHO
AcOOAc
OAc
BnO
OOBn
OBnAcO
OHO
AcOOAc
OAc
BnO
O
OBn
OBnO
+
Bu3SnH AIBN291
292
293 81
1 Na[Al(OC2H4OMe)2(OEt)H]2 Ac2O pyr
294 56 over 2 steps
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1425
Scheme (52)
Scheme (53)
OBnO
BnOOBn
OBn O
OH
O
OBnO
BnO
OHOBn
OBn O
O
O
O
O
O
OBnO
BnOOBn
OBnO
OAcOAc
OAc
OBnO
BnO
OHOBn
OBn
IBu3SnH AIBN
295 297 26
1 BF3 OEt2 Et3SiH
2 L-Selectride THF
1 Pd(OH)2C C6H10 EtOH
2 EtSiOSO2CF3 Ac2O
298 89 over 2 steps299
296
O
O
PhSeClO
O
PhSeCl
Bu3 SnH
O
O
PhSeCl
R
H
O
OAc
R
Cl
O
AcO
OAc
OAc
OAcOH
Cl
NHAc
R
OAc
AcHN
OH
O
OH OAc
OH
OHO
HO
OH
O
AcO
OAc
OAc
OAcBr
O
O
PhSeCl
O
O
PhSeCl
R
O
OTIPSAcHNR
OAc OAc
O
OHAcHN
COOMe
R
OAc
1 Bu4NF
2 NH3MeOH
1 (Me3Si)2NLi THF2 Me2N=CHI
1 Bu3 SnH AIBN2
1 NaBH42 mCPBA3 Ac2O pyr
1 H+ MeCN
2 H2 O NaHCO3
R =
1 O3MeOH
2 Me2S NaHCO3
1 TIPSOTf 26-lut idine2 LiBH43 Ac2 O pyr DMAP
furanoses +
304 56
305 68 306 84307 50
308 46
300 301 302
303
309
1426 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
The reduction of 317 and treatment with DOWEX-H+ resinprovided the desired C-fucoside 318 in 70 (Scheme 54)
62 Intramolecular Radical Approaches
One disadvantage with the intermolecular approaches isthat during such radical mediated reactions electrondeficient alkenes are required to facilitate C-C bondformation The intramolecular approach of Sinayuml overcomes
this drawback by bring two substrates together via atemporary covalent silaketal connector This enables the useof a wider range of alkenes which can include alkene-functionalized sugars thus leading to the generation of C-disaccharides [63] Based on the early work of Stork Sinayumlemployed the tether reaction in the synthesis of both α- andβ-C-disaccharides with this work subsequently beingemployed in the synthesis of biologically significant natural
Scheme (54)
O
OH
Fuc
Cl
O
O
ClPhSe
OOAc
NHAcOHFuc
O
AcOOAc
AcO
Br
O
O
PhSeCl
O
AcOOAc
AcO
O
OH
PhSe Cl
Fuc
OOAc
NHAc
OMe
Fuc
O
AcHN
OH OAc
OH
O
OH
Me
OH
O
O
Fuc
ClSePh
O
HO
Fuc
ClSePh
+
Ph3SnHAIBN
78 combined yield
Fuc
310
+
1 NaBH4 MeOHTHF2 Chromatography
313 40 314 355
1 mCPBA
2 Ac2O pyr DMAP
+
315 75
1 TfOH MeCN
2 NaHCO3 O3 -78 oC
316 10 over 2 steps
1 Cl3 CCN NaH
2 MeOH BF3 OEt2
317 79
1 LiBH4 THF
2 Dowex-H+
311
312a312b
318 70 for 2 steps
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1427
products [64] The availability of different hydroxyl groupson each monosaccharide unit allowed the fine-tuning ofstereochemical outcome by selective positioning of the silyltether [65] Development of this early stereochemical controlled to the tethering of the donor 320 with alcohol 319through a di-isopropyl silicon tether 321 Subsequent treat-ment with Bu3SnH and AIBN led to a 9-endo-trigcyclization to form the C-disaccharide 322 in an 80 yieldwith exclusive formation of the α-product The silyl tetherwas removed with Bu4NF and deprotection under standardconditions afforded the desired disaccharide 323 in excellentyield (Scheme 55)
In parallel the development of a 32rsquo silyl tether allowedaccess to the β-linked product as demonstrated in Sinayumlrsquossynthesis of methyl β-C-lactoside 328 [66] Alcohol 324 and320 were connected via the dimethylsilyl tether an 8-endo-trig cyclization followed to exclusively afford the β-
disaccharide 326 in 45 yield Removal of the tether anddeprotection of benzyl ether gave β-C-disaccharide 328(Scheme 56)
This group also selected iodosugars bearing a freehydroxyl group as progenitors of the radical donors [67] In atypical experiment the radical donor 329 was connected tothe radical acceptor 330 through a silaketal tether followingtheir procedure Tributyltinhydride mediated 8-endo-trigradical cyclization of compound 331 gave after detetheringof the non isolated intermediate 332 the protected β-C-disaccharide 333 in 37 overall yield (from startingmaterials 330 and 329) Peracetate 335 was achieved afterhydrogenolysis The C-laminaribioside 334 is of potentialbiological interest as it mimics the repeating disaccharideunit of fungal β-(1rarr3)-glucans which have antitumor andimmunomodulating properties (Scheme 57)
Scheme (55)
Scheme (56)
OO
OHSePh
OTBDPSO O
OO
SePh
OTBDPSO
OO
OBnOMe
OBn
Si
O
HOOBn
OMe
OBn
O
HOOH
OHHO
O
HOOH
OMe
OH
OTBDPSO
O
HOOBn
OMe
OBnO
OOH
1 n-BuLi THF
2 iPr2SiCl2 -78 oC
3 DMAP THF rt
1 Bu4NF THF
2 Dowex-H+
3 H2 PdC
Bu3SnH AIBN toluene
319
320
321
322323
OBnO
OHSePh
OBnBnO
OHO
OBnOMe
OBn
ROO
ROOH
OR
OHO
OROMe
OR
OBnO
O
OBnBnO
OO
OBnOMe
OBn
Si
SePh
OBnO
O
OBnBnOO
OOBn
OMe
OBn
Si
1 PhSeH Me2SiCl2
BuLi -78 oC
2 imidazole rt
Bu3SnH AIBN toluene
H2 PdC327 R = Bn
328 R = H
Bu4NF THF
324
320
325
326 45
1428 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
CONCLUSIONS
In this paper the biological importance of C-oligo-saccharides as subunits of natural products and as a newgeneration of carbohydrate based on therapeutics has beenillustrated Different methods are available for the synthesisof C-oligosaccharides As with traditional saccharidesynthesis it has been necessary to develop a number ofspecific approaches to facilitate the regioselective andstereoselective preparation of the desired targets Work inthis area continues and it is expected that many interestingnew C-oligosaccharides will be prepared using the chemistrydescribed in this review It is also likely that new chemistrywill be developed in the future for the preparation of thesebiologically important targets
ACKNOWLEDGEMENTS
The authors thank Dr Sultan Baytas for her criticalreading of this manuscript
REFERENCES
[1] Kennedy J F White C A Bioactive Carbohydrates InChemistry Biochemistry and Biology Ellis Horwood LtdChichesterUK 1983
[2] Wassarman PW Mammalian Fertilization Molecular Aspects ofGamete Adhesion xocytosion Exocytosis and Fusion Cell 199996 175-183
[3] Carbohydrate-based Drug Discovery Wong C-H EdWeinheim Cambridge Wiley-VCH 2003
[4] (a) Sharon N Lis H Lectins as Cell Recognition MoleculesScience 1987 246 227-234 (b) Dwek RA Chem Rev 1996 96683-720
[5] Postema M C-Glycoside synthesis CRC Boc Ratom 1995[6] (a) Weatherman R V Mortell K H Cheruenak MKiessling
L L Toone E J Specificity of C-Glycoside Complexation byMannoseGlucose Specific Lectins Biochem 1996 35 3619-3624(b) Ravishankar R Surolia A Vijayan M Lim S Kishi YPreferred Conformation of C-Lactose at the Free and Peanut LectinBound States J Am Chem Soc1998 120 11297-11303
[7] (a)Wong C-H Halcomb R L Ichikawa Y and Kajimoto TEnzymes in organic synthesis Application to the problems ofcarbohydrate recognition part2 Angew Chem Int Ed Engl 199534 521-546 (b)Howard S Withers SG Bromoketone C-Glycosides a New Class of βminusGlucanase Inactivators J AmChem Soc 1998 120 10326-10331(c) Wang Q Wolff MPolat T Du Y Linhardt R J C-glycoside of Neuraminic Acidsas Neura-minidase Inhibitors Bioorg Med Lett 2000 10 941-944 (d) Phili R Chang J Partis R A Mueller R A ChrestF J Passaniti A The Alpha-glucosidase I InhibitorCastanospermine Alters Endothelial cell Glycosylation PreventsAngiogenesis and Inhibits Tumor Growth Cancer Res 1995 552927-2935
[8] Ossor A Elbein A D In Carbohydrates in Chemistry andBiology Vol 3(II) WileyVCH 2000 pp 513-539
[9] (a) Sinayuml P Synthesis of oligosaccharide Mimetics Pure ApplChem 1997 69 459-463 (b) Beau J-M Gallagher TNucleophilic C-glycosyl Donors for C-glycoside Synthesis Top inCurr Chem 1997 187 1-54 (c) Nicotra F Synthesis of C-glycosides of Biological Interest Top in Curr Chem 1997 187
Scheme (57)
O
O
O
Ph
I
OMe
OHO
BnO
OH
OH
BnOOH
O
BnO
Si
O
O O
Ph
I
OMe
O
O
BnO
OR4O
R5O
OMe
OR2
OR3O
R3O
OR1
R3O
Bu3 SnH AIBN
332 R1 R2 = SiMe2 R3 = Bn R4 R5 = CHPhTBAF THF
333 R1 = R2 = H R3 = Bn R4 = R5 = CHPh 37 from 11
334 R1 = R2 = R3 = R4 = R5 = H
335 R1 = R2 = R3 = R4 = R5 = Ac
329
H2 PdC MeOH
Ac2 O pyr
1 BuLi THF -78 oC
2 Me2SiCl2
3 DMAP
330
331
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1429
55-83 (d) Du Y Linhardt R Y Recent Adv in Stereo-SelectiveC-Glycoside Synthesis Tetrahedron Lett 1998 54 9913-9959 (e)Liu L Mckee M and Postema M H D Synthesis of C-saccharides and Higher Congeners Current Org Chem 2001 51133-1167
[10] Jarosz S Fraser-Reid B Synthesis of A Higher Carbon Sugar ViaDirected Aldol Condensation Tetrahedron Lett 1989 30 2359-2362
[11] Lichtenthaler F W Lergenmiiller M Schwidetzky S C-Glycosidations of 2-Ketohexosyl With Electrophilic Radical andNudeophilic Anomeric Carbons Eur J Org Chem 2003 3094-3103
[12] Baudat A Vogel P Aza-C-disaccharides Synthesis of 6-Deoxygalactonojirimycin-β-C(1rarr3) Linked with D-Altrofuranosides and D-Galactose J Org Chem 1997 62 6252-6260
[13] Turner D Vogel P Synthesis of 4-Hydroxy-26-Bis(hydroxymethyl) tetrahydropyran-2-Carbaldehyde DerivativesSynlett 1998 304-306
[14] Zhu Y-H Vogel P Short Stereoselective Synthesis of C-(1rarr3)-Linked Disaccharides Tetrahedron Lett 1998 39 31-34
[15] Zhu Y-H Vogel P Synthesis of a (2R 6R)-2-(Hydroxymethyl)-6-Propa-1 2-Dienyl-2H-Pyran-3(6H)-One Derivative A NewEnone for The Convergent Construction of C-Glycosides of C-Disaccharides Synlett 2001 82-86
[16] Baumberger F Vasella A Deoxynitrosugars The 6th
Communication Stereolectronic Control in the reductivedenitration of tertiary nitro ethers A Synthesis of ldquoC-glycosidesrdquoHelv Chim Acta 1983 66 2210-2221
[17] Martin O R Lai W Synthesis and Conformational Studies of β-(1rarr6)- and ββ-(1rarr1)-Linked C-disaccharides J Org Chem1993 58 176-185
[18] Spak S J Martin R The synthesis of an analogue of Methyl OC-Analogue of Methyl 4rsquo-O-β-D-GlucopyranosylgentiobiosideTetrahedron 2000 56 217-224
[19] Kobertz W R Bertozzi C R Bednarski M D C-GlycosylAldehyde Synthons for C-Linked Disaccharides J Org Chem1996 61 1894-1897
[20] Gurjar M K Nagaprasad R and Ramana CV First Synthesis ofMethyl α-C-D-Arabino-furanosyl-(1rarr5)-αminusD-Arabinofuranosidethe C-Disaccharide Segment of Motif C of MycobateriumTuberculosis Tetrahedron Lett 2000 43 7577-7579
[21] Witczak Z J Synthesis of C-Glycosyl Compounds and OtherNatural Products from Levoglucosenone Pure Appl Chem 199466 2189-2192
[22] Griffin F K Paterson D Taylor R J K Ramberg-BacklundApproaches to the Synthesis of C-Linked Disaccharides AngewChem Int Engl 1999 38 2939-2942
[23] Paterson B E Griffin F K Alcaraz M-L and Taylor R J KA Ramberg-Baumlcklund Approach to the Synthesis of C-GlycosidesC-Linked Disaccharides and C-Glycosyl Amino Acids Eur JOrg Chem 2002 1323-1336
[24] McAllister G D Paterson D E Taylor R J K A SimplifiedRamberg-Bachlund Approach to Novel C-Glycosides and C-Linked Disaccharides Angew Chem Int Ed Engl 2003 42 1387-1391
[25] McCartney J L Christopher T M Cicchillo R M BernardinaM D Wagner T R and Norris P J Org Chem 2003 6810152-10155
[26] Dondoni A Zuurmond H M Bascarate A Synthesis of α-andβ-D-(1rarr6)-C-Disaccharides by Witting Olefination of Formyl C-Glycosides with Glycopyranose 6-phosphoranes J Org Chem1997 62 8114-8124
[27] Dondoni A Kleban M Zuurmond H Marra A Synthesis of(1rarr6)-C-Oligogalactosides by Interative Wittig OlefinationTetrahedron Lett 1998 39 7991-7994
[28] Dondoni A Marra A A New Synthetic Approach toMycobacterial Cell Wall α-(1rarr5)-D-Arabinofuranosyl C-Oligosaccharides Teterahedron Lett 2003 44 4067-4071
[29] Colinas P A Ponzinibbio A Lieberknecht A and Bravo R OWittig Reaction of Glycosyl Phosphonium Salts A StereoselectiveRoute to C-Disaccharides and C O-Trisaccharides TetrahedronLett 2003 44 7985-7988
[30] Schmidt R R Preuss R Synthesis of Carbon Tetrahedron Lett1989 30 3409-3412
[31] Dietrich H Schmidt R R Synthesis of Carbon-Bridged C-Lactose and Derivatives Liebigs Ann Chem 1994 975-981
[32] Rouzaud D Sinayuml P The First Synthesis of a ldquoC-DisacchariderdquoJ Chem Soc Chem Commun 1983 1353-1354
[33] Xin Y-C Zhang Y-M Mallet J-M Glaudemans C P JSinayuml P Synthesis of C-Oligosaccharides That Mimie TheirNatural O-Analogues Immunodeterminants in Binding toMonoclonal Immunoglobulins Eur J Org Chem 1999 471-476
[34] Streicher H Geyer A Schmidt R R C-Disaccharides ofKetoses Chem Eur J 1996 2 502-510
[35] Leeuwenburgh M A Timmers C M Vander Marel G A VanBoom J H Mallet J-M Sinayuml P G Stereoselective Synthesisof α-C-(Alkynyl)-Glycosides Via Ring-Opening of α-12-Anhydrous Tetrahedron Lett 1997 38 6251-6254
[36] Aslam T Fuchs M G G Le Formal A Wightman R HSynthesis of C-Disaccharide Analogue of the α-D-Arabinofuranosyl-(1rarr5)-α-Arabinofuranosyl Motif ofMycobacterial Cells Walls via Alkynyl Intermediates TetrahedronLett 2005 46 3249-3252
[37] (a) Girad P Namy J L Kagan H B Divalent LanthanideDerivative in Organic Synthesis 1 Mild Preparation of SamariumIodide and Ytterbium Iodide and Their Use as Reducing orCoupling Agents J Am Chem Soc 1980 102 2693-2698 (b)Molander G A Harris C R Sequencing Reactions withSamarium(II) Iodide Chem Rev 1996 96 307-338
[38] (a) Mazeacuteas D Skrydstrup T Doumeix O Beau J-MSamarium Iodide-Induced Intramolecular C-Glycoside FormationEfficient Radical Formation in the Absence of an Additive AngewChem Int Ed Engl 1994 33 1383-1386 (b) Mazeacuteas DSkrydstrup T Beau J-M A Highly Stereoselective Synthesis of1 2-trans-C-Glycosides Via Glycosyl Samarium(III) CompoundsAngew Chem Int Ed Engl 1995 34 909-912 (c) Jarreton OSkrydstrup T Beau J-M The Stereospecific Synthesis of Methylα-C-Mannobioside A Potential Inhibitor of M TuberculosisBinding to Human Macrophages J Chem Soc Chem Commun1996 1661-1662 (d) Jarreton O Skrydstrup T Espionosa J-FJimeacutenez-Barbero J Beau J-M Samarium Diiode Prompted C-Glycosylation An Application to The Stereospecific Synthesis ofα-(1rarr2)-C-Mannobioside and Its Derivatives Chem Eur J 19995 430-441 (e) Mipuel N Doisneau G Beau J-M ReductiveSamariation of Anomeric 2-Pyridyl Sulfones with Catalytic AnUnexpected Improvement in The Synthesis of 12-Trans-Diequatorial C-Glycosyl Compounds Angew Chem Int Ed Engl 2000 39 4111-4114
[39] Vlahov I R Vlahova P I Linhardt R J DiastereocontrolledSynthesis of Carbon Glycosides of N-Acetylneuraminic Acid ViaGlycosyl Samarium(III) Intermediates JAmChem Soc 1997 1191480-1481
[40] Kuberan B Sikkander S ATomiyama H Linhardt R JSynthesis of a C-Glycoside Analogue of sTn An HIV-and Tumor-Associated Antigen Angew Chem Int Ed Engl 2003 42 2073-2075
[41] Bazin H G Du Y Polat T Linhardt R J Synthesis of aVersatile Neuraminic Acid ldquoCrdquo-Disaccharide Precursor for theSynthesis of C-Glycoside Analogues of Gangliosides J OrgChem 1999 64 7254-7259
[42] Chen C-C Ress D K Linhardt RJ Samarium Iodide-Mediated Synthesis of Neuraminic Acid C-Glycosides InSynthesis of Glycommetics Roy R Ed ACS Syposium Series2004 896 53-80
[43] Abdallah Z Doisneau G Beau J-M Synthesis of a Carbon-Linked Mimic of The Disaccharide Component of The Tumor-Relate SialyTn Antigen Angew Chem Int Ed Engl 2003 425209-5212
[44] Lay L Nicotra F Panza L Russo G Caneva E Synthesis ofC-disaccharides through dimerization of exo-glycals J Org Chem1992 57 1304-1306
[45] Isobe M Nishizawa R Hosokawa S Nishikawa TStereocontrolled Synthesis and Reactivity of Sugar Acetylenes JChem Soc Chem Commun 1998 2665-2676
[46] Saeeng R Sirion U Sahakitpichan P Isobe M IodineCatalyzes C-Glycosidation of D-Glucal with SilylacetykeneTetrahedron Lett 2003 44 6211-6215
[47] (a) Babirad S A Wang Y Kishi Y Synthesis of C-Disaccharides J Org Chem 1987 52 1370-1372 (b) Wang YBabirad S A Kishi Y Preferred Conformation of C-Glycosides
1430 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
8 Synthesis of 14-Linked Carbon Disaccharides J Org Chem1992 57 468-481
[48] Armstrong R W Sutherlin D P Strategies for the Synthesis ofC-Disaccharides Containing D and L Sugars Tetrahedron Lett1994 35 7743-7746
[49] Wei A Kishi Y Preferred Conformation of C-Glycosides 12Synthesis and Conformational Analysis of αα- α β- and β β-Trehaloses J Org Chem 1994 59 88-96
[50] Haneda T Goekjian P G Kim S H Kishi Y PreferredConformation of C-Glycosides 10 Synthesis and ConformationAnalysis of Carbon Trisaccharides J Org Chem 1992 57 490-498
[51] Sutherlin D P Armstrong R W Synthesis of 12 Stereochemistryand Structurally Diverse C-Trisaccharides J Org Chem 1997 625267-5283
[52] Notz W Hartel C Waldscheck B Schmidt R R De NovoSynthesis of a Methylene-Bridged Neu5Ac-α-(23)-Gal C-Disaccharide J Org Chem 2001 66 4250-4260
[53] (a) Postema M H D Calimente D Liu L Behrmanm T L AnOlefin Metathesis Route for the Preparation of (1rarr6)-Linked-C-Disaccharide Glycals A Convergent and Flexible Approach to C-Saccharide Synthesis J Org Chem 2000 65 6061-6068(b) Postema M H Piper J L Liu L Faust M Andreana PSynthesis and Partial Biological Evaluation of a Small Library ofDifferentially Linked β-C-Disaccharide J Org Chem 2003 684748-4754
[54] Nelson A The Development of Strategies and Methods for TheSynthesis of Biologically Active Compounds New J Chem 200428 771-776
[55] Togo H He W Waki Y Yokoyama M C-GlycosylationTechnology With Free Radiant Reactions Synlett 1998 700-717
[56] Giese B Dupuis J Diastereoselective Synthesis of C-Glycopyranosides Angew Chem Int Ed Engl 1983 22 622-623
[57] Adlington R M Baldwin J E Basak A Kozyrod RPApplication of Radical Addition Reactions to tho Synthesis of a C-Glucoside and A Functionalized Amino Acid J Chem SocChem Commun 1983 144-145
[58] Giese B Gonzaacutelez-Goacutemez J A Witzel T The Scope of RadicalCC-Coupling by The ldquoTin Methodrdquo Angew Chem Int Ed Engl1984 23 69-70
[59] Giese B Witzel T Synthesis of ldquoC-Disaccharidesrdquo by RadicalC-C Bond Formation Angew Chem Int Ed Engl 1986 25 450-451
[60] Witczak Z J Chhabra R Chojnacki J C-Disaccharides IStereoselective Approach to β-(1rarr4)-3-Deoxy-C-Disaccharidesfrom Levoglucosenone Carb Res 1997 301 167-175
[61] Vogel P Synthesis of Rare Carbohydrates and Analogues Startingfrom Enantiomerically Pure 7-Oxabicyclo[221]heptyl Derivatives(ldquoNaked Sugarsrdquo) Current Org Chem 2000 4 455-480
[62] Viodeacute C Vogel P Synthesis of The C-Disaccharide α-C(1rarr3)-L-Fucopyranoside of N-Acetylgalactosamine J Carb Chem2001 20 733-746
[63] Xin Y C Mallet J M Sinayuml P An Expeditious Synthesis of AC-Disaccharide Using A Temporary Silaketal Connection J ChemSoc Chem Commun 1993 864-865
[64] (a) Petitou M Herault P Lormeau J-C Helmboldt A MalletJ-M Sinayuml P Herbert J-M Introducing A C-InterglycosidicBond in A Biologically Active Pentasaccharide Hardly Affects ItsBiological Properties Bioorg Med Chem 1998 6 1509-1516 (b)Sinayuml P Advances in The Synthesis of the Carbohydrate MimicsPure Appl Chem 1998 70 1495-1499
[65] Sinayuml P Chemical Synthesis of Oligosaccharide Mimetics PureAppl Chem 1998 70 407-410
[66] Sinayuml P Chemical Synthesis of Oligosaccharide Mimetics PureAppl Chem 1998 69 459-463
[67] Vauzeilles B Sinayuml P Selective Radical Synthesis of β-C-Disaccharides Tetrahedron Lett 2001 42 7269-7272
1394 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
organization of this review is based on the type of chemistryused to assemble the target C-oligosaccharides The chemistryinvolved includes anionic and cationic chemistry reductivesamariation cyclization methodology and free radicalapproaches Methods that afford the C-oligosaccharides withhigh stereoselectivity at the anomeric center (α or β) areclearly desirable This selectivity can be controlled by eitherstarting with a stereochemically defined C-glycoside whichis then coupled with another sugar or by controlling thestereochemistry of the newly formed center
2 ANIONIC APPROACHES
21 Enolate Anions
Fraser-Reid and Jarosz coupled two monosaccharideunits through a directed aldol reaction [10] Aldehyde 1 wasdeprotonated with (Me3Si)2NLi (LiHMDS) to give thechelated enolate 2 which was condensed with aldehyde 3 togive 4a as the major product (Scheme 1)
The zinc-copper-mediated reaction between 5 and 6 givesrise to the generation of single product 7 in 78 yielddemonstrating a remarkable double stereoselectivity with astrong preference for α-C-glycosylation of the ulosyl bromide
together with the elaboration of the (R) configuration for theCHOH group linking the pyranoid moieties (Scheme 2) [11]
Vogel utilized a ldquonaked sugarrdquo approach for the synthesisof an aza-C-disaccharide Enolate derived from 8 wascoupled with aldehyde 9 to give the adduct 10 in 61 yieldThe ketone was reduced and the resulting diol wasacetylated This was followed by selenoxide elimination toafford olefin 11 which was converted to 12 as shown inScheme 3 [12]
Cross-aldol reaction of racemic aldehyde 14 with enan-tiomerically pure lithium enolate of (-)-(1R4R5R6R)- or (-)-(1S4S5S6S)-13 results in mixtures composed mostly ofenantiomerically pure (+)-15 and (-)-15 respectively in 37-48 (only one of the isomers is shown in Scheme 4) [13]
Vogel and co-workers use a novel approach to C-disaccharide synthesis that involves conjugate addition andenolate trapping [14] Levoglucosenone 16 was treated withMe2AlSPh to give the aluminium enolate 17 Condensationof 17 with aldehyde 18 gave the aldol product that wasreduced with DIBAL to 20 Treatment of 20 with acidicmethanol afforded the (1rarr3)-C-disaccharide 21 (Scheme 5)
Scheme (1)
Scheme (2)
OO
OOBn
CHO
LiHMDS
5R
OO
OOBn
OHC
O
OBn OMe
OBn
OBn
C
OH6R
OO
OBnO
CHOLi
5S
OO
OOBn
OHC
O
OBn OMe
OBn
OBn
C
OH
O
OBn OMe
OBn
OBn
CHO
6S
+
1 2 3
4a 4b
O
O
Br
OBz
BzO
BzO
OO
O
O
O
O
O
O
OBz
BzO
BzO
OH
O
O
O
OO
5
1 Zn-Cu THF -35degC
2 NaHCO3
6
7 78
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1395
Enone 22 was synthesized and condensation of trappingenolate with aldehyde 23 led to a mixture of aldols 24 and 25that were separated by column chromatography on silica geland isolated in 15 and 29 yield respectively Reductionof the major aldol 25 with NaBH4 in MeOHTHF was highlystereoselective and provided the C-disaccharide 26 in 77yield (Scheme 6) [15]
When reacted with PhMe2SiZnMe2Li in THF at -78 ordmCenone 27 afforded a single adduct 28 Treatment of ketone28 with dicyclohexylboron chloride and Et3N at -15 ordmCfollowed by addition of 29 the resulting aldol-borate wasoxidized with 35 H2O2 giving adduct 30 in 24 yieldStereoselective reduction of aldol 30 with Me4NBH(AcO)3
afforded diol 31 in 59 yield (Scheme 7) [15]
22 Nitro Stabilized Anions
Vasella and Martin pioneered the use of nitro-basedanions for C-saccharide synthesis Anomeric nitro derivative32 was treated with TBAF and exposed to aldehyde 33 togive the adduct 34 in 78 yield Acetylation of 34 followedby reductive denitration afforded 35 (Scheme 8) [16]
Martinrsquos work has also relied on the Henry reactionAldol condensation of nitro sugar 36 with aldehyde 33 gave37 Dehydration of 37 and conjugate reduction led to 38Removal of nitro group by radical-based reduction followedby the removal of protecting groups gave rise to the (1rarr6)-β-C-disaccharide 40 (Scheme 9) [17]
Scheme (3)
Scheme (4)
NCbz
BnO
O
O
O
Cl
OAc
OAc
NCbzBnO
OO
O
PhSe
Cl O
OH
NCbz
CHO
OBnO
O
HO
N
OBn
OAc
CO2Me
AcO
OMe
CbzOMe
OAc OAc
O
PhSe
Cl OTHF -95 o C
1 NaBH42 Ac2O Pyr3 mCPBA
1 SOCl2 MeOH2 Ac2O Pyr3 Me3NO OsO44 Ac2O Pyr5mCPBA
LiHMDS -78 oC
8
9
10
1112
O
BnO
TBSO
O
OBnO
BzO
OBz
Br
CHO
OTIPS
O
BnO
TBSO
O
OBnO
BzO
OBz
Br
OTIPS
OH1 LiHMDS
2
1315
14
1396 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (5)
Scheme (6)
OO
O
Me2AlSPh OAlMe2O
O
SPh
O
OH
O
O
OO
O
OH
SPh
OH
O
HO
HO
OMeOH
OMe
HO
O
O
SPhO
O
O
OO
H
HO
HO
OO
O
SPhO
O
OO
HOH
DIBAL
MeOHTsOH
50 o C
16 17
18
19
2021
OO
bull
OR
O
CHOOMe
OO
NaBH4
OOH
bull
OR
OOMe
OO
OH
OO
bull
OR
OOMe
OO
HO
OO
bull
OR
OOMe
OO
OH
Me2AlSPh -78 degC
R = (t-Bu)Me2Si
22
23
24 15
+
25 2926 77
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1397
Scheme (7)
Scheme (8)
An open chain sugar derived aldehyde was used to accessa C-trehalose derivative through the Henry reactionCondensation of 36 with aldehyde 41 in the presence of KFand crown ether 18-crown-6 gave adduct 42 which wasimmediately converted to 43 with a sequence of reactions in29 overall yield The intermediate was finally transformedto the C-linked-(1rarr1)-disaccharide 44 (C-ββ-trehalose)(Scheme 10) [17]
Martin and coworkers applied the same methodologyto prepare an OC-trisaccharide namely methyl O-β-D-glucopyranosyl-(1rarr4)-C-β-D-glucopyranosyl-(1rarr6)-D-
glucopyranoside 48 [18] The condensation of compound 45with 6-aldehydo-glucopyranoside 46 in the presence of KFin an aprotic medium afforded the desired pseudotri-saccharide 47 in 73 yield Application of the samechemistry to 47 gave the target compound 48 (Scheme 11)
Kobertz and coworkers utilized Martinrsquos methodology toprepare C-allolactose Nitro sugar 49 was condensed withaldehyde 50 afforded the adduct 51 as a mixture ofdiastereomers The hydroxyl group was converted to thecorresponding phenyl thiocarbonate ester 52 Treatment withtin hydride and a radical initiator effected elimination
OO
OR OR
O SiMePh
O
HO
PhMe2SiZnMe2 Li
O
TBSO
TBSO
OTBS
OTBS
H
O
O
OR
SiMePh
TBSO
OTBS
OTBS
OH
HOHO
TBSO
O
O
TBSO
TBSO
OTBS
OTBS
OH
H
O
OR
SiMePh
Me4NBH(OAc)3
R = (t-Bu)Me2Si
+
1 THF -78 oC
2 NH4Cl H2O
3 HCl H2O 20 oC
1 (c-hex) 2BCl Et3N
2
27
28
29
30 24 over 2 steps31 59
O
O
O
O O
NO2
TBAF
O
OH
OO
OO
O
O
OO O
NO2
OO
O
OO
OH
O
O
OO O
OO
O
OO
H
OAc
32
3334 78
1 Ac2O Pyr2 Bu3SnH AIBN
35 89
1398 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
reaction yielding only E-olefin 53 Finally the olefin wasreduced with dimide (generated in situ) and benzyl etherswere removed by dissolving metal reduction to afford thetarget disaccharide 54 (Scheme 12) [19]
Gurjar et al synthesized the first methyl α-C-D-araf-(1rarr5)-α-D-araf 60 the C-disaccharide segment of motif Cof Mycobacterium tuberculosis through nitro-aldol conden-
sation The coupling reaction between 55 and 56 gavediasteromeric mixture 57 which was subjected to threesubsequent steps ie dehydration selective reduction ofconjugated olefin and denitration to give the penta-O-benzylC-disaccharide 59 (Scheme 13) [20]
Witczak has used nitro anions for C-disaccharidesynthesis Michael addition of the nitro anion derived from
Scheme (9)
Scheme (10)
OAcO
AcOOAc
OAc
NO2O
OH
O
O
OO
OHO
HOOH
OH
O
HO
HOOH
OH
Bu3 SnH
OAcO
AcOOAc
OAc
NO2
OO
O
OO
OH
OAcO
AcOOAc
OAc
X
OO
O
OO
KF 18-C-6 MeCN
1 Ac2O Pyr2 NaBH4 EtOH
38 X = NO 2
39 X = H 57
1 NaOMe
2 H3O+
36
33
37
40 89 over 2 st eps
CHO
O
O
O
O
CH2OPiv
OAcO
AcOOAc
OAc
NO2
OHO
HOOH
OH
O OH
OH
HO
OH
OAcO
AcOOAc
OAc
NO2
PivO
OH
O
O
O
O
OAcO
AcOOAc
OAc
NO2
PivO
O
O
O
O
1 Ac2O Pyr2 80 AcOH3 Ac2O Pyr
1 AcOH
2 Ac2O-BF3 OEt
KF 18-C-6 MeCN
41 36
42
4344
3 Bu3SnH AIBN
4 NaOMe
5 H3O+
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1399
61 to levoglucosenone 62 gave adduct 63 in 43 yield Thesterics in 62 dictates the facial bias of the addition whichcan only occur from the α-face Reductive denitrationfollowed by reduction of lactol and ketone afforded 64 Ringopening deprotection and acetylation gave 65 (Scheme 14)[21]
23 Sulfur Stabilized Anions
The Taylor group employed the Meyers variant of theRamberg-Baumlcklund reaction to synthesize C-disaccharides[22] The penta-O-benzyl thioglucose 66 was coupled withiodide compound 67 followed by oxidation of the formedsulfide gave sulfone 68 Exposure of the sulfone to theMeyers variant of the Ramberg-Baumlcklund reaction affordedexo-glycal 69 as a mixture of isomers in 48 yieldHydrogenation of this mixture stereoselectively reduceddouble bond and cleaved the benzyl groups Peracetylated C-
trehalose 70 was furnished by acetylation of free sugar(Scheme 15)
This approach is well suited to analog synthesis simplyby varying the alkylating agent Thus the homologous(1rarr1rsquo)-C-disaccharide containing a two-carbon bridge(ldquohomoisotrehaloserdquo) was readily prepared (Scheme 16)[23] Lactol 71 was converted into sulfonate 74 by astraightforward three-step sequence involving Moffat-typeC-glycosylation to give ester 72 followed by reduction andmesylation Next 74 was coupled with thiol 75 in a similaralkylation-oxidation sequence to that above The resultingsulfone 77 underwent a halogenative Ramberg-Baumlcklundrearrangement (RBR) to give exo-glycal 78 as a 8812mixture of (Z)- and (E)-isomers in 57 yield Subsequentreductiondebenzylation followed by acetylation producedthe novel ethylene-bridged disaccahride 79
Scheme (11)
Scheme (12)
OBnO
OBnOMe
BnO
NO2
OBnO
OBn
BnO
OBn
CHO
OHO
OH
HO
OH
OHO
OHOMe
HO
OBnO
OBn
BnO
OBn
OBnO
OBnOMe
BnO
NO2R
OBnO
OBn
BnO
OBn
OBnO
OBnOMe
BnO
KF 18-C-6 MeCN+
1 n-BuLi2 PTC-Cl
51 R = OH
52 R = OC(S)OPh
Bu3 SnH AIBN
1 TsNHNH NaOAc
2 Na NH3
49
50
5354
OAcO
OAc
AcOO
OAcO
OAc
OAc
NO2OAc
OAc
AcO
OAcO
BnOOBn
OMe
BnO
OO
AcOOAc
OAc
OAcO
OMe
BnO O
BnOOBn
O
OO
AcOOAc
OAc
NO2
OAcO
OAc
AcO
OAcO
BnOOBn
OMe
BnO
OH
KF 18-C-6 MeCN
1 Ac2O Pyr2 NaBH4 EtOH3 Bu3SnH AIBN4 H2 Pd(OH)2
5 NaOMe MeOH
45
46
47
48
1400 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
This group also reported a rapid synthesis of a range ofC-disaccharides involving a tandem Horner-Wadsworth-Emmons (HWE)conjugate-addition C-glycosylation followedby a tandem halogenation-RBR sequence utilizing Meyersvariant of the RBR [24] The HWE reagent 81 proceeded theHWEconjugate-addition sequence with diisopropylidenemannofuranose 80 in 86 yield to produce the adductsulfone 82 (as a mixture of diastereomers) The keyhalogenation-RBR was carried out using the conditions
devised by Chan et al giving E-alkene 83 as the onlyisolable product Alkene hydrogenation and concomitantdebenzylation followed by acetylation for characterizationpurposes gave the novel disaccharide 84 in 69 yield overthe two reactions (Scheme 17)
A two-directional variant of this methodology can beused to prepare symmetrical C-disaccharides as shown inScheme 18 [24] The double HWE reaction on diisopro-pylidene mannofuranose 80 worked extremely well in the
Scheme (13)
Scheme (14)
BnO
OBn
O2N
OMe
O
CHO
OBnO
OBn
BnO
OMe
OHO
OH
OHO
OH
HO
OMe
OBnO
OBn
OBnO
OBn
BnO
HO
NO2
OMe
OBnO
OBn
OBnO
OBn
BnO
X
+
KF 18-C-6 MeCN
1 Ac2O Pyr2 NaBH4 EtOH
58 X = NO 2
59 X = H 44 over 3 st eps
Bu3SnH AIBN
Pd(OH)2 H2
rt 1 atm 24 h
40
60 74
55
56
57
O
BnOOBn
BnO
OBn
OH
O
OHNO2
O
O
BnOOBn
BnO
OBn
OH
O
ONO2
O
O
O
O
O
AcOOAc
AcO
OAc
O
OAc OAc
OAc
O
BnOOBn
BnO
OBn
NO2OH
Et3 N MeCN
1Bu3 SnH AIBN
2 BF OEt Et3SH
3 L-SelectrideTHF
64 61 in 3 steps
1 Pd(OH)2 C6 H10
2 Ac2O TESOTF
61 63 43
62
65
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1401
HWEconjugation-addition C-glycosydation sequence givingdiastereomeric sulfones 85 in a combined yield of 75RBR of the major stereoisomer (βα-79) using the Meyers-
Chan procedure gave alkene 86 in 66 unoptimized yieldand hydrogenation produced the novel C-linked bisfuranosedisaccharide 87 in 76 yield
Scheme (15)
Scheme (16)
OBnO
BnO
H
OBn
OH
OOBn
BnO
OBn
OBn
BnO
OBn
OBn
OBnO
BnO
OBn
OH
SO2
O
OBn
O O
AcO
AcO
AcO
OAc
OAc
OAc
OAc
OAc
OBnO
BnO
OBn
OH
I
O
HS
OBn
BnO
OBn
OBn
68 90 over 2 steps
KOH CCl4 t-BuOH H2O
1 H2 PdC
2 Ac2O Pyr
70 69 over 2 steps
+
1 K2CO3
2 mCPA66
67
69
O
BnOOBn
BnO
OBn
OH
(EtO)2P(O)CH2CO2Et
OBn
OBn
OBnO
OBn
OBnO
BnOOBn
OBn
X
O OBn
OBn
BnOOBn
OBnO
BnOOBn
OBn
OBnO
BnOOBn
OBn
R
OBnO
BnOOBn
OBn
SH
LiAlH4
OAc
AcOOAc
O OAcOAcOAcO
OAc
OAc
1 H2 Pd(OH)2C
2 Ac2 O Pyr
NaH THF
72 R = CO2Et
73 R = CH2OH
66 over 3 steps
K2CO3 acetone
76 X = S
77 X = SO2 79
Oxone THF MeOH H2 O
KOH CCl4 aq tBuOH
78 57ZE 8812
79
71
75
MsCl Et3N 74 R = CH2 OMs
1402 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Norris et al deprotonated 88 with n-BuLi and theresulting anion was coupled with an excess lactone 89 at lowtemperature to afford the adduct 90 in 77 yield SPhgroups were removed with Raney nickel and lactol 91 wasisolated as a syrup that contained two components in
approximately a 41 ratio The two compounds were thoughtto be α- and β-lactols with the latter being major It wasstraightforward to reduce the lactols with a high degree ofstereocontrol to afford the C-disaccharide 92 with a 51isolated yield (Scheme 19) [25]
Scheme (17)
Scheme (18)
O
O O
O
O OH
O OMe
OBnBnO
SO2
P
EtO
EtO
O
OBn
O
OMe
OAc
OAc
OAcO
O O
O
O
O
OO OMe
OBnBnO
SO2
OBn
O
O O
O
O O
O
O
O
OMe
OBn
OBn
OBn
83 50 E only
80
+
NaH THF -78 oC
82 86αβ 11
KOHAl2O3
CBr2F2 CH2Cl2
tBuOH 5 oC
2 h
1 H2PdC EtOAc RT 7h
2 Ac2 O Pyr RT
84 69 over 2 st eps
81
O
O O
O
O OH POEt
OEt
O
SO2
P
EtO
EtOO
O
O
O
OO
O
O
O
O O
O
O
O O
O
O
O
O SO2
O
O
O
O
O
O O
O
OO
O
O
85 75βαββ ca 31
86 66β αββ = 141 E only
H2PdC EtOAc
87 76βαβ β = 141
21 NaH THF -78 o C
80 (2 equiv)
KOHAl2O3CBr2F2 CH2Cl2tBuOH
on majorβα is omer
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1403
24 Phosphorous Stabilized Anions
The most common type of reaction discussed in thissection is Wittig approach to C-oligosaccharide synthesisThis methodology is particularly suited for synthesis of(1rarr6)-C-saccharides since one sugar can hold the aldehydewhile the other the ylid or phosphonate anion
Dondoni has utilized this approach to prepare a variety ofβ-D-(1rarr6)-C- disaccharides The general approach is shownin Scheme 20 Coupling of β-linked galactopyranosyl ormannofuranosyl derivative (93 94 95 or 96) with ylidefrom phosphonium iodide 97 or 98 gave alkene 99 Alkenewas reduced and removal of deprotecting groups gave thecorresponding β-D-(1rarr6)-C- disaccharide 100 [26]
α-D-(1rarr6)-C-disaccharide 103 was also synthesizedusing the approach (Scheme 21)
Dondoni applied this methodology in an iterative fashionto prepare the corresponding β-(1rarr6)-C-trigalactosides andβ-(1rarr6)-C-tetragalactosides [27] Starting with coupling ofylide 104 generated in situ with aldehyde 33 gave adduct105 (EZ 19) Removal of silyl protecting group followed byoxidation led to aldehyde 106 which was coupled with theylide from 104 to give C-trisaccharide 107 in 36 yield Thesame sequence was repeated with 107 afforded the protectedC-tetrasaccharide alkene 108 Compounds 108 wasdesilylated and exposed to hydrogen over Pd(OH)2 oncarbon followed to peracetylation gave protected C-tetrasaccharide 109 (Scheme 22)
Taking advantage of their experience on the stereo-selective synthesis of C-oligosaccharides by iterative Wittigolefination this group developed new building blocks and amodified protocol for the straightforward assembly of C-α-(1rarr5)-D-oligoarabinofuranosides [28] While the twomonofunctionalized sugar moieties 110 and 111 weresuitable precursors to the head and tail of the oligo-saccharidic chain the difunctionalized compound 114 was arepeating unit (Scheme 23) Building block 114 wasdesigned to allow after the Wittig coupling for regenerationof the formyl group in a single step under conditions that donot affect the chemical and stereochemical integrity of thegrowing saccharidic chain (Scheme 24)
Colinas et al reported a method for the synthesis of C-disaccharides by a sequence involving the Wittig reaction askey step and further glycosydation of these compounds toafford new C O-trisaccharides [29] The enol ether 122a-bwere prepared by the Wittig reaction of the α β mixture of2-deoxiglycosyl phosphonium salts 120a-b with aldehyde121 Hydrogenation of the exo-glycals afforded the β-C-disaccharides with good yields The O-glycosidationemploying the exo-glycals and the glycosyl acceptor 124 isillustrated in Scheme 25
25 C-1 Vinyl Anions
Schmidt was the first to explore the addition of sulfoxide-stabilized vinyl C-1-organolithiums to carbohydrate-basedcarbonyl compounds [30] The vinyl sulfoxide 126 was
Scheme (19)
OCH3
O O
OPhS
PhS
O O
OO
OCH3
O O
OO O
O H
OCH3
O O
OPhSPhS
O O
O OH
OCH3
O O
OO O
O OH
+
n-BuLi THF -78 oC
Raney Ni EtOH H2O rt
Et3SiH BF3 OEt2
90 77
92 51 over 2 steps 91 is omers rati o βα = 41
-78 oC
88
89
1404 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
deprotonated with LDA to give 127 Addition of 127 toaldehyde 128 gave a mixture of diastereoisomers of whichthe major 129 was formed in a 101 ratio Desulfurizationhydroboration and removal of benzyl groups gave the(1rarr5)- βminusC-disaccharide 130 (Scheme 26)
Schmidt and coworkers used this methodology for ahighly efficient synthesis of an analog of C-trehalose 134Scheme 27 [31] Anion 131 was converted to aldehyde 132
and condensation of this aldehyde with the same anion gaveadduct 133 which was then converted to the target C-disaccharide 134
26 Acetylide-Based Anions
Sinayuml was the first to prepare a C-disaccharide Hisapproach involved the coupling of a C-6 alkyne with ananomeric lactone followed by reduction of the formedhemiacetal [32] Aldehyde 135 was converted to the
Scheme (20)
Scheme (21)
OO O
O
O CHO
O
BnOOBn
BnO
OBn
CHO
OBn
CHO
BnO
O
BnOBnO
O
BnOOBn
BnO OBn
CHO
PPh3I-
OO
O
OO
O
OMeOBn
OBn
OBn
PPh3I-
OCHO
O
PPh3I-
ORRO
RO
OO
ORRHO
OO
OR
+ +
+
( 93 - 96 )
( 97 - 98 )
BuLi THF-HMPA
-30 iexclaelig
99
Reduction
100
+
93 9495
96 97 98
O
OBnBnO
BnO
OO
O
OO
HO
O
O
OO
PPh3I-
O
OHHO
HO
O
HOOH OH
HO
OBnBnO
CHO
BnO
O
+
BuLi THF-HMPA
-30 oC
1 p-MeC 6H4SO2-
NH2NH2 AcONa
2 H2 Pd(OH)2 3 bar
3 Amberli te H+
+
10197
102
103
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1405
dibromoalkene 136 which was treated with n-butyllithium togive an intermediate acetylide 137 The latter uponnucleophilic addition to lactone 138 gave a mixture of lactol139 in high yield Stereoselective reduction of lactol 139 wasfollowed by hydrogenation of benzyl groups and the triplebond affording the (1rarr6)-β-C-disaccharide 140 (Scheme28)
The lactone-addition methodology was later applied bySinayuml and co-workers in an iterative fashion for the
preparation of higher homologues [33] Hydroxylmethylenein compound 141 was converted to acetylide lithium incompound 142 by a sequence of reactions Condensation ofcompound 142 with the galacto lactone 143 gave 144 asmixture of anomers The lactol were stereoselectivelyreduced to and triple bond was hydrogenated to give 145Methyl glycoside 145 was hydrolyzed to the correspondinglactols which were oxidized to lactone 146 The samesequence was then repeated twice to give C-trisaccharide147 and C-tetrasaccharide 148 (Scheme 29)
Scheme (22)
O
BnOOBn
BnO OTBDPS
PPh3I-
BnO
H
O
BnOOBn
OTBDPS
OO
O
OO
O
CHOO
O
OO
O
BnO
O
BnOOBn
BnO
OO
O
OO
H
HOBn
BnO OTBDPS
O
BnOOBn
BnO O
OO
O
OO
H
OBn
BnO OTBDPS
PPh3I-
O
BnO
O
BnOOBn
BnO OTBDPS
PPh3I-
O
AcOOAc
AcO
O
AcOOAc
AcO
OO
O
OO
O
AcOOAc
AcO OAc
O
BnOOBn
BnO
O
BnOOBn
BnO
OO
O
OO
H
H
O
BnOOBn
BnO OTBDPS
H
1 TBAF2 PCC
+107 36
+
1 TBAF2 PCC3
+
1 TBAF2 H2 Pd(OH)2 C3 Ac2 O Pyr
104
33
105
106104
104
108109
BuLi THF-HMPA
-50 o C
70EZ 19
BuLi THF-HMPA
-50 o C
1406 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
The di- tri- and tetrasaccharide derivatives (145 147 and148) were all debenzylated and tested for their bindingaffinity to three different monoclonal immunoglobulins withspecificity for different O-β-(1rarr6)-D-galactopyranosyl deter-minants These C-saccharide analogs had similar bindingproperties to the corresponding O-saccharides
Schmidt has also used acetylide-lactone condensation toassemble C-disaccharides of ketoses [34] Lithium acetylide149 was condensed with ketone 150 to give a mixture ofalcohol 151 after removal of the pivoloyl group Attemptedcyclization under Lewis acid catalysis resulted only in theremoval of the acetonide Accordingly the diol was tiedback as the carbonate and the acetylene complex as thedicobalt species 152 The isomers were then separately
cyclized to give a 11 mixture of C-disaccharide 153 Thecobalt complex on α-C-disaccharide was removed understandard conditions to give 154 and deprotection of thecarbonate was followed by hydrogenation and peracetylationto give 155 (Scheme 30) Similar chemistry was also carriedout with the corresponding β-isomer
Van Boom and co-workers used lithiated alkynylderivative 156 in presence of ZnCl2 to selectively open ringof the 12-anhydrosugar 157 affording the α-C-(alkynyl)-glycoside 158 Hydrogenolysis of the benzyl groups wasfollowed by peracetylation to give the (1rarr6)-α-C-disaccharide 159 (Scheme 31) [35]
Normally attack of the nucleophile proceeds from anequatorial direction to give the β-isomer The unexpected
Scheme (23)
Scheme (24)
BnOO
OBnCHO
OBn
O
OBn
PPh3I-
OBn
OBn
O
OBn
BnOBnO
O
OBnOBn
OBnH
O
OH
HOHO
O
OHOH
OH+
BuLi
THF-HMPA
-20 oC+
1 TBAF2 H2 Pd(OH)2C
112 65 113 100
110
111
O
OBnCHO
OBnBnO
O
OBn
BnOBnO
O
OBnCH(OiPr)2
OBnH
O
OBnCH(OiPr)2
PPh3I-
OBn
O
OBn
BnOBnO
O
OBn
OBnH
O
OBnOBn
BnOH
O
OH
HOHO
O
OH
OH
O
OHOH
HO
++
BuLi
THF-HMPA
-20 oC
BuLi
THF-HMPA
-20 oC
TFA H2 O THF rt
115 49
116 R = CH(OiPr)2
117 R = CHO
118 45
H2 Pd(OH)2C
110
114
114
119
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1407
Scheme (25)
Scheme (26)
OBn
R1
R2
PPh3BF4-O
O
OOHC
O
O
O
O
O
O
O
O
HO
O
O
O
O
O O
OBn
R1
R2
O
O
O
O
O
O
H
O
OBn
R1
R2
O
O
O
O
O
O
O
O
OBn
R1
R2
O
O
O
+
BCl3 (005 equiv)
MS 4A CH2 Cl2 0 o C
+
BuLi THF -90 oC -90 o C
to rtH2 (1 atm) PdC Et3N MeOH
R1 R2 = OBn H
120a - b
121
122a - b
123a - b
124
125a - b
OTBDPS
BnO X
SO Ph
O
BnO
OHCO
BnO
OMeOBn
OBn
O
BnO
OTBDPS
BnO
SO Ph
O
BnO
OMeOBn
OBn
O
HO
OMeOH
OHO
HOHO
OH
OH
128
229 74
1 RaNi (74)
2 BH3 DMS
NaOH H 2O2 (74)
3 H2 PdC (70)
130 74
LDA THF
-100 oC
126 X = H
127 X = Li
1408 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (27)
Scheme (28)
stereochemical outcome is rationalized by the generation ofan initial zinc acetylide species which facilitates intra-molecular delivery to the α-face (Scheme 32)
Wightman synthesized C-disaccharide analogs of the α-D-arabinofuranosyl-(1rarr5)-α-D-arabinofuranosyl motif ofmycobacterial cell walls through alkynyl intermediates [36]The lactone 164 was treated with lithio(trimethylsilyl)ethyneat low temperature to give lactol in 66 yield of 165Treatment of this with triethylsilane and BF3
Et2O gavethe separable isomers 166α (60) and 166β (13)Desilylation of the major isomer 166α gave 167 in 97yield Treatment of 167 with n-BuLi followed by addition oflactone 164 gave 85 yield of the hemiacetal 168 which onreduction with Et3SiH and BF3
Et2O gave the disubstitutedalkyne 169 (83) as the major product Reduction-
hydrogenolysis of 169 then gave the C-disaccharide 170 innear-quantitative yield (Scheme 33)
3 REDUCTIVE GLYCOSYL SAMARIUM SPECIES
The introduction of SmI2 as reducing agent can becredited to Kagan and has since been utilized in numeroussynthetic schemes [37] Sinayuml and Beau introduced SmI2
chemistry into C-glycoside synthesis through intermolecularreactions with appropriate electrophiles and intramolecularreactions of silyl tethered substrates [38] Anomericsamarium species are highly stable and not likely to undergoβ-elimination Treatment of the aryl sulfone 171 with SmI2
affords the nucleophilic intermediate 172 through two singleelectron transfer processes Introduction of a suitableelectrophile (carbonyl compounds) affords the α-C-manno-
O
BnO
OTBDPS
BnO X
SO Ph
O
BnO
OBn
BnO Li
SO Ph
DMF
OHO
HOOH
OH
O OH
OH
HO
OHOH
O
BnO
OTBDPS
BnO
SO Ph
O
OBn
OBnOBnSO
Ph
OH
131 X = Li
132 X = CHO
THF -100 oC
1 Ra-Ni
2 BH3 DMS NaOH H2O2
3 H2 PdC
131
133
134
OBnO
OBnOMe
BnO
Li
OBnO
BnOOBn
OBn
OOBn
OBnOMeBnO
OH
OBnO
BnOOBn
OBn
O
n-BuLi
BnO
OMe
BnO
BrBr
O
OBn
OHO
OH
OH
HO
OHO
OH
HO
OMe
O
BnO
OMeOBn
O
BnO
139 92
1BF3 OEt2 EtOH
2 H2 PdC AcOH
140 52 over 2 steps
135 136 137
138
CBr4 PPh3
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1409
pyrannoside 173 in good yield and with excellent stereo-selectivity (Scheme 34) [38a]
Preparation of C-glycosides of ulosonic acids using SmI2
was pioneered by Linhardt and coworkers [39] Coupling ofpyridyl sulfone 174 with aldehyde 175 in the presence ofSmI2 gave an excellent yield of the N-acetylneuraminic acidC-disaccharide 176 as single isomer This stereochemicaloutcome was rationalized on the basis of the Felkin-Anhmodel for predicting the stereochemical outcome of akinetically controlled addition of a nucleophile to a chiraladehyde (Scheme 35 A)
Reductive samarium method was utilized to synthesizesialo-antigen C-analogs by the Linhardt group A fullyprotected C-analogue of the SialylTn antigen α-D-Neu5Ac-(2rarr6)α-D-GalNAc-(1rarrO)-Ser 182 was prepared [40] C-glycosylation of the neuraminic acid sulfone donor with
aldehyde acceptor in presence of excess SmI2 afforded the α-C-glycoside 180 as an RS mixture (11) The criticalintermediate aldehyde acceptor 178 was prepared in 13steps Chemoselective resolution to compound 180 wasundertaken by oxidation with DMSOAc2O to keto-bridgedcompound 181 followed by stereoselective reduction withZn(BH4)2 to regenerate the bridge hydroxyl function gave182 in gt90 de (Scheme 36)
A common versatile N-acetylneuraminic acid C-disaccharide precursor of the C-glycoside analogs ofgangliosides GM4 and GM3 has been synthesized [41]Samarium(II) iodide coupling of N-acetylneuraminic acidsulfone 179 with a 3-formyl galactopyranoside derivative183 afforded the corresponding C-disaccharide 184 as amixture of (R) and (S) isomers at the newly formedhydroxymethylene bridge This diastereoisomeric mixturewas resolved after debenzylation of the galactoside residue
Scheme (29)
O
BnO
BnOOBn
OBn
OOBn
OBnOMe
OBnOH
O
BnO
BnO
OBn
OBn
O
O
BnOOBn
OMe
BnO
Li
OBnO
OBn
OBn
OBnO
OBn
OBn
OMe
OBnO
OBn
OBnBnO
OBnO
OBn
OBn
OBnO
OBn
OBn
OMe
OBnO
OBn
OBnOBnO
OBn
OBnBnO
O
BnO
BnO
OBn
O
OBnO
OBn
OBnBnO
OBnO
OBn
OBnBnO
OBnO
OBn
OBn
OMe
OBnO
OBn
OBnBnO
OMe
1 PCC2 CBr4 Ph3P3 n-BuLi
144 overall yield 54
1 BF3 OEt2 Et3 OH
2 H2 PtO2 EtOAc
145 76
1 H2 SO4 AcOH
2 PCC
146 62
repeat steps
repeat st eps
141 142
143
147
148
1410 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (30)
Scheme (31)
O
BnOOBn
OMe
Li
BnO
OPivBnO
OBn
OBn
BnO
O OO
BF3 OEt2
OBnO
OBn
OBn
BnO
OO
O
OMe
BnOOBn
BnO
Co(CO)3
Co(CO)3
O
CAN
OBnO
OBn
OBn
BnO
OO
OO
BnOOBn
BnO
OMe
OHBnO
OBn
OBn
BnO
OHO
O
O
OMe
BnOOBn
BnO
Co(CO)3
Co(CO)3
O
OPivBnO
OBn
OBn
BnO
OH OO
O
OMe
BnOOBn
BnO
OAcO
OAc
OAc
AcO
OAcOAc
OAcO
OAc
AcO
OMe
1
2 NaOMe MeOH
1 Lewis acid2 ClCO2CCl3 Pyr3 Co2(CO)8
with a-isomer
1 Et3N Pyr H2O
2 H2 PdC H+
3 Ac2 O Pyr
149 151
152153
154 155
150
OBn
BnO
OBnO
OBn
BnO
OBnO
BnO
MeO
OBnO
OBn
BnO
O
OMe
AcO
OAcO
OAc
OAc
AcO
OAcO
OAc
O
BnOOBn
OMe
BnO
159 74 over 2 steps
+
BuLi ZnCl2 THF
1 H2 PdC2 Ac2O Pyr
156 157
158 59
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1411
Scheme (32)
Scheme (33)
and the chirality of each isomer assigned after acetylationConversion of the p-methoxyphenyl group in the peracety-lated (S) isomer 187 into the corresponding thiophenylglycoside 188 was accomplished affording the key inter-mediate for the synthesis of C-glycoside analogs of GM4GM3 and other related gangliosides (Scheme 37)
Ganglioside GM4 is a very important cell adhesionmolecule The C-disaccharide of GM4 is currently beingsynthesized in Linhardtrsquos lab using standard O-glycosylationof C-disaccharide with protected ceramide Once theceramide has been attached it can be oxidized to afford analdehyde group for coupling to keyhole limpet hemocyanin
OBnO
OBn
BnO
O
OBnO
ClZnO
OBn
BnOCl
R
OBnO
O
OBn
BnOCl
ZnR
O
ZnR
OBnO
OBn
BnO
160 161
162163
O
OBn
OBnBnO
O
O
OBn
OBnBnO H
TMS
O
OBn
OBnBnO H
O
OBn
BnO
OBnHO
O
OBn
OBnBnO OH
TMS
OBnBnO HO
OBn
TMS
O
OR
ORRO H
O
OR
RO
OR
OBn
OBnBnO
H
TMS
O+
K2CO3 MeOH
1 n-BuLi THF -78 oC
2 164
164165 66
166α 60 166β 13167 97
BF3 Et 2O Et 3SiH -78 oC
168 85
169 R = Bn 83
170 R = H near quantitative yield
H2 (1 atm)Pd(OH) 2C
TMS-acetyl ene
n-BuLi THF -78 oC BF3 Et2O Et3SiH
-78 o C
1412 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
O
OHCOBn
OBnBnO
OMe
O
CO2MeAcO
OAcAcHN
OAc
SO2
NAcO
OBnH
H
OBn
OBn
H
O
OMeH HH
A
O
CO2MeAcO
OAcAcHN
OAc
O
OBnOMe
OBnOBn
HO
AcO
+
Nu
174175
176
SmI2 THF
Scheme (34)
Scheme (35)
Scheme (36)
O
BnO
BnO
BnO
Si lylO
O2S N
O
BnO
HO R2R1
BnOBnO
SilylO
OBnO
BnO
BnO
SilylO
Sm(III)
R1COR2 SmI2 THF
171 172
173
NHBoc
OAcO
AcO
AcHN O
O
CO2BnO
OO
OO
OH
O
CO2MeAcO
OAcAcHN
OAc
AcO
SO2Ph
R2
O
CO2Me
AcHN
OAc
AcO
R1
AcO
AcO
AcHNO CO2Bn
NHBoc
AcO
OAc
O
Zn(BH4)2
180 R1 R2 = H OH ( RS 11)
181 R1 R2 = O
182 R1 = H R2 = OH de gt 90
DMSO Ac2O
177178
179
13 steps
22 equiv SmI2 THF
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1413
Scheme (37)
Fig (2)
(KLH) by reductive amination for use as carbohydrate-basedvaccine GM3 a related trisaccharide containg gangliosideplays an important role in cell growth and differentiationFig 2 The synthesis of C-oligosaccharide GM3 is currentlyunderway following a similar route to that of C-GM4synthesis [42]
Beau also reported a sialyl C-disaccharide synthesiswhich relied on the unprecedented use of a stable andcrystalline 2-pyridyl sulfide of the N-acetylneuraminic acidderivative 189 as the anomeric precursor in a samarium-Reformastky procedure [43] The coupling procedure withsulfide 189 and aldehyde 190 afforded the carbon-linkeddimer 191 in 93 yield as a 11 diastereomeric mixture
Alcohols 191 were converted into thiocarbonates anddeoxygenated by employing triphenyltin hydride catalyticAIBN and pentafluorophenol which yielded C-disaccharide192 as a single compound in 65 yield for the 2 stepsDesilylation hydrogenolysis acetylation and finalacetolysis of the methyl glycoside provided the carbon-linked mimic 193 of the disaccharidic component of thesialylTn tumor antigen (Scheme 38)
4 CATIONIC METHODS
This section is categorized according to reactions thatinvolve the generation of anomeric ions followed by thecapture with sugar-based nucleophiles
OAcAcHN
OAc
AcO
O
OBnBnO
OBnOMP
HO
O
MeO2CAcO
O
MeO2CAcO
OAcAcHN
OAc
AcO
O
OHHO
OHOMP
HO
O
OBnOHC
OBnBnO
OMP
O
MeO2CAcO
OAcAcHN
OAc
AcO
O
OHHO
OHOMP
HO
O
CO2MeAcO
OAcAcHN
OAc
AcO
SO2Ph
O
MeO2CAcO
OAcAcHN
OAc
AcO
O
OAcAcO
OAcX
AcO
H2 PdC EtOAc CH3OHH2O
+
Ac2O Pyr
187 X = OMP
188 X = SPh 73
184 85 R and S mixture
186 90 for two i somers
+
SmI2 THF183
179
185
O
HO2 CHO
OAcAcHN
OH
HO
O
OHHO
OH
OAcO
(CH2 )12 CH3
HN
OH
(CH2)14CH3
O
O
O
OHHO
OH
O
O
HO2 CHO
OAcAcHN
OH
HO
O
OHHO
OH
O(CH2)12CH3
HN
OH
(CH2)1 4CH3
GM4
GM3
1414 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
41 Exo-glycals as Nucleophiles
Nitotra et al have found that treatment of exo-glycal 194with BF 3
OEt2 followed by a water quench afforded the C-disaccharide 195 (Scheme 39) It is noteworthy tonoteworthy that the attack of the enol ether on the anomericoxonium ion occurs with high stereoselectivity on the α-face only 195 was obtained [44]
42 Silyl-based Nucleophiles
Isobe has designed and developed alkynylation as a keyreaction for the introduction of a carbon chain onto sugarsThose alkynylated compounds are called ldquosugar acetylenesrdquo[45] The mechanism includes eliminative formation ofcation to which silylacetylene can coordinate on the α-face(Scheme 40)
Double C-glycosylation between glycal 198 and bis(silylacetylene) gave C-disaccharide ldquolikerdquo compounds 199and 200 (Scheme 41)
Silylpropargyl-sugar 201 smoothly reacted with D-glucalto furnish exclusively the α-acetylene glycoside product 202in 88 (Scheme 42) [46]
5 CYCLIZATION METHODOLOGY
This approach to C-oligosaccharide synthesis relies onthe coupling of an open chain fragment with an intact
monosaccharide to give an intermediate that is then cyclizedto deliver the C-oligosaccharide target This section isdivided by the type of chemistry used to initially assemblethe two pre-cyclization fragments
51 Wittig Reaction-Cyclization
The Kishi group was the first to use Wittig-cyclizationapproach to synthesize C-disaccharides Starting with Wittigreaction between 203 and 204 the intermediate 205 wasafforded as a single stereoisomer in 82 yield Osmylationthen gave a mixture of diols with the major one formed in a61 ratio Selective protection of the diols gave 206a and206b The mono-para-methoxybenzyl ether 206a was thentransformed into the hemiketal 207 in 75 overall yield inthree steps ie (1) Swern oxidation (2) acetonide hydro-lysis (4 N HClTHFrt) and (3) benzoylation (3 equiv ofPhCOClpyCH2Cl2rt) Silane reduction of 207 in an acidicmedium should preferentially yield the equatorially substi-tuted β-C-glycoside which was deblocked and converted tothe methyl- βminusC-disaccharide 209 Exact parallel experi-ments applied to the minor isomer gave the correspondingC-disaccharide 210 (Scheme 43) [47]
Armstrong has employed Wittig-osmylation protocol forthe preparation of a small library of α-C-(1rarr6)-disaccha-rides [48] Readily available allyl C-glycoside 211 washomologated to diene ester 212 and subjected to osmylation
Scheme (38)
O
CO2MeAcO
OAcAcHN
OAc
AcO
S(2-Py)
O
TESO
AcHNOMe
O
HO
O
CO2MeAcO
OAcAcHN
OAc
AcO
O NHAcOAc
OAc
OAc
O
CO2MeAcO
OAcAcHN
OAc
AcO
O NHAcOBn
OTES
OMe
OAc
AcO
O NHAcOBn
OTES
OMeOH
O
CO2 MeAcO
OAcAcHN
+
192 65
1 MeOHHCl2 H2 PdC EtOH3 Ac2O Pyr4 Ac2OAcOHH2SO4
193 59 overall yield
25 equiv SmI2 THF
1 11-thiocarbonyldiimidazole DMAP2 Ph3SnH cat AIBN
191 93
189
190
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1415
Scheme (39)
Scheme (40)
Scheme (41)
OBnO
OBn
OBn
OBnO
OBn
OBn
OBnO
OBn
OBn
OBnO
OBnCH3
BnO
OH
CH2
OBnO
OBn
CH3
OBn
H2 O
BF3 OEt2 MeCN
194
195 96
OOAc
OAc
AcO
R SiMe3
SnCl4
O
OAc
AcO
R
O
OAc
AcO
O
OAc
AcO
Me3Si
R
SiMe3
196
197
Me3 Si SiMe3
O
AcO
OAc
OAc
SiMe3
SiMe3
O
AcO
OAc
O
OAc
OAc
O
AcO
AcOO
OAc
OAc
SnCl4 CH2Cl2
SnCl4 CH2Cl2198
199
200
1416 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (42)
Scheme (43)
AcO
OAc
OAc
Me3 Si
BnO
OBn
BnO
OBn
AcO
OAc
BnO
OBn
BnO
OBn
+ I2 CH2Cl2
202 88
198 201
O
OBn
OBn
O
O
O
OBn
OBn
O
O
OBn
OBn O
OBn
OBn
O
OPBH2M
OH
OBnO
BnO
BnO
O
OBn
OBn
O
OHOPMB
OHO
HO
HO
O
OH
OHOH
OH
HOOMe
O
OBnOBn
O
Ph3P
O
O
OBn
OBn O
OBn
OBn
O
OPBM
OH
O O
CHO
OBn
BnO
OO
OBn
OBn
O
OHOPMB
BnO
BnO
BnO
OHO
HO
HO
O
OH
OHOH
OH
HOOMe
+ THF -78 oC
1 OsO4 pyr THF
2 NaH PMBBr
206a 206b 206a206b 61
1 Swern [O]2 4N HCl3 PhCOCl pyr
1 Swern [O]2 4N HCl3 PhCOCl pyr
1 PrSiH BF3 OEt2
2 H2 Pd(OH)2C
3 HCl MeOH 90 oC
1 PrSiH BF3 OEt2
2 H2 Pd(OH)2C
3 HCl MeOH 90 o C
203
204
205
207
209
208
210
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1417
followed by reduction to afford a 51 mixture (213214215216) of lactols that were readily separable by chromato-graphy Following a deprotection of an equimolar mixture of213 and 214 217 and the DL hybrid C-disaccharide of D-glucose-O-(1rarr6)-L-galactose 218 were obtained The DDand DL derivatives 219 and 220 of glucose-α-(1rarr6)-idosewere also obtained as a near equimolar mixture afterdeprotection of 215 and 216 (Scheme 44)
52 Anion Addition-Cyclization
Kishi developed an approach for the synthesis of theCndashtrehalo sugars which relied on nucleophilic addition ofone intact sugar fragment to a fundamental aldehyde ieKishi-Nozaki reaction [49] Coupling of monosaccharide221 and aldehyde 222 gave 223 The triple bond waspartially reduced and osmylation was followed by selectiveprotection to afford 224 The acetonide was converted toepoxide 225 by standard methods and removal of the PMBgroup Acid-catalyzed cyclization followed by aglyconichydrolysis and protection of hydroxyl group with (p-methoxyphenyl)diphenylmethyl chloride (MMTrCl) gave226 Inversion of the C-2 hydroxyl and removal of protectinggroups delivered α α-C-trehalose 227 (Scheme 44)
Kishi and co-workers also employed aldol reactions as anefficient access to the C-trisaccharide related to the type IIABO(H) blood group determinant [50] Aldol condensationof the enolate of methyl ketone 228 with aldehyde 229 gavea 41 mixture of hydroxy ketones 230 and 231 The majorketol was cyclized desulfurized and oxidized to afford thedisaccharide ketone 233 The ketone in THF was treatedwith LiHMDS (3 equiv) and TMEDA followed by theaddition of MgBr2 Addition of the aldehyde 234 led toalmost exclusive formation of the equatorial products 235and 236 in a 12 ratio Mesylation of 235 and 236 followedby treatment with liquid ammonia gave enones 237a and237b which were reduced to yield exclusively the C-2rsquo-equatorial ketone 238 Sodium borohydride reduction of theC-3rsquo carbonyl proceeded with the desired stereoselectivity toyield the protected C-trisaccharide 239 which wasdeblocked to provide the polyol 240 (Scheme 46)
Sutherlin and Amstrong cleverly applied a recursivestereochemical deconvolution (RSD) combinatorial approachfor the synthesis of a small library of C-trisaccharides aspotential inhibitors for the cell surface proteins of bacteriumHelicobactor pylori [51] The workers chose to carry outvariations in galactose ring of these trisaccharides An
Scheme (44)
OBnO
BnOOBn
OBn
P O
OEtOEtO
EtO
R H
OH
OH
OH
OH
O
R H
OH
OH
OH
OH
O
OHO
HOOH
OH
O
HO
OHOH
OH
OHO
HOOH
OH
O
HO
OH
OH
OHO
HOOH
OH
O
HO
OH
OHOH
R H
OH
OH
OH
OH
O
R
OBnO
BnOOBn
OBn
O
OHO
HOOH
OH
OO
HOHO
OH
R H
OH
OH
OH
OH
O
1 OsO4 NMO 50
2 DIBAL -32 oC 40
++ +
213 214 215 216
217 218 219 220
1 9-BBN H2O22 Swern [O]
3 t-BuOK
4 I2 C6H6212
211
1418 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
efficient Nozaki-Kishi coupling of vinyl bromide 241 withaldehyde 242 in a diasteromeric ratio of 12 followed byprotection with TBSOTf led to 243 and 244 Hydroborationfollowed by oxidation gave aldehydes 245 and 246respectively Addition of allylmagnesium bromide toaldehyde 245 followed by removal of the silyl groupafforded 247 to 246 giving 248 and 249 Epoxidation gave a11 mixture of the corresponding epoxides which werecyclized to give the C-trisaccharide 250-255 after removalof the benzyl groups (Scheme 47)
Schmidt reported a stereoselective 6-exo-trig selectiveelectrophilic cylization approach for de novo synthesis of amethylene-bridged Neu5Ac-α-(23)-Gal C-disaccharide theC-analog of an important motif in glycosphingolipids [52]The open chain precusors 259ab (a 32-mixture ofdiaseteromeric alcohols) were formed by the addition oflithiated iodide 256 to open chain aldehyde 258 Subsequent
C1 incorporation using Tebbe-reagent formation of a cycliccarbonate and deprotection of the two isopropylidene ketalsafforded tetrol 264 which upon treatment with phenylselenyltrifilate was steroselectively cyclized in a 6-exo-trigselective manner affording a diasteromeric mixture of 251and 252 in a ratio of 71 A seleno-Pummerer rearrangementto afford aldehyde 267 in 5 steps in 90 overall yieldOxidation of the aldehyde and subsequent steps led to thedesired C-disaccharide 268 (Scheme 48)
53 Esterification-Cyclization
Work from the Postema group has focused on a ringclosing metathesis (RCM) approach for the synthesis of C-saccharides [53a] The chemistry is versatile and has beenused for the synthesis of a small library of differentiallylinked β-C-disaccharides through a radical allylation-RCMstrategy [53b] The synthesis of the β-(1rarr4)-glucopyranosyl
Scheme (45)
O
OBn
BnO
BnO
BnO
I
CrCl2-NiCl2O
OBn
OH
BnO
BnO
BnO
O
O
O
O
O
H
OBn
O
O
OBnBnO
BnO
BnO
OOBn
OBn
OAc
PMBOHOO
OBn
BnO
BnO
BnO
O
OBn
OBn
OAc
O
OH
HO
HO
HO
OH
OH
OH
O
OH
O
OBn
BnO
BnO
BnO
OBn
OBn
OAc
O
MMTr
+
1 p-TsOH2 K2CO3 MeOH3 MMTrCl pyr
1 Swern [O]2 BH3 THF
3 AcOH-H2 O4 H2 Pd(OH)2
221
222
223
1 Pd-Pb CaCO3 H22 NaH BnBr3 OsO44 Bu2 SnO5 CsF PMB-Cl6 Ac2 O 4-DMAP
1 AcOH2 TsCl pyr
3 NaH-imid4 DDQ
224225
226 227
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1419
Scheme (46)
OBnO O
OBn
OMe
OBn
XY
SMe
OBnBnO
O
OBn
OBn
OBn
OBn
O
BnO
YX
OBn
TBSO
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnOOBn
H
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnO
OBn
OHC OBn
OBn
OTBS
OMe
BnOOBn
CHO
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnOOBn
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnO
OBn
YX
OBnO O
OBn
OMe
OBn
OBn
O
BnO
O
OBn
OBn
OBn
OBn
O 1 LiHMDS
2
228
1 TBAF THF
2 MeSH BF3 OEt2
230 X = OH Y = H231 X = H Y = OH
230231 41
1 Bu3SnH AIBN2 Swern [O]
1 LiHMDS THF-TMEDA2 MgBr23
1 MsCl
2 liquid NH3
235 X = OH Y = H236 X = H Y = OH Bu3 SnH AIBN
237a and 237b
NaBH4 MeOH
238
239 X = OBn
240 X = OHH2 Pd(OH)2
229
232233
234
1420 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (47)
OH C
O
O BnAcHN
OO
O
OBn OBnOBn
Br
O
OBn OBnOBn
O
OBnA cHN
OO
O TBSO
OBn O BnO Bn
O
OBnAcHN
OO
OTBS
S2
S1
S2
OTBSS1
O H
S2
OT BSS1
O H
MgBrMgBr
S2
O TBSS1
O H
S2
OHS1
OH
S2
OTBSS1
OH
O
OHHO
O H
O
HO
H OO
OBnA cH N
HO
H O
O
O HHO
OH
O
HOHO
O
OBnA cH N
HO
H O
O
OHH O
OH
O
H O
HOO
OBnAcHN
HO
HO
O
O HH O
OH
O
H O
H O O
OBnA cHN
HO
HO
O
O HH O
O H
O
HO
H O O
OBnAcHN
HO
HO
O
OHHO
OH
O
H O
O
OBnA cHN
HO
HOHO
+
241 242
1 CrCl2-NiCl2 T HF-DMF 722 TBSOTf 2 6-lutidine 91
243 244
1 9-BBN 602 Dess-Mart in period inane 97
1 9 -BBN 552 D ess-Martin periodinane 98
245 246
1
2 T BAF 74
1
2 TBAF 88
247 248 249
250
251
250 251 1 1 252 253 1 1 254 255 1 1
252
253
254
255
1 MCPBA2 CSA CH 2Cl2 61 fo r 2 steps3 H 2 Pd (O H)2C 95
1 MCPBA2 CSA CH 2Cl2 63 fo r 2 s teps3 H 2 Pd (OH)2C 87
1 MCPBA2 CSA CH2Cl2 80 for 2 steps3 H2 Pd(O H)2C 95
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1421
Scheme (48)
O
OO
Se Ph
R
O
HO OHOH
O
OB n O B n
OB n
O B nO O
O O
R O OR
X
O
OO
R
Se Ph
O
HOOH
OH
O
OB nOB n
O Bn
OB n
O O
O O
R O O R
O H
O
O B n OB n
O B n
OB n
O
C HO
O
O O
R O OR
OAc HN
OAc
C O2NH 4HOOH
OH
O
OH O H
OH OH
O
OB n O B n
OB n
OB nO O
O O
R O OR
X
O
O
OAcOAc
C HOA cOOAc
OAc
O
OB n O B n
OB n
OB n
O
O Bn OB n
OB n
OB n
X
OH
OO
HOOH
OH
O
O
OMeOB n
OB nOB n
R
t-B uL i256 R = Li
257 R = L i
258
(R = t-B uMe 2Si )
(R = t-B uMe 2Si )
259ab (32) 79 com bine d yi eld
De ss-Ma rtin pe riodinane
260 X = O R = t-B uMe 2Si ) 95
261 X = O R = t -B uMe2S i) 62
T e bbe re age nt
TB A F THF262 X = O R = H 94
diphosge ne
C H2C l 2Pyr
263 95
T HFH2O T FAr t
264 quant it a ti ve yie ld
PhSe C l AgOT f
EtC N -80 oC
265
266
Quant it at i ve yi l ed 25 26 7 1
+
R =
1 Ac 2OPyr
2 mC PB A3 Ac 2ONa OAc
4 NaO HT HFMe OH
5 Ac2O P yr
267 90 overa ll yi e ld
ste ps
268
1422 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
glucopyranoside 280 represents an example of thischemistry The known triacetyl glucopyranoside 269 wasconverted to iodide 270 in good yield Radical allylation of271 proceeded to afford a mixture of equatorial and axialallylation products in a 61 ratio Oxidative cleavage of thedouble bond gave the corresponding aldehydes 273a and273b which were separable Pinnick oxidation of the majoraldehyde 273a then gave the C-4 equatorial acid 274 DCC-mediated coupling of alcohol 275 and acid 274 proceeded toafford ester 276 in good yield Methylenation of 276 gave277 and exposure to catalysist 278 gave a 41 yield of theC-disaccharide glycal which was exposed to an excess ofBH3
THF to give 64 yield of the β-C-disaccharide 279Removal of the benzyl groups and global peracetylation gavethe peracetylated (1rarr4)-β-C-disaccharide 281 in good yield(Scheme 49)
54 Ring Expansion-Cyclization
Nelson developed a new strategy for asymmetric andstereoselective synthesis of C-linked disaccharide mimeticsthe C58-C71 fragment of palytoxin [54] The diol (RR)-282was converted into the di-dihydropyran (DHP) template 283284 and 285 The di-DHPs were functionized in a twodirectional sense using dihydroxylation reactions The two-directional approach was often very efficient indeed forexample in the synthesis of 286 six new stereogenic centerswere introduced with almost complete stereocontrol using areduction and a dihydroxylation reaction The approach isnot restricted to the synthesis of C2-symmetricaldisaccharide mimetics Using the unsymmetrical template285 which has both a pseudo-axial and a pseudo-equatorialhydroxyl groups the unsymmetrical mimetics 289 and 290were prepared (Scheme 50)
6 RADICAL APPROACHES
The radical approach for C-C bond formation is a popularmethod within organic chemistry The use of radicalchemistry in carbohydrate synthesis has certain advantagesFirstly the reaction conditions are very mild and tolerant ofa range of functional and protecting groups Secondanomeric radicals are stable with respect to elimination andepimeration Most significantly the chemistry required toincorporate an appropriate substitute at C-1 employed in theinitial hemolytic cleavage step is common within carbo-hydrate chemistry [55] The use of such radical techniquecan be subdivided into two classes intermolecular andintramolecular approaches
61 Intermolecular Radical Approaches
Giese was the first to employ an intermolecular radical-based approach for synthesis of C-disaccharides [56]Addition of an alkene to an anomeric radical underappropriate conditions allowed exclusive entry to the α-linked C-glycoside a result which was mirrored by the workof Baldwin [57] The high α-selectivity of the reaction wasin contrast with other reports Thus radicals generated at theC-2 C-3 and C-4 centers all preferred to occupy equatorialpositions [58] When the anomeric bromide 291 was treatedwith tin hydride and AIBN resulting anomeric radical andreacted with lactone 292 in a Michael addition it afforded293 In this reaction hydrogen abstraction at the resulting
radical center occurs from axial face to selectively generatethe equatorial C-2rsquo substituent Reduction and acetylation of293 furnished C-disaccharide 294 (Scheme 51) [59]
Witczak used the facial bias of levoglucosene tostereoselectively add a carbohydrate-based radical in thepreparation of the 3-deoxy-(1rarr4)-β-C-disaccharide 299[60] Addition of the radical derived from iodide 295 to 296gave adduct 297 in 26 yield Removal of the anomerichydroxyl of 297 was achieved by treatment with triethylsilane borontrifluoride ether complex followed bystereoselective reduction of the keto function at C-2rsquo withthe formation of 298 in 89 yield Debenzylation followedby acetolysis of 16-anhydro ring produced the peracetylatedtarget C-disaccharide 299 in 19 overall yield from 295(Scheme 52)
Vogel has developed general methods to transformenantiomerically pure 7-oxabicyclo[221]heptyl derivatives(ldquonaked sugarsrdquo) into C-disaccharides Because of thesechiral bicyclic skeletons they undergo highly stereoselectivereactions with predictable diasteroselectivities An arsenal ofmethods is available that allow to substitute these ldquonakedrdquocarbon centers with a variety of functional groups with allpossible relative configurations The methods allowpreparation of both enantiomers of a given target with thesame ease Predictably high stereoselectivity of the reactionsof the bicyclic chirons adds to the flexibility of approachwhich can lead to high molecular diversity [61]
α-C-(1rarr3)-mannopyranoside of N-acetyl-galactosaminepotent β-galactosidase inhibitors was synthesized by thisapproach [61] Enone 302 was readily prepared from 300The addition of the radical derived from bromide 303 toenone 302 afforded the αminusisomer 304 The ketone was thenreduced and the selenide eliminated via the intermediacy ofthe selenoxide to give 305 Acid-promoted (CF3SO3H) 7-oxa ring opening of 305 in MeCN produced the amino-conduritol derivative 306 resulting from the quenching of theallylic cation intermediate by the solvent (Ritter reaction)Ozonolysis of the chloroalkene 306 generated an acylchloride-aldehyde intermediate that reacted with MeOH toproduce a mixture of methyl uronates The major compound307 was silylated and reduced The crude polyol obtainedwas acetylated to produce 308 Desilylated and ammonolysisafforded a mixture of α-β-pyranoses 309 and correspondingα-β-furanoses (Scheme 53)
Similar chemistry was carried out to synthesize non-protected α-C(1rarr2)-L-fucopyranoside of D-galactopyrano-side corresponding to a blood group mimetic [62] Giesersquosradical fucosidation of racemic enone 310 with α-L-bromoacetofucose 311 provided the mixture of diastereo-meric α-C-fucoside 312a and 312b in reproducible yield of78 Reduction of the mixture gave a 11 mixture of endo-alcohols 313 and 314 which were isolated pure in 40 and355 yield respectively Oxidative elimination of thebenzeneselenyl group of 313 followed by acetylation gaveendo acetate 315 in 85 yield Acid-promoted ring openingof 315 and ozonolysis of the resulted chloroalkene gavemethyl uronic ester 316 in modest yield (10) Treatment of316 with Cl3CCN and NaH followed with BF3
OEt2
furnished the totally protected C-disaccharide 317 in 79
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1423
Scheme (49)
Bu3SnO
HOAcO
OMeOAc
OAc
O
AcO
OMeOAc
OAcI
AIBN
O
AcO
OMeOBn
OBn
HO2C O
AcO
OMeOR
ORY
X
OHBnO
BnO
OBn
OBnO
BnO
OBn
O
AcO
OMeOBn
OBnX
i-Pr i-Pr
N
Mo C(Me2 Ph)((CF3)2 MeCO)2
O
RO
OMeOR
O
RO
OR
OR
RO
OR
278
I2 Ph3P
imidazole
269 270 93
271a X = CH2CH=CH2 Y = H R = Ac 64271b Y = CH2CH=CH2 X = H R = Ac 11272a X = CH2CH=CH2 Y = H R = Bn 75272b Y = CH2CH=CH2 X = H R = Bn 75273a X = CH2CHO Y = H R = Bn 79273a Y = CH2CHO X = H R = Bn 79
1 NaOMe MeOH2 NaOH BnBr DMF
OsO4 NaIO4
NaClO2 NaH2PO4
274 96
275
DCC 4-DMAP
276 X = O 82
277 X = CH2 51
TiCl4 Zn dust TMEDA CH2Br2PbCl2 (Cat )
1
2 BH3 THF H2O2 NaOH
H2 PdC EtOH
Ac2 O Pyr 4-DMAP
279 R = Bn R = H 64
280 R = R = H 99
281 R = R =Ac 97
1424 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (50)
Scheme (51)
O OOH
OH
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
286
1 VO(acac)2 t-BuOH 95
2 (MeO)3CH BF3 90
1 P-O2NC6H4 CO2H Ph3P DIAD2 K2CO3 MeOH 82 over 2 steps
1 PhCOCl Et3N DMAP 402 P-O2NC6H4 CO2H Ph3P DIAD3 KOH THF-H2O 75 over 2 steps
TMEDA OsO4
Cat OsO4 NMO 287
Cat OsO4 NMO288
TMEDA OsO4
Cat OsO4 NMO
290
289
(RR)-282283
284
285
OHO
AcO
BrOAc
OAc
BnO
O
OBn
OBnO
OHO
AcOOAc
OAc
BnO
OOBn
OBnAcO
OHO
AcOOAc
OAc
BnO
O
OBn
OBnO
+
Bu3SnH AIBN291
292
293 81
1 Na[Al(OC2H4OMe)2(OEt)H]2 Ac2O pyr
294 56 over 2 steps
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1425
Scheme (52)
Scheme (53)
OBnO
BnOOBn
OBn O
OH
O
OBnO
BnO
OHOBn
OBn O
O
O
O
O
O
OBnO
BnOOBn
OBnO
OAcOAc
OAc
OBnO
BnO
OHOBn
OBn
IBu3SnH AIBN
295 297 26
1 BF3 OEt2 Et3SiH
2 L-Selectride THF
1 Pd(OH)2C C6H10 EtOH
2 EtSiOSO2CF3 Ac2O
298 89 over 2 steps299
296
O
O
PhSeClO
O
PhSeCl
Bu3 SnH
O
O
PhSeCl
R
H
O
OAc
R
Cl
O
AcO
OAc
OAc
OAcOH
Cl
NHAc
R
OAc
AcHN
OH
O
OH OAc
OH
OHO
HO
OH
O
AcO
OAc
OAc
OAcBr
O
O
PhSeCl
O
O
PhSeCl
R
O
OTIPSAcHNR
OAc OAc
O
OHAcHN
COOMe
R
OAc
1 Bu4NF
2 NH3MeOH
1 (Me3Si)2NLi THF2 Me2N=CHI
1 Bu3 SnH AIBN2
1 NaBH42 mCPBA3 Ac2O pyr
1 H+ MeCN
2 H2 O NaHCO3
R =
1 O3MeOH
2 Me2S NaHCO3
1 TIPSOTf 26-lut idine2 LiBH43 Ac2 O pyr DMAP
furanoses +
304 56
305 68 306 84307 50
308 46
300 301 302
303
309
1426 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
The reduction of 317 and treatment with DOWEX-H+ resinprovided the desired C-fucoside 318 in 70 (Scheme 54)
62 Intramolecular Radical Approaches
One disadvantage with the intermolecular approaches isthat during such radical mediated reactions electrondeficient alkenes are required to facilitate C-C bondformation The intramolecular approach of Sinayuml overcomes
this drawback by bring two substrates together via atemporary covalent silaketal connector This enables the useof a wider range of alkenes which can include alkene-functionalized sugars thus leading to the generation of C-disaccharides [63] Based on the early work of Stork Sinayumlemployed the tether reaction in the synthesis of both α- andβ-C-disaccharides with this work subsequently beingemployed in the synthesis of biologically significant natural
Scheme (54)
O
OH
Fuc
Cl
O
O
ClPhSe
OOAc
NHAcOHFuc
O
AcOOAc
AcO
Br
O
O
PhSeCl
O
AcOOAc
AcO
O
OH
PhSe Cl
Fuc
OOAc
NHAc
OMe
Fuc
O
AcHN
OH OAc
OH
O
OH
Me
OH
O
O
Fuc
ClSePh
O
HO
Fuc
ClSePh
+
Ph3SnHAIBN
78 combined yield
Fuc
310
+
1 NaBH4 MeOHTHF2 Chromatography
313 40 314 355
1 mCPBA
2 Ac2O pyr DMAP
+
315 75
1 TfOH MeCN
2 NaHCO3 O3 -78 oC
316 10 over 2 steps
1 Cl3 CCN NaH
2 MeOH BF3 OEt2
317 79
1 LiBH4 THF
2 Dowex-H+
311
312a312b
318 70 for 2 steps
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1427
products [64] The availability of different hydroxyl groupson each monosaccharide unit allowed the fine-tuning ofstereochemical outcome by selective positioning of the silyltether [65] Development of this early stereochemical controlled to the tethering of the donor 320 with alcohol 319through a di-isopropyl silicon tether 321 Subsequent treat-ment with Bu3SnH and AIBN led to a 9-endo-trigcyclization to form the C-disaccharide 322 in an 80 yieldwith exclusive formation of the α-product The silyl tetherwas removed with Bu4NF and deprotection under standardconditions afforded the desired disaccharide 323 in excellentyield (Scheme 55)
In parallel the development of a 32rsquo silyl tether allowedaccess to the β-linked product as demonstrated in Sinayumlrsquossynthesis of methyl β-C-lactoside 328 [66] Alcohol 324 and320 were connected via the dimethylsilyl tether an 8-endo-trig cyclization followed to exclusively afford the β-
disaccharide 326 in 45 yield Removal of the tether anddeprotection of benzyl ether gave β-C-disaccharide 328(Scheme 56)
This group also selected iodosugars bearing a freehydroxyl group as progenitors of the radical donors [67] In atypical experiment the radical donor 329 was connected tothe radical acceptor 330 through a silaketal tether followingtheir procedure Tributyltinhydride mediated 8-endo-trigradical cyclization of compound 331 gave after detetheringof the non isolated intermediate 332 the protected β-C-disaccharide 333 in 37 overall yield (from startingmaterials 330 and 329) Peracetate 335 was achieved afterhydrogenolysis The C-laminaribioside 334 is of potentialbiological interest as it mimics the repeating disaccharideunit of fungal β-(1rarr3)-glucans which have antitumor andimmunomodulating properties (Scheme 57)
Scheme (55)
Scheme (56)
OO
OHSePh
OTBDPSO O
OO
SePh
OTBDPSO
OO
OBnOMe
OBn
Si
O
HOOBn
OMe
OBn
O
HOOH
OHHO
O
HOOH
OMe
OH
OTBDPSO
O
HOOBn
OMe
OBnO
OOH
1 n-BuLi THF
2 iPr2SiCl2 -78 oC
3 DMAP THF rt
1 Bu4NF THF
2 Dowex-H+
3 H2 PdC
Bu3SnH AIBN toluene
319
320
321
322323
OBnO
OHSePh
OBnBnO
OHO
OBnOMe
OBn
ROO
ROOH
OR
OHO
OROMe
OR
OBnO
O
OBnBnO
OO
OBnOMe
OBn
Si
SePh
OBnO
O
OBnBnOO
OOBn
OMe
OBn
Si
1 PhSeH Me2SiCl2
BuLi -78 oC
2 imidazole rt
Bu3SnH AIBN toluene
H2 PdC327 R = Bn
328 R = H
Bu4NF THF
324
320
325
326 45
1428 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
CONCLUSIONS
In this paper the biological importance of C-oligo-saccharides as subunits of natural products and as a newgeneration of carbohydrate based on therapeutics has beenillustrated Different methods are available for the synthesisof C-oligosaccharides As with traditional saccharidesynthesis it has been necessary to develop a number ofspecific approaches to facilitate the regioselective andstereoselective preparation of the desired targets Work inthis area continues and it is expected that many interestingnew C-oligosaccharides will be prepared using the chemistrydescribed in this review It is also likely that new chemistrywill be developed in the future for the preparation of thesebiologically important targets
ACKNOWLEDGEMENTS
The authors thank Dr Sultan Baytas for her criticalreading of this manuscript
REFERENCES
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[2] Wassarman PW Mammalian Fertilization Molecular Aspects ofGamete Adhesion xocytosion Exocytosis and Fusion Cell 199996 175-183
[3] Carbohydrate-based Drug Discovery Wong C-H EdWeinheim Cambridge Wiley-VCH 2003
[4] (a) Sharon N Lis H Lectins as Cell Recognition MoleculesScience 1987 246 227-234 (b) Dwek RA Chem Rev 1996 96683-720
[5] Postema M C-Glycoside synthesis CRC Boc Ratom 1995[6] (a) Weatherman R V Mortell K H Cheruenak MKiessling
L L Toone E J Specificity of C-Glycoside Complexation byMannoseGlucose Specific Lectins Biochem 1996 35 3619-3624(b) Ravishankar R Surolia A Vijayan M Lim S Kishi YPreferred Conformation of C-Lactose at the Free and Peanut LectinBound States J Am Chem Soc1998 120 11297-11303
[7] (a)Wong C-H Halcomb R L Ichikawa Y and Kajimoto TEnzymes in organic synthesis Application to the problems ofcarbohydrate recognition part2 Angew Chem Int Ed Engl 199534 521-546 (b)Howard S Withers SG Bromoketone C-Glycosides a New Class of βminusGlucanase Inactivators J AmChem Soc 1998 120 10326-10331(c) Wang Q Wolff MPolat T Du Y Linhardt R J C-glycoside of Neuraminic Acidsas Neura-minidase Inhibitors Bioorg Med Lett 2000 10 941-944 (d) Phili R Chang J Partis R A Mueller R A ChrestF J Passaniti A The Alpha-glucosidase I InhibitorCastanospermine Alters Endothelial cell Glycosylation PreventsAngiogenesis and Inhibits Tumor Growth Cancer Res 1995 552927-2935
[8] Ossor A Elbein A D In Carbohydrates in Chemistry andBiology Vol 3(II) WileyVCH 2000 pp 513-539
[9] (a) Sinayuml P Synthesis of oligosaccharide Mimetics Pure ApplChem 1997 69 459-463 (b) Beau J-M Gallagher TNucleophilic C-glycosyl Donors for C-glycoside Synthesis Top inCurr Chem 1997 187 1-54 (c) Nicotra F Synthesis of C-glycosides of Biological Interest Top in Curr Chem 1997 187
Scheme (57)
O
O
O
Ph
I
OMe
OHO
BnO
OH
OH
BnOOH
O
BnO
Si
O
O O
Ph
I
OMe
O
O
BnO
OR4O
R5O
OMe
OR2
OR3O
R3O
OR1
R3O
Bu3 SnH AIBN
332 R1 R2 = SiMe2 R3 = Bn R4 R5 = CHPhTBAF THF
333 R1 = R2 = H R3 = Bn R4 = R5 = CHPh 37 from 11
334 R1 = R2 = R3 = R4 = R5 = H
335 R1 = R2 = R3 = R4 = R5 = Ac
329
H2 PdC MeOH
Ac2 O pyr
1 BuLi THF -78 oC
2 Me2SiCl2
3 DMAP
330
331
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1429
55-83 (d) Du Y Linhardt R Y Recent Adv in Stereo-SelectiveC-Glycoside Synthesis Tetrahedron Lett 1998 54 9913-9959 (e)Liu L Mckee M and Postema M H D Synthesis of C-saccharides and Higher Congeners Current Org Chem 2001 51133-1167
[10] Jarosz S Fraser-Reid B Synthesis of A Higher Carbon Sugar ViaDirected Aldol Condensation Tetrahedron Lett 1989 30 2359-2362
[11] Lichtenthaler F W Lergenmiiller M Schwidetzky S C-Glycosidations of 2-Ketohexosyl With Electrophilic Radical andNudeophilic Anomeric Carbons Eur J Org Chem 2003 3094-3103
[12] Baudat A Vogel P Aza-C-disaccharides Synthesis of 6-Deoxygalactonojirimycin-β-C(1rarr3) Linked with D-Altrofuranosides and D-Galactose J Org Chem 1997 62 6252-6260
[13] Turner D Vogel P Synthesis of 4-Hydroxy-26-Bis(hydroxymethyl) tetrahydropyran-2-Carbaldehyde DerivativesSynlett 1998 304-306
[14] Zhu Y-H Vogel P Short Stereoselective Synthesis of C-(1rarr3)-Linked Disaccharides Tetrahedron Lett 1998 39 31-34
[15] Zhu Y-H Vogel P Synthesis of a (2R 6R)-2-(Hydroxymethyl)-6-Propa-1 2-Dienyl-2H-Pyran-3(6H)-One Derivative A NewEnone for The Convergent Construction of C-Glycosides of C-Disaccharides Synlett 2001 82-86
[16] Baumberger F Vasella A Deoxynitrosugars The 6th
Communication Stereolectronic Control in the reductivedenitration of tertiary nitro ethers A Synthesis of ldquoC-glycosidesrdquoHelv Chim Acta 1983 66 2210-2221
[17] Martin O R Lai W Synthesis and Conformational Studies of β-(1rarr6)- and ββ-(1rarr1)-Linked C-disaccharides J Org Chem1993 58 176-185
[18] Spak S J Martin R The synthesis of an analogue of Methyl OC-Analogue of Methyl 4rsquo-O-β-D-GlucopyranosylgentiobiosideTetrahedron 2000 56 217-224
[19] Kobertz W R Bertozzi C R Bednarski M D C-GlycosylAldehyde Synthons for C-Linked Disaccharides J Org Chem1996 61 1894-1897
[20] Gurjar M K Nagaprasad R and Ramana CV First Synthesis ofMethyl α-C-D-Arabino-furanosyl-(1rarr5)-αminusD-Arabinofuranosidethe C-Disaccharide Segment of Motif C of MycobateriumTuberculosis Tetrahedron Lett 2000 43 7577-7579
[21] Witczak Z J Synthesis of C-Glycosyl Compounds and OtherNatural Products from Levoglucosenone Pure Appl Chem 199466 2189-2192
[22] Griffin F K Paterson D Taylor R J K Ramberg-BacklundApproaches to the Synthesis of C-Linked Disaccharides AngewChem Int Engl 1999 38 2939-2942
[23] Paterson B E Griffin F K Alcaraz M-L and Taylor R J KA Ramberg-Baumlcklund Approach to the Synthesis of C-GlycosidesC-Linked Disaccharides and C-Glycosyl Amino Acids Eur JOrg Chem 2002 1323-1336
[24] McAllister G D Paterson D E Taylor R J K A SimplifiedRamberg-Bachlund Approach to Novel C-Glycosides and C-Linked Disaccharides Angew Chem Int Ed Engl 2003 42 1387-1391
[25] McCartney J L Christopher T M Cicchillo R M BernardinaM D Wagner T R and Norris P J Org Chem 2003 6810152-10155
[26] Dondoni A Zuurmond H M Bascarate A Synthesis of α-andβ-D-(1rarr6)-C-Disaccharides by Witting Olefination of Formyl C-Glycosides with Glycopyranose 6-phosphoranes J Org Chem1997 62 8114-8124
[27] Dondoni A Kleban M Zuurmond H Marra A Synthesis of(1rarr6)-C-Oligogalactosides by Interative Wittig OlefinationTetrahedron Lett 1998 39 7991-7994
[28] Dondoni A Marra A A New Synthetic Approach toMycobacterial Cell Wall α-(1rarr5)-D-Arabinofuranosyl C-Oligosaccharides Teterahedron Lett 2003 44 4067-4071
[29] Colinas P A Ponzinibbio A Lieberknecht A and Bravo R OWittig Reaction of Glycosyl Phosphonium Salts A StereoselectiveRoute to C-Disaccharides and C O-Trisaccharides TetrahedronLett 2003 44 7985-7988
[30] Schmidt R R Preuss R Synthesis of Carbon Tetrahedron Lett1989 30 3409-3412
[31] Dietrich H Schmidt R R Synthesis of Carbon-Bridged C-Lactose and Derivatives Liebigs Ann Chem 1994 975-981
[32] Rouzaud D Sinayuml P The First Synthesis of a ldquoC-DisacchariderdquoJ Chem Soc Chem Commun 1983 1353-1354
[33] Xin Y-C Zhang Y-M Mallet J-M Glaudemans C P JSinayuml P Synthesis of C-Oligosaccharides That Mimie TheirNatural O-Analogues Immunodeterminants in Binding toMonoclonal Immunoglobulins Eur J Org Chem 1999 471-476
[34] Streicher H Geyer A Schmidt R R C-Disaccharides ofKetoses Chem Eur J 1996 2 502-510
[35] Leeuwenburgh M A Timmers C M Vander Marel G A VanBoom J H Mallet J-M Sinayuml P G Stereoselective Synthesisof α-C-(Alkynyl)-Glycosides Via Ring-Opening of α-12-Anhydrous Tetrahedron Lett 1997 38 6251-6254
[36] Aslam T Fuchs M G G Le Formal A Wightman R HSynthesis of C-Disaccharide Analogue of the α-D-Arabinofuranosyl-(1rarr5)-α-Arabinofuranosyl Motif ofMycobacterial Cells Walls via Alkynyl Intermediates TetrahedronLett 2005 46 3249-3252
[37] (a) Girad P Namy J L Kagan H B Divalent LanthanideDerivative in Organic Synthesis 1 Mild Preparation of SamariumIodide and Ytterbium Iodide and Their Use as Reducing orCoupling Agents J Am Chem Soc 1980 102 2693-2698 (b)Molander G A Harris C R Sequencing Reactions withSamarium(II) Iodide Chem Rev 1996 96 307-338
[38] (a) Mazeacuteas D Skrydstrup T Doumeix O Beau J-MSamarium Iodide-Induced Intramolecular C-Glycoside FormationEfficient Radical Formation in the Absence of an Additive AngewChem Int Ed Engl 1994 33 1383-1386 (b) Mazeacuteas DSkrydstrup T Beau J-M A Highly Stereoselective Synthesis of1 2-trans-C-Glycosides Via Glycosyl Samarium(III) CompoundsAngew Chem Int Ed Engl 1995 34 909-912 (c) Jarreton OSkrydstrup T Beau J-M The Stereospecific Synthesis of Methylα-C-Mannobioside A Potential Inhibitor of M TuberculosisBinding to Human Macrophages J Chem Soc Chem Commun1996 1661-1662 (d) Jarreton O Skrydstrup T Espionosa J-FJimeacutenez-Barbero J Beau J-M Samarium Diiode Prompted C-Glycosylation An Application to The Stereospecific Synthesis ofα-(1rarr2)-C-Mannobioside and Its Derivatives Chem Eur J 19995 430-441 (e) Mipuel N Doisneau G Beau J-M ReductiveSamariation of Anomeric 2-Pyridyl Sulfones with Catalytic AnUnexpected Improvement in The Synthesis of 12-Trans-Diequatorial C-Glycosyl Compounds Angew Chem Int Ed Engl 2000 39 4111-4114
[39] Vlahov I R Vlahova P I Linhardt R J DiastereocontrolledSynthesis of Carbon Glycosides of N-Acetylneuraminic Acid ViaGlycosyl Samarium(III) Intermediates JAmChem Soc 1997 1191480-1481
[40] Kuberan B Sikkander S ATomiyama H Linhardt R JSynthesis of a C-Glycoside Analogue of sTn An HIV-and Tumor-Associated Antigen Angew Chem Int Ed Engl 2003 42 2073-2075
[41] Bazin H G Du Y Polat T Linhardt R J Synthesis of aVersatile Neuraminic Acid ldquoCrdquo-Disaccharide Precursor for theSynthesis of C-Glycoside Analogues of Gangliosides J OrgChem 1999 64 7254-7259
[42] Chen C-C Ress D K Linhardt RJ Samarium Iodide-Mediated Synthesis of Neuraminic Acid C-Glycosides InSynthesis of Glycommetics Roy R Ed ACS Syposium Series2004 896 53-80
[43] Abdallah Z Doisneau G Beau J-M Synthesis of a Carbon-Linked Mimic of The Disaccharide Component of The Tumor-Relate SialyTn Antigen Angew Chem Int Ed Engl 2003 425209-5212
[44] Lay L Nicotra F Panza L Russo G Caneva E Synthesis ofC-disaccharides through dimerization of exo-glycals J Org Chem1992 57 1304-1306
[45] Isobe M Nishizawa R Hosokawa S Nishikawa TStereocontrolled Synthesis and Reactivity of Sugar Acetylenes JChem Soc Chem Commun 1998 2665-2676
[46] Saeeng R Sirion U Sahakitpichan P Isobe M IodineCatalyzes C-Glycosidation of D-Glucal with SilylacetykeneTetrahedron Lett 2003 44 6211-6215
[47] (a) Babirad S A Wang Y Kishi Y Synthesis of C-Disaccharides J Org Chem 1987 52 1370-1372 (b) Wang YBabirad S A Kishi Y Preferred Conformation of C-Glycosides
1430 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
8 Synthesis of 14-Linked Carbon Disaccharides J Org Chem1992 57 468-481
[48] Armstrong R W Sutherlin D P Strategies for the Synthesis ofC-Disaccharides Containing D and L Sugars Tetrahedron Lett1994 35 7743-7746
[49] Wei A Kishi Y Preferred Conformation of C-Glycosides 12Synthesis and Conformational Analysis of αα- α β- and β β-Trehaloses J Org Chem 1994 59 88-96
[50] Haneda T Goekjian P G Kim S H Kishi Y PreferredConformation of C-Glycosides 10 Synthesis and ConformationAnalysis of Carbon Trisaccharides J Org Chem 1992 57 490-498
[51] Sutherlin D P Armstrong R W Synthesis of 12 Stereochemistryand Structurally Diverse C-Trisaccharides J Org Chem 1997 625267-5283
[52] Notz W Hartel C Waldscheck B Schmidt R R De NovoSynthesis of a Methylene-Bridged Neu5Ac-α-(23)-Gal C-Disaccharide J Org Chem 2001 66 4250-4260
[53] (a) Postema M H D Calimente D Liu L Behrmanm T L AnOlefin Metathesis Route for the Preparation of (1rarr6)-Linked-C-Disaccharide Glycals A Convergent and Flexible Approach to C-Saccharide Synthesis J Org Chem 2000 65 6061-6068(b) Postema M H Piper J L Liu L Faust M Andreana PSynthesis and Partial Biological Evaluation of a Small Library ofDifferentially Linked β-C-Disaccharide J Org Chem 2003 684748-4754
[54] Nelson A The Development of Strategies and Methods for TheSynthesis of Biologically Active Compounds New J Chem 200428 771-776
[55] Togo H He W Waki Y Yokoyama M C-GlycosylationTechnology With Free Radiant Reactions Synlett 1998 700-717
[56] Giese B Dupuis J Diastereoselective Synthesis of C-Glycopyranosides Angew Chem Int Ed Engl 1983 22 622-623
[57] Adlington R M Baldwin J E Basak A Kozyrod RPApplication of Radical Addition Reactions to tho Synthesis of a C-Glucoside and A Functionalized Amino Acid J Chem SocChem Commun 1983 144-145
[58] Giese B Gonzaacutelez-Goacutemez J A Witzel T The Scope of RadicalCC-Coupling by The ldquoTin Methodrdquo Angew Chem Int Ed Engl1984 23 69-70
[59] Giese B Witzel T Synthesis of ldquoC-Disaccharidesrdquo by RadicalC-C Bond Formation Angew Chem Int Ed Engl 1986 25 450-451
[60] Witczak Z J Chhabra R Chojnacki J C-Disaccharides IStereoselective Approach to β-(1rarr4)-3-Deoxy-C-Disaccharidesfrom Levoglucosenone Carb Res 1997 301 167-175
[61] Vogel P Synthesis of Rare Carbohydrates and Analogues Startingfrom Enantiomerically Pure 7-Oxabicyclo[221]heptyl Derivatives(ldquoNaked Sugarsrdquo) Current Org Chem 2000 4 455-480
[62] Viodeacute C Vogel P Synthesis of The C-Disaccharide α-C(1rarr3)-L-Fucopyranoside of N-Acetylgalactosamine J Carb Chem2001 20 733-746
[63] Xin Y C Mallet J M Sinayuml P An Expeditious Synthesis of AC-Disaccharide Using A Temporary Silaketal Connection J ChemSoc Chem Commun 1993 864-865
[64] (a) Petitou M Herault P Lormeau J-C Helmboldt A MalletJ-M Sinayuml P Herbert J-M Introducing A C-InterglycosidicBond in A Biologically Active Pentasaccharide Hardly Affects ItsBiological Properties Bioorg Med Chem 1998 6 1509-1516 (b)Sinayuml P Advances in The Synthesis of the Carbohydrate MimicsPure Appl Chem 1998 70 1495-1499
[65] Sinayuml P Chemical Synthesis of Oligosaccharide Mimetics PureAppl Chem 1998 70 407-410
[66] Sinayuml P Chemical Synthesis of Oligosaccharide Mimetics PureAppl Chem 1998 69 459-463
[67] Vauzeilles B Sinayuml P Selective Radical Synthesis of β-C-Disaccharides Tetrahedron Lett 2001 42 7269-7272
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1395
Enone 22 was synthesized and condensation of trappingenolate with aldehyde 23 led to a mixture of aldols 24 and 25that were separated by column chromatography on silica geland isolated in 15 and 29 yield respectively Reductionof the major aldol 25 with NaBH4 in MeOHTHF was highlystereoselective and provided the C-disaccharide 26 in 77yield (Scheme 6) [15]
When reacted with PhMe2SiZnMe2Li in THF at -78 ordmCenone 27 afforded a single adduct 28 Treatment of ketone28 with dicyclohexylboron chloride and Et3N at -15 ordmCfollowed by addition of 29 the resulting aldol-borate wasoxidized with 35 H2O2 giving adduct 30 in 24 yieldStereoselective reduction of aldol 30 with Me4NBH(AcO)3
afforded diol 31 in 59 yield (Scheme 7) [15]
22 Nitro Stabilized Anions
Vasella and Martin pioneered the use of nitro-basedanions for C-saccharide synthesis Anomeric nitro derivative32 was treated with TBAF and exposed to aldehyde 33 togive the adduct 34 in 78 yield Acetylation of 34 followedby reductive denitration afforded 35 (Scheme 8) [16]
Martinrsquos work has also relied on the Henry reactionAldol condensation of nitro sugar 36 with aldehyde 33 gave37 Dehydration of 37 and conjugate reduction led to 38Removal of nitro group by radical-based reduction followedby the removal of protecting groups gave rise to the (1rarr6)-β-C-disaccharide 40 (Scheme 9) [17]
Scheme (3)
Scheme (4)
NCbz
BnO
O
O
O
Cl
OAc
OAc
NCbzBnO
OO
O
PhSe
Cl O
OH
NCbz
CHO
OBnO
O
HO
N
OBn
OAc
CO2Me
AcO
OMe
CbzOMe
OAc OAc
O
PhSe
Cl OTHF -95 o C
1 NaBH42 Ac2O Pyr3 mCPBA
1 SOCl2 MeOH2 Ac2O Pyr3 Me3NO OsO44 Ac2O Pyr5mCPBA
LiHMDS -78 oC
8
9
10
1112
O
BnO
TBSO
O
OBnO
BzO
OBz
Br
CHO
OTIPS
O
BnO
TBSO
O
OBnO
BzO
OBz
Br
OTIPS
OH1 LiHMDS
2
1315
14
1396 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (5)
Scheme (6)
OO
O
Me2AlSPh OAlMe2O
O
SPh
O
OH
O
O
OO
O
OH
SPh
OH
O
HO
HO
OMeOH
OMe
HO
O
O
SPhO
O
O
OO
H
HO
HO
OO
O
SPhO
O
OO
HOH
DIBAL
MeOHTsOH
50 o C
16 17
18
19
2021
OO
bull
OR
O
CHOOMe
OO
NaBH4
OOH
bull
OR
OOMe
OO
OH
OO
bull
OR
OOMe
OO
HO
OO
bull
OR
OOMe
OO
OH
Me2AlSPh -78 degC
R = (t-Bu)Me2Si
22
23
24 15
+
25 2926 77
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1397
Scheme (7)
Scheme (8)
An open chain sugar derived aldehyde was used to accessa C-trehalose derivative through the Henry reactionCondensation of 36 with aldehyde 41 in the presence of KFand crown ether 18-crown-6 gave adduct 42 which wasimmediately converted to 43 with a sequence of reactions in29 overall yield The intermediate was finally transformedto the C-linked-(1rarr1)-disaccharide 44 (C-ββ-trehalose)(Scheme 10) [17]
Martin and coworkers applied the same methodologyto prepare an OC-trisaccharide namely methyl O-β-D-glucopyranosyl-(1rarr4)-C-β-D-glucopyranosyl-(1rarr6)-D-
glucopyranoside 48 [18] The condensation of compound 45with 6-aldehydo-glucopyranoside 46 in the presence of KFin an aprotic medium afforded the desired pseudotri-saccharide 47 in 73 yield Application of the samechemistry to 47 gave the target compound 48 (Scheme 11)
Kobertz and coworkers utilized Martinrsquos methodology toprepare C-allolactose Nitro sugar 49 was condensed withaldehyde 50 afforded the adduct 51 as a mixture ofdiastereomers The hydroxyl group was converted to thecorresponding phenyl thiocarbonate ester 52 Treatment withtin hydride and a radical initiator effected elimination
OO
OR OR
O SiMePh
O
HO
PhMe2SiZnMe2 Li
O
TBSO
TBSO
OTBS
OTBS
H
O
O
OR
SiMePh
TBSO
OTBS
OTBS
OH
HOHO
TBSO
O
O
TBSO
TBSO
OTBS
OTBS
OH
H
O
OR
SiMePh
Me4NBH(OAc)3
R = (t-Bu)Me2Si
+
1 THF -78 oC
2 NH4Cl H2O
3 HCl H2O 20 oC
1 (c-hex) 2BCl Et3N
2
27
28
29
30 24 over 2 steps31 59
O
O
O
O O
NO2
TBAF
O
OH
OO
OO
O
O
OO O
NO2
OO
O
OO
OH
O
O
OO O
OO
O
OO
H
OAc
32
3334 78
1 Ac2O Pyr2 Bu3SnH AIBN
35 89
1398 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
reaction yielding only E-olefin 53 Finally the olefin wasreduced with dimide (generated in situ) and benzyl etherswere removed by dissolving metal reduction to afford thetarget disaccharide 54 (Scheme 12) [19]
Gurjar et al synthesized the first methyl α-C-D-araf-(1rarr5)-α-D-araf 60 the C-disaccharide segment of motif Cof Mycobacterium tuberculosis through nitro-aldol conden-
sation The coupling reaction between 55 and 56 gavediasteromeric mixture 57 which was subjected to threesubsequent steps ie dehydration selective reduction ofconjugated olefin and denitration to give the penta-O-benzylC-disaccharide 59 (Scheme 13) [20]
Witczak has used nitro anions for C-disaccharidesynthesis Michael addition of the nitro anion derived from
Scheme (9)
Scheme (10)
OAcO
AcOOAc
OAc
NO2O
OH
O
O
OO
OHO
HOOH
OH
O
HO
HOOH
OH
Bu3 SnH
OAcO
AcOOAc
OAc
NO2
OO
O
OO
OH
OAcO
AcOOAc
OAc
X
OO
O
OO
KF 18-C-6 MeCN
1 Ac2O Pyr2 NaBH4 EtOH
38 X = NO 2
39 X = H 57
1 NaOMe
2 H3O+
36
33
37
40 89 over 2 st eps
CHO
O
O
O
O
CH2OPiv
OAcO
AcOOAc
OAc
NO2
OHO
HOOH
OH
O OH
OH
HO
OH
OAcO
AcOOAc
OAc
NO2
PivO
OH
O
O
O
O
OAcO
AcOOAc
OAc
NO2
PivO
O
O
O
O
1 Ac2O Pyr2 80 AcOH3 Ac2O Pyr
1 AcOH
2 Ac2O-BF3 OEt
KF 18-C-6 MeCN
41 36
42
4344
3 Bu3SnH AIBN
4 NaOMe
5 H3O+
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1399
61 to levoglucosenone 62 gave adduct 63 in 43 yield Thesterics in 62 dictates the facial bias of the addition whichcan only occur from the α-face Reductive denitrationfollowed by reduction of lactol and ketone afforded 64 Ringopening deprotection and acetylation gave 65 (Scheme 14)[21]
23 Sulfur Stabilized Anions
The Taylor group employed the Meyers variant of theRamberg-Baumlcklund reaction to synthesize C-disaccharides[22] The penta-O-benzyl thioglucose 66 was coupled withiodide compound 67 followed by oxidation of the formedsulfide gave sulfone 68 Exposure of the sulfone to theMeyers variant of the Ramberg-Baumlcklund reaction affordedexo-glycal 69 as a mixture of isomers in 48 yieldHydrogenation of this mixture stereoselectively reduceddouble bond and cleaved the benzyl groups Peracetylated C-
trehalose 70 was furnished by acetylation of free sugar(Scheme 15)
This approach is well suited to analog synthesis simplyby varying the alkylating agent Thus the homologous(1rarr1rsquo)-C-disaccharide containing a two-carbon bridge(ldquohomoisotrehaloserdquo) was readily prepared (Scheme 16)[23] Lactol 71 was converted into sulfonate 74 by astraightforward three-step sequence involving Moffat-typeC-glycosylation to give ester 72 followed by reduction andmesylation Next 74 was coupled with thiol 75 in a similaralkylation-oxidation sequence to that above The resultingsulfone 77 underwent a halogenative Ramberg-Baumlcklundrearrangement (RBR) to give exo-glycal 78 as a 8812mixture of (Z)- and (E)-isomers in 57 yield Subsequentreductiondebenzylation followed by acetylation producedthe novel ethylene-bridged disaccahride 79
Scheme (11)
Scheme (12)
OBnO
OBnOMe
BnO
NO2
OBnO
OBn
BnO
OBn
CHO
OHO
OH
HO
OH
OHO
OHOMe
HO
OBnO
OBn
BnO
OBn
OBnO
OBnOMe
BnO
NO2R
OBnO
OBn
BnO
OBn
OBnO
OBnOMe
BnO
KF 18-C-6 MeCN+
1 n-BuLi2 PTC-Cl
51 R = OH
52 R = OC(S)OPh
Bu3 SnH AIBN
1 TsNHNH NaOAc
2 Na NH3
49
50
5354
OAcO
OAc
AcOO
OAcO
OAc
OAc
NO2OAc
OAc
AcO
OAcO
BnOOBn
OMe
BnO
OO
AcOOAc
OAc
OAcO
OMe
BnO O
BnOOBn
O
OO
AcOOAc
OAc
NO2
OAcO
OAc
AcO
OAcO
BnOOBn
OMe
BnO
OH
KF 18-C-6 MeCN
1 Ac2O Pyr2 NaBH4 EtOH3 Bu3SnH AIBN4 H2 Pd(OH)2
5 NaOMe MeOH
45
46
47
48
1400 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
This group also reported a rapid synthesis of a range ofC-disaccharides involving a tandem Horner-Wadsworth-Emmons (HWE)conjugate-addition C-glycosylation followedby a tandem halogenation-RBR sequence utilizing Meyersvariant of the RBR [24] The HWE reagent 81 proceeded theHWEconjugate-addition sequence with diisopropylidenemannofuranose 80 in 86 yield to produce the adductsulfone 82 (as a mixture of diastereomers) The keyhalogenation-RBR was carried out using the conditions
devised by Chan et al giving E-alkene 83 as the onlyisolable product Alkene hydrogenation and concomitantdebenzylation followed by acetylation for characterizationpurposes gave the novel disaccharide 84 in 69 yield overthe two reactions (Scheme 17)
A two-directional variant of this methodology can beused to prepare symmetrical C-disaccharides as shown inScheme 18 [24] The double HWE reaction on diisopro-pylidene mannofuranose 80 worked extremely well in the
Scheme (13)
Scheme (14)
BnO
OBn
O2N
OMe
O
CHO
OBnO
OBn
BnO
OMe
OHO
OH
OHO
OH
HO
OMe
OBnO
OBn
OBnO
OBn
BnO
HO
NO2
OMe
OBnO
OBn
OBnO
OBn
BnO
X
+
KF 18-C-6 MeCN
1 Ac2O Pyr2 NaBH4 EtOH
58 X = NO 2
59 X = H 44 over 3 st eps
Bu3SnH AIBN
Pd(OH)2 H2
rt 1 atm 24 h
40
60 74
55
56
57
O
BnOOBn
BnO
OBn
OH
O
OHNO2
O
O
BnOOBn
BnO
OBn
OH
O
ONO2
O
O
O
O
O
AcOOAc
AcO
OAc
O
OAc OAc
OAc
O
BnOOBn
BnO
OBn
NO2OH
Et3 N MeCN
1Bu3 SnH AIBN
2 BF OEt Et3SH
3 L-SelectrideTHF
64 61 in 3 steps
1 Pd(OH)2 C6 H10
2 Ac2O TESOTF
61 63 43
62
65
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1401
HWEconjugation-addition C-glycosydation sequence givingdiastereomeric sulfones 85 in a combined yield of 75RBR of the major stereoisomer (βα-79) using the Meyers-
Chan procedure gave alkene 86 in 66 unoptimized yieldand hydrogenation produced the novel C-linked bisfuranosedisaccharide 87 in 76 yield
Scheme (15)
Scheme (16)
OBnO
BnO
H
OBn
OH
OOBn
BnO
OBn
OBn
BnO
OBn
OBn
OBnO
BnO
OBn
OH
SO2
O
OBn
O O
AcO
AcO
AcO
OAc
OAc
OAc
OAc
OAc
OBnO
BnO
OBn
OH
I
O
HS
OBn
BnO
OBn
OBn
68 90 over 2 steps
KOH CCl4 t-BuOH H2O
1 H2 PdC
2 Ac2O Pyr
70 69 over 2 steps
+
1 K2CO3
2 mCPA66
67
69
O
BnOOBn
BnO
OBn
OH
(EtO)2P(O)CH2CO2Et
OBn
OBn
OBnO
OBn
OBnO
BnOOBn
OBn
X
O OBn
OBn
BnOOBn
OBnO
BnOOBn
OBn
OBnO
BnOOBn
OBn
R
OBnO
BnOOBn
OBn
SH
LiAlH4
OAc
AcOOAc
O OAcOAcOAcO
OAc
OAc
1 H2 Pd(OH)2C
2 Ac2 O Pyr
NaH THF
72 R = CO2Et
73 R = CH2OH
66 over 3 steps
K2CO3 acetone
76 X = S
77 X = SO2 79
Oxone THF MeOH H2 O
KOH CCl4 aq tBuOH
78 57ZE 8812
79
71
75
MsCl Et3N 74 R = CH2 OMs
1402 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Norris et al deprotonated 88 with n-BuLi and theresulting anion was coupled with an excess lactone 89 at lowtemperature to afford the adduct 90 in 77 yield SPhgroups were removed with Raney nickel and lactol 91 wasisolated as a syrup that contained two components in
approximately a 41 ratio The two compounds were thoughtto be α- and β-lactols with the latter being major It wasstraightforward to reduce the lactols with a high degree ofstereocontrol to afford the C-disaccharide 92 with a 51isolated yield (Scheme 19) [25]
Scheme (17)
Scheme (18)
O
O O
O
O OH
O OMe
OBnBnO
SO2
P
EtO
EtO
O
OBn
O
OMe
OAc
OAc
OAcO
O O
O
O
O
OO OMe
OBnBnO
SO2
OBn
O
O O
O
O O
O
O
O
OMe
OBn
OBn
OBn
83 50 E only
80
+
NaH THF -78 oC
82 86αβ 11
KOHAl2O3
CBr2F2 CH2Cl2
tBuOH 5 oC
2 h
1 H2PdC EtOAc RT 7h
2 Ac2 O Pyr RT
84 69 over 2 st eps
81
O
O O
O
O OH POEt
OEt
O
SO2
P
EtO
EtOO
O
O
O
OO
O
O
O
O O
O
O
O O
O
O
O
O SO2
O
O
O
O
O
O O
O
OO
O
O
85 75βαββ ca 31
86 66β αββ = 141 E only
H2PdC EtOAc
87 76βαβ β = 141
21 NaH THF -78 o C
80 (2 equiv)
KOHAl2O3CBr2F2 CH2Cl2tBuOH
on majorβα is omer
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1403
24 Phosphorous Stabilized Anions
The most common type of reaction discussed in thissection is Wittig approach to C-oligosaccharide synthesisThis methodology is particularly suited for synthesis of(1rarr6)-C-saccharides since one sugar can hold the aldehydewhile the other the ylid or phosphonate anion
Dondoni has utilized this approach to prepare a variety ofβ-D-(1rarr6)-C- disaccharides The general approach is shownin Scheme 20 Coupling of β-linked galactopyranosyl ormannofuranosyl derivative (93 94 95 or 96) with ylidefrom phosphonium iodide 97 or 98 gave alkene 99 Alkenewas reduced and removal of deprotecting groups gave thecorresponding β-D-(1rarr6)-C- disaccharide 100 [26]
α-D-(1rarr6)-C-disaccharide 103 was also synthesizedusing the approach (Scheme 21)
Dondoni applied this methodology in an iterative fashionto prepare the corresponding β-(1rarr6)-C-trigalactosides andβ-(1rarr6)-C-tetragalactosides [27] Starting with coupling ofylide 104 generated in situ with aldehyde 33 gave adduct105 (EZ 19) Removal of silyl protecting group followed byoxidation led to aldehyde 106 which was coupled with theylide from 104 to give C-trisaccharide 107 in 36 yield Thesame sequence was repeated with 107 afforded the protectedC-tetrasaccharide alkene 108 Compounds 108 wasdesilylated and exposed to hydrogen over Pd(OH)2 oncarbon followed to peracetylation gave protected C-tetrasaccharide 109 (Scheme 22)
Taking advantage of their experience on the stereo-selective synthesis of C-oligosaccharides by iterative Wittigolefination this group developed new building blocks and amodified protocol for the straightforward assembly of C-α-(1rarr5)-D-oligoarabinofuranosides [28] While the twomonofunctionalized sugar moieties 110 and 111 weresuitable precursors to the head and tail of the oligo-saccharidic chain the difunctionalized compound 114 was arepeating unit (Scheme 23) Building block 114 wasdesigned to allow after the Wittig coupling for regenerationof the formyl group in a single step under conditions that donot affect the chemical and stereochemical integrity of thegrowing saccharidic chain (Scheme 24)
Colinas et al reported a method for the synthesis of C-disaccharides by a sequence involving the Wittig reaction askey step and further glycosydation of these compounds toafford new C O-trisaccharides [29] The enol ether 122a-bwere prepared by the Wittig reaction of the α β mixture of2-deoxiglycosyl phosphonium salts 120a-b with aldehyde121 Hydrogenation of the exo-glycals afforded the β-C-disaccharides with good yields The O-glycosidationemploying the exo-glycals and the glycosyl acceptor 124 isillustrated in Scheme 25
25 C-1 Vinyl Anions
Schmidt was the first to explore the addition of sulfoxide-stabilized vinyl C-1-organolithiums to carbohydrate-basedcarbonyl compounds [30] The vinyl sulfoxide 126 was
Scheme (19)
OCH3
O O
OPhS
PhS
O O
OO
OCH3
O O
OO O
O H
OCH3
O O
OPhSPhS
O O
O OH
OCH3
O O
OO O
O OH
+
n-BuLi THF -78 oC
Raney Ni EtOH H2O rt
Et3SiH BF3 OEt2
90 77
92 51 over 2 steps 91 is omers rati o βα = 41
-78 oC
88
89
1404 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
deprotonated with LDA to give 127 Addition of 127 toaldehyde 128 gave a mixture of diastereoisomers of whichthe major 129 was formed in a 101 ratio Desulfurizationhydroboration and removal of benzyl groups gave the(1rarr5)- βminusC-disaccharide 130 (Scheme 26)
Schmidt and coworkers used this methodology for ahighly efficient synthesis of an analog of C-trehalose 134Scheme 27 [31] Anion 131 was converted to aldehyde 132
and condensation of this aldehyde with the same anion gaveadduct 133 which was then converted to the target C-disaccharide 134
26 Acetylide-Based Anions
Sinayuml was the first to prepare a C-disaccharide Hisapproach involved the coupling of a C-6 alkyne with ananomeric lactone followed by reduction of the formedhemiacetal [32] Aldehyde 135 was converted to the
Scheme (20)
Scheme (21)
OO O
O
O CHO
O
BnOOBn
BnO
OBn
CHO
OBn
CHO
BnO
O
BnOBnO
O
BnOOBn
BnO OBn
CHO
PPh3I-
OO
O
OO
O
OMeOBn
OBn
OBn
PPh3I-
OCHO
O
PPh3I-
ORRO
RO
OO
ORRHO
OO
OR
+ +
+
( 93 - 96 )
( 97 - 98 )
BuLi THF-HMPA
-30 iexclaelig
99
Reduction
100
+
93 9495
96 97 98
O
OBnBnO
BnO
OO
O
OO
HO
O
O
OO
PPh3I-
O
OHHO
HO
O
HOOH OH
HO
OBnBnO
CHO
BnO
O
+
BuLi THF-HMPA
-30 oC
1 p-MeC 6H4SO2-
NH2NH2 AcONa
2 H2 Pd(OH)2 3 bar
3 Amberli te H+
+
10197
102
103
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1405
dibromoalkene 136 which was treated with n-butyllithium togive an intermediate acetylide 137 The latter uponnucleophilic addition to lactone 138 gave a mixture of lactol139 in high yield Stereoselective reduction of lactol 139 wasfollowed by hydrogenation of benzyl groups and the triplebond affording the (1rarr6)-β-C-disaccharide 140 (Scheme28)
The lactone-addition methodology was later applied bySinayuml and co-workers in an iterative fashion for the
preparation of higher homologues [33] Hydroxylmethylenein compound 141 was converted to acetylide lithium incompound 142 by a sequence of reactions Condensation ofcompound 142 with the galacto lactone 143 gave 144 asmixture of anomers The lactol were stereoselectivelyreduced to and triple bond was hydrogenated to give 145Methyl glycoside 145 was hydrolyzed to the correspondinglactols which were oxidized to lactone 146 The samesequence was then repeated twice to give C-trisaccharide147 and C-tetrasaccharide 148 (Scheme 29)
Scheme (22)
O
BnOOBn
BnO OTBDPS
PPh3I-
BnO
H
O
BnOOBn
OTBDPS
OO
O
OO
O
CHOO
O
OO
O
BnO
O
BnOOBn
BnO
OO
O
OO
H
HOBn
BnO OTBDPS
O
BnOOBn
BnO O
OO
O
OO
H
OBn
BnO OTBDPS
PPh3I-
O
BnO
O
BnOOBn
BnO OTBDPS
PPh3I-
O
AcOOAc
AcO
O
AcOOAc
AcO
OO
O
OO
O
AcOOAc
AcO OAc
O
BnOOBn
BnO
O
BnOOBn
BnO
OO
O
OO
H
H
O
BnOOBn
BnO OTBDPS
H
1 TBAF2 PCC
+107 36
+
1 TBAF2 PCC3
+
1 TBAF2 H2 Pd(OH)2 C3 Ac2 O Pyr
104
33
105
106104
104
108109
BuLi THF-HMPA
-50 o C
70EZ 19
BuLi THF-HMPA
-50 o C
1406 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
The di- tri- and tetrasaccharide derivatives (145 147 and148) were all debenzylated and tested for their bindingaffinity to three different monoclonal immunoglobulins withspecificity for different O-β-(1rarr6)-D-galactopyranosyl deter-minants These C-saccharide analogs had similar bindingproperties to the corresponding O-saccharides
Schmidt has also used acetylide-lactone condensation toassemble C-disaccharides of ketoses [34] Lithium acetylide149 was condensed with ketone 150 to give a mixture ofalcohol 151 after removal of the pivoloyl group Attemptedcyclization under Lewis acid catalysis resulted only in theremoval of the acetonide Accordingly the diol was tiedback as the carbonate and the acetylene complex as thedicobalt species 152 The isomers were then separately
cyclized to give a 11 mixture of C-disaccharide 153 Thecobalt complex on α-C-disaccharide was removed understandard conditions to give 154 and deprotection of thecarbonate was followed by hydrogenation and peracetylationto give 155 (Scheme 30) Similar chemistry was also carriedout with the corresponding β-isomer
Van Boom and co-workers used lithiated alkynylderivative 156 in presence of ZnCl2 to selectively open ringof the 12-anhydrosugar 157 affording the α-C-(alkynyl)-glycoside 158 Hydrogenolysis of the benzyl groups wasfollowed by peracetylation to give the (1rarr6)-α-C-disaccharide 159 (Scheme 31) [35]
Normally attack of the nucleophile proceeds from anequatorial direction to give the β-isomer The unexpected
Scheme (23)
Scheme (24)
BnOO
OBnCHO
OBn
O
OBn
PPh3I-
OBn
OBn
O
OBn
BnOBnO
O
OBnOBn
OBnH
O
OH
HOHO
O
OHOH
OH+
BuLi
THF-HMPA
-20 oC+
1 TBAF2 H2 Pd(OH)2C
112 65 113 100
110
111
O
OBnCHO
OBnBnO
O
OBn
BnOBnO
O
OBnCH(OiPr)2
OBnH
O
OBnCH(OiPr)2
PPh3I-
OBn
O
OBn
BnOBnO
O
OBn
OBnH
O
OBnOBn
BnOH
O
OH
HOHO
O
OH
OH
O
OHOH
HO
++
BuLi
THF-HMPA
-20 oC
BuLi
THF-HMPA
-20 oC
TFA H2 O THF rt
115 49
116 R = CH(OiPr)2
117 R = CHO
118 45
H2 Pd(OH)2C
110
114
114
119
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1407
Scheme (25)
Scheme (26)
OBn
R1
R2
PPh3BF4-O
O
OOHC
O
O
O
O
O
O
O
O
HO
O
O
O
O
O O
OBn
R1
R2
O
O
O
O
O
O
H
O
OBn
R1
R2
O
O
O
O
O
O
O
O
OBn
R1
R2
O
O
O
+
BCl3 (005 equiv)
MS 4A CH2 Cl2 0 o C
+
BuLi THF -90 oC -90 o C
to rtH2 (1 atm) PdC Et3N MeOH
R1 R2 = OBn H
120a - b
121
122a - b
123a - b
124
125a - b
OTBDPS
BnO X
SO Ph
O
BnO
OHCO
BnO
OMeOBn
OBn
O
BnO
OTBDPS
BnO
SO Ph
O
BnO
OMeOBn
OBn
O
HO
OMeOH
OHO
HOHO
OH
OH
128
229 74
1 RaNi (74)
2 BH3 DMS
NaOH H 2O2 (74)
3 H2 PdC (70)
130 74
LDA THF
-100 oC
126 X = H
127 X = Li
1408 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (27)
Scheme (28)
stereochemical outcome is rationalized by the generation ofan initial zinc acetylide species which facilitates intra-molecular delivery to the α-face (Scheme 32)
Wightman synthesized C-disaccharide analogs of the α-D-arabinofuranosyl-(1rarr5)-α-D-arabinofuranosyl motif ofmycobacterial cell walls through alkynyl intermediates [36]The lactone 164 was treated with lithio(trimethylsilyl)ethyneat low temperature to give lactol in 66 yield of 165Treatment of this with triethylsilane and BF3
Et2O gavethe separable isomers 166α (60) and 166β (13)Desilylation of the major isomer 166α gave 167 in 97yield Treatment of 167 with n-BuLi followed by addition oflactone 164 gave 85 yield of the hemiacetal 168 which onreduction with Et3SiH and BF3
Et2O gave the disubstitutedalkyne 169 (83) as the major product Reduction-
hydrogenolysis of 169 then gave the C-disaccharide 170 innear-quantitative yield (Scheme 33)
3 REDUCTIVE GLYCOSYL SAMARIUM SPECIES
The introduction of SmI2 as reducing agent can becredited to Kagan and has since been utilized in numeroussynthetic schemes [37] Sinayuml and Beau introduced SmI2
chemistry into C-glycoside synthesis through intermolecularreactions with appropriate electrophiles and intramolecularreactions of silyl tethered substrates [38] Anomericsamarium species are highly stable and not likely to undergoβ-elimination Treatment of the aryl sulfone 171 with SmI2
affords the nucleophilic intermediate 172 through two singleelectron transfer processes Introduction of a suitableelectrophile (carbonyl compounds) affords the α-C-manno-
O
BnO
OTBDPS
BnO X
SO Ph
O
BnO
OBn
BnO Li
SO Ph
DMF
OHO
HOOH
OH
O OH
OH
HO
OHOH
O
BnO
OTBDPS
BnO
SO Ph
O
OBn
OBnOBnSO
Ph
OH
131 X = Li
132 X = CHO
THF -100 oC
1 Ra-Ni
2 BH3 DMS NaOH H2O2
3 H2 PdC
131
133
134
OBnO
OBnOMe
BnO
Li
OBnO
BnOOBn
OBn
OOBn
OBnOMeBnO
OH
OBnO
BnOOBn
OBn
O
n-BuLi
BnO
OMe
BnO
BrBr
O
OBn
OHO
OH
OH
HO
OHO
OH
HO
OMe
O
BnO
OMeOBn
O
BnO
139 92
1BF3 OEt2 EtOH
2 H2 PdC AcOH
140 52 over 2 steps
135 136 137
138
CBr4 PPh3
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1409
pyrannoside 173 in good yield and with excellent stereo-selectivity (Scheme 34) [38a]
Preparation of C-glycosides of ulosonic acids using SmI2
was pioneered by Linhardt and coworkers [39] Coupling ofpyridyl sulfone 174 with aldehyde 175 in the presence ofSmI2 gave an excellent yield of the N-acetylneuraminic acidC-disaccharide 176 as single isomer This stereochemicaloutcome was rationalized on the basis of the Felkin-Anhmodel for predicting the stereochemical outcome of akinetically controlled addition of a nucleophile to a chiraladehyde (Scheme 35 A)
Reductive samarium method was utilized to synthesizesialo-antigen C-analogs by the Linhardt group A fullyprotected C-analogue of the SialylTn antigen α-D-Neu5Ac-(2rarr6)α-D-GalNAc-(1rarrO)-Ser 182 was prepared [40] C-glycosylation of the neuraminic acid sulfone donor with
aldehyde acceptor in presence of excess SmI2 afforded the α-C-glycoside 180 as an RS mixture (11) The criticalintermediate aldehyde acceptor 178 was prepared in 13steps Chemoselective resolution to compound 180 wasundertaken by oxidation with DMSOAc2O to keto-bridgedcompound 181 followed by stereoselective reduction withZn(BH4)2 to regenerate the bridge hydroxyl function gave182 in gt90 de (Scheme 36)
A common versatile N-acetylneuraminic acid C-disaccharide precursor of the C-glycoside analogs ofgangliosides GM4 and GM3 has been synthesized [41]Samarium(II) iodide coupling of N-acetylneuraminic acidsulfone 179 with a 3-formyl galactopyranoside derivative183 afforded the corresponding C-disaccharide 184 as amixture of (R) and (S) isomers at the newly formedhydroxymethylene bridge This diastereoisomeric mixturewas resolved after debenzylation of the galactoside residue
Scheme (29)
O
BnO
BnOOBn
OBn
OOBn
OBnOMe
OBnOH
O
BnO
BnO
OBn
OBn
O
O
BnOOBn
OMe
BnO
Li
OBnO
OBn
OBn
OBnO
OBn
OBn
OMe
OBnO
OBn
OBnBnO
OBnO
OBn
OBn
OBnO
OBn
OBn
OMe
OBnO
OBn
OBnOBnO
OBn
OBnBnO
O
BnO
BnO
OBn
O
OBnO
OBn
OBnBnO
OBnO
OBn
OBnBnO
OBnO
OBn
OBn
OMe
OBnO
OBn
OBnBnO
OMe
1 PCC2 CBr4 Ph3P3 n-BuLi
144 overall yield 54
1 BF3 OEt2 Et3 OH
2 H2 PtO2 EtOAc
145 76
1 H2 SO4 AcOH
2 PCC
146 62
repeat steps
repeat st eps
141 142
143
147
148
1410 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (30)
Scheme (31)
O
BnOOBn
OMe
Li
BnO
OPivBnO
OBn
OBn
BnO
O OO
BF3 OEt2
OBnO
OBn
OBn
BnO
OO
O
OMe
BnOOBn
BnO
Co(CO)3
Co(CO)3
O
CAN
OBnO
OBn
OBn
BnO
OO
OO
BnOOBn
BnO
OMe
OHBnO
OBn
OBn
BnO
OHO
O
O
OMe
BnOOBn
BnO
Co(CO)3
Co(CO)3
O
OPivBnO
OBn
OBn
BnO
OH OO
O
OMe
BnOOBn
BnO
OAcO
OAc
OAc
AcO
OAcOAc
OAcO
OAc
AcO
OMe
1
2 NaOMe MeOH
1 Lewis acid2 ClCO2CCl3 Pyr3 Co2(CO)8
with a-isomer
1 Et3N Pyr H2O
2 H2 PdC H+
3 Ac2 O Pyr
149 151
152153
154 155
150
OBn
BnO
OBnO
OBn
BnO
OBnO
BnO
MeO
OBnO
OBn
BnO
O
OMe
AcO
OAcO
OAc
OAc
AcO
OAcO
OAc
O
BnOOBn
OMe
BnO
159 74 over 2 steps
+
BuLi ZnCl2 THF
1 H2 PdC2 Ac2O Pyr
156 157
158 59
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1411
Scheme (32)
Scheme (33)
and the chirality of each isomer assigned after acetylationConversion of the p-methoxyphenyl group in the peracety-lated (S) isomer 187 into the corresponding thiophenylglycoside 188 was accomplished affording the key inter-mediate for the synthesis of C-glycoside analogs of GM4GM3 and other related gangliosides (Scheme 37)
Ganglioside GM4 is a very important cell adhesionmolecule The C-disaccharide of GM4 is currently beingsynthesized in Linhardtrsquos lab using standard O-glycosylationof C-disaccharide with protected ceramide Once theceramide has been attached it can be oxidized to afford analdehyde group for coupling to keyhole limpet hemocyanin
OBnO
OBn
BnO
O
OBnO
ClZnO
OBn
BnOCl
R
OBnO
O
OBn
BnOCl
ZnR
O
ZnR
OBnO
OBn
BnO
160 161
162163
O
OBn
OBnBnO
O
O
OBn
OBnBnO H
TMS
O
OBn
OBnBnO H
O
OBn
BnO
OBnHO
O
OBn
OBnBnO OH
TMS
OBnBnO HO
OBn
TMS
O
OR
ORRO H
O
OR
RO
OR
OBn
OBnBnO
H
TMS
O+
K2CO3 MeOH
1 n-BuLi THF -78 oC
2 164
164165 66
166α 60 166β 13167 97
BF3 Et 2O Et 3SiH -78 oC
168 85
169 R = Bn 83
170 R = H near quantitative yield
H2 (1 atm)Pd(OH) 2C
TMS-acetyl ene
n-BuLi THF -78 oC BF3 Et2O Et3SiH
-78 o C
1412 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
O
OHCOBn
OBnBnO
OMe
O
CO2MeAcO
OAcAcHN
OAc
SO2
NAcO
OBnH
H
OBn
OBn
H
O
OMeH HH
A
O
CO2MeAcO
OAcAcHN
OAc
O
OBnOMe
OBnOBn
HO
AcO
+
Nu
174175
176
SmI2 THF
Scheme (34)
Scheme (35)
Scheme (36)
O
BnO
BnO
BnO
Si lylO
O2S N
O
BnO
HO R2R1
BnOBnO
SilylO
OBnO
BnO
BnO
SilylO
Sm(III)
R1COR2 SmI2 THF
171 172
173
NHBoc
OAcO
AcO
AcHN O
O
CO2BnO
OO
OO
OH
O
CO2MeAcO
OAcAcHN
OAc
AcO
SO2Ph
R2
O
CO2Me
AcHN
OAc
AcO
R1
AcO
AcO
AcHNO CO2Bn
NHBoc
AcO
OAc
O
Zn(BH4)2
180 R1 R2 = H OH ( RS 11)
181 R1 R2 = O
182 R1 = H R2 = OH de gt 90
DMSO Ac2O
177178
179
13 steps
22 equiv SmI2 THF
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1413
Scheme (37)
Fig (2)
(KLH) by reductive amination for use as carbohydrate-basedvaccine GM3 a related trisaccharide containg gangliosideplays an important role in cell growth and differentiationFig 2 The synthesis of C-oligosaccharide GM3 is currentlyunderway following a similar route to that of C-GM4synthesis [42]
Beau also reported a sialyl C-disaccharide synthesiswhich relied on the unprecedented use of a stable andcrystalline 2-pyridyl sulfide of the N-acetylneuraminic acidderivative 189 as the anomeric precursor in a samarium-Reformastky procedure [43] The coupling procedure withsulfide 189 and aldehyde 190 afforded the carbon-linkeddimer 191 in 93 yield as a 11 diastereomeric mixture
Alcohols 191 were converted into thiocarbonates anddeoxygenated by employing triphenyltin hydride catalyticAIBN and pentafluorophenol which yielded C-disaccharide192 as a single compound in 65 yield for the 2 stepsDesilylation hydrogenolysis acetylation and finalacetolysis of the methyl glycoside provided the carbon-linked mimic 193 of the disaccharidic component of thesialylTn tumor antigen (Scheme 38)
4 CATIONIC METHODS
This section is categorized according to reactions thatinvolve the generation of anomeric ions followed by thecapture with sugar-based nucleophiles
OAcAcHN
OAc
AcO
O
OBnBnO
OBnOMP
HO
O
MeO2CAcO
O
MeO2CAcO
OAcAcHN
OAc
AcO
O
OHHO
OHOMP
HO
O
OBnOHC
OBnBnO
OMP
O
MeO2CAcO
OAcAcHN
OAc
AcO
O
OHHO
OHOMP
HO
O
CO2MeAcO
OAcAcHN
OAc
AcO
SO2Ph
O
MeO2CAcO
OAcAcHN
OAc
AcO
O
OAcAcO
OAcX
AcO
H2 PdC EtOAc CH3OHH2O
+
Ac2O Pyr
187 X = OMP
188 X = SPh 73
184 85 R and S mixture
186 90 for two i somers
+
SmI2 THF183
179
185
O
HO2 CHO
OAcAcHN
OH
HO
O
OHHO
OH
OAcO
(CH2 )12 CH3
HN
OH
(CH2)14CH3
O
O
O
OHHO
OH
O
O
HO2 CHO
OAcAcHN
OH
HO
O
OHHO
OH
O(CH2)12CH3
HN
OH
(CH2)1 4CH3
GM4
GM3
1414 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
41 Exo-glycals as Nucleophiles
Nitotra et al have found that treatment of exo-glycal 194with BF 3
OEt2 followed by a water quench afforded the C-disaccharide 195 (Scheme 39) It is noteworthy tonoteworthy that the attack of the enol ether on the anomericoxonium ion occurs with high stereoselectivity on the α-face only 195 was obtained [44]
42 Silyl-based Nucleophiles
Isobe has designed and developed alkynylation as a keyreaction for the introduction of a carbon chain onto sugarsThose alkynylated compounds are called ldquosugar acetylenesrdquo[45] The mechanism includes eliminative formation ofcation to which silylacetylene can coordinate on the α-face(Scheme 40)
Double C-glycosylation between glycal 198 and bis(silylacetylene) gave C-disaccharide ldquolikerdquo compounds 199and 200 (Scheme 41)
Silylpropargyl-sugar 201 smoothly reacted with D-glucalto furnish exclusively the α-acetylene glycoside product 202in 88 (Scheme 42) [46]
5 CYCLIZATION METHODOLOGY
This approach to C-oligosaccharide synthesis relies onthe coupling of an open chain fragment with an intact
monosaccharide to give an intermediate that is then cyclizedto deliver the C-oligosaccharide target This section isdivided by the type of chemistry used to initially assemblethe two pre-cyclization fragments
51 Wittig Reaction-Cyclization
The Kishi group was the first to use Wittig-cyclizationapproach to synthesize C-disaccharides Starting with Wittigreaction between 203 and 204 the intermediate 205 wasafforded as a single stereoisomer in 82 yield Osmylationthen gave a mixture of diols with the major one formed in a61 ratio Selective protection of the diols gave 206a and206b The mono-para-methoxybenzyl ether 206a was thentransformed into the hemiketal 207 in 75 overall yield inthree steps ie (1) Swern oxidation (2) acetonide hydro-lysis (4 N HClTHFrt) and (3) benzoylation (3 equiv ofPhCOClpyCH2Cl2rt) Silane reduction of 207 in an acidicmedium should preferentially yield the equatorially substi-tuted β-C-glycoside which was deblocked and converted tothe methyl- βminusC-disaccharide 209 Exact parallel experi-ments applied to the minor isomer gave the correspondingC-disaccharide 210 (Scheme 43) [47]
Armstrong has employed Wittig-osmylation protocol forthe preparation of a small library of α-C-(1rarr6)-disaccha-rides [48] Readily available allyl C-glycoside 211 washomologated to diene ester 212 and subjected to osmylation
Scheme (38)
O
CO2MeAcO
OAcAcHN
OAc
AcO
S(2-Py)
O
TESO
AcHNOMe
O
HO
O
CO2MeAcO
OAcAcHN
OAc
AcO
O NHAcOAc
OAc
OAc
O
CO2MeAcO
OAcAcHN
OAc
AcO
O NHAcOBn
OTES
OMe
OAc
AcO
O NHAcOBn
OTES
OMeOH
O
CO2 MeAcO
OAcAcHN
+
192 65
1 MeOHHCl2 H2 PdC EtOH3 Ac2O Pyr4 Ac2OAcOHH2SO4
193 59 overall yield
25 equiv SmI2 THF
1 11-thiocarbonyldiimidazole DMAP2 Ph3SnH cat AIBN
191 93
189
190
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1415
Scheme (39)
Scheme (40)
Scheme (41)
OBnO
OBn
OBn
OBnO
OBn
OBn
OBnO
OBn
OBn
OBnO
OBnCH3
BnO
OH
CH2
OBnO
OBn
CH3
OBn
H2 O
BF3 OEt2 MeCN
194
195 96
OOAc
OAc
AcO
R SiMe3
SnCl4
O
OAc
AcO
R
O
OAc
AcO
O
OAc
AcO
Me3Si
R
SiMe3
196
197
Me3 Si SiMe3
O
AcO
OAc
OAc
SiMe3
SiMe3
O
AcO
OAc
O
OAc
OAc
O
AcO
AcOO
OAc
OAc
SnCl4 CH2Cl2
SnCl4 CH2Cl2198
199
200
1416 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (42)
Scheme (43)
AcO
OAc
OAc
Me3 Si
BnO
OBn
BnO
OBn
AcO
OAc
BnO
OBn
BnO
OBn
+ I2 CH2Cl2
202 88
198 201
O
OBn
OBn
O
O
O
OBn
OBn
O
O
OBn
OBn O
OBn
OBn
O
OPBH2M
OH
OBnO
BnO
BnO
O
OBn
OBn
O
OHOPMB
OHO
HO
HO
O
OH
OHOH
OH
HOOMe
O
OBnOBn
O
Ph3P
O
O
OBn
OBn O
OBn
OBn
O
OPBM
OH
O O
CHO
OBn
BnO
OO
OBn
OBn
O
OHOPMB
BnO
BnO
BnO
OHO
HO
HO
O
OH
OHOH
OH
HOOMe
+ THF -78 oC
1 OsO4 pyr THF
2 NaH PMBBr
206a 206b 206a206b 61
1 Swern [O]2 4N HCl3 PhCOCl pyr
1 Swern [O]2 4N HCl3 PhCOCl pyr
1 PrSiH BF3 OEt2
2 H2 Pd(OH)2C
3 HCl MeOH 90 oC
1 PrSiH BF3 OEt2
2 H2 Pd(OH)2C
3 HCl MeOH 90 o C
203
204
205
207
209
208
210
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1417
followed by reduction to afford a 51 mixture (213214215216) of lactols that were readily separable by chromato-graphy Following a deprotection of an equimolar mixture of213 and 214 217 and the DL hybrid C-disaccharide of D-glucose-O-(1rarr6)-L-galactose 218 were obtained The DDand DL derivatives 219 and 220 of glucose-α-(1rarr6)-idosewere also obtained as a near equimolar mixture afterdeprotection of 215 and 216 (Scheme 44)
52 Anion Addition-Cyclization
Kishi developed an approach for the synthesis of theCndashtrehalo sugars which relied on nucleophilic addition ofone intact sugar fragment to a fundamental aldehyde ieKishi-Nozaki reaction [49] Coupling of monosaccharide221 and aldehyde 222 gave 223 The triple bond waspartially reduced and osmylation was followed by selectiveprotection to afford 224 The acetonide was converted toepoxide 225 by standard methods and removal of the PMBgroup Acid-catalyzed cyclization followed by aglyconichydrolysis and protection of hydroxyl group with (p-methoxyphenyl)diphenylmethyl chloride (MMTrCl) gave226 Inversion of the C-2 hydroxyl and removal of protectinggroups delivered α α-C-trehalose 227 (Scheme 44)
Kishi and co-workers also employed aldol reactions as anefficient access to the C-trisaccharide related to the type IIABO(H) blood group determinant [50] Aldol condensationof the enolate of methyl ketone 228 with aldehyde 229 gavea 41 mixture of hydroxy ketones 230 and 231 The majorketol was cyclized desulfurized and oxidized to afford thedisaccharide ketone 233 The ketone in THF was treatedwith LiHMDS (3 equiv) and TMEDA followed by theaddition of MgBr2 Addition of the aldehyde 234 led toalmost exclusive formation of the equatorial products 235and 236 in a 12 ratio Mesylation of 235 and 236 followedby treatment with liquid ammonia gave enones 237a and237b which were reduced to yield exclusively the C-2rsquo-equatorial ketone 238 Sodium borohydride reduction of theC-3rsquo carbonyl proceeded with the desired stereoselectivity toyield the protected C-trisaccharide 239 which wasdeblocked to provide the polyol 240 (Scheme 46)
Sutherlin and Amstrong cleverly applied a recursivestereochemical deconvolution (RSD) combinatorial approachfor the synthesis of a small library of C-trisaccharides aspotential inhibitors for the cell surface proteins of bacteriumHelicobactor pylori [51] The workers chose to carry outvariations in galactose ring of these trisaccharides An
Scheme (44)
OBnO
BnOOBn
OBn
P O
OEtOEtO
EtO
R H
OH
OH
OH
OH
O
R H
OH
OH
OH
OH
O
OHO
HOOH
OH
O
HO
OHOH
OH
OHO
HOOH
OH
O
HO
OH
OH
OHO
HOOH
OH
O
HO
OH
OHOH
R H
OH
OH
OH
OH
O
R
OBnO
BnOOBn
OBn
O
OHO
HOOH
OH
OO
HOHO
OH
R H
OH
OH
OH
OH
O
1 OsO4 NMO 50
2 DIBAL -32 oC 40
++ +
213 214 215 216
217 218 219 220
1 9-BBN H2O22 Swern [O]
3 t-BuOK
4 I2 C6H6212
211
1418 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
efficient Nozaki-Kishi coupling of vinyl bromide 241 withaldehyde 242 in a diasteromeric ratio of 12 followed byprotection with TBSOTf led to 243 and 244 Hydroborationfollowed by oxidation gave aldehydes 245 and 246respectively Addition of allylmagnesium bromide toaldehyde 245 followed by removal of the silyl groupafforded 247 to 246 giving 248 and 249 Epoxidation gave a11 mixture of the corresponding epoxides which werecyclized to give the C-trisaccharide 250-255 after removalof the benzyl groups (Scheme 47)
Schmidt reported a stereoselective 6-exo-trig selectiveelectrophilic cylization approach for de novo synthesis of amethylene-bridged Neu5Ac-α-(23)-Gal C-disaccharide theC-analog of an important motif in glycosphingolipids [52]The open chain precusors 259ab (a 32-mixture ofdiaseteromeric alcohols) were formed by the addition oflithiated iodide 256 to open chain aldehyde 258 Subsequent
C1 incorporation using Tebbe-reagent formation of a cycliccarbonate and deprotection of the two isopropylidene ketalsafforded tetrol 264 which upon treatment with phenylselenyltrifilate was steroselectively cyclized in a 6-exo-trigselective manner affording a diasteromeric mixture of 251and 252 in a ratio of 71 A seleno-Pummerer rearrangementto afford aldehyde 267 in 5 steps in 90 overall yieldOxidation of the aldehyde and subsequent steps led to thedesired C-disaccharide 268 (Scheme 48)
53 Esterification-Cyclization
Work from the Postema group has focused on a ringclosing metathesis (RCM) approach for the synthesis of C-saccharides [53a] The chemistry is versatile and has beenused for the synthesis of a small library of differentiallylinked β-C-disaccharides through a radical allylation-RCMstrategy [53b] The synthesis of the β-(1rarr4)-glucopyranosyl
Scheme (45)
O
OBn
BnO
BnO
BnO
I
CrCl2-NiCl2O
OBn
OH
BnO
BnO
BnO
O
O
O
O
O
H
OBn
O
O
OBnBnO
BnO
BnO
OOBn
OBn
OAc
PMBOHOO
OBn
BnO
BnO
BnO
O
OBn
OBn
OAc
O
OH
HO
HO
HO
OH
OH
OH
O
OH
O
OBn
BnO
BnO
BnO
OBn
OBn
OAc
O
MMTr
+
1 p-TsOH2 K2CO3 MeOH3 MMTrCl pyr
1 Swern [O]2 BH3 THF
3 AcOH-H2 O4 H2 Pd(OH)2
221
222
223
1 Pd-Pb CaCO3 H22 NaH BnBr3 OsO44 Bu2 SnO5 CsF PMB-Cl6 Ac2 O 4-DMAP
1 AcOH2 TsCl pyr
3 NaH-imid4 DDQ
224225
226 227
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1419
Scheme (46)
OBnO O
OBn
OMe
OBn
XY
SMe
OBnBnO
O
OBn
OBn
OBn
OBn
O
BnO
YX
OBn
TBSO
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnOOBn
H
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnO
OBn
OHC OBn
OBn
OTBS
OMe
BnOOBn
CHO
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnOOBn
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnO
OBn
YX
OBnO O
OBn
OMe
OBn
OBn
O
BnO
O
OBn
OBn
OBn
OBn
O 1 LiHMDS
2
228
1 TBAF THF
2 MeSH BF3 OEt2
230 X = OH Y = H231 X = H Y = OH
230231 41
1 Bu3SnH AIBN2 Swern [O]
1 LiHMDS THF-TMEDA2 MgBr23
1 MsCl
2 liquid NH3
235 X = OH Y = H236 X = H Y = OH Bu3 SnH AIBN
237a and 237b
NaBH4 MeOH
238
239 X = OBn
240 X = OHH2 Pd(OH)2
229
232233
234
1420 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (47)
OH C
O
O BnAcHN
OO
O
OBn OBnOBn
Br
O
OBn OBnOBn
O
OBnA cHN
OO
O TBSO
OBn O BnO Bn
O
OBnAcHN
OO
OTBS
S2
S1
S2
OTBSS1
O H
S2
OT BSS1
O H
MgBrMgBr
S2
O TBSS1
O H
S2
OHS1
OH
S2
OTBSS1
OH
O
OHHO
O H
O
HO
H OO
OBnA cH N
HO
H O
O
O HHO
OH
O
HOHO
O
OBnA cH N
HO
H O
O
OHH O
OH
O
H O
HOO
OBnAcHN
HO
HO
O
O HH O
OH
O
H O
H O O
OBnA cHN
HO
HO
O
O HH O
O H
O
HO
H O O
OBnAcHN
HO
HO
O
OHHO
OH
O
H O
O
OBnA cHN
HO
HOHO
+
241 242
1 CrCl2-NiCl2 T HF-DMF 722 TBSOTf 2 6-lutidine 91
243 244
1 9-BBN 602 Dess-Mart in period inane 97
1 9 -BBN 552 D ess-Martin periodinane 98
245 246
1
2 T BAF 74
1
2 TBAF 88
247 248 249
250
251
250 251 1 1 252 253 1 1 254 255 1 1
252
253
254
255
1 MCPBA2 CSA CH 2Cl2 61 fo r 2 steps3 H 2 Pd (O H)2C 95
1 MCPBA2 CSA CH 2Cl2 63 fo r 2 s teps3 H 2 Pd (OH)2C 87
1 MCPBA2 CSA CH2Cl2 80 for 2 steps3 H2 Pd(O H)2C 95
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1421
Scheme (48)
O
OO
Se Ph
R
O
HO OHOH
O
OB n O B n
OB n
O B nO O
O O
R O OR
X
O
OO
R
Se Ph
O
HOOH
OH
O
OB nOB n
O Bn
OB n
O O
O O
R O O R
O H
O
O B n OB n
O B n
OB n
O
C HO
O
O O
R O OR
OAc HN
OAc
C O2NH 4HOOH
OH
O
OH O H
OH OH
O
OB n O B n
OB n
OB nO O
O O
R O OR
X
O
O
OAcOAc
C HOA cOOAc
OAc
O
OB n O B n
OB n
OB n
O
O Bn OB n
OB n
OB n
X
OH
OO
HOOH
OH
O
O
OMeOB n
OB nOB n
R
t-B uL i256 R = Li
257 R = L i
258
(R = t-B uMe 2Si )
(R = t-B uMe 2Si )
259ab (32) 79 com bine d yi eld
De ss-Ma rtin pe riodinane
260 X = O R = t-B uMe 2Si ) 95
261 X = O R = t -B uMe2S i) 62
T e bbe re age nt
TB A F THF262 X = O R = H 94
diphosge ne
C H2C l 2Pyr
263 95
T HFH2O T FAr t
264 quant it a ti ve yie ld
PhSe C l AgOT f
EtC N -80 oC
265
266
Quant it at i ve yi l ed 25 26 7 1
+
R =
1 Ac 2OPyr
2 mC PB A3 Ac 2ONa OAc
4 NaO HT HFMe OH
5 Ac2O P yr
267 90 overa ll yi e ld
ste ps
268
1422 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
glucopyranoside 280 represents an example of thischemistry The known triacetyl glucopyranoside 269 wasconverted to iodide 270 in good yield Radical allylation of271 proceeded to afford a mixture of equatorial and axialallylation products in a 61 ratio Oxidative cleavage of thedouble bond gave the corresponding aldehydes 273a and273b which were separable Pinnick oxidation of the majoraldehyde 273a then gave the C-4 equatorial acid 274 DCC-mediated coupling of alcohol 275 and acid 274 proceeded toafford ester 276 in good yield Methylenation of 276 gave277 and exposure to catalysist 278 gave a 41 yield of theC-disaccharide glycal which was exposed to an excess ofBH3
THF to give 64 yield of the β-C-disaccharide 279Removal of the benzyl groups and global peracetylation gavethe peracetylated (1rarr4)-β-C-disaccharide 281 in good yield(Scheme 49)
54 Ring Expansion-Cyclization
Nelson developed a new strategy for asymmetric andstereoselective synthesis of C-linked disaccharide mimeticsthe C58-C71 fragment of palytoxin [54] The diol (RR)-282was converted into the di-dihydropyran (DHP) template 283284 and 285 The di-DHPs were functionized in a twodirectional sense using dihydroxylation reactions The two-directional approach was often very efficient indeed forexample in the synthesis of 286 six new stereogenic centerswere introduced with almost complete stereocontrol using areduction and a dihydroxylation reaction The approach isnot restricted to the synthesis of C2-symmetricaldisaccharide mimetics Using the unsymmetrical template285 which has both a pseudo-axial and a pseudo-equatorialhydroxyl groups the unsymmetrical mimetics 289 and 290were prepared (Scheme 50)
6 RADICAL APPROACHES
The radical approach for C-C bond formation is a popularmethod within organic chemistry The use of radicalchemistry in carbohydrate synthesis has certain advantagesFirstly the reaction conditions are very mild and tolerant ofa range of functional and protecting groups Secondanomeric radicals are stable with respect to elimination andepimeration Most significantly the chemistry required toincorporate an appropriate substitute at C-1 employed in theinitial hemolytic cleavage step is common within carbo-hydrate chemistry [55] The use of such radical techniquecan be subdivided into two classes intermolecular andintramolecular approaches
61 Intermolecular Radical Approaches
Giese was the first to employ an intermolecular radical-based approach for synthesis of C-disaccharides [56]Addition of an alkene to an anomeric radical underappropriate conditions allowed exclusive entry to the α-linked C-glycoside a result which was mirrored by the workof Baldwin [57] The high α-selectivity of the reaction wasin contrast with other reports Thus radicals generated at theC-2 C-3 and C-4 centers all preferred to occupy equatorialpositions [58] When the anomeric bromide 291 was treatedwith tin hydride and AIBN resulting anomeric radical andreacted with lactone 292 in a Michael addition it afforded293 In this reaction hydrogen abstraction at the resulting
radical center occurs from axial face to selectively generatethe equatorial C-2rsquo substituent Reduction and acetylation of293 furnished C-disaccharide 294 (Scheme 51) [59]
Witczak used the facial bias of levoglucosene tostereoselectively add a carbohydrate-based radical in thepreparation of the 3-deoxy-(1rarr4)-β-C-disaccharide 299[60] Addition of the radical derived from iodide 295 to 296gave adduct 297 in 26 yield Removal of the anomerichydroxyl of 297 was achieved by treatment with triethylsilane borontrifluoride ether complex followed bystereoselective reduction of the keto function at C-2rsquo withthe formation of 298 in 89 yield Debenzylation followedby acetolysis of 16-anhydro ring produced the peracetylatedtarget C-disaccharide 299 in 19 overall yield from 295(Scheme 52)
Vogel has developed general methods to transformenantiomerically pure 7-oxabicyclo[221]heptyl derivatives(ldquonaked sugarsrdquo) into C-disaccharides Because of thesechiral bicyclic skeletons they undergo highly stereoselectivereactions with predictable diasteroselectivities An arsenal ofmethods is available that allow to substitute these ldquonakedrdquocarbon centers with a variety of functional groups with allpossible relative configurations The methods allowpreparation of both enantiomers of a given target with thesame ease Predictably high stereoselectivity of the reactionsof the bicyclic chirons adds to the flexibility of approachwhich can lead to high molecular diversity [61]
α-C-(1rarr3)-mannopyranoside of N-acetyl-galactosaminepotent β-galactosidase inhibitors was synthesized by thisapproach [61] Enone 302 was readily prepared from 300The addition of the radical derived from bromide 303 toenone 302 afforded the αminusisomer 304 The ketone was thenreduced and the selenide eliminated via the intermediacy ofthe selenoxide to give 305 Acid-promoted (CF3SO3H) 7-oxa ring opening of 305 in MeCN produced the amino-conduritol derivative 306 resulting from the quenching of theallylic cation intermediate by the solvent (Ritter reaction)Ozonolysis of the chloroalkene 306 generated an acylchloride-aldehyde intermediate that reacted with MeOH toproduce a mixture of methyl uronates The major compound307 was silylated and reduced The crude polyol obtainedwas acetylated to produce 308 Desilylated and ammonolysisafforded a mixture of α-β-pyranoses 309 and correspondingα-β-furanoses (Scheme 53)
Similar chemistry was carried out to synthesize non-protected α-C(1rarr2)-L-fucopyranoside of D-galactopyrano-side corresponding to a blood group mimetic [62] Giesersquosradical fucosidation of racemic enone 310 with α-L-bromoacetofucose 311 provided the mixture of diastereo-meric α-C-fucoside 312a and 312b in reproducible yield of78 Reduction of the mixture gave a 11 mixture of endo-alcohols 313 and 314 which were isolated pure in 40 and355 yield respectively Oxidative elimination of thebenzeneselenyl group of 313 followed by acetylation gaveendo acetate 315 in 85 yield Acid-promoted ring openingof 315 and ozonolysis of the resulted chloroalkene gavemethyl uronic ester 316 in modest yield (10) Treatment of316 with Cl3CCN and NaH followed with BF3
OEt2
furnished the totally protected C-disaccharide 317 in 79
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1423
Scheme (49)
Bu3SnO
HOAcO
OMeOAc
OAc
O
AcO
OMeOAc
OAcI
AIBN
O
AcO
OMeOBn
OBn
HO2C O
AcO
OMeOR
ORY
X
OHBnO
BnO
OBn
OBnO
BnO
OBn
O
AcO
OMeOBn
OBnX
i-Pr i-Pr
N
Mo C(Me2 Ph)((CF3)2 MeCO)2
O
RO
OMeOR
O
RO
OR
OR
RO
OR
278
I2 Ph3P
imidazole
269 270 93
271a X = CH2CH=CH2 Y = H R = Ac 64271b Y = CH2CH=CH2 X = H R = Ac 11272a X = CH2CH=CH2 Y = H R = Bn 75272b Y = CH2CH=CH2 X = H R = Bn 75273a X = CH2CHO Y = H R = Bn 79273a Y = CH2CHO X = H R = Bn 79
1 NaOMe MeOH2 NaOH BnBr DMF
OsO4 NaIO4
NaClO2 NaH2PO4
274 96
275
DCC 4-DMAP
276 X = O 82
277 X = CH2 51
TiCl4 Zn dust TMEDA CH2Br2PbCl2 (Cat )
1
2 BH3 THF H2O2 NaOH
H2 PdC EtOH
Ac2 O Pyr 4-DMAP
279 R = Bn R = H 64
280 R = R = H 99
281 R = R =Ac 97
1424 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (50)
Scheme (51)
O OOH
OH
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
286
1 VO(acac)2 t-BuOH 95
2 (MeO)3CH BF3 90
1 P-O2NC6H4 CO2H Ph3P DIAD2 K2CO3 MeOH 82 over 2 steps
1 PhCOCl Et3N DMAP 402 P-O2NC6H4 CO2H Ph3P DIAD3 KOH THF-H2O 75 over 2 steps
TMEDA OsO4
Cat OsO4 NMO 287
Cat OsO4 NMO288
TMEDA OsO4
Cat OsO4 NMO
290
289
(RR)-282283
284
285
OHO
AcO
BrOAc
OAc
BnO
O
OBn
OBnO
OHO
AcOOAc
OAc
BnO
OOBn
OBnAcO
OHO
AcOOAc
OAc
BnO
O
OBn
OBnO
+
Bu3SnH AIBN291
292
293 81
1 Na[Al(OC2H4OMe)2(OEt)H]2 Ac2O pyr
294 56 over 2 steps
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1425
Scheme (52)
Scheme (53)
OBnO
BnOOBn
OBn O
OH
O
OBnO
BnO
OHOBn
OBn O
O
O
O
O
O
OBnO
BnOOBn
OBnO
OAcOAc
OAc
OBnO
BnO
OHOBn
OBn
IBu3SnH AIBN
295 297 26
1 BF3 OEt2 Et3SiH
2 L-Selectride THF
1 Pd(OH)2C C6H10 EtOH
2 EtSiOSO2CF3 Ac2O
298 89 over 2 steps299
296
O
O
PhSeClO
O
PhSeCl
Bu3 SnH
O
O
PhSeCl
R
H
O
OAc
R
Cl
O
AcO
OAc
OAc
OAcOH
Cl
NHAc
R
OAc
AcHN
OH
O
OH OAc
OH
OHO
HO
OH
O
AcO
OAc
OAc
OAcBr
O
O
PhSeCl
O
O
PhSeCl
R
O
OTIPSAcHNR
OAc OAc
O
OHAcHN
COOMe
R
OAc
1 Bu4NF
2 NH3MeOH
1 (Me3Si)2NLi THF2 Me2N=CHI
1 Bu3 SnH AIBN2
1 NaBH42 mCPBA3 Ac2O pyr
1 H+ MeCN
2 H2 O NaHCO3
R =
1 O3MeOH
2 Me2S NaHCO3
1 TIPSOTf 26-lut idine2 LiBH43 Ac2 O pyr DMAP
furanoses +
304 56
305 68 306 84307 50
308 46
300 301 302
303
309
1426 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
The reduction of 317 and treatment with DOWEX-H+ resinprovided the desired C-fucoside 318 in 70 (Scheme 54)
62 Intramolecular Radical Approaches
One disadvantage with the intermolecular approaches isthat during such radical mediated reactions electrondeficient alkenes are required to facilitate C-C bondformation The intramolecular approach of Sinayuml overcomes
this drawback by bring two substrates together via atemporary covalent silaketal connector This enables the useof a wider range of alkenes which can include alkene-functionalized sugars thus leading to the generation of C-disaccharides [63] Based on the early work of Stork Sinayumlemployed the tether reaction in the synthesis of both α- andβ-C-disaccharides with this work subsequently beingemployed in the synthesis of biologically significant natural
Scheme (54)
O
OH
Fuc
Cl
O
O
ClPhSe
OOAc
NHAcOHFuc
O
AcOOAc
AcO
Br
O
O
PhSeCl
O
AcOOAc
AcO
O
OH
PhSe Cl
Fuc
OOAc
NHAc
OMe
Fuc
O
AcHN
OH OAc
OH
O
OH
Me
OH
O
O
Fuc
ClSePh
O
HO
Fuc
ClSePh
+
Ph3SnHAIBN
78 combined yield
Fuc
310
+
1 NaBH4 MeOHTHF2 Chromatography
313 40 314 355
1 mCPBA
2 Ac2O pyr DMAP
+
315 75
1 TfOH MeCN
2 NaHCO3 O3 -78 oC
316 10 over 2 steps
1 Cl3 CCN NaH
2 MeOH BF3 OEt2
317 79
1 LiBH4 THF
2 Dowex-H+
311
312a312b
318 70 for 2 steps
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1427
products [64] The availability of different hydroxyl groupson each monosaccharide unit allowed the fine-tuning ofstereochemical outcome by selective positioning of the silyltether [65] Development of this early stereochemical controlled to the tethering of the donor 320 with alcohol 319through a di-isopropyl silicon tether 321 Subsequent treat-ment with Bu3SnH and AIBN led to a 9-endo-trigcyclization to form the C-disaccharide 322 in an 80 yieldwith exclusive formation of the α-product The silyl tetherwas removed with Bu4NF and deprotection under standardconditions afforded the desired disaccharide 323 in excellentyield (Scheme 55)
In parallel the development of a 32rsquo silyl tether allowedaccess to the β-linked product as demonstrated in Sinayumlrsquossynthesis of methyl β-C-lactoside 328 [66] Alcohol 324 and320 were connected via the dimethylsilyl tether an 8-endo-trig cyclization followed to exclusively afford the β-
disaccharide 326 in 45 yield Removal of the tether anddeprotection of benzyl ether gave β-C-disaccharide 328(Scheme 56)
This group also selected iodosugars bearing a freehydroxyl group as progenitors of the radical donors [67] In atypical experiment the radical donor 329 was connected tothe radical acceptor 330 through a silaketal tether followingtheir procedure Tributyltinhydride mediated 8-endo-trigradical cyclization of compound 331 gave after detetheringof the non isolated intermediate 332 the protected β-C-disaccharide 333 in 37 overall yield (from startingmaterials 330 and 329) Peracetate 335 was achieved afterhydrogenolysis The C-laminaribioside 334 is of potentialbiological interest as it mimics the repeating disaccharideunit of fungal β-(1rarr3)-glucans which have antitumor andimmunomodulating properties (Scheme 57)
Scheme (55)
Scheme (56)
OO
OHSePh
OTBDPSO O
OO
SePh
OTBDPSO
OO
OBnOMe
OBn
Si
O
HOOBn
OMe
OBn
O
HOOH
OHHO
O
HOOH
OMe
OH
OTBDPSO
O
HOOBn
OMe
OBnO
OOH
1 n-BuLi THF
2 iPr2SiCl2 -78 oC
3 DMAP THF rt
1 Bu4NF THF
2 Dowex-H+
3 H2 PdC
Bu3SnH AIBN toluene
319
320
321
322323
OBnO
OHSePh
OBnBnO
OHO
OBnOMe
OBn
ROO
ROOH
OR
OHO
OROMe
OR
OBnO
O
OBnBnO
OO
OBnOMe
OBn
Si
SePh
OBnO
O
OBnBnOO
OOBn
OMe
OBn
Si
1 PhSeH Me2SiCl2
BuLi -78 oC
2 imidazole rt
Bu3SnH AIBN toluene
H2 PdC327 R = Bn
328 R = H
Bu4NF THF
324
320
325
326 45
1428 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
CONCLUSIONS
In this paper the biological importance of C-oligo-saccharides as subunits of natural products and as a newgeneration of carbohydrate based on therapeutics has beenillustrated Different methods are available for the synthesisof C-oligosaccharides As with traditional saccharidesynthesis it has been necessary to develop a number ofspecific approaches to facilitate the regioselective andstereoselective preparation of the desired targets Work inthis area continues and it is expected that many interestingnew C-oligosaccharides will be prepared using the chemistrydescribed in this review It is also likely that new chemistrywill be developed in the future for the preparation of thesebiologically important targets
ACKNOWLEDGEMENTS
The authors thank Dr Sultan Baytas for her criticalreading of this manuscript
REFERENCES
[1] Kennedy J F White C A Bioactive Carbohydrates InChemistry Biochemistry and Biology Ellis Horwood LtdChichesterUK 1983
[2] Wassarman PW Mammalian Fertilization Molecular Aspects ofGamete Adhesion xocytosion Exocytosis and Fusion Cell 199996 175-183
[3] Carbohydrate-based Drug Discovery Wong C-H EdWeinheim Cambridge Wiley-VCH 2003
[4] (a) Sharon N Lis H Lectins as Cell Recognition MoleculesScience 1987 246 227-234 (b) Dwek RA Chem Rev 1996 96683-720
[5] Postema M C-Glycoside synthesis CRC Boc Ratom 1995[6] (a) Weatherman R V Mortell K H Cheruenak MKiessling
L L Toone E J Specificity of C-Glycoside Complexation byMannoseGlucose Specific Lectins Biochem 1996 35 3619-3624(b) Ravishankar R Surolia A Vijayan M Lim S Kishi YPreferred Conformation of C-Lactose at the Free and Peanut LectinBound States J Am Chem Soc1998 120 11297-11303
[7] (a)Wong C-H Halcomb R L Ichikawa Y and Kajimoto TEnzymes in organic synthesis Application to the problems ofcarbohydrate recognition part2 Angew Chem Int Ed Engl 199534 521-546 (b)Howard S Withers SG Bromoketone C-Glycosides a New Class of βminusGlucanase Inactivators J AmChem Soc 1998 120 10326-10331(c) Wang Q Wolff MPolat T Du Y Linhardt R J C-glycoside of Neuraminic Acidsas Neura-minidase Inhibitors Bioorg Med Lett 2000 10 941-944 (d) Phili R Chang J Partis R A Mueller R A ChrestF J Passaniti A The Alpha-glucosidase I InhibitorCastanospermine Alters Endothelial cell Glycosylation PreventsAngiogenesis and Inhibits Tumor Growth Cancer Res 1995 552927-2935
[8] Ossor A Elbein A D In Carbohydrates in Chemistry andBiology Vol 3(II) WileyVCH 2000 pp 513-539
[9] (a) Sinayuml P Synthesis of oligosaccharide Mimetics Pure ApplChem 1997 69 459-463 (b) Beau J-M Gallagher TNucleophilic C-glycosyl Donors for C-glycoside Synthesis Top inCurr Chem 1997 187 1-54 (c) Nicotra F Synthesis of C-glycosides of Biological Interest Top in Curr Chem 1997 187
Scheme (57)
O
O
O
Ph
I
OMe
OHO
BnO
OH
OH
BnOOH
O
BnO
Si
O
O O
Ph
I
OMe
O
O
BnO
OR4O
R5O
OMe
OR2
OR3O
R3O
OR1
R3O
Bu3 SnH AIBN
332 R1 R2 = SiMe2 R3 = Bn R4 R5 = CHPhTBAF THF
333 R1 = R2 = H R3 = Bn R4 = R5 = CHPh 37 from 11
334 R1 = R2 = R3 = R4 = R5 = H
335 R1 = R2 = R3 = R4 = R5 = Ac
329
H2 PdC MeOH
Ac2 O pyr
1 BuLi THF -78 oC
2 Me2SiCl2
3 DMAP
330
331
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1429
55-83 (d) Du Y Linhardt R Y Recent Adv in Stereo-SelectiveC-Glycoside Synthesis Tetrahedron Lett 1998 54 9913-9959 (e)Liu L Mckee M and Postema M H D Synthesis of C-saccharides and Higher Congeners Current Org Chem 2001 51133-1167
[10] Jarosz S Fraser-Reid B Synthesis of A Higher Carbon Sugar ViaDirected Aldol Condensation Tetrahedron Lett 1989 30 2359-2362
[11] Lichtenthaler F W Lergenmiiller M Schwidetzky S C-Glycosidations of 2-Ketohexosyl With Electrophilic Radical andNudeophilic Anomeric Carbons Eur J Org Chem 2003 3094-3103
[12] Baudat A Vogel P Aza-C-disaccharides Synthesis of 6-Deoxygalactonojirimycin-β-C(1rarr3) Linked with D-Altrofuranosides and D-Galactose J Org Chem 1997 62 6252-6260
[13] Turner D Vogel P Synthesis of 4-Hydroxy-26-Bis(hydroxymethyl) tetrahydropyran-2-Carbaldehyde DerivativesSynlett 1998 304-306
[14] Zhu Y-H Vogel P Short Stereoselective Synthesis of C-(1rarr3)-Linked Disaccharides Tetrahedron Lett 1998 39 31-34
[15] Zhu Y-H Vogel P Synthesis of a (2R 6R)-2-(Hydroxymethyl)-6-Propa-1 2-Dienyl-2H-Pyran-3(6H)-One Derivative A NewEnone for The Convergent Construction of C-Glycosides of C-Disaccharides Synlett 2001 82-86
[16] Baumberger F Vasella A Deoxynitrosugars The 6th
Communication Stereolectronic Control in the reductivedenitration of tertiary nitro ethers A Synthesis of ldquoC-glycosidesrdquoHelv Chim Acta 1983 66 2210-2221
[17] Martin O R Lai W Synthesis and Conformational Studies of β-(1rarr6)- and ββ-(1rarr1)-Linked C-disaccharides J Org Chem1993 58 176-185
[18] Spak S J Martin R The synthesis of an analogue of Methyl OC-Analogue of Methyl 4rsquo-O-β-D-GlucopyranosylgentiobiosideTetrahedron 2000 56 217-224
[19] Kobertz W R Bertozzi C R Bednarski M D C-GlycosylAldehyde Synthons for C-Linked Disaccharides J Org Chem1996 61 1894-1897
[20] Gurjar M K Nagaprasad R and Ramana CV First Synthesis ofMethyl α-C-D-Arabino-furanosyl-(1rarr5)-αminusD-Arabinofuranosidethe C-Disaccharide Segment of Motif C of MycobateriumTuberculosis Tetrahedron Lett 2000 43 7577-7579
[21] Witczak Z J Synthesis of C-Glycosyl Compounds and OtherNatural Products from Levoglucosenone Pure Appl Chem 199466 2189-2192
[22] Griffin F K Paterson D Taylor R J K Ramberg-BacklundApproaches to the Synthesis of C-Linked Disaccharides AngewChem Int Engl 1999 38 2939-2942
[23] Paterson B E Griffin F K Alcaraz M-L and Taylor R J KA Ramberg-Baumlcklund Approach to the Synthesis of C-GlycosidesC-Linked Disaccharides and C-Glycosyl Amino Acids Eur JOrg Chem 2002 1323-1336
[24] McAllister G D Paterson D E Taylor R J K A SimplifiedRamberg-Bachlund Approach to Novel C-Glycosides and C-Linked Disaccharides Angew Chem Int Ed Engl 2003 42 1387-1391
[25] McCartney J L Christopher T M Cicchillo R M BernardinaM D Wagner T R and Norris P J Org Chem 2003 6810152-10155
[26] Dondoni A Zuurmond H M Bascarate A Synthesis of α-andβ-D-(1rarr6)-C-Disaccharides by Witting Olefination of Formyl C-Glycosides with Glycopyranose 6-phosphoranes J Org Chem1997 62 8114-8124
[27] Dondoni A Kleban M Zuurmond H Marra A Synthesis of(1rarr6)-C-Oligogalactosides by Interative Wittig OlefinationTetrahedron Lett 1998 39 7991-7994
[28] Dondoni A Marra A A New Synthetic Approach toMycobacterial Cell Wall α-(1rarr5)-D-Arabinofuranosyl C-Oligosaccharides Teterahedron Lett 2003 44 4067-4071
[29] Colinas P A Ponzinibbio A Lieberknecht A and Bravo R OWittig Reaction of Glycosyl Phosphonium Salts A StereoselectiveRoute to C-Disaccharides and C O-Trisaccharides TetrahedronLett 2003 44 7985-7988
[30] Schmidt R R Preuss R Synthesis of Carbon Tetrahedron Lett1989 30 3409-3412
[31] Dietrich H Schmidt R R Synthesis of Carbon-Bridged C-Lactose and Derivatives Liebigs Ann Chem 1994 975-981
[32] Rouzaud D Sinayuml P The First Synthesis of a ldquoC-DisacchariderdquoJ Chem Soc Chem Commun 1983 1353-1354
[33] Xin Y-C Zhang Y-M Mallet J-M Glaudemans C P JSinayuml P Synthesis of C-Oligosaccharides That Mimie TheirNatural O-Analogues Immunodeterminants in Binding toMonoclonal Immunoglobulins Eur J Org Chem 1999 471-476
[34] Streicher H Geyer A Schmidt R R C-Disaccharides ofKetoses Chem Eur J 1996 2 502-510
[35] Leeuwenburgh M A Timmers C M Vander Marel G A VanBoom J H Mallet J-M Sinayuml P G Stereoselective Synthesisof α-C-(Alkynyl)-Glycosides Via Ring-Opening of α-12-Anhydrous Tetrahedron Lett 1997 38 6251-6254
[36] Aslam T Fuchs M G G Le Formal A Wightman R HSynthesis of C-Disaccharide Analogue of the α-D-Arabinofuranosyl-(1rarr5)-α-Arabinofuranosyl Motif ofMycobacterial Cells Walls via Alkynyl Intermediates TetrahedronLett 2005 46 3249-3252
[37] (a) Girad P Namy J L Kagan H B Divalent LanthanideDerivative in Organic Synthesis 1 Mild Preparation of SamariumIodide and Ytterbium Iodide and Their Use as Reducing orCoupling Agents J Am Chem Soc 1980 102 2693-2698 (b)Molander G A Harris C R Sequencing Reactions withSamarium(II) Iodide Chem Rev 1996 96 307-338
[38] (a) Mazeacuteas D Skrydstrup T Doumeix O Beau J-MSamarium Iodide-Induced Intramolecular C-Glycoside FormationEfficient Radical Formation in the Absence of an Additive AngewChem Int Ed Engl 1994 33 1383-1386 (b) Mazeacuteas DSkrydstrup T Beau J-M A Highly Stereoselective Synthesis of1 2-trans-C-Glycosides Via Glycosyl Samarium(III) CompoundsAngew Chem Int Ed Engl 1995 34 909-912 (c) Jarreton OSkrydstrup T Beau J-M The Stereospecific Synthesis of Methylα-C-Mannobioside A Potential Inhibitor of M TuberculosisBinding to Human Macrophages J Chem Soc Chem Commun1996 1661-1662 (d) Jarreton O Skrydstrup T Espionosa J-FJimeacutenez-Barbero J Beau J-M Samarium Diiode Prompted C-Glycosylation An Application to The Stereospecific Synthesis ofα-(1rarr2)-C-Mannobioside and Its Derivatives Chem Eur J 19995 430-441 (e) Mipuel N Doisneau G Beau J-M ReductiveSamariation of Anomeric 2-Pyridyl Sulfones with Catalytic AnUnexpected Improvement in The Synthesis of 12-Trans-Diequatorial C-Glycosyl Compounds Angew Chem Int Ed Engl 2000 39 4111-4114
[39] Vlahov I R Vlahova P I Linhardt R J DiastereocontrolledSynthesis of Carbon Glycosides of N-Acetylneuraminic Acid ViaGlycosyl Samarium(III) Intermediates JAmChem Soc 1997 1191480-1481
[40] Kuberan B Sikkander S ATomiyama H Linhardt R JSynthesis of a C-Glycoside Analogue of sTn An HIV-and Tumor-Associated Antigen Angew Chem Int Ed Engl 2003 42 2073-2075
[41] Bazin H G Du Y Polat T Linhardt R J Synthesis of aVersatile Neuraminic Acid ldquoCrdquo-Disaccharide Precursor for theSynthesis of C-Glycoside Analogues of Gangliosides J OrgChem 1999 64 7254-7259
[42] Chen C-C Ress D K Linhardt RJ Samarium Iodide-Mediated Synthesis of Neuraminic Acid C-Glycosides InSynthesis of Glycommetics Roy R Ed ACS Syposium Series2004 896 53-80
[43] Abdallah Z Doisneau G Beau J-M Synthesis of a Carbon-Linked Mimic of The Disaccharide Component of The Tumor-Relate SialyTn Antigen Angew Chem Int Ed Engl 2003 425209-5212
[44] Lay L Nicotra F Panza L Russo G Caneva E Synthesis ofC-disaccharides through dimerization of exo-glycals J Org Chem1992 57 1304-1306
[45] Isobe M Nishizawa R Hosokawa S Nishikawa TStereocontrolled Synthesis and Reactivity of Sugar Acetylenes JChem Soc Chem Commun 1998 2665-2676
[46] Saeeng R Sirion U Sahakitpichan P Isobe M IodineCatalyzes C-Glycosidation of D-Glucal with SilylacetykeneTetrahedron Lett 2003 44 6211-6215
[47] (a) Babirad S A Wang Y Kishi Y Synthesis of C-Disaccharides J Org Chem 1987 52 1370-1372 (b) Wang YBabirad S A Kishi Y Preferred Conformation of C-Glycosides
1430 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
8 Synthesis of 14-Linked Carbon Disaccharides J Org Chem1992 57 468-481
[48] Armstrong R W Sutherlin D P Strategies for the Synthesis ofC-Disaccharides Containing D and L Sugars Tetrahedron Lett1994 35 7743-7746
[49] Wei A Kishi Y Preferred Conformation of C-Glycosides 12Synthesis and Conformational Analysis of αα- α β- and β β-Trehaloses J Org Chem 1994 59 88-96
[50] Haneda T Goekjian P G Kim S H Kishi Y PreferredConformation of C-Glycosides 10 Synthesis and ConformationAnalysis of Carbon Trisaccharides J Org Chem 1992 57 490-498
[51] Sutherlin D P Armstrong R W Synthesis of 12 Stereochemistryand Structurally Diverse C-Trisaccharides J Org Chem 1997 625267-5283
[52] Notz W Hartel C Waldscheck B Schmidt R R De NovoSynthesis of a Methylene-Bridged Neu5Ac-α-(23)-Gal C-Disaccharide J Org Chem 2001 66 4250-4260
[53] (a) Postema M H D Calimente D Liu L Behrmanm T L AnOlefin Metathesis Route for the Preparation of (1rarr6)-Linked-C-Disaccharide Glycals A Convergent and Flexible Approach to C-Saccharide Synthesis J Org Chem 2000 65 6061-6068(b) Postema M H Piper J L Liu L Faust M Andreana PSynthesis and Partial Biological Evaluation of a Small Library ofDifferentially Linked β-C-Disaccharide J Org Chem 2003 684748-4754
[54] Nelson A The Development of Strategies and Methods for TheSynthesis of Biologically Active Compounds New J Chem 200428 771-776
[55] Togo H He W Waki Y Yokoyama M C-GlycosylationTechnology With Free Radiant Reactions Synlett 1998 700-717
[56] Giese B Dupuis J Diastereoselective Synthesis of C-Glycopyranosides Angew Chem Int Ed Engl 1983 22 622-623
[57] Adlington R M Baldwin J E Basak A Kozyrod RPApplication of Radical Addition Reactions to tho Synthesis of a C-Glucoside and A Functionalized Amino Acid J Chem SocChem Commun 1983 144-145
[58] Giese B Gonzaacutelez-Goacutemez J A Witzel T The Scope of RadicalCC-Coupling by The ldquoTin Methodrdquo Angew Chem Int Ed Engl1984 23 69-70
[59] Giese B Witzel T Synthesis of ldquoC-Disaccharidesrdquo by RadicalC-C Bond Formation Angew Chem Int Ed Engl 1986 25 450-451
[60] Witczak Z J Chhabra R Chojnacki J C-Disaccharides IStereoselective Approach to β-(1rarr4)-3-Deoxy-C-Disaccharidesfrom Levoglucosenone Carb Res 1997 301 167-175
[61] Vogel P Synthesis of Rare Carbohydrates and Analogues Startingfrom Enantiomerically Pure 7-Oxabicyclo[221]heptyl Derivatives(ldquoNaked Sugarsrdquo) Current Org Chem 2000 4 455-480
[62] Viodeacute C Vogel P Synthesis of The C-Disaccharide α-C(1rarr3)-L-Fucopyranoside of N-Acetylgalactosamine J Carb Chem2001 20 733-746
[63] Xin Y C Mallet J M Sinayuml P An Expeditious Synthesis of AC-Disaccharide Using A Temporary Silaketal Connection J ChemSoc Chem Commun 1993 864-865
[64] (a) Petitou M Herault P Lormeau J-C Helmboldt A MalletJ-M Sinayuml P Herbert J-M Introducing A C-InterglycosidicBond in A Biologically Active Pentasaccharide Hardly Affects ItsBiological Properties Bioorg Med Chem 1998 6 1509-1516 (b)Sinayuml P Advances in The Synthesis of the Carbohydrate MimicsPure Appl Chem 1998 70 1495-1499
[65] Sinayuml P Chemical Synthesis of Oligosaccharide Mimetics PureAppl Chem 1998 70 407-410
[66] Sinayuml P Chemical Synthesis of Oligosaccharide Mimetics PureAppl Chem 1998 69 459-463
[67] Vauzeilles B Sinayuml P Selective Radical Synthesis of β-C-Disaccharides Tetrahedron Lett 2001 42 7269-7272
1396 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (5)
Scheme (6)
OO
O
Me2AlSPh OAlMe2O
O
SPh
O
OH
O
O
OO
O
OH
SPh
OH
O
HO
HO
OMeOH
OMe
HO
O
O
SPhO
O
O
OO
H
HO
HO
OO
O
SPhO
O
OO
HOH
DIBAL
MeOHTsOH
50 o C
16 17
18
19
2021
OO
bull
OR
O
CHOOMe
OO
NaBH4
OOH
bull
OR
OOMe
OO
OH
OO
bull
OR
OOMe
OO
HO
OO
bull
OR
OOMe
OO
OH
Me2AlSPh -78 degC
R = (t-Bu)Me2Si
22
23
24 15
+
25 2926 77
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1397
Scheme (7)
Scheme (8)
An open chain sugar derived aldehyde was used to accessa C-trehalose derivative through the Henry reactionCondensation of 36 with aldehyde 41 in the presence of KFand crown ether 18-crown-6 gave adduct 42 which wasimmediately converted to 43 with a sequence of reactions in29 overall yield The intermediate was finally transformedto the C-linked-(1rarr1)-disaccharide 44 (C-ββ-trehalose)(Scheme 10) [17]
Martin and coworkers applied the same methodologyto prepare an OC-trisaccharide namely methyl O-β-D-glucopyranosyl-(1rarr4)-C-β-D-glucopyranosyl-(1rarr6)-D-
glucopyranoside 48 [18] The condensation of compound 45with 6-aldehydo-glucopyranoside 46 in the presence of KFin an aprotic medium afforded the desired pseudotri-saccharide 47 in 73 yield Application of the samechemistry to 47 gave the target compound 48 (Scheme 11)
Kobertz and coworkers utilized Martinrsquos methodology toprepare C-allolactose Nitro sugar 49 was condensed withaldehyde 50 afforded the adduct 51 as a mixture ofdiastereomers The hydroxyl group was converted to thecorresponding phenyl thiocarbonate ester 52 Treatment withtin hydride and a radical initiator effected elimination
OO
OR OR
O SiMePh
O
HO
PhMe2SiZnMe2 Li
O
TBSO
TBSO
OTBS
OTBS
H
O
O
OR
SiMePh
TBSO
OTBS
OTBS
OH
HOHO
TBSO
O
O
TBSO
TBSO
OTBS
OTBS
OH
H
O
OR
SiMePh
Me4NBH(OAc)3
R = (t-Bu)Me2Si
+
1 THF -78 oC
2 NH4Cl H2O
3 HCl H2O 20 oC
1 (c-hex) 2BCl Et3N
2
27
28
29
30 24 over 2 steps31 59
O
O
O
O O
NO2
TBAF
O
OH
OO
OO
O
O
OO O
NO2
OO
O
OO
OH
O
O
OO O
OO
O
OO
H
OAc
32
3334 78
1 Ac2O Pyr2 Bu3SnH AIBN
35 89
1398 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
reaction yielding only E-olefin 53 Finally the olefin wasreduced with dimide (generated in situ) and benzyl etherswere removed by dissolving metal reduction to afford thetarget disaccharide 54 (Scheme 12) [19]
Gurjar et al synthesized the first methyl α-C-D-araf-(1rarr5)-α-D-araf 60 the C-disaccharide segment of motif Cof Mycobacterium tuberculosis through nitro-aldol conden-
sation The coupling reaction between 55 and 56 gavediasteromeric mixture 57 which was subjected to threesubsequent steps ie dehydration selective reduction ofconjugated olefin and denitration to give the penta-O-benzylC-disaccharide 59 (Scheme 13) [20]
Witczak has used nitro anions for C-disaccharidesynthesis Michael addition of the nitro anion derived from
Scheme (9)
Scheme (10)
OAcO
AcOOAc
OAc
NO2O
OH
O
O
OO
OHO
HOOH
OH
O
HO
HOOH
OH
Bu3 SnH
OAcO
AcOOAc
OAc
NO2
OO
O
OO
OH
OAcO
AcOOAc
OAc
X
OO
O
OO
KF 18-C-6 MeCN
1 Ac2O Pyr2 NaBH4 EtOH
38 X = NO 2
39 X = H 57
1 NaOMe
2 H3O+
36
33
37
40 89 over 2 st eps
CHO
O
O
O
O
CH2OPiv
OAcO
AcOOAc
OAc
NO2
OHO
HOOH
OH
O OH
OH
HO
OH
OAcO
AcOOAc
OAc
NO2
PivO
OH
O
O
O
O
OAcO
AcOOAc
OAc
NO2
PivO
O
O
O
O
1 Ac2O Pyr2 80 AcOH3 Ac2O Pyr
1 AcOH
2 Ac2O-BF3 OEt
KF 18-C-6 MeCN
41 36
42
4344
3 Bu3SnH AIBN
4 NaOMe
5 H3O+
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1399
61 to levoglucosenone 62 gave adduct 63 in 43 yield Thesterics in 62 dictates the facial bias of the addition whichcan only occur from the α-face Reductive denitrationfollowed by reduction of lactol and ketone afforded 64 Ringopening deprotection and acetylation gave 65 (Scheme 14)[21]
23 Sulfur Stabilized Anions
The Taylor group employed the Meyers variant of theRamberg-Baumlcklund reaction to synthesize C-disaccharides[22] The penta-O-benzyl thioglucose 66 was coupled withiodide compound 67 followed by oxidation of the formedsulfide gave sulfone 68 Exposure of the sulfone to theMeyers variant of the Ramberg-Baumlcklund reaction affordedexo-glycal 69 as a mixture of isomers in 48 yieldHydrogenation of this mixture stereoselectively reduceddouble bond and cleaved the benzyl groups Peracetylated C-
trehalose 70 was furnished by acetylation of free sugar(Scheme 15)
This approach is well suited to analog synthesis simplyby varying the alkylating agent Thus the homologous(1rarr1rsquo)-C-disaccharide containing a two-carbon bridge(ldquohomoisotrehaloserdquo) was readily prepared (Scheme 16)[23] Lactol 71 was converted into sulfonate 74 by astraightforward three-step sequence involving Moffat-typeC-glycosylation to give ester 72 followed by reduction andmesylation Next 74 was coupled with thiol 75 in a similaralkylation-oxidation sequence to that above The resultingsulfone 77 underwent a halogenative Ramberg-Baumlcklundrearrangement (RBR) to give exo-glycal 78 as a 8812mixture of (Z)- and (E)-isomers in 57 yield Subsequentreductiondebenzylation followed by acetylation producedthe novel ethylene-bridged disaccahride 79
Scheme (11)
Scheme (12)
OBnO
OBnOMe
BnO
NO2
OBnO
OBn
BnO
OBn
CHO
OHO
OH
HO
OH
OHO
OHOMe
HO
OBnO
OBn
BnO
OBn
OBnO
OBnOMe
BnO
NO2R
OBnO
OBn
BnO
OBn
OBnO
OBnOMe
BnO
KF 18-C-6 MeCN+
1 n-BuLi2 PTC-Cl
51 R = OH
52 R = OC(S)OPh
Bu3 SnH AIBN
1 TsNHNH NaOAc
2 Na NH3
49
50
5354
OAcO
OAc
AcOO
OAcO
OAc
OAc
NO2OAc
OAc
AcO
OAcO
BnOOBn
OMe
BnO
OO
AcOOAc
OAc
OAcO
OMe
BnO O
BnOOBn
O
OO
AcOOAc
OAc
NO2
OAcO
OAc
AcO
OAcO
BnOOBn
OMe
BnO
OH
KF 18-C-6 MeCN
1 Ac2O Pyr2 NaBH4 EtOH3 Bu3SnH AIBN4 H2 Pd(OH)2
5 NaOMe MeOH
45
46
47
48
1400 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
This group also reported a rapid synthesis of a range ofC-disaccharides involving a tandem Horner-Wadsworth-Emmons (HWE)conjugate-addition C-glycosylation followedby a tandem halogenation-RBR sequence utilizing Meyersvariant of the RBR [24] The HWE reagent 81 proceeded theHWEconjugate-addition sequence with diisopropylidenemannofuranose 80 in 86 yield to produce the adductsulfone 82 (as a mixture of diastereomers) The keyhalogenation-RBR was carried out using the conditions
devised by Chan et al giving E-alkene 83 as the onlyisolable product Alkene hydrogenation and concomitantdebenzylation followed by acetylation for characterizationpurposes gave the novel disaccharide 84 in 69 yield overthe two reactions (Scheme 17)
A two-directional variant of this methodology can beused to prepare symmetrical C-disaccharides as shown inScheme 18 [24] The double HWE reaction on diisopro-pylidene mannofuranose 80 worked extremely well in the
Scheme (13)
Scheme (14)
BnO
OBn
O2N
OMe
O
CHO
OBnO
OBn
BnO
OMe
OHO
OH
OHO
OH
HO
OMe
OBnO
OBn
OBnO
OBn
BnO
HO
NO2
OMe
OBnO
OBn
OBnO
OBn
BnO
X
+
KF 18-C-6 MeCN
1 Ac2O Pyr2 NaBH4 EtOH
58 X = NO 2
59 X = H 44 over 3 st eps
Bu3SnH AIBN
Pd(OH)2 H2
rt 1 atm 24 h
40
60 74
55
56
57
O
BnOOBn
BnO
OBn
OH
O
OHNO2
O
O
BnOOBn
BnO
OBn
OH
O
ONO2
O
O
O
O
O
AcOOAc
AcO
OAc
O
OAc OAc
OAc
O
BnOOBn
BnO
OBn
NO2OH
Et3 N MeCN
1Bu3 SnH AIBN
2 BF OEt Et3SH
3 L-SelectrideTHF
64 61 in 3 steps
1 Pd(OH)2 C6 H10
2 Ac2O TESOTF
61 63 43
62
65
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1401
HWEconjugation-addition C-glycosydation sequence givingdiastereomeric sulfones 85 in a combined yield of 75RBR of the major stereoisomer (βα-79) using the Meyers-
Chan procedure gave alkene 86 in 66 unoptimized yieldand hydrogenation produced the novel C-linked bisfuranosedisaccharide 87 in 76 yield
Scheme (15)
Scheme (16)
OBnO
BnO
H
OBn
OH
OOBn
BnO
OBn
OBn
BnO
OBn
OBn
OBnO
BnO
OBn
OH
SO2
O
OBn
O O
AcO
AcO
AcO
OAc
OAc
OAc
OAc
OAc
OBnO
BnO
OBn
OH
I
O
HS
OBn
BnO
OBn
OBn
68 90 over 2 steps
KOH CCl4 t-BuOH H2O
1 H2 PdC
2 Ac2O Pyr
70 69 over 2 steps
+
1 K2CO3
2 mCPA66
67
69
O
BnOOBn
BnO
OBn
OH
(EtO)2P(O)CH2CO2Et
OBn
OBn
OBnO
OBn
OBnO
BnOOBn
OBn
X
O OBn
OBn
BnOOBn
OBnO
BnOOBn
OBn
OBnO
BnOOBn
OBn
R
OBnO
BnOOBn
OBn
SH
LiAlH4
OAc
AcOOAc
O OAcOAcOAcO
OAc
OAc
1 H2 Pd(OH)2C
2 Ac2 O Pyr
NaH THF
72 R = CO2Et
73 R = CH2OH
66 over 3 steps
K2CO3 acetone
76 X = S
77 X = SO2 79
Oxone THF MeOH H2 O
KOH CCl4 aq tBuOH
78 57ZE 8812
79
71
75
MsCl Et3N 74 R = CH2 OMs
1402 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Norris et al deprotonated 88 with n-BuLi and theresulting anion was coupled with an excess lactone 89 at lowtemperature to afford the adduct 90 in 77 yield SPhgroups were removed with Raney nickel and lactol 91 wasisolated as a syrup that contained two components in
approximately a 41 ratio The two compounds were thoughtto be α- and β-lactols with the latter being major It wasstraightforward to reduce the lactols with a high degree ofstereocontrol to afford the C-disaccharide 92 with a 51isolated yield (Scheme 19) [25]
Scheme (17)
Scheme (18)
O
O O
O
O OH
O OMe
OBnBnO
SO2
P
EtO
EtO
O
OBn
O
OMe
OAc
OAc
OAcO
O O
O
O
O
OO OMe
OBnBnO
SO2
OBn
O
O O
O
O O
O
O
O
OMe
OBn
OBn
OBn
83 50 E only
80
+
NaH THF -78 oC
82 86αβ 11
KOHAl2O3
CBr2F2 CH2Cl2
tBuOH 5 oC
2 h
1 H2PdC EtOAc RT 7h
2 Ac2 O Pyr RT
84 69 over 2 st eps
81
O
O O
O
O OH POEt
OEt
O
SO2
P
EtO
EtOO
O
O
O
OO
O
O
O
O O
O
O
O O
O
O
O
O SO2
O
O
O
O
O
O O
O
OO
O
O
85 75βαββ ca 31
86 66β αββ = 141 E only
H2PdC EtOAc
87 76βαβ β = 141
21 NaH THF -78 o C
80 (2 equiv)
KOHAl2O3CBr2F2 CH2Cl2tBuOH
on majorβα is omer
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1403
24 Phosphorous Stabilized Anions
The most common type of reaction discussed in thissection is Wittig approach to C-oligosaccharide synthesisThis methodology is particularly suited for synthesis of(1rarr6)-C-saccharides since one sugar can hold the aldehydewhile the other the ylid or phosphonate anion
Dondoni has utilized this approach to prepare a variety ofβ-D-(1rarr6)-C- disaccharides The general approach is shownin Scheme 20 Coupling of β-linked galactopyranosyl ormannofuranosyl derivative (93 94 95 or 96) with ylidefrom phosphonium iodide 97 or 98 gave alkene 99 Alkenewas reduced and removal of deprotecting groups gave thecorresponding β-D-(1rarr6)-C- disaccharide 100 [26]
α-D-(1rarr6)-C-disaccharide 103 was also synthesizedusing the approach (Scheme 21)
Dondoni applied this methodology in an iterative fashionto prepare the corresponding β-(1rarr6)-C-trigalactosides andβ-(1rarr6)-C-tetragalactosides [27] Starting with coupling ofylide 104 generated in situ with aldehyde 33 gave adduct105 (EZ 19) Removal of silyl protecting group followed byoxidation led to aldehyde 106 which was coupled with theylide from 104 to give C-trisaccharide 107 in 36 yield Thesame sequence was repeated with 107 afforded the protectedC-tetrasaccharide alkene 108 Compounds 108 wasdesilylated and exposed to hydrogen over Pd(OH)2 oncarbon followed to peracetylation gave protected C-tetrasaccharide 109 (Scheme 22)
Taking advantage of their experience on the stereo-selective synthesis of C-oligosaccharides by iterative Wittigolefination this group developed new building blocks and amodified protocol for the straightforward assembly of C-α-(1rarr5)-D-oligoarabinofuranosides [28] While the twomonofunctionalized sugar moieties 110 and 111 weresuitable precursors to the head and tail of the oligo-saccharidic chain the difunctionalized compound 114 was arepeating unit (Scheme 23) Building block 114 wasdesigned to allow after the Wittig coupling for regenerationof the formyl group in a single step under conditions that donot affect the chemical and stereochemical integrity of thegrowing saccharidic chain (Scheme 24)
Colinas et al reported a method for the synthesis of C-disaccharides by a sequence involving the Wittig reaction askey step and further glycosydation of these compounds toafford new C O-trisaccharides [29] The enol ether 122a-bwere prepared by the Wittig reaction of the α β mixture of2-deoxiglycosyl phosphonium salts 120a-b with aldehyde121 Hydrogenation of the exo-glycals afforded the β-C-disaccharides with good yields The O-glycosidationemploying the exo-glycals and the glycosyl acceptor 124 isillustrated in Scheme 25
25 C-1 Vinyl Anions
Schmidt was the first to explore the addition of sulfoxide-stabilized vinyl C-1-organolithiums to carbohydrate-basedcarbonyl compounds [30] The vinyl sulfoxide 126 was
Scheme (19)
OCH3
O O
OPhS
PhS
O O
OO
OCH3
O O
OO O
O H
OCH3
O O
OPhSPhS
O O
O OH
OCH3
O O
OO O
O OH
+
n-BuLi THF -78 oC
Raney Ni EtOH H2O rt
Et3SiH BF3 OEt2
90 77
92 51 over 2 steps 91 is omers rati o βα = 41
-78 oC
88
89
1404 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
deprotonated with LDA to give 127 Addition of 127 toaldehyde 128 gave a mixture of diastereoisomers of whichthe major 129 was formed in a 101 ratio Desulfurizationhydroboration and removal of benzyl groups gave the(1rarr5)- βminusC-disaccharide 130 (Scheme 26)
Schmidt and coworkers used this methodology for ahighly efficient synthesis of an analog of C-trehalose 134Scheme 27 [31] Anion 131 was converted to aldehyde 132
and condensation of this aldehyde with the same anion gaveadduct 133 which was then converted to the target C-disaccharide 134
26 Acetylide-Based Anions
Sinayuml was the first to prepare a C-disaccharide Hisapproach involved the coupling of a C-6 alkyne with ananomeric lactone followed by reduction of the formedhemiacetal [32] Aldehyde 135 was converted to the
Scheme (20)
Scheme (21)
OO O
O
O CHO
O
BnOOBn
BnO
OBn
CHO
OBn
CHO
BnO
O
BnOBnO
O
BnOOBn
BnO OBn
CHO
PPh3I-
OO
O
OO
O
OMeOBn
OBn
OBn
PPh3I-
OCHO
O
PPh3I-
ORRO
RO
OO
ORRHO
OO
OR
+ +
+
( 93 - 96 )
( 97 - 98 )
BuLi THF-HMPA
-30 iexclaelig
99
Reduction
100
+
93 9495
96 97 98
O
OBnBnO
BnO
OO
O
OO
HO
O
O
OO
PPh3I-
O
OHHO
HO
O
HOOH OH
HO
OBnBnO
CHO
BnO
O
+
BuLi THF-HMPA
-30 oC
1 p-MeC 6H4SO2-
NH2NH2 AcONa
2 H2 Pd(OH)2 3 bar
3 Amberli te H+
+
10197
102
103
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1405
dibromoalkene 136 which was treated with n-butyllithium togive an intermediate acetylide 137 The latter uponnucleophilic addition to lactone 138 gave a mixture of lactol139 in high yield Stereoselective reduction of lactol 139 wasfollowed by hydrogenation of benzyl groups and the triplebond affording the (1rarr6)-β-C-disaccharide 140 (Scheme28)
The lactone-addition methodology was later applied bySinayuml and co-workers in an iterative fashion for the
preparation of higher homologues [33] Hydroxylmethylenein compound 141 was converted to acetylide lithium incompound 142 by a sequence of reactions Condensation ofcompound 142 with the galacto lactone 143 gave 144 asmixture of anomers The lactol were stereoselectivelyreduced to and triple bond was hydrogenated to give 145Methyl glycoside 145 was hydrolyzed to the correspondinglactols which were oxidized to lactone 146 The samesequence was then repeated twice to give C-trisaccharide147 and C-tetrasaccharide 148 (Scheme 29)
Scheme (22)
O
BnOOBn
BnO OTBDPS
PPh3I-
BnO
H
O
BnOOBn
OTBDPS
OO
O
OO
O
CHOO
O
OO
O
BnO
O
BnOOBn
BnO
OO
O
OO
H
HOBn
BnO OTBDPS
O
BnOOBn
BnO O
OO
O
OO
H
OBn
BnO OTBDPS
PPh3I-
O
BnO
O
BnOOBn
BnO OTBDPS
PPh3I-
O
AcOOAc
AcO
O
AcOOAc
AcO
OO
O
OO
O
AcOOAc
AcO OAc
O
BnOOBn
BnO
O
BnOOBn
BnO
OO
O
OO
H
H
O
BnOOBn
BnO OTBDPS
H
1 TBAF2 PCC
+107 36
+
1 TBAF2 PCC3
+
1 TBAF2 H2 Pd(OH)2 C3 Ac2 O Pyr
104
33
105
106104
104
108109
BuLi THF-HMPA
-50 o C
70EZ 19
BuLi THF-HMPA
-50 o C
1406 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
The di- tri- and tetrasaccharide derivatives (145 147 and148) were all debenzylated and tested for their bindingaffinity to three different monoclonal immunoglobulins withspecificity for different O-β-(1rarr6)-D-galactopyranosyl deter-minants These C-saccharide analogs had similar bindingproperties to the corresponding O-saccharides
Schmidt has also used acetylide-lactone condensation toassemble C-disaccharides of ketoses [34] Lithium acetylide149 was condensed with ketone 150 to give a mixture ofalcohol 151 after removal of the pivoloyl group Attemptedcyclization under Lewis acid catalysis resulted only in theremoval of the acetonide Accordingly the diol was tiedback as the carbonate and the acetylene complex as thedicobalt species 152 The isomers were then separately
cyclized to give a 11 mixture of C-disaccharide 153 Thecobalt complex on α-C-disaccharide was removed understandard conditions to give 154 and deprotection of thecarbonate was followed by hydrogenation and peracetylationto give 155 (Scheme 30) Similar chemistry was also carriedout with the corresponding β-isomer
Van Boom and co-workers used lithiated alkynylderivative 156 in presence of ZnCl2 to selectively open ringof the 12-anhydrosugar 157 affording the α-C-(alkynyl)-glycoside 158 Hydrogenolysis of the benzyl groups wasfollowed by peracetylation to give the (1rarr6)-α-C-disaccharide 159 (Scheme 31) [35]
Normally attack of the nucleophile proceeds from anequatorial direction to give the β-isomer The unexpected
Scheme (23)
Scheme (24)
BnOO
OBnCHO
OBn
O
OBn
PPh3I-
OBn
OBn
O
OBn
BnOBnO
O
OBnOBn
OBnH
O
OH
HOHO
O
OHOH
OH+
BuLi
THF-HMPA
-20 oC+
1 TBAF2 H2 Pd(OH)2C
112 65 113 100
110
111
O
OBnCHO
OBnBnO
O
OBn
BnOBnO
O
OBnCH(OiPr)2
OBnH
O
OBnCH(OiPr)2
PPh3I-
OBn
O
OBn
BnOBnO
O
OBn
OBnH
O
OBnOBn
BnOH
O
OH
HOHO
O
OH
OH
O
OHOH
HO
++
BuLi
THF-HMPA
-20 oC
BuLi
THF-HMPA
-20 oC
TFA H2 O THF rt
115 49
116 R = CH(OiPr)2
117 R = CHO
118 45
H2 Pd(OH)2C
110
114
114
119
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1407
Scheme (25)
Scheme (26)
OBn
R1
R2
PPh3BF4-O
O
OOHC
O
O
O
O
O
O
O
O
HO
O
O
O
O
O O
OBn
R1
R2
O
O
O
O
O
O
H
O
OBn
R1
R2
O
O
O
O
O
O
O
O
OBn
R1
R2
O
O
O
+
BCl3 (005 equiv)
MS 4A CH2 Cl2 0 o C
+
BuLi THF -90 oC -90 o C
to rtH2 (1 atm) PdC Et3N MeOH
R1 R2 = OBn H
120a - b
121
122a - b
123a - b
124
125a - b
OTBDPS
BnO X
SO Ph
O
BnO
OHCO
BnO
OMeOBn
OBn
O
BnO
OTBDPS
BnO
SO Ph
O
BnO
OMeOBn
OBn
O
HO
OMeOH
OHO
HOHO
OH
OH
128
229 74
1 RaNi (74)
2 BH3 DMS
NaOH H 2O2 (74)
3 H2 PdC (70)
130 74
LDA THF
-100 oC
126 X = H
127 X = Li
1408 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (27)
Scheme (28)
stereochemical outcome is rationalized by the generation ofan initial zinc acetylide species which facilitates intra-molecular delivery to the α-face (Scheme 32)
Wightman synthesized C-disaccharide analogs of the α-D-arabinofuranosyl-(1rarr5)-α-D-arabinofuranosyl motif ofmycobacterial cell walls through alkynyl intermediates [36]The lactone 164 was treated with lithio(trimethylsilyl)ethyneat low temperature to give lactol in 66 yield of 165Treatment of this with triethylsilane and BF3
Et2O gavethe separable isomers 166α (60) and 166β (13)Desilylation of the major isomer 166α gave 167 in 97yield Treatment of 167 with n-BuLi followed by addition oflactone 164 gave 85 yield of the hemiacetal 168 which onreduction with Et3SiH and BF3
Et2O gave the disubstitutedalkyne 169 (83) as the major product Reduction-
hydrogenolysis of 169 then gave the C-disaccharide 170 innear-quantitative yield (Scheme 33)
3 REDUCTIVE GLYCOSYL SAMARIUM SPECIES
The introduction of SmI2 as reducing agent can becredited to Kagan and has since been utilized in numeroussynthetic schemes [37] Sinayuml and Beau introduced SmI2
chemistry into C-glycoside synthesis through intermolecularreactions with appropriate electrophiles and intramolecularreactions of silyl tethered substrates [38] Anomericsamarium species are highly stable and not likely to undergoβ-elimination Treatment of the aryl sulfone 171 with SmI2
affords the nucleophilic intermediate 172 through two singleelectron transfer processes Introduction of a suitableelectrophile (carbonyl compounds) affords the α-C-manno-
O
BnO
OTBDPS
BnO X
SO Ph
O
BnO
OBn
BnO Li
SO Ph
DMF
OHO
HOOH
OH
O OH
OH
HO
OHOH
O
BnO
OTBDPS
BnO
SO Ph
O
OBn
OBnOBnSO
Ph
OH
131 X = Li
132 X = CHO
THF -100 oC
1 Ra-Ni
2 BH3 DMS NaOH H2O2
3 H2 PdC
131
133
134
OBnO
OBnOMe
BnO
Li
OBnO
BnOOBn
OBn
OOBn
OBnOMeBnO
OH
OBnO
BnOOBn
OBn
O
n-BuLi
BnO
OMe
BnO
BrBr
O
OBn
OHO
OH
OH
HO
OHO
OH
HO
OMe
O
BnO
OMeOBn
O
BnO
139 92
1BF3 OEt2 EtOH
2 H2 PdC AcOH
140 52 over 2 steps
135 136 137
138
CBr4 PPh3
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1409
pyrannoside 173 in good yield and with excellent stereo-selectivity (Scheme 34) [38a]
Preparation of C-glycosides of ulosonic acids using SmI2
was pioneered by Linhardt and coworkers [39] Coupling ofpyridyl sulfone 174 with aldehyde 175 in the presence ofSmI2 gave an excellent yield of the N-acetylneuraminic acidC-disaccharide 176 as single isomer This stereochemicaloutcome was rationalized on the basis of the Felkin-Anhmodel for predicting the stereochemical outcome of akinetically controlled addition of a nucleophile to a chiraladehyde (Scheme 35 A)
Reductive samarium method was utilized to synthesizesialo-antigen C-analogs by the Linhardt group A fullyprotected C-analogue of the SialylTn antigen α-D-Neu5Ac-(2rarr6)α-D-GalNAc-(1rarrO)-Ser 182 was prepared [40] C-glycosylation of the neuraminic acid sulfone donor with
aldehyde acceptor in presence of excess SmI2 afforded the α-C-glycoside 180 as an RS mixture (11) The criticalintermediate aldehyde acceptor 178 was prepared in 13steps Chemoselective resolution to compound 180 wasundertaken by oxidation with DMSOAc2O to keto-bridgedcompound 181 followed by stereoselective reduction withZn(BH4)2 to regenerate the bridge hydroxyl function gave182 in gt90 de (Scheme 36)
A common versatile N-acetylneuraminic acid C-disaccharide precursor of the C-glycoside analogs ofgangliosides GM4 and GM3 has been synthesized [41]Samarium(II) iodide coupling of N-acetylneuraminic acidsulfone 179 with a 3-formyl galactopyranoside derivative183 afforded the corresponding C-disaccharide 184 as amixture of (R) and (S) isomers at the newly formedhydroxymethylene bridge This diastereoisomeric mixturewas resolved after debenzylation of the galactoside residue
Scheme (29)
O
BnO
BnOOBn
OBn
OOBn
OBnOMe
OBnOH
O
BnO
BnO
OBn
OBn
O
O
BnOOBn
OMe
BnO
Li
OBnO
OBn
OBn
OBnO
OBn
OBn
OMe
OBnO
OBn
OBnBnO
OBnO
OBn
OBn
OBnO
OBn
OBn
OMe
OBnO
OBn
OBnOBnO
OBn
OBnBnO
O
BnO
BnO
OBn
O
OBnO
OBn
OBnBnO
OBnO
OBn
OBnBnO
OBnO
OBn
OBn
OMe
OBnO
OBn
OBnBnO
OMe
1 PCC2 CBr4 Ph3P3 n-BuLi
144 overall yield 54
1 BF3 OEt2 Et3 OH
2 H2 PtO2 EtOAc
145 76
1 H2 SO4 AcOH
2 PCC
146 62
repeat steps
repeat st eps
141 142
143
147
148
1410 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (30)
Scheme (31)
O
BnOOBn
OMe
Li
BnO
OPivBnO
OBn
OBn
BnO
O OO
BF3 OEt2
OBnO
OBn
OBn
BnO
OO
O
OMe
BnOOBn
BnO
Co(CO)3
Co(CO)3
O
CAN
OBnO
OBn
OBn
BnO
OO
OO
BnOOBn
BnO
OMe
OHBnO
OBn
OBn
BnO
OHO
O
O
OMe
BnOOBn
BnO
Co(CO)3
Co(CO)3
O
OPivBnO
OBn
OBn
BnO
OH OO
O
OMe
BnOOBn
BnO
OAcO
OAc
OAc
AcO
OAcOAc
OAcO
OAc
AcO
OMe
1
2 NaOMe MeOH
1 Lewis acid2 ClCO2CCl3 Pyr3 Co2(CO)8
with a-isomer
1 Et3N Pyr H2O
2 H2 PdC H+
3 Ac2 O Pyr
149 151
152153
154 155
150
OBn
BnO
OBnO
OBn
BnO
OBnO
BnO
MeO
OBnO
OBn
BnO
O
OMe
AcO
OAcO
OAc
OAc
AcO
OAcO
OAc
O
BnOOBn
OMe
BnO
159 74 over 2 steps
+
BuLi ZnCl2 THF
1 H2 PdC2 Ac2O Pyr
156 157
158 59
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1411
Scheme (32)
Scheme (33)
and the chirality of each isomer assigned after acetylationConversion of the p-methoxyphenyl group in the peracety-lated (S) isomer 187 into the corresponding thiophenylglycoside 188 was accomplished affording the key inter-mediate for the synthesis of C-glycoside analogs of GM4GM3 and other related gangliosides (Scheme 37)
Ganglioside GM4 is a very important cell adhesionmolecule The C-disaccharide of GM4 is currently beingsynthesized in Linhardtrsquos lab using standard O-glycosylationof C-disaccharide with protected ceramide Once theceramide has been attached it can be oxidized to afford analdehyde group for coupling to keyhole limpet hemocyanin
OBnO
OBn
BnO
O
OBnO
ClZnO
OBn
BnOCl
R
OBnO
O
OBn
BnOCl
ZnR
O
ZnR
OBnO
OBn
BnO
160 161
162163
O
OBn
OBnBnO
O
O
OBn
OBnBnO H
TMS
O
OBn
OBnBnO H
O
OBn
BnO
OBnHO
O
OBn
OBnBnO OH
TMS
OBnBnO HO
OBn
TMS
O
OR
ORRO H
O
OR
RO
OR
OBn
OBnBnO
H
TMS
O+
K2CO3 MeOH
1 n-BuLi THF -78 oC
2 164
164165 66
166α 60 166β 13167 97
BF3 Et 2O Et 3SiH -78 oC
168 85
169 R = Bn 83
170 R = H near quantitative yield
H2 (1 atm)Pd(OH) 2C
TMS-acetyl ene
n-BuLi THF -78 oC BF3 Et2O Et3SiH
-78 o C
1412 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
O
OHCOBn
OBnBnO
OMe
O
CO2MeAcO
OAcAcHN
OAc
SO2
NAcO
OBnH
H
OBn
OBn
H
O
OMeH HH
A
O
CO2MeAcO
OAcAcHN
OAc
O
OBnOMe
OBnOBn
HO
AcO
+
Nu
174175
176
SmI2 THF
Scheme (34)
Scheme (35)
Scheme (36)
O
BnO
BnO
BnO
Si lylO
O2S N
O
BnO
HO R2R1
BnOBnO
SilylO
OBnO
BnO
BnO
SilylO
Sm(III)
R1COR2 SmI2 THF
171 172
173
NHBoc
OAcO
AcO
AcHN O
O
CO2BnO
OO
OO
OH
O
CO2MeAcO
OAcAcHN
OAc
AcO
SO2Ph
R2
O
CO2Me
AcHN
OAc
AcO
R1
AcO
AcO
AcHNO CO2Bn
NHBoc
AcO
OAc
O
Zn(BH4)2
180 R1 R2 = H OH ( RS 11)
181 R1 R2 = O
182 R1 = H R2 = OH de gt 90
DMSO Ac2O
177178
179
13 steps
22 equiv SmI2 THF
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1413
Scheme (37)
Fig (2)
(KLH) by reductive amination for use as carbohydrate-basedvaccine GM3 a related trisaccharide containg gangliosideplays an important role in cell growth and differentiationFig 2 The synthesis of C-oligosaccharide GM3 is currentlyunderway following a similar route to that of C-GM4synthesis [42]
Beau also reported a sialyl C-disaccharide synthesiswhich relied on the unprecedented use of a stable andcrystalline 2-pyridyl sulfide of the N-acetylneuraminic acidderivative 189 as the anomeric precursor in a samarium-Reformastky procedure [43] The coupling procedure withsulfide 189 and aldehyde 190 afforded the carbon-linkeddimer 191 in 93 yield as a 11 diastereomeric mixture
Alcohols 191 were converted into thiocarbonates anddeoxygenated by employing triphenyltin hydride catalyticAIBN and pentafluorophenol which yielded C-disaccharide192 as a single compound in 65 yield for the 2 stepsDesilylation hydrogenolysis acetylation and finalacetolysis of the methyl glycoside provided the carbon-linked mimic 193 of the disaccharidic component of thesialylTn tumor antigen (Scheme 38)
4 CATIONIC METHODS
This section is categorized according to reactions thatinvolve the generation of anomeric ions followed by thecapture with sugar-based nucleophiles
OAcAcHN
OAc
AcO
O
OBnBnO
OBnOMP
HO
O
MeO2CAcO
O
MeO2CAcO
OAcAcHN
OAc
AcO
O
OHHO
OHOMP
HO
O
OBnOHC
OBnBnO
OMP
O
MeO2CAcO
OAcAcHN
OAc
AcO
O
OHHO
OHOMP
HO
O
CO2MeAcO
OAcAcHN
OAc
AcO
SO2Ph
O
MeO2CAcO
OAcAcHN
OAc
AcO
O
OAcAcO
OAcX
AcO
H2 PdC EtOAc CH3OHH2O
+
Ac2O Pyr
187 X = OMP
188 X = SPh 73
184 85 R and S mixture
186 90 for two i somers
+
SmI2 THF183
179
185
O
HO2 CHO
OAcAcHN
OH
HO
O
OHHO
OH
OAcO
(CH2 )12 CH3
HN
OH
(CH2)14CH3
O
O
O
OHHO
OH
O
O
HO2 CHO
OAcAcHN
OH
HO
O
OHHO
OH
O(CH2)12CH3
HN
OH
(CH2)1 4CH3
GM4
GM3
1414 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
41 Exo-glycals as Nucleophiles
Nitotra et al have found that treatment of exo-glycal 194with BF 3
OEt2 followed by a water quench afforded the C-disaccharide 195 (Scheme 39) It is noteworthy tonoteworthy that the attack of the enol ether on the anomericoxonium ion occurs with high stereoselectivity on the α-face only 195 was obtained [44]
42 Silyl-based Nucleophiles
Isobe has designed and developed alkynylation as a keyreaction for the introduction of a carbon chain onto sugarsThose alkynylated compounds are called ldquosugar acetylenesrdquo[45] The mechanism includes eliminative formation ofcation to which silylacetylene can coordinate on the α-face(Scheme 40)
Double C-glycosylation between glycal 198 and bis(silylacetylene) gave C-disaccharide ldquolikerdquo compounds 199and 200 (Scheme 41)
Silylpropargyl-sugar 201 smoothly reacted with D-glucalto furnish exclusively the α-acetylene glycoside product 202in 88 (Scheme 42) [46]
5 CYCLIZATION METHODOLOGY
This approach to C-oligosaccharide synthesis relies onthe coupling of an open chain fragment with an intact
monosaccharide to give an intermediate that is then cyclizedto deliver the C-oligosaccharide target This section isdivided by the type of chemistry used to initially assemblethe two pre-cyclization fragments
51 Wittig Reaction-Cyclization
The Kishi group was the first to use Wittig-cyclizationapproach to synthesize C-disaccharides Starting with Wittigreaction between 203 and 204 the intermediate 205 wasafforded as a single stereoisomer in 82 yield Osmylationthen gave a mixture of diols with the major one formed in a61 ratio Selective protection of the diols gave 206a and206b The mono-para-methoxybenzyl ether 206a was thentransformed into the hemiketal 207 in 75 overall yield inthree steps ie (1) Swern oxidation (2) acetonide hydro-lysis (4 N HClTHFrt) and (3) benzoylation (3 equiv ofPhCOClpyCH2Cl2rt) Silane reduction of 207 in an acidicmedium should preferentially yield the equatorially substi-tuted β-C-glycoside which was deblocked and converted tothe methyl- βminusC-disaccharide 209 Exact parallel experi-ments applied to the minor isomer gave the correspondingC-disaccharide 210 (Scheme 43) [47]
Armstrong has employed Wittig-osmylation protocol forthe preparation of a small library of α-C-(1rarr6)-disaccha-rides [48] Readily available allyl C-glycoside 211 washomologated to diene ester 212 and subjected to osmylation
Scheme (38)
O
CO2MeAcO
OAcAcHN
OAc
AcO
S(2-Py)
O
TESO
AcHNOMe
O
HO
O
CO2MeAcO
OAcAcHN
OAc
AcO
O NHAcOAc
OAc
OAc
O
CO2MeAcO
OAcAcHN
OAc
AcO
O NHAcOBn
OTES
OMe
OAc
AcO
O NHAcOBn
OTES
OMeOH
O
CO2 MeAcO
OAcAcHN
+
192 65
1 MeOHHCl2 H2 PdC EtOH3 Ac2O Pyr4 Ac2OAcOHH2SO4
193 59 overall yield
25 equiv SmI2 THF
1 11-thiocarbonyldiimidazole DMAP2 Ph3SnH cat AIBN
191 93
189
190
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1415
Scheme (39)
Scheme (40)
Scheme (41)
OBnO
OBn
OBn
OBnO
OBn
OBn
OBnO
OBn
OBn
OBnO
OBnCH3
BnO
OH
CH2
OBnO
OBn
CH3
OBn
H2 O
BF3 OEt2 MeCN
194
195 96
OOAc
OAc
AcO
R SiMe3
SnCl4
O
OAc
AcO
R
O
OAc
AcO
O
OAc
AcO
Me3Si
R
SiMe3
196
197
Me3 Si SiMe3
O
AcO
OAc
OAc
SiMe3
SiMe3
O
AcO
OAc
O
OAc
OAc
O
AcO
AcOO
OAc
OAc
SnCl4 CH2Cl2
SnCl4 CH2Cl2198
199
200
1416 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (42)
Scheme (43)
AcO
OAc
OAc
Me3 Si
BnO
OBn
BnO
OBn
AcO
OAc
BnO
OBn
BnO
OBn
+ I2 CH2Cl2
202 88
198 201
O
OBn
OBn
O
O
O
OBn
OBn
O
O
OBn
OBn O
OBn
OBn
O
OPBH2M
OH
OBnO
BnO
BnO
O
OBn
OBn
O
OHOPMB
OHO
HO
HO
O
OH
OHOH
OH
HOOMe
O
OBnOBn
O
Ph3P
O
O
OBn
OBn O
OBn
OBn
O
OPBM
OH
O O
CHO
OBn
BnO
OO
OBn
OBn
O
OHOPMB
BnO
BnO
BnO
OHO
HO
HO
O
OH
OHOH
OH
HOOMe
+ THF -78 oC
1 OsO4 pyr THF
2 NaH PMBBr
206a 206b 206a206b 61
1 Swern [O]2 4N HCl3 PhCOCl pyr
1 Swern [O]2 4N HCl3 PhCOCl pyr
1 PrSiH BF3 OEt2
2 H2 Pd(OH)2C
3 HCl MeOH 90 oC
1 PrSiH BF3 OEt2
2 H2 Pd(OH)2C
3 HCl MeOH 90 o C
203
204
205
207
209
208
210
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1417
followed by reduction to afford a 51 mixture (213214215216) of lactols that were readily separable by chromato-graphy Following a deprotection of an equimolar mixture of213 and 214 217 and the DL hybrid C-disaccharide of D-glucose-O-(1rarr6)-L-galactose 218 were obtained The DDand DL derivatives 219 and 220 of glucose-α-(1rarr6)-idosewere also obtained as a near equimolar mixture afterdeprotection of 215 and 216 (Scheme 44)
52 Anion Addition-Cyclization
Kishi developed an approach for the synthesis of theCndashtrehalo sugars which relied on nucleophilic addition ofone intact sugar fragment to a fundamental aldehyde ieKishi-Nozaki reaction [49] Coupling of monosaccharide221 and aldehyde 222 gave 223 The triple bond waspartially reduced and osmylation was followed by selectiveprotection to afford 224 The acetonide was converted toepoxide 225 by standard methods and removal of the PMBgroup Acid-catalyzed cyclization followed by aglyconichydrolysis and protection of hydroxyl group with (p-methoxyphenyl)diphenylmethyl chloride (MMTrCl) gave226 Inversion of the C-2 hydroxyl and removal of protectinggroups delivered α α-C-trehalose 227 (Scheme 44)
Kishi and co-workers also employed aldol reactions as anefficient access to the C-trisaccharide related to the type IIABO(H) blood group determinant [50] Aldol condensationof the enolate of methyl ketone 228 with aldehyde 229 gavea 41 mixture of hydroxy ketones 230 and 231 The majorketol was cyclized desulfurized and oxidized to afford thedisaccharide ketone 233 The ketone in THF was treatedwith LiHMDS (3 equiv) and TMEDA followed by theaddition of MgBr2 Addition of the aldehyde 234 led toalmost exclusive formation of the equatorial products 235and 236 in a 12 ratio Mesylation of 235 and 236 followedby treatment with liquid ammonia gave enones 237a and237b which were reduced to yield exclusively the C-2rsquo-equatorial ketone 238 Sodium borohydride reduction of theC-3rsquo carbonyl proceeded with the desired stereoselectivity toyield the protected C-trisaccharide 239 which wasdeblocked to provide the polyol 240 (Scheme 46)
Sutherlin and Amstrong cleverly applied a recursivestereochemical deconvolution (RSD) combinatorial approachfor the synthesis of a small library of C-trisaccharides aspotential inhibitors for the cell surface proteins of bacteriumHelicobactor pylori [51] The workers chose to carry outvariations in galactose ring of these trisaccharides An
Scheme (44)
OBnO
BnOOBn
OBn
P O
OEtOEtO
EtO
R H
OH
OH
OH
OH
O
R H
OH
OH
OH
OH
O
OHO
HOOH
OH
O
HO
OHOH
OH
OHO
HOOH
OH
O
HO
OH
OH
OHO
HOOH
OH
O
HO
OH
OHOH
R H
OH
OH
OH
OH
O
R
OBnO
BnOOBn
OBn
O
OHO
HOOH
OH
OO
HOHO
OH
R H
OH
OH
OH
OH
O
1 OsO4 NMO 50
2 DIBAL -32 oC 40
++ +
213 214 215 216
217 218 219 220
1 9-BBN H2O22 Swern [O]
3 t-BuOK
4 I2 C6H6212
211
1418 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
efficient Nozaki-Kishi coupling of vinyl bromide 241 withaldehyde 242 in a diasteromeric ratio of 12 followed byprotection with TBSOTf led to 243 and 244 Hydroborationfollowed by oxidation gave aldehydes 245 and 246respectively Addition of allylmagnesium bromide toaldehyde 245 followed by removal of the silyl groupafforded 247 to 246 giving 248 and 249 Epoxidation gave a11 mixture of the corresponding epoxides which werecyclized to give the C-trisaccharide 250-255 after removalof the benzyl groups (Scheme 47)
Schmidt reported a stereoselective 6-exo-trig selectiveelectrophilic cylization approach for de novo synthesis of amethylene-bridged Neu5Ac-α-(23)-Gal C-disaccharide theC-analog of an important motif in glycosphingolipids [52]The open chain precusors 259ab (a 32-mixture ofdiaseteromeric alcohols) were formed by the addition oflithiated iodide 256 to open chain aldehyde 258 Subsequent
C1 incorporation using Tebbe-reagent formation of a cycliccarbonate and deprotection of the two isopropylidene ketalsafforded tetrol 264 which upon treatment with phenylselenyltrifilate was steroselectively cyclized in a 6-exo-trigselective manner affording a diasteromeric mixture of 251and 252 in a ratio of 71 A seleno-Pummerer rearrangementto afford aldehyde 267 in 5 steps in 90 overall yieldOxidation of the aldehyde and subsequent steps led to thedesired C-disaccharide 268 (Scheme 48)
53 Esterification-Cyclization
Work from the Postema group has focused on a ringclosing metathesis (RCM) approach for the synthesis of C-saccharides [53a] The chemistry is versatile and has beenused for the synthesis of a small library of differentiallylinked β-C-disaccharides through a radical allylation-RCMstrategy [53b] The synthesis of the β-(1rarr4)-glucopyranosyl
Scheme (45)
O
OBn
BnO
BnO
BnO
I
CrCl2-NiCl2O
OBn
OH
BnO
BnO
BnO
O
O
O
O
O
H
OBn
O
O
OBnBnO
BnO
BnO
OOBn
OBn
OAc
PMBOHOO
OBn
BnO
BnO
BnO
O
OBn
OBn
OAc
O
OH
HO
HO
HO
OH
OH
OH
O
OH
O
OBn
BnO
BnO
BnO
OBn
OBn
OAc
O
MMTr
+
1 p-TsOH2 K2CO3 MeOH3 MMTrCl pyr
1 Swern [O]2 BH3 THF
3 AcOH-H2 O4 H2 Pd(OH)2
221
222
223
1 Pd-Pb CaCO3 H22 NaH BnBr3 OsO44 Bu2 SnO5 CsF PMB-Cl6 Ac2 O 4-DMAP
1 AcOH2 TsCl pyr
3 NaH-imid4 DDQ
224225
226 227
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1419
Scheme (46)
OBnO O
OBn
OMe
OBn
XY
SMe
OBnBnO
O
OBn
OBn
OBn
OBn
O
BnO
YX
OBn
TBSO
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnOOBn
H
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnO
OBn
OHC OBn
OBn
OTBS
OMe
BnOOBn
CHO
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnOOBn
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnO
OBn
YX
OBnO O
OBn
OMe
OBn
OBn
O
BnO
O
OBn
OBn
OBn
OBn
O 1 LiHMDS
2
228
1 TBAF THF
2 MeSH BF3 OEt2
230 X = OH Y = H231 X = H Y = OH
230231 41
1 Bu3SnH AIBN2 Swern [O]
1 LiHMDS THF-TMEDA2 MgBr23
1 MsCl
2 liquid NH3
235 X = OH Y = H236 X = H Y = OH Bu3 SnH AIBN
237a and 237b
NaBH4 MeOH
238
239 X = OBn
240 X = OHH2 Pd(OH)2
229
232233
234
1420 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (47)
OH C
O
O BnAcHN
OO
O
OBn OBnOBn
Br
O
OBn OBnOBn
O
OBnA cHN
OO
O TBSO
OBn O BnO Bn
O
OBnAcHN
OO
OTBS
S2
S1
S2
OTBSS1
O H
S2
OT BSS1
O H
MgBrMgBr
S2
O TBSS1
O H
S2
OHS1
OH
S2
OTBSS1
OH
O
OHHO
O H
O
HO
H OO
OBnA cH N
HO
H O
O
O HHO
OH
O
HOHO
O
OBnA cH N
HO
H O
O
OHH O
OH
O
H O
HOO
OBnAcHN
HO
HO
O
O HH O
OH
O
H O
H O O
OBnA cHN
HO
HO
O
O HH O
O H
O
HO
H O O
OBnAcHN
HO
HO
O
OHHO
OH
O
H O
O
OBnA cHN
HO
HOHO
+
241 242
1 CrCl2-NiCl2 T HF-DMF 722 TBSOTf 2 6-lutidine 91
243 244
1 9-BBN 602 Dess-Mart in period inane 97
1 9 -BBN 552 D ess-Martin periodinane 98
245 246
1
2 T BAF 74
1
2 TBAF 88
247 248 249
250
251
250 251 1 1 252 253 1 1 254 255 1 1
252
253
254
255
1 MCPBA2 CSA CH 2Cl2 61 fo r 2 steps3 H 2 Pd (O H)2C 95
1 MCPBA2 CSA CH 2Cl2 63 fo r 2 s teps3 H 2 Pd (OH)2C 87
1 MCPBA2 CSA CH2Cl2 80 for 2 steps3 H2 Pd(O H)2C 95
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1421
Scheme (48)
O
OO
Se Ph
R
O
HO OHOH
O
OB n O B n
OB n
O B nO O
O O
R O OR
X
O
OO
R
Se Ph
O
HOOH
OH
O
OB nOB n
O Bn
OB n
O O
O O
R O O R
O H
O
O B n OB n
O B n
OB n
O
C HO
O
O O
R O OR
OAc HN
OAc
C O2NH 4HOOH
OH
O
OH O H
OH OH
O
OB n O B n
OB n
OB nO O
O O
R O OR
X
O
O
OAcOAc
C HOA cOOAc
OAc
O
OB n O B n
OB n
OB n
O
O Bn OB n
OB n
OB n
X
OH
OO
HOOH
OH
O
O
OMeOB n
OB nOB n
R
t-B uL i256 R = Li
257 R = L i
258
(R = t-B uMe 2Si )
(R = t-B uMe 2Si )
259ab (32) 79 com bine d yi eld
De ss-Ma rtin pe riodinane
260 X = O R = t-B uMe 2Si ) 95
261 X = O R = t -B uMe2S i) 62
T e bbe re age nt
TB A F THF262 X = O R = H 94
diphosge ne
C H2C l 2Pyr
263 95
T HFH2O T FAr t
264 quant it a ti ve yie ld
PhSe C l AgOT f
EtC N -80 oC
265
266
Quant it at i ve yi l ed 25 26 7 1
+
R =
1 Ac 2OPyr
2 mC PB A3 Ac 2ONa OAc
4 NaO HT HFMe OH
5 Ac2O P yr
267 90 overa ll yi e ld
ste ps
268
1422 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
glucopyranoside 280 represents an example of thischemistry The known triacetyl glucopyranoside 269 wasconverted to iodide 270 in good yield Radical allylation of271 proceeded to afford a mixture of equatorial and axialallylation products in a 61 ratio Oxidative cleavage of thedouble bond gave the corresponding aldehydes 273a and273b which were separable Pinnick oxidation of the majoraldehyde 273a then gave the C-4 equatorial acid 274 DCC-mediated coupling of alcohol 275 and acid 274 proceeded toafford ester 276 in good yield Methylenation of 276 gave277 and exposure to catalysist 278 gave a 41 yield of theC-disaccharide glycal which was exposed to an excess ofBH3
THF to give 64 yield of the β-C-disaccharide 279Removal of the benzyl groups and global peracetylation gavethe peracetylated (1rarr4)-β-C-disaccharide 281 in good yield(Scheme 49)
54 Ring Expansion-Cyclization
Nelson developed a new strategy for asymmetric andstereoselective synthesis of C-linked disaccharide mimeticsthe C58-C71 fragment of palytoxin [54] The diol (RR)-282was converted into the di-dihydropyran (DHP) template 283284 and 285 The di-DHPs were functionized in a twodirectional sense using dihydroxylation reactions The two-directional approach was often very efficient indeed forexample in the synthesis of 286 six new stereogenic centerswere introduced with almost complete stereocontrol using areduction and a dihydroxylation reaction The approach isnot restricted to the synthesis of C2-symmetricaldisaccharide mimetics Using the unsymmetrical template285 which has both a pseudo-axial and a pseudo-equatorialhydroxyl groups the unsymmetrical mimetics 289 and 290were prepared (Scheme 50)
6 RADICAL APPROACHES
The radical approach for C-C bond formation is a popularmethod within organic chemistry The use of radicalchemistry in carbohydrate synthesis has certain advantagesFirstly the reaction conditions are very mild and tolerant ofa range of functional and protecting groups Secondanomeric radicals are stable with respect to elimination andepimeration Most significantly the chemistry required toincorporate an appropriate substitute at C-1 employed in theinitial hemolytic cleavage step is common within carbo-hydrate chemistry [55] The use of such radical techniquecan be subdivided into two classes intermolecular andintramolecular approaches
61 Intermolecular Radical Approaches
Giese was the first to employ an intermolecular radical-based approach for synthesis of C-disaccharides [56]Addition of an alkene to an anomeric radical underappropriate conditions allowed exclusive entry to the α-linked C-glycoside a result which was mirrored by the workof Baldwin [57] The high α-selectivity of the reaction wasin contrast with other reports Thus radicals generated at theC-2 C-3 and C-4 centers all preferred to occupy equatorialpositions [58] When the anomeric bromide 291 was treatedwith tin hydride and AIBN resulting anomeric radical andreacted with lactone 292 in a Michael addition it afforded293 In this reaction hydrogen abstraction at the resulting
radical center occurs from axial face to selectively generatethe equatorial C-2rsquo substituent Reduction and acetylation of293 furnished C-disaccharide 294 (Scheme 51) [59]
Witczak used the facial bias of levoglucosene tostereoselectively add a carbohydrate-based radical in thepreparation of the 3-deoxy-(1rarr4)-β-C-disaccharide 299[60] Addition of the radical derived from iodide 295 to 296gave adduct 297 in 26 yield Removal of the anomerichydroxyl of 297 was achieved by treatment with triethylsilane borontrifluoride ether complex followed bystereoselective reduction of the keto function at C-2rsquo withthe formation of 298 in 89 yield Debenzylation followedby acetolysis of 16-anhydro ring produced the peracetylatedtarget C-disaccharide 299 in 19 overall yield from 295(Scheme 52)
Vogel has developed general methods to transformenantiomerically pure 7-oxabicyclo[221]heptyl derivatives(ldquonaked sugarsrdquo) into C-disaccharides Because of thesechiral bicyclic skeletons they undergo highly stereoselectivereactions with predictable diasteroselectivities An arsenal ofmethods is available that allow to substitute these ldquonakedrdquocarbon centers with a variety of functional groups with allpossible relative configurations The methods allowpreparation of both enantiomers of a given target with thesame ease Predictably high stereoselectivity of the reactionsof the bicyclic chirons adds to the flexibility of approachwhich can lead to high molecular diversity [61]
α-C-(1rarr3)-mannopyranoside of N-acetyl-galactosaminepotent β-galactosidase inhibitors was synthesized by thisapproach [61] Enone 302 was readily prepared from 300The addition of the radical derived from bromide 303 toenone 302 afforded the αminusisomer 304 The ketone was thenreduced and the selenide eliminated via the intermediacy ofthe selenoxide to give 305 Acid-promoted (CF3SO3H) 7-oxa ring opening of 305 in MeCN produced the amino-conduritol derivative 306 resulting from the quenching of theallylic cation intermediate by the solvent (Ritter reaction)Ozonolysis of the chloroalkene 306 generated an acylchloride-aldehyde intermediate that reacted with MeOH toproduce a mixture of methyl uronates The major compound307 was silylated and reduced The crude polyol obtainedwas acetylated to produce 308 Desilylated and ammonolysisafforded a mixture of α-β-pyranoses 309 and correspondingα-β-furanoses (Scheme 53)
Similar chemistry was carried out to synthesize non-protected α-C(1rarr2)-L-fucopyranoside of D-galactopyrano-side corresponding to a blood group mimetic [62] Giesersquosradical fucosidation of racemic enone 310 with α-L-bromoacetofucose 311 provided the mixture of diastereo-meric α-C-fucoside 312a and 312b in reproducible yield of78 Reduction of the mixture gave a 11 mixture of endo-alcohols 313 and 314 which were isolated pure in 40 and355 yield respectively Oxidative elimination of thebenzeneselenyl group of 313 followed by acetylation gaveendo acetate 315 in 85 yield Acid-promoted ring openingof 315 and ozonolysis of the resulted chloroalkene gavemethyl uronic ester 316 in modest yield (10) Treatment of316 with Cl3CCN and NaH followed with BF3
OEt2
furnished the totally protected C-disaccharide 317 in 79
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1423
Scheme (49)
Bu3SnO
HOAcO
OMeOAc
OAc
O
AcO
OMeOAc
OAcI
AIBN
O
AcO
OMeOBn
OBn
HO2C O
AcO
OMeOR
ORY
X
OHBnO
BnO
OBn
OBnO
BnO
OBn
O
AcO
OMeOBn
OBnX
i-Pr i-Pr
N
Mo C(Me2 Ph)((CF3)2 MeCO)2
O
RO
OMeOR
O
RO
OR
OR
RO
OR
278
I2 Ph3P
imidazole
269 270 93
271a X = CH2CH=CH2 Y = H R = Ac 64271b Y = CH2CH=CH2 X = H R = Ac 11272a X = CH2CH=CH2 Y = H R = Bn 75272b Y = CH2CH=CH2 X = H R = Bn 75273a X = CH2CHO Y = H R = Bn 79273a Y = CH2CHO X = H R = Bn 79
1 NaOMe MeOH2 NaOH BnBr DMF
OsO4 NaIO4
NaClO2 NaH2PO4
274 96
275
DCC 4-DMAP
276 X = O 82
277 X = CH2 51
TiCl4 Zn dust TMEDA CH2Br2PbCl2 (Cat )
1
2 BH3 THF H2O2 NaOH
H2 PdC EtOH
Ac2 O Pyr 4-DMAP
279 R = Bn R = H 64
280 R = R = H 99
281 R = R =Ac 97
1424 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (50)
Scheme (51)
O OOH
OH
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
286
1 VO(acac)2 t-BuOH 95
2 (MeO)3CH BF3 90
1 P-O2NC6H4 CO2H Ph3P DIAD2 K2CO3 MeOH 82 over 2 steps
1 PhCOCl Et3N DMAP 402 P-O2NC6H4 CO2H Ph3P DIAD3 KOH THF-H2O 75 over 2 steps
TMEDA OsO4
Cat OsO4 NMO 287
Cat OsO4 NMO288
TMEDA OsO4
Cat OsO4 NMO
290
289
(RR)-282283
284
285
OHO
AcO
BrOAc
OAc
BnO
O
OBn
OBnO
OHO
AcOOAc
OAc
BnO
OOBn
OBnAcO
OHO
AcOOAc
OAc
BnO
O
OBn
OBnO
+
Bu3SnH AIBN291
292
293 81
1 Na[Al(OC2H4OMe)2(OEt)H]2 Ac2O pyr
294 56 over 2 steps
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1425
Scheme (52)
Scheme (53)
OBnO
BnOOBn
OBn O
OH
O
OBnO
BnO
OHOBn
OBn O
O
O
O
O
O
OBnO
BnOOBn
OBnO
OAcOAc
OAc
OBnO
BnO
OHOBn
OBn
IBu3SnH AIBN
295 297 26
1 BF3 OEt2 Et3SiH
2 L-Selectride THF
1 Pd(OH)2C C6H10 EtOH
2 EtSiOSO2CF3 Ac2O
298 89 over 2 steps299
296
O
O
PhSeClO
O
PhSeCl
Bu3 SnH
O
O
PhSeCl
R
H
O
OAc
R
Cl
O
AcO
OAc
OAc
OAcOH
Cl
NHAc
R
OAc
AcHN
OH
O
OH OAc
OH
OHO
HO
OH
O
AcO
OAc
OAc
OAcBr
O
O
PhSeCl
O
O
PhSeCl
R
O
OTIPSAcHNR
OAc OAc
O
OHAcHN
COOMe
R
OAc
1 Bu4NF
2 NH3MeOH
1 (Me3Si)2NLi THF2 Me2N=CHI
1 Bu3 SnH AIBN2
1 NaBH42 mCPBA3 Ac2O pyr
1 H+ MeCN
2 H2 O NaHCO3
R =
1 O3MeOH
2 Me2S NaHCO3
1 TIPSOTf 26-lut idine2 LiBH43 Ac2 O pyr DMAP
furanoses +
304 56
305 68 306 84307 50
308 46
300 301 302
303
309
1426 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
The reduction of 317 and treatment with DOWEX-H+ resinprovided the desired C-fucoside 318 in 70 (Scheme 54)
62 Intramolecular Radical Approaches
One disadvantage with the intermolecular approaches isthat during such radical mediated reactions electrondeficient alkenes are required to facilitate C-C bondformation The intramolecular approach of Sinayuml overcomes
this drawback by bring two substrates together via atemporary covalent silaketal connector This enables the useof a wider range of alkenes which can include alkene-functionalized sugars thus leading to the generation of C-disaccharides [63] Based on the early work of Stork Sinayumlemployed the tether reaction in the synthesis of both α- andβ-C-disaccharides with this work subsequently beingemployed in the synthesis of biologically significant natural
Scheme (54)
O
OH
Fuc
Cl
O
O
ClPhSe
OOAc
NHAcOHFuc
O
AcOOAc
AcO
Br
O
O
PhSeCl
O
AcOOAc
AcO
O
OH
PhSe Cl
Fuc
OOAc
NHAc
OMe
Fuc
O
AcHN
OH OAc
OH
O
OH
Me
OH
O
O
Fuc
ClSePh
O
HO
Fuc
ClSePh
+
Ph3SnHAIBN
78 combined yield
Fuc
310
+
1 NaBH4 MeOHTHF2 Chromatography
313 40 314 355
1 mCPBA
2 Ac2O pyr DMAP
+
315 75
1 TfOH MeCN
2 NaHCO3 O3 -78 oC
316 10 over 2 steps
1 Cl3 CCN NaH
2 MeOH BF3 OEt2
317 79
1 LiBH4 THF
2 Dowex-H+
311
312a312b
318 70 for 2 steps
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1427
products [64] The availability of different hydroxyl groupson each monosaccharide unit allowed the fine-tuning ofstereochemical outcome by selective positioning of the silyltether [65] Development of this early stereochemical controlled to the tethering of the donor 320 with alcohol 319through a di-isopropyl silicon tether 321 Subsequent treat-ment with Bu3SnH and AIBN led to a 9-endo-trigcyclization to form the C-disaccharide 322 in an 80 yieldwith exclusive formation of the α-product The silyl tetherwas removed with Bu4NF and deprotection under standardconditions afforded the desired disaccharide 323 in excellentyield (Scheme 55)
In parallel the development of a 32rsquo silyl tether allowedaccess to the β-linked product as demonstrated in Sinayumlrsquossynthesis of methyl β-C-lactoside 328 [66] Alcohol 324 and320 were connected via the dimethylsilyl tether an 8-endo-trig cyclization followed to exclusively afford the β-
disaccharide 326 in 45 yield Removal of the tether anddeprotection of benzyl ether gave β-C-disaccharide 328(Scheme 56)
This group also selected iodosugars bearing a freehydroxyl group as progenitors of the radical donors [67] In atypical experiment the radical donor 329 was connected tothe radical acceptor 330 through a silaketal tether followingtheir procedure Tributyltinhydride mediated 8-endo-trigradical cyclization of compound 331 gave after detetheringof the non isolated intermediate 332 the protected β-C-disaccharide 333 in 37 overall yield (from startingmaterials 330 and 329) Peracetate 335 was achieved afterhydrogenolysis The C-laminaribioside 334 is of potentialbiological interest as it mimics the repeating disaccharideunit of fungal β-(1rarr3)-glucans which have antitumor andimmunomodulating properties (Scheme 57)
Scheme (55)
Scheme (56)
OO
OHSePh
OTBDPSO O
OO
SePh
OTBDPSO
OO
OBnOMe
OBn
Si
O
HOOBn
OMe
OBn
O
HOOH
OHHO
O
HOOH
OMe
OH
OTBDPSO
O
HOOBn
OMe
OBnO
OOH
1 n-BuLi THF
2 iPr2SiCl2 -78 oC
3 DMAP THF rt
1 Bu4NF THF
2 Dowex-H+
3 H2 PdC
Bu3SnH AIBN toluene
319
320
321
322323
OBnO
OHSePh
OBnBnO
OHO
OBnOMe
OBn
ROO
ROOH
OR
OHO
OROMe
OR
OBnO
O
OBnBnO
OO
OBnOMe
OBn
Si
SePh
OBnO
O
OBnBnOO
OOBn
OMe
OBn
Si
1 PhSeH Me2SiCl2
BuLi -78 oC
2 imidazole rt
Bu3SnH AIBN toluene
H2 PdC327 R = Bn
328 R = H
Bu4NF THF
324
320
325
326 45
1428 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
CONCLUSIONS
In this paper the biological importance of C-oligo-saccharides as subunits of natural products and as a newgeneration of carbohydrate based on therapeutics has beenillustrated Different methods are available for the synthesisof C-oligosaccharides As with traditional saccharidesynthesis it has been necessary to develop a number ofspecific approaches to facilitate the regioselective andstereoselective preparation of the desired targets Work inthis area continues and it is expected that many interestingnew C-oligosaccharides will be prepared using the chemistrydescribed in this review It is also likely that new chemistrywill be developed in the future for the preparation of thesebiologically important targets
ACKNOWLEDGEMENTS
The authors thank Dr Sultan Baytas for her criticalreading of this manuscript
REFERENCES
[1] Kennedy J F White C A Bioactive Carbohydrates InChemistry Biochemistry and Biology Ellis Horwood LtdChichesterUK 1983
[2] Wassarman PW Mammalian Fertilization Molecular Aspects ofGamete Adhesion xocytosion Exocytosis and Fusion Cell 199996 175-183
[3] Carbohydrate-based Drug Discovery Wong C-H EdWeinheim Cambridge Wiley-VCH 2003
[4] (a) Sharon N Lis H Lectins as Cell Recognition MoleculesScience 1987 246 227-234 (b) Dwek RA Chem Rev 1996 96683-720
[5] Postema M C-Glycoside synthesis CRC Boc Ratom 1995[6] (a) Weatherman R V Mortell K H Cheruenak MKiessling
L L Toone E J Specificity of C-Glycoside Complexation byMannoseGlucose Specific Lectins Biochem 1996 35 3619-3624(b) Ravishankar R Surolia A Vijayan M Lim S Kishi YPreferred Conformation of C-Lactose at the Free and Peanut LectinBound States J Am Chem Soc1998 120 11297-11303
[7] (a)Wong C-H Halcomb R L Ichikawa Y and Kajimoto TEnzymes in organic synthesis Application to the problems ofcarbohydrate recognition part2 Angew Chem Int Ed Engl 199534 521-546 (b)Howard S Withers SG Bromoketone C-Glycosides a New Class of βminusGlucanase Inactivators J AmChem Soc 1998 120 10326-10331(c) Wang Q Wolff MPolat T Du Y Linhardt R J C-glycoside of Neuraminic Acidsas Neura-minidase Inhibitors Bioorg Med Lett 2000 10 941-944 (d) Phili R Chang J Partis R A Mueller R A ChrestF J Passaniti A The Alpha-glucosidase I InhibitorCastanospermine Alters Endothelial cell Glycosylation PreventsAngiogenesis and Inhibits Tumor Growth Cancer Res 1995 552927-2935
[8] Ossor A Elbein A D In Carbohydrates in Chemistry andBiology Vol 3(II) WileyVCH 2000 pp 513-539
[9] (a) Sinayuml P Synthesis of oligosaccharide Mimetics Pure ApplChem 1997 69 459-463 (b) Beau J-M Gallagher TNucleophilic C-glycosyl Donors for C-glycoside Synthesis Top inCurr Chem 1997 187 1-54 (c) Nicotra F Synthesis of C-glycosides of Biological Interest Top in Curr Chem 1997 187
Scheme (57)
O
O
O
Ph
I
OMe
OHO
BnO
OH
OH
BnOOH
O
BnO
Si
O
O O
Ph
I
OMe
O
O
BnO
OR4O
R5O
OMe
OR2
OR3O
R3O
OR1
R3O
Bu3 SnH AIBN
332 R1 R2 = SiMe2 R3 = Bn R4 R5 = CHPhTBAF THF
333 R1 = R2 = H R3 = Bn R4 = R5 = CHPh 37 from 11
334 R1 = R2 = R3 = R4 = R5 = H
335 R1 = R2 = R3 = R4 = R5 = Ac
329
H2 PdC MeOH
Ac2 O pyr
1 BuLi THF -78 oC
2 Me2SiCl2
3 DMAP
330
331
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1429
55-83 (d) Du Y Linhardt R Y Recent Adv in Stereo-SelectiveC-Glycoside Synthesis Tetrahedron Lett 1998 54 9913-9959 (e)Liu L Mckee M and Postema M H D Synthesis of C-saccharides and Higher Congeners Current Org Chem 2001 51133-1167
[10] Jarosz S Fraser-Reid B Synthesis of A Higher Carbon Sugar ViaDirected Aldol Condensation Tetrahedron Lett 1989 30 2359-2362
[11] Lichtenthaler F W Lergenmiiller M Schwidetzky S C-Glycosidations of 2-Ketohexosyl With Electrophilic Radical andNudeophilic Anomeric Carbons Eur J Org Chem 2003 3094-3103
[12] Baudat A Vogel P Aza-C-disaccharides Synthesis of 6-Deoxygalactonojirimycin-β-C(1rarr3) Linked with D-Altrofuranosides and D-Galactose J Org Chem 1997 62 6252-6260
[13] Turner D Vogel P Synthesis of 4-Hydroxy-26-Bis(hydroxymethyl) tetrahydropyran-2-Carbaldehyde DerivativesSynlett 1998 304-306
[14] Zhu Y-H Vogel P Short Stereoselective Synthesis of C-(1rarr3)-Linked Disaccharides Tetrahedron Lett 1998 39 31-34
[15] Zhu Y-H Vogel P Synthesis of a (2R 6R)-2-(Hydroxymethyl)-6-Propa-1 2-Dienyl-2H-Pyran-3(6H)-One Derivative A NewEnone for The Convergent Construction of C-Glycosides of C-Disaccharides Synlett 2001 82-86
[16] Baumberger F Vasella A Deoxynitrosugars The 6th
Communication Stereolectronic Control in the reductivedenitration of tertiary nitro ethers A Synthesis of ldquoC-glycosidesrdquoHelv Chim Acta 1983 66 2210-2221
[17] Martin O R Lai W Synthesis and Conformational Studies of β-(1rarr6)- and ββ-(1rarr1)-Linked C-disaccharides J Org Chem1993 58 176-185
[18] Spak S J Martin R The synthesis of an analogue of Methyl OC-Analogue of Methyl 4rsquo-O-β-D-GlucopyranosylgentiobiosideTetrahedron 2000 56 217-224
[19] Kobertz W R Bertozzi C R Bednarski M D C-GlycosylAldehyde Synthons for C-Linked Disaccharides J Org Chem1996 61 1894-1897
[20] Gurjar M K Nagaprasad R and Ramana CV First Synthesis ofMethyl α-C-D-Arabino-furanosyl-(1rarr5)-αminusD-Arabinofuranosidethe C-Disaccharide Segment of Motif C of MycobateriumTuberculosis Tetrahedron Lett 2000 43 7577-7579
[21] Witczak Z J Synthesis of C-Glycosyl Compounds and OtherNatural Products from Levoglucosenone Pure Appl Chem 199466 2189-2192
[22] Griffin F K Paterson D Taylor R J K Ramberg-BacklundApproaches to the Synthesis of C-Linked Disaccharides AngewChem Int Engl 1999 38 2939-2942
[23] Paterson B E Griffin F K Alcaraz M-L and Taylor R J KA Ramberg-Baumlcklund Approach to the Synthesis of C-GlycosidesC-Linked Disaccharides and C-Glycosyl Amino Acids Eur JOrg Chem 2002 1323-1336
[24] McAllister G D Paterson D E Taylor R J K A SimplifiedRamberg-Bachlund Approach to Novel C-Glycosides and C-Linked Disaccharides Angew Chem Int Ed Engl 2003 42 1387-1391
[25] McCartney J L Christopher T M Cicchillo R M BernardinaM D Wagner T R and Norris P J Org Chem 2003 6810152-10155
[26] Dondoni A Zuurmond H M Bascarate A Synthesis of α-andβ-D-(1rarr6)-C-Disaccharides by Witting Olefination of Formyl C-Glycosides with Glycopyranose 6-phosphoranes J Org Chem1997 62 8114-8124
[27] Dondoni A Kleban M Zuurmond H Marra A Synthesis of(1rarr6)-C-Oligogalactosides by Interative Wittig OlefinationTetrahedron Lett 1998 39 7991-7994
[28] Dondoni A Marra A A New Synthetic Approach toMycobacterial Cell Wall α-(1rarr5)-D-Arabinofuranosyl C-Oligosaccharides Teterahedron Lett 2003 44 4067-4071
[29] Colinas P A Ponzinibbio A Lieberknecht A and Bravo R OWittig Reaction of Glycosyl Phosphonium Salts A StereoselectiveRoute to C-Disaccharides and C O-Trisaccharides TetrahedronLett 2003 44 7985-7988
[30] Schmidt R R Preuss R Synthesis of Carbon Tetrahedron Lett1989 30 3409-3412
[31] Dietrich H Schmidt R R Synthesis of Carbon-Bridged C-Lactose and Derivatives Liebigs Ann Chem 1994 975-981
[32] Rouzaud D Sinayuml P The First Synthesis of a ldquoC-DisacchariderdquoJ Chem Soc Chem Commun 1983 1353-1354
[33] Xin Y-C Zhang Y-M Mallet J-M Glaudemans C P JSinayuml P Synthesis of C-Oligosaccharides That Mimie TheirNatural O-Analogues Immunodeterminants in Binding toMonoclonal Immunoglobulins Eur J Org Chem 1999 471-476
[34] Streicher H Geyer A Schmidt R R C-Disaccharides ofKetoses Chem Eur J 1996 2 502-510
[35] Leeuwenburgh M A Timmers C M Vander Marel G A VanBoom J H Mallet J-M Sinayuml P G Stereoselective Synthesisof α-C-(Alkynyl)-Glycosides Via Ring-Opening of α-12-Anhydrous Tetrahedron Lett 1997 38 6251-6254
[36] Aslam T Fuchs M G G Le Formal A Wightman R HSynthesis of C-Disaccharide Analogue of the α-D-Arabinofuranosyl-(1rarr5)-α-Arabinofuranosyl Motif ofMycobacterial Cells Walls via Alkynyl Intermediates TetrahedronLett 2005 46 3249-3252
[37] (a) Girad P Namy J L Kagan H B Divalent LanthanideDerivative in Organic Synthesis 1 Mild Preparation of SamariumIodide and Ytterbium Iodide and Their Use as Reducing orCoupling Agents J Am Chem Soc 1980 102 2693-2698 (b)Molander G A Harris C R Sequencing Reactions withSamarium(II) Iodide Chem Rev 1996 96 307-338
[38] (a) Mazeacuteas D Skrydstrup T Doumeix O Beau J-MSamarium Iodide-Induced Intramolecular C-Glycoside FormationEfficient Radical Formation in the Absence of an Additive AngewChem Int Ed Engl 1994 33 1383-1386 (b) Mazeacuteas DSkrydstrup T Beau J-M A Highly Stereoselective Synthesis of1 2-trans-C-Glycosides Via Glycosyl Samarium(III) CompoundsAngew Chem Int Ed Engl 1995 34 909-912 (c) Jarreton OSkrydstrup T Beau J-M The Stereospecific Synthesis of Methylα-C-Mannobioside A Potential Inhibitor of M TuberculosisBinding to Human Macrophages J Chem Soc Chem Commun1996 1661-1662 (d) Jarreton O Skrydstrup T Espionosa J-FJimeacutenez-Barbero J Beau J-M Samarium Diiode Prompted C-Glycosylation An Application to The Stereospecific Synthesis ofα-(1rarr2)-C-Mannobioside and Its Derivatives Chem Eur J 19995 430-441 (e) Mipuel N Doisneau G Beau J-M ReductiveSamariation of Anomeric 2-Pyridyl Sulfones with Catalytic AnUnexpected Improvement in The Synthesis of 12-Trans-Diequatorial C-Glycosyl Compounds Angew Chem Int Ed Engl 2000 39 4111-4114
[39] Vlahov I R Vlahova P I Linhardt R J DiastereocontrolledSynthesis of Carbon Glycosides of N-Acetylneuraminic Acid ViaGlycosyl Samarium(III) Intermediates JAmChem Soc 1997 1191480-1481
[40] Kuberan B Sikkander S ATomiyama H Linhardt R JSynthesis of a C-Glycoside Analogue of sTn An HIV-and Tumor-Associated Antigen Angew Chem Int Ed Engl 2003 42 2073-2075
[41] Bazin H G Du Y Polat T Linhardt R J Synthesis of aVersatile Neuraminic Acid ldquoCrdquo-Disaccharide Precursor for theSynthesis of C-Glycoside Analogues of Gangliosides J OrgChem 1999 64 7254-7259
[42] Chen C-C Ress D K Linhardt RJ Samarium Iodide-Mediated Synthesis of Neuraminic Acid C-Glycosides InSynthesis of Glycommetics Roy R Ed ACS Syposium Series2004 896 53-80
[43] Abdallah Z Doisneau G Beau J-M Synthesis of a Carbon-Linked Mimic of The Disaccharide Component of The Tumor-Relate SialyTn Antigen Angew Chem Int Ed Engl 2003 425209-5212
[44] Lay L Nicotra F Panza L Russo G Caneva E Synthesis ofC-disaccharides through dimerization of exo-glycals J Org Chem1992 57 1304-1306
[45] Isobe M Nishizawa R Hosokawa S Nishikawa TStereocontrolled Synthesis and Reactivity of Sugar Acetylenes JChem Soc Chem Commun 1998 2665-2676
[46] Saeeng R Sirion U Sahakitpichan P Isobe M IodineCatalyzes C-Glycosidation of D-Glucal with SilylacetykeneTetrahedron Lett 2003 44 6211-6215
[47] (a) Babirad S A Wang Y Kishi Y Synthesis of C-Disaccharides J Org Chem 1987 52 1370-1372 (b) Wang YBabirad S A Kishi Y Preferred Conformation of C-Glycosides
1430 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
8 Synthesis of 14-Linked Carbon Disaccharides J Org Chem1992 57 468-481
[48] Armstrong R W Sutherlin D P Strategies for the Synthesis ofC-Disaccharides Containing D and L Sugars Tetrahedron Lett1994 35 7743-7746
[49] Wei A Kishi Y Preferred Conformation of C-Glycosides 12Synthesis and Conformational Analysis of αα- α β- and β β-Trehaloses J Org Chem 1994 59 88-96
[50] Haneda T Goekjian P G Kim S H Kishi Y PreferredConformation of C-Glycosides 10 Synthesis and ConformationAnalysis of Carbon Trisaccharides J Org Chem 1992 57 490-498
[51] Sutherlin D P Armstrong R W Synthesis of 12 Stereochemistryand Structurally Diverse C-Trisaccharides J Org Chem 1997 625267-5283
[52] Notz W Hartel C Waldscheck B Schmidt R R De NovoSynthesis of a Methylene-Bridged Neu5Ac-α-(23)-Gal C-Disaccharide J Org Chem 2001 66 4250-4260
[53] (a) Postema M H D Calimente D Liu L Behrmanm T L AnOlefin Metathesis Route for the Preparation of (1rarr6)-Linked-C-Disaccharide Glycals A Convergent and Flexible Approach to C-Saccharide Synthesis J Org Chem 2000 65 6061-6068(b) Postema M H Piper J L Liu L Faust M Andreana PSynthesis and Partial Biological Evaluation of a Small Library ofDifferentially Linked β-C-Disaccharide J Org Chem 2003 684748-4754
[54] Nelson A The Development of Strategies and Methods for TheSynthesis of Biologically Active Compounds New J Chem 200428 771-776
[55] Togo H He W Waki Y Yokoyama M C-GlycosylationTechnology With Free Radiant Reactions Synlett 1998 700-717
[56] Giese B Dupuis J Diastereoselective Synthesis of C-Glycopyranosides Angew Chem Int Ed Engl 1983 22 622-623
[57] Adlington R M Baldwin J E Basak A Kozyrod RPApplication of Radical Addition Reactions to tho Synthesis of a C-Glucoside and A Functionalized Amino Acid J Chem SocChem Commun 1983 144-145
[58] Giese B Gonzaacutelez-Goacutemez J A Witzel T The Scope of RadicalCC-Coupling by The ldquoTin Methodrdquo Angew Chem Int Ed Engl1984 23 69-70
[59] Giese B Witzel T Synthesis of ldquoC-Disaccharidesrdquo by RadicalC-C Bond Formation Angew Chem Int Ed Engl 1986 25 450-451
[60] Witczak Z J Chhabra R Chojnacki J C-Disaccharides IStereoselective Approach to β-(1rarr4)-3-Deoxy-C-Disaccharidesfrom Levoglucosenone Carb Res 1997 301 167-175
[61] Vogel P Synthesis of Rare Carbohydrates and Analogues Startingfrom Enantiomerically Pure 7-Oxabicyclo[221]heptyl Derivatives(ldquoNaked Sugarsrdquo) Current Org Chem 2000 4 455-480
[62] Viodeacute C Vogel P Synthesis of The C-Disaccharide α-C(1rarr3)-L-Fucopyranoside of N-Acetylgalactosamine J Carb Chem2001 20 733-746
[63] Xin Y C Mallet J M Sinayuml P An Expeditious Synthesis of AC-Disaccharide Using A Temporary Silaketal Connection J ChemSoc Chem Commun 1993 864-865
[64] (a) Petitou M Herault P Lormeau J-C Helmboldt A MalletJ-M Sinayuml P Herbert J-M Introducing A C-InterglycosidicBond in A Biologically Active Pentasaccharide Hardly Affects ItsBiological Properties Bioorg Med Chem 1998 6 1509-1516 (b)Sinayuml P Advances in The Synthesis of the Carbohydrate MimicsPure Appl Chem 1998 70 1495-1499
[65] Sinayuml P Chemical Synthesis of Oligosaccharide Mimetics PureAppl Chem 1998 70 407-410
[66] Sinayuml P Chemical Synthesis of Oligosaccharide Mimetics PureAppl Chem 1998 69 459-463
[67] Vauzeilles B Sinayuml P Selective Radical Synthesis of β-C-Disaccharides Tetrahedron Lett 2001 42 7269-7272
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1397
Scheme (7)
Scheme (8)
An open chain sugar derived aldehyde was used to accessa C-trehalose derivative through the Henry reactionCondensation of 36 with aldehyde 41 in the presence of KFand crown ether 18-crown-6 gave adduct 42 which wasimmediately converted to 43 with a sequence of reactions in29 overall yield The intermediate was finally transformedto the C-linked-(1rarr1)-disaccharide 44 (C-ββ-trehalose)(Scheme 10) [17]
Martin and coworkers applied the same methodologyto prepare an OC-trisaccharide namely methyl O-β-D-glucopyranosyl-(1rarr4)-C-β-D-glucopyranosyl-(1rarr6)-D-
glucopyranoside 48 [18] The condensation of compound 45with 6-aldehydo-glucopyranoside 46 in the presence of KFin an aprotic medium afforded the desired pseudotri-saccharide 47 in 73 yield Application of the samechemistry to 47 gave the target compound 48 (Scheme 11)
Kobertz and coworkers utilized Martinrsquos methodology toprepare C-allolactose Nitro sugar 49 was condensed withaldehyde 50 afforded the adduct 51 as a mixture ofdiastereomers The hydroxyl group was converted to thecorresponding phenyl thiocarbonate ester 52 Treatment withtin hydride and a radical initiator effected elimination
OO
OR OR
O SiMePh
O
HO
PhMe2SiZnMe2 Li
O
TBSO
TBSO
OTBS
OTBS
H
O
O
OR
SiMePh
TBSO
OTBS
OTBS
OH
HOHO
TBSO
O
O
TBSO
TBSO
OTBS
OTBS
OH
H
O
OR
SiMePh
Me4NBH(OAc)3
R = (t-Bu)Me2Si
+
1 THF -78 oC
2 NH4Cl H2O
3 HCl H2O 20 oC
1 (c-hex) 2BCl Et3N
2
27
28
29
30 24 over 2 steps31 59
O
O
O
O O
NO2
TBAF
O
OH
OO
OO
O
O
OO O
NO2
OO
O
OO
OH
O
O
OO O
OO
O
OO
H
OAc
32
3334 78
1 Ac2O Pyr2 Bu3SnH AIBN
35 89
1398 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
reaction yielding only E-olefin 53 Finally the olefin wasreduced with dimide (generated in situ) and benzyl etherswere removed by dissolving metal reduction to afford thetarget disaccharide 54 (Scheme 12) [19]
Gurjar et al synthesized the first methyl α-C-D-araf-(1rarr5)-α-D-araf 60 the C-disaccharide segment of motif Cof Mycobacterium tuberculosis through nitro-aldol conden-
sation The coupling reaction between 55 and 56 gavediasteromeric mixture 57 which was subjected to threesubsequent steps ie dehydration selective reduction ofconjugated olefin and denitration to give the penta-O-benzylC-disaccharide 59 (Scheme 13) [20]
Witczak has used nitro anions for C-disaccharidesynthesis Michael addition of the nitro anion derived from
Scheme (9)
Scheme (10)
OAcO
AcOOAc
OAc
NO2O
OH
O
O
OO
OHO
HOOH
OH
O
HO
HOOH
OH
Bu3 SnH
OAcO
AcOOAc
OAc
NO2
OO
O
OO
OH
OAcO
AcOOAc
OAc
X
OO
O
OO
KF 18-C-6 MeCN
1 Ac2O Pyr2 NaBH4 EtOH
38 X = NO 2
39 X = H 57
1 NaOMe
2 H3O+
36
33
37
40 89 over 2 st eps
CHO
O
O
O
O
CH2OPiv
OAcO
AcOOAc
OAc
NO2
OHO
HOOH
OH
O OH
OH
HO
OH
OAcO
AcOOAc
OAc
NO2
PivO
OH
O
O
O
O
OAcO
AcOOAc
OAc
NO2
PivO
O
O
O
O
1 Ac2O Pyr2 80 AcOH3 Ac2O Pyr
1 AcOH
2 Ac2O-BF3 OEt
KF 18-C-6 MeCN
41 36
42
4344
3 Bu3SnH AIBN
4 NaOMe
5 H3O+
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1399
61 to levoglucosenone 62 gave adduct 63 in 43 yield Thesterics in 62 dictates the facial bias of the addition whichcan only occur from the α-face Reductive denitrationfollowed by reduction of lactol and ketone afforded 64 Ringopening deprotection and acetylation gave 65 (Scheme 14)[21]
23 Sulfur Stabilized Anions
The Taylor group employed the Meyers variant of theRamberg-Baumlcklund reaction to synthesize C-disaccharides[22] The penta-O-benzyl thioglucose 66 was coupled withiodide compound 67 followed by oxidation of the formedsulfide gave sulfone 68 Exposure of the sulfone to theMeyers variant of the Ramberg-Baumlcklund reaction affordedexo-glycal 69 as a mixture of isomers in 48 yieldHydrogenation of this mixture stereoselectively reduceddouble bond and cleaved the benzyl groups Peracetylated C-
trehalose 70 was furnished by acetylation of free sugar(Scheme 15)
This approach is well suited to analog synthesis simplyby varying the alkylating agent Thus the homologous(1rarr1rsquo)-C-disaccharide containing a two-carbon bridge(ldquohomoisotrehaloserdquo) was readily prepared (Scheme 16)[23] Lactol 71 was converted into sulfonate 74 by astraightforward three-step sequence involving Moffat-typeC-glycosylation to give ester 72 followed by reduction andmesylation Next 74 was coupled with thiol 75 in a similaralkylation-oxidation sequence to that above The resultingsulfone 77 underwent a halogenative Ramberg-Baumlcklundrearrangement (RBR) to give exo-glycal 78 as a 8812mixture of (Z)- and (E)-isomers in 57 yield Subsequentreductiondebenzylation followed by acetylation producedthe novel ethylene-bridged disaccahride 79
Scheme (11)
Scheme (12)
OBnO
OBnOMe
BnO
NO2
OBnO
OBn
BnO
OBn
CHO
OHO
OH
HO
OH
OHO
OHOMe
HO
OBnO
OBn
BnO
OBn
OBnO
OBnOMe
BnO
NO2R
OBnO
OBn
BnO
OBn
OBnO
OBnOMe
BnO
KF 18-C-6 MeCN+
1 n-BuLi2 PTC-Cl
51 R = OH
52 R = OC(S)OPh
Bu3 SnH AIBN
1 TsNHNH NaOAc
2 Na NH3
49
50
5354
OAcO
OAc
AcOO
OAcO
OAc
OAc
NO2OAc
OAc
AcO
OAcO
BnOOBn
OMe
BnO
OO
AcOOAc
OAc
OAcO
OMe
BnO O
BnOOBn
O
OO
AcOOAc
OAc
NO2
OAcO
OAc
AcO
OAcO
BnOOBn
OMe
BnO
OH
KF 18-C-6 MeCN
1 Ac2O Pyr2 NaBH4 EtOH3 Bu3SnH AIBN4 H2 Pd(OH)2
5 NaOMe MeOH
45
46
47
48
1400 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
This group also reported a rapid synthesis of a range ofC-disaccharides involving a tandem Horner-Wadsworth-Emmons (HWE)conjugate-addition C-glycosylation followedby a tandem halogenation-RBR sequence utilizing Meyersvariant of the RBR [24] The HWE reagent 81 proceeded theHWEconjugate-addition sequence with diisopropylidenemannofuranose 80 in 86 yield to produce the adductsulfone 82 (as a mixture of diastereomers) The keyhalogenation-RBR was carried out using the conditions
devised by Chan et al giving E-alkene 83 as the onlyisolable product Alkene hydrogenation and concomitantdebenzylation followed by acetylation for characterizationpurposes gave the novel disaccharide 84 in 69 yield overthe two reactions (Scheme 17)
A two-directional variant of this methodology can beused to prepare symmetrical C-disaccharides as shown inScheme 18 [24] The double HWE reaction on diisopro-pylidene mannofuranose 80 worked extremely well in the
Scheme (13)
Scheme (14)
BnO
OBn
O2N
OMe
O
CHO
OBnO
OBn
BnO
OMe
OHO
OH
OHO
OH
HO
OMe
OBnO
OBn
OBnO
OBn
BnO
HO
NO2
OMe
OBnO
OBn
OBnO
OBn
BnO
X
+
KF 18-C-6 MeCN
1 Ac2O Pyr2 NaBH4 EtOH
58 X = NO 2
59 X = H 44 over 3 st eps
Bu3SnH AIBN
Pd(OH)2 H2
rt 1 atm 24 h
40
60 74
55
56
57
O
BnOOBn
BnO
OBn
OH
O
OHNO2
O
O
BnOOBn
BnO
OBn
OH
O
ONO2
O
O
O
O
O
AcOOAc
AcO
OAc
O
OAc OAc
OAc
O
BnOOBn
BnO
OBn
NO2OH
Et3 N MeCN
1Bu3 SnH AIBN
2 BF OEt Et3SH
3 L-SelectrideTHF
64 61 in 3 steps
1 Pd(OH)2 C6 H10
2 Ac2O TESOTF
61 63 43
62
65
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1401
HWEconjugation-addition C-glycosydation sequence givingdiastereomeric sulfones 85 in a combined yield of 75RBR of the major stereoisomer (βα-79) using the Meyers-
Chan procedure gave alkene 86 in 66 unoptimized yieldand hydrogenation produced the novel C-linked bisfuranosedisaccharide 87 in 76 yield
Scheme (15)
Scheme (16)
OBnO
BnO
H
OBn
OH
OOBn
BnO
OBn
OBn
BnO
OBn
OBn
OBnO
BnO
OBn
OH
SO2
O
OBn
O O
AcO
AcO
AcO
OAc
OAc
OAc
OAc
OAc
OBnO
BnO
OBn
OH
I
O
HS
OBn
BnO
OBn
OBn
68 90 over 2 steps
KOH CCl4 t-BuOH H2O
1 H2 PdC
2 Ac2O Pyr
70 69 over 2 steps
+
1 K2CO3
2 mCPA66
67
69
O
BnOOBn
BnO
OBn
OH
(EtO)2P(O)CH2CO2Et
OBn
OBn
OBnO
OBn
OBnO
BnOOBn
OBn
X
O OBn
OBn
BnOOBn
OBnO
BnOOBn
OBn
OBnO
BnOOBn
OBn
R
OBnO
BnOOBn
OBn
SH
LiAlH4
OAc
AcOOAc
O OAcOAcOAcO
OAc
OAc
1 H2 Pd(OH)2C
2 Ac2 O Pyr
NaH THF
72 R = CO2Et
73 R = CH2OH
66 over 3 steps
K2CO3 acetone
76 X = S
77 X = SO2 79
Oxone THF MeOH H2 O
KOH CCl4 aq tBuOH
78 57ZE 8812
79
71
75
MsCl Et3N 74 R = CH2 OMs
1402 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Norris et al deprotonated 88 with n-BuLi and theresulting anion was coupled with an excess lactone 89 at lowtemperature to afford the adduct 90 in 77 yield SPhgroups were removed with Raney nickel and lactol 91 wasisolated as a syrup that contained two components in
approximately a 41 ratio The two compounds were thoughtto be α- and β-lactols with the latter being major It wasstraightforward to reduce the lactols with a high degree ofstereocontrol to afford the C-disaccharide 92 with a 51isolated yield (Scheme 19) [25]
Scheme (17)
Scheme (18)
O
O O
O
O OH
O OMe
OBnBnO
SO2
P
EtO
EtO
O
OBn
O
OMe
OAc
OAc
OAcO
O O
O
O
O
OO OMe
OBnBnO
SO2
OBn
O
O O
O
O O
O
O
O
OMe
OBn
OBn
OBn
83 50 E only
80
+
NaH THF -78 oC
82 86αβ 11
KOHAl2O3
CBr2F2 CH2Cl2
tBuOH 5 oC
2 h
1 H2PdC EtOAc RT 7h
2 Ac2 O Pyr RT
84 69 over 2 st eps
81
O
O O
O
O OH POEt
OEt
O
SO2
P
EtO
EtOO
O
O
O
OO
O
O
O
O O
O
O
O O
O
O
O
O SO2
O
O
O
O
O
O O
O
OO
O
O
85 75βαββ ca 31
86 66β αββ = 141 E only
H2PdC EtOAc
87 76βαβ β = 141
21 NaH THF -78 o C
80 (2 equiv)
KOHAl2O3CBr2F2 CH2Cl2tBuOH
on majorβα is omer
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1403
24 Phosphorous Stabilized Anions
The most common type of reaction discussed in thissection is Wittig approach to C-oligosaccharide synthesisThis methodology is particularly suited for synthesis of(1rarr6)-C-saccharides since one sugar can hold the aldehydewhile the other the ylid or phosphonate anion
Dondoni has utilized this approach to prepare a variety ofβ-D-(1rarr6)-C- disaccharides The general approach is shownin Scheme 20 Coupling of β-linked galactopyranosyl ormannofuranosyl derivative (93 94 95 or 96) with ylidefrom phosphonium iodide 97 or 98 gave alkene 99 Alkenewas reduced and removal of deprotecting groups gave thecorresponding β-D-(1rarr6)-C- disaccharide 100 [26]
α-D-(1rarr6)-C-disaccharide 103 was also synthesizedusing the approach (Scheme 21)
Dondoni applied this methodology in an iterative fashionto prepare the corresponding β-(1rarr6)-C-trigalactosides andβ-(1rarr6)-C-tetragalactosides [27] Starting with coupling ofylide 104 generated in situ with aldehyde 33 gave adduct105 (EZ 19) Removal of silyl protecting group followed byoxidation led to aldehyde 106 which was coupled with theylide from 104 to give C-trisaccharide 107 in 36 yield Thesame sequence was repeated with 107 afforded the protectedC-tetrasaccharide alkene 108 Compounds 108 wasdesilylated and exposed to hydrogen over Pd(OH)2 oncarbon followed to peracetylation gave protected C-tetrasaccharide 109 (Scheme 22)
Taking advantage of their experience on the stereo-selective synthesis of C-oligosaccharides by iterative Wittigolefination this group developed new building blocks and amodified protocol for the straightforward assembly of C-α-(1rarr5)-D-oligoarabinofuranosides [28] While the twomonofunctionalized sugar moieties 110 and 111 weresuitable precursors to the head and tail of the oligo-saccharidic chain the difunctionalized compound 114 was arepeating unit (Scheme 23) Building block 114 wasdesigned to allow after the Wittig coupling for regenerationof the formyl group in a single step under conditions that donot affect the chemical and stereochemical integrity of thegrowing saccharidic chain (Scheme 24)
Colinas et al reported a method for the synthesis of C-disaccharides by a sequence involving the Wittig reaction askey step and further glycosydation of these compounds toafford new C O-trisaccharides [29] The enol ether 122a-bwere prepared by the Wittig reaction of the α β mixture of2-deoxiglycosyl phosphonium salts 120a-b with aldehyde121 Hydrogenation of the exo-glycals afforded the β-C-disaccharides with good yields The O-glycosidationemploying the exo-glycals and the glycosyl acceptor 124 isillustrated in Scheme 25
25 C-1 Vinyl Anions
Schmidt was the first to explore the addition of sulfoxide-stabilized vinyl C-1-organolithiums to carbohydrate-basedcarbonyl compounds [30] The vinyl sulfoxide 126 was
Scheme (19)
OCH3
O O
OPhS
PhS
O O
OO
OCH3
O O
OO O
O H
OCH3
O O
OPhSPhS
O O
O OH
OCH3
O O
OO O
O OH
+
n-BuLi THF -78 oC
Raney Ni EtOH H2O rt
Et3SiH BF3 OEt2
90 77
92 51 over 2 steps 91 is omers rati o βα = 41
-78 oC
88
89
1404 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
deprotonated with LDA to give 127 Addition of 127 toaldehyde 128 gave a mixture of diastereoisomers of whichthe major 129 was formed in a 101 ratio Desulfurizationhydroboration and removal of benzyl groups gave the(1rarr5)- βminusC-disaccharide 130 (Scheme 26)
Schmidt and coworkers used this methodology for ahighly efficient synthesis of an analog of C-trehalose 134Scheme 27 [31] Anion 131 was converted to aldehyde 132
and condensation of this aldehyde with the same anion gaveadduct 133 which was then converted to the target C-disaccharide 134
26 Acetylide-Based Anions
Sinayuml was the first to prepare a C-disaccharide Hisapproach involved the coupling of a C-6 alkyne with ananomeric lactone followed by reduction of the formedhemiacetal [32] Aldehyde 135 was converted to the
Scheme (20)
Scheme (21)
OO O
O
O CHO
O
BnOOBn
BnO
OBn
CHO
OBn
CHO
BnO
O
BnOBnO
O
BnOOBn
BnO OBn
CHO
PPh3I-
OO
O
OO
O
OMeOBn
OBn
OBn
PPh3I-
OCHO
O
PPh3I-
ORRO
RO
OO
ORRHO
OO
OR
+ +
+
( 93 - 96 )
( 97 - 98 )
BuLi THF-HMPA
-30 iexclaelig
99
Reduction
100
+
93 9495
96 97 98
O
OBnBnO
BnO
OO
O
OO
HO
O
O
OO
PPh3I-
O
OHHO
HO
O
HOOH OH
HO
OBnBnO
CHO
BnO
O
+
BuLi THF-HMPA
-30 oC
1 p-MeC 6H4SO2-
NH2NH2 AcONa
2 H2 Pd(OH)2 3 bar
3 Amberli te H+
+
10197
102
103
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1405
dibromoalkene 136 which was treated with n-butyllithium togive an intermediate acetylide 137 The latter uponnucleophilic addition to lactone 138 gave a mixture of lactol139 in high yield Stereoselective reduction of lactol 139 wasfollowed by hydrogenation of benzyl groups and the triplebond affording the (1rarr6)-β-C-disaccharide 140 (Scheme28)
The lactone-addition methodology was later applied bySinayuml and co-workers in an iterative fashion for the
preparation of higher homologues [33] Hydroxylmethylenein compound 141 was converted to acetylide lithium incompound 142 by a sequence of reactions Condensation ofcompound 142 with the galacto lactone 143 gave 144 asmixture of anomers The lactol were stereoselectivelyreduced to and triple bond was hydrogenated to give 145Methyl glycoside 145 was hydrolyzed to the correspondinglactols which were oxidized to lactone 146 The samesequence was then repeated twice to give C-trisaccharide147 and C-tetrasaccharide 148 (Scheme 29)
Scheme (22)
O
BnOOBn
BnO OTBDPS
PPh3I-
BnO
H
O
BnOOBn
OTBDPS
OO
O
OO
O
CHOO
O
OO
O
BnO
O
BnOOBn
BnO
OO
O
OO
H
HOBn
BnO OTBDPS
O
BnOOBn
BnO O
OO
O
OO
H
OBn
BnO OTBDPS
PPh3I-
O
BnO
O
BnOOBn
BnO OTBDPS
PPh3I-
O
AcOOAc
AcO
O
AcOOAc
AcO
OO
O
OO
O
AcOOAc
AcO OAc
O
BnOOBn
BnO
O
BnOOBn
BnO
OO
O
OO
H
H
O
BnOOBn
BnO OTBDPS
H
1 TBAF2 PCC
+107 36
+
1 TBAF2 PCC3
+
1 TBAF2 H2 Pd(OH)2 C3 Ac2 O Pyr
104
33
105
106104
104
108109
BuLi THF-HMPA
-50 o C
70EZ 19
BuLi THF-HMPA
-50 o C
1406 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
The di- tri- and tetrasaccharide derivatives (145 147 and148) were all debenzylated and tested for their bindingaffinity to three different monoclonal immunoglobulins withspecificity for different O-β-(1rarr6)-D-galactopyranosyl deter-minants These C-saccharide analogs had similar bindingproperties to the corresponding O-saccharides
Schmidt has also used acetylide-lactone condensation toassemble C-disaccharides of ketoses [34] Lithium acetylide149 was condensed with ketone 150 to give a mixture ofalcohol 151 after removal of the pivoloyl group Attemptedcyclization under Lewis acid catalysis resulted only in theremoval of the acetonide Accordingly the diol was tiedback as the carbonate and the acetylene complex as thedicobalt species 152 The isomers were then separately
cyclized to give a 11 mixture of C-disaccharide 153 Thecobalt complex on α-C-disaccharide was removed understandard conditions to give 154 and deprotection of thecarbonate was followed by hydrogenation and peracetylationto give 155 (Scheme 30) Similar chemistry was also carriedout with the corresponding β-isomer
Van Boom and co-workers used lithiated alkynylderivative 156 in presence of ZnCl2 to selectively open ringof the 12-anhydrosugar 157 affording the α-C-(alkynyl)-glycoside 158 Hydrogenolysis of the benzyl groups wasfollowed by peracetylation to give the (1rarr6)-α-C-disaccharide 159 (Scheme 31) [35]
Normally attack of the nucleophile proceeds from anequatorial direction to give the β-isomer The unexpected
Scheme (23)
Scheme (24)
BnOO
OBnCHO
OBn
O
OBn
PPh3I-
OBn
OBn
O
OBn
BnOBnO
O
OBnOBn
OBnH
O
OH
HOHO
O
OHOH
OH+
BuLi
THF-HMPA
-20 oC+
1 TBAF2 H2 Pd(OH)2C
112 65 113 100
110
111
O
OBnCHO
OBnBnO
O
OBn
BnOBnO
O
OBnCH(OiPr)2
OBnH
O
OBnCH(OiPr)2
PPh3I-
OBn
O
OBn
BnOBnO
O
OBn
OBnH
O
OBnOBn
BnOH
O
OH
HOHO
O
OH
OH
O
OHOH
HO
++
BuLi
THF-HMPA
-20 oC
BuLi
THF-HMPA
-20 oC
TFA H2 O THF rt
115 49
116 R = CH(OiPr)2
117 R = CHO
118 45
H2 Pd(OH)2C
110
114
114
119
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1407
Scheme (25)
Scheme (26)
OBn
R1
R2
PPh3BF4-O
O
OOHC
O
O
O
O
O
O
O
O
HO
O
O
O
O
O O
OBn
R1
R2
O
O
O
O
O
O
H
O
OBn
R1
R2
O
O
O
O
O
O
O
O
OBn
R1
R2
O
O
O
+
BCl3 (005 equiv)
MS 4A CH2 Cl2 0 o C
+
BuLi THF -90 oC -90 o C
to rtH2 (1 atm) PdC Et3N MeOH
R1 R2 = OBn H
120a - b
121
122a - b
123a - b
124
125a - b
OTBDPS
BnO X
SO Ph
O
BnO
OHCO
BnO
OMeOBn
OBn
O
BnO
OTBDPS
BnO
SO Ph
O
BnO
OMeOBn
OBn
O
HO
OMeOH
OHO
HOHO
OH
OH
128
229 74
1 RaNi (74)
2 BH3 DMS
NaOH H 2O2 (74)
3 H2 PdC (70)
130 74
LDA THF
-100 oC
126 X = H
127 X = Li
1408 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (27)
Scheme (28)
stereochemical outcome is rationalized by the generation ofan initial zinc acetylide species which facilitates intra-molecular delivery to the α-face (Scheme 32)
Wightman synthesized C-disaccharide analogs of the α-D-arabinofuranosyl-(1rarr5)-α-D-arabinofuranosyl motif ofmycobacterial cell walls through alkynyl intermediates [36]The lactone 164 was treated with lithio(trimethylsilyl)ethyneat low temperature to give lactol in 66 yield of 165Treatment of this with triethylsilane and BF3
Et2O gavethe separable isomers 166α (60) and 166β (13)Desilylation of the major isomer 166α gave 167 in 97yield Treatment of 167 with n-BuLi followed by addition oflactone 164 gave 85 yield of the hemiacetal 168 which onreduction with Et3SiH and BF3
Et2O gave the disubstitutedalkyne 169 (83) as the major product Reduction-
hydrogenolysis of 169 then gave the C-disaccharide 170 innear-quantitative yield (Scheme 33)
3 REDUCTIVE GLYCOSYL SAMARIUM SPECIES
The introduction of SmI2 as reducing agent can becredited to Kagan and has since been utilized in numeroussynthetic schemes [37] Sinayuml and Beau introduced SmI2
chemistry into C-glycoside synthesis through intermolecularreactions with appropriate electrophiles and intramolecularreactions of silyl tethered substrates [38] Anomericsamarium species are highly stable and not likely to undergoβ-elimination Treatment of the aryl sulfone 171 with SmI2
affords the nucleophilic intermediate 172 through two singleelectron transfer processes Introduction of a suitableelectrophile (carbonyl compounds) affords the α-C-manno-
O
BnO
OTBDPS
BnO X
SO Ph
O
BnO
OBn
BnO Li
SO Ph
DMF
OHO
HOOH
OH
O OH
OH
HO
OHOH
O
BnO
OTBDPS
BnO
SO Ph
O
OBn
OBnOBnSO
Ph
OH
131 X = Li
132 X = CHO
THF -100 oC
1 Ra-Ni
2 BH3 DMS NaOH H2O2
3 H2 PdC
131
133
134
OBnO
OBnOMe
BnO
Li
OBnO
BnOOBn
OBn
OOBn
OBnOMeBnO
OH
OBnO
BnOOBn
OBn
O
n-BuLi
BnO
OMe
BnO
BrBr
O
OBn
OHO
OH
OH
HO
OHO
OH
HO
OMe
O
BnO
OMeOBn
O
BnO
139 92
1BF3 OEt2 EtOH
2 H2 PdC AcOH
140 52 over 2 steps
135 136 137
138
CBr4 PPh3
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1409
pyrannoside 173 in good yield and with excellent stereo-selectivity (Scheme 34) [38a]
Preparation of C-glycosides of ulosonic acids using SmI2
was pioneered by Linhardt and coworkers [39] Coupling ofpyridyl sulfone 174 with aldehyde 175 in the presence ofSmI2 gave an excellent yield of the N-acetylneuraminic acidC-disaccharide 176 as single isomer This stereochemicaloutcome was rationalized on the basis of the Felkin-Anhmodel for predicting the stereochemical outcome of akinetically controlled addition of a nucleophile to a chiraladehyde (Scheme 35 A)
Reductive samarium method was utilized to synthesizesialo-antigen C-analogs by the Linhardt group A fullyprotected C-analogue of the SialylTn antigen α-D-Neu5Ac-(2rarr6)α-D-GalNAc-(1rarrO)-Ser 182 was prepared [40] C-glycosylation of the neuraminic acid sulfone donor with
aldehyde acceptor in presence of excess SmI2 afforded the α-C-glycoside 180 as an RS mixture (11) The criticalintermediate aldehyde acceptor 178 was prepared in 13steps Chemoselective resolution to compound 180 wasundertaken by oxidation with DMSOAc2O to keto-bridgedcompound 181 followed by stereoselective reduction withZn(BH4)2 to regenerate the bridge hydroxyl function gave182 in gt90 de (Scheme 36)
A common versatile N-acetylneuraminic acid C-disaccharide precursor of the C-glycoside analogs ofgangliosides GM4 and GM3 has been synthesized [41]Samarium(II) iodide coupling of N-acetylneuraminic acidsulfone 179 with a 3-formyl galactopyranoside derivative183 afforded the corresponding C-disaccharide 184 as amixture of (R) and (S) isomers at the newly formedhydroxymethylene bridge This diastereoisomeric mixturewas resolved after debenzylation of the galactoside residue
Scheme (29)
O
BnO
BnOOBn
OBn
OOBn
OBnOMe
OBnOH
O
BnO
BnO
OBn
OBn
O
O
BnOOBn
OMe
BnO
Li
OBnO
OBn
OBn
OBnO
OBn
OBn
OMe
OBnO
OBn
OBnBnO
OBnO
OBn
OBn
OBnO
OBn
OBn
OMe
OBnO
OBn
OBnOBnO
OBn
OBnBnO
O
BnO
BnO
OBn
O
OBnO
OBn
OBnBnO
OBnO
OBn
OBnBnO
OBnO
OBn
OBn
OMe
OBnO
OBn
OBnBnO
OMe
1 PCC2 CBr4 Ph3P3 n-BuLi
144 overall yield 54
1 BF3 OEt2 Et3 OH
2 H2 PtO2 EtOAc
145 76
1 H2 SO4 AcOH
2 PCC
146 62
repeat steps
repeat st eps
141 142
143
147
148
1410 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (30)
Scheme (31)
O
BnOOBn
OMe
Li
BnO
OPivBnO
OBn
OBn
BnO
O OO
BF3 OEt2
OBnO
OBn
OBn
BnO
OO
O
OMe
BnOOBn
BnO
Co(CO)3
Co(CO)3
O
CAN
OBnO
OBn
OBn
BnO
OO
OO
BnOOBn
BnO
OMe
OHBnO
OBn
OBn
BnO
OHO
O
O
OMe
BnOOBn
BnO
Co(CO)3
Co(CO)3
O
OPivBnO
OBn
OBn
BnO
OH OO
O
OMe
BnOOBn
BnO
OAcO
OAc
OAc
AcO
OAcOAc
OAcO
OAc
AcO
OMe
1
2 NaOMe MeOH
1 Lewis acid2 ClCO2CCl3 Pyr3 Co2(CO)8
with a-isomer
1 Et3N Pyr H2O
2 H2 PdC H+
3 Ac2 O Pyr
149 151
152153
154 155
150
OBn
BnO
OBnO
OBn
BnO
OBnO
BnO
MeO
OBnO
OBn
BnO
O
OMe
AcO
OAcO
OAc
OAc
AcO
OAcO
OAc
O
BnOOBn
OMe
BnO
159 74 over 2 steps
+
BuLi ZnCl2 THF
1 H2 PdC2 Ac2O Pyr
156 157
158 59
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1411
Scheme (32)
Scheme (33)
and the chirality of each isomer assigned after acetylationConversion of the p-methoxyphenyl group in the peracety-lated (S) isomer 187 into the corresponding thiophenylglycoside 188 was accomplished affording the key inter-mediate for the synthesis of C-glycoside analogs of GM4GM3 and other related gangliosides (Scheme 37)
Ganglioside GM4 is a very important cell adhesionmolecule The C-disaccharide of GM4 is currently beingsynthesized in Linhardtrsquos lab using standard O-glycosylationof C-disaccharide with protected ceramide Once theceramide has been attached it can be oxidized to afford analdehyde group for coupling to keyhole limpet hemocyanin
OBnO
OBn
BnO
O
OBnO
ClZnO
OBn
BnOCl
R
OBnO
O
OBn
BnOCl
ZnR
O
ZnR
OBnO
OBn
BnO
160 161
162163
O
OBn
OBnBnO
O
O
OBn
OBnBnO H
TMS
O
OBn
OBnBnO H
O
OBn
BnO
OBnHO
O
OBn
OBnBnO OH
TMS
OBnBnO HO
OBn
TMS
O
OR
ORRO H
O
OR
RO
OR
OBn
OBnBnO
H
TMS
O+
K2CO3 MeOH
1 n-BuLi THF -78 oC
2 164
164165 66
166α 60 166β 13167 97
BF3 Et 2O Et 3SiH -78 oC
168 85
169 R = Bn 83
170 R = H near quantitative yield
H2 (1 atm)Pd(OH) 2C
TMS-acetyl ene
n-BuLi THF -78 oC BF3 Et2O Et3SiH
-78 o C
1412 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
O
OHCOBn
OBnBnO
OMe
O
CO2MeAcO
OAcAcHN
OAc
SO2
NAcO
OBnH
H
OBn
OBn
H
O
OMeH HH
A
O
CO2MeAcO
OAcAcHN
OAc
O
OBnOMe
OBnOBn
HO
AcO
+
Nu
174175
176
SmI2 THF
Scheme (34)
Scheme (35)
Scheme (36)
O
BnO
BnO
BnO
Si lylO
O2S N
O
BnO
HO R2R1
BnOBnO
SilylO
OBnO
BnO
BnO
SilylO
Sm(III)
R1COR2 SmI2 THF
171 172
173
NHBoc
OAcO
AcO
AcHN O
O
CO2BnO
OO
OO
OH
O
CO2MeAcO
OAcAcHN
OAc
AcO
SO2Ph
R2
O
CO2Me
AcHN
OAc
AcO
R1
AcO
AcO
AcHNO CO2Bn
NHBoc
AcO
OAc
O
Zn(BH4)2
180 R1 R2 = H OH ( RS 11)
181 R1 R2 = O
182 R1 = H R2 = OH de gt 90
DMSO Ac2O
177178
179
13 steps
22 equiv SmI2 THF
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1413
Scheme (37)
Fig (2)
(KLH) by reductive amination for use as carbohydrate-basedvaccine GM3 a related trisaccharide containg gangliosideplays an important role in cell growth and differentiationFig 2 The synthesis of C-oligosaccharide GM3 is currentlyunderway following a similar route to that of C-GM4synthesis [42]
Beau also reported a sialyl C-disaccharide synthesiswhich relied on the unprecedented use of a stable andcrystalline 2-pyridyl sulfide of the N-acetylneuraminic acidderivative 189 as the anomeric precursor in a samarium-Reformastky procedure [43] The coupling procedure withsulfide 189 and aldehyde 190 afforded the carbon-linkeddimer 191 in 93 yield as a 11 diastereomeric mixture
Alcohols 191 were converted into thiocarbonates anddeoxygenated by employing triphenyltin hydride catalyticAIBN and pentafluorophenol which yielded C-disaccharide192 as a single compound in 65 yield for the 2 stepsDesilylation hydrogenolysis acetylation and finalacetolysis of the methyl glycoside provided the carbon-linked mimic 193 of the disaccharidic component of thesialylTn tumor antigen (Scheme 38)
4 CATIONIC METHODS
This section is categorized according to reactions thatinvolve the generation of anomeric ions followed by thecapture with sugar-based nucleophiles
OAcAcHN
OAc
AcO
O
OBnBnO
OBnOMP
HO
O
MeO2CAcO
O
MeO2CAcO
OAcAcHN
OAc
AcO
O
OHHO
OHOMP
HO
O
OBnOHC
OBnBnO
OMP
O
MeO2CAcO
OAcAcHN
OAc
AcO
O
OHHO
OHOMP
HO
O
CO2MeAcO
OAcAcHN
OAc
AcO
SO2Ph
O
MeO2CAcO
OAcAcHN
OAc
AcO
O
OAcAcO
OAcX
AcO
H2 PdC EtOAc CH3OHH2O
+
Ac2O Pyr
187 X = OMP
188 X = SPh 73
184 85 R and S mixture
186 90 for two i somers
+
SmI2 THF183
179
185
O
HO2 CHO
OAcAcHN
OH
HO
O
OHHO
OH
OAcO
(CH2 )12 CH3
HN
OH
(CH2)14CH3
O
O
O
OHHO
OH
O
O
HO2 CHO
OAcAcHN
OH
HO
O
OHHO
OH
O(CH2)12CH3
HN
OH
(CH2)1 4CH3
GM4
GM3
1414 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
41 Exo-glycals as Nucleophiles
Nitotra et al have found that treatment of exo-glycal 194with BF 3
OEt2 followed by a water quench afforded the C-disaccharide 195 (Scheme 39) It is noteworthy tonoteworthy that the attack of the enol ether on the anomericoxonium ion occurs with high stereoselectivity on the α-face only 195 was obtained [44]
42 Silyl-based Nucleophiles
Isobe has designed and developed alkynylation as a keyreaction for the introduction of a carbon chain onto sugarsThose alkynylated compounds are called ldquosugar acetylenesrdquo[45] The mechanism includes eliminative formation ofcation to which silylacetylene can coordinate on the α-face(Scheme 40)
Double C-glycosylation between glycal 198 and bis(silylacetylene) gave C-disaccharide ldquolikerdquo compounds 199and 200 (Scheme 41)
Silylpropargyl-sugar 201 smoothly reacted with D-glucalto furnish exclusively the α-acetylene glycoside product 202in 88 (Scheme 42) [46]
5 CYCLIZATION METHODOLOGY
This approach to C-oligosaccharide synthesis relies onthe coupling of an open chain fragment with an intact
monosaccharide to give an intermediate that is then cyclizedto deliver the C-oligosaccharide target This section isdivided by the type of chemistry used to initially assemblethe two pre-cyclization fragments
51 Wittig Reaction-Cyclization
The Kishi group was the first to use Wittig-cyclizationapproach to synthesize C-disaccharides Starting with Wittigreaction between 203 and 204 the intermediate 205 wasafforded as a single stereoisomer in 82 yield Osmylationthen gave a mixture of diols with the major one formed in a61 ratio Selective protection of the diols gave 206a and206b The mono-para-methoxybenzyl ether 206a was thentransformed into the hemiketal 207 in 75 overall yield inthree steps ie (1) Swern oxidation (2) acetonide hydro-lysis (4 N HClTHFrt) and (3) benzoylation (3 equiv ofPhCOClpyCH2Cl2rt) Silane reduction of 207 in an acidicmedium should preferentially yield the equatorially substi-tuted β-C-glycoside which was deblocked and converted tothe methyl- βminusC-disaccharide 209 Exact parallel experi-ments applied to the minor isomer gave the correspondingC-disaccharide 210 (Scheme 43) [47]
Armstrong has employed Wittig-osmylation protocol forthe preparation of a small library of α-C-(1rarr6)-disaccha-rides [48] Readily available allyl C-glycoside 211 washomologated to diene ester 212 and subjected to osmylation
Scheme (38)
O
CO2MeAcO
OAcAcHN
OAc
AcO
S(2-Py)
O
TESO
AcHNOMe
O
HO
O
CO2MeAcO
OAcAcHN
OAc
AcO
O NHAcOAc
OAc
OAc
O
CO2MeAcO
OAcAcHN
OAc
AcO
O NHAcOBn
OTES
OMe
OAc
AcO
O NHAcOBn
OTES
OMeOH
O
CO2 MeAcO
OAcAcHN
+
192 65
1 MeOHHCl2 H2 PdC EtOH3 Ac2O Pyr4 Ac2OAcOHH2SO4
193 59 overall yield
25 equiv SmI2 THF
1 11-thiocarbonyldiimidazole DMAP2 Ph3SnH cat AIBN
191 93
189
190
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1415
Scheme (39)
Scheme (40)
Scheme (41)
OBnO
OBn
OBn
OBnO
OBn
OBn
OBnO
OBn
OBn
OBnO
OBnCH3
BnO
OH
CH2
OBnO
OBn
CH3
OBn
H2 O
BF3 OEt2 MeCN
194
195 96
OOAc
OAc
AcO
R SiMe3
SnCl4
O
OAc
AcO
R
O
OAc
AcO
O
OAc
AcO
Me3Si
R
SiMe3
196
197
Me3 Si SiMe3
O
AcO
OAc
OAc
SiMe3
SiMe3
O
AcO
OAc
O
OAc
OAc
O
AcO
AcOO
OAc
OAc
SnCl4 CH2Cl2
SnCl4 CH2Cl2198
199
200
1416 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (42)
Scheme (43)
AcO
OAc
OAc
Me3 Si
BnO
OBn
BnO
OBn
AcO
OAc
BnO
OBn
BnO
OBn
+ I2 CH2Cl2
202 88
198 201
O
OBn
OBn
O
O
O
OBn
OBn
O
O
OBn
OBn O
OBn
OBn
O
OPBH2M
OH
OBnO
BnO
BnO
O
OBn
OBn
O
OHOPMB
OHO
HO
HO
O
OH
OHOH
OH
HOOMe
O
OBnOBn
O
Ph3P
O
O
OBn
OBn O
OBn
OBn
O
OPBM
OH
O O
CHO
OBn
BnO
OO
OBn
OBn
O
OHOPMB
BnO
BnO
BnO
OHO
HO
HO
O
OH
OHOH
OH
HOOMe
+ THF -78 oC
1 OsO4 pyr THF
2 NaH PMBBr
206a 206b 206a206b 61
1 Swern [O]2 4N HCl3 PhCOCl pyr
1 Swern [O]2 4N HCl3 PhCOCl pyr
1 PrSiH BF3 OEt2
2 H2 Pd(OH)2C
3 HCl MeOH 90 oC
1 PrSiH BF3 OEt2
2 H2 Pd(OH)2C
3 HCl MeOH 90 o C
203
204
205
207
209
208
210
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1417
followed by reduction to afford a 51 mixture (213214215216) of lactols that were readily separable by chromato-graphy Following a deprotection of an equimolar mixture of213 and 214 217 and the DL hybrid C-disaccharide of D-glucose-O-(1rarr6)-L-galactose 218 were obtained The DDand DL derivatives 219 and 220 of glucose-α-(1rarr6)-idosewere also obtained as a near equimolar mixture afterdeprotection of 215 and 216 (Scheme 44)
52 Anion Addition-Cyclization
Kishi developed an approach for the synthesis of theCndashtrehalo sugars which relied on nucleophilic addition ofone intact sugar fragment to a fundamental aldehyde ieKishi-Nozaki reaction [49] Coupling of monosaccharide221 and aldehyde 222 gave 223 The triple bond waspartially reduced and osmylation was followed by selectiveprotection to afford 224 The acetonide was converted toepoxide 225 by standard methods and removal of the PMBgroup Acid-catalyzed cyclization followed by aglyconichydrolysis and protection of hydroxyl group with (p-methoxyphenyl)diphenylmethyl chloride (MMTrCl) gave226 Inversion of the C-2 hydroxyl and removal of protectinggroups delivered α α-C-trehalose 227 (Scheme 44)
Kishi and co-workers also employed aldol reactions as anefficient access to the C-trisaccharide related to the type IIABO(H) blood group determinant [50] Aldol condensationof the enolate of methyl ketone 228 with aldehyde 229 gavea 41 mixture of hydroxy ketones 230 and 231 The majorketol was cyclized desulfurized and oxidized to afford thedisaccharide ketone 233 The ketone in THF was treatedwith LiHMDS (3 equiv) and TMEDA followed by theaddition of MgBr2 Addition of the aldehyde 234 led toalmost exclusive formation of the equatorial products 235and 236 in a 12 ratio Mesylation of 235 and 236 followedby treatment with liquid ammonia gave enones 237a and237b which were reduced to yield exclusively the C-2rsquo-equatorial ketone 238 Sodium borohydride reduction of theC-3rsquo carbonyl proceeded with the desired stereoselectivity toyield the protected C-trisaccharide 239 which wasdeblocked to provide the polyol 240 (Scheme 46)
Sutherlin and Amstrong cleverly applied a recursivestereochemical deconvolution (RSD) combinatorial approachfor the synthesis of a small library of C-trisaccharides aspotential inhibitors for the cell surface proteins of bacteriumHelicobactor pylori [51] The workers chose to carry outvariations in galactose ring of these trisaccharides An
Scheme (44)
OBnO
BnOOBn
OBn
P O
OEtOEtO
EtO
R H
OH
OH
OH
OH
O
R H
OH
OH
OH
OH
O
OHO
HOOH
OH
O
HO
OHOH
OH
OHO
HOOH
OH
O
HO
OH
OH
OHO
HOOH
OH
O
HO
OH
OHOH
R H
OH
OH
OH
OH
O
R
OBnO
BnOOBn
OBn
O
OHO
HOOH
OH
OO
HOHO
OH
R H
OH
OH
OH
OH
O
1 OsO4 NMO 50
2 DIBAL -32 oC 40
++ +
213 214 215 216
217 218 219 220
1 9-BBN H2O22 Swern [O]
3 t-BuOK
4 I2 C6H6212
211
1418 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
efficient Nozaki-Kishi coupling of vinyl bromide 241 withaldehyde 242 in a diasteromeric ratio of 12 followed byprotection with TBSOTf led to 243 and 244 Hydroborationfollowed by oxidation gave aldehydes 245 and 246respectively Addition of allylmagnesium bromide toaldehyde 245 followed by removal of the silyl groupafforded 247 to 246 giving 248 and 249 Epoxidation gave a11 mixture of the corresponding epoxides which werecyclized to give the C-trisaccharide 250-255 after removalof the benzyl groups (Scheme 47)
Schmidt reported a stereoselective 6-exo-trig selectiveelectrophilic cylization approach for de novo synthesis of amethylene-bridged Neu5Ac-α-(23)-Gal C-disaccharide theC-analog of an important motif in glycosphingolipids [52]The open chain precusors 259ab (a 32-mixture ofdiaseteromeric alcohols) were formed by the addition oflithiated iodide 256 to open chain aldehyde 258 Subsequent
C1 incorporation using Tebbe-reagent formation of a cycliccarbonate and deprotection of the two isopropylidene ketalsafforded tetrol 264 which upon treatment with phenylselenyltrifilate was steroselectively cyclized in a 6-exo-trigselective manner affording a diasteromeric mixture of 251and 252 in a ratio of 71 A seleno-Pummerer rearrangementto afford aldehyde 267 in 5 steps in 90 overall yieldOxidation of the aldehyde and subsequent steps led to thedesired C-disaccharide 268 (Scheme 48)
53 Esterification-Cyclization
Work from the Postema group has focused on a ringclosing metathesis (RCM) approach for the synthesis of C-saccharides [53a] The chemistry is versatile and has beenused for the synthesis of a small library of differentiallylinked β-C-disaccharides through a radical allylation-RCMstrategy [53b] The synthesis of the β-(1rarr4)-glucopyranosyl
Scheme (45)
O
OBn
BnO
BnO
BnO
I
CrCl2-NiCl2O
OBn
OH
BnO
BnO
BnO
O
O
O
O
O
H
OBn
O
O
OBnBnO
BnO
BnO
OOBn
OBn
OAc
PMBOHOO
OBn
BnO
BnO
BnO
O
OBn
OBn
OAc
O
OH
HO
HO
HO
OH
OH
OH
O
OH
O
OBn
BnO
BnO
BnO
OBn
OBn
OAc
O
MMTr
+
1 p-TsOH2 K2CO3 MeOH3 MMTrCl pyr
1 Swern [O]2 BH3 THF
3 AcOH-H2 O4 H2 Pd(OH)2
221
222
223
1 Pd-Pb CaCO3 H22 NaH BnBr3 OsO44 Bu2 SnO5 CsF PMB-Cl6 Ac2 O 4-DMAP
1 AcOH2 TsCl pyr
3 NaH-imid4 DDQ
224225
226 227
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1419
Scheme (46)
OBnO O
OBn
OMe
OBn
XY
SMe
OBnBnO
O
OBn
OBn
OBn
OBn
O
BnO
YX
OBn
TBSO
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnOOBn
H
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnO
OBn
OHC OBn
OBn
OTBS
OMe
BnOOBn
CHO
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnOOBn
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnO
OBn
YX
OBnO O
OBn
OMe
OBn
OBn
O
BnO
O
OBn
OBn
OBn
OBn
O 1 LiHMDS
2
228
1 TBAF THF
2 MeSH BF3 OEt2
230 X = OH Y = H231 X = H Y = OH
230231 41
1 Bu3SnH AIBN2 Swern [O]
1 LiHMDS THF-TMEDA2 MgBr23
1 MsCl
2 liquid NH3
235 X = OH Y = H236 X = H Y = OH Bu3 SnH AIBN
237a and 237b
NaBH4 MeOH
238
239 X = OBn
240 X = OHH2 Pd(OH)2
229
232233
234
1420 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (47)
OH C
O
O BnAcHN
OO
O
OBn OBnOBn
Br
O
OBn OBnOBn
O
OBnA cHN
OO
O TBSO
OBn O BnO Bn
O
OBnAcHN
OO
OTBS
S2
S1
S2
OTBSS1
O H
S2
OT BSS1
O H
MgBrMgBr
S2
O TBSS1
O H
S2
OHS1
OH
S2
OTBSS1
OH
O
OHHO
O H
O
HO
H OO
OBnA cH N
HO
H O
O
O HHO
OH
O
HOHO
O
OBnA cH N
HO
H O
O
OHH O
OH
O
H O
HOO
OBnAcHN
HO
HO
O
O HH O
OH
O
H O
H O O
OBnA cHN
HO
HO
O
O HH O
O H
O
HO
H O O
OBnAcHN
HO
HO
O
OHHO
OH
O
H O
O
OBnA cHN
HO
HOHO
+
241 242
1 CrCl2-NiCl2 T HF-DMF 722 TBSOTf 2 6-lutidine 91
243 244
1 9-BBN 602 Dess-Mart in period inane 97
1 9 -BBN 552 D ess-Martin periodinane 98
245 246
1
2 T BAF 74
1
2 TBAF 88
247 248 249
250
251
250 251 1 1 252 253 1 1 254 255 1 1
252
253
254
255
1 MCPBA2 CSA CH 2Cl2 61 fo r 2 steps3 H 2 Pd (O H)2C 95
1 MCPBA2 CSA CH 2Cl2 63 fo r 2 s teps3 H 2 Pd (OH)2C 87
1 MCPBA2 CSA CH2Cl2 80 for 2 steps3 H2 Pd(O H)2C 95
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1421
Scheme (48)
O
OO
Se Ph
R
O
HO OHOH
O
OB n O B n
OB n
O B nO O
O O
R O OR
X
O
OO
R
Se Ph
O
HOOH
OH
O
OB nOB n
O Bn
OB n
O O
O O
R O O R
O H
O
O B n OB n
O B n
OB n
O
C HO
O
O O
R O OR
OAc HN
OAc
C O2NH 4HOOH
OH
O
OH O H
OH OH
O
OB n O B n
OB n
OB nO O
O O
R O OR
X
O
O
OAcOAc
C HOA cOOAc
OAc
O
OB n O B n
OB n
OB n
O
O Bn OB n
OB n
OB n
X
OH
OO
HOOH
OH
O
O
OMeOB n
OB nOB n
R
t-B uL i256 R = Li
257 R = L i
258
(R = t-B uMe 2Si )
(R = t-B uMe 2Si )
259ab (32) 79 com bine d yi eld
De ss-Ma rtin pe riodinane
260 X = O R = t-B uMe 2Si ) 95
261 X = O R = t -B uMe2S i) 62
T e bbe re age nt
TB A F THF262 X = O R = H 94
diphosge ne
C H2C l 2Pyr
263 95
T HFH2O T FAr t
264 quant it a ti ve yie ld
PhSe C l AgOT f
EtC N -80 oC
265
266
Quant it at i ve yi l ed 25 26 7 1
+
R =
1 Ac 2OPyr
2 mC PB A3 Ac 2ONa OAc
4 NaO HT HFMe OH
5 Ac2O P yr
267 90 overa ll yi e ld
ste ps
268
1422 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
glucopyranoside 280 represents an example of thischemistry The known triacetyl glucopyranoside 269 wasconverted to iodide 270 in good yield Radical allylation of271 proceeded to afford a mixture of equatorial and axialallylation products in a 61 ratio Oxidative cleavage of thedouble bond gave the corresponding aldehydes 273a and273b which were separable Pinnick oxidation of the majoraldehyde 273a then gave the C-4 equatorial acid 274 DCC-mediated coupling of alcohol 275 and acid 274 proceeded toafford ester 276 in good yield Methylenation of 276 gave277 and exposure to catalysist 278 gave a 41 yield of theC-disaccharide glycal which was exposed to an excess ofBH3
THF to give 64 yield of the β-C-disaccharide 279Removal of the benzyl groups and global peracetylation gavethe peracetylated (1rarr4)-β-C-disaccharide 281 in good yield(Scheme 49)
54 Ring Expansion-Cyclization
Nelson developed a new strategy for asymmetric andstereoselective synthesis of C-linked disaccharide mimeticsthe C58-C71 fragment of palytoxin [54] The diol (RR)-282was converted into the di-dihydropyran (DHP) template 283284 and 285 The di-DHPs were functionized in a twodirectional sense using dihydroxylation reactions The two-directional approach was often very efficient indeed forexample in the synthesis of 286 six new stereogenic centerswere introduced with almost complete stereocontrol using areduction and a dihydroxylation reaction The approach isnot restricted to the synthesis of C2-symmetricaldisaccharide mimetics Using the unsymmetrical template285 which has both a pseudo-axial and a pseudo-equatorialhydroxyl groups the unsymmetrical mimetics 289 and 290were prepared (Scheme 50)
6 RADICAL APPROACHES
The radical approach for C-C bond formation is a popularmethod within organic chemistry The use of radicalchemistry in carbohydrate synthesis has certain advantagesFirstly the reaction conditions are very mild and tolerant ofa range of functional and protecting groups Secondanomeric radicals are stable with respect to elimination andepimeration Most significantly the chemistry required toincorporate an appropriate substitute at C-1 employed in theinitial hemolytic cleavage step is common within carbo-hydrate chemistry [55] The use of such radical techniquecan be subdivided into two classes intermolecular andintramolecular approaches
61 Intermolecular Radical Approaches
Giese was the first to employ an intermolecular radical-based approach for synthesis of C-disaccharides [56]Addition of an alkene to an anomeric radical underappropriate conditions allowed exclusive entry to the α-linked C-glycoside a result which was mirrored by the workof Baldwin [57] The high α-selectivity of the reaction wasin contrast with other reports Thus radicals generated at theC-2 C-3 and C-4 centers all preferred to occupy equatorialpositions [58] When the anomeric bromide 291 was treatedwith tin hydride and AIBN resulting anomeric radical andreacted with lactone 292 in a Michael addition it afforded293 In this reaction hydrogen abstraction at the resulting
radical center occurs from axial face to selectively generatethe equatorial C-2rsquo substituent Reduction and acetylation of293 furnished C-disaccharide 294 (Scheme 51) [59]
Witczak used the facial bias of levoglucosene tostereoselectively add a carbohydrate-based radical in thepreparation of the 3-deoxy-(1rarr4)-β-C-disaccharide 299[60] Addition of the radical derived from iodide 295 to 296gave adduct 297 in 26 yield Removal of the anomerichydroxyl of 297 was achieved by treatment with triethylsilane borontrifluoride ether complex followed bystereoselective reduction of the keto function at C-2rsquo withthe formation of 298 in 89 yield Debenzylation followedby acetolysis of 16-anhydro ring produced the peracetylatedtarget C-disaccharide 299 in 19 overall yield from 295(Scheme 52)
Vogel has developed general methods to transformenantiomerically pure 7-oxabicyclo[221]heptyl derivatives(ldquonaked sugarsrdquo) into C-disaccharides Because of thesechiral bicyclic skeletons they undergo highly stereoselectivereactions with predictable diasteroselectivities An arsenal ofmethods is available that allow to substitute these ldquonakedrdquocarbon centers with a variety of functional groups with allpossible relative configurations The methods allowpreparation of both enantiomers of a given target with thesame ease Predictably high stereoselectivity of the reactionsof the bicyclic chirons adds to the flexibility of approachwhich can lead to high molecular diversity [61]
α-C-(1rarr3)-mannopyranoside of N-acetyl-galactosaminepotent β-galactosidase inhibitors was synthesized by thisapproach [61] Enone 302 was readily prepared from 300The addition of the radical derived from bromide 303 toenone 302 afforded the αminusisomer 304 The ketone was thenreduced and the selenide eliminated via the intermediacy ofthe selenoxide to give 305 Acid-promoted (CF3SO3H) 7-oxa ring opening of 305 in MeCN produced the amino-conduritol derivative 306 resulting from the quenching of theallylic cation intermediate by the solvent (Ritter reaction)Ozonolysis of the chloroalkene 306 generated an acylchloride-aldehyde intermediate that reacted with MeOH toproduce a mixture of methyl uronates The major compound307 was silylated and reduced The crude polyol obtainedwas acetylated to produce 308 Desilylated and ammonolysisafforded a mixture of α-β-pyranoses 309 and correspondingα-β-furanoses (Scheme 53)
Similar chemistry was carried out to synthesize non-protected α-C(1rarr2)-L-fucopyranoside of D-galactopyrano-side corresponding to a blood group mimetic [62] Giesersquosradical fucosidation of racemic enone 310 with α-L-bromoacetofucose 311 provided the mixture of diastereo-meric α-C-fucoside 312a and 312b in reproducible yield of78 Reduction of the mixture gave a 11 mixture of endo-alcohols 313 and 314 which were isolated pure in 40 and355 yield respectively Oxidative elimination of thebenzeneselenyl group of 313 followed by acetylation gaveendo acetate 315 in 85 yield Acid-promoted ring openingof 315 and ozonolysis of the resulted chloroalkene gavemethyl uronic ester 316 in modest yield (10) Treatment of316 with Cl3CCN and NaH followed with BF3
OEt2
furnished the totally protected C-disaccharide 317 in 79
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1423
Scheme (49)
Bu3SnO
HOAcO
OMeOAc
OAc
O
AcO
OMeOAc
OAcI
AIBN
O
AcO
OMeOBn
OBn
HO2C O
AcO
OMeOR
ORY
X
OHBnO
BnO
OBn
OBnO
BnO
OBn
O
AcO
OMeOBn
OBnX
i-Pr i-Pr
N
Mo C(Me2 Ph)((CF3)2 MeCO)2
O
RO
OMeOR
O
RO
OR
OR
RO
OR
278
I2 Ph3P
imidazole
269 270 93
271a X = CH2CH=CH2 Y = H R = Ac 64271b Y = CH2CH=CH2 X = H R = Ac 11272a X = CH2CH=CH2 Y = H R = Bn 75272b Y = CH2CH=CH2 X = H R = Bn 75273a X = CH2CHO Y = H R = Bn 79273a Y = CH2CHO X = H R = Bn 79
1 NaOMe MeOH2 NaOH BnBr DMF
OsO4 NaIO4
NaClO2 NaH2PO4
274 96
275
DCC 4-DMAP
276 X = O 82
277 X = CH2 51
TiCl4 Zn dust TMEDA CH2Br2PbCl2 (Cat )
1
2 BH3 THF H2O2 NaOH
H2 PdC EtOH
Ac2 O Pyr 4-DMAP
279 R = Bn R = H 64
280 R = R = H 99
281 R = R =Ac 97
1424 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (50)
Scheme (51)
O OOH
OH
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
286
1 VO(acac)2 t-BuOH 95
2 (MeO)3CH BF3 90
1 P-O2NC6H4 CO2H Ph3P DIAD2 K2CO3 MeOH 82 over 2 steps
1 PhCOCl Et3N DMAP 402 P-O2NC6H4 CO2H Ph3P DIAD3 KOH THF-H2O 75 over 2 steps
TMEDA OsO4
Cat OsO4 NMO 287
Cat OsO4 NMO288
TMEDA OsO4
Cat OsO4 NMO
290
289
(RR)-282283
284
285
OHO
AcO
BrOAc
OAc
BnO
O
OBn
OBnO
OHO
AcOOAc
OAc
BnO
OOBn
OBnAcO
OHO
AcOOAc
OAc
BnO
O
OBn
OBnO
+
Bu3SnH AIBN291
292
293 81
1 Na[Al(OC2H4OMe)2(OEt)H]2 Ac2O pyr
294 56 over 2 steps
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1425
Scheme (52)
Scheme (53)
OBnO
BnOOBn
OBn O
OH
O
OBnO
BnO
OHOBn
OBn O
O
O
O
O
O
OBnO
BnOOBn
OBnO
OAcOAc
OAc
OBnO
BnO
OHOBn
OBn
IBu3SnH AIBN
295 297 26
1 BF3 OEt2 Et3SiH
2 L-Selectride THF
1 Pd(OH)2C C6H10 EtOH
2 EtSiOSO2CF3 Ac2O
298 89 over 2 steps299
296
O
O
PhSeClO
O
PhSeCl
Bu3 SnH
O
O
PhSeCl
R
H
O
OAc
R
Cl
O
AcO
OAc
OAc
OAcOH
Cl
NHAc
R
OAc
AcHN
OH
O
OH OAc
OH
OHO
HO
OH
O
AcO
OAc
OAc
OAcBr
O
O
PhSeCl
O
O
PhSeCl
R
O
OTIPSAcHNR
OAc OAc
O
OHAcHN
COOMe
R
OAc
1 Bu4NF
2 NH3MeOH
1 (Me3Si)2NLi THF2 Me2N=CHI
1 Bu3 SnH AIBN2
1 NaBH42 mCPBA3 Ac2O pyr
1 H+ MeCN
2 H2 O NaHCO3
R =
1 O3MeOH
2 Me2S NaHCO3
1 TIPSOTf 26-lut idine2 LiBH43 Ac2 O pyr DMAP
furanoses +
304 56
305 68 306 84307 50
308 46
300 301 302
303
309
1426 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
The reduction of 317 and treatment with DOWEX-H+ resinprovided the desired C-fucoside 318 in 70 (Scheme 54)
62 Intramolecular Radical Approaches
One disadvantage with the intermolecular approaches isthat during such radical mediated reactions electrondeficient alkenes are required to facilitate C-C bondformation The intramolecular approach of Sinayuml overcomes
this drawback by bring two substrates together via atemporary covalent silaketal connector This enables the useof a wider range of alkenes which can include alkene-functionalized sugars thus leading to the generation of C-disaccharides [63] Based on the early work of Stork Sinayumlemployed the tether reaction in the synthesis of both α- andβ-C-disaccharides with this work subsequently beingemployed in the synthesis of biologically significant natural
Scheme (54)
O
OH
Fuc
Cl
O
O
ClPhSe
OOAc
NHAcOHFuc
O
AcOOAc
AcO
Br
O
O
PhSeCl
O
AcOOAc
AcO
O
OH
PhSe Cl
Fuc
OOAc
NHAc
OMe
Fuc
O
AcHN
OH OAc
OH
O
OH
Me
OH
O
O
Fuc
ClSePh
O
HO
Fuc
ClSePh
+
Ph3SnHAIBN
78 combined yield
Fuc
310
+
1 NaBH4 MeOHTHF2 Chromatography
313 40 314 355
1 mCPBA
2 Ac2O pyr DMAP
+
315 75
1 TfOH MeCN
2 NaHCO3 O3 -78 oC
316 10 over 2 steps
1 Cl3 CCN NaH
2 MeOH BF3 OEt2
317 79
1 LiBH4 THF
2 Dowex-H+
311
312a312b
318 70 for 2 steps
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1427
products [64] The availability of different hydroxyl groupson each monosaccharide unit allowed the fine-tuning ofstereochemical outcome by selective positioning of the silyltether [65] Development of this early stereochemical controlled to the tethering of the donor 320 with alcohol 319through a di-isopropyl silicon tether 321 Subsequent treat-ment with Bu3SnH and AIBN led to a 9-endo-trigcyclization to form the C-disaccharide 322 in an 80 yieldwith exclusive formation of the α-product The silyl tetherwas removed with Bu4NF and deprotection under standardconditions afforded the desired disaccharide 323 in excellentyield (Scheme 55)
In parallel the development of a 32rsquo silyl tether allowedaccess to the β-linked product as demonstrated in Sinayumlrsquossynthesis of methyl β-C-lactoside 328 [66] Alcohol 324 and320 were connected via the dimethylsilyl tether an 8-endo-trig cyclization followed to exclusively afford the β-
disaccharide 326 in 45 yield Removal of the tether anddeprotection of benzyl ether gave β-C-disaccharide 328(Scheme 56)
This group also selected iodosugars bearing a freehydroxyl group as progenitors of the radical donors [67] In atypical experiment the radical donor 329 was connected tothe radical acceptor 330 through a silaketal tether followingtheir procedure Tributyltinhydride mediated 8-endo-trigradical cyclization of compound 331 gave after detetheringof the non isolated intermediate 332 the protected β-C-disaccharide 333 in 37 overall yield (from startingmaterials 330 and 329) Peracetate 335 was achieved afterhydrogenolysis The C-laminaribioside 334 is of potentialbiological interest as it mimics the repeating disaccharideunit of fungal β-(1rarr3)-glucans which have antitumor andimmunomodulating properties (Scheme 57)
Scheme (55)
Scheme (56)
OO
OHSePh
OTBDPSO O
OO
SePh
OTBDPSO
OO
OBnOMe
OBn
Si
O
HOOBn
OMe
OBn
O
HOOH
OHHO
O
HOOH
OMe
OH
OTBDPSO
O
HOOBn
OMe
OBnO
OOH
1 n-BuLi THF
2 iPr2SiCl2 -78 oC
3 DMAP THF rt
1 Bu4NF THF
2 Dowex-H+
3 H2 PdC
Bu3SnH AIBN toluene
319
320
321
322323
OBnO
OHSePh
OBnBnO
OHO
OBnOMe
OBn
ROO
ROOH
OR
OHO
OROMe
OR
OBnO
O
OBnBnO
OO
OBnOMe
OBn
Si
SePh
OBnO
O
OBnBnOO
OOBn
OMe
OBn
Si
1 PhSeH Me2SiCl2
BuLi -78 oC
2 imidazole rt
Bu3SnH AIBN toluene
H2 PdC327 R = Bn
328 R = H
Bu4NF THF
324
320
325
326 45
1428 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
CONCLUSIONS
In this paper the biological importance of C-oligo-saccharides as subunits of natural products and as a newgeneration of carbohydrate based on therapeutics has beenillustrated Different methods are available for the synthesisof C-oligosaccharides As with traditional saccharidesynthesis it has been necessary to develop a number ofspecific approaches to facilitate the regioselective andstereoselective preparation of the desired targets Work inthis area continues and it is expected that many interestingnew C-oligosaccharides will be prepared using the chemistrydescribed in this review It is also likely that new chemistrywill be developed in the future for the preparation of thesebiologically important targets
ACKNOWLEDGEMENTS
The authors thank Dr Sultan Baytas for her criticalreading of this manuscript
REFERENCES
[1] Kennedy J F White C A Bioactive Carbohydrates InChemistry Biochemistry and Biology Ellis Horwood LtdChichesterUK 1983
[2] Wassarman PW Mammalian Fertilization Molecular Aspects ofGamete Adhesion xocytosion Exocytosis and Fusion Cell 199996 175-183
[3] Carbohydrate-based Drug Discovery Wong C-H EdWeinheim Cambridge Wiley-VCH 2003
[4] (a) Sharon N Lis H Lectins as Cell Recognition MoleculesScience 1987 246 227-234 (b) Dwek RA Chem Rev 1996 96683-720
[5] Postema M C-Glycoside synthesis CRC Boc Ratom 1995[6] (a) Weatherman R V Mortell K H Cheruenak MKiessling
L L Toone E J Specificity of C-Glycoside Complexation byMannoseGlucose Specific Lectins Biochem 1996 35 3619-3624(b) Ravishankar R Surolia A Vijayan M Lim S Kishi YPreferred Conformation of C-Lactose at the Free and Peanut LectinBound States J Am Chem Soc1998 120 11297-11303
[7] (a)Wong C-H Halcomb R L Ichikawa Y and Kajimoto TEnzymes in organic synthesis Application to the problems ofcarbohydrate recognition part2 Angew Chem Int Ed Engl 199534 521-546 (b)Howard S Withers SG Bromoketone C-Glycosides a New Class of βminusGlucanase Inactivators J AmChem Soc 1998 120 10326-10331(c) Wang Q Wolff MPolat T Du Y Linhardt R J C-glycoside of Neuraminic Acidsas Neura-minidase Inhibitors Bioorg Med Lett 2000 10 941-944 (d) Phili R Chang J Partis R A Mueller R A ChrestF J Passaniti A The Alpha-glucosidase I InhibitorCastanospermine Alters Endothelial cell Glycosylation PreventsAngiogenesis and Inhibits Tumor Growth Cancer Res 1995 552927-2935
[8] Ossor A Elbein A D In Carbohydrates in Chemistry andBiology Vol 3(II) WileyVCH 2000 pp 513-539
[9] (a) Sinayuml P Synthesis of oligosaccharide Mimetics Pure ApplChem 1997 69 459-463 (b) Beau J-M Gallagher TNucleophilic C-glycosyl Donors for C-glycoside Synthesis Top inCurr Chem 1997 187 1-54 (c) Nicotra F Synthesis of C-glycosides of Biological Interest Top in Curr Chem 1997 187
Scheme (57)
O
O
O
Ph
I
OMe
OHO
BnO
OH
OH
BnOOH
O
BnO
Si
O
O O
Ph
I
OMe
O
O
BnO
OR4O
R5O
OMe
OR2
OR3O
R3O
OR1
R3O
Bu3 SnH AIBN
332 R1 R2 = SiMe2 R3 = Bn R4 R5 = CHPhTBAF THF
333 R1 = R2 = H R3 = Bn R4 = R5 = CHPh 37 from 11
334 R1 = R2 = R3 = R4 = R5 = H
335 R1 = R2 = R3 = R4 = R5 = Ac
329
H2 PdC MeOH
Ac2 O pyr
1 BuLi THF -78 oC
2 Me2SiCl2
3 DMAP
330
331
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1429
55-83 (d) Du Y Linhardt R Y Recent Adv in Stereo-SelectiveC-Glycoside Synthesis Tetrahedron Lett 1998 54 9913-9959 (e)Liu L Mckee M and Postema M H D Synthesis of C-saccharides and Higher Congeners Current Org Chem 2001 51133-1167
[10] Jarosz S Fraser-Reid B Synthesis of A Higher Carbon Sugar ViaDirected Aldol Condensation Tetrahedron Lett 1989 30 2359-2362
[11] Lichtenthaler F W Lergenmiiller M Schwidetzky S C-Glycosidations of 2-Ketohexosyl With Electrophilic Radical andNudeophilic Anomeric Carbons Eur J Org Chem 2003 3094-3103
[12] Baudat A Vogel P Aza-C-disaccharides Synthesis of 6-Deoxygalactonojirimycin-β-C(1rarr3) Linked with D-Altrofuranosides and D-Galactose J Org Chem 1997 62 6252-6260
[13] Turner D Vogel P Synthesis of 4-Hydroxy-26-Bis(hydroxymethyl) tetrahydropyran-2-Carbaldehyde DerivativesSynlett 1998 304-306
[14] Zhu Y-H Vogel P Short Stereoselective Synthesis of C-(1rarr3)-Linked Disaccharides Tetrahedron Lett 1998 39 31-34
[15] Zhu Y-H Vogel P Synthesis of a (2R 6R)-2-(Hydroxymethyl)-6-Propa-1 2-Dienyl-2H-Pyran-3(6H)-One Derivative A NewEnone for The Convergent Construction of C-Glycosides of C-Disaccharides Synlett 2001 82-86
[16] Baumberger F Vasella A Deoxynitrosugars The 6th
Communication Stereolectronic Control in the reductivedenitration of tertiary nitro ethers A Synthesis of ldquoC-glycosidesrdquoHelv Chim Acta 1983 66 2210-2221
[17] Martin O R Lai W Synthesis and Conformational Studies of β-(1rarr6)- and ββ-(1rarr1)-Linked C-disaccharides J Org Chem1993 58 176-185
[18] Spak S J Martin R The synthesis of an analogue of Methyl OC-Analogue of Methyl 4rsquo-O-β-D-GlucopyranosylgentiobiosideTetrahedron 2000 56 217-224
[19] Kobertz W R Bertozzi C R Bednarski M D C-GlycosylAldehyde Synthons for C-Linked Disaccharides J Org Chem1996 61 1894-1897
[20] Gurjar M K Nagaprasad R and Ramana CV First Synthesis ofMethyl α-C-D-Arabino-furanosyl-(1rarr5)-αminusD-Arabinofuranosidethe C-Disaccharide Segment of Motif C of MycobateriumTuberculosis Tetrahedron Lett 2000 43 7577-7579
[21] Witczak Z J Synthesis of C-Glycosyl Compounds and OtherNatural Products from Levoglucosenone Pure Appl Chem 199466 2189-2192
[22] Griffin F K Paterson D Taylor R J K Ramberg-BacklundApproaches to the Synthesis of C-Linked Disaccharides AngewChem Int Engl 1999 38 2939-2942
[23] Paterson B E Griffin F K Alcaraz M-L and Taylor R J KA Ramberg-Baumlcklund Approach to the Synthesis of C-GlycosidesC-Linked Disaccharides and C-Glycosyl Amino Acids Eur JOrg Chem 2002 1323-1336
[24] McAllister G D Paterson D E Taylor R J K A SimplifiedRamberg-Bachlund Approach to Novel C-Glycosides and C-Linked Disaccharides Angew Chem Int Ed Engl 2003 42 1387-1391
[25] McCartney J L Christopher T M Cicchillo R M BernardinaM D Wagner T R and Norris P J Org Chem 2003 6810152-10155
[26] Dondoni A Zuurmond H M Bascarate A Synthesis of α-andβ-D-(1rarr6)-C-Disaccharides by Witting Olefination of Formyl C-Glycosides with Glycopyranose 6-phosphoranes J Org Chem1997 62 8114-8124
[27] Dondoni A Kleban M Zuurmond H Marra A Synthesis of(1rarr6)-C-Oligogalactosides by Interative Wittig OlefinationTetrahedron Lett 1998 39 7991-7994
[28] Dondoni A Marra A A New Synthetic Approach toMycobacterial Cell Wall α-(1rarr5)-D-Arabinofuranosyl C-Oligosaccharides Teterahedron Lett 2003 44 4067-4071
[29] Colinas P A Ponzinibbio A Lieberknecht A and Bravo R OWittig Reaction of Glycosyl Phosphonium Salts A StereoselectiveRoute to C-Disaccharides and C O-Trisaccharides TetrahedronLett 2003 44 7985-7988
[30] Schmidt R R Preuss R Synthesis of Carbon Tetrahedron Lett1989 30 3409-3412
[31] Dietrich H Schmidt R R Synthesis of Carbon-Bridged C-Lactose and Derivatives Liebigs Ann Chem 1994 975-981
[32] Rouzaud D Sinayuml P The First Synthesis of a ldquoC-DisacchariderdquoJ Chem Soc Chem Commun 1983 1353-1354
[33] Xin Y-C Zhang Y-M Mallet J-M Glaudemans C P JSinayuml P Synthesis of C-Oligosaccharides That Mimie TheirNatural O-Analogues Immunodeterminants in Binding toMonoclonal Immunoglobulins Eur J Org Chem 1999 471-476
[34] Streicher H Geyer A Schmidt R R C-Disaccharides ofKetoses Chem Eur J 1996 2 502-510
[35] Leeuwenburgh M A Timmers C M Vander Marel G A VanBoom J H Mallet J-M Sinayuml P G Stereoselective Synthesisof α-C-(Alkynyl)-Glycosides Via Ring-Opening of α-12-Anhydrous Tetrahedron Lett 1997 38 6251-6254
[36] Aslam T Fuchs M G G Le Formal A Wightman R HSynthesis of C-Disaccharide Analogue of the α-D-Arabinofuranosyl-(1rarr5)-α-Arabinofuranosyl Motif ofMycobacterial Cells Walls via Alkynyl Intermediates TetrahedronLett 2005 46 3249-3252
[37] (a) Girad P Namy J L Kagan H B Divalent LanthanideDerivative in Organic Synthesis 1 Mild Preparation of SamariumIodide and Ytterbium Iodide and Their Use as Reducing orCoupling Agents J Am Chem Soc 1980 102 2693-2698 (b)Molander G A Harris C R Sequencing Reactions withSamarium(II) Iodide Chem Rev 1996 96 307-338
[38] (a) Mazeacuteas D Skrydstrup T Doumeix O Beau J-MSamarium Iodide-Induced Intramolecular C-Glycoside FormationEfficient Radical Formation in the Absence of an Additive AngewChem Int Ed Engl 1994 33 1383-1386 (b) Mazeacuteas DSkrydstrup T Beau J-M A Highly Stereoselective Synthesis of1 2-trans-C-Glycosides Via Glycosyl Samarium(III) CompoundsAngew Chem Int Ed Engl 1995 34 909-912 (c) Jarreton OSkrydstrup T Beau J-M The Stereospecific Synthesis of Methylα-C-Mannobioside A Potential Inhibitor of M TuberculosisBinding to Human Macrophages J Chem Soc Chem Commun1996 1661-1662 (d) Jarreton O Skrydstrup T Espionosa J-FJimeacutenez-Barbero J Beau J-M Samarium Diiode Prompted C-Glycosylation An Application to The Stereospecific Synthesis ofα-(1rarr2)-C-Mannobioside and Its Derivatives Chem Eur J 19995 430-441 (e) Mipuel N Doisneau G Beau J-M ReductiveSamariation of Anomeric 2-Pyridyl Sulfones with Catalytic AnUnexpected Improvement in The Synthesis of 12-Trans-Diequatorial C-Glycosyl Compounds Angew Chem Int Ed Engl 2000 39 4111-4114
[39] Vlahov I R Vlahova P I Linhardt R J DiastereocontrolledSynthesis of Carbon Glycosides of N-Acetylneuraminic Acid ViaGlycosyl Samarium(III) Intermediates JAmChem Soc 1997 1191480-1481
[40] Kuberan B Sikkander S ATomiyama H Linhardt R JSynthesis of a C-Glycoside Analogue of sTn An HIV-and Tumor-Associated Antigen Angew Chem Int Ed Engl 2003 42 2073-2075
[41] Bazin H G Du Y Polat T Linhardt R J Synthesis of aVersatile Neuraminic Acid ldquoCrdquo-Disaccharide Precursor for theSynthesis of C-Glycoside Analogues of Gangliosides J OrgChem 1999 64 7254-7259
[42] Chen C-C Ress D K Linhardt RJ Samarium Iodide-Mediated Synthesis of Neuraminic Acid C-Glycosides InSynthesis of Glycommetics Roy R Ed ACS Syposium Series2004 896 53-80
[43] Abdallah Z Doisneau G Beau J-M Synthesis of a Carbon-Linked Mimic of The Disaccharide Component of The Tumor-Relate SialyTn Antigen Angew Chem Int Ed Engl 2003 425209-5212
[44] Lay L Nicotra F Panza L Russo G Caneva E Synthesis ofC-disaccharides through dimerization of exo-glycals J Org Chem1992 57 1304-1306
[45] Isobe M Nishizawa R Hosokawa S Nishikawa TStereocontrolled Synthesis and Reactivity of Sugar Acetylenes JChem Soc Chem Commun 1998 2665-2676
[46] Saeeng R Sirion U Sahakitpichan P Isobe M IodineCatalyzes C-Glycosidation of D-Glucal with SilylacetykeneTetrahedron Lett 2003 44 6211-6215
[47] (a) Babirad S A Wang Y Kishi Y Synthesis of C-Disaccharides J Org Chem 1987 52 1370-1372 (b) Wang YBabirad S A Kishi Y Preferred Conformation of C-Glycosides
1430 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
8 Synthesis of 14-Linked Carbon Disaccharides J Org Chem1992 57 468-481
[48] Armstrong R W Sutherlin D P Strategies for the Synthesis ofC-Disaccharides Containing D and L Sugars Tetrahedron Lett1994 35 7743-7746
[49] Wei A Kishi Y Preferred Conformation of C-Glycosides 12Synthesis and Conformational Analysis of αα- α β- and β β-Trehaloses J Org Chem 1994 59 88-96
[50] Haneda T Goekjian P G Kim S H Kishi Y PreferredConformation of C-Glycosides 10 Synthesis and ConformationAnalysis of Carbon Trisaccharides J Org Chem 1992 57 490-498
[51] Sutherlin D P Armstrong R W Synthesis of 12 Stereochemistryand Structurally Diverse C-Trisaccharides J Org Chem 1997 625267-5283
[52] Notz W Hartel C Waldscheck B Schmidt R R De NovoSynthesis of a Methylene-Bridged Neu5Ac-α-(23)-Gal C-Disaccharide J Org Chem 2001 66 4250-4260
[53] (a) Postema M H D Calimente D Liu L Behrmanm T L AnOlefin Metathesis Route for the Preparation of (1rarr6)-Linked-C-Disaccharide Glycals A Convergent and Flexible Approach to C-Saccharide Synthesis J Org Chem 2000 65 6061-6068(b) Postema M H Piper J L Liu L Faust M Andreana PSynthesis and Partial Biological Evaluation of a Small Library ofDifferentially Linked β-C-Disaccharide J Org Chem 2003 684748-4754
[54] Nelson A The Development of Strategies and Methods for TheSynthesis of Biologically Active Compounds New J Chem 200428 771-776
[55] Togo H He W Waki Y Yokoyama M C-GlycosylationTechnology With Free Radiant Reactions Synlett 1998 700-717
[56] Giese B Dupuis J Diastereoselective Synthesis of C-Glycopyranosides Angew Chem Int Ed Engl 1983 22 622-623
[57] Adlington R M Baldwin J E Basak A Kozyrod RPApplication of Radical Addition Reactions to tho Synthesis of a C-Glucoside and A Functionalized Amino Acid J Chem SocChem Commun 1983 144-145
[58] Giese B Gonzaacutelez-Goacutemez J A Witzel T The Scope of RadicalCC-Coupling by The ldquoTin Methodrdquo Angew Chem Int Ed Engl1984 23 69-70
[59] Giese B Witzel T Synthesis of ldquoC-Disaccharidesrdquo by RadicalC-C Bond Formation Angew Chem Int Ed Engl 1986 25 450-451
[60] Witczak Z J Chhabra R Chojnacki J C-Disaccharides IStereoselective Approach to β-(1rarr4)-3-Deoxy-C-Disaccharidesfrom Levoglucosenone Carb Res 1997 301 167-175
[61] Vogel P Synthesis of Rare Carbohydrates and Analogues Startingfrom Enantiomerically Pure 7-Oxabicyclo[221]heptyl Derivatives(ldquoNaked Sugarsrdquo) Current Org Chem 2000 4 455-480
[62] Viodeacute C Vogel P Synthesis of The C-Disaccharide α-C(1rarr3)-L-Fucopyranoside of N-Acetylgalactosamine J Carb Chem2001 20 733-746
[63] Xin Y C Mallet J M Sinayuml P An Expeditious Synthesis of AC-Disaccharide Using A Temporary Silaketal Connection J ChemSoc Chem Commun 1993 864-865
[64] (a) Petitou M Herault P Lormeau J-C Helmboldt A MalletJ-M Sinayuml P Herbert J-M Introducing A C-InterglycosidicBond in A Biologically Active Pentasaccharide Hardly Affects ItsBiological Properties Bioorg Med Chem 1998 6 1509-1516 (b)Sinayuml P Advances in The Synthesis of the Carbohydrate MimicsPure Appl Chem 1998 70 1495-1499
[65] Sinayuml P Chemical Synthesis of Oligosaccharide Mimetics PureAppl Chem 1998 70 407-410
[66] Sinayuml P Chemical Synthesis of Oligosaccharide Mimetics PureAppl Chem 1998 69 459-463
[67] Vauzeilles B Sinayuml P Selective Radical Synthesis of β-C-Disaccharides Tetrahedron Lett 2001 42 7269-7272
1398 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
reaction yielding only E-olefin 53 Finally the olefin wasreduced with dimide (generated in situ) and benzyl etherswere removed by dissolving metal reduction to afford thetarget disaccharide 54 (Scheme 12) [19]
Gurjar et al synthesized the first methyl α-C-D-araf-(1rarr5)-α-D-araf 60 the C-disaccharide segment of motif Cof Mycobacterium tuberculosis through nitro-aldol conden-
sation The coupling reaction between 55 and 56 gavediasteromeric mixture 57 which was subjected to threesubsequent steps ie dehydration selective reduction ofconjugated olefin and denitration to give the penta-O-benzylC-disaccharide 59 (Scheme 13) [20]
Witczak has used nitro anions for C-disaccharidesynthesis Michael addition of the nitro anion derived from
Scheme (9)
Scheme (10)
OAcO
AcOOAc
OAc
NO2O
OH
O
O
OO
OHO
HOOH
OH
O
HO
HOOH
OH
Bu3 SnH
OAcO
AcOOAc
OAc
NO2
OO
O
OO
OH
OAcO
AcOOAc
OAc
X
OO
O
OO
KF 18-C-6 MeCN
1 Ac2O Pyr2 NaBH4 EtOH
38 X = NO 2
39 X = H 57
1 NaOMe
2 H3O+
36
33
37
40 89 over 2 st eps
CHO
O
O
O
O
CH2OPiv
OAcO
AcOOAc
OAc
NO2
OHO
HOOH
OH
O OH
OH
HO
OH
OAcO
AcOOAc
OAc
NO2
PivO
OH
O
O
O
O
OAcO
AcOOAc
OAc
NO2
PivO
O
O
O
O
1 Ac2O Pyr2 80 AcOH3 Ac2O Pyr
1 AcOH
2 Ac2O-BF3 OEt
KF 18-C-6 MeCN
41 36
42
4344
3 Bu3SnH AIBN
4 NaOMe
5 H3O+
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1399
61 to levoglucosenone 62 gave adduct 63 in 43 yield Thesterics in 62 dictates the facial bias of the addition whichcan only occur from the α-face Reductive denitrationfollowed by reduction of lactol and ketone afforded 64 Ringopening deprotection and acetylation gave 65 (Scheme 14)[21]
23 Sulfur Stabilized Anions
The Taylor group employed the Meyers variant of theRamberg-Baumlcklund reaction to synthesize C-disaccharides[22] The penta-O-benzyl thioglucose 66 was coupled withiodide compound 67 followed by oxidation of the formedsulfide gave sulfone 68 Exposure of the sulfone to theMeyers variant of the Ramberg-Baumlcklund reaction affordedexo-glycal 69 as a mixture of isomers in 48 yieldHydrogenation of this mixture stereoselectively reduceddouble bond and cleaved the benzyl groups Peracetylated C-
trehalose 70 was furnished by acetylation of free sugar(Scheme 15)
This approach is well suited to analog synthesis simplyby varying the alkylating agent Thus the homologous(1rarr1rsquo)-C-disaccharide containing a two-carbon bridge(ldquohomoisotrehaloserdquo) was readily prepared (Scheme 16)[23] Lactol 71 was converted into sulfonate 74 by astraightforward three-step sequence involving Moffat-typeC-glycosylation to give ester 72 followed by reduction andmesylation Next 74 was coupled with thiol 75 in a similaralkylation-oxidation sequence to that above The resultingsulfone 77 underwent a halogenative Ramberg-Baumlcklundrearrangement (RBR) to give exo-glycal 78 as a 8812mixture of (Z)- and (E)-isomers in 57 yield Subsequentreductiondebenzylation followed by acetylation producedthe novel ethylene-bridged disaccahride 79
Scheme (11)
Scheme (12)
OBnO
OBnOMe
BnO
NO2
OBnO
OBn
BnO
OBn
CHO
OHO
OH
HO
OH
OHO
OHOMe
HO
OBnO
OBn
BnO
OBn
OBnO
OBnOMe
BnO
NO2R
OBnO
OBn
BnO
OBn
OBnO
OBnOMe
BnO
KF 18-C-6 MeCN+
1 n-BuLi2 PTC-Cl
51 R = OH
52 R = OC(S)OPh
Bu3 SnH AIBN
1 TsNHNH NaOAc
2 Na NH3
49
50
5354
OAcO
OAc
AcOO
OAcO
OAc
OAc
NO2OAc
OAc
AcO
OAcO
BnOOBn
OMe
BnO
OO
AcOOAc
OAc
OAcO
OMe
BnO O
BnOOBn
O
OO
AcOOAc
OAc
NO2
OAcO
OAc
AcO
OAcO
BnOOBn
OMe
BnO
OH
KF 18-C-6 MeCN
1 Ac2O Pyr2 NaBH4 EtOH3 Bu3SnH AIBN4 H2 Pd(OH)2
5 NaOMe MeOH
45
46
47
48
1400 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
This group also reported a rapid synthesis of a range ofC-disaccharides involving a tandem Horner-Wadsworth-Emmons (HWE)conjugate-addition C-glycosylation followedby a tandem halogenation-RBR sequence utilizing Meyersvariant of the RBR [24] The HWE reagent 81 proceeded theHWEconjugate-addition sequence with diisopropylidenemannofuranose 80 in 86 yield to produce the adductsulfone 82 (as a mixture of diastereomers) The keyhalogenation-RBR was carried out using the conditions
devised by Chan et al giving E-alkene 83 as the onlyisolable product Alkene hydrogenation and concomitantdebenzylation followed by acetylation for characterizationpurposes gave the novel disaccharide 84 in 69 yield overthe two reactions (Scheme 17)
A two-directional variant of this methodology can beused to prepare symmetrical C-disaccharides as shown inScheme 18 [24] The double HWE reaction on diisopro-pylidene mannofuranose 80 worked extremely well in the
Scheme (13)
Scheme (14)
BnO
OBn
O2N
OMe
O
CHO
OBnO
OBn
BnO
OMe
OHO
OH
OHO
OH
HO
OMe
OBnO
OBn
OBnO
OBn
BnO
HO
NO2
OMe
OBnO
OBn
OBnO
OBn
BnO
X
+
KF 18-C-6 MeCN
1 Ac2O Pyr2 NaBH4 EtOH
58 X = NO 2
59 X = H 44 over 3 st eps
Bu3SnH AIBN
Pd(OH)2 H2
rt 1 atm 24 h
40
60 74
55
56
57
O
BnOOBn
BnO
OBn
OH
O
OHNO2
O
O
BnOOBn
BnO
OBn
OH
O
ONO2
O
O
O
O
O
AcOOAc
AcO
OAc
O
OAc OAc
OAc
O
BnOOBn
BnO
OBn
NO2OH
Et3 N MeCN
1Bu3 SnH AIBN
2 BF OEt Et3SH
3 L-SelectrideTHF
64 61 in 3 steps
1 Pd(OH)2 C6 H10
2 Ac2O TESOTF
61 63 43
62
65
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1401
HWEconjugation-addition C-glycosydation sequence givingdiastereomeric sulfones 85 in a combined yield of 75RBR of the major stereoisomer (βα-79) using the Meyers-
Chan procedure gave alkene 86 in 66 unoptimized yieldand hydrogenation produced the novel C-linked bisfuranosedisaccharide 87 in 76 yield
Scheme (15)
Scheme (16)
OBnO
BnO
H
OBn
OH
OOBn
BnO
OBn
OBn
BnO
OBn
OBn
OBnO
BnO
OBn
OH
SO2
O
OBn
O O
AcO
AcO
AcO
OAc
OAc
OAc
OAc
OAc
OBnO
BnO
OBn
OH
I
O
HS
OBn
BnO
OBn
OBn
68 90 over 2 steps
KOH CCl4 t-BuOH H2O
1 H2 PdC
2 Ac2O Pyr
70 69 over 2 steps
+
1 K2CO3
2 mCPA66
67
69
O
BnOOBn
BnO
OBn
OH
(EtO)2P(O)CH2CO2Et
OBn
OBn
OBnO
OBn
OBnO
BnOOBn
OBn
X
O OBn
OBn
BnOOBn
OBnO
BnOOBn
OBn
OBnO
BnOOBn
OBn
R
OBnO
BnOOBn
OBn
SH
LiAlH4
OAc
AcOOAc
O OAcOAcOAcO
OAc
OAc
1 H2 Pd(OH)2C
2 Ac2 O Pyr
NaH THF
72 R = CO2Et
73 R = CH2OH
66 over 3 steps
K2CO3 acetone
76 X = S
77 X = SO2 79
Oxone THF MeOH H2 O
KOH CCl4 aq tBuOH
78 57ZE 8812
79
71
75
MsCl Et3N 74 R = CH2 OMs
1402 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Norris et al deprotonated 88 with n-BuLi and theresulting anion was coupled with an excess lactone 89 at lowtemperature to afford the adduct 90 in 77 yield SPhgroups were removed with Raney nickel and lactol 91 wasisolated as a syrup that contained two components in
approximately a 41 ratio The two compounds were thoughtto be α- and β-lactols with the latter being major It wasstraightforward to reduce the lactols with a high degree ofstereocontrol to afford the C-disaccharide 92 with a 51isolated yield (Scheme 19) [25]
Scheme (17)
Scheme (18)
O
O O
O
O OH
O OMe
OBnBnO
SO2
P
EtO
EtO
O
OBn
O
OMe
OAc
OAc
OAcO
O O
O
O
O
OO OMe
OBnBnO
SO2
OBn
O
O O
O
O O
O
O
O
OMe
OBn
OBn
OBn
83 50 E only
80
+
NaH THF -78 oC
82 86αβ 11
KOHAl2O3
CBr2F2 CH2Cl2
tBuOH 5 oC
2 h
1 H2PdC EtOAc RT 7h
2 Ac2 O Pyr RT
84 69 over 2 st eps
81
O
O O
O
O OH POEt
OEt
O
SO2
P
EtO
EtOO
O
O
O
OO
O
O
O
O O
O
O
O O
O
O
O
O SO2
O
O
O
O
O
O O
O
OO
O
O
85 75βαββ ca 31
86 66β αββ = 141 E only
H2PdC EtOAc
87 76βαβ β = 141
21 NaH THF -78 o C
80 (2 equiv)
KOHAl2O3CBr2F2 CH2Cl2tBuOH
on majorβα is omer
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1403
24 Phosphorous Stabilized Anions
The most common type of reaction discussed in thissection is Wittig approach to C-oligosaccharide synthesisThis methodology is particularly suited for synthesis of(1rarr6)-C-saccharides since one sugar can hold the aldehydewhile the other the ylid or phosphonate anion
Dondoni has utilized this approach to prepare a variety ofβ-D-(1rarr6)-C- disaccharides The general approach is shownin Scheme 20 Coupling of β-linked galactopyranosyl ormannofuranosyl derivative (93 94 95 or 96) with ylidefrom phosphonium iodide 97 or 98 gave alkene 99 Alkenewas reduced and removal of deprotecting groups gave thecorresponding β-D-(1rarr6)-C- disaccharide 100 [26]
α-D-(1rarr6)-C-disaccharide 103 was also synthesizedusing the approach (Scheme 21)
Dondoni applied this methodology in an iterative fashionto prepare the corresponding β-(1rarr6)-C-trigalactosides andβ-(1rarr6)-C-tetragalactosides [27] Starting with coupling ofylide 104 generated in situ with aldehyde 33 gave adduct105 (EZ 19) Removal of silyl protecting group followed byoxidation led to aldehyde 106 which was coupled with theylide from 104 to give C-trisaccharide 107 in 36 yield Thesame sequence was repeated with 107 afforded the protectedC-tetrasaccharide alkene 108 Compounds 108 wasdesilylated and exposed to hydrogen over Pd(OH)2 oncarbon followed to peracetylation gave protected C-tetrasaccharide 109 (Scheme 22)
Taking advantage of their experience on the stereo-selective synthesis of C-oligosaccharides by iterative Wittigolefination this group developed new building blocks and amodified protocol for the straightforward assembly of C-α-(1rarr5)-D-oligoarabinofuranosides [28] While the twomonofunctionalized sugar moieties 110 and 111 weresuitable precursors to the head and tail of the oligo-saccharidic chain the difunctionalized compound 114 was arepeating unit (Scheme 23) Building block 114 wasdesigned to allow after the Wittig coupling for regenerationof the formyl group in a single step under conditions that donot affect the chemical and stereochemical integrity of thegrowing saccharidic chain (Scheme 24)
Colinas et al reported a method for the synthesis of C-disaccharides by a sequence involving the Wittig reaction askey step and further glycosydation of these compounds toafford new C O-trisaccharides [29] The enol ether 122a-bwere prepared by the Wittig reaction of the α β mixture of2-deoxiglycosyl phosphonium salts 120a-b with aldehyde121 Hydrogenation of the exo-glycals afforded the β-C-disaccharides with good yields The O-glycosidationemploying the exo-glycals and the glycosyl acceptor 124 isillustrated in Scheme 25
25 C-1 Vinyl Anions
Schmidt was the first to explore the addition of sulfoxide-stabilized vinyl C-1-organolithiums to carbohydrate-basedcarbonyl compounds [30] The vinyl sulfoxide 126 was
Scheme (19)
OCH3
O O
OPhS
PhS
O O
OO
OCH3
O O
OO O
O H
OCH3
O O
OPhSPhS
O O
O OH
OCH3
O O
OO O
O OH
+
n-BuLi THF -78 oC
Raney Ni EtOH H2O rt
Et3SiH BF3 OEt2
90 77
92 51 over 2 steps 91 is omers rati o βα = 41
-78 oC
88
89
1404 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
deprotonated with LDA to give 127 Addition of 127 toaldehyde 128 gave a mixture of diastereoisomers of whichthe major 129 was formed in a 101 ratio Desulfurizationhydroboration and removal of benzyl groups gave the(1rarr5)- βminusC-disaccharide 130 (Scheme 26)
Schmidt and coworkers used this methodology for ahighly efficient synthesis of an analog of C-trehalose 134Scheme 27 [31] Anion 131 was converted to aldehyde 132
and condensation of this aldehyde with the same anion gaveadduct 133 which was then converted to the target C-disaccharide 134
26 Acetylide-Based Anions
Sinayuml was the first to prepare a C-disaccharide Hisapproach involved the coupling of a C-6 alkyne with ananomeric lactone followed by reduction of the formedhemiacetal [32] Aldehyde 135 was converted to the
Scheme (20)
Scheme (21)
OO O
O
O CHO
O
BnOOBn
BnO
OBn
CHO
OBn
CHO
BnO
O
BnOBnO
O
BnOOBn
BnO OBn
CHO
PPh3I-
OO
O
OO
O
OMeOBn
OBn
OBn
PPh3I-
OCHO
O
PPh3I-
ORRO
RO
OO
ORRHO
OO
OR
+ +
+
( 93 - 96 )
( 97 - 98 )
BuLi THF-HMPA
-30 iexclaelig
99
Reduction
100
+
93 9495
96 97 98
O
OBnBnO
BnO
OO
O
OO
HO
O
O
OO
PPh3I-
O
OHHO
HO
O
HOOH OH
HO
OBnBnO
CHO
BnO
O
+
BuLi THF-HMPA
-30 oC
1 p-MeC 6H4SO2-
NH2NH2 AcONa
2 H2 Pd(OH)2 3 bar
3 Amberli te H+
+
10197
102
103
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1405
dibromoalkene 136 which was treated with n-butyllithium togive an intermediate acetylide 137 The latter uponnucleophilic addition to lactone 138 gave a mixture of lactol139 in high yield Stereoselective reduction of lactol 139 wasfollowed by hydrogenation of benzyl groups and the triplebond affording the (1rarr6)-β-C-disaccharide 140 (Scheme28)
The lactone-addition methodology was later applied bySinayuml and co-workers in an iterative fashion for the
preparation of higher homologues [33] Hydroxylmethylenein compound 141 was converted to acetylide lithium incompound 142 by a sequence of reactions Condensation ofcompound 142 with the galacto lactone 143 gave 144 asmixture of anomers The lactol were stereoselectivelyreduced to and triple bond was hydrogenated to give 145Methyl glycoside 145 was hydrolyzed to the correspondinglactols which were oxidized to lactone 146 The samesequence was then repeated twice to give C-trisaccharide147 and C-tetrasaccharide 148 (Scheme 29)
Scheme (22)
O
BnOOBn
BnO OTBDPS
PPh3I-
BnO
H
O
BnOOBn
OTBDPS
OO
O
OO
O
CHOO
O
OO
O
BnO
O
BnOOBn
BnO
OO
O
OO
H
HOBn
BnO OTBDPS
O
BnOOBn
BnO O
OO
O
OO
H
OBn
BnO OTBDPS
PPh3I-
O
BnO
O
BnOOBn
BnO OTBDPS
PPh3I-
O
AcOOAc
AcO
O
AcOOAc
AcO
OO
O
OO
O
AcOOAc
AcO OAc
O
BnOOBn
BnO
O
BnOOBn
BnO
OO
O
OO
H
H
O
BnOOBn
BnO OTBDPS
H
1 TBAF2 PCC
+107 36
+
1 TBAF2 PCC3
+
1 TBAF2 H2 Pd(OH)2 C3 Ac2 O Pyr
104
33
105
106104
104
108109
BuLi THF-HMPA
-50 o C
70EZ 19
BuLi THF-HMPA
-50 o C
1406 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
The di- tri- and tetrasaccharide derivatives (145 147 and148) were all debenzylated and tested for their bindingaffinity to three different monoclonal immunoglobulins withspecificity for different O-β-(1rarr6)-D-galactopyranosyl deter-minants These C-saccharide analogs had similar bindingproperties to the corresponding O-saccharides
Schmidt has also used acetylide-lactone condensation toassemble C-disaccharides of ketoses [34] Lithium acetylide149 was condensed with ketone 150 to give a mixture ofalcohol 151 after removal of the pivoloyl group Attemptedcyclization under Lewis acid catalysis resulted only in theremoval of the acetonide Accordingly the diol was tiedback as the carbonate and the acetylene complex as thedicobalt species 152 The isomers were then separately
cyclized to give a 11 mixture of C-disaccharide 153 Thecobalt complex on α-C-disaccharide was removed understandard conditions to give 154 and deprotection of thecarbonate was followed by hydrogenation and peracetylationto give 155 (Scheme 30) Similar chemistry was also carriedout with the corresponding β-isomer
Van Boom and co-workers used lithiated alkynylderivative 156 in presence of ZnCl2 to selectively open ringof the 12-anhydrosugar 157 affording the α-C-(alkynyl)-glycoside 158 Hydrogenolysis of the benzyl groups wasfollowed by peracetylation to give the (1rarr6)-α-C-disaccharide 159 (Scheme 31) [35]
Normally attack of the nucleophile proceeds from anequatorial direction to give the β-isomer The unexpected
Scheme (23)
Scheme (24)
BnOO
OBnCHO
OBn
O
OBn
PPh3I-
OBn
OBn
O
OBn
BnOBnO
O
OBnOBn
OBnH
O
OH
HOHO
O
OHOH
OH+
BuLi
THF-HMPA
-20 oC+
1 TBAF2 H2 Pd(OH)2C
112 65 113 100
110
111
O
OBnCHO
OBnBnO
O
OBn
BnOBnO
O
OBnCH(OiPr)2
OBnH
O
OBnCH(OiPr)2
PPh3I-
OBn
O
OBn
BnOBnO
O
OBn
OBnH
O
OBnOBn
BnOH
O
OH
HOHO
O
OH
OH
O
OHOH
HO
++
BuLi
THF-HMPA
-20 oC
BuLi
THF-HMPA
-20 oC
TFA H2 O THF rt
115 49
116 R = CH(OiPr)2
117 R = CHO
118 45
H2 Pd(OH)2C
110
114
114
119
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1407
Scheme (25)
Scheme (26)
OBn
R1
R2
PPh3BF4-O
O
OOHC
O
O
O
O
O
O
O
O
HO
O
O
O
O
O O
OBn
R1
R2
O
O
O
O
O
O
H
O
OBn
R1
R2
O
O
O
O
O
O
O
O
OBn
R1
R2
O
O
O
+
BCl3 (005 equiv)
MS 4A CH2 Cl2 0 o C
+
BuLi THF -90 oC -90 o C
to rtH2 (1 atm) PdC Et3N MeOH
R1 R2 = OBn H
120a - b
121
122a - b
123a - b
124
125a - b
OTBDPS
BnO X
SO Ph
O
BnO
OHCO
BnO
OMeOBn
OBn
O
BnO
OTBDPS
BnO
SO Ph
O
BnO
OMeOBn
OBn
O
HO
OMeOH
OHO
HOHO
OH
OH
128
229 74
1 RaNi (74)
2 BH3 DMS
NaOH H 2O2 (74)
3 H2 PdC (70)
130 74
LDA THF
-100 oC
126 X = H
127 X = Li
1408 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (27)
Scheme (28)
stereochemical outcome is rationalized by the generation ofan initial zinc acetylide species which facilitates intra-molecular delivery to the α-face (Scheme 32)
Wightman synthesized C-disaccharide analogs of the α-D-arabinofuranosyl-(1rarr5)-α-D-arabinofuranosyl motif ofmycobacterial cell walls through alkynyl intermediates [36]The lactone 164 was treated with lithio(trimethylsilyl)ethyneat low temperature to give lactol in 66 yield of 165Treatment of this with triethylsilane and BF3
Et2O gavethe separable isomers 166α (60) and 166β (13)Desilylation of the major isomer 166α gave 167 in 97yield Treatment of 167 with n-BuLi followed by addition oflactone 164 gave 85 yield of the hemiacetal 168 which onreduction with Et3SiH and BF3
Et2O gave the disubstitutedalkyne 169 (83) as the major product Reduction-
hydrogenolysis of 169 then gave the C-disaccharide 170 innear-quantitative yield (Scheme 33)
3 REDUCTIVE GLYCOSYL SAMARIUM SPECIES
The introduction of SmI2 as reducing agent can becredited to Kagan and has since been utilized in numeroussynthetic schemes [37] Sinayuml and Beau introduced SmI2
chemistry into C-glycoside synthesis through intermolecularreactions with appropriate electrophiles and intramolecularreactions of silyl tethered substrates [38] Anomericsamarium species are highly stable and not likely to undergoβ-elimination Treatment of the aryl sulfone 171 with SmI2
affords the nucleophilic intermediate 172 through two singleelectron transfer processes Introduction of a suitableelectrophile (carbonyl compounds) affords the α-C-manno-
O
BnO
OTBDPS
BnO X
SO Ph
O
BnO
OBn
BnO Li
SO Ph
DMF
OHO
HOOH
OH
O OH
OH
HO
OHOH
O
BnO
OTBDPS
BnO
SO Ph
O
OBn
OBnOBnSO
Ph
OH
131 X = Li
132 X = CHO
THF -100 oC
1 Ra-Ni
2 BH3 DMS NaOH H2O2
3 H2 PdC
131
133
134
OBnO
OBnOMe
BnO
Li
OBnO
BnOOBn
OBn
OOBn
OBnOMeBnO
OH
OBnO
BnOOBn
OBn
O
n-BuLi
BnO
OMe
BnO
BrBr
O
OBn
OHO
OH
OH
HO
OHO
OH
HO
OMe
O
BnO
OMeOBn
O
BnO
139 92
1BF3 OEt2 EtOH
2 H2 PdC AcOH
140 52 over 2 steps
135 136 137
138
CBr4 PPh3
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1409
pyrannoside 173 in good yield and with excellent stereo-selectivity (Scheme 34) [38a]
Preparation of C-glycosides of ulosonic acids using SmI2
was pioneered by Linhardt and coworkers [39] Coupling ofpyridyl sulfone 174 with aldehyde 175 in the presence ofSmI2 gave an excellent yield of the N-acetylneuraminic acidC-disaccharide 176 as single isomer This stereochemicaloutcome was rationalized on the basis of the Felkin-Anhmodel for predicting the stereochemical outcome of akinetically controlled addition of a nucleophile to a chiraladehyde (Scheme 35 A)
Reductive samarium method was utilized to synthesizesialo-antigen C-analogs by the Linhardt group A fullyprotected C-analogue of the SialylTn antigen α-D-Neu5Ac-(2rarr6)α-D-GalNAc-(1rarrO)-Ser 182 was prepared [40] C-glycosylation of the neuraminic acid sulfone donor with
aldehyde acceptor in presence of excess SmI2 afforded the α-C-glycoside 180 as an RS mixture (11) The criticalintermediate aldehyde acceptor 178 was prepared in 13steps Chemoselective resolution to compound 180 wasundertaken by oxidation with DMSOAc2O to keto-bridgedcompound 181 followed by stereoselective reduction withZn(BH4)2 to regenerate the bridge hydroxyl function gave182 in gt90 de (Scheme 36)
A common versatile N-acetylneuraminic acid C-disaccharide precursor of the C-glycoside analogs ofgangliosides GM4 and GM3 has been synthesized [41]Samarium(II) iodide coupling of N-acetylneuraminic acidsulfone 179 with a 3-formyl galactopyranoside derivative183 afforded the corresponding C-disaccharide 184 as amixture of (R) and (S) isomers at the newly formedhydroxymethylene bridge This diastereoisomeric mixturewas resolved after debenzylation of the galactoside residue
Scheme (29)
O
BnO
BnOOBn
OBn
OOBn
OBnOMe
OBnOH
O
BnO
BnO
OBn
OBn
O
O
BnOOBn
OMe
BnO
Li
OBnO
OBn
OBn
OBnO
OBn
OBn
OMe
OBnO
OBn
OBnBnO
OBnO
OBn
OBn
OBnO
OBn
OBn
OMe
OBnO
OBn
OBnOBnO
OBn
OBnBnO
O
BnO
BnO
OBn
O
OBnO
OBn
OBnBnO
OBnO
OBn
OBnBnO
OBnO
OBn
OBn
OMe
OBnO
OBn
OBnBnO
OMe
1 PCC2 CBr4 Ph3P3 n-BuLi
144 overall yield 54
1 BF3 OEt2 Et3 OH
2 H2 PtO2 EtOAc
145 76
1 H2 SO4 AcOH
2 PCC
146 62
repeat steps
repeat st eps
141 142
143
147
148
1410 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (30)
Scheme (31)
O
BnOOBn
OMe
Li
BnO
OPivBnO
OBn
OBn
BnO
O OO
BF3 OEt2
OBnO
OBn
OBn
BnO
OO
O
OMe
BnOOBn
BnO
Co(CO)3
Co(CO)3
O
CAN
OBnO
OBn
OBn
BnO
OO
OO
BnOOBn
BnO
OMe
OHBnO
OBn
OBn
BnO
OHO
O
O
OMe
BnOOBn
BnO
Co(CO)3
Co(CO)3
O
OPivBnO
OBn
OBn
BnO
OH OO
O
OMe
BnOOBn
BnO
OAcO
OAc
OAc
AcO
OAcOAc
OAcO
OAc
AcO
OMe
1
2 NaOMe MeOH
1 Lewis acid2 ClCO2CCl3 Pyr3 Co2(CO)8
with a-isomer
1 Et3N Pyr H2O
2 H2 PdC H+
3 Ac2 O Pyr
149 151
152153
154 155
150
OBn
BnO
OBnO
OBn
BnO
OBnO
BnO
MeO
OBnO
OBn
BnO
O
OMe
AcO
OAcO
OAc
OAc
AcO
OAcO
OAc
O
BnOOBn
OMe
BnO
159 74 over 2 steps
+
BuLi ZnCl2 THF
1 H2 PdC2 Ac2O Pyr
156 157
158 59
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1411
Scheme (32)
Scheme (33)
and the chirality of each isomer assigned after acetylationConversion of the p-methoxyphenyl group in the peracety-lated (S) isomer 187 into the corresponding thiophenylglycoside 188 was accomplished affording the key inter-mediate for the synthesis of C-glycoside analogs of GM4GM3 and other related gangliosides (Scheme 37)
Ganglioside GM4 is a very important cell adhesionmolecule The C-disaccharide of GM4 is currently beingsynthesized in Linhardtrsquos lab using standard O-glycosylationof C-disaccharide with protected ceramide Once theceramide has been attached it can be oxidized to afford analdehyde group for coupling to keyhole limpet hemocyanin
OBnO
OBn
BnO
O
OBnO
ClZnO
OBn
BnOCl
R
OBnO
O
OBn
BnOCl
ZnR
O
ZnR
OBnO
OBn
BnO
160 161
162163
O
OBn
OBnBnO
O
O
OBn
OBnBnO H
TMS
O
OBn
OBnBnO H
O
OBn
BnO
OBnHO
O
OBn
OBnBnO OH
TMS
OBnBnO HO
OBn
TMS
O
OR
ORRO H
O
OR
RO
OR
OBn
OBnBnO
H
TMS
O+
K2CO3 MeOH
1 n-BuLi THF -78 oC
2 164
164165 66
166α 60 166β 13167 97
BF3 Et 2O Et 3SiH -78 oC
168 85
169 R = Bn 83
170 R = H near quantitative yield
H2 (1 atm)Pd(OH) 2C
TMS-acetyl ene
n-BuLi THF -78 oC BF3 Et2O Et3SiH
-78 o C
1412 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
O
OHCOBn
OBnBnO
OMe
O
CO2MeAcO
OAcAcHN
OAc
SO2
NAcO
OBnH
H
OBn
OBn
H
O
OMeH HH
A
O
CO2MeAcO
OAcAcHN
OAc
O
OBnOMe
OBnOBn
HO
AcO
+
Nu
174175
176
SmI2 THF
Scheme (34)
Scheme (35)
Scheme (36)
O
BnO
BnO
BnO
Si lylO
O2S N
O
BnO
HO R2R1
BnOBnO
SilylO
OBnO
BnO
BnO
SilylO
Sm(III)
R1COR2 SmI2 THF
171 172
173
NHBoc
OAcO
AcO
AcHN O
O
CO2BnO
OO
OO
OH
O
CO2MeAcO
OAcAcHN
OAc
AcO
SO2Ph
R2
O
CO2Me
AcHN
OAc
AcO
R1
AcO
AcO
AcHNO CO2Bn
NHBoc
AcO
OAc
O
Zn(BH4)2
180 R1 R2 = H OH ( RS 11)
181 R1 R2 = O
182 R1 = H R2 = OH de gt 90
DMSO Ac2O
177178
179
13 steps
22 equiv SmI2 THF
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1413
Scheme (37)
Fig (2)
(KLH) by reductive amination for use as carbohydrate-basedvaccine GM3 a related trisaccharide containg gangliosideplays an important role in cell growth and differentiationFig 2 The synthesis of C-oligosaccharide GM3 is currentlyunderway following a similar route to that of C-GM4synthesis [42]
Beau also reported a sialyl C-disaccharide synthesiswhich relied on the unprecedented use of a stable andcrystalline 2-pyridyl sulfide of the N-acetylneuraminic acidderivative 189 as the anomeric precursor in a samarium-Reformastky procedure [43] The coupling procedure withsulfide 189 and aldehyde 190 afforded the carbon-linkeddimer 191 in 93 yield as a 11 diastereomeric mixture
Alcohols 191 were converted into thiocarbonates anddeoxygenated by employing triphenyltin hydride catalyticAIBN and pentafluorophenol which yielded C-disaccharide192 as a single compound in 65 yield for the 2 stepsDesilylation hydrogenolysis acetylation and finalacetolysis of the methyl glycoside provided the carbon-linked mimic 193 of the disaccharidic component of thesialylTn tumor antigen (Scheme 38)
4 CATIONIC METHODS
This section is categorized according to reactions thatinvolve the generation of anomeric ions followed by thecapture with sugar-based nucleophiles
OAcAcHN
OAc
AcO
O
OBnBnO
OBnOMP
HO
O
MeO2CAcO
O
MeO2CAcO
OAcAcHN
OAc
AcO
O
OHHO
OHOMP
HO
O
OBnOHC
OBnBnO
OMP
O
MeO2CAcO
OAcAcHN
OAc
AcO
O
OHHO
OHOMP
HO
O
CO2MeAcO
OAcAcHN
OAc
AcO
SO2Ph
O
MeO2CAcO
OAcAcHN
OAc
AcO
O
OAcAcO
OAcX
AcO
H2 PdC EtOAc CH3OHH2O
+
Ac2O Pyr
187 X = OMP
188 X = SPh 73
184 85 R and S mixture
186 90 for two i somers
+
SmI2 THF183
179
185
O
HO2 CHO
OAcAcHN
OH
HO
O
OHHO
OH
OAcO
(CH2 )12 CH3
HN
OH
(CH2)14CH3
O
O
O
OHHO
OH
O
O
HO2 CHO
OAcAcHN
OH
HO
O
OHHO
OH
O(CH2)12CH3
HN
OH
(CH2)1 4CH3
GM4
GM3
1414 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
41 Exo-glycals as Nucleophiles
Nitotra et al have found that treatment of exo-glycal 194with BF 3
OEt2 followed by a water quench afforded the C-disaccharide 195 (Scheme 39) It is noteworthy tonoteworthy that the attack of the enol ether on the anomericoxonium ion occurs with high stereoselectivity on the α-face only 195 was obtained [44]
42 Silyl-based Nucleophiles
Isobe has designed and developed alkynylation as a keyreaction for the introduction of a carbon chain onto sugarsThose alkynylated compounds are called ldquosugar acetylenesrdquo[45] The mechanism includes eliminative formation ofcation to which silylacetylene can coordinate on the α-face(Scheme 40)
Double C-glycosylation between glycal 198 and bis(silylacetylene) gave C-disaccharide ldquolikerdquo compounds 199and 200 (Scheme 41)
Silylpropargyl-sugar 201 smoothly reacted with D-glucalto furnish exclusively the α-acetylene glycoside product 202in 88 (Scheme 42) [46]
5 CYCLIZATION METHODOLOGY
This approach to C-oligosaccharide synthesis relies onthe coupling of an open chain fragment with an intact
monosaccharide to give an intermediate that is then cyclizedto deliver the C-oligosaccharide target This section isdivided by the type of chemistry used to initially assemblethe two pre-cyclization fragments
51 Wittig Reaction-Cyclization
The Kishi group was the first to use Wittig-cyclizationapproach to synthesize C-disaccharides Starting with Wittigreaction between 203 and 204 the intermediate 205 wasafforded as a single stereoisomer in 82 yield Osmylationthen gave a mixture of diols with the major one formed in a61 ratio Selective protection of the diols gave 206a and206b The mono-para-methoxybenzyl ether 206a was thentransformed into the hemiketal 207 in 75 overall yield inthree steps ie (1) Swern oxidation (2) acetonide hydro-lysis (4 N HClTHFrt) and (3) benzoylation (3 equiv ofPhCOClpyCH2Cl2rt) Silane reduction of 207 in an acidicmedium should preferentially yield the equatorially substi-tuted β-C-glycoside which was deblocked and converted tothe methyl- βminusC-disaccharide 209 Exact parallel experi-ments applied to the minor isomer gave the correspondingC-disaccharide 210 (Scheme 43) [47]
Armstrong has employed Wittig-osmylation protocol forthe preparation of a small library of α-C-(1rarr6)-disaccha-rides [48] Readily available allyl C-glycoside 211 washomologated to diene ester 212 and subjected to osmylation
Scheme (38)
O
CO2MeAcO
OAcAcHN
OAc
AcO
S(2-Py)
O
TESO
AcHNOMe
O
HO
O
CO2MeAcO
OAcAcHN
OAc
AcO
O NHAcOAc
OAc
OAc
O
CO2MeAcO
OAcAcHN
OAc
AcO
O NHAcOBn
OTES
OMe
OAc
AcO
O NHAcOBn
OTES
OMeOH
O
CO2 MeAcO
OAcAcHN
+
192 65
1 MeOHHCl2 H2 PdC EtOH3 Ac2O Pyr4 Ac2OAcOHH2SO4
193 59 overall yield
25 equiv SmI2 THF
1 11-thiocarbonyldiimidazole DMAP2 Ph3SnH cat AIBN
191 93
189
190
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1415
Scheme (39)
Scheme (40)
Scheme (41)
OBnO
OBn
OBn
OBnO
OBn
OBn
OBnO
OBn
OBn
OBnO
OBnCH3
BnO
OH
CH2
OBnO
OBn
CH3
OBn
H2 O
BF3 OEt2 MeCN
194
195 96
OOAc
OAc
AcO
R SiMe3
SnCl4
O
OAc
AcO
R
O
OAc
AcO
O
OAc
AcO
Me3Si
R
SiMe3
196
197
Me3 Si SiMe3
O
AcO
OAc
OAc
SiMe3
SiMe3
O
AcO
OAc
O
OAc
OAc
O
AcO
AcOO
OAc
OAc
SnCl4 CH2Cl2
SnCl4 CH2Cl2198
199
200
1416 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (42)
Scheme (43)
AcO
OAc
OAc
Me3 Si
BnO
OBn
BnO
OBn
AcO
OAc
BnO
OBn
BnO
OBn
+ I2 CH2Cl2
202 88
198 201
O
OBn
OBn
O
O
O
OBn
OBn
O
O
OBn
OBn O
OBn
OBn
O
OPBH2M
OH
OBnO
BnO
BnO
O
OBn
OBn
O
OHOPMB
OHO
HO
HO
O
OH
OHOH
OH
HOOMe
O
OBnOBn
O
Ph3P
O
O
OBn
OBn O
OBn
OBn
O
OPBM
OH
O O
CHO
OBn
BnO
OO
OBn
OBn
O
OHOPMB
BnO
BnO
BnO
OHO
HO
HO
O
OH
OHOH
OH
HOOMe
+ THF -78 oC
1 OsO4 pyr THF
2 NaH PMBBr
206a 206b 206a206b 61
1 Swern [O]2 4N HCl3 PhCOCl pyr
1 Swern [O]2 4N HCl3 PhCOCl pyr
1 PrSiH BF3 OEt2
2 H2 Pd(OH)2C
3 HCl MeOH 90 oC
1 PrSiH BF3 OEt2
2 H2 Pd(OH)2C
3 HCl MeOH 90 o C
203
204
205
207
209
208
210
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1417
followed by reduction to afford a 51 mixture (213214215216) of lactols that were readily separable by chromato-graphy Following a deprotection of an equimolar mixture of213 and 214 217 and the DL hybrid C-disaccharide of D-glucose-O-(1rarr6)-L-galactose 218 were obtained The DDand DL derivatives 219 and 220 of glucose-α-(1rarr6)-idosewere also obtained as a near equimolar mixture afterdeprotection of 215 and 216 (Scheme 44)
52 Anion Addition-Cyclization
Kishi developed an approach for the synthesis of theCndashtrehalo sugars which relied on nucleophilic addition ofone intact sugar fragment to a fundamental aldehyde ieKishi-Nozaki reaction [49] Coupling of monosaccharide221 and aldehyde 222 gave 223 The triple bond waspartially reduced and osmylation was followed by selectiveprotection to afford 224 The acetonide was converted toepoxide 225 by standard methods and removal of the PMBgroup Acid-catalyzed cyclization followed by aglyconichydrolysis and protection of hydroxyl group with (p-methoxyphenyl)diphenylmethyl chloride (MMTrCl) gave226 Inversion of the C-2 hydroxyl and removal of protectinggroups delivered α α-C-trehalose 227 (Scheme 44)
Kishi and co-workers also employed aldol reactions as anefficient access to the C-trisaccharide related to the type IIABO(H) blood group determinant [50] Aldol condensationof the enolate of methyl ketone 228 with aldehyde 229 gavea 41 mixture of hydroxy ketones 230 and 231 The majorketol was cyclized desulfurized and oxidized to afford thedisaccharide ketone 233 The ketone in THF was treatedwith LiHMDS (3 equiv) and TMEDA followed by theaddition of MgBr2 Addition of the aldehyde 234 led toalmost exclusive formation of the equatorial products 235and 236 in a 12 ratio Mesylation of 235 and 236 followedby treatment with liquid ammonia gave enones 237a and237b which were reduced to yield exclusively the C-2rsquo-equatorial ketone 238 Sodium borohydride reduction of theC-3rsquo carbonyl proceeded with the desired stereoselectivity toyield the protected C-trisaccharide 239 which wasdeblocked to provide the polyol 240 (Scheme 46)
Sutherlin and Amstrong cleverly applied a recursivestereochemical deconvolution (RSD) combinatorial approachfor the synthesis of a small library of C-trisaccharides aspotential inhibitors for the cell surface proteins of bacteriumHelicobactor pylori [51] The workers chose to carry outvariations in galactose ring of these trisaccharides An
Scheme (44)
OBnO
BnOOBn
OBn
P O
OEtOEtO
EtO
R H
OH
OH
OH
OH
O
R H
OH
OH
OH
OH
O
OHO
HOOH
OH
O
HO
OHOH
OH
OHO
HOOH
OH
O
HO
OH
OH
OHO
HOOH
OH
O
HO
OH
OHOH
R H
OH
OH
OH
OH
O
R
OBnO
BnOOBn
OBn
O
OHO
HOOH
OH
OO
HOHO
OH
R H
OH
OH
OH
OH
O
1 OsO4 NMO 50
2 DIBAL -32 oC 40
++ +
213 214 215 216
217 218 219 220
1 9-BBN H2O22 Swern [O]
3 t-BuOK
4 I2 C6H6212
211
1418 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
efficient Nozaki-Kishi coupling of vinyl bromide 241 withaldehyde 242 in a diasteromeric ratio of 12 followed byprotection with TBSOTf led to 243 and 244 Hydroborationfollowed by oxidation gave aldehydes 245 and 246respectively Addition of allylmagnesium bromide toaldehyde 245 followed by removal of the silyl groupafforded 247 to 246 giving 248 and 249 Epoxidation gave a11 mixture of the corresponding epoxides which werecyclized to give the C-trisaccharide 250-255 after removalof the benzyl groups (Scheme 47)
Schmidt reported a stereoselective 6-exo-trig selectiveelectrophilic cylization approach for de novo synthesis of amethylene-bridged Neu5Ac-α-(23)-Gal C-disaccharide theC-analog of an important motif in glycosphingolipids [52]The open chain precusors 259ab (a 32-mixture ofdiaseteromeric alcohols) were formed by the addition oflithiated iodide 256 to open chain aldehyde 258 Subsequent
C1 incorporation using Tebbe-reagent formation of a cycliccarbonate and deprotection of the two isopropylidene ketalsafforded tetrol 264 which upon treatment with phenylselenyltrifilate was steroselectively cyclized in a 6-exo-trigselective manner affording a diasteromeric mixture of 251and 252 in a ratio of 71 A seleno-Pummerer rearrangementto afford aldehyde 267 in 5 steps in 90 overall yieldOxidation of the aldehyde and subsequent steps led to thedesired C-disaccharide 268 (Scheme 48)
53 Esterification-Cyclization
Work from the Postema group has focused on a ringclosing metathesis (RCM) approach for the synthesis of C-saccharides [53a] The chemistry is versatile and has beenused for the synthesis of a small library of differentiallylinked β-C-disaccharides through a radical allylation-RCMstrategy [53b] The synthesis of the β-(1rarr4)-glucopyranosyl
Scheme (45)
O
OBn
BnO
BnO
BnO
I
CrCl2-NiCl2O
OBn
OH
BnO
BnO
BnO
O
O
O
O
O
H
OBn
O
O
OBnBnO
BnO
BnO
OOBn
OBn
OAc
PMBOHOO
OBn
BnO
BnO
BnO
O
OBn
OBn
OAc
O
OH
HO
HO
HO
OH
OH
OH
O
OH
O
OBn
BnO
BnO
BnO
OBn
OBn
OAc
O
MMTr
+
1 p-TsOH2 K2CO3 MeOH3 MMTrCl pyr
1 Swern [O]2 BH3 THF
3 AcOH-H2 O4 H2 Pd(OH)2
221
222
223
1 Pd-Pb CaCO3 H22 NaH BnBr3 OsO44 Bu2 SnO5 CsF PMB-Cl6 Ac2 O 4-DMAP
1 AcOH2 TsCl pyr
3 NaH-imid4 DDQ
224225
226 227
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1419
Scheme (46)
OBnO O
OBn
OMe
OBn
XY
SMe
OBnBnO
O
OBn
OBn
OBn
OBn
O
BnO
YX
OBn
TBSO
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnOOBn
H
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnO
OBn
OHC OBn
OBn
OTBS
OMe
BnOOBn
CHO
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnOOBn
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnO
OBn
YX
OBnO O
OBn
OMe
OBn
OBn
O
BnO
O
OBn
OBn
OBn
OBn
O 1 LiHMDS
2
228
1 TBAF THF
2 MeSH BF3 OEt2
230 X = OH Y = H231 X = H Y = OH
230231 41
1 Bu3SnH AIBN2 Swern [O]
1 LiHMDS THF-TMEDA2 MgBr23
1 MsCl
2 liquid NH3
235 X = OH Y = H236 X = H Y = OH Bu3 SnH AIBN
237a and 237b
NaBH4 MeOH
238
239 X = OBn
240 X = OHH2 Pd(OH)2
229
232233
234
1420 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (47)
OH C
O
O BnAcHN
OO
O
OBn OBnOBn
Br
O
OBn OBnOBn
O
OBnA cHN
OO
O TBSO
OBn O BnO Bn
O
OBnAcHN
OO
OTBS
S2
S1
S2
OTBSS1
O H
S2
OT BSS1
O H
MgBrMgBr
S2
O TBSS1
O H
S2
OHS1
OH
S2
OTBSS1
OH
O
OHHO
O H
O
HO
H OO
OBnA cH N
HO
H O
O
O HHO
OH
O
HOHO
O
OBnA cH N
HO
H O
O
OHH O
OH
O
H O
HOO
OBnAcHN
HO
HO
O
O HH O
OH
O
H O
H O O
OBnA cHN
HO
HO
O
O HH O
O H
O
HO
H O O
OBnAcHN
HO
HO
O
OHHO
OH
O
H O
O
OBnA cHN
HO
HOHO
+
241 242
1 CrCl2-NiCl2 T HF-DMF 722 TBSOTf 2 6-lutidine 91
243 244
1 9-BBN 602 Dess-Mart in period inane 97
1 9 -BBN 552 D ess-Martin periodinane 98
245 246
1
2 T BAF 74
1
2 TBAF 88
247 248 249
250
251
250 251 1 1 252 253 1 1 254 255 1 1
252
253
254
255
1 MCPBA2 CSA CH 2Cl2 61 fo r 2 steps3 H 2 Pd (O H)2C 95
1 MCPBA2 CSA CH 2Cl2 63 fo r 2 s teps3 H 2 Pd (OH)2C 87
1 MCPBA2 CSA CH2Cl2 80 for 2 steps3 H2 Pd(O H)2C 95
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1421
Scheme (48)
O
OO
Se Ph
R
O
HO OHOH
O
OB n O B n
OB n
O B nO O
O O
R O OR
X
O
OO
R
Se Ph
O
HOOH
OH
O
OB nOB n
O Bn
OB n
O O
O O
R O O R
O H
O
O B n OB n
O B n
OB n
O
C HO
O
O O
R O OR
OAc HN
OAc
C O2NH 4HOOH
OH
O
OH O H
OH OH
O
OB n O B n
OB n
OB nO O
O O
R O OR
X
O
O
OAcOAc
C HOA cOOAc
OAc
O
OB n O B n
OB n
OB n
O
O Bn OB n
OB n
OB n
X
OH
OO
HOOH
OH
O
O
OMeOB n
OB nOB n
R
t-B uL i256 R = Li
257 R = L i
258
(R = t-B uMe 2Si )
(R = t-B uMe 2Si )
259ab (32) 79 com bine d yi eld
De ss-Ma rtin pe riodinane
260 X = O R = t-B uMe 2Si ) 95
261 X = O R = t -B uMe2S i) 62
T e bbe re age nt
TB A F THF262 X = O R = H 94
diphosge ne
C H2C l 2Pyr
263 95
T HFH2O T FAr t
264 quant it a ti ve yie ld
PhSe C l AgOT f
EtC N -80 oC
265
266
Quant it at i ve yi l ed 25 26 7 1
+
R =
1 Ac 2OPyr
2 mC PB A3 Ac 2ONa OAc
4 NaO HT HFMe OH
5 Ac2O P yr
267 90 overa ll yi e ld
ste ps
268
1422 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
glucopyranoside 280 represents an example of thischemistry The known triacetyl glucopyranoside 269 wasconverted to iodide 270 in good yield Radical allylation of271 proceeded to afford a mixture of equatorial and axialallylation products in a 61 ratio Oxidative cleavage of thedouble bond gave the corresponding aldehydes 273a and273b which were separable Pinnick oxidation of the majoraldehyde 273a then gave the C-4 equatorial acid 274 DCC-mediated coupling of alcohol 275 and acid 274 proceeded toafford ester 276 in good yield Methylenation of 276 gave277 and exposure to catalysist 278 gave a 41 yield of theC-disaccharide glycal which was exposed to an excess ofBH3
THF to give 64 yield of the β-C-disaccharide 279Removal of the benzyl groups and global peracetylation gavethe peracetylated (1rarr4)-β-C-disaccharide 281 in good yield(Scheme 49)
54 Ring Expansion-Cyclization
Nelson developed a new strategy for asymmetric andstereoselective synthesis of C-linked disaccharide mimeticsthe C58-C71 fragment of palytoxin [54] The diol (RR)-282was converted into the di-dihydropyran (DHP) template 283284 and 285 The di-DHPs were functionized in a twodirectional sense using dihydroxylation reactions The two-directional approach was often very efficient indeed forexample in the synthesis of 286 six new stereogenic centerswere introduced with almost complete stereocontrol using areduction and a dihydroxylation reaction The approach isnot restricted to the synthesis of C2-symmetricaldisaccharide mimetics Using the unsymmetrical template285 which has both a pseudo-axial and a pseudo-equatorialhydroxyl groups the unsymmetrical mimetics 289 and 290were prepared (Scheme 50)
6 RADICAL APPROACHES
The radical approach for C-C bond formation is a popularmethod within organic chemistry The use of radicalchemistry in carbohydrate synthesis has certain advantagesFirstly the reaction conditions are very mild and tolerant ofa range of functional and protecting groups Secondanomeric radicals are stable with respect to elimination andepimeration Most significantly the chemistry required toincorporate an appropriate substitute at C-1 employed in theinitial hemolytic cleavage step is common within carbo-hydrate chemistry [55] The use of such radical techniquecan be subdivided into two classes intermolecular andintramolecular approaches
61 Intermolecular Radical Approaches
Giese was the first to employ an intermolecular radical-based approach for synthesis of C-disaccharides [56]Addition of an alkene to an anomeric radical underappropriate conditions allowed exclusive entry to the α-linked C-glycoside a result which was mirrored by the workof Baldwin [57] The high α-selectivity of the reaction wasin contrast with other reports Thus radicals generated at theC-2 C-3 and C-4 centers all preferred to occupy equatorialpositions [58] When the anomeric bromide 291 was treatedwith tin hydride and AIBN resulting anomeric radical andreacted with lactone 292 in a Michael addition it afforded293 In this reaction hydrogen abstraction at the resulting
radical center occurs from axial face to selectively generatethe equatorial C-2rsquo substituent Reduction and acetylation of293 furnished C-disaccharide 294 (Scheme 51) [59]
Witczak used the facial bias of levoglucosene tostereoselectively add a carbohydrate-based radical in thepreparation of the 3-deoxy-(1rarr4)-β-C-disaccharide 299[60] Addition of the radical derived from iodide 295 to 296gave adduct 297 in 26 yield Removal of the anomerichydroxyl of 297 was achieved by treatment with triethylsilane borontrifluoride ether complex followed bystereoselective reduction of the keto function at C-2rsquo withthe formation of 298 in 89 yield Debenzylation followedby acetolysis of 16-anhydro ring produced the peracetylatedtarget C-disaccharide 299 in 19 overall yield from 295(Scheme 52)
Vogel has developed general methods to transformenantiomerically pure 7-oxabicyclo[221]heptyl derivatives(ldquonaked sugarsrdquo) into C-disaccharides Because of thesechiral bicyclic skeletons they undergo highly stereoselectivereactions with predictable diasteroselectivities An arsenal ofmethods is available that allow to substitute these ldquonakedrdquocarbon centers with a variety of functional groups with allpossible relative configurations The methods allowpreparation of both enantiomers of a given target with thesame ease Predictably high stereoselectivity of the reactionsof the bicyclic chirons adds to the flexibility of approachwhich can lead to high molecular diversity [61]
α-C-(1rarr3)-mannopyranoside of N-acetyl-galactosaminepotent β-galactosidase inhibitors was synthesized by thisapproach [61] Enone 302 was readily prepared from 300The addition of the radical derived from bromide 303 toenone 302 afforded the αminusisomer 304 The ketone was thenreduced and the selenide eliminated via the intermediacy ofthe selenoxide to give 305 Acid-promoted (CF3SO3H) 7-oxa ring opening of 305 in MeCN produced the amino-conduritol derivative 306 resulting from the quenching of theallylic cation intermediate by the solvent (Ritter reaction)Ozonolysis of the chloroalkene 306 generated an acylchloride-aldehyde intermediate that reacted with MeOH toproduce a mixture of methyl uronates The major compound307 was silylated and reduced The crude polyol obtainedwas acetylated to produce 308 Desilylated and ammonolysisafforded a mixture of α-β-pyranoses 309 and correspondingα-β-furanoses (Scheme 53)
Similar chemistry was carried out to synthesize non-protected α-C(1rarr2)-L-fucopyranoside of D-galactopyrano-side corresponding to a blood group mimetic [62] Giesersquosradical fucosidation of racemic enone 310 with α-L-bromoacetofucose 311 provided the mixture of diastereo-meric α-C-fucoside 312a and 312b in reproducible yield of78 Reduction of the mixture gave a 11 mixture of endo-alcohols 313 and 314 which were isolated pure in 40 and355 yield respectively Oxidative elimination of thebenzeneselenyl group of 313 followed by acetylation gaveendo acetate 315 in 85 yield Acid-promoted ring openingof 315 and ozonolysis of the resulted chloroalkene gavemethyl uronic ester 316 in modest yield (10) Treatment of316 with Cl3CCN and NaH followed with BF3
OEt2
furnished the totally protected C-disaccharide 317 in 79
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1423
Scheme (49)
Bu3SnO
HOAcO
OMeOAc
OAc
O
AcO
OMeOAc
OAcI
AIBN
O
AcO
OMeOBn
OBn
HO2C O
AcO
OMeOR
ORY
X
OHBnO
BnO
OBn
OBnO
BnO
OBn
O
AcO
OMeOBn
OBnX
i-Pr i-Pr
N
Mo C(Me2 Ph)((CF3)2 MeCO)2
O
RO
OMeOR
O
RO
OR
OR
RO
OR
278
I2 Ph3P
imidazole
269 270 93
271a X = CH2CH=CH2 Y = H R = Ac 64271b Y = CH2CH=CH2 X = H R = Ac 11272a X = CH2CH=CH2 Y = H R = Bn 75272b Y = CH2CH=CH2 X = H R = Bn 75273a X = CH2CHO Y = H R = Bn 79273a Y = CH2CHO X = H R = Bn 79
1 NaOMe MeOH2 NaOH BnBr DMF
OsO4 NaIO4
NaClO2 NaH2PO4
274 96
275
DCC 4-DMAP
276 X = O 82
277 X = CH2 51
TiCl4 Zn dust TMEDA CH2Br2PbCl2 (Cat )
1
2 BH3 THF H2O2 NaOH
H2 PdC EtOH
Ac2 O Pyr 4-DMAP
279 R = Bn R = H 64
280 R = R = H 99
281 R = R =Ac 97
1424 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (50)
Scheme (51)
O OOH
OH
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
286
1 VO(acac)2 t-BuOH 95
2 (MeO)3CH BF3 90
1 P-O2NC6H4 CO2H Ph3P DIAD2 K2CO3 MeOH 82 over 2 steps
1 PhCOCl Et3N DMAP 402 P-O2NC6H4 CO2H Ph3P DIAD3 KOH THF-H2O 75 over 2 steps
TMEDA OsO4
Cat OsO4 NMO 287
Cat OsO4 NMO288
TMEDA OsO4
Cat OsO4 NMO
290
289
(RR)-282283
284
285
OHO
AcO
BrOAc
OAc
BnO
O
OBn
OBnO
OHO
AcOOAc
OAc
BnO
OOBn
OBnAcO
OHO
AcOOAc
OAc
BnO
O
OBn
OBnO
+
Bu3SnH AIBN291
292
293 81
1 Na[Al(OC2H4OMe)2(OEt)H]2 Ac2O pyr
294 56 over 2 steps
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1425
Scheme (52)
Scheme (53)
OBnO
BnOOBn
OBn O
OH
O
OBnO
BnO
OHOBn
OBn O
O
O
O
O
O
OBnO
BnOOBn
OBnO
OAcOAc
OAc
OBnO
BnO
OHOBn
OBn
IBu3SnH AIBN
295 297 26
1 BF3 OEt2 Et3SiH
2 L-Selectride THF
1 Pd(OH)2C C6H10 EtOH
2 EtSiOSO2CF3 Ac2O
298 89 over 2 steps299
296
O
O
PhSeClO
O
PhSeCl
Bu3 SnH
O
O
PhSeCl
R
H
O
OAc
R
Cl
O
AcO
OAc
OAc
OAcOH
Cl
NHAc
R
OAc
AcHN
OH
O
OH OAc
OH
OHO
HO
OH
O
AcO
OAc
OAc
OAcBr
O
O
PhSeCl
O
O
PhSeCl
R
O
OTIPSAcHNR
OAc OAc
O
OHAcHN
COOMe
R
OAc
1 Bu4NF
2 NH3MeOH
1 (Me3Si)2NLi THF2 Me2N=CHI
1 Bu3 SnH AIBN2
1 NaBH42 mCPBA3 Ac2O pyr
1 H+ MeCN
2 H2 O NaHCO3
R =
1 O3MeOH
2 Me2S NaHCO3
1 TIPSOTf 26-lut idine2 LiBH43 Ac2 O pyr DMAP
furanoses +
304 56
305 68 306 84307 50
308 46
300 301 302
303
309
1426 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
The reduction of 317 and treatment with DOWEX-H+ resinprovided the desired C-fucoside 318 in 70 (Scheme 54)
62 Intramolecular Radical Approaches
One disadvantage with the intermolecular approaches isthat during such radical mediated reactions electrondeficient alkenes are required to facilitate C-C bondformation The intramolecular approach of Sinayuml overcomes
this drawback by bring two substrates together via atemporary covalent silaketal connector This enables the useof a wider range of alkenes which can include alkene-functionalized sugars thus leading to the generation of C-disaccharides [63] Based on the early work of Stork Sinayumlemployed the tether reaction in the synthesis of both α- andβ-C-disaccharides with this work subsequently beingemployed in the synthesis of biologically significant natural
Scheme (54)
O
OH
Fuc
Cl
O
O
ClPhSe
OOAc
NHAcOHFuc
O
AcOOAc
AcO
Br
O
O
PhSeCl
O
AcOOAc
AcO
O
OH
PhSe Cl
Fuc
OOAc
NHAc
OMe
Fuc
O
AcHN
OH OAc
OH
O
OH
Me
OH
O
O
Fuc
ClSePh
O
HO
Fuc
ClSePh
+
Ph3SnHAIBN
78 combined yield
Fuc
310
+
1 NaBH4 MeOHTHF2 Chromatography
313 40 314 355
1 mCPBA
2 Ac2O pyr DMAP
+
315 75
1 TfOH MeCN
2 NaHCO3 O3 -78 oC
316 10 over 2 steps
1 Cl3 CCN NaH
2 MeOH BF3 OEt2
317 79
1 LiBH4 THF
2 Dowex-H+
311
312a312b
318 70 for 2 steps
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1427
products [64] The availability of different hydroxyl groupson each monosaccharide unit allowed the fine-tuning ofstereochemical outcome by selective positioning of the silyltether [65] Development of this early stereochemical controlled to the tethering of the donor 320 with alcohol 319through a di-isopropyl silicon tether 321 Subsequent treat-ment with Bu3SnH and AIBN led to a 9-endo-trigcyclization to form the C-disaccharide 322 in an 80 yieldwith exclusive formation of the α-product The silyl tetherwas removed with Bu4NF and deprotection under standardconditions afforded the desired disaccharide 323 in excellentyield (Scheme 55)
In parallel the development of a 32rsquo silyl tether allowedaccess to the β-linked product as demonstrated in Sinayumlrsquossynthesis of methyl β-C-lactoside 328 [66] Alcohol 324 and320 were connected via the dimethylsilyl tether an 8-endo-trig cyclization followed to exclusively afford the β-
disaccharide 326 in 45 yield Removal of the tether anddeprotection of benzyl ether gave β-C-disaccharide 328(Scheme 56)
This group also selected iodosugars bearing a freehydroxyl group as progenitors of the radical donors [67] In atypical experiment the radical donor 329 was connected tothe radical acceptor 330 through a silaketal tether followingtheir procedure Tributyltinhydride mediated 8-endo-trigradical cyclization of compound 331 gave after detetheringof the non isolated intermediate 332 the protected β-C-disaccharide 333 in 37 overall yield (from startingmaterials 330 and 329) Peracetate 335 was achieved afterhydrogenolysis The C-laminaribioside 334 is of potentialbiological interest as it mimics the repeating disaccharideunit of fungal β-(1rarr3)-glucans which have antitumor andimmunomodulating properties (Scheme 57)
Scheme (55)
Scheme (56)
OO
OHSePh
OTBDPSO O
OO
SePh
OTBDPSO
OO
OBnOMe
OBn
Si
O
HOOBn
OMe
OBn
O
HOOH
OHHO
O
HOOH
OMe
OH
OTBDPSO
O
HOOBn
OMe
OBnO
OOH
1 n-BuLi THF
2 iPr2SiCl2 -78 oC
3 DMAP THF rt
1 Bu4NF THF
2 Dowex-H+
3 H2 PdC
Bu3SnH AIBN toluene
319
320
321
322323
OBnO
OHSePh
OBnBnO
OHO
OBnOMe
OBn
ROO
ROOH
OR
OHO
OROMe
OR
OBnO
O
OBnBnO
OO
OBnOMe
OBn
Si
SePh
OBnO
O
OBnBnOO
OOBn
OMe
OBn
Si
1 PhSeH Me2SiCl2
BuLi -78 oC
2 imidazole rt
Bu3SnH AIBN toluene
H2 PdC327 R = Bn
328 R = H
Bu4NF THF
324
320
325
326 45
1428 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
CONCLUSIONS
In this paper the biological importance of C-oligo-saccharides as subunits of natural products and as a newgeneration of carbohydrate based on therapeutics has beenillustrated Different methods are available for the synthesisof C-oligosaccharides As with traditional saccharidesynthesis it has been necessary to develop a number ofspecific approaches to facilitate the regioselective andstereoselective preparation of the desired targets Work inthis area continues and it is expected that many interestingnew C-oligosaccharides will be prepared using the chemistrydescribed in this review It is also likely that new chemistrywill be developed in the future for the preparation of thesebiologically important targets
ACKNOWLEDGEMENTS
The authors thank Dr Sultan Baytas for her criticalreading of this manuscript
REFERENCES
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[2] Wassarman PW Mammalian Fertilization Molecular Aspects ofGamete Adhesion xocytosion Exocytosis and Fusion Cell 199996 175-183
[3] Carbohydrate-based Drug Discovery Wong C-H EdWeinheim Cambridge Wiley-VCH 2003
[4] (a) Sharon N Lis H Lectins as Cell Recognition MoleculesScience 1987 246 227-234 (b) Dwek RA Chem Rev 1996 96683-720
[5] Postema M C-Glycoside synthesis CRC Boc Ratom 1995[6] (a) Weatherman R V Mortell K H Cheruenak MKiessling
L L Toone E J Specificity of C-Glycoside Complexation byMannoseGlucose Specific Lectins Biochem 1996 35 3619-3624(b) Ravishankar R Surolia A Vijayan M Lim S Kishi YPreferred Conformation of C-Lactose at the Free and Peanut LectinBound States J Am Chem Soc1998 120 11297-11303
[7] (a)Wong C-H Halcomb R L Ichikawa Y and Kajimoto TEnzymes in organic synthesis Application to the problems ofcarbohydrate recognition part2 Angew Chem Int Ed Engl 199534 521-546 (b)Howard S Withers SG Bromoketone C-Glycosides a New Class of βminusGlucanase Inactivators J AmChem Soc 1998 120 10326-10331(c) Wang Q Wolff MPolat T Du Y Linhardt R J C-glycoside of Neuraminic Acidsas Neura-minidase Inhibitors Bioorg Med Lett 2000 10 941-944 (d) Phili R Chang J Partis R A Mueller R A ChrestF J Passaniti A The Alpha-glucosidase I InhibitorCastanospermine Alters Endothelial cell Glycosylation PreventsAngiogenesis and Inhibits Tumor Growth Cancer Res 1995 552927-2935
[8] Ossor A Elbein A D In Carbohydrates in Chemistry andBiology Vol 3(II) WileyVCH 2000 pp 513-539
[9] (a) Sinayuml P Synthesis of oligosaccharide Mimetics Pure ApplChem 1997 69 459-463 (b) Beau J-M Gallagher TNucleophilic C-glycosyl Donors for C-glycoside Synthesis Top inCurr Chem 1997 187 1-54 (c) Nicotra F Synthesis of C-glycosides of Biological Interest Top in Curr Chem 1997 187
Scheme (57)
O
O
O
Ph
I
OMe
OHO
BnO
OH
OH
BnOOH
O
BnO
Si
O
O O
Ph
I
OMe
O
O
BnO
OR4O
R5O
OMe
OR2
OR3O
R3O
OR1
R3O
Bu3 SnH AIBN
332 R1 R2 = SiMe2 R3 = Bn R4 R5 = CHPhTBAF THF
333 R1 = R2 = H R3 = Bn R4 = R5 = CHPh 37 from 11
334 R1 = R2 = R3 = R4 = R5 = H
335 R1 = R2 = R3 = R4 = R5 = Ac
329
H2 PdC MeOH
Ac2 O pyr
1 BuLi THF -78 oC
2 Me2SiCl2
3 DMAP
330
331
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1429
55-83 (d) Du Y Linhardt R Y Recent Adv in Stereo-SelectiveC-Glycoside Synthesis Tetrahedron Lett 1998 54 9913-9959 (e)Liu L Mckee M and Postema M H D Synthesis of C-saccharides and Higher Congeners Current Org Chem 2001 51133-1167
[10] Jarosz S Fraser-Reid B Synthesis of A Higher Carbon Sugar ViaDirected Aldol Condensation Tetrahedron Lett 1989 30 2359-2362
[11] Lichtenthaler F W Lergenmiiller M Schwidetzky S C-Glycosidations of 2-Ketohexosyl With Electrophilic Radical andNudeophilic Anomeric Carbons Eur J Org Chem 2003 3094-3103
[12] Baudat A Vogel P Aza-C-disaccharides Synthesis of 6-Deoxygalactonojirimycin-β-C(1rarr3) Linked with D-Altrofuranosides and D-Galactose J Org Chem 1997 62 6252-6260
[13] Turner D Vogel P Synthesis of 4-Hydroxy-26-Bis(hydroxymethyl) tetrahydropyran-2-Carbaldehyde DerivativesSynlett 1998 304-306
[14] Zhu Y-H Vogel P Short Stereoselective Synthesis of C-(1rarr3)-Linked Disaccharides Tetrahedron Lett 1998 39 31-34
[15] Zhu Y-H Vogel P Synthesis of a (2R 6R)-2-(Hydroxymethyl)-6-Propa-1 2-Dienyl-2H-Pyran-3(6H)-One Derivative A NewEnone for The Convergent Construction of C-Glycosides of C-Disaccharides Synlett 2001 82-86
[16] Baumberger F Vasella A Deoxynitrosugars The 6th
Communication Stereolectronic Control in the reductivedenitration of tertiary nitro ethers A Synthesis of ldquoC-glycosidesrdquoHelv Chim Acta 1983 66 2210-2221
[17] Martin O R Lai W Synthesis and Conformational Studies of β-(1rarr6)- and ββ-(1rarr1)-Linked C-disaccharides J Org Chem1993 58 176-185
[18] Spak S J Martin R The synthesis of an analogue of Methyl OC-Analogue of Methyl 4rsquo-O-β-D-GlucopyranosylgentiobiosideTetrahedron 2000 56 217-224
[19] Kobertz W R Bertozzi C R Bednarski M D C-GlycosylAldehyde Synthons for C-Linked Disaccharides J Org Chem1996 61 1894-1897
[20] Gurjar M K Nagaprasad R and Ramana CV First Synthesis ofMethyl α-C-D-Arabino-furanosyl-(1rarr5)-αminusD-Arabinofuranosidethe C-Disaccharide Segment of Motif C of MycobateriumTuberculosis Tetrahedron Lett 2000 43 7577-7579
[21] Witczak Z J Synthesis of C-Glycosyl Compounds and OtherNatural Products from Levoglucosenone Pure Appl Chem 199466 2189-2192
[22] Griffin F K Paterson D Taylor R J K Ramberg-BacklundApproaches to the Synthesis of C-Linked Disaccharides AngewChem Int Engl 1999 38 2939-2942
[23] Paterson B E Griffin F K Alcaraz M-L and Taylor R J KA Ramberg-Baumlcklund Approach to the Synthesis of C-GlycosidesC-Linked Disaccharides and C-Glycosyl Amino Acids Eur JOrg Chem 2002 1323-1336
[24] McAllister G D Paterson D E Taylor R J K A SimplifiedRamberg-Bachlund Approach to Novel C-Glycosides and C-Linked Disaccharides Angew Chem Int Ed Engl 2003 42 1387-1391
[25] McCartney J L Christopher T M Cicchillo R M BernardinaM D Wagner T R and Norris P J Org Chem 2003 6810152-10155
[26] Dondoni A Zuurmond H M Bascarate A Synthesis of α-andβ-D-(1rarr6)-C-Disaccharides by Witting Olefination of Formyl C-Glycosides with Glycopyranose 6-phosphoranes J Org Chem1997 62 8114-8124
[27] Dondoni A Kleban M Zuurmond H Marra A Synthesis of(1rarr6)-C-Oligogalactosides by Interative Wittig OlefinationTetrahedron Lett 1998 39 7991-7994
[28] Dondoni A Marra A A New Synthetic Approach toMycobacterial Cell Wall α-(1rarr5)-D-Arabinofuranosyl C-Oligosaccharides Teterahedron Lett 2003 44 4067-4071
[29] Colinas P A Ponzinibbio A Lieberknecht A and Bravo R OWittig Reaction of Glycosyl Phosphonium Salts A StereoselectiveRoute to C-Disaccharides and C O-Trisaccharides TetrahedronLett 2003 44 7985-7988
[30] Schmidt R R Preuss R Synthesis of Carbon Tetrahedron Lett1989 30 3409-3412
[31] Dietrich H Schmidt R R Synthesis of Carbon-Bridged C-Lactose and Derivatives Liebigs Ann Chem 1994 975-981
[32] Rouzaud D Sinayuml P The First Synthesis of a ldquoC-DisacchariderdquoJ Chem Soc Chem Commun 1983 1353-1354
[33] Xin Y-C Zhang Y-M Mallet J-M Glaudemans C P JSinayuml P Synthesis of C-Oligosaccharides That Mimie TheirNatural O-Analogues Immunodeterminants in Binding toMonoclonal Immunoglobulins Eur J Org Chem 1999 471-476
[34] Streicher H Geyer A Schmidt R R C-Disaccharides ofKetoses Chem Eur J 1996 2 502-510
[35] Leeuwenburgh M A Timmers C M Vander Marel G A VanBoom J H Mallet J-M Sinayuml P G Stereoselective Synthesisof α-C-(Alkynyl)-Glycosides Via Ring-Opening of α-12-Anhydrous Tetrahedron Lett 1997 38 6251-6254
[36] Aslam T Fuchs M G G Le Formal A Wightman R HSynthesis of C-Disaccharide Analogue of the α-D-Arabinofuranosyl-(1rarr5)-α-Arabinofuranosyl Motif ofMycobacterial Cells Walls via Alkynyl Intermediates TetrahedronLett 2005 46 3249-3252
[37] (a) Girad P Namy J L Kagan H B Divalent LanthanideDerivative in Organic Synthesis 1 Mild Preparation of SamariumIodide and Ytterbium Iodide and Their Use as Reducing orCoupling Agents J Am Chem Soc 1980 102 2693-2698 (b)Molander G A Harris C R Sequencing Reactions withSamarium(II) Iodide Chem Rev 1996 96 307-338
[38] (a) Mazeacuteas D Skrydstrup T Doumeix O Beau J-MSamarium Iodide-Induced Intramolecular C-Glycoside FormationEfficient Radical Formation in the Absence of an Additive AngewChem Int Ed Engl 1994 33 1383-1386 (b) Mazeacuteas DSkrydstrup T Beau J-M A Highly Stereoselective Synthesis of1 2-trans-C-Glycosides Via Glycosyl Samarium(III) CompoundsAngew Chem Int Ed Engl 1995 34 909-912 (c) Jarreton OSkrydstrup T Beau J-M The Stereospecific Synthesis of Methylα-C-Mannobioside A Potential Inhibitor of M TuberculosisBinding to Human Macrophages J Chem Soc Chem Commun1996 1661-1662 (d) Jarreton O Skrydstrup T Espionosa J-FJimeacutenez-Barbero J Beau J-M Samarium Diiode Prompted C-Glycosylation An Application to The Stereospecific Synthesis ofα-(1rarr2)-C-Mannobioside and Its Derivatives Chem Eur J 19995 430-441 (e) Mipuel N Doisneau G Beau J-M ReductiveSamariation of Anomeric 2-Pyridyl Sulfones with Catalytic AnUnexpected Improvement in The Synthesis of 12-Trans-Diequatorial C-Glycosyl Compounds Angew Chem Int Ed Engl 2000 39 4111-4114
[39] Vlahov I R Vlahova P I Linhardt R J DiastereocontrolledSynthesis of Carbon Glycosides of N-Acetylneuraminic Acid ViaGlycosyl Samarium(III) Intermediates JAmChem Soc 1997 1191480-1481
[40] Kuberan B Sikkander S ATomiyama H Linhardt R JSynthesis of a C-Glycoside Analogue of sTn An HIV-and Tumor-Associated Antigen Angew Chem Int Ed Engl 2003 42 2073-2075
[41] Bazin H G Du Y Polat T Linhardt R J Synthesis of aVersatile Neuraminic Acid ldquoCrdquo-Disaccharide Precursor for theSynthesis of C-Glycoside Analogues of Gangliosides J OrgChem 1999 64 7254-7259
[42] Chen C-C Ress D K Linhardt RJ Samarium Iodide-Mediated Synthesis of Neuraminic Acid C-Glycosides InSynthesis of Glycommetics Roy R Ed ACS Syposium Series2004 896 53-80
[43] Abdallah Z Doisneau G Beau J-M Synthesis of a Carbon-Linked Mimic of The Disaccharide Component of The Tumor-Relate SialyTn Antigen Angew Chem Int Ed Engl 2003 425209-5212
[44] Lay L Nicotra F Panza L Russo G Caneva E Synthesis ofC-disaccharides through dimerization of exo-glycals J Org Chem1992 57 1304-1306
[45] Isobe M Nishizawa R Hosokawa S Nishikawa TStereocontrolled Synthesis and Reactivity of Sugar Acetylenes JChem Soc Chem Commun 1998 2665-2676
[46] Saeeng R Sirion U Sahakitpichan P Isobe M IodineCatalyzes C-Glycosidation of D-Glucal with SilylacetykeneTetrahedron Lett 2003 44 6211-6215
[47] (a) Babirad S A Wang Y Kishi Y Synthesis of C-Disaccharides J Org Chem 1987 52 1370-1372 (b) Wang YBabirad S A Kishi Y Preferred Conformation of C-Glycosides
1430 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
8 Synthesis of 14-Linked Carbon Disaccharides J Org Chem1992 57 468-481
[48] Armstrong R W Sutherlin D P Strategies for the Synthesis ofC-Disaccharides Containing D and L Sugars Tetrahedron Lett1994 35 7743-7746
[49] Wei A Kishi Y Preferred Conformation of C-Glycosides 12Synthesis and Conformational Analysis of αα- α β- and β β-Trehaloses J Org Chem 1994 59 88-96
[50] Haneda T Goekjian P G Kim S H Kishi Y PreferredConformation of C-Glycosides 10 Synthesis and ConformationAnalysis of Carbon Trisaccharides J Org Chem 1992 57 490-498
[51] Sutherlin D P Armstrong R W Synthesis of 12 Stereochemistryand Structurally Diverse C-Trisaccharides J Org Chem 1997 625267-5283
[52] Notz W Hartel C Waldscheck B Schmidt R R De NovoSynthesis of a Methylene-Bridged Neu5Ac-α-(23)-Gal C-Disaccharide J Org Chem 2001 66 4250-4260
[53] (a) Postema M H D Calimente D Liu L Behrmanm T L AnOlefin Metathesis Route for the Preparation of (1rarr6)-Linked-C-Disaccharide Glycals A Convergent and Flexible Approach to C-Saccharide Synthesis J Org Chem 2000 65 6061-6068(b) Postema M H Piper J L Liu L Faust M Andreana PSynthesis and Partial Biological Evaluation of a Small Library ofDifferentially Linked β-C-Disaccharide J Org Chem 2003 684748-4754
[54] Nelson A The Development of Strategies and Methods for TheSynthesis of Biologically Active Compounds New J Chem 200428 771-776
[55] Togo H He W Waki Y Yokoyama M C-GlycosylationTechnology With Free Radiant Reactions Synlett 1998 700-717
[56] Giese B Dupuis J Diastereoselective Synthesis of C-Glycopyranosides Angew Chem Int Ed Engl 1983 22 622-623
[57] Adlington R M Baldwin J E Basak A Kozyrod RPApplication of Radical Addition Reactions to tho Synthesis of a C-Glucoside and A Functionalized Amino Acid J Chem SocChem Commun 1983 144-145
[58] Giese B Gonzaacutelez-Goacutemez J A Witzel T The Scope of RadicalCC-Coupling by The ldquoTin Methodrdquo Angew Chem Int Ed Engl1984 23 69-70
[59] Giese B Witzel T Synthesis of ldquoC-Disaccharidesrdquo by RadicalC-C Bond Formation Angew Chem Int Ed Engl 1986 25 450-451
[60] Witczak Z J Chhabra R Chojnacki J C-Disaccharides IStereoselective Approach to β-(1rarr4)-3-Deoxy-C-Disaccharidesfrom Levoglucosenone Carb Res 1997 301 167-175
[61] Vogel P Synthesis of Rare Carbohydrates and Analogues Startingfrom Enantiomerically Pure 7-Oxabicyclo[221]heptyl Derivatives(ldquoNaked Sugarsrdquo) Current Org Chem 2000 4 455-480
[62] Viodeacute C Vogel P Synthesis of The C-Disaccharide α-C(1rarr3)-L-Fucopyranoside of N-Acetylgalactosamine J Carb Chem2001 20 733-746
[63] Xin Y C Mallet J M Sinayuml P An Expeditious Synthesis of AC-Disaccharide Using A Temporary Silaketal Connection J ChemSoc Chem Commun 1993 864-865
[64] (a) Petitou M Herault P Lormeau J-C Helmboldt A MalletJ-M Sinayuml P Herbert J-M Introducing A C-InterglycosidicBond in A Biologically Active Pentasaccharide Hardly Affects ItsBiological Properties Bioorg Med Chem 1998 6 1509-1516 (b)Sinayuml P Advances in The Synthesis of the Carbohydrate MimicsPure Appl Chem 1998 70 1495-1499
[65] Sinayuml P Chemical Synthesis of Oligosaccharide Mimetics PureAppl Chem 1998 70 407-410
[66] Sinayuml P Chemical Synthesis of Oligosaccharide Mimetics PureAppl Chem 1998 69 459-463
[67] Vauzeilles B Sinayuml P Selective Radical Synthesis of β-C-Disaccharides Tetrahedron Lett 2001 42 7269-7272
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1399
61 to levoglucosenone 62 gave adduct 63 in 43 yield Thesterics in 62 dictates the facial bias of the addition whichcan only occur from the α-face Reductive denitrationfollowed by reduction of lactol and ketone afforded 64 Ringopening deprotection and acetylation gave 65 (Scheme 14)[21]
23 Sulfur Stabilized Anions
The Taylor group employed the Meyers variant of theRamberg-Baumlcklund reaction to synthesize C-disaccharides[22] The penta-O-benzyl thioglucose 66 was coupled withiodide compound 67 followed by oxidation of the formedsulfide gave sulfone 68 Exposure of the sulfone to theMeyers variant of the Ramberg-Baumlcklund reaction affordedexo-glycal 69 as a mixture of isomers in 48 yieldHydrogenation of this mixture stereoselectively reduceddouble bond and cleaved the benzyl groups Peracetylated C-
trehalose 70 was furnished by acetylation of free sugar(Scheme 15)
This approach is well suited to analog synthesis simplyby varying the alkylating agent Thus the homologous(1rarr1rsquo)-C-disaccharide containing a two-carbon bridge(ldquohomoisotrehaloserdquo) was readily prepared (Scheme 16)[23] Lactol 71 was converted into sulfonate 74 by astraightforward three-step sequence involving Moffat-typeC-glycosylation to give ester 72 followed by reduction andmesylation Next 74 was coupled with thiol 75 in a similaralkylation-oxidation sequence to that above The resultingsulfone 77 underwent a halogenative Ramberg-Baumlcklundrearrangement (RBR) to give exo-glycal 78 as a 8812mixture of (Z)- and (E)-isomers in 57 yield Subsequentreductiondebenzylation followed by acetylation producedthe novel ethylene-bridged disaccahride 79
Scheme (11)
Scheme (12)
OBnO
OBnOMe
BnO
NO2
OBnO
OBn
BnO
OBn
CHO
OHO
OH
HO
OH
OHO
OHOMe
HO
OBnO
OBn
BnO
OBn
OBnO
OBnOMe
BnO
NO2R
OBnO
OBn
BnO
OBn
OBnO
OBnOMe
BnO
KF 18-C-6 MeCN+
1 n-BuLi2 PTC-Cl
51 R = OH
52 R = OC(S)OPh
Bu3 SnH AIBN
1 TsNHNH NaOAc
2 Na NH3
49
50
5354
OAcO
OAc
AcOO
OAcO
OAc
OAc
NO2OAc
OAc
AcO
OAcO
BnOOBn
OMe
BnO
OO
AcOOAc
OAc
OAcO
OMe
BnO O
BnOOBn
O
OO
AcOOAc
OAc
NO2
OAcO
OAc
AcO
OAcO
BnOOBn
OMe
BnO
OH
KF 18-C-6 MeCN
1 Ac2O Pyr2 NaBH4 EtOH3 Bu3SnH AIBN4 H2 Pd(OH)2
5 NaOMe MeOH
45
46
47
48
1400 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
This group also reported a rapid synthesis of a range ofC-disaccharides involving a tandem Horner-Wadsworth-Emmons (HWE)conjugate-addition C-glycosylation followedby a tandem halogenation-RBR sequence utilizing Meyersvariant of the RBR [24] The HWE reagent 81 proceeded theHWEconjugate-addition sequence with diisopropylidenemannofuranose 80 in 86 yield to produce the adductsulfone 82 (as a mixture of diastereomers) The keyhalogenation-RBR was carried out using the conditions
devised by Chan et al giving E-alkene 83 as the onlyisolable product Alkene hydrogenation and concomitantdebenzylation followed by acetylation for characterizationpurposes gave the novel disaccharide 84 in 69 yield overthe two reactions (Scheme 17)
A two-directional variant of this methodology can beused to prepare symmetrical C-disaccharides as shown inScheme 18 [24] The double HWE reaction on diisopro-pylidene mannofuranose 80 worked extremely well in the
Scheme (13)
Scheme (14)
BnO
OBn
O2N
OMe
O
CHO
OBnO
OBn
BnO
OMe
OHO
OH
OHO
OH
HO
OMe
OBnO
OBn
OBnO
OBn
BnO
HO
NO2
OMe
OBnO
OBn
OBnO
OBn
BnO
X
+
KF 18-C-6 MeCN
1 Ac2O Pyr2 NaBH4 EtOH
58 X = NO 2
59 X = H 44 over 3 st eps
Bu3SnH AIBN
Pd(OH)2 H2
rt 1 atm 24 h
40
60 74
55
56
57
O
BnOOBn
BnO
OBn
OH
O
OHNO2
O
O
BnOOBn
BnO
OBn
OH
O
ONO2
O
O
O
O
O
AcOOAc
AcO
OAc
O
OAc OAc
OAc
O
BnOOBn
BnO
OBn
NO2OH
Et3 N MeCN
1Bu3 SnH AIBN
2 BF OEt Et3SH
3 L-SelectrideTHF
64 61 in 3 steps
1 Pd(OH)2 C6 H10
2 Ac2O TESOTF
61 63 43
62
65
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1401
HWEconjugation-addition C-glycosydation sequence givingdiastereomeric sulfones 85 in a combined yield of 75RBR of the major stereoisomer (βα-79) using the Meyers-
Chan procedure gave alkene 86 in 66 unoptimized yieldand hydrogenation produced the novel C-linked bisfuranosedisaccharide 87 in 76 yield
Scheme (15)
Scheme (16)
OBnO
BnO
H
OBn
OH
OOBn
BnO
OBn
OBn
BnO
OBn
OBn
OBnO
BnO
OBn
OH
SO2
O
OBn
O O
AcO
AcO
AcO
OAc
OAc
OAc
OAc
OAc
OBnO
BnO
OBn
OH
I
O
HS
OBn
BnO
OBn
OBn
68 90 over 2 steps
KOH CCl4 t-BuOH H2O
1 H2 PdC
2 Ac2O Pyr
70 69 over 2 steps
+
1 K2CO3
2 mCPA66
67
69
O
BnOOBn
BnO
OBn
OH
(EtO)2P(O)CH2CO2Et
OBn
OBn
OBnO
OBn
OBnO
BnOOBn
OBn
X
O OBn
OBn
BnOOBn
OBnO
BnOOBn
OBn
OBnO
BnOOBn
OBn
R
OBnO
BnOOBn
OBn
SH
LiAlH4
OAc
AcOOAc
O OAcOAcOAcO
OAc
OAc
1 H2 Pd(OH)2C
2 Ac2 O Pyr
NaH THF
72 R = CO2Et
73 R = CH2OH
66 over 3 steps
K2CO3 acetone
76 X = S
77 X = SO2 79
Oxone THF MeOH H2 O
KOH CCl4 aq tBuOH
78 57ZE 8812
79
71
75
MsCl Et3N 74 R = CH2 OMs
1402 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Norris et al deprotonated 88 with n-BuLi and theresulting anion was coupled with an excess lactone 89 at lowtemperature to afford the adduct 90 in 77 yield SPhgroups were removed with Raney nickel and lactol 91 wasisolated as a syrup that contained two components in
approximately a 41 ratio The two compounds were thoughtto be α- and β-lactols with the latter being major It wasstraightforward to reduce the lactols with a high degree ofstereocontrol to afford the C-disaccharide 92 with a 51isolated yield (Scheme 19) [25]
Scheme (17)
Scheme (18)
O
O O
O
O OH
O OMe
OBnBnO
SO2
P
EtO
EtO
O
OBn
O
OMe
OAc
OAc
OAcO
O O
O
O
O
OO OMe
OBnBnO
SO2
OBn
O
O O
O
O O
O
O
O
OMe
OBn
OBn
OBn
83 50 E only
80
+
NaH THF -78 oC
82 86αβ 11
KOHAl2O3
CBr2F2 CH2Cl2
tBuOH 5 oC
2 h
1 H2PdC EtOAc RT 7h
2 Ac2 O Pyr RT
84 69 over 2 st eps
81
O
O O
O
O OH POEt
OEt
O
SO2
P
EtO
EtOO
O
O
O
OO
O
O
O
O O
O
O
O O
O
O
O
O SO2
O
O
O
O
O
O O
O
OO
O
O
85 75βαββ ca 31
86 66β αββ = 141 E only
H2PdC EtOAc
87 76βαβ β = 141
21 NaH THF -78 o C
80 (2 equiv)
KOHAl2O3CBr2F2 CH2Cl2tBuOH
on majorβα is omer
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1403
24 Phosphorous Stabilized Anions
The most common type of reaction discussed in thissection is Wittig approach to C-oligosaccharide synthesisThis methodology is particularly suited for synthesis of(1rarr6)-C-saccharides since one sugar can hold the aldehydewhile the other the ylid or phosphonate anion
Dondoni has utilized this approach to prepare a variety ofβ-D-(1rarr6)-C- disaccharides The general approach is shownin Scheme 20 Coupling of β-linked galactopyranosyl ormannofuranosyl derivative (93 94 95 or 96) with ylidefrom phosphonium iodide 97 or 98 gave alkene 99 Alkenewas reduced and removal of deprotecting groups gave thecorresponding β-D-(1rarr6)-C- disaccharide 100 [26]
α-D-(1rarr6)-C-disaccharide 103 was also synthesizedusing the approach (Scheme 21)
Dondoni applied this methodology in an iterative fashionto prepare the corresponding β-(1rarr6)-C-trigalactosides andβ-(1rarr6)-C-tetragalactosides [27] Starting with coupling ofylide 104 generated in situ with aldehyde 33 gave adduct105 (EZ 19) Removal of silyl protecting group followed byoxidation led to aldehyde 106 which was coupled with theylide from 104 to give C-trisaccharide 107 in 36 yield Thesame sequence was repeated with 107 afforded the protectedC-tetrasaccharide alkene 108 Compounds 108 wasdesilylated and exposed to hydrogen over Pd(OH)2 oncarbon followed to peracetylation gave protected C-tetrasaccharide 109 (Scheme 22)
Taking advantage of their experience on the stereo-selective synthesis of C-oligosaccharides by iterative Wittigolefination this group developed new building blocks and amodified protocol for the straightforward assembly of C-α-(1rarr5)-D-oligoarabinofuranosides [28] While the twomonofunctionalized sugar moieties 110 and 111 weresuitable precursors to the head and tail of the oligo-saccharidic chain the difunctionalized compound 114 was arepeating unit (Scheme 23) Building block 114 wasdesigned to allow after the Wittig coupling for regenerationof the formyl group in a single step under conditions that donot affect the chemical and stereochemical integrity of thegrowing saccharidic chain (Scheme 24)
Colinas et al reported a method for the synthesis of C-disaccharides by a sequence involving the Wittig reaction askey step and further glycosydation of these compounds toafford new C O-trisaccharides [29] The enol ether 122a-bwere prepared by the Wittig reaction of the α β mixture of2-deoxiglycosyl phosphonium salts 120a-b with aldehyde121 Hydrogenation of the exo-glycals afforded the β-C-disaccharides with good yields The O-glycosidationemploying the exo-glycals and the glycosyl acceptor 124 isillustrated in Scheme 25
25 C-1 Vinyl Anions
Schmidt was the first to explore the addition of sulfoxide-stabilized vinyl C-1-organolithiums to carbohydrate-basedcarbonyl compounds [30] The vinyl sulfoxide 126 was
Scheme (19)
OCH3
O O
OPhS
PhS
O O
OO
OCH3
O O
OO O
O H
OCH3
O O
OPhSPhS
O O
O OH
OCH3
O O
OO O
O OH
+
n-BuLi THF -78 oC
Raney Ni EtOH H2O rt
Et3SiH BF3 OEt2
90 77
92 51 over 2 steps 91 is omers rati o βα = 41
-78 oC
88
89
1404 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
deprotonated with LDA to give 127 Addition of 127 toaldehyde 128 gave a mixture of diastereoisomers of whichthe major 129 was formed in a 101 ratio Desulfurizationhydroboration and removal of benzyl groups gave the(1rarr5)- βminusC-disaccharide 130 (Scheme 26)
Schmidt and coworkers used this methodology for ahighly efficient synthesis of an analog of C-trehalose 134Scheme 27 [31] Anion 131 was converted to aldehyde 132
and condensation of this aldehyde with the same anion gaveadduct 133 which was then converted to the target C-disaccharide 134
26 Acetylide-Based Anions
Sinayuml was the first to prepare a C-disaccharide Hisapproach involved the coupling of a C-6 alkyne with ananomeric lactone followed by reduction of the formedhemiacetal [32] Aldehyde 135 was converted to the
Scheme (20)
Scheme (21)
OO O
O
O CHO
O
BnOOBn
BnO
OBn
CHO
OBn
CHO
BnO
O
BnOBnO
O
BnOOBn
BnO OBn
CHO
PPh3I-
OO
O
OO
O
OMeOBn
OBn
OBn
PPh3I-
OCHO
O
PPh3I-
ORRO
RO
OO
ORRHO
OO
OR
+ +
+
( 93 - 96 )
( 97 - 98 )
BuLi THF-HMPA
-30 iexclaelig
99
Reduction
100
+
93 9495
96 97 98
O
OBnBnO
BnO
OO
O
OO
HO
O
O
OO
PPh3I-
O
OHHO
HO
O
HOOH OH
HO
OBnBnO
CHO
BnO
O
+
BuLi THF-HMPA
-30 oC
1 p-MeC 6H4SO2-
NH2NH2 AcONa
2 H2 Pd(OH)2 3 bar
3 Amberli te H+
+
10197
102
103
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1405
dibromoalkene 136 which was treated with n-butyllithium togive an intermediate acetylide 137 The latter uponnucleophilic addition to lactone 138 gave a mixture of lactol139 in high yield Stereoselective reduction of lactol 139 wasfollowed by hydrogenation of benzyl groups and the triplebond affording the (1rarr6)-β-C-disaccharide 140 (Scheme28)
The lactone-addition methodology was later applied bySinayuml and co-workers in an iterative fashion for the
preparation of higher homologues [33] Hydroxylmethylenein compound 141 was converted to acetylide lithium incompound 142 by a sequence of reactions Condensation ofcompound 142 with the galacto lactone 143 gave 144 asmixture of anomers The lactol were stereoselectivelyreduced to and triple bond was hydrogenated to give 145Methyl glycoside 145 was hydrolyzed to the correspondinglactols which were oxidized to lactone 146 The samesequence was then repeated twice to give C-trisaccharide147 and C-tetrasaccharide 148 (Scheme 29)
Scheme (22)
O
BnOOBn
BnO OTBDPS
PPh3I-
BnO
H
O
BnOOBn
OTBDPS
OO
O
OO
O
CHOO
O
OO
O
BnO
O
BnOOBn
BnO
OO
O
OO
H
HOBn
BnO OTBDPS
O
BnOOBn
BnO O
OO
O
OO
H
OBn
BnO OTBDPS
PPh3I-
O
BnO
O
BnOOBn
BnO OTBDPS
PPh3I-
O
AcOOAc
AcO
O
AcOOAc
AcO
OO
O
OO
O
AcOOAc
AcO OAc
O
BnOOBn
BnO
O
BnOOBn
BnO
OO
O
OO
H
H
O
BnOOBn
BnO OTBDPS
H
1 TBAF2 PCC
+107 36
+
1 TBAF2 PCC3
+
1 TBAF2 H2 Pd(OH)2 C3 Ac2 O Pyr
104
33
105
106104
104
108109
BuLi THF-HMPA
-50 o C
70EZ 19
BuLi THF-HMPA
-50 o C
1406 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
The di- tri- and tetrasaccharide derivatives (145 147 and148) were all debenzylated and tested for their bindingaffinity to three different monoclonal immunoglobulins withspecificity for different O-β-(1rarr6)-D-galactopyranosyl deter-minants These C-saccharide analogs had similar bindingproperties to the corresponding O-saccharides
Schmidt has also used acetylide-lactone condensation toassemble C-disaccharides of ketoses [34] Lithium acetylide149 was condensed with ketone 150 to give a mixture ofalcohol 151 after removal of the pivoloyl group Attemptedcyclization under Lewis acid catalysis resulted only in theremoval of the acetonide Accordingly the diol was tiedback as the carbonate and the acetylene complex as thedicobalt species 152 The isomers were then separately
cyclized to give a 11 mixture of C-disaccharide 153 Thecobalt complex on α-C-disaccharide was removed understandard conditions to give 154 and deprotection of thecarbonate was followed by hydrogenation and peracetylationto give 155 (Scheme 30) Similar chemistry was also carriedout with the corresponding β-isomer
Van Boom and co-workers used lithiated alkynylderivative 156 in presence of ZnCl2 to selectively open ringof the 12-anhydrosugar 157 affording the α-C-(alkynyl)-glycoside 158 Hydrogenolysis of the benzyl groups wasfollowed by peracetylation to give the (1rarr6)-α-C-disaccharide 159 (Scheme 31) [35]
Normally attack of the nucleophile proceeds from anequatorial direction to give the β-isomer The unexpected
Scheme (23)
Scheme (24)
BnOO
OBnCHO
OBn
O
OBn
PPh3I-
OBn
OBn
O
OBn
BnOBnO
O
OBnOBn
OBnH
O
OH
HOHO
O
OHOH
OH+
BuLi
THF-HMPA
-20 oC+
1 TBAF2 H2 Pd(OH)2C
112 65 113 100
110
111
O
OBnCHO
OBnBnO
O
OBn
BnOBnO
O
OBnCH(OiPr)2
OBnH
O
OBnCH(OiPr)2
PPh3I-
OBn
O
OBn
BnOBnO
O
OBn
OBnH
O
OBnOBn
BnOH
O
OH
HOHO
O
OH
OH
O
OHOH
HO
++
BuLi
THF-HMPA
-20 oC
BuLi
THF-HMPA
-20 oC
TFA H2 O THF rt
115 49
116 R = CH(OiPr)2
117 R = CHO
118 45
H2 Pd(OH)2C
110
114
114
119
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1407
Scheme (25)
Scheme (26)
OBn
R1
R2
PPh3BF4-O
O
OOHC
O
O
O
O
O
O
O
O
HO
O
O
O
O
O O
OBn
R1
R2
O
O
O
O
O
O
H
O
OBn
R1
R2
O
O
O
O
O
O
O
O
OBn
R1
R2
O
O
O
+
BCl3 (005 equiv)
MS 4A CH2 Cl2 0 o C
+
BuLi THF -90 oC -90 o C
to rtH2 (1 atm) PdC Et3N MeOH
R1 R2 = OBn H
120a - b
121
122a - b
123a - b
124
125a - b
OTBDPS
BnO X
SO Ph
O
BnO
OHCO
BnO
OMeOBn
OBn
O
BnO
OTBDPS
BnO
SO Ph
O
BnO
OMeOBn
OBn
O
HO
OMeOH
OHO
HOHO
OH
OH
128
229 74
1 RaNi (74)
2 BH3 DMS
NaOH H 2O2 (74)
3 H2 PdC (70)
130 74
LDA THF
-100 oC
126 X = H
127 X = Li
1408 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (27)
Scheme (28)
stereochemical outcome is rationalized by the generation ofan initial zinc acetylide species which facilitates intra-molecular delivery to the α-face (Scheme 32)
Wightman synthesized C-disaccharide analogs of the α-D-arabinofuranosyl-(1rarr5)-α-D-arabinofuranosyl motif ofmycobacterial cell walls through alkynyl intermediates [36]The lactone 164 was treated with lithio(trimethylsilyl)ethyneat low temperature to give lactol in 66 yield of 165Treatment of this with triethylsilane and BF3
Et2O gavethe separable isomers 166α (60) and 166β (13)Desilylation of the major isomer 166α gave 167 in 97yield Treatment of 167 with n-BuLi followed by addition oflactone 164 gave 85 yield of the hemiacetal 168 which onreduction with Et3SiH and BF3
Et2O gave the disubstitutedalkyne 169 (83) as the major product Reduction-
hydrogenolysis of 169 then gave the C-disaccharide 170 innear-quantitative yield (Scheme 33)
3 REDUCTIVE GLYCOSYL SAMARIUM SPECIES
The introduction of SmI2 as reducing agent can becredited to Kagan and has since been utilized in numeroussynthetic schemes [37] Sinayuml and Beau introduced SmI2
chemistry into C-glycoside synthesis through intermolecularreactions with appropriate electrophiles and intramolecularreactions of silyl tethered substrates [38] Anomericsamarium species are highly stable and not likely to undergoβ-elimination Treatment of the aryl sulfone 171 with SmI2
affords the nucleophilic intermediate 172 through two singleelectron transfer processes Introduction of a suitableelectrophile (carbonyl compounds) affords the α-C-manno-
O
BnO
OTBDPS
BnO X
SO Ph
O
BnO
OBn
BnO Li
SO Ph
DMF
OHO
HOOH
OH
O OH
OH
HO
OHOH
O
BnO
OTBDPS
BnO
SO Ph
O
OBn
OBnOBnSO
Ph
OH
131 X = Li
132 X = CHO
THF -100 oC
1 Ra-Ni
2 BH3 DMS NaOH H2O2
3 H2 PdC
131
133
134
OBnO
OBnOMe
BnO
Li
OBnO
BnOOBn
OBn
OOBn
OBnOMeBnO
OH
OBnO
BnOOBn
OBn
O
n-BuLi
BnO
OMe
BnO
BrBr
O
OBn
OHO
OH
OH
HO
OHO
OH
HO
OMe
O
BnO
OMeOBn
O
BnO
139 92
1BF3 OEt2 EtOH
2 H2 PdC AcOH
140 52 over 2 steps
135 136 137
138
CBr4 PPh3
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1409
pyrannoside 173 in good yield and with excellent stereo-selectivity (Scheme 34) [38a]
Preparation of C-glycosides of ulosonic acids using SmI2
was pioneered by Linhardt and coworkers [39] Coupling ofpyridyl sulfone 174 with aldehyde 175 in the presence ofSmI2 gave an excellent yield of the N-acetylneuraminic acidC-disaccharide 176 as single isomer This stereochemicaloutcome was rationalized on the basis of the Felkin-Anhmodel for predicting the stereochemical outcome of akinetically controlled addition of a nucleophile to a chiraladehyde (Scheme 35 A)
Reductive samarium method was utilized to synthesizesialo-antigen C-analogs by the Linhardt group A fullyprotected C-analogue of the SialylTn antigen α-D-Neu5Ac-(2rarr6)α-D-GalNAc-(1rarrO)-Ser 182 was prepared [40] C-glycosylation of the neuraminic acid sulfone donor with
aldehyde acceptor in presence of excess SmI2 afforded the α-C-glycoside 180 as an RS mixture (11) The criticalintermediate aldehyde acceptor 178 was prepared in 13steps Chemoselective resolution to compound 180 wasundertaken by oxidation with DMSOAc2O to keto-bridgedcompound 181 followed by stereoselective reduction withZn(BH4)2 to regenerate the bridge hydroxyl function gave182 in gt90 de (Scheme 36)
A common versatile N-acetylneuraminic acid C-disaccharide precursor of the C-glycoside analogs ofgangliosides GM4 and GM3 has been synthesized [41]Samarium(II) iodide coupling of N-acetylneuraminic acidsulfone 179 with a 3-formyl galactopyranoside derivative183 afforded the corresponding C-disaccharide 184 as amixture of (R) and (S) isomers at the newly formedhydroxymethylene bridge This diastereoisomeric mixturewas resolved after debenzylation of the galactoside residue
Scheme (29)
O
BnO
BnOOBn
OBn
OOBn
OBnOMe
OBnOH
O
BnO
BnO
OBn
OBn
O
O
BnOOBn
OMe
BnO
Li
OBnO
OBn
OBn
OBnO
OBn
OBn
OMe
OBnO
OBn
OBnBnO
OBnO
OBn
OBn
OBnO
OBn
OBn
OMe
OBnO
OBn
OBnOBnO
OBn
OBnBnO
O
BnO
BnO
OBn
O
OBnO
OBn
OBnBnO
OBnO
OBn
OBnBnO
OBnO
OBn
OBn
OMe
OBnO
OBn
OBnBnO
OMe
1 PCC2 CBr4 Ph3P3 n-BuLi
144 overall yield 54
1 BF3 OEt2 Et3 OH
2 H2 PtO2 EtOAc
145 76
1 H2 SO4 AcOH
2 PCC
146 62
repeat steps
repeat st eps
141 142
143
147
148
1410 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (30)
Scheme (31)
O
BnOOBn
OMe
Li
BnO
OPivBnO
OBn
OBn
BnO
O OO
BF3 OEt2
OBnO
OBn
OBn
BnO
OO
O
OMe
BnOOBn
BnO
Co(CO)3
Co(CO)3
O
CAN
OBnO
OBn
OBn
BnO
OO
OO
BnOOBn
BnO
OMe
OHBnO
OBn
OBn
BnO
OHO
O
O
OMe
BnOOBn
BnO
Co(CO)3
Co(CO)3
O
OPivBnO
OBn
OBn
BnO
OH OO
O
OMe
BnOOBn
BnO
OAcO
OAc
OAc
AcO
OAcOAc
OAcO
OAc
AcO
OMe
1
2 NaOMe MeOH
1 Lewis acid2 ClCO2CCl3 Pyr3 Co2(CO)8
with a-isomer
1 Et3N Pyr H2O
2 H2 PdC H+
3 Ac2 O Pyr
149 151
152153
154 155
150
OBn
BnO
OBnO
OBn
BnO
OBnO
BnO
MeO
OBnO
OBn
BnO
O
OMe
AcO
OAcO
OAc
OAc
AcO
OAcO
OAc
O
BnOOBn
OMe
BnO
159 74 over 2 steps
+
BuLi ZnCl2 THF
1 H2 PdC2 Ac2O Pyr
156 157
158 59
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1411
Scheme (32)
Scheme (33)
and the chirality of each isomer assigned after acetylationConversion of the p-methoxyphenyl group in the peracety-lated (S) isomer 187 into the corresponding thiophenylglycoside 188 was accomplished affording the key inter-mediate for the synthesis of C-glycoside analogs of GM4GM3 and other related gangliosides (Scheme 37)
Ganglioside GM4 is a very important cell adhesionmolecule The C-disaccharide of GM4 is currently beingsynthesized in Linhardtrsquos lab using standard O-glycosylationof C-disaccharide with protected ceramide Once theceramide has been attached it can be oxidized to afford analdehyde group for coupling to keyhole limpet hemocyanin
OBnO
OBn
BnO
O
OBnO
ClZnO
OBn
BnOCl
R
OBnO
O
OBn
BnOCl
ZnR
O
ZnR
OBnO
OBn
BnO
160 161
162163
O
OBn
OBnBnO
O
O
OBn
OBnBnO H
TMS
O
OBn
OBnBnO H
O
OBn
BnO
OBnHO
O
OBn
OBnBnO OH
TMS
OBnBnO HO
OBn
TMS
O
OR
ORRO H
O
OR
RO
OR
OBn
OBnBnO
H
TMS
O+
K2CO3 MeOH
1 n-BuLi THF -78 oC
2 164
164165 66
166α 60 166β 13167 97
BF3 Et 2O Et 3SiH -78 oC
168 85
169 R = Bn 83
170 R = H near quantitative yield
H2 (1 atm)Pd(OH) 2C
TMS-acetyl ene
n-BuLi THF -78 oC BF3 Et2O Et3SiH
-78 o C
1412 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
O
OHCOBn
OBnBnO
OMe
O
CO2MeAcO
OAcAcHN
OAc
SO2
NAcO
OBnH
H
OBn
OBn
H
O
OMeH HH
A
O
CO2MeAcO
OAcAcHN
OAc
O
OBnOMe
OBnOBn
HO
AcO
+
Nu
174175
176
SmI2 THF
Scheme (34)
Scheme (35)
Scheme (36)
O
BnO
BnO
BnO
Si lylO
O2S N
O
BnO
HO R2R1
BnOBnO
SilylO
OBnO
BnO
BnO
SilylO
Sm(III)
R1COR2 SmI2 THF
171 172
173
NHBoc
OAcO
AcO
AcHN O
O
CO2BnO
OO
OO
OH
O
CO2MeAcO
OAcAcHN
OAc
AcO
SO2Ph
R2
O
CO2Me
AcHN
OAc
AcO
R1
AcO
AcO
AcHNO CO2Bn
NHBoc
AcO
OAc
O
Zn(BH4)2
180 R1 R2 = H OH ( RS 11)
181 R1 R2 = O
182 R1 = H R2 = OH de gt 90
DMSO Ac2O
177178
179
13 steps
22 equiv SmI2 THF
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1413
Scheme (37)
Fig (2)
(KLH) by reductive amination for use as carbohydrate-basedvaccine GM3 a related trisaccharide containg gangliosideplays an important role in cell growth and differentiationFig 2 The synthesis of C-oligosaccharide GM3 is currentlyunderway following a similar route to that of C-GM4synthesis [42]
Beau also reported a sialyl C-disaccharide synthesiswhich relied on the unprecedented use of a stable andcrystalline 2-pyridyl sulfide of the N-acetylneuraminic acidderivative 189 as the anomeric precursor in a samarium-Reformastky procedure [43] The coupling procedure withsulfide 189 and aldehyde 190 afforded the carbon-linkeddimer 191 in 93 yield as a 11 diastereomeric mixture
Alcohols 191 were converted into thiocarbonates anddeoxygenated by employing triphenyltin hydride catalyticAIBN and pentafluorophenol which yielded C-disaccharide192 as a single compound in 65 yield for the 2 stepsDesilylation hydrogenolysis acetylation and finalacetolysis of the methyl glycoside provided the carbon-linked mimic 193 of the disaccharidic component of thesialylTn tumor antigen (Scheme 38)
4 CATIONIC METHODS
This section is categorized according to reactions thatinvolve the generation of anomeric ions followed by thecapture with sugar-based nucleophiles
OAcAcHN
OAc
AcO
O
OBnBnO
OBnOMP
HO
O
MeO2CAcO
O
MeO2CAcO
OAcAcHN
OAc
AcO
O
OHHO
OHOMP
HO
O
OBnOHC
OBnBnO
OMP
O
MeO2CAcO
OAcAcHN
OAc
AcO
O
OHHO
OHOMP
HO
O
CO2MeAcO
OAcAcHN
OAc
AcO
SO2Ph
O
MeO2CAcO
OAcAcHN
OAc
AcO
O
OAcAcO
OAcX
AcO
H2 PdC EtOAc CH3OHH2O
+
Ac2O Pyr
187 X = OMP
188 X = SPh 73
184 85 R and S mixture
186 90 for two i somers
+
SmI2 THF183
179
185
O
HO2 CHO
OAcAcHN
OH
HO
O
OHHO
OH
OAcO
(CH2 )12 CH3
HN
OH
(CH2)14CH3
O
O
O
OHHO
OH
O
O
HO2 CHO
OAcAcHN
OH
HO
O
OHHO
OH
O(CH2)12CH3
HN
OH
(CH2)1 4CH3
GM4
GM3
1414 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
41 Exo-glycals as Nucleophiles
Nitotra et al have found that treatment of exo-glycal 194with BF 3
OEt2 followed by a water quench afforded the C-disaccharide 195 (Scheme 39) It is noteworthy tonoteworthy that the attack of the enol ether on the anomericoxonium ion occurs with high stereoselectivity on the α-face only 195 was obtained [44]
42 Silyl-based Nucleophiles
Isobe has designed and developed alkynylation as a keyreaction for the introduction of a carbon chain onto sugarsThose alkynylated compounds are called ldquosugar acetylenesrdquo[45] The mechanism includes eliminative formation ofcation to which silylacetylene can coordinate on the α-face(Scheme 40)
Double C-glycosylation between glycal 198 and bis(silylacetylene) gave C-disaccharide ldquolikerdquo compounds 199and 200 (Scheme 41)
Silylpropargyl-sugar 201 smoothly reacted with D-glucalto furnish exclusively the α-acetylene glycoside product 202in 88 (Scheme 42) [46]
5 CYCLIZATION METHODOLOGY
This approach to C-oligosaccharide synthesis relies onthe coupling of an open chain fragment with an intact
monosaccharide to give an intermediate that is then cyclizedto deliver the C-oligosaccharide target This section isdivided by the type of chemistry used to initially assemblethe two pre-cyclization fragments
51 Wittig Reaction-Cyclization
The Kishi group was the first to use Wittig-cyclizationapproach to synthesize C-disaccharides Starting with Wittigreaction between 203 and 204 the intermediate 205 wasafforded as a single stereoisomer in 82 yield Osmylationthen gave a mixture of diols with the major one formed in a61 ratio Selective protection of the diols gave 206a and206b The mono-para-methoxybenzyl ether 206a was thentransformed into the hemiketal 207 in 75 overall yield inthree steps ie (1) Swern oxidation (2) acetonide hydro-lysis (4 N HClTHFrt) and (3) benzoylation (3 equiv ofPhCOClpyCH2Cl2rt) Silane reduction of 207 in an acidicmedium should preferentially yield the equatorially substi-tuted β-C-glycoside which was deblocked and converted tothe methyl- βminusC-disaccharide 209 Exact parallel experi-ments applied to the minor isomer gave the correspondingC-disaccharide 210 (Scheme 43) [47]
Armstrong has employed Wittig-osmylation protocol forthe preparation of a small library of α-C-(1rarr6)-disaccha-rides [48] Readily available allyl C-glycoside 211 washomologated to diene ester 212 and subjected to osmylation
Scheme (38)
O
CO2MeAcO
OAcAcHN
OAc
AcO
S(2-Py)
O
TESO
AcHNOMe
O
HO
O
CO2MeAcO
OAcAcHN
OAc
AcO
O NHAcOAc
OAc
OAc
O
CO2MeAcO
OAcAcHN
OAc
AcO
O NHAcOBn
OTES
OMe
OAc
AcO
O NHAcOBn
OTES
OMeOH
O
CO2 MeAcO
OAcAcHN
+
192 65
1 MeOHHCl2 H2 PdC EtOH3 Ac2O Pyr4 Ac2OAcOHH2SO4
193 59 overall yield
25 equiv SmI2 THF
1 11-thiocarbonyldiimidazole DMAP2 Ph3SnH cat AIBN
191 93
189
190
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1415
Scheme (39)
Scheme (40)
Scheme (41)
OBnO
OBn
OBn
OBnO
OBn
OBn
OBnO
OBn
OBn
OBnO
OBnCH3
BnO
OH
CH2
OBnO
OBn
CH3
OBn
H2 O
BF3 OEt2 MeCN
194
195 96
OOAc
OAc
AcO
R SiMe3
SnCl4
O
OAc
AcO
R
O
OAc
AcO
O
OAc
AcO
Me3Si
R
SiMe3
196
197
Me3 Si SiMe3
O
AcO
OAc
OAc
SiMe3
SiMe3
O
AcO
OAc
O
OAc
OAc
O
AcO
AcOO
OAc
OAc
SnCl4 CH2Cl2
SnCl4 CH2Cl2198
199
200
1416 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (42)
Scheme (43)
AcO
OAc
OAc
Me3 Si
BnO
OBn
BnO
OBn
AcO
OAc
BnO
OBn
BnO
OBn
+ I2 CH2Cl2
202 88
198 201
O
OBn
OBn
O
O
O
OBn
OBn
O
O
OBn
OBn O
OBn
OBn
O
OPBH2M
OH
OBnO
BnO
BnO
O
OBn
OBn
O
OHOPMB
OHO
HO
HO
O
OH
OHOH
OH
HOOMe
O
OBnOBn
O
Ph3P
O
O
OBn
OBn O
OBn
OBn
O
OPBM
OH
O O
CHO
OBn
BnO
OO
OBn
OBn
O
OHOPMB
BnO
BnO
BnO
OHO
HO
HO
O
OH
OHOH
OH
HOOMe
+ THF -78 oC
1 OsO4 pyr THF
2 NaH PMBBr
206a 206b 206a206b 61
1 Swern [O]2 4N HCl3 PhCOCl pyr
1 Swern [O]2 4N HCl3 PhCOCl pyr
1 PrSiH BF3 OEt2
2 H2 Pd(OH)2C
3 HCl MeOH 90 oC
1 PrSiH BF3 OEt2
2 H2 Pd(OH)2C
3 HCl MeOH 90 o C
203
204
205
207
209
208
210
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1417
followed by reduction to afford a 51 mixture (213214215216) of lactols that were readily separable by chromato-graphy Following a deprotection of an equimolar mixture of213 and 214 217 and the DL hybrid C-disaccharide of D-glucose-O-(1rarr6)-L-galactose 218 were obtained The DDand DL derivatives 219 and 220 of glucose-α-(1rarr6)-idosewere also obtained as a near equimolar mixture afterdeprotection of 215 and 216 (Scheme 44)
52 Anion Addition-Cyclization
Kishi developed an approach for the synthesis of theCndashtrehalo sugars which relied on nucleophilic addition ofone intact sugar fragment to a fundamental aldehyde ieKishi-Nozaki reaction [49] Coupling of monosaccharide221 and aldehyde 222 gave 223 The triple bond waspartially reduced and osmylation was followed by selectiveprotection to afford 224 The acetonide was converted toepoxide 225 by standard methods and removal of the PMBgroup Acid-catalyzed cyclization followed by aglyconichydrolysis and protection of hydroxyl group with (p-methoxyphenyl)diphenylmethyl chloride (MMTrCl) gave226 Inversion of the C-2 hydroxyl and removal of protectinggroups delivered α α-C-trehalose 227 (Scheme 44)
Kishi and co-workers also employed aldol reactions as anefficient access to the C-trisaccharide related to the type IIABO(H) blood group determinant [50] Aldol condensationof the enolate of methyl ketone 228 with aldehyde 229 gavea 41 mixture of hydroxy ketones 230 and 231 The majorketol was cyclized desulfurized and oxidized to afford thedisaccharide ketone 233 The ketone in THF was treatedwith LiHMDS (3 equiv) and TMEDA followed by theaddition of MgBr2 Addition of the aldehyde 234 led toalmost exclusive formation of the equatorial products 235and 236 in a 12 ratio Mesylation of 235 and 236 followedby treatment with liquid ammonia gave enones 237a and237b which were reduced to yield exclusively the C-2rsquo-equatorial ketone 238 Sodium borohydride reduction of theC-3rsquo carbonyl proceeded with the desired stereoselectivity toyield the protected C-trisaccharide 239 which wasdeblocked to provide the polyol 240 (Scheme 46)
Sutherlin and Amstrong cleverly applied a recursivestereochemical deconvolution (RSD) combinatorial approachfor the synthesis of a small library of C-trisaccharides aspotential inhibitors for the cell surface proteins of bacteriumHelicobactor pylori [51] The workers chose to carry outvariations in galactose ring of these trisaccharides An
Scheme (44)
OBnO
BnOOBn
OBn
P O
OEtOEtO
EtO
R H
OH
OH
OH
OH
O
R H
OH
OH
OH
OH
O
OHO
HOOH
OH
O
HO
OHOH
OH
OHO
HOOH
OH
O
HO
OH
OH
OHO
HOOH
OH
O
HO
OH
OHOH
R H
OH
OH
OH
OH
O
R
OBnO
BnOOBn
OBn
O
OHO
HOOH
OH
OO
HOHO
OH
R H
OH
OH
OH
OH
O
1 OsO4 NMO 50
2 DIBAL -32 oC 40
++ +
213 214 215 216
217 218 219 220
1 9-BBN H2O22 Swern [O]
3 t-BuOK
4 I2 C6H6212
211
1418 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
efficient Nozaki-Kishi coupling of vinyl bromide 241 withaldehyde 242 in a diasteromeric ratio of 12 followed byprotection with TBSOTf led to 243 and 244 Hydroborationfollowed by oxidation gave aldehydes 245 and 246respectively Addition of allylmagnesium bromide toaldehyde 245 followed by removal of the silyl groupafforded 247 to 246 giving 248 and 249 Epoxidation gave a11 mixture of the corresponding epoxides which werecyclized to give the C-trisaccharide 250-255 after removalof the benzyl groups (Scheme 47)
Schmidt reported a stereoselective 6-exo-trig selectiveelectrophilic cylization approach for de novo synthesis of amethylene-bridged Neu5Ac-α-(23)-Gal C-disaccharide theC-analog of an important motif in glycosphingolipids [52]The open chain precusors 259ab (a 32-mixture ofdiaseteromeric alcohols) were formed by the addition oflithiated iodide 256 to open chain aldehyde 258 Subsequent
C1 incorporation using Tebbe-reagent formation of a cycliccarbonate and deprotection of the two isopropylidene ketalsafforded tetrol 264 which upon treatment with phenylselenyltrifilate was steroselectively cyclized in a 6-exo-trigselective manner affording a diasteromeric mixture of 251and 252 in a ratio of 71 A seleno-Pummerer rearrangementto afford aldehyde 267 in 5 steps in 90 overall yieldOxidation of the aldehyde and subsequent steps led to thedesired C-disaccharide 268 (Scheme 48)
53 Esterification-Cyclization
Work from the Postema group has focused on a ringclosing metathesis (RCM) approach for the synthesis of C-saccharides [53a] The chemistry is versatile and has beenused for the synthesis of a small library of differentiallylinked β-C-disaccharides through a radical allylation-RCMstrategy [53b] The synthesis of the β-(1rarr4)-glucopyranosyl
Scheme (45)
O
OBn
BnO
BnO
BnO
I
CrCl2-NiCl2O
OBn
OH
BnO
BnO
BnO
O
O
O
O
O
H
OBn
O
O
OBnBnO
BnO
BnO
OOBn
OBn
OAc
PMBOHOO
OBn
BnO
BnO
BnO
O
OBn
OBn
OAc
O
OH
HO
HO
HO
OH
OH
OH
O
OH
O
OBn
BnO
BnO
BnO
OBn
OBn
OAc
O
MMTr
+
1 p-TsOH2 K2CO3 MeOH3 MMTrCl pyr
1 Swern [O]2 BH3 THF
3 AcOH-H2 O4 H2 Pd(OH)2
221
222
223
1 Pd-Pb CaCO3 H22 NaH BnBr3 OsO44 Bu2 SnO5 CsF PMB-Cl6 Ac2 O 4-DMAP
1 AcOH2 TsCl pyr
3 NaH-imid4 DDQ
224225
226 227
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1419
Scheme (46)
OBnO O
OBn
OMe
OBn
XY
SMe
OBnBnO
O
OBn
OBn
OBn
OBn
O
BnO
YX
OBn
TBSO
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnOOBn
H
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnO
OBn
OHC OBn
OBn
OTBS
OMe
BnOOBn
CHO
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnOOBn
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnO
OBn
YX
OBnO O
OBn
OMe
OBn
OBn
O
BnO
O
OBn
OBn
OBn
OBn
O 1 LiHMDS
2
228
1 TBAF THF
2 MeSH BF3 OEt2
230 X = OH Y = H231 X = H Y = OH
230231 41
1 Bu3SnH AIBN2 Swern [O]
1 LiHMDS THF-TMEDA2 MgBr23
1 MsCl
2 liquid NH3
235 X = OH Y = H236 X = H Y = OH Bu3 SnH AIBN
237a and 237b
NaBH4 MeOH
238
239 X = OBn
240 X = OHH2 Pd(OH)2
229
232233
234
1420 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (47)
OH C
O
O BnAcHN
OO
O
OBn OBnOBn
Br
O
OBn OBnOBn
O
OBnA cHN
OO
O TBSO
OBn O BnO Bn
O
OBnAcHN
OO
OTBS
S2
S1
S2
OTBSS1
O H
S2
OT BSS1
O H
MgBrMgBr
S2
O TBSS1
O H
S2
OHS1
OH
S2
OTBSS1
OH
O
OHHO
O H
O
HO
H OO
OBnA cH N
HO
H O
O
O HHO
OH
O
HOHO
O
OBnA cH N
HO
H O
O
OHH O
OH
O
H O
HOO
OBnAcHN
HO
HO
O
O HH O
OH
O
H O
H O O
OBnA cHN
HO
HO
O
O HH O
O H
O
HO
H O O
OBnAcHN
HO
HO
O
OHHO
OH
O
H O
O
OBnA cHN
HO
HOHO
+
241 242
1 CrCl2-NiCl2 T HF-DMF 722 TBSOTf 2 6-lutidine 91
243 244
1 9-BBN 602 Dess-Mart in period inane 97
1 9 -BBN 552 D ess-Martin periodinane 98
245 246
1
2 T BAF 74
1
2 TBAF 88
247 248 249
250
251
250 251 1 1 252 253 1 1 254 255 1 1
252
253
254
255
1 MCPBA2 CSA CH 2Cl2 61 fo r 2 steps3 H 2 Pd (O H)2C 95
1 MCPBA2 CSA CH 2Cl2 63 fo r 2 s teps3 H 2 Pd (OH)2C 87
1 MCPBA2 CSA CH2Cl2 80 for 2 steps3 H2 Pd(O H)2C 95
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1421
Scheme (48)
O
OO
Se Ph
R
O
HO OHOH
O
OB n O B n
OB n
O B nO O
O O
R O OR
X
O
OO
R
Se Ph
O
HOOH
OH
O
OB nOB n
O Bn
OB n
O O
O O
R O O R
O H
O
O B n OB n
O B n
OB n
O
C HO
O
O O
R O OR
OAc HN
OAc
C O2NH 4HOOH
OH
O
OH O H
OH OH
O
OB n O B n
OB n
OB nO O
O O
R O OR
X
O
O
OAcOAc
C HOA cOOAc
OAc
O
OB n O B n
OB n
OB n
O
O Bn OB n
OB n
OB n
X
OH
OO
HOOH
OH
O
O
OMeOB n
OB nOB n
R
t-B uL i256 R = Li
257 R = L i
258
(R = t-B uMe 2Si )
(R = t-B uMe 2Si )
259ab (32) 79 com bine d yi eld
De ss-Ma rtin pe riodinane
260 X = O R = t-B uMe 2Si ) 95
261 X = O R = t -B uMe2S i) 62
T e bbe re age nt
TB A F THF262 X = O R = H 94
diphosge ne
C H2C l 2Pyr
263 95
T HFH2O T FAr t
264 quant it a ti ve yie ld
PhSe C l AgOT f
EtC N -80 oC
265
266
Quant it at i ve yi l ed 25 26 7 1
+
R =
1 Ac 2OPyr
2 mC PB A3 Ac 2ONa OAc
4 NaO HT HFMe OH
5 Ac2O P yr
267 90 overa ll yi e ld
ste ps
268
1422 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
glucopyranoside 280 represents an example of thischemistry The known triacetyl glucopyranoside 269 wasconverted to iodide 270 in good yield Radical allylation of271 proceeded to afford a mixture of equatorial and axialallylation products in a 61 ratio Oxidative cleavage of thedouble bond gave the corresponding aldehydes 273a and273b which were separable Pinnick oxidation of the majoraldehyde 273a then gave the C-4 equatorial acid 274 DCC-mediated coupling of alcohol 275 and acid 274 proceeded toafford ester 276 in good yield Methylenation of 276 gave277 and exposure to catalysist 278 gave a 41 yield of theC-disaccharide glycal which was exposed to an excess ofBH3
THF to give 64 yield of the β-C-disaccharide 279Removal of the benzyl groups and global peracetylation gavethe peracetylated (1rarr4)-β-C-disaccharide 281 in good yield(Scheme 49)
54 Ring Expansion-Cyclization
Nelson developed a new strategy for asymmetric andstereoselective synthesis of C-linked disaccharide mimeticsthe C58-C71 fragment of palytoxin [54] The diol (RR)-282was converted into the di-dihydropyran (DHP) template 283284 and 285 The di-DHPs were functionized in a twodirectional sense using dihydroxylation reactions The two-directional approach was often very efficient indeed forexample in the synthesis of 286 six new stereogenic centerswere introduced with almost complete stereocontrol using areduction and a dihydroxylation reaction The approach isnot restricted to the synthesis of C2-symmetricaldisaccharide mimetics Using the unsymmetrical template285 which has both a pseudo-axial and a pseudo-equatorialhydroxyl groups the unsymmetrical mimetics 289 and 290were prepared (Scheme 50)
6 RADICAL APPROACHES
The radical approach for C-C bond formation is a popularmethod within organic chemistry The use of radicalchemistry in carbohydrate synthesis has certain advantagesFirstly the reaction conditions are very mild and tolerant ofa range of functional and protecting groups Secondanomeric radicals are stable with respect to elimination andepimeration Most significantly the chemistry required toincorporate an appropriate substitute at C-1 employed in theinitial hemolytic cleavage step is common within carbo-hydrate chemistry [55] The use of such radical techniquecan be subdivided into two classes intermolecular andintramolecular approaches
61 Intermolecular Radical Approaches
Giese was the first to employ an intermolecular radical-based approach for synthesis of C-disaccharides [56]Addition of an alkene to an anomeric radical underappropriate conditions allowed exclusive entry to the α-linked C-glycoside a result which was mirrored by the workof Baldwin [57] The high α-selectivity of the reaction wasin contrast with other reports Thus radicals generated at theC-2 C-3 and C-4 centers all preferred to occupy equatorialpositions [58] When the anomeric bromide 291 was treatedwith tin hydride and AIBN resulting anomeric radical andreacted with lactone 292 in a Michael addition it afforded293 In this reaction hydrogen abstraction at the resulting
radical center occurs from axial face to selectively generatethe equatorial C-2rsquo substituent Reduction and acetylation of293 furnished C-disaccharide 294 (Scheme 51) [59]
Witczak used the facial bias of levoglucosene tostereoselectively add a carbohydrate-based radical in thepreparation of the 3-deoxy-(1rarr4)-β-C-disaccharide 299[60] Addition of the radical derived from iodide 295 to 296gave adduct 297 in 26 yield Removal of the anomerichydroxyl of 297 was achieved by treatment with triethylsilane borontrifluoride ether complex followed bystereoselective reduction of the keto function at C-2rsquo withthe formation of 298 in 89 yield Debenzylation followedby acetolysis of 16-anhydro ring produced the peracetylatedtarget C-disaccharide 299 in 19 overall yield from 295(Scheme 52)
Vogel has developed general methods to transformenantiomerically pure 7-oxabicyclo[221]heptyl derivatives(ldquonaked sugarsrdquo) into C-disaccharides Because of thesechiral bicyclic skeletons they undergo highly stereoselectivereactions with predictable diasteroselectivities An arsenal ofmethods is available that allow to substitute these ldquonakedrdquocarbon centers with a variety of functional groups with allpossible relative configurations The methods allowpreparation of both enantiomers of a given target with thesame ease Predictably high stereoselectivity of the reactionsof the bicyclic chirons adds to the flexibility of approachwhich can lead to high molecular diversity [61]
α-C-(1rarr3)-mannopyranoside of N-acetyl-galactosaminepotent β-galactosidase inhibitors was synthesized by thisapproach [61] Enone 302 was readily prepared from 300The addition of the radical derived from bromide 303 toenone 302 afforded the αminusisomer 304 The ketone was thenreduced and the selenide eliminated via the intermediacy ofthe selenoxide to give 305 Acid-promoted (CF3SO3H) 7-oxa ring opening of 305 in MeCN produced the amino-conduritol derivative 306 resulting from the quenching of theallylic cation intermediate by the solvent (Ritter reaction)Ozonolysis of the chloroalkene 306 generated an acylchloride-aldehyde intermediate that reacted with MeOH toproduce a mixture of methyl uronates The major compound307 was silylated and reduced The crude polyol obtainedwas acetylated to produce 308 Desilylated and ammonolysisafforded a mixture of α-β-pyranoses 309 and correspondingα-β-furanoses (Scheme 53)
Similar chemistry was carried out to synthesize non-protected α-C(1rarr2)-L-fucopyranoside of D-galactopyrano-side corresponding to a blood group mimetic [62] Giesersquosradical fucosidation of racemic enone 310 with α-L-bromoacetofucose 311 provided the mixture of diastereo-meric α-C-fucoside 312a and 312b in reproducible yield of78 Reduction of the mixture gave a 11 mixture of endo-alcohols 313 and 314 which were isolated pure in 40 and355 yield respectively Oxidative elimination of thebenzeneselenyl group of 313 followed by acetylation gaveendo acetate 315 in 85 yield Acid-promoted ring openingof 315 and ozonolysis of the resulted chloroalkene gavemethyl uronic ester 316 in modest yield (10) Treatment of316 with Cl3CCN and NaH followed with BF3
OEt2
furnished the totally protected C-disaccharide 317 in 79
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1423
Scheme (49)
Bu3SnO
HOAcO
OMeOAc
OAc
O
AcO
OMeOAc
OAcI
AIBN
O
AcO
OMeOBn
OBn
HO2C O
AcO
OMeOR
ORY
X
OHBnO
BnO
OBn
OBnO
BnO
OBn
O
AcO
OMeOBn
OBnX
i-Pr i-Pr
N
Mo C(Me2 Ph)((CF3)2 MeCO)2
O
RO
OMeOR
O
RO
OR
OR
RO
OR
278
I2 Ph3P
imidazole
269 270 93
271a X = CH2CH=CH2 Y = H R = Ac 64271b Y = CH2CH=CH2 X = H R = Ac 11272a X = CH2CH=CH2 Y = H R = Bn 75272b Y = CH2CH=CH2 X = H R = Bn 75273a X = CH2CHO Y = H R = Bn 79273a Y = CH2CHO X = H R = Bn 79
1 NaOMe MeOH2 NaOH BnBr DMF
OsO4 NaIO4
NaClO2 NaH2PO4
274 96
275
DCC 4-DMAP
276 X = O 82
277 X = CH2 51
TiCl4 Zn dust TMEDA CH2Br2PbCl2 (Cat )
1
2 BH3 THF H2O2 NaOH
H2 PdC EtOH
Ac2 O Pyr 4-DMAP
279 R = Bn R = H 64
280 R = R = H 99
281 R = R =Ac 97
1424 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (50)
Scheme (51)
O OOH
OH
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
286
1 VO(acac)2 t-BuOH 95
2 (MeO)3CH BF3 90
1 P-O2NC6H4 CO2H Ph3P DIAD2 K2CO3 MeOH 82 over 2 steps
1 PhCOCl Et3N DMAP 402 P-O2NC6H4 CO2H Ph3P DIAD3 KOH THF-H2O 75 over 2 steps
TMEDA OsO4
Cat OsO4 NMO 287
Cat OsO4 NMO288
TMEDA OsO4
Cat OsO4 NMO
290
289
(RR)-282283
284
285
OHO
AcO
BrOAc
OAc
BnO
O
OBn
OBnO
OHO
AcOOAc
OAc
BnO
OOBn
OBnAcO
OHO
AcOOAc
OAc
BnO
O
OBn
OBnO
+
Bu3SnH AIBN291
292
293 81
1 Na[Al(OC2H4OMe)2(OEt)H]2 Ac2O pyr
294 56 over 2 steps
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1425
Scheme (52)
Scheme (53)
OBnO
BnOOBn
OBn O
OH
O
OBnO
BnO
OHOBn
OBn O
O
O
O
O
O
OBnO
BnOOBn
OBnO
OAcOAc
OAc
OBnO
BnO
OHOBn
OBn
IBu3SnH AIBN
295 297 26
1 BF3 OEt2 Et3SiH
2 L-Selectride THF
1 Pd(OH)2C C6H10 EtOH
2 EtSiOSO2CF3 Ac2O
298 89 over 2 steps299
296
O
O
PhSeClO
O
PhSeCl
Bu3 SnH
O
O
PhSeCl
R
H
O
OAc
R
Cl
O
AcO
OAc
OAc
OAcOH
Cl
NHAc
R
OAc
AcHN
OH
O
OH OAc
OH
OHO
HO
OH
O
AcO
OAc
OAc
OAcBr
O
O
PhSeCl
O
O
PhSeCl
R
O
OTIPSAcHNR
OAc OAc
O
OHAcHN
COOMe
R
OAc
1 Bu4NF
2 NH3MeOH
1 (Me3Si)2NLi THF2 Me2N=CHI
1 Bu3 SnH AIBN2
1 NaBH42 mCPBA3 Ac2O pyr
1 H+ MeCN
2 H2 O NaHCO3
R =
1 O3MeOH
2 Me2S NaHCO3
1 TIPSOTf 26-lut idine2 LiBH43 Ac2 O pyr DMAP
furanoses +
304 56
305 68 306 84307 50
308 46
300 301 302
303
309
1426 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
The reduction of 317 and treatment with DOWEX-H+ resinprovided the desired C-fucoside 318 in 70 (Scheme 54)
62 Intramolecular Radical Approaches
One disadvantage with the intermolecular approaches isthat during such radical mediated reactions electrondeficient alkenes are required to facilitate C-C bondformation The intramolecular approach of Sinayuml overcomes
this drawback by bring two substrates together via atemporary covalent silaketal connector This enables the useof a wider range of alkenes which can include alkene-functionalized sugars thus leading to the generation of C-disaccharides [63] Based on the early work of Stork Sinayumlemployed the tether reaction in the synthesis of both α- andβ-C-disaccharides with this work subsequently beingemployed in the synthesis of biologically significant natural
Scheme (54)
O
OH
Fuc
Cl
O
O
ClPhSe
OOAc
NHAcOHFuc
O
AcOOAc
AcO
Br
O
O
PhSeCl
O
AcOOAc
AcO
O
OH
PhSe Cl
Fuc
OOAc
NHAc
OMe
Fuc
O
AcHN
OH OAc
OH
O
OH
Me
OH
O
O
Fuc
ClSePh
O
HO
Fuc
ClSePh
+
Ph3SnHAIBN
78 combined yield
Fuc
310
+
1 NaBH4 MeOHTHF2 Chromatography
313 40 314 355
1 mCPBA
2 Ac2O pyr DMAP
+
315 75
1 TfOH MeCN
2 NaHCO3 O3 -78 oC
316 10 over 2 steps
1 Cl3 CCN NaH
2 MeOH BF3 OEt2
317 79
1 LiBH4 THF
2 Dowex-H+
311
312a312b
318 70 for 2 steps
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1427
products [64] The availability of different hydroxyl groupson each monosaccharide unit allowed the fine-tuning ofstereochemical outcome by selective positioning of the silyltether [65] Development of this early stereochemical controlled to the tethering of the donor 320 with alcohol 319through a di-isopropyl silicon tether 321 Subsequent treat-ment with Bu3SnH and AIBN led to a 9-endo-trigcyclization to form the C-disaccharide 322 in an 80 yieldwith exclusive formation of the α-product The silyl tetherwas removed with Bu4NF and deprotection under standardconditions afforded the desired disaccharide 323 in excellentyield (Scheme 55)
In parallel the development of a 32rsquo silyl tether allowedaccess to the β-linked product as demonstrated in Sinayumlrsquossynthesis of methyl β-C-lactoside 328 [66] Alcohol 324 and320 were connected via the dimethylsilyl tether an 8-endo-trig cyclization followed to exclusively afford the β-
disaccharide 326 in 45 yield Removal of the tether anddeprotection of benzyl ether gave β-C-disaccharide 328(Scheme 56)
This group also selected iodosugars bearing a freehydroxyl group as progenitors of the radical donors [67] In atypical experiment the radical donor 329 was connected tothe radical acceptor 330 through a silaketal tether followingtheir procedure Tributyltinhydride mediated 8-endo-trigradical cyclization of compound 331 gave after detetheringof the non isolated intermediate 332 the protected β-C-disaccharide 333 in 37 overall yield (from startingmaterials 330 and 329) Peracetate 335 was achieved afterhydrogenolysis The C-laminaribioside 334 is of potentialbiological interest as it mimics the repeating disaccharideunit of fungal β-(1rarr3)-glucans which have antitumor andimmunomodulating properties (Scheme 57)
Scheme (55)
Scheme (56)
OO
OHSePh
OTBDPSO O
OO
SePh
OTBDPSO
OO
OBnOMe
OBn
Si
O
HOOBn
OMe
OBn
O
HOOH
OHHO
O
HOOH
OMe
OH
OTBDPSO
O
HOOBn
OMe
OBnO
OOH
1 n-BuLi THF
2 iPr2SiCl2 -78 oC
3 DMAP THF rt
1 Bu4NF THF
2 Dowex-H+
3 H2 PdC
Bu3SnH AIBN toluene
319
320
321
322323
OBnO
OHSePh
OBnBnO
OHO
OBnOMe
OBn
ROO
ROOH
OR
OHO
OROMe
OR
OBnO
O
OBnBnO
OO
OBnOMe
OBn
Si
SePh
OBnO
O
OBnBnOO
OOBn
OMe
OBn
Si
1 PhSeH Me2SiCl2
BuLi -78 oC
2 imidazole rt
Bu3SnH AIBN toluene
H2 PdC327 R = Bn
328 R = H
Bu4NF THF
324
320
325
326 45
1428 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
CONCLUSIONS
In this paper the biological importance of C-oligo-saccharides as subunits of natural products and as a newgeneration of carbohydrate based on therapeutics has beenillustrated Different methods are available for the synthesisof C-oligosaccharides As with traditional saccharidesynthesis it has been necessary to develop a number ofspecific approaches to facilitate the regioselective andstereoselective preparation of the desired targets Work inthis area continues and it is expected that many interestingnew C-oligosaccharides will be prepared using the chemistrydescribed in this review It is also likely that new chemistrywill be developed in the future for the preparation of thesebiologically important targets
ACKNOWLEDGEMENTS
The authors thank Dr Sultan Baytas for her criticalreading of this manuscript
REFERENCES
[1] Kennedy J F White C A Bioactive Carbohydrates InChemistry Biochemistry and Biology Ellis Horwood LtdChichesterUK 1983
[2] Wassarman PW Mammalian Fertilization Molecular Aspects ofGamete Adhesion xocytosion Exocytosis and Fusion Cell 199996 175-183
[3] Carbohydrate-based Drug Discovery Wong C-H EdWeinheim Cambridge Wiley-VCH 2003
[4] (a) Sharon N Lis H Lectins as Cell Recognition MoleculesScience 1987 246 227-234 (b) Dwek RA Chem Rev 1996 96683-720
[5] Postema M C-Glycoside synthesis CRC Boc Ratom 1995[6] (a) Weatherman R V Mortell K H Cheruenak MKiessling
L L Toone E J Specificity of C-Glycoside Complexation byMannoseGlucose Specific Lectins Biochem 1996 35 3619-3624(b) Ravishankar R Surolia A Vijayan M Lim S Kishi YPreferred Conformation of C-Lactose at the Free and Peanut LectinBound States J Am Chem Soc1998 120 11297-11303
[7] (a)Wong C-H Halcomb R L Ichikawa Y and Kajimoto TEnzymes in organic synthesis Application to the problems ofcarbohydrate recognition part2 Angew Chem Int Ed Engl 199534 521-546 (b)Howard S Withers SG Bromoketone C-Glycosides a New Class of βminusGlucanase Inactivators J AmChem Soc 1998 120 10326-10331(c) Wang Q Wolff MPolat T Du Y Linhardt R J C-glycoside of Neuraminic Acidsas Neura-minidase Inhibitors Bioorg Med Lett 2000 10 941-944 (d) Phili R Chang J Partis R A Mueller R A ChrestF J Passaniti A The Alpha-glucosidase I InhibitorCastanospermine Alters Endothelial cell Glycosylation PreventsAngiogenesis and Inhibits Tumor Growth Cancer Res 1995 552927-2935
[8] Ossor A Elbein A D In Carbohydrates in Chemistry andBiology Vol 3(II) WileyVCH 2000 pp 513-539
[9] (a) Sinayuml P Synthesis of oligosaccharide Mimetics Pure ApplChem 1997 69 459-463 (b) Beau J-M Gallagher TNucleophilic C-glycosyl Donors for C-glycoside Synthesis Top inCurr Chem 1997 187 1-54 (c) Nicotra F Synthesis of C-glycosides of Biological Interest Top in Curr Chem 1997 187
Scheme (57)
O
O
O
Ph
I
OMe
OHO
BnO
OH
OH
BnOOH
O
BnO
Si
O
O O
Ph
I
OMe
O
O
BnO
OR4O
R5O
OMe
OR2
OR3O
R3O
OR1
R3O
Bu3 SnH AIBN
332 R1 R2 = SiMe2 R3 = Bn R4 R5 = CHPhTBAF THF
333 R1 = R2 = H R3 = Bn R4 = R5 = CHPh 37 from 11
334 R1 = R2 = R3 = R4 = R5 = H
335 R1 = R2 = R3 = R4 = R5 = Ac
329
H2 PdC MeOH
Ac2 O pyr
1 BuLi THF -78 oC
2 Me2SiCl2
3 DMAP
330
331
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1429
55-83 (d) Du Y Linhardt R Y Recent Adv in Stereo-SelectiveC-Glycoside Synthesis Tetrahedron Lett 1998 54 9913-9959 (e)Liu L Mckee M and Postema M H D Synthesis of C-saccharides and Higher Congeners Current Org Chem 2001 51133-1167
[10] Jarosz S Fraser-Reid B Synthesis of A Higher Carbon Sugar ViaDirected Aldol Condensation Tetrahedron Lett 1989 30 2359-2362
[11] Lichtenthaler F W Lergenmiiller M Schwidetzky S C-Glycosidations of 2-Ketohexosyl With Electrophilic Radical andNudeophilic Anomeric Carbons Eur J Org Chem 2003 3094-3103
[12] Baudat A Vogel P Aza-C-disaccharides Synthesis of 6-Deoxygalactonojirimycin-β-C(1rarr3) Linked with D-Altrofuranosides and D-Galactose J Org Chem 1997 62 6252-6260
[13] Turner D Vogel P Synthesis of 4-Hydroxy-26-Bis(hydroxymethyl) tetrahydropyran-2-Carbaldehyde DerivativesSynlett 1998 304-306
[14] Zhu Y-H Vogel P Short Stereoselective Synthesis of C-(1rarr3)-Linked Disaccharides Tetrahedron Lett 1998 39 31-34
[15] Zhu Y-H Vogel P Synthesis of a (2R 6R)-2-(Hydroxymethyl)-6-Propa-1 2-Dienyl-2H-Pyran-3(6H)-One Derivative A NewEnone for The Convergent Construction of C-Glycosides of C-Disaccharides Synlett 2001 82-86
[16] Baumberger F Vasella A Deoxynitrosugars The 6th
Communication Stereolectronic Control in the reductivedenitration of tertiary nitro ethers A Synthesis of ldquoC-glycosidesrdquoHelv Chim Acta 1983 66 2210-2221
[17] Martin O R Lai W Synthesis and Conformational Studies of β-(1rarr6)- and ββ-(1rarr1)-Linked C-disaccharides J Org Chem1993 58 176-185
[18] Spak S J Martin R The synthesis of an analogue of Methyl OC-Analogue of Methyl 4rsquo-O-β-D-GlucopyranosylgentiobiosideTetrahedron 2000 56 217-224
[19] Kobertz W R Bertozzi C R Bednarski M D C-GlycosylAldehyde Synthons for C-Linked Disaccharides J Org Chem1996 61 1894-1897
[20] Gurjar M K Nagaprasad R and Ramana CV First Synthesis ofMethyl α-C-D-Arabino-furanosyl-(1rarr5)-αminusD-Arabinofuranosidethe C-Disaccharide Segment of Motif C of MycobateriumTuberculosis Tetrahedron Lett 2000 43 7577-7579
[21] Witczak Z J Synthesis of C-Glycosyl Compounds and OtherNatural Products from Levoglucosenone Pure Appl Chem 199466 2189-2192
[22] Griffin F K Paterson D Taylor R J K Ramberg-BacklundApproaches to the Synthesis of C-Linked Disaccharides AngewChem Int Engl 1999 38 2939-2942
[23] Paterson B E Griffin F K Alcaraz M-L and Taylor R J KA Ramberg-Baumlcklund Approach to the Synthesis of C-GlycosidesC-Linked Disaccharides and C-Glycosyl Amino Acids Eur JOrg Chem 2002 1323-1336
[24] McAllister G D Paterson D E Taylor R J K A SimplifiedRamberg-Bachlund Approach to Novel C-Glycosides and C-Linked Disaccharides Angew Chem Int Ed Engl 2003 42 1387-1391
[25] McCartney J L Christopher T M Cicchillo R M BernardinaM D Wagner T R and Norris P J Org Chem 2003 6810152-10155
[26] Dondoni A Zuurmond H M Bascarate A Synthesis of α-andβ-D-(1rarr6)-C-Disaccharides by Witting Olefination of Formyl C-Glycosides with Glycopyranose 6-phosphoranes J Org Chem1997 62 8114-8124
[27] Dondoni A Kleban M Zuurmond H Marra A Synthesis of(1rarr6)-C-Oligogalactosides by Interative Wittig OlefinationTetrahedron Lett 1998 39 7991-7994
[28] Dondoni A Marra A A New Synthetic Approach toMycobacterial Cell Wall α-(1rarr5)-D-Arabinofuranosyl C-Oligosaccharides Teterahedron Lett 2003 44 4067-4071
[29] Colinas P A Ponzinibbio A Lieberknecht A and Bravo R OWittig Reaction of Glycosyl Phosphonium Salts A StereoselectiveRoute to C-Disaccharides and C O-Trisaccharides TetrahedronLett 2003 44 7985-7988
[30] Schmidt R R Preuss R Synthesis of Carbon Tetrahedron Lett1989 30 3409-3412
[31] Dietrich H Schmidt R R Synthesis of Carbon-Bridged C-Lactose and Derivatives Liebigs Ann Chem 1994 975-981
[32] Rouzaud D Sinayuml P The First Synthesis of a ldquoC-DisacchariderdquoJ Chem Soc Chem Commun 1983 1353-1354
[33] Xin Y-C Zhang Y-M Mallet J-M Glaudemans C P JSinayuml P Synthesis of C-Oligosaccharides That Mimie TheirNatural O-Analogues Immunodeterminants in Binding toMonoclonal Immunoglobulins Eur J Org Chem 1999 471-476
[34] Streicher H Geyer A Schmidt R R C-Disaccharides ofKetoses Chem Eur J 1996 2 502-510
[35] Leeuwenburgh M A Timmers C M Vander Marel G A VanBoom J H Mallet J-M Sinayuml P G Stereoselective Synthesisof α-C-(Alkynyl)-Glycosides Via Ring-Opening of α-12-Anhydrous Tetrahedron Lett 1997 38 6251-6254
[36] Aslam T Fuchs M G G Le Formal A Wightman R HSynthesis of C-Disaccharide Analogue of the α-D-Arabinofuranosyl-(1rarr5)-α-Arabinofuranosyl Motif ofMycobacterial Cells Walls via Alkynyl Intermediates TetrahedronLett 2005 46 3249-3252
[37] (a) Girad P Namy J L Kagan H B Divalent LanthanideDerivative in Organic Synthesis 1 Mild Preparation of SamariumIodide and Ytterbium Iodide and Their Use as Reducing orCoupling Agents J Am Chem Soc 1980 102 2693-2698 (b)Molander G A Harris C R Sequencing Reactions withSamarium(II) Iodide Chem Rev 1996 96 307-338
[38] (a) Mazeacuteas D Skrydstrup T Doumeix O Beau J-MSamarium Iodide-Induced Intramolecular C-Glycoside FormationEfficient Radical Formation in the Absence of an Additive AngewChem Int Ed Engl 1994 33 1383-1386 (b) Mazeacuteas DSkrydstrup T Beau J-M A Highly Stereoselective Synthesis of1 2-trans-C-Glycosides Via Glycosyl Samarium(III) CompoundsAngew Chem Int Ed Engl 1995 34 909-912 (c) Jarreton OSkrydstrup T Beau J-M The Stereospecific Synthesis of Methylα-C-Mannobioside A Potential Inhibitor of M TuberculosisBinding to Human Macrophages J Chem Soc Chem Commun1996 1661-1662 (d) Jarreton O Skrydstrup T Espionosa J-FJimeacutenez-Barbero J Beau J-M Samarium Diiode Prompted C-Glycosylation An Application to The Stereospecific Synthesis ofα-(1rarr2)-C-Mannobioside and Its Derivatives Chem Eur J 19995 430-441 (e) Mipuel N Doisneau G Beau J-M ReductiveSamariation of Anomeric 2-Pyridyl Sulfones with Catalytic AnUnexpected Improvement in The Synthesis of 12-Trans-Diequatorial C-Glycosyl Compounds Angew Chem Int Ed Engl 2000 39 4111-4114
[39] Vlahov I R Vlahova P I Linhardt R J DiastereocontrolledSynthesis of Carbon Glycosides of N-Acetylneuraminic Acid ViaGlycosyl Samarium(III) Intermediates JAmChem Soc 1997 1191480-1481
[40] Kuberan B Sikkander S ATomiyama H Linhardt R JSynthesis of a C-Glycoside Analogue of sTn An HIV-and Tumor-Associated Antigen Angew Chem Int Ed Engl 2003 42 2073-2075
[41] Bazin H G Du Y Polat T Linhardt R J Synthesis of aVersatile Neuraminic Acid ldquoCrdquo-Disaccharide Precursor for theSynthesis of C-Glycoside Analogues of Gangliosides J OrgChem 1999 64 7254-7259
[42] Chen C-C Ress D K Linhardt RJ Samarium Iodide-Mediated Synthesis of Neuraminic Acid C-Glycosides InSynthesis of Glycommetics Roy R Ed ACS Syposium Series2004 896 53-80
[43] Abdallah Z Doisneau G Beau J-M Synthesis of a Carbon-Linked Mimic of The Disaccharide Component of The Tumor-Relate SialyTn Antigen Angew Chem Int Ed Engl 2003 425209-5212
[44] Lay L Nicotra F Panza L Russo G Caneva E Synthesis ofC-disaccharides through dimerization of exo-glycals J Org Chem1992 57 1304-1306
[45] Isobe M Nishizawa R Hosokawa S Nishikawa TStereocontrolled Synthesis and Reactivity of Sugar Acetylenes JChem Soc Chem Commun 1998 2665-2676
[46] Saeeng R Sirion U Sahakitpichan P Isobe M IodineCatalyzes C-Glycosidation of D-Glucal with SilylacetykeneTetrahedron Lett 2003 44 6211-6215
[47] (a) Babirad S A Wang Y Kishi Y Synthesis of C-Disaccharides J Org Chem 1987 52 1370-1372 (b) Wang YBabirad S A Kishi Y Preferred Conformation of C-Glycosides
1430 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
8 Synthesis of 14-Linked Carbon Disaccharides J Org Chem1992 57 468-481
[48] Armstrong R W Sutherlin D P Strategies for the Synthesis ofC-Disaccharides Containing D and L Sugars Tetrahedron Lett1994 35 7743-7746
[49] Wei A Kishi Y Preferred Conformation of C-Glycosides 12Synthesis and Conformational Analysis of αα- α β- and β β-Trehaloses J Org Chem 1994 59 88-96
[50] Haneda T Goekjian P G Kim S H Kishi Y PreferredConformation of C-Glycosides 10 Synthesis and ConformationAnalysis of Carbon Trisaccharides J Org Chem 1992 57 490-498
[51] Sutherlin D P Armstrong R W Synthesis of 12 Stereochemistryand Structurally Diverse C-Trisaccharides J Org Chem 1997 625267-5283
[52] Notz W Hartel C Waldscheck B Schmidt R R De NovoSynthesis of a Methylene-Bridged Neu5Ac-α-(23)-Gal C-Disaccharide J Org Chem 2001 66 4250-4260
[53] (a) Postema M H D Calimente D Liu L Behrmanm T L AnOlefin Metathesis Route for the Preparation of (1rarr6)-Linked-C-Disaccharide Glycals A Convergent and Flexible Approach to C-Saccharide Synthesis J Org Chem 2000 65 6061-6068(b) Postema M H Piper J L Liu L Faust M Andreana PSynthesis and Partial Biological Evaluation of a Small Library ofDifferentially Linked β-C-Disaccharide J Org Chem 2003 684748-4754
[54] Nelson A The Development of Strategies and Methods for TheSynthesis of Biologically Active Compounds New J Chem 200428 771-776
[55] Togo H He W Waki Y Yokoyama M C-GlycosylationTechnology With Free Radiant Reactions Synlett 1998 700-717
[56] Giese B Dupuis J Diastereoselective Synthesis of C-Glycopyranosides Angew Chem Int Ed Engl 1983 22 622-623
[57] Adlington R M Baldwin J E Basak A Kozyrod RPApplication of Radical Addition Reactions to tho Synthesis of a C-Glucoside and A Functionalized Amino Acid J Chem SocChem Commun 1983 144-145
[58] Giese B Gonzaacutelez-Goacutemez J A Witzel T The Scope of RadicalCC-Coupling by The ldquoTin Methodrdquo Angew Chem Int Ed Engl1984 23 69-70
[59] Giese B Witzel T Synthesis of ldquoC-Disaccharidesrdquo by RadicalC-C Bond Formation Angew Chem Int Ed Engl 1986 25 450-451
[60] Witczak Z J Chhabra R Chojnacki J C-Disaccharides IStereoselective Approach to β-(1rarr4)-3-Deoxy-C-Disaccharidesfrom Levoglucosenone Carb Res 1997 301 167-175
[61] Vogel P Synthesis of Rare Carbohydrates and Analogues Startingfrom Enantiomerically Pure 7-Oxabicyclo[221]heptyl Derivatives(ldquoNaked Sugarsrdquo) Current Org Chem 2000 4 455-480
[62] Viodeacute C Vogel P Synthesis of The C-Disaccharide α-C(1rarr3)-L-Fucopyranoside of N-Acetylgalactosamine J Carb Chem2001 20 733-746
[63] Xin Y C Mallet J M Sinayuml P An Expeditious Synthesis of AC-Disaccharide Using A Temporary Silaketal Connection J ChemSoc Chem Commun 1993 864-865
[64] (a) Petitou M Herault P Lormeau J-C Helmboldt A MalletJ-M Sinayuml P Herbert J-M Introducing A C-InterglycosidicBond in A Biologically Active Pentasaccharide Hardly Affects ItsBiological Properties Bioorg Med Chem 1998 6 1509-1516 (b)Sinayuml P Advances in The Synthesis of the Carbohydrate MimicsPure Appl Chem 1998 70 1495-1499
[65] Sinayuml P Chemical Synthesis of Oligosaccharide Mimetics PureAppl Chem 1998 70 407-410
[66] Sinayuml P Chemical Synthesis of Oligosaccharide Mimetics PureAppl Chem 1998 69 459-463
[67] Vauzeilles B Sinayuml P Selective Radical Synthesis of β-C-Disaccharides Tetrahedron Lett 2001 42 7269-7272
1400 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
This group also reported a rapid synthesis of a range ofC-disaccharides involving a tandem Horner-Wadsworth-Emmons (HWE)conjugate-addition C-glycosylation followedby a tandem halogenation-RBR sequence utilizing Meyersvariant of the RBR [24] The HWE reagent 81 proceeded theHWEconjugate-addition sequence with diisopropylidenemannofuranose 80 in 86 yield to produce the adductsulfone 82 (as a mixture of diastereomers) The keyhalogenation-RBR was carried out using the conditions
devised by Chan et al giving E-alkene 83 as the onlyisolable product Alkene hydrogenation and concomitantdebenzylation followed by acetylation for characterizationpurposes gave the novel disaccharide 84 in 69 yield overthe two reactions (Scheme 17)
A two-directional variant of this methodology can beused to prepare symmetrical C-disaccharides as shown inScheme 18 [24] The double HWE reaction on diisopro-pylidene mannofuranose 80 worked extremely well in the
Scheme (13)
Scheme (14)
BnO
OBn
O2N
OMe
O
CHO
OBnO
OBn
BnO
OMe
OHO
OH
OHO
OH
HO
OMe
OBnO
OBn
OBnO
OBn
BnO
HO
NO2
OMe
OBnO
OBn
OBnO
OBn
BnO
X
+
KF 18-C-6 MeCN
1 Ac2O Pyr2 NaBH4 EtOH
58 X = NO 2
59 X = H 44 over 3 st eps
Bu3SnH AIBN
Pd(OH)2 H2
rt 1 atm 24 h
40
60 74
55
56
57
O
BnOOBn
BnO
OBn
OH
O
OHNO2
O
O
BnOOBn
BnO
OBn
OH
O
ONO2
O
O
O
O
O
AcOOAc
AcO
OAc
O
OAc OAc
OAc
O
BnOOBn
BnO
OBn
NO2OH
Et3 N MeCN
1Bu3 SnH AIBN
2 BF OEt Et3SH
3 L-SelectrideTHF
64 61 in 3 steps
1 Pd(OH)2 C6 H10
2 Ac2O TESOTF
61 63 43
62
65
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1401
HWEconjugation-addition C-glycosydation sequence givingdiastereomeric sulfones 85 in a combined yield of 75RBR of the major stereoisomer (βα-79) using the Meyers-
Chan procedure gave alkene 86 in 66 unoptimized yieldand hydrogenation produced the novel C-linked bisfuranosedisaccharide 87 in 76 yield
Scheme (15)
Scheme (16)
OBnO
BnO
H
OBn
OH
OOBn
BnO
OBn
OBn
BnO
OBn
OBn
OBnO
BnO
OBn
OH
SO2
O
OBn
O O
AcO
AcO
AcO
OAc
OAc
OAc
OAc
OAc
OBnO
BnO
OBn
OH
I
O
HS
OBn
BnO
OBn
OBn
68 90 over 2 steps
KOH CCl4 t-BuOH H2O
1 H2 PdC
2 Ac2O Pyr
70 69 over 2 steps
+
1 K2CO3
2 mCPA66
67
69
O
BnOOBn
BnO
OBn
OH
(EtO)2P(O)CH2CO2Et
OBn
OBn
OBnO
OBn
OBnO
BnOOBn
OBn
X
O OBn
OBn
BnOOBn
OBnO
BnOOBn
OBn
OBnO
BnOOBn
OBn
R
OBnO
BnOOBn
OBn
SH
LiAlH4
OAc
AcOOAc
O OAcOAcOAcO
OAc
OAc
1 H2 Pd(OH)2C
2 Ac2 O Pyr
NaH THF
72 R = CO2Et
73 R = CH2OH
66 over 3 steps
K2CO3 acetone
76 X = S
77 X = SO2 79
Oxone THF MeOH H2 O
KOH CCl4 aq tBuOH
78 57ZE 8812
79
71
75
MsCl Et3N 74 R = CH2 OMs
1402 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Norris et al deprotonated 88 with n-BuLi and theresulting anion was coupled with an excess lactone 89 at lowtemperature to afford the adduct 90 in 77 yield SPhgroups were removed with Raney nickel and lactol 91 wasisolated as a syrup that contained two components in
approximately a 41 ratio The two compounds were thoughtto be α- and β-lactols with the latter being major It wasstraightforward to reduce the lactols with a high degree ofstereocontrol to afford the C-disaccharide 92 with a 51isolated yield (Scheme 19) [25]
Scheme (17)
Scheme (18)
O
O O
O
O OH
O OMe
OBnBnO
SO2
P
EtO
EtO
O
OBn
O
OMe
OAc
OAc
OAcO
O O
O
O
O
OO OMe
OBnBnO
SO2
OBn
O
O O
O
O O
O
O
O
OMe
OBn
OBn
OBn
83 50 E only
80
+
NaH THF -78 oC
82 86αβ 11
KOHAl2O3
CBr2F2 CH2Cl2
tBuOH 5 oC
2 h
1 H2PdC EtOAc RT 7h
2 Ac2 O Pyr RT
84 69 over 2 st eps
81
O
O O
O
O OH POEt
OEt
O
SO2
P
EtO
EtOO
O
O
O
OO
O
O
O
O O
O
O
O O
O
O
O
O SO2
O
O
O
O
O
O O
O
OO
O
O
85 75βαββ ca 31
86 66β αββ = 141 E only
H2PdC EtOAc
87 76βαβ β = 141
21 NaH THF -78 o C
80 (2 equiv)
KOHAl2O3CBr2F2 CH2Cl2tBuOH
on majorβα is omer
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1403
24 Phosphorous Stabilized Anions
The most common type of reaction discussed in thissection is Wittig approach to C-oligosaccharide synthesisThis methodology is particularly suited for synthesis of(1rarr6)-C-saccharides since one sugar can hold the aldehydewhile the other the ylid or phosphonate anion
Dondoni has utilized this approach to prepare a variety ofβ-D-(1rarr6)-C- disaccharides The general approach is shownin Scheme 20 Coupling of β-linked galactopyranosyl ormannofuranosyl derivative (93 94 95 or 96) with ylidefrom phosphonium iodide 97 or 98 gave alkene 99 Alkenewas reduced and removal of deprotecting groups gave thecorresponding β-D-(1rarr6)-C- disaccharide 100 [26]
α-D-(1rarr6)-C-disaccharide 103 was also synthesizedusing the approach (Scheme 21)
Dondoni applied this methodology in an iterative fashionto prepare the corresponding β-(1rarr6)-C-trigalactosides andβ-(1rarr6)-C-tetragalactosides [27] Starting with coupling ofylide 104 generated in situ with aldehyde 33 gave adduct105 (EZ 19) Removal of silyl protecting group followed byoxidation led to aldehyde 106 which was coupled with theylide from 104 to give C-trisaccharide 107 in 36 yield Thesame sequence was repeated with 107 afforded the protectedC-tetrasaccharide alkene 108 Compounds 108 wasdesilylated and exposed to hydrogen over Pd(OH)2 oncarbon followed to peracetylation gave protected C-tetrasaccharide 109 (Scheme 22)
Taking advantage of their experience on the stereo-selective synthesis of C-oligosaccharides by iterative Wittigolefination this group developed new building blocks and amodified protocol for the straightforward assembly of C-α-(1rarr5)-D-oligoarabinofuranosides [28] While the twomonofunctionalized sugar moieties 110 and 111 weresuitable precursors to the head and tail of the oligo-saccharidic chain the difunctionalized compound 114 was arepeating unit (Scheme 23) Building block 114 wasdesigned to allow after the Wittig coupling for regenerationof the formyl group in a single step under conditions that donot affect the chemical and stereochemical integrity of thegrowing saccharidic chain (Scheme 24)
Colinas et al reported a method for the synthesis of C-disaccharides by a sequence involving the Wittig reaction askey step and further glycosydation of these compounds toafford new C O-trisaccharides [29] The enol ether 122a-bwere prepared by the Wittig reaction of the α β mixture of2-deoxiglycosyl phosphonium salts 120a-b with aldehyde121 Hydrogenation of the exo-glycals afforded the β-C-disaccharides with good yields The O-glycosidationemploying the exo-glycals and the glycosyl acceptor 124 isillustrated in Scheme 25
25 C-1 Vinyl Anions
Schmidt was the first to explore the addition of sulfoxide-stabilized vinyl C-1-organolithiums to carbohydrate-basedcarbonyl compounds [30] The vinyl sulfoxide 126 was
Scheme (19)
OCH3
O O
OPhS
PhS
O O
OO
OCH3
O O
OO O
O H
OCH3
O O
OPhSPhS
O O
O OH
OCH3
O O
OO O
O OH
+
n-BuLi THF -78 oC
Raney Ni EtOH H2O rt
Et3SiH BF3 OEt2
90 77
92 51 over 2 steps 91 is omers rati o βα = 41
-78 oC
88
89
1404 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
deprotonated with LDA to give 127 Addition of 127 toaldehyde 128 gave a mixture of diastereoisomers of whichthe major 129 was formed in a 101 ratio Desulfurizationhydroboration and removal of benzyl groups gave the(1rarr5)- βminusC-disaccharide 130 (Scheme 26)
Schmidt and coworkers used this methodology for ahighly efficient synthesis of an analog of C-trehalose 134Scheme 27 [31] Anion 131 was converted to aldehyde 132
and condensation of this aldehyde with the same anion gaveadduct 133 which was then converted to the target C-disaccharide 134
26 Acetylide-Based Anions
Sinayuml was the first to prepare a C-disaccharide Hisapproach involved the coupling of a C-6 alkyne with ananomeric lactone followed by reduction of the formedhemiacetal [32] Aldehyde 135 was converted to the
Scheme (20)
Scheme (21)
OO O
O
O CHO
O
BnOOBn
BnO
OBn
CHO
OBn
CHO
BnO
O
BnOBnO
O
BnOOBn
BnO OBn
CHO
PPh3I-
OO
O
OO
O
OMeOBn
OBn
OBn
PPh3I-
OCHO
O
PPh3I-
ORRO
RO
OO
ORRHO
OO
OR
+ +
+
( 93 - 96 )
( 97 - 98 )
BuLi THF-HMPA
-30 iexclaelig
99
Reduction
100
+
93 9495
96 97 98
O
OBnBnO
BnO
OO
O
OO
HO
O
O
OO
PPh3I-
O
OHHO
HO
O
HOOH OH
HO
OBnBnO
CHO
BnO
O
+
BuLi THF-HMPA
-30 oC
1 p-MeC 6H4SO2-
NH2NH2 AcONa
2 H2 Pd(OH)2 3 bar
3 Amberli te H+
+
10197
102
103
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1405
dibromoalkene 136 which was treated with n-butyllithium togive an intermediate acetylide 137 The latter uponnucleophilic addition to lactone 138 gave a mixture of lactol139 in high yield Stereoselective reduction of lactol 139 wasfollowed by hydrogenation of benzyl groups and the triplebond affording the (1rarr6)-β-C-disaccharide 140 (Scheme28)
The lactone-addition methodology was later applied bySinayuml and co-workers in an iterative fashion for the
preparation of higher homologues [33] Hydroxylmethylenein compound 141 was converted to acetylide lithium incompound 142 by a sequence of reactions Condensation ofcompound 142 with the galacto lactone 143 gave 144 asmixture of anomers The lactol were stereoselectivelyreduced to and triple bond was hydrogenated to give 145Methyl glycoside 145 was hydrolyzed to the correspondinglactols which were oxidized to lactone 146 The samesequence was then repeated twice to give C-trisaccharide147 and C-tetrasaccharide 148 (Scheme 29)
Scheme (22)
O
BnOOBn
BnO OTBDPS
PPh3I-
BnO
H
O
BnOOBn
OTBDPS
OO
O
OO
O
CHOO
O
OO
O
BnO
O
BnOOBn
BnO
OO
O
OO
H
HOBn
BnO OTBDPS
O
BnOOBn
BnO O
OO
O
OO
H
OBn
BnO OTBDPS
PPh3I-
O
BnO
O
BnOOBn
BnO OTBDPS
PPh3I-
O
AcOOAc
AcO
O
AcOOAc
AcO
OO
O
OO
O
AcOOAc
AcO OAc
O
BnOOBn
BnO
O
BnOOBn
BnO
OO
O
OO
H
H
O
BnOOBn
BnO OTBDPS
H
1 TBAF2 PCC
+107 36
+
1 TBAF2 PCC3
+
1 TBAF2 H2 Pd(OH)2 C3 Ac2 O Pyr
104
33
105
106104
104
108109
BuLi THF-HMPA
-50 o C
70EZ 19
BuLi THF-HMPA
-50 o C
1406 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
The di- tri- and tetrasaccharide derivatives (145 147 and148) were all debenzylated and tested for their bindingaffinity to three different monoclonal immunoglobulins withspecificity for different O-β-(1rarr6)-D-galactopyranosyl deter-minants These C-saccharide analogs had similar bindingproperties to the corresponding O-saccharides
Schmidt has also used acetylide-lactone condensation toassemble C-disaccharides of ketoses [34] Lithium acetylide149 was condensed with ketone 150 to give a mixture ofalcohol 151 after removal of the pivoloyl group Attemptedcyclization under Lewis acid catalysis resulted only in theremoval of the acetonide Accordingly the diol was tiedback as the carbonate and the acetylene complex as thedicobalt species 152 The isomers were then separately
cyclized to give a 11 mixture of C-disaccharide 153 Thecobalt complex on α-C-disaccharide was removed understandard conditions to give 154 and deprotection of thecarbonate was followed by hydrogenation and peracetylationto give 155 (Scheme 30) Similar chemistry was also carriedout with the corresponding β-isomer
Van Boom and co-workers used lithiated alkynylderivative 156 in presence of ZnCl2 to selectively open ringof the 12-anhydrosugar 157 affording the α-C-(alkynyl)-glycoside 158 Hydrogenolysis of the benzyl groups wasfollowed by peracetylation to give the (1rarr6)-α-C-disaccharide 159 (Scheme 31) [35]
Normally attack of the nucleophile proceeds from anequatorial direction to give the β-isomer The unexpected
Scheme (23)
Scheme (24)
BnOO
OBnCHO
OBn
O
OBn
PPh3I-
OBn
OBn
O
OBn
BnOBnO
O
OBnOBn
OBnH
O
OH
HOHO
O
OHOH
OH+
BuLi
THF-HMPA
-20 oC+
1 TBAF2 H2 Pd(OH)2C
112 65 113 100
110
111
O
OBnCHO
OBnBnO
O
OBn
BnOBnO
O
OBnCH(OiPr)2
OBnH
O
OBnCH(OiPr)2
PPh3I-
OBn
O
OBn
BnOBnO
O
OBn
OBnH
O
OBnOBn
BnOH
O
OH
HOHO
O
OH
OH
O
OHOH
HO
++
BuLi
THF-HMPA
-20 oC
BuLi
THF-HMPA
-20 oC
TFA H2 O THF rt
115 49
116 R = CH(OiPr)2
117 R = CHO
118 45
H2 Pd(OH)2C
110
114
114
119
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1407
Scheme (25)
Scheme (26)
OBn
R1
R2
PPh3BF4-O
O
OOHC
O
O
O
O
O
O
O
O
HO
O
O
O
O
O O
OBn
R1
R2
O
O
O
O
O
O
H
O
OBn
R1
R2
O
O
O
O
O
O
O
O
OBn
R1
R2
O
O
O
+
BCl3 (005 equiv)
MS 4A CH2 Cl2 0 o C
+
BuLi THF -90 oC -90 o C
to rtH2 (1 atm) PdC Et3N MeOH
R1 R2 = OBn H
120a - b
121
122a - b
123a - b
124
125a - b
OTBDPS
BnO X
SO Ph
O
BnO
OHCO
BnO
OMeOBn
OBn
O
BnO
OTBDPS
BnO
SO Ph
O
BnO
OMeOBn
OBn
O
HO
OMeOH
OHO
HOHO
OH
OH
128
229 74
1 RaNi (74)
2 BH3 DMS
NaOH H 2O2 (74)
3 H2 PdC (70)
130 74
LDA THF
-100 oC
126 X = H
127 X = Li
1408 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (27)
Scheme (28)
stereochemical outcome is rationalized by the generation ofan initial zinc acetylide species which facilitates intra-molecular delivery to the α-face (Scheme 32)
Wightman synthesized C-disaccharide analogs of the α-D-arabinofuranosyl-(1rarr5)-α-D-arabinofuranosyl motif ofmycobacterial cell walls through alkynyl intermediates [36]The lactone 164 was treated with lithio(trimethylsilyl)ethyneat low temperature to give lactol in 66 yield of 165Treatment of this with triethylsilane and BF3
Et2O gavethe separable isomers 166α (60) and 166β (13)Desilylation of the major isomer 166α gave 167 in 97yield Treatment of 167 with n-BuLi followed by addition oflactone 164 gave 85 yield of the hemiacetal 168 which onreduction with Et3SiH and BF3
Et2O gave the disubstitutedalkyne 169 (83) as the major product Reduction-
hydrogenolysis of 169 then gave the C-disaccharide 170 innear-quantitative yield (Scheme 33)
3 REDUCTIVE GLYCOSYL SAMARIUM SPECIES
The introduction of SmI2 as reducing agent can becredited to Kagan and has since been utilized in numeroussynthetic schemes [37] Sinayuml and Beau introduced SmI2
chemistry into C-glycoside synthesis through intermolecularreactions with appropriate electrophiles and intramolecularreactions of silyl tethered substrates [38] Anomericsamarium species are highly stable and not likely to undergoβ-elimination Treatment of the aryl sulfone 171 with SmI2
affords the nucleophilic intermediate 172 through two singleelectron transfer processes Introduction of a suitableelectrophile (carbonyl compounds) affords the α-C-manno-
O
BnO
OTBDPS
BnO X
SO Ph
O
BnO
OBn
BnO Li
SO Ph
DMF
OHO
HOOH
OH
O OH
OH
HO
OHOH
O
BnO
OTBDPS
BnO
SO Ph
O
OBn
OBnOBnSO
Ph
OH
131 X = Li
132 X = CHO
THF -100 oC
1 Ra-Ni
2 BH3 DMS NaOH H2O2
3 H2 PdC
131
133
134
OBnO
OBnOMe
BnO
Li
OBnO
BnOOBn
OBn
OOBn
OBnOMeBnO
OH
OBnO
BnOOBn
OBn
O
n-BuLi
BnO
OMe
BnO
BrBr
O
OBn
OHO
OH
OH
HO
OHO
OH
HO
OMe
O
BnO
OMeOBn
O
BnO
139 92
1BF3 OEt2 EtOH
2 H2 PdC AcOH
140 52 over 2 steps
135 136 137
138
CBr4 PPh3
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1409
pyrannoside 173 in good yield and with excellent stereo-selectivity (Scheme 34) [38a]
Preparation of C-glycosides of ulosonic acids using SmI2
was pioneered by Linhardt and coworkers [39] Coupling ofpyridyl sulfone 174 with aldehyde 175 in the presence ofSmI2 gave an excellent yield of the N-acetylneuraminic acidC-disaccharide 176 as single isomer This stereochemicaloutcome was rationalized on the basis of the Felkin-Anhmodel for predicting the stereochemical outcome of akinetically controlled addition of a nucleophile to a chiraladehyde (Scheme 35 A)
Reductive samarium method was utilized to synthesizesialo-antigen C-analogs by the Linhardt group A fullyprotected C-analogue of the SialylTn antigen α-D-Neu5Ac-(2rarr6)α-D-GalNAc-(1rarrO)-Ser 182 was prepared [40] C-glycosylation of the neuraminic acid sulfone donor with
aldehyde acceptor in presence of excess SmI2 afforded the α-C-glycoside 180 as an RS mixture (11) The criticalintermediate aldehyde acceptor 178 was prepared in 13steps Chemoselective resolution to compound 180 wasundertaken by oxidation with DMSOAc2O to keto-bridgedcompound 181 followed by stereoselective reduction withZn(BH4)2 to regenerate the bridge hydroxyl function gave182 in gt90 de (Scheme 36)
A common versatile N-acetylneuraminic acid C-disaccharide precursor of the C-glycoside analogs ofgangliosides GM4 and GM3 has been synthesized [41]Samarium(II) iodide coupling of N-acetylneuraminic acidsulfone 179 with a 3-formyl galactopyranoside derivative183 afforded the corresponding C-disaccharide 184 as amixture of (R) and (S) isomers at the newly formedhydroxymethylene bridge This diastereoisomeric mixturewas resolved after debenzylation of the galactoside residue
Scheme (29)
O
BnO
BnOOBn
OBn
OOBn
OBnOMe
OBnOH
O
BnO
BnO
OBn
OBn
O
O
BnOOBn
OMe
BnO
Li
OBnO
OBn
OBn
OBnO
OBn
OBn
OMe
OBnO
OBn
OBnBnO
OBnO
OBn
OBn
OBnO
OBn
OBn
OMe
OBnO
OBn
OBnOBnO
OBn
OBnBnO
O
BnO
BnO
OBn
O
OBnO
OBn
OBnBnO
OBnO
OBn
OBnBnO
OBnO
OBn
OBn
OMe
OBnO
OBn
OBnBnO
OMe
1 PCC2 CBr4 Ph3P3 n-BuLi
144 overall yield 54
1 BF3 OEt2 Et3 OH
2 H2 PtO2 EtOAc
145 76
1 H2 SO4 AcOH
2 PCC
146 62
repeat steps
repeat st eps
141 142
143
147
148
1410 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (30)
Scheme (31)
O
BnOOBn
OMe
Li
BnO
OPivBnO
OBn
OBn
BnO
O OO
BF3 OEt2
OBnO
OBn
OBn
BnO
OO
O
OMe
BnOOBn
BnO
Co(CO)3
Co(CO)3
O
CAN
OBnO
OBn
OBn
BnO
OO
OO
BnOOBn
BnO
OMe
OHBnO
OBn
OBn
BnO
OHO
O
O
OMe
BnOOBn
BnO
Co(CO)3
Co(CO)3
O
OPivBnO
OBn
OBn
BnO
OH OO
O
OMe
BnOOBn
BnO
OAcO
OAc
OAc
AcO
OAcOAc
OAcO
OAc
AcO
OMe
1
2 NaOMe MeOH
1 Lewis acid2 ClCO2CCl3 Pyr3 Co2(CO)8
with a-isomer
1 Et3N Pyr H2O
2 H2 PdC H+
3 Ac2 O Pyr
149 151
152153
154 155
150
OBn
BnO
OBnO
OBn
BnO
OBnO
BnO
MeO
OBnO
OBn
BnO
O
OMe
AcO
OAcO
OAc
OAc
AcO
OAcO
OAc
O
BnOOBn
OMe
BnO
159 74 over 2 steps
+
BuLi ZnCl2 THF
1 H2 PdC2 Ac2O Pyr
156 157
158 59
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1411
Scheme (32)
Scheme (33)
and the chirality of each isomer assigned after acetylationConversion of the p-methoxyphenyl group in the peracety-lated (S) isomer 187 into the corresponding thiophenylglycoside 188 was accomplished affording the key inter-mediate for the synthesis of C-glycoside analogs of GM4GM3 and other related gangliosides (Scheme 37)
Ganglioside GM4 is a very important cell adhesionmolecule The C-disaccharide of GM4 is currently beingsynthesized in Linhardtrsquos lab using standard O-glycosylationof C-disaccharide with protected ceramide Once theceramide has been attached it can be oxidized to afford analdehyde group for coupling to keyhole limpet hemocyanin
OBnO
OBn
BnO
O
OBnO
ClZnO
OBn
BnOCl
R
OBnO
O
OBn
BnOCl
ZnR
O
ZnR
OBnO
OBn
BnO
160 161
162163
O
OBn
OBnBnO
O
O
OBn
OBnBnO H
TMS
O
OBn
OBnBnO H
O
OBn
BnO
OBnHO
O
OBn
OBnBnO OH
TMS
OBnBnO HO
OBn
TMS
O
OR
ORRO H
O
OR
RO
OR
OBn
OBnBnO
H
TMS
O+
K2CO3 MeOH
1 n-BuLi THF -78 oC
2 164
164165 66
166α 60 166β 13167 97
BF3 Et 2O Et 3SiH -78 oC
168 85
169 R = Bn 83
170 R = H near quantitative yield
H2 (1 atm)Pd(OH) 2C
TMS-acetyl ene
n-BuLi THF -78 oC BF3 Et2O Et3SiH
-78 o C
1412 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
O
OHCOBn
OBnBnO
OMe
O
CO2MeAcO
OAcAcHN
OAc
SO2
NAcO
OBnH
H
OBn
OBn
H
O
OMeH HH
A
O
CO2MeAcO
OAcAcHN
OAc
O
OBnOMe
OBnOBn
HO
AcO
+
Nu
174175
176
SmI2 THF
Scheme (34)
Scheme (35)
Scheme (36)
O
BnO
BnO
BnO
Si lylO
O2S N
O
BnO
HO R2R1
BnOBnO
SilylO
OBnO
BnO
BnO
SilylO
Sm(III)
R1COR2 SmI2 THF
171 172
173
NHBoc
OAcO
AcO
AcHN O
O
CO2BnO
OO
OO
OH
O
CO2MeAcO
OAcAcHN
OAc
AcO
SO2Ph
R2
O
CO2Me
AcHN
OAc
AcO
R1
AcO
AcO
AcHNO CO2Bn
NHBoc
AcO
OAc
O
Zn(BH4)2
180 R1 R2 = H OH ( RS 11)
181 R1 R2 = O
182 R1 = H R2 = OH de gt 90
DMSO Ac2O
177178
179
13 steps
22 equiv SmI2 THF
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1413
Scheme (37)
Fig (2)
(KLH) by reductive amination for use as carbohydrate-basedvaccine GM3 a related trisaccharide containg gangliosideplays an important role in cell growth and differentiationFig 2 The synthesis of C-oligosaccharide GM3 is currentlyunderway following a similar route to that of C-GM4synthesis [42]
Beau also reported a sialyl C-disaccharide synthesiswhich relied on the unprecedented use of a stable andcrystalline 2-pyridyl sulfide of the N-acetylneuraminic acidderivative 189 as the anomeric precursor in a samarium-Reformastky procedure [43] The coupling procedure withsulfide 189 and aldehyde 190 afforded the carbon-linkeddimer 191 in 93 yield as a 11 diastereomeric mixture
Alcohols 191 were converted into thiocarbonates anddeoxygenated by employing triphenyltin hydride catalyticAIBN and pentafluorophenol which yielded C-disaccharide192 as a single compound in 65 yield for the 2 stepsDesilylation hydrogenolysis acetylation and finalacetolysis of the methyl glycoside provided the carbon-linked mimic 193 of the disaccharidic component of thesialylTn tumor antigen (Scheme 38)
4 CATIONIC METHODS
This section is categorized according to reactions thatinvolve the generation of anomeric ions followed by thecapture with sugar-based nucleophiles
OAcAcHN
OAc
AcO
O
OBnBnO
OBnOMP
HO
O
MeO2CAcO
O
MeO2CAcO
OAcAcHN
OAc
AcO
O
OHHO
OHOMP
HO
O
OBnOHC
OBnBnO
OMP
O
MeO2CAcO
OAcAcHN
OAc
AcO
O
OHHO
OHOMP
HO
O
CO2MeAcO
OAcAcHN
OAc
AcO
SO2Ph
O
MeO2CAcO
OAcAcHN
OAc
AcO
O
OAcAcO
OAcX
AcO
H2 PdC EtOAc CH3OHH2O
+
Ac2O Pyr
187 X = OMP
188 X = SPh 73
184 85 R and S mixture
186 90 for two i somers
+
SmI2 THF183
179
185
O
HO2 CHO
OAcAcHN
OH
HO
O
OHHO
OH
OAcO
(CH2 )12 CH3
HN
OH
(CH2)14CH3
O
O
O
OHHO
OH
O
O
HO2 CHO
OAcAcHN
OH
HO
O
OHHO
OH
O(CH2)12CH3
HN
OH
(CH2)1 4CH3
GM4
GM3
1414 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
41 Exo-glycals as Nucleophiles
Nitotra et al have found that treatment of exo-glycal 194with BF 3
OEt2 followed by a water quench afforded the C-disaccharide 195 (Scheme 39) It is noteworthy tonoteworthy that the attack of the enol ether on the anomericoxonium ion occurs with high stereoselectivity on the α-face only 195 was obtained [44]
42 Silyl-based Nucleophiles
Isobe has designed and developed alkynylation as a keyreaction for the introduction of a carbon chain onto sugarsThose alkynylated compounds are called ldquosugar acetylenesrdquo[45] The mechanism includes eliminative formation ofcation to which silylacetylene can coordinate on the α-face(Scheme 40)
Double C-glycosylation between glycal 198 and bis(silylacetylene) gave C-disaccharide ldquolikerdquo compounds 199and 200 (Scheme 41)
Silylpropargyl-sugar 201 smoothly reacted with D-glucalto furnish exclusively the α-acetylene glycoside product 202in 88 (Scheme 42) [46]
5 CYCLIZATION METHODOLOGY
This approach to C-oligosaccharide synthesis relies onthe coupling of an open chain fragment with an intact
monosaccharide to give an intermediate that is then cyclizedto deliver the C-oligosaccharide target This section isdivided by the type of chemistry used to initially assemblethe two pre-cyclization fragments
51 Wittig Reaction-Cyclization
The Kishi group was the first to use Wittig-cyclizationapproach to synthesize C-disaccharides Starting with Wittigreaction between 203 and 204 the intermediate 205 wasafforded as a single stereoisomer in 82 yield Osmylationthen gave a mixture of diols with the major one formed in a61 ratio Selective protection of the diols gave 206a and206b The mono-para-methoxybenzyl ether 206a was thentransformed into the hemiketal 207 in 75 overall yield inthree steps ie (1) Swern oxidation (2) acetonide hydro-lysis (4 N HClTHFrt) and (3) benzoylation (3 equiv ofPhCOClpyCH2Cl2rt) Silane reduction of 207 in an acidicmedium should preferentially yield the equatorially substi-tuted β-C-glycoside which was deblocked and converted tothe methyl- βminusC-disaccharide 209 Exact parallel experi-ments applied to the minor isomer gave the correspondingC-disaccharide 210 (Scheme 43) [47]
Armstrong has employed Wittig-osmylation protocol forthe preparation of a small library of α-C-(1rarr6)-disaccha-rides [48] Readily available allyl C-glycoside 211 washomologated to diene ester 212 and subjected to osmylation
Scheme (38)
O
CO2MeAcO
OAcAcHN
OAc
AcO
S(2-Py)
O
TESO
AcHNOMe
O
HO
O
CO2MeAcO
OAcAcHN
OAc
AcO
O NHAcOAc
OAc
OAc
O
CO2MeAcO
OAcAcHN
OAc
AcO
O NHAcOBn
OTES
OMe
OAc
AcO
O NHAcOBn
OTES
OMeOH
O
CO2 MeAcO
OAcAcHN
+
192 65
1 MeOHHCl2 H2 PdC EtOH3 Ac2O Pyr4 Ac2OAcOHH2SO4
193 59 overall yield
25 equiv SmI2 THF
1 11-thiocarbonyldiimidazole DMAP2 Ph3SnH cat AIBN
191 93
189
190
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1415
Scheme (39)
Scheme (40)
Scheme (41)
OBnO
OBn
OBn
OBnO
OBn
OBn
OBnO
OBn
OBn
OBnO
OBnCH3
BnO
OH
CH2
OBnO
OBn
CH3
OBn
H2 O
BF3 OEt2 MeCN
194
195 96
OOAc
OAc
AcO
R SiMe3
SnCl4
O
OAc
AcO
R
O
OAc
AcO
O
OAc
AcO
Me3Si
R
SiMe3
196
197
Me3 Si SiMe3
O
AcO
OAc
OAc
SiMe3
SiMe3
O
AcO
OAc
O
OAc
OAc
O
AcO
AcOO
OAc
OAc
SnCl4 CH2Cl2
SnCl4 CH2Cl2198
199
200
1416 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (42)
Scheme (43)
AcO
OAc
OAc
Me3 Si
BnO
OBn
BnO
OBn
AcO
OAc
BnO
OBn
BnO
OBn
+ I2 CH2Cl2
202 88
198 201
O
OBn
OBn
O
O
O
OBn
OBn
O
O
OBn
OBn O
OBn
OBn
O
OPBH2M
OH
OBnO
BnO
BnO
O
OBn
OBn
O
OHOPMB
OHO
HO
HO
O
OH
OHOH
OH
HOOMe
O
OBnOBn
O
Ph3P
O
O
OBn
OBn O
OBn
OBn
O
OPBM
OH
O O
CHO
OBn
BnO
OO
OBn
OBn
O
OHOPMB
BnO
BnO
BnO
OHO
HO
HO
O
OH
OHOH
OH
HOOMe
+ THF -78 oC
1 OsO4 pyr THF
2 NaH PMBBr
206a 206b 206a206b 61
1 Swern [O]2 4N HCl3 PhCOCl pyr
1 Swern [O]2 4N HCl3 PhCOCl pyr
1 PrSiH BF3 OEt2
2 H2 Pd(OH)2C
3 HCl MeOH 90 oC
1 PrSiH BF3 OEt2
2 H2 Pd(OH)2C
3 HCl MeOH 90 o C
203
204
205
207
209
208
210
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1417
followed by reduction to afford a 51 mixture (213214215216) of lactols that were readily separable by chromato-graphy Following a deprotection of an equimolar mixture of213 and 214 217 and the DL hybrid C-disaccharide of D-glucose-O-(1rarr6)-L-galactose 218 were obtained The DDand DL derivatives 219 and 220 of glucose-α-(1rarr6)-idosewere also obtained as a near equimolar mixture afterdeprotection of 215 and 216 (Scheme 44)
52 Anion Addition-Cyclization
Kishi developed an approach for the synthesis of theCndashtrehalo sugars which relied on nucleophilic addition ofone intact sugar fragment to a fundamental aldehyde ieKishi-Nozaki reaction [49] Coupling of monosaccharide221 and aldehyde 222 gave 223 The triple bond waspartially reduced and osmylation was followed by selectiveprotection to afford 224 The acetonide was converted toepoxide 225 by standard methods and removal of the PMBgroup Acid-catalyzed cyclization followed by aglyconichydrolysis and protection of hydroxyl group with (p-methoxyphenyl)diphenylmethyl chloride (MMTrCl) gave226 Inversion of the C-2 hydroxyl and removal of protectinggroups delivered α α-C-trehalose 227 (Scheme 44)
Kishi and co-workers also employed aldol reactions as anefficient access to the C-trisaccharide related to the type IIABO(H) blood group determinant [50] Aldol condensationof the enolate of methyl ketone 228 with aldehyde 229 gavea 41 mixture of hydroxy ketones 230 and 231 The majorketol was cyclized desulfurized and oxidized to afford thedisaccharide ketone 233 The ketone in THF was treatedwith LiHMDS (3 equiv) and TMEDA followed by theaddition of MgBr2 Addition of the aldehyde 234 led toalmost exclusive formation of the equatorial products 235and 236 in a 12 ratio Mesylation of 235 and 236 followedby treatment with liquid ammonia gave enones 237a and237b which were reduced to yield exclusively the C-2rsquo-equatorial ketone 238 Sodium borohydride reduction of theC-3rsquo carbonyl proceeded with the desired stereoselectivity toyield the protected C-trisaccharide 239 which wasdeblocked to provide the polyol 240 (Scheme 46)
Sutherlin and Amstrong cleverly applied a recursivestereochemical deconvolution (RSD) combinatorial approachfor the synthesis of a small library of C-trisaccharides aspotential inhibitors for the cell surface proteins of bacteriumHelicobactor pylori [51] The workers chose to carry outvariations in galactose ring of these trisaccharides An
Scheme (44)
OBnO
BnOOBn
OBn
P O
OEtOEtO
EtO
R H
OH
OH
OH
OH
O
R H
OH
OH
OH
OH
O
OHO
HOOH
OH
O
HO
OHOH
OH
OHO
HOOH
OH
O
HO
OH
OH
OHO
HOOH
OH
O
HO
OH
OHOH
R H
OH
OH
OH
OH
O
R
OBnO
BnOOBn
OBn
O
OHO
HOOH
OH
OO
HOHO
OH
R H
OH
OH
OH
OH
O
1 OsO4 NMO 50
2 DIBAL -32 oC 40
++ +
213 214 215 216
217 218 219 220
1 9-BBN H2O22 Swern [O]
3 t-BuOK
4 I2 C6H6212
211
1418 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
efficient Nozaki-Kishi coupling of vinyl bromide 241 withaldehyde 242 in a diasteromeric ratio of 12 followed byprotection with TBSOTf led to 243 and 244 Hydroborationfollowed by oxidation gave aldehydes 245 and 246respectively Addition of allylmagnesium bromide toaldehyde 245 followed by removal of the silyl groupafforded 247 to 246 giving 248 and 249 Epoxidation gave a11 mixture of the corresponding epoxides which werecyclized to give the C-trisaccharide 250-255 after removalof the benzyl groups (Scheme 47)
Schmidt reported a stereoselective 6-exo-trig selectiveelectrophilic cylization approach for de novo synthesis of amethylene-bridged Neu5Ac-α-(23)-Gal C-disaccharide theC-analog of an important motif in glycosphingolipids [52]The open chain precusors 259ab (a 32-mixture ofdiaseteromeric alcohols) were formed by the addition oflithiated iodide 256 to open chain aldehyde 258 Subsequent
C1 incorporation using Tebbe-reagent formation of a cycliccarbonate and deprotection of the two isopropylidene ketalsafforded tetrol 264 which upon treatment with phenylselenyltrifilate was steroselectively cyclized in a 6-exo-trigselective manner affording a diasteromeric mixture of 251and 252 in a ratio of 71 A seleno-Pummerer rearrangementto afford aldehyde 267 in 5 steps in 90 overall yieldOxidation of the aldehyde and subsequent steps led to thedesired C-disaccharide 268 (Scheme 48)
53 Esterification-Cyclization
Work from the Postema group has focused on a ringclosing metathesis (RCM) approach for the synthesis of C-saccharides [53a] The chemistry is versatile and has beenused for the synthesis of a small library of differentiallylinked β-C-disaccharides through a radical allylation-RCMstrategy [53b] The synthesis of the β-(1rarr4)-glucopyranosyl
Scheme (45)
O
OBn
BnO
BnO
BnO
I
CrCl2-NiCl2O
OBn
OH
BnO
BnO
BnO
O
O
O
O
O
H
OBn
O
O
OBnBnO
BnO
BnO
OOBn
OBn
OAc
PMBOHOO
OBn
BnO
BnO
BnO
O
OBn
OBn
OAc
O
OH
HO
HO
HO
OH
OH
OH
O
OH
O
OBn
BnO
BnO
BnO
OBn
OBn
OAc
O
MMTr
+
1 p-TsOH2 K2CO3 MeOH3 MMTrCl pyr
1 Swern [O]2 BH3 THF
3 AcOH-H2 O4 H2 Pd(OH)2
221
222
223
1 Pd-Pb CaCO3 H22 NaH BnBr3 OsO44 Bu2 SnO5 CsF PMB-Cl6 Ac2 O 4-DMAP
1 AcOH2 TsCl pyr
3 NaH-imid4 DDQ
224225
226 227
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1419
Scheme (46)
OBnO O
OBn
OMe
OBn
XY
SMe
OBnBnO
O
OBn
OBn
OBn
OBn
O
BnO
YX
OBn
TBSO
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnOOBn
H
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnO
OBn
OHC OBn
OBn
OTBS
OMe
BnOOBn
CHO
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnOOBn
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnO
OBn
YX
OBnO O
OBn
OMe
OBn
OBn
O
BnO
O
OBn
OBn
OBn
OBn
O 1 LiHMDS
2
228
1 TBAF THF
2 MeSH BF3 OEt2
230 X = OH Y = H231 X = H Y = OH
230231 41
1 Bu3SnH AIBN2 Swern [O]
1 LiHMDS THF-TMEDA2 MgBr23
1 MsCl
2 liquid NH3
235 X = OH Y = H236 X = H Y = OH Bu3 SnH AIBN
237a and 237b
NaBH4 MeOH
238
239 X = OBn
240 X = OHH2 Pd(OH)2
229
232233
234
1420 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (47)
OH C
O
O BnAcHN
OO
O
OBn OBnOBn
Br
O
OBn OBnOBn
O
OBnA cHN
OO
O TBSO
OBn O BnO Bn
O
OBnAcHN
OO
OTBS
S2
S1
S2
OTBSS1
O H
S2
OT BSS1
O H
MgBrMgBr
S2
O TBSS1
O H
S2
OHS1
OH
S2
OTBSS1
OH
O
OHHO
O H
O
HO
H OO
OBnA cH N
HO
H O
O
O HHO
OH
O
HOHO
O
OBnA cH N
HO
H O
O
OHH O
OH
O
H O
HOO
OBnAcHN
HO
HO
O
O HH O
OH
O
H O
H O O
OBnA cHN
HO
HO
O
O HH O
O H
O
HO
H O O
OBnAcHN
HO
HO
O
OHHO
OH
O
H O
O
OBnA cHN
HO
HOHO
+
241 242
1 CrCl2-NiCl2 T HF-DMF 722 TBSOTf 2 6-lutidine 91
243 244
1 9-BBN 602 Dess-Mart in period inane 97
1 9 -BBN 552 D ess-Martin periodinane 98
245 246
1
2 T BAF 74
1
2 TBAF 88
247 248 249
250
251
250 251 1 1 252 253 1 1 254 255 1 1
252
253
254
255
1 MCPBA2 CSA CH 2Cl2 61 fo r 2 steps3 H 2 Pd (O H)2C 95
1 MCPBA2 CSA CH 2Cl2 63 fo r 2 s teps3 H 2 Pd (OH)2C 87
1 MCPBA2 CSA CH2Cl2 80 for 2 steps3 H2 Pd(O H)2C 95
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1421
Scheme (48)
O
OO
Se Ph
R
O
HO OHOH
O
OB n O B n
OB n
O B nO O
O O
R O OR
X
O
OO
R
Se Ph
O
HOOH
OH
O
OB nOB n
O Bn
OB n
O O
O O
R O O R
O H
O
O B n OB n
O B n
OB n
O
C HO
O
O O
R O OR
OAc HN
OAc
C O2NH 4HOOH
OH
O
OH O H
OH OH
O
OB n O B n
OB n
OB nO O
O O
R O OR
X
O
O
OAcOAc
C HOA cOOAc
OAc
O
OB n O B n
OB n
OB n
O
O Bn OB n
OB n
OB n
X
OH
OO
HOOH
OH
O
O
OMeOB n
OB nOB n
R
t-B uL i256 R = Li
257 R = L i
258
(R = t-B uMe 2Si )
(R = t-B uMe 2Si )
259ab (32) 79 com bine d yi eld
De ss-Ma rtin pe riodinane
260 X = O R = t-B uMe 2Si ) 95
261 X = O R = t -B uMe2S i) 62
T e bbe re age nt
TB A F THF262 X = O R = H 94
diphosge ne
C H2C l 2Pyr
263 95
T HFH2O T FAr t
264 quant it a ti ve yie ld
PhSe C l AgOT f
EtC N -80 oC
265
266
Quant it at i ve yi l ed 25 26 7 1
+
R =
1 Ac 2OPyr
2 mC PB A3 Ac 2ONa OAc
4 NaO HT HFMe OH
5 Ac2O P yr
267 90 overa ll yi e ld
ste ps
268
1422 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
glucopyranoside 280 represents an example of thischemistry The known triacetyl glucopyranoside 269 wasconverted to iodide 270 in good yield Radical allylation of271 proceeded to afford a mixture of equatorial and axialallylation products in a 61 ratio Oxidative cleavage of thedouble bond gave the corresponding aldehydes 273a and273b which were separable Pinnick oxidation of the majoraldehyde 273a then gave the C-4 equatorial acid 274 DCC-mediated coupling of alcohol 275 and acid 274 proceeded toafford ester 276 in good yield Methylenation of 276 gave277 and exposure to catalysist 278 gave a 41 yield of theC-disaccharide glycal which was exposed to an excess ofBH3
THF to give 64 yield of the β-C-disaccharide 279Removal of the benzyl groups and global peracetylation gavethe peracetylated (1rarr4)-β-C-disaccharide 281 in good yield(Scheme 49)
54 Ring Expansion-Cyclization
Nelson developed a new strategy for asymmetric andstereoselective synthesis of C-linked disaccharide mimeticsthe C58-C71 fragment of palytoxin [54] The diol (RR)-282was converted into the di-dihydropyran (DHP) template 283284 and 285 The di-DHPs were functionized in a twodirectional sense using dihydroxylation reactions The two-directional approach was often very efficient indeed forexample in the synthesis of 286 six new stereogenic centerswere introduced with almost complete stereocontrol using areduction and a dihydroxylation reaction The approach isnot restricted to the synthesis of C2-symmetricaldisaccharide mimetics Using the unsymmetrical template285 which has both a pseudo-axial and a pseudo-equatorialhydroxyl groups the unsymmetrical mimetics 289 and 290were prepared (Scheme 50)
6 RADICAL APPROACHES
The radical approach for C-C bond formation is a popularmethod within organic chemistry The use of radicalchemistry in carbohydrate synthesis has certain advantagesFirstly the reaction conditions are very mild and tolerant ofa range of functional and protecting groups Secondanomeric radicals are stable with respect to elimination andepimeration Most significantly the chemistry required toincorporate an appropriate substitute at C-1 employed in theinitial hemolytic cleavage step is common within carbo-hydrate chemistry [55] The use of such radical techniquecan be subdivided into two classes intermolecular andintramolecular approaches
61 Intermolecular Radical Approaches
Giese was the first to employ an intermolecular radical-based approach for synthesis of C-disaccharides [56]Addition of an alkene to an anomeric radical underappropriate conditions allowed exclusive entry to the α-linked C-glycoside a result which was mirrored by the workof Baldwin [57] The high α-selectivity of the reaction wasin contrast with other reports Thus radicals generated at theC-2 C-3 and C-4 centers all preferred to occupy equatorialpositions [58] When the anomeric bromide 291 was treatedwith tin hydride and AIBN resulting anomeric radical andreacted with lactone 292 in a Michael addition it afforded293 In this reaction hydrogen abstraction at the resulting
radical center occurs from axial face to selectively generatethe equatorial C-2rsquo substituent Reduction and acetylation of293 furnished C-disaccharide 294 (Scheme 51) [59]
Witczak used the facial bias of levoglucosene tostereoselectively add a carbohydrate-based radical in thepreparation of the 3-deoxy-(1rarr4)-β-C-disaccharide 299[60] Addition of the radical derived from iodide 295 to 296gave adduct 297 in 26 yield Removal of the anomerichydroxyl of 297 was achieved by treatment with triethylsilane borontrifluoride ether complex followed bystereoselective reduction of the keto function at C-2rsquo withthe formation of 298 in 89 yield Debenzylation followedby acetolysis of 16-anhydro ring produced the peracetylatedtarget C-disaccharide 299 in 19 overall yield from 295(Scheme 52)
Vogel has developed general methods to transformenantiomerically pure 7-oxabicyclo[221]heptyl derivatives(ldquonaked sugarsrdquo) into C-disaccharides Because of thesechiral bicyclic skeletons they undergo highly stereoselectivereactions with predictable diasteroselectivities An arsenal ofmethods is available that allow to substitute these ldquonakedrdquocarbon centers with a variety of functional groups with allpossible relative configurations The methods allowpreparation of both enantiomers of a given target with thesame ease Predictably high stereoselectivity of the reactionsof the bicyclic chirons adds to the flexibility of approachwhich can lead to high molecular diversity [61]
α-C-(1rarr3)-mannopyranoside of N-acetyl-galactosaminepotent β-galactosidase inhibitors was synthesized by thisapproach [61] Enone 302 was readily prepared from 300The addition of the radical derived from bromide 303 toenone 302 afforded the αminusisomer 304 The ketone was thenreduced and the selenide eliminated via the intermediacy ofthe selenoxide to give 305 Acid-promoted (CF3SO3H) 7-oxa ring opening of 305 in MeCN produced the amino-conduritol derivative 306 resulting from the quenching of theallylic cation intermediate by the solvent (Ritter reaction)Ozonolysis of the chloroalkene 306 generated an acylchloride-aldehyde intermediate that reacted with MeOH toproduce a mixture of methyl uronates The major compound307 was silylated and reduced The crude polyol obtainedwas acetylated to produce 308 Desilylated and ammonolysisafforded a mixture of α-β-pyranoses 309 and correspondingα-β-furanoses (Scheme 53)
Similar chemistry was carried out to synthesize non-protected α-C(1rarr2)-L-fucopyranoside of D-galactopyrano-side corresponding to a blood group mimetic [62] Giesersquosradical fucosidation of racemic enone 310 with α-L-bromoacetofucose 311 provided the mixture of diastereo-meric α-C-fucoside 312a and 312b in reproducible yield of78 Reduction of the mixture gave a 11 mixture of endo-alcohols 313 and 314 which were isolated pure in 40 and355 yield respectively Oxidative elimination of thebenzeneselenyl group of 313 followed by acetylation gaveendo acetate 315 in 85 yield Acid-promoted ring openingof 315 and ozonolysis of the resulted chloroalkene gavemethyl uronic ester 316 in modest yield (10) Treatment of316 with Cl3CCN and NaH followed with BF3
OEt2
furnished the totally protected C-disaccharide 317 in 79
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1423
Scheme (49)
Bu3SnO
HOAcO
OMeOAc
OAc
O
AcO
OMeOAc
OAcI
AIBN
O
AcO
OMeOBn
OBn
HO2C O
AcO
OMeOR
ORY
X
OHBnO
BnO
OBn
OBnO
BnO
OBn
O
AcO
OMeOBn
OBnX
i-Pr i-Pr
N
Mo C(Me2 Ph)((CF3)2 MeCO)2
O
RO
OMeOR
O
RO
OR
OR
RO
OR
278
I2 Ph3P
imidazole
269 270 93
271a X = CH2CH=CH2 Y = H R = Ac 64271b Y = CH2CH=CH2 X = H R = Ac 11272a X = CH2CH=CH2 Y = H R = Bn 75272b Y = CH2CH=CH2 X = H R = Bn 75273a X = CH2CHO Y = H R = Bn 79273a Y = CH2CHO X = H R = Bn 79
1 NaOMe MeOH2 NaOH BnBr DMF
OsO4 NaIO4
NaClO2 NaH2PO4
274 96
275
DCC 4-DMAP
276 X = O 82
277 X = CH2 51
TiCl4 Zn dust TMEDA CH2Br2PbCl2 (Cat )
1
2 BH3 THF H2O2 NaOH
H2 PdC EtOH
Ac2 O Pyr 4-DMAP
279 R = Bn R = H 64
280 R = R = H 99
281 R = R =Ac 97
1424 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (50)
Scheme (51)
O OOH
OH
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
286
1 VO(acac)2 t-BuOH 95
2 (MeO)3CH BF3 90
1 P-O2NC6H4 CO2H Ph3P DIAD2 K2CO3 MeOH 82 over 2 steps
1 PhCOCl Et3N DMAP 402 P-O2NC6H4 CO2H Ph3P DIAD3 KOH THF-H2O 75 over 2 steps
TMEDA OsO4
Cat OsO4 NMO 287
Cat OsO4 NMO288
TMEDA OsO4
Cat OsO4 NMO
290
289
(RR)-282283
284
285
OHO
AcO
BrOAc
OAc
BnO
O
OBn
OBnO
OHO
AcOOAc
OAc
BnO
OOBn
OBnAcO
OHO
AcOOAc
OAc
BnO
O
OBn
OBnO
+
Bu3SnH AIBN291
292
293 81
1 Na[Al(OC2H4OMe)2(OEt)H]2 Ac2O pyr
294 56 over 2 steps
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1425
Scheme (52)
Scheme (53)
OBnO
BnOOBn
OBn O
OH
O
OBnO
BnO
OHOBn
OBn O
O
O
O
O
O
OBnO
BnOOBn
OBnO
OAcOAc
OAc
OBnO
BnO
OHOBn
OBn
IBu3SnH AIBN
295 297 26
1 BF3 OEt2 Et3SiH
2 L-Selectride THF
1 Pd(OH)2C C6H10 EtOH
2 EtSiOSO2CF3 Ac2O
298 89 over 2 steps299
296
O
O
PhSeClO
O
PhSeCl
Bu3 SnH
O
O
PhSeCl
R
H
O
OAc
R
Cl
O
AcO
OAc
OAc
OAcOH
Cl
NHAc
R
OAc
AcHN
OH
O
OH OAc
OH
OHO
HO
OH
O
AcO
OAc
OAc
OAcBr
O
O
PhSeCl
O
O
PhSeCl
R
O
OTIPSAcHNR
OAc OAc
O
OHAcHN
COOMe
R
OAc
1 Bu4NF
2 NH3MeOH
1 (Me3Si)2NLi THF2 Me2N=CHI
1 Bu3 SnH AIBN2
1 NaBH42 mCPBA3 Ac2O pyr
1 H+ MeCN
2 H2 O NaHCO3
R =
1 O3MeOH
2 Me2S NaHCO3
1 TIPSOTf 26-lut idine2 LiBH43 Ac2 O pyr DMAP
furanoses +
304 56
305 68 306 84307 50
308 46
300 301 302
303
309
1426 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
The reduction of 317 and treatment with DOWEX-H+ resinprovided the desired C-fucoside 318 in 70 (Scheme 54)
62 Intramolecular Radical Approaches
One disadvantage with the intermolecular approaches isthat during such radical mediated reactions electrondeficient alkenes are required to facilitate C-C bondformation The intramolecular approach of Sinayuml overcomes
this drawback by bring two substrates together via atemporary covalent silaketal connector This enables the useof a wider range of alkenes which can include alkene-functionalized sugars thus leading to the generation of C-disaccharides [63] Based on the early work of Stork Sinayumlemployed the tether reaction in the synthesis of both α- andβ-C-disaccharides with this work subsequently beingemployed in the synthesis of biologically significant natural
Scheme (54)
O
OH
Fuc
Cl
O
O
ClPhSe
OOAc
NHAcOHFuc
O
AcOOAc
AcO
Br
O
O
PhSeCl
O
AcOOAc
AcO
O
OH
PhSe Cl
Fuc
OOAc
NHAc
OMe
Fuc
O
AcHN
OH OAc
OH
O
OH
Me
OH
O
O
Fuc
ClSePh
O
HO
Fuc
ClSePh
+
Ph3SnHAIBN
78 combined yield
Fuc
310
+
1 NaBH4 MeOHTHF2 Chromatography
313 40 314 355
1 mCPBA
2 Ac2O pyr DMAP
+
315 75
1 TfOH MeCN
2 NaHCO3 O3 -78 oC
316 10 over 2 steps
1 Cl3 CCN NaH
2 MeOH BF3 OEt2
317 79
1 LiBH4 THF
2 Dowex-H+
311
312a312b
318 70 for 2 steps
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1427
products [64] The availability of different hydroxyl groupson each monosaccharide unit allowed the fine-tuning ofstereochemical outcome by selective positioning of the silyltether [65] Development of this early stereochemical controlled to the tethering of the donor 320 with alcohol 319through a di-isopropyl silicon tether 321 Subsequent treat-ment with Bu3SnH and AIBN led to a 9-endo-trigcyclization to form the C-disaccharide 322 in an 80 yieldwith exclusive formation of the α-product The silyl tetherwas removed with Bu4NF and deprotection under standardconditions afforded the desired disaccharide 323 in excellentyield (Scheme 55)
In parallel the development of a 32rsquo silyl tether allowedaccess to the β-linked product as demonstrated in Sinayumlrsquossynthesis of methyl β-C-lactoside 328 [66] Alcohol 324 and320 were connected via the dimethylsilyl tether an 8-endo-trig cyclization followed to exclusively afford the β-
disaccharide 326 in 45 yield Removal of the tether anddeprotection of benzyl ether gave β-C-disaccharide 328(Scheme 56)
This group also selected iodosugars bearing a freehydroxyl group as progenitors of the radical donors [67] In atypical experiment the radical donor 329 was connected tothe radical acceptor 330 through a silaketal tether followingtheir procedure Tributyltinhydride mediated 8-endo-trigradical cyclization of compound 331 gave after detetheringof the non isolated intermediate 332 the protected β-C-disaccharide 333 in 37 overall yield (from startingmaterials 330 and 329) Peracetate 335 was achieved afterhydrogenolysis The C-laminaribioside 334 is of potentialbiological interest as it mimics the repeating disaccharideunit of fungal β-(1rarr3)-glucans which have antitumor andimmunomodulating properties (Scheme 57)
Scheme (55)
Scheme (56)
OO
OHSePh
OTBDPSO O
OO
SePh
OTBDPSO
OO
OBnOMe
OBn
Si
O
HOOBn
OMe
OBn
O
HOOH
OHHO
O
HOOH
OMe
OH
OTBDPSO
O
HOOBn
OMe
OBnO
OOH
1 n-BuLi THF
2 iPr2SiCl2 -78 oC
3 DMAP THF rt
1 Bu4NF THF
2 Dowex-H+
3 H2 PdC
Bu3SnH AIBN toluene
319
320
321
322323
OBnO
OHSePh
OBnBnO
OHO
OBnOMe
OBn
ROO
ROOH
OR
OHO
OROMe
OR
OBnO
O
OBnBnO
OO
OBnOMe
OBn
Si
SePh
OBnO
O
OBnBnOO
OOBn
OMe
OBn
Si
1 PhSeH Me2SiCl2
BuLi -78 oC
2 imidazole rt
Bu3SnH AIBN toluene
H2 PdC327 R = Bn
328 R = H
Bu4NF THF
324
320
325
326 45
1428 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
CONCLUSIONS
In this paper the biological importance of C-oligo-saccharides as subunits of natural products and as a newgeneration of carbohydrate based on therapeutics has beenillustrated Different methods are available for the synthesisof C-oligosaccharides As with traditional saccharidesynthesis it has been necessary to develop a number ofspecific approaches to facilitate the regioselective andstereoselective preparation of the desired targets Work inthis area continues and it is expected that many interestingnew C-oligosaccharides will be prepared using the chemistrydescribed in this review It is also likely that new chemistrywill be developed in the future for the preparation of thesebiologically important targets
ACKNOWLEDGEMENTS
The authors thank Dr Sultan Baytas for her criticalreading of this manuscript
REFERENCES
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[2] Wassarman PW Mammalian Fertilization Molecular Aspects ofGamete Adhesion xocytosion Exocytosis and Fusion Cell 199996 175-183
[3] Carbohydrate-based Drug Discovery Wong C-H EdWeinheim Cambridge Wiley-VCH 2003
[4] (a) Sharon N Lis H Lectins as Cell Recognition MoleculesScience 1987 246 227-234 (b) Dwek RA Chem Rev 1996 96683-720
[5] Postema M C-Glycoside synthesis CRC Boc Ratom 1995[6] (a) Weatherman R V Mortell K H Cheruenak MKiessling
L L Toone E J Specificity of C-Glycoside Complexation byMannoseGlucose Specific Lectins Biochem 1996 35 3619-3624(b) Ravishankar R Surolia A Vijayan M Lim S Kishi YPreferred Conformation of C-Lactose at the Free and Peanut LectinBound States J Am Chem Soc1998 120 11297-11303
[7] (a)Wong C-H Halcomb R L Ichikawa Y and Kajimoto TEnzymes in organic synthesis Application to the problems ofcarbohydrate recognition part2 Angew Chem Int Ed Engl 199534 521-546 (b)Howard S Withers SG Bromoketone C-Glycosides a New Class of βminusGlucanase Inactivators J AmChem Soc 1998 120 10326-10331(c) Wang Q Wolff MPolat T Du Y Linhardt R J C-glycoside of Neuraminic Acidsas Neura-minidase Inhibitors Bioorg Med Lett 2000 10 941-944 (d) Phili R Chang J Partis R A Mueller R A ChrestF J Passaniti A The Alpha-glucosidase I InhibitorCastanospermine Alters Endothelial cell Glycosylation PreventsAngiogenesis and Inhibits Tumor Growth Cancer Res 1995 552927-2935
[8] Ossor A Elbein A D In Carbohydrates in Chemistry andBiology Vol 3(II) WileyVCH 2000 pp 513-539
[9] (a) Sinayuml P Synthesis of oligosaccharide Mimetics Pure ApplChem 1997 69 459-463 (b) Beau J-M Gallagher TNucleophilic C-glycosyl Donors for C-glycoside Synthesis Top inCurr Chem 1997 187 1-54 (c) Nicotra F Synthesis of C-glycosides of Biological Interest Top in Curr Chem 1997 187
Scheme (57)
O
O
O
Ph
I
OMe
OHO
BnO
OH
OH
BnOOH
O
BnO
Si
O
O O
Ph
I
OMe
O
O
BnO
OR4O
R5O
OMe
OR2
OR3O
R3O
OR1
R3O
Bu3 SnH AIBN
332 R1 R2 = SiMe2 R3 = Bn R4 R5 = CHPhTBAF THF
333 R1 = R2 = H R3 = Bn R4 = R5 = CHPh 37 from 11
334 R1 = R2 = R3 = R4 = R5 = H
335 R1 = R2 = R3 = R4 = R5 = Ac
329
H2 PdC MeOH
Ac2 O pyr
1 BuLi THF -78 oC
2 Me2SiCl2
3 DMAP
330
331
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1429
55-83 (d) Du Y Linhardt R Y Recent Adv in Stereo-SelectiveC-Glycoside Synthesis Tetrahedron Lett 1998 54 9913-9959 (e)Liu L Mckee M and Postema M H D Synthesis of C-saccharides and Higher Congeners Current Org Chem 2001 51133-1167
[10] Jarosz S Fraser-Reid B Synthesis of A Higher Carbon Sugar ViaDirected Aldol Condensation Tetrahedron Lett 1989 30 2359-2362
[11] Lichtenthaler F W Lergenmiiller M Schwidetzky S C-Glycosidations of 2-Ketohexosyl With Electrophilic Radical andNudeophilic Anomeric Carbons Eur J Org Chem 2003 3094-3103
[12] Baudat A Vogel P Aza-C-disaccharides Synthesis of 6-Deoxygalactonojirimycin-β-C(1rarr3) Linked with D-Altrofuranosides and D-Galactose J Org Chem 1997 62 6252-6260
[13] Turner D Vogel P Synthesis of 4-Hydroxy-26-Bis(hydroxymethyl) tetrahydropyran-2-Carbaldehyde DerivativesSynlett 1998 304-306
[14] Zhu Y-H Vogel P Short Stereoselective Synthesis of C-(1rarr3)-Linked Disaccharides Tetrahedron Lett 1998 39 31-34
[15] Zhu Y-H Vogel P Synthesis of a (2R 6R)-2-(Hydroxymethyl)-6-Propa-1 2-Dienyl-2H-Pyran-3(6H)-One Derivative A NewEnone for The Convergent Construction of C-Glycosides of C-Disaccharides Synlett 2001 82-86
[16] Baumberger F Vasella A Deoxynitrosugars The 6th
Communication Stereolectronic Control in the reductivedenitration of tertiary nitro ethers A Synthesis of ldquoC-glycosidesrdquoHelv Chim Acta 1983 66 2210-2221
[17] Martin O R Lai W Synthesis and Conformational Studies of β-(1rarr6)- and ββ-(1rarr1)-Linked C-disaccharides J Org Chem1993 58 176-185
[18] Spak S J Martin R The synthesis of an analogue of Methyl OC-Analogue of Methyl 4rsquo-O-β-D-GlucopyranosylgentiobiosideTetrahedron 2000 56 217-224
[19] Kobertz W R Bertozzi C R Bednarski M D C-GlycosylAldehyde Synthons for C-Linked Disaccharides J Org Chem1996 61 1894-1897
[20] Gurjar M K Nagaprasad R and Ramana CV First Synthesis ofMethyl α-C-D-Arabino-furanosyl-(1rarr5)-αminusD-Arabinofuranosidethe C-Disaccharide Segment of Motif C of MycobateriumTuberculosis Tetrahedron Lett 2000 43 7577-7579
[21] Witczak Z J Synthesis of C-Glycosyl Compounds and OtherNatural Products from Levoglucosenone Pure Appl Chem 199466 2189-2192
[22] Griffin F K Paterson D Taylor R J K Ramberg-BacklundApproaches to the Synthesis of C-Linked Disaccharides AngewChem Int Engl 1999 38 2939-2942
[23] Paterson B E Griffin F K Alcaraz M-L and Taylor R J KA Ramberg-Baumlcklund Approach to the Synthesis of C-GlycosidesC-Linked Disaccharides and C-Glycosyl Amino Acids Eur JOrg Chem 2002 1323-1336
[24] McAllister G D Paterson D E Taylor R J K A SimplifiedRamberg-Bachlund Approach to Novel C-Glycosides and C-Linked Disaccharides Angew Chem Int Ed Engl 2003 42 1387-1391
[25] McCartney J L Christopher T M Cicchillo R M BernardinaM D Wagner T R and Norris P J Org Chem 2003 6810152-10155
[26] Dondoni A Zuurmond H M Bascarate A Synthesis of α-andβ-D-(1rarr6)-C-Disaccharides by Witting Olefination of Formyl C-Glycosides with Glycopyranose 6-phosphoranes J Org Chem1997 62 8114-8124
[27] Dondoni A Kleban M Zuurmond H Marra A Synthesis of(1rarr6)-C-Oligogalactosides by Interative Wittig OlefinationTetrahedron Lett 1998 39 7991-7994
[28] Dondoni A Marra A A New Synthetic Approach toMycobacterial Cell Wall α-(1rarr5)-D-Arabinofuranosyl C-Oligosaccharides Teterahedron Lett 2003 44 4067-4071
[29] Colinas P A Ponzinibbio A Lieberknecht A and Bravo R OWittig Reaction of Glycosyl Phosphonium Salts A StereoselectiveRoute to C-Disaccharides and C O-Trisaccharides TetrahedronLett 2003 44 7985-7988
[30] Schmidt R R Preuss R Synthesis of Carbon Tetrahedron Lett1989 30 3409-3412
[31] Dietrich H Schmidt R R Synthesis of Carbon-Bridged C-Lactose and Derivatives Liebigs Ann Chem 1994 975-981
[32] Rouzaud D Sinayuml P The First Synthesis of a ldquoC-DisacchariderdquoJ Chem Soc Chem Commun 1983 1353-1354
[33] Xin Y-C Zhang Y-M Mallet J-M Glaudemans C P JSinayuml P Synthesis of C-Oligosaccharides That Mimie TheirNatural O-Analogues Immunodeterminants in Binding toMonoclonal Immunoglobulins Eur J Org Chem 1999 471-476
[34] Streicher H Geyer A Schmidt R R C-Disaccharides ofKetoses Chem Eur J 1996 2 502-510
[35] Leeuwenburgh M A Timmers C M Vander Marel G A VanBoom J H Mallet J-M Sinayuml P G Stereoselective Synthesisof α-C-(Alkynyl)-Glycosides Via Ring-Opening of α-12-Anhydrous Tetrahedron Lett 1997 38 6251-6254
[36] Aslam T Fuchs M G G Le Formal A Wightman R HSynthesis of C-Disaccharide Analogue of the α-D-Arabinofuranosyl-(1rarr5)-α-Arabinofuranosyl Motif ofMycobacterial Cells Walls via Alkynyl Intermediates TetrahedronLett 2005 46 3249-3252
[37] (a) Girad P Namy J L Kagan H B Divalent LanthanideDerivative in Organic Synthesis 1 Mild Preparation of SamariumIodide and Ytterbium Iodide and Their Use as Reducing orCoupling Agents J Am Chem Soc 1980 102 2693-2698 (b)Molander G A Harris C R Sequencing Reactions withSamarium(II) Iodide Chem Rev 1996 96 307-338
[38] (a) Mazeacuteas D Skrydstrup T Doumeix O Beau J-MSamarium Iodide-Induced Intramolecular C-Glycoside FormationEfficient Radical Formation in the Absence of an Additive AngewChem Int Ed Engl 1994 33 1383-1386 (b) Mazeacuteas DSkrydstrup T Beau J-M A Highly Stereoselective Synthesis of1 2-trans-C-Glycosides Via Glycosyl Samarium(III) CompoundsAngew Chem Int Ed Engl 1995 34 909-912 (c) Jarreton OSkrydstrup T Beau J-M The Stereospecific Synthesis of Methylα-C-Mannobioside A Potential Inhibitor of M TuberculosisBinding to Human Macrophages J Chem Soc Chem Commun1996 1661-1662 (d) Jarreton O Skrydstrup T Espionosa J-FJimeacutenez-Barbero J Beau J-M Samarium Diiode Prompted C-Glycosylation An Application to The Stereospecific Synthesis ofα-(1rarr2)-C-Mannobioside and Its Derivatives Chem Eur J 19995 430-441 (e) Mipuel N Doisneau G Beau J-M ReductiveSamariation of Anomeric 2-Pyridyl Sulfones with Catalytic AnUnexpected Improvement in The Synthesis of 12-Trans-Diequatorial C-Glycosyl Compounds Angew Chem Int Ed Engl 2000 39 4111-4114
[39] Vlahov I R Vlahova P I Linhardt R J DiastereocontrolledSynthesis of Carbon Glycosides of N-Acetylneuraminic Acid ViaGlycosyl Samarium(III) Intermediates JAmChem Soc 1997 1191480-1481
[40] Kuberan B Sikkander S ATomiyama H Linhardt R JSynthesis of a C-Glycoside Analogue of sTn An HIV-and Tumor-Associated Antigen Angew Chem Int Ed Engl 2003 42 2073-2075
[41] Bazin H G Du Y Polat T Linhardt R J Synthesis of aVersatile Neuraminic Acid ldquoCrdquo-Disaccharide Precursor for theSynthesis of C-Glycoside Analogues of Gangliosides J OrgChem 1999 64 7254-7259
[42] Chen C-C Ress D K Linhardt RJ Samarium Iodide-Mediated Synthesis of Neuraminic Acid C-Glycosides InSynthesis of Glycommetics Roy R Ed ACS Syposium Series2004 896 53-80
[43] Abdallah Z Doisneau G Beau J-M Synthesis of a Carbon-Linked Mimic of The Disaccharide Component of The Tumor-Relate SialyTn Antigen Angew Chem Int Ed Engl 2003 425209-5212
[44] Lay L Nicotra F Panza L Russo G Caneva E Synthesis ofC-disaccharides through dimerization of exo-glycals J Org Chem1992 57 1304-1306
[45] Isobe M Nishizawa R Hosokawa S Nishikawa TStereocontrolled Synthesis and Reactivity of Sugar Acetylenes JChem Soc Chem Commun 1998 2665-2676
[46] Saeeng R Sirion U Sahakitpichan P Isobe M IodineCatalyzes C-Glycosidation of D-Glucal with SilylacetykeneTetrahedron Lett 2003 44 6211-6215
[47] (a) Babirad S A Wang Y Kishi Y Synthesis of C-Disaccharides J Org Chem 1987 52 1370-1372 (b) Wang YBabirad S A Kishi Y Preferred Conformation of C-Glycosides
1430 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
8 Synthesis of 14-Linked Carbon Disaccharides J Org Chem1992 57 468-481
[48] Armstrong R W Sutherlin D P Strategies for the Synthesis ofC-Disaccharides Containing D and L Sugars Tetrahedron Lett1994 35 7743-7746
[49] Wei A Kishi Y Preferred Conformation of C-Glycosides 12Synthesis and Conformational Analysis of αα- α β- and β β-Trehaloses J Org Chem 1994 59 88-96
[50] Haneda T Goekjian P G Kim S H Kishi Y PreferredConformation of C-Glycosides 10 Synthesis and ConformationAnalysis of Carbon Trisaccharides J Org Chem 1992 57 490-498
[51] Sutherlin D P Armstrong R W Synthesis of 12 Stereochemistryand Structurally Diverse C-Trisaccharides J Org Chem 1997 625267-5283
[52] Notz W Hartel C Waldscheck B Schmidt R R De NovoSynthesis of a Methylene-Bridged Neu5Ac-α-(23)-Gal C-Disaccharide J Org Chem 2001 66 4250-4260
[53] (a) Postema M H D Calimente D Liu L Behrmanm T L AnOlefin Metathesis Route for the Preparation of (1rarr6)-Linked-C-Disaccharide Glycals A Convergent and Flexible Approach to C-Saccharide Synthesis J Org Chem 2000 65 6061-6068(b) Postema M H Piper J L Liu L Faust M Andreana PSynthesis and Partial Biological Evaluation of a Small Library ofDifferentially Linked β-C-Disaccharide J Org Chem 2003 684748-4754
[54] Nelson A The Development of Strategies and Methods for TheSynthesis of Biologically Active Compounds New J Chem 200428 771-776
[55] Togo H He W Waki Y Yokoyama M C-GlycosylationTechnology With Free Radiant Reactions Synlett 1998 700-717
[56] Giese B Dupuis J Diastereoselective Synthesis of C-Glycopyranosides Angew Chem Int Ed Engl 1983 22 622-623
[57] Adlington R M Baldwin J E Basak A Kozyrod RPApplication of Radical Addition Reactions to tho Synthesis of a C-Glucoside and A Functionalized Amino Acid J Chem SocChem Commun 1983 144-145
[58] Giese B Gonzaacutelez-Goacutemez J A Witzel T The Scope of RadicalCC-Coupling by The ldquoTin Methodrdquo Angew Chem Int Ed Engl1984 23 69-70
[59] Giese B Witzel T Synthesis of ldquoC-Disaccharidesrdquo by RadicalC-C Bond Formation Angew Chem Int Ed Engl 1986 25 450-451
[60] Witczak Z J Chhabra R Chojnacki J C-Disaccharides IStereoselective Approach to β-(1rarr4)-3-Deoxy-C-Disaccharidesfrom Levoglucosenone Carb Res 1997 301 167-175
[61] Vogel P Synthesis of Rare Carbohydrates and Analogues Startingfrom Enantiomerically Pure 7-Oxabicyclo[221]heptyl Derivatives(ldquoNaked Sugarsrdquo) Current Org Chem 2000 4 455-480
[62] Viodeacute C Vogel P Synthesis of The C-Disaccharide α-C(1rarr3)-L-Fucopyranoside of N-Acetylgalactosamine J Carb Chem2001 20 733-746
[63] Xin Y C Mallet J M Sinayuml P An Expeditious Synthesis of AC-Disaccharide Using A Temporary Silaketal Connection J ChemSoc Chem Commun 1993 864-865
[64] (a) Petitou M Herault P Lormeau J-C Helmboldt A MalletJ-M Sinayuml P Herbert J-M Introducing A C-InterglycosidicBond in A Biologically Active Pentasaccharide Hardly Affects ItsBiological Properties Bioorg Med Chem 1998 6 1509-1516 (b)Sinayuml P Advances in The Synthesis of the Carbohydrate MimicsPure Appl Chem 1998 70 1495-1499
[65] Sinayuml P Chemical Synthesis of Oligosaccharide Mimetics PureAppl Chem 1998 70 407-410
[66] Sinayuml P Chemical Synthesis of Oligosaccharide Mimetics PureAppl Chem 1998 69 459-463
[67] Vauzeilles B Sinayuml P Selective Radical Synthesis of β-C-Disaccharides Tetrahedron Lett 2001 42 7269-7272
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1401
HWEconjugation-addition C-glycosydation sequence givingdiastereomeric sulfones 85 in a combined yield of 75RBR of the major stereoisomer (βα-79) using the Meyers-
Chan procedure gave alkene 86 in 66 unoptimized yieldand hydrogenation produced the novel C-linked bisfuranosedisaccharide 87 in 76 yield
Scheme (15)
Scheme (16)
OBnO
BnO
H
OBn
OH
OOBn
BnO
OBn
OBn
BnO
OBn
OBn
OBnO
BnO
OBn
OH
SO2
O
OBn
O O
AcO
AcO
AcO
OAc
OAc
OAc
OAc
OAc
OBnO
BnO
OBn
OH
I
O
HS
OBn
BnO
OBn
OBn
68 90 over 2 steps
KOH CCl4 t-BuOH H2O
1 H2 PdC
2 Ac2O Pyr
70 69 over 2 steps
+
1 K2CO3
2 mCPA66
67
69
O
BnOOBn
BnO
OBn
OH
(EtO)2P(O)CH2CO2Et
OBn
OBn
OBnO
OBn
OBnO
BnOOBn
OBn
X
O OBn
OBn
BnOOBn
OBnO
BnOOBn
OBn
OBnO
BnOOBn
OBn
R
OBnO
BnOOBn
OBn
SH
LiAlH4
OAc
AcOOAc
O OAcOAcOAcO
OAc
OAc
1 H2 Pd(OH)2C
2 Ac2 O Pyr
NaH THF
72 R = CO2Et
73 R = CH2OH
66 over 3 steps
K2CO3 acetone
76 X = S
77 X = SO2 79
Oxone THF MeOH H2 O
KOH CCl4 aq tBuOH
78 57ZE 8812
79
71
75
MsCl Et3N 74 R = CH2 OMs
1402 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Norris et al deprotonated 88 with n-BuLi and theresulting anion was coupled with an excess lactone 89 at lowtemperature to afford the adduct 90 in 77 yield SPhgroups were removed with Raney nickel and lactol 91 wasisolated as a syrup that contained two components in
approximately a 41 ratio The two compounds were thoughtto be α- and β-lactols with the latter being major It wasstraightforward to reduce the lactols with a high degree ofstereocontrol to afford the C-disaccharide 92 with a 51isolated yield (Scheme 19) [25]
Scheme (17)
Scheme (18)
O
O O
O
O OH
O OMe
OBnBnO
SO2
P
EtO
EtO
O
OBn
O
OMe
OAc
OAc
OAcO
O O
O
O
O
OO OMe
OBnBnO
SO2
OBn
O
O O
O
O O
O
O
O
OMe
OBn
OBn
OBn
83 50 E only
80
+
NaH THF -78 oC
82 86αβ 11
KOHAl2O3
CBr2F2 CH2Cl2
tBuOH 5 oC
2 h
1 H2PdC EtOAc RT 7h
2 Ac2 O Pyr RT
84 69 over 2 st eps
81
O
O O
O
O OH POEt
OEt
O
SO2
P
EtO
EtOO
O
O
O
OO
O
O
O
O O
O
O
O O
O
O
O
O SO2
O
O
O
O
O
O O
O
OO
O
O
85 75βαββ ca 31
86 66β αββ = 141 E only
H2PdC EtOAc
87 76βαβ β = 141
21 NaH THF -78 o C
80 (2 equiv)
KOHAl2O3CBr2F2 CH2Cl2tBuOH
on majorβα is omer
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1403
24 Phosphorous Stabilized Anions
The most common type of reaction discussed in thissection is Wittig approach to C-oligosaccharide synthesisThis methodology is particularly suited for synthesis of(1rarr6)-C-saccharides since one sugar can hold the aldehydewhile the other the ylid or phosphonate anion
Dondoni has utilized this approach to prepare a variety ofβ-D-(1rarr6)-C- disaccharides The general approach is shownin Scheme 20 Coupling of β-linked galactopyranosyl ormannofuranosyl derivative (93 94 95 or 96) with ylidefrom phosphonium iodide 97 or 98 gave alkene 99 Alkenewas reduced and removal of deprotecting groups gave thecorresponding β-D-(1rarr6)-C- disaccharide 100 [26]
α-D-(1rarr6)-C-disaccharide 103 was also synthesizedusing the approach (Scheme 21)
Dondoni applied this methodology in an iterative fashionto prepare the corresponding β-(1rarr6)-C-trigalactosides andβ-(1rarr6)-C-tetragalactosides [27] Starting with coupling ofylide 104 generated in situ with aldehyde 33 gave adduct105 (EZ 19) Removal of silyl protecting group followed byoxidation led to aldehyde 106 which was coupled with theylide from 104 to give C-trisaccharide 107 in 36 yield Thesame sequence was repeated with 107 afforded the protectedC-tetrasaccharide alkene 108 Compounds 108 wasdesilylated and exposed to hydrogen over Pd(OH)2 oncarbon followed to peracetylation gave protected C-tetrasaccharide 109 (Scheme 22)
Taking advantage of their experience on the stereo-selective synthesis of C-oligosaccharides by iterative Wittigolefination this group developed new building blocks and amodified protocol for the straightforward assembly of C-α-(1rarr5)-D-oligoarabinofuranosides [28] While the twomonofunctionalized sugar moieties 110 and 111 weresuitable precursors to the head and tail of the oligo-saccharidic chain the difunctionalized compound 114 was arepeating unit (Scheme 23) Building block 114 wasdesigned to allow after the Wittig coupling for regenerationof the formyl group in a single step under conditions that donot affect the chemical and stereochemical integrity of thegrowing saccharidic chain (Scheme 24)
Colinas et al reported a method for the synthesis of C-disaccharides by a sequence involving the Wittig reaction askey step and further glycosydation of these compounds toafford new C O-trisaccharides [29] The enol ether 122a-bwere prepared by the Wittig reaction of the α β mixture of2-deoxiglycosyl phosphonium salts 120a-b with aldehyde121 Hydrogenation of the exo-glycals afforded the β-C-disaccharides with good yields The O-glycosidationemploying the exo-glycals and the glycosyl acceptor 124 isillustrated in Scheme 25
25 C-1 Vinyl Anions
Schmidt was the first to explore the addition of sulfoxide-stabilized vinyl C-1-organolithiums to carbohydrate-basedcarbonyl compounds [30] The vinyl sulfoxide 126 was
Scheme (19)
OCH3
O O
OPhS
PhS
O O
OO
OCH3
O O
OO O
O H
OCH3
O O
OPhSPhS
O O
O OH
OCH3
O O
OO O
O OH
+
n-BuLi THF -78 oC
Raney Ni EtOH H2O rt
Et3SiH BF3 OEt2
90 77
92 51 over 2 steps 91 is omers rati o βα = 41
-78 oC
88
89
1404 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
deprotonated with LDA to give 127 Addition of 127 toaldehyde 128 gave a mixture of diastereoisomers of whichthe major 129 was formed in a 101 ratio Desulfurizationhydroboration and removal of benzyl groups gave the(1rarr5)- βminusC-disaccharide 130 (Scheme 26)
Schmidt and coworkers used this methodology for ahighly efficient synthesis of an analog of C-trehalose 134Scheme 27 [31] Anion 131 was converted to aldehyde 132
and condensation of this aldehyde with the same anion gaveadduct 133 which was then converted to the target C-disaccharide 134
26 Acetylide-Based Anions
Sinayuml was the first to prepare a C-disaccharide Hisapproach involved the coupling of a C-6 alkyne with ananomeric lactone followed by reduction of the formedhemiacetal [32] Aldehyde 135 was converted to the
Scheme (20)
Scheme (21)
OO O
O
O CHO
O
BnOOBn
BnO
OBn
CHO
OBn
CHO
BnO
O
BnOBnO
O
BnOOBn
BnO OBn
CHO
PPh3I-
OO
O
OO
O
OMeOBn
OBn
OBn
PPh3I-
OCHO
O
PPh3I-
ORRO
RO
OO
ORRHO
OO
OR
+ +
+
( 93 - 96 )
( 97 - 98 )
BuLi THF-HMPA
-30 iexclaelig
99
Reduction
100
+
93 9495
96 97 98
O
OBnBnO
BnO
OO
O
OO
HO
O
O
OO
PPh3I-
O
OHHO
HO
O
HOOH OH
HO
OBnBnO
CHO
BnO
O
+
BuLi THF-HMPA
-30 oC
1 p-MeC 6H4SO2-
NH2NH2 AcONa
2 H2 Pd(OH)2 3 bar
3 Amberli te H+
+
10197
102
103
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1405
dibromoalkene 136 which was treated with n-butyllithium togive an intermediate acetylide 137 The latter uponnucleophilic addition to lactone 138 gave a mixture of lactol139 in high yield Stereoselective reduction of lactol 139 wasfollowed by hydrogenation of benzyl groups and the triplebond affording the (1rarr6)-β-C-disaccharide 140 (Scheme28)
The lactone-addition methodology was later applied bySinayuml and co-workers in an iterative fashion for the
preparation of higher homologues [33] Hydroxylmethylenein compound 141 was converted to acetylide lithium incompound 142 by a sequence of reactions Condensation ofcompound 142 with the galacto lactone 143 gave 144 asmixture of anomers The lactol were stereoselectivelyreduced to and triple bond was hydrogenated to give 145Methyl glycoside 145 was hydrolyzed to the correspondinglactols which were oxidized to lactone 146 The samesequence was then repeated twice to give C-trisaccharide147 and C-tetrasaccharide 148 (Scheme 29)
Scheme (22)
O
BnOOBn
BnO OTBDPS
PPh3I-
BnO
H
O
BnOOBn
OTBDPS
OO
O
OO
O
CHOO
O
OO
O
BnO
O
BnOOBn
BnO
OO
O
OO
H
HOBn
BnO OTBDPS
O
BnOOBn
BnO O
OO
O
OO
H
OBn
BnO OTBDPS
PPh3I-
O
BnO
O
BnOOBn
BnO OTBDPS
PPh3I-
O
AcOOAc
AcO
O
AcOOAc
AcO
OO
O
OO
O
AcOOAc
AcO OAc
O
BnOOBn
BnO
O
BnOOBn
BnO
OO
O
OO
H
H
O
BnOOBn
BnO OTBDPS
H
1 TBAF2 PCC
+107 36
+
1 TBAF2 PCC3
+
1 TBAF2 H2 Pd(OH)2 C3 Ac2 O Pyr
104
33
105
106104
104
108109
BuLi THF-HMPA
-50 o C
70EZ 19
BuLi THF-HMPA
-50 o C
1406 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
The di- tri- and tetrasaccharide derivatives (145 147 and148) were all debenzylated and tested for their bindingaffinity to three different monoclonal immunoglobulins withspecificity for different O-β-(1rarr6)-D-galactopyranosyl deter-minants These C-saccharide analogs had similar bindingproperties to the corresponding O-saccharides
Schmidt has also used acetylide-lactone condensation toassemble C-disaccharides of ketoses [34] Lithium acetylide149 was condensed with ketone 150 to give a mixture ofalcohol 151 after removal of the pivoloyl group Attemptedcyclization under Lewis acid catalysis resulted only in theremoval of the acetonide Accordingly the diol was tiedback as the carbonate and the acetylene complex as thedicobalt species 152 The isomers were then separately
cyclized to give a 11 mixture of C-disaccharide 153 Thecobalt complex on α-C-disaccharide was removed understandard conditions to give 154 and deprotection of thecarbonate was followed by hydrogenation and peracetylationto give 155 (Scheme 30) Similar chemistry was also carriedout with the corresponding β-isomer
Van Boom and co-workers used lithiated alkynylderivative 156 in presence of ZnCl2 to selectively open ringof the 12-anhydrosugar 157 affording the α-C-(alkynyl)-glycoside 158 Hydrogenolysis of the benzyl groups wasfollowed by peracetylation to give the (1rarr6)-α-C-disaccharide 159 (Scheme 31) [35]
Normally attack of the nucleophile proceeds from anequatorial direction to give the β-isomer The unexpected
Scheme (23)
Scheme (24)
BnOO
OBnCHO
OBn
O
OBn
PPh3I-
OBn
OBn
O
OBn
BnOBnO
O
OBnOBn
OBnH
O
OH
HOHO
O
OHOH
OH+
BuLi
THF-HMPA
-20 oC+
1 TBAF2 H2 Pd(OH)2C
112 65 113 100
110
111
O
OBnCHO
OBnBnO
O
OBn
BnOBnO
O
OBnCH(OiPr)2
OBnH
O
OBnCH(OiPr)2
PPh3I-
OBn
O
OBn
BnOBnO
O
OBn
OBnH
O
OBnOBn
BnOH
O
OH
HOHO
O
OH
OH
O
OHOH
HO
++
BuLi
THF-HMPA
-20 oC
BuLi
THF-HMPA
-20 oC
TFA H2 O THF rt
115 49
116 R = CH(OiPr)2
117 R = CHO
118 45
H2 Pd(OH)2C
110
114
114
119
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1407
Scheme (25)
Scheme (26)
OBn
R1
R2
PPh3BF4-O
O
OOHC
O
O
O
O
O
O
O
O
HO
O
O
O
O
O O
OBn
R1
R2
O
O
O
O
O
O
H
O
OBn
R1
R2
O
O
O
O
O
O
O
O
OBn
R1
R2
O
O
O
+
BCl3 (005 equiv)
MS 4A CH2 Cl2 0 o C
+
BuLi THF -90 oC -90 o C
to rtH2 (1 atm) PdC Et3N MeOH
R1 R2 = OBn H
120a - b
121
122a - b
123a - b
124
125a - b
OTBDPS
BnO X
SO Ph
O
BnO
OHCO
BnO
OMeOBn
OBn
O
BnO
OTBDPS
BnO
SO Ph
O
BnO
OMeOBn
OBn
O
HO
OMeOH
OHO
HOHO
OH
OH
128
229 74
1 RaNi (74)
2 BH3 DMS
NaOH H 2O2 (74)
3 H2 PdC (70)
130 74
LDA THF
-100 oC
126 X = H
127 X = Li
1408 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (27)
Scheme (28)
stereochemical outcome is rationalized by the generation ofan initial zinc acetylide species which facilitates intra-molecular delivery to the α-face (Scheme 32)
Wightman synthesized C-disaccharide analogs of the α-D-arabinofuranosyl-(1rarr5)-α-D-arabinofuranosyl motif ofmycobacterial cell walls through alkynyl intermediates [36]The lactone 164 was treated with lithio(trimethylsilyl)ethyneat low temperature to give lactol in 66 yield of 165Treatment of this with triethylsilane and BF3
Et2O gavethe separable isomers 166α (60) and 166β (13)Desilylation of the major isomer 166α gave 167 in 97yield Treatment of 167 with n-BuLi followed by addition oflactone 164 gave 85 yield of the hemiacetal 168 which onreduction with Et3SiH and BF3
Et2O gave the disubstitutedalkyne 169 (83) as the major product Reduction-
hydrogenolysis of 169 then gave the C-disaccharide 170 innear-quantitative yield (Scheme 33)
3 REDUCTIVE GLYCOSYL SAMARIUM SPECIES
The introduction of SmI2 as reducing agent can becredited to Kagan and has since been utilized in numeroussynthetic schemes [37] Sinayuml and Beau introduced SmI2
chemistry into C-glycoside synthesis through intermolecularreactions with appropriate electrophiles and intramolecularreactions of silyl tethered substrates [38] Anomericsamarium species are highly stable and not likely to undergoβ-elimination Treatment of the aryl sulfone 171 with SmI2
affords the nucleophilic intermediate 172 through two singleelectron transfer processes Introduction of a suitableelectrophile (carbonyl compounds) affords the α-C-manno-
O
BnO
OTBDPS
BnO X
SO Ph
O
BnO
OBn
BnO Li
SO Ph
DMF
OHO
HOOH
OH
O OH
OH
HO
OHOH
O
BnO
OTBDPS
BnO
SO Ph
O
OBn
OBnOBnSO
Ph
OH
131 X = Li
132 X = CHO
THF -100 oC
1 Ra-Ni
2 BH3 DMS NaOH H2O2
3 H2 PdC
131
133
134
OBnO
OBnOMe
BnO
Li
OBnO
BnOOBn
OBn
OOBn
OBnOMeBnO
OH
OBnO
BnOOBn
OBn
O
n-BuLi
BnO
OMe
BnO
BrBr
O
OBn
OHO
OH
OH
HO
OHO
OH
HO
OMe
O
BnO
OMeOBn
O
BnO
139 92
1BF3 OEt2 EtOH
2 H2 PdC AcOH
140 52 over 2 steps
135 136 137
138
CBr4 PPh3
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1409
pyrannoside 173 in good yield and with excellent stereo-selectivity (Scheme 34) [38a]
Preparation of C-glycosides of ulosonic acids using SmI2
was pioneered by Linhardt and coworkers [39] Coupling ofpyridyl sulfone 174 with aldehyde 175 in the presence ofSmI2 gave an excellent yield of the N-acetylneuraminic acidC-disaccharide 176 as single isomer This stereochemicaloutcome was rationalized on the basis of the Felkin-Anhmodel for predicting the stereochemical outcome of akinetically controlled addition of a nucleophile to a chiraladehyde (Scheme 35 A)
Reductive samarium method was utilized to synthesizesialo-antigen C-analogs by the Linhardt group A fullyprotected C-analogue of the SialylTn antigen α-D-Neu5Ac-(2rarr6)α-D-GalNAc-(1rarrO)-Ser 182 was prepared [40] C-glycosylation of the neuraminic acid sulfone donor with
aldehyde acceptor in presence of excess SmI2 afforded the α-C-glycoside 180 as an RS mixture (11) The criticalintermediate aldehyde acceptor 178 was prepared in 13steps Chemoselective resolution to compound 180 wasundertaken by oxidation with DMSOAc2O to keto-bridgedcompound 181 followed by stereoselective reduction withZn(BH4)2 to regenerate the bridge hydroxyl function gave182 in gt90 de (Scheme 36)
A common versatile N-acetylneuraminic acid C-disaccharide precursor of the C-glycoside analogs ofgangliosides GM4 and GM3 has been synthesized [41]Samarium(II) iodide coupling of N-acetylneuraminic acidsulfone 179 with a 3-formyl galactopyranoside derivative183 afforded the corresponding C-disaccharide 184 as amixture of (R) and (S) isomers at the newly formedhydroxymethylene bridge This diastereoisomeric mixturewas resolved after debenzylation of the galactoside residue
Scheme (29)
O
BnO
BnOOBn
OBn
OOBn
OBnOMe
OBnOH
O
BnO
BnO
OBn
OBn
O
O
BnOOBn
OMe
BnO
Li
OBnO
OBn
OBn
OBnO
OBn
OBn
OMe
OBnO
OBn
OBnBnO
OBnO
OBn
OBn
OBnO
OBn
OBn
OMe
OBnO
OBn
OBnOBnO
OBn
OBnBnO
O
BnO
BnO
OBn
O
OBnO
OBn
OBnBnO
OBnO
OBn
OBnBnO
OBnO
OBn
OBn
OMe
OBnO
OBn
OBnBnO
OMe
1 PCC2 CBr4 Ph3P3 n-BuLi
144 overall yield 54
1 BF3 OEt2 Et3 OH
2 H2 PtO2 EtOAc
145 76
1 H2 SO4 AcOH
2 PCC
146 62
repeat steps
repeat st eps
141 142
143
147
148
1410 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (30)
Scheme (31)
O
BnOOBn
OMe
Li
BnO
OPivBnO
OBn
OBn
BnO
O OO
BF3 OEt2
OBnO
OBn
OBn
BnO
OO
O
OMe
BnOOBn
BnO
Co(CO)3
Co(CO)3
O
CAN
OBnO
OBn
OBn
BnO
OO
OO
BnOOBn
BnO
OMe
OHBnO
OBn
OBn
BnO
OHO
O
O
OMe
BnOOBn
BnO
Co(CO)3
Co(CO)3
O
OPivBnO
OBn
OBn
BnO
OH OO
O
OMe
BnOOBn
BnO
OAcO
OAc
OAc
AcO
OAcOAc
OAcO
OAc
AcO
OMe
1
2 NaOMe MeOH
1 Lewis acid2 ClCO2CCl3 Pyr3 Co2(CO)8
with a-isomer
1 Et3N Pyr H2O
2 H2 PdC H+
3 Ac2 O Pyr
149 151
152153
154 155
150
OBn
BnO
OBnO
OBn
BnO
OBnO
BnO
MeO
OBnO
OBn
BnO
O
OMe
AcO
OAcO
OAc
OAc
AcO
OAcO
OAc
O
BnOOBn
OMe
BnO
159 74 over 2 steps
+
BuLi ZnCl2 THF
1 H2 PdC2 Ac2O Pyr
156 157
158 59
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1411
Scheme (32)
Scheme (33)
and the chirality of each isomer assigned after acetylationConversion of the p-methoxyphenyl group in the peracety-lated (S) isomer 187 into the corresponding thiophenylglycoside 188 was accomplished affording the key inter-mediate for the synthesis of C-glycoside analogs of GM4GM3 and other related gangliosides (Scheme 37)
Ganglioside GM4 is a very important cell adhesionmolecule The C-disaccharide of GM4 is currently beingsynthesized in Linhardtrsquos lab using standard O-glycosylationof C-disaccharide with protected ceramide Once theceramide has been attached it can be oxidized to afford analdehyde group for coupling to keyhole limpet hemocyanin
OBnO
OBn
BnO
O
OBnO
ClZnO
OBn
BnOCl
R
OBnO
O
OBn
BnOCl
ZnR
O
ZnR
OBnO
OBn
BnO
160 161
162163
O
OBn
OBnBnO
O
O
OBn
OBnBnO H
TMS
O
OBn
OBnBnO H
O
OBn
BnO
OBnHO
O
OBn
OBnBnO OH
TMS
OBnBnO HO
OBn
TMS
O
OR
ORRO H
O
OR
RO
OR
OBn
OBnBnO
H
TMS
O+
K2CO3 MeOH
1 n-BuLi THF -78 oC
2 164
164165 66
166α 60 166β 13167 97
BF3 Et 2O Et 3SiH -78 oC
168 85
169 R = Bn 83
170 R = H near quantitative yield
H2 (1 atm)Pd(OH) 2C
TMS-acetyl ene
n-BuLi THF -78 oC BF3 Et2O Et3SiH
-78 o C
1412 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
O
OHCOBn
OBnBnO
OMe
O
CO2MeAcO
OAcAcHN
OAc
SO2
NAcO
OBnH
H
OBn
OBn
H
O
OMeH HH
A
O
CO2MeAcO
OAcAcHN
OAc
O
OBnOMe
OBnOBn
HO
AcO
+
Nu
174175
176
SmI2 THF
Scheme (34)
Scheme (35)
Scheme (36)
O
BnO
BnO
BnO
Si lylO
O2S N
O
BnO
HO R2R1
BnOBnO
SilylO
OBnO
BnO
BnO
SilylO
Sm(III)
R1COR2 SmI2 THF
171 172
173
NHBoc
OAcO
AcO
AcHN O
O
CO2BnO
OO
OO
OH
O
CO2MeAcO
OAcAcHN
OAc
AcO
SO2Ph
R2
O
CO2Me
AcHN
OAc
AcO
R1
AcO
AcO
AcHNO CO2Bn
NHBoc
AcO
OAc
O
Zn(BH4)2
180 R1 R2 = H OH ( RS 11)
181 R1 R2 = O
182 R1 = H R2 = OH de gt 90
DMSO Ac2O
177178
179
13 steps
22 equiv SmI2 THF
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1413
Scheme (37)
Fig (2)
(KLH) by reductive amination for use as carbohydrate-basedvaccine GM3 a related trisaccharide containg gangliosideplays an important role in cell growth and differentiationFig 2 The synthesis of C-oligosaccharide GM3 is currentlyunderway following a similar route to that of C-GM4synthesis [42]
Beau also reported a sialyl C-disaccharide synthesiswhich relied on the unprecedented use of a stable andcrystalline 2-pyridyl sulfide of the N-acetylneuraminic acidderivative 189 as the anomeric precursor in a samarium-Reformastky procedure [43] The coupling procedure withsulfide 189 and aldehyde 190 afforded the carbon-linkeddimer 191 in 93 yield as a 11 diastereomeric mixture
Alcohols 191 were converted into thiocarbonates anddeoxygenated by employing triphenyltin hydride catalyticAIBN and pentafluorophenol which yielded C-disaccharide192 as a single compound in 65 yield for the 2 stepsDesilylation hydrogenolysis acetylation and finalacetolysis of the methyl glycoside provided the carbon-linked mimic 193 of the disaccharidic component of thesialylTn tumor antigen (Scheme 38)
4 CATIONIC METHODS
This section is categorized according to reactions thatinvolve the generation of anomeric ions followed by thecapture with sugar-based nucleophiles
OAcAcHN
OAc
AcO
O
OBnBnO
OBnOMP
HO
O
MeO2CAcO
O
MeO2CAcO
OAcAcHN
OAc
AcO
O
OHHO
OHOMP
HO
O
OBnOHC
OBnBnO
OMP
O
MeO2CAcO
OAcAcHN
OAc
AcO
O
OHHO
OHOMP
HO
O
CO2MeAcO
OAcAcHN
OAc
AcO
SO2Ph
O
MeO2CAcO
OAcAcHN
OAc
AcO
O
OAcAcO
OAcX
AcO
H2 PdC EtOAc CH3OHH2O
+
Ac2O Pyr
187 X = OMP
188 X = SPh 73
184 85 R and S mixture
186 90 for two i somers
+
SmI2 THF183
179
185
O
HO2 CHO
OAcAcHN
OH
HO
O
OHHO
OH
OAcO
(CH2 )12 CH3
HN
OH
(CH2)14CH3
O
O
O
OHHO
OH
O
O
HO2 CHO
OAcAcHN
OH
HO
O
OHHO
OH
O(CH2)12CH3
HN
OH
(CH2)1 4CH3
GM4
GM3
1414 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
41 Exo-glycals as Nucleophiles
Nitotra et al have found that treatment of exo-glycal 194with BF 3
OEt2 followed by a water quench afforded the C-disaccharide 195 (Scheme 39) It is noteworthy tonoteworthy that the attack of the enol ether on the anomericoxonium ion occurs with high stereoselectivity on the α-face only 195 was obtained [44]
42 Silyl-based Nucleophiles
Isobe has designed and developed alkynylation as a keyreaction for the introduction of a carbon chain onto sugarsThose alkynylated compounds are called ldquosugar acetylenesrdquo[45] The mechanism includes eliminative formation ofcation to which silylacetylene can coordinate on the α-face(Scheme 40)
Double C-glycosylation between glycal 198 and bis(silylacetylene) gave C-disaccharide ldquolikerdquo compounds 199and 200 (Scheme 41)
Silylpropargyl-sugar 201 smoothly reacted with D-glucalto furnish exclusively the α-acetylene glycoside product 202in 88 (Scheme 42) [46]
5 CYCLIZATION METHODOLOGY
This approach to C-oligosaccharide synthesis relies onthe coupling of an open chain fragment with an intact
monosaccharide to give an intermediate that is then cyclizedto deliver the C-oligosaccharide target This section isdivided by the type of chemistry used to initially assemblethe two pre-cyclization fragments
51 Wittig Reaction-Cyclization
The Kishi group was the first to use Wittig-cyclizationapproach to synthesize C-disaccharides Starting with Wittigreaction between 203 and 204 the intermediate 205 wasafforded as a single stereoisomer in 82 yield Osmylationthen gave a mixture of diols with the major one formed in a61 ratio Selective protection of the diols gave 206a and206b The mono-para-methoxybenzyl ether 206a was thentransformed into the hemiketal 207 in 75 overall yield inthree steps ie (1) Swern oxidation (2) acetonide hydro-lysis (4 N HClTHFrt) and (3) benzoylation (3 equiv ofPhCOClpyCH2Cl2rt) Silane reduction of 207 in an acidicmedium should preferentially yield the equatorially substi-tuted β-C-glycoside which was deblocked and converted tothe methyl- βminusC-disaccharide 209 Exact parallel experi-ments applied to the minor isomer gave the correspondingC-disaccharide 210 (Scheme 43) [47]
Armstrong has employed Wittig-osmylation protocol forthe preparation of a small library of α-C-(1rarr6)-disaccha-rides [48] Readily available allyl C-glycoside 211 washomologated to diene ester 212 and subjected to osmylation
Scheme (38)
O
CO2MeAcO
OAcAcHN
OAc
AcO
S(2-Py)
O
TESO
AcHNOMe
O
HO
O
CO2MeAcO
OAcAcHN
OAc
AcO
O NHAcOAc
OAc
OAc
O
CO2MeAcO
OAcAcHN
OAc
AcO
O NHAcOBn
OTES
OMe
OAc
AcO
O NHAcOBn
OTES
OMeOH
O
CO2 MeAcO
OAcAcHN
+
192 65
1 MeOHHCl2 H2 PdC EtOH3 Ac2O Pyr4 Ac2OAcOHH2SO4
193 59 overall yield
25 equiv SmI2 THF
1 11-thiocarbonyldiimidazole DMAP2 Ph3SnH cat AIBN
191 93
189
190
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1415
Scheme (39)
Scheme (40)
Scheme (41)
OBnO
OBn
OBn
OBnO
OBn
OBn
OBnO
OBn
OBn
OBnO
OBnCH3
BnO
OH
CH2
OBnO
OBn
CH3
OBn
H2 O
BF3 OEt2 MeCN
194
195 96
OOAc
OAc
AcO
R SiMe3
SnCl4
O
OAc
AcO
R
O
OAc
AcO
O
OAc
AcO
Me3Si
R
SiMe3
196
197
Me3 Si SiMe3
O
AcO
OAc
OAc
SiMe3
SiMe3
O
AcO
OAc
O
OAc
OAc
O
AcO
AcOO
OAc
OAc
SnCl4 CH2Cl2
SnCl4 CH2Cl2198
199
200
1416 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (42)
Scheme (43)
AcO
OAc
OAc
Me3 Si
BnO
OBn
BnO
OBn
AcO
OAc
BnO
OBn
BnO
OBn
+ I2 CH2Cl2
202 88
198 201
O
OBn
OBn
O
O
O
OBn
OBn
O
O
OBn
OBn O
OBn
OBn
O
OPBH2M
OH
OBnO
BnO
BnO
O
OBn
OBn
O
OHOPMB
OHO
HO
HO
O
OH
OHOH
OH
HOOMe
O
OBnOBn
O
Ph3P
O
O
OBn
OBn O
OBn
OBn
O
OPBM
OH
O O
CHO
OBn
BnO
OO
OBn
OBn
O
OHOPMB
BnO
BnO
BnO
OHO
HO
HO
O
OH
OHOH
OH
HOOMe
+ THF -78 oC
1 OsO4 pyr THF
2 NaH PMBBr
206a 206b 206a206b 61
1 Swern [O]2 4N HCl3 PhCOCl pyr
1 Swern [O]2 4N HCl3 PhCOCl pyr
1 PrSiH BF3 OEt2
2 H2 Pd(OH)2C
3 HCl MeOH 90 oC
1 PrSiH BF3 OEt2
2 H2 Pd(OH)2C
3 HCl MeOH 90 o C
203
204
205
207
209
208
210
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1417
followed by reduction to afford a 51 mixture (213214215216) of lactols that were readily separable by chromato-graphy Following a deprotection of an equimolar mixture of213 and 214 217 and the DL hybrid C-disaccharide of D-glucose-O-(1rarr6)-L-galactose 218 were obtained The DDand DL derivatives 219 and 220 of glucose-α-(1rarr6)-idosewere also obtained as a near equimolar mixture afterdeprotection of 215 and 216 (Scheme 44)
52 Anion Addition-Cyclization
Kishi developed an approach for the synthesis of theCndashtrehalo sugars which relied on nucleophilic addition ofone intact sugar fragment to a fundamental aldehyde ieKishi-Nozaki reaction [49] Coupling of monosaccharide221 and aldehyde 222 gave 223 The triple bond waspartially reduced and osmylation was followed by selectiveprotection to afford 224 The acetonide was converted toepoxide 225 by standard methods and removal of the PMBgroup Acid-catalyzed cyclization followed by aglyconichydrolysis and protection of hydroxyl group with (p-methoxyphenyl)diphenylmethyl chloride (MMTrCl) gave226 Inversion of the C-2 hydroxyl and removal of protectinggroups delivered α α-C-trehalose 227 (Scheme 44)
Kishi and co-workers also employed aldol reactions as anefficient access to the C-trisaccharide related to the type IIABO(H) blood group determinant [50] Aldol condensationof the enolate of methyl ketone 228 with aldehyde 229 gavea 41 mixture of hydroxy ketones 230 and 231 The majorketol was cyclized desulfurized and oxidized to afford thedisaccharide ketone 233 The ketone in THF was treatedwith LiHMDS (3 equiv) and TMEDA followed by theaddition of MgBr2 Addition of the aldehyde 234 led toalmost exclusive formation of the equatorial products 235and 236 in a 12 ratio Mesylation of 235 and 236 followedby treatment with liquid ammonia gave enones 237a and237b which were reduced to yield exclusively the C-2rsquo-equatorial ketone 238 Sodium borohydride reduction of theC-3rsquo carbonyl proceeded with the desired stereoselectivity toyield the protected C-trisaccharide 239 which wasdeblocked to provide the polyol 240 (Scheme 46)
Sutherlin and Amstrong cleverly applied a recursivestereochemical deconvolution (RSD) combinatorial approachfor the synthesis of a small library of C-trisaccharides aspotential inhibitors for the cell surface proteins of bacteriumHelicobactor pylori [51] The workers chose to carry outvariations in galactose ring of these trisaccharides An
Scheme (44)
OBnO
BnOOBn
OBn
P O
OEtOEtO
EtO
R H
OH
OH
OH
OH
O
R H
OH
OH
OH
OH
O
OHO
HOOH
OH
O
HO
OHOH
OH
OHO
HOOH
OH
O
HO
OH
OH
OHO
HOOH
OH
O
HO
OH
OHOH
R H
OH
OH
OH
OH
O
R
OBnO
BnOOBn
OBn
O
OHO
HOOH
OH
OO
HOHO
OH
R H
OH
OH
OH
OH
O
1 OsO4 NMO 50
2 DIBAL -32 oC 40
++ +
213 214 215 216
217 218 219 220
1 9-BBN H2O22 Swern [O]
3 t-BuOK
4 I2 C6H6212
211
1418 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
efficient Nozaki-Kishi coupling of vinyl bromide 241 withaldehyde 242 in a diasteromeric ratio of 12 followed byprotection with TBSOTf led to 243 and 244 Hydroborationfollowed by oxidation gave aldehydes 245 and 246respectively Addition of allylmagnesium bromide toaldehyde 245 followed by removal of the silyl groupafforded 247 to 246 giving 248 and 249 Epoxidation gave a11 mixture of the corresponding epoxides which werecyclized to give the C-trisaccharide 250-255 after removalof the benzyl groups (Scheme 47)
Schmidt reported a stereoselective 6-exo-trig selectiveelectrophilic cylization approach for de novo synthesis of amethylene-bridged Neu5Ac-α-(23)-Gal C-disaccharide theC-analog of an important motif in glycosphingolipids [52]The open chain precusors 259ab (a 32-mixture ofdiaseteromeric alcohols) were formed by the addition oflithiated iodide 256 to open chain aldehyde 258 Subsequent
C1 incorporation using Tebbe-reagent formation of a cycliccarbonate and deprotection of the two isopropylidene ketalsafforded tetrol 264 which upon treatment with phenylselenyltrifilate was steroselectively cyclized in a 6-exo-trigselective manner affording a diasteromeric mixture of 251and 252 in a ratio of 71 A seleno-Pummerer rearrangementto afford aldehyde 267 in 5 steps in 90 overall yieldOxidation of the aldehyde and subsequent steps led to thedesired C-disaccharide 268 (Scheme 48)
53 Esterification-Cyclization
Work from the Postema group has focused on a ringclosing metathesis (RCM) approach for the synthesis of C-saccharides [53a] The chemistry is versatile and has beenused for the synthesis of a small library of differentiallylinked β-C-disaccharides through a radical allylation-RCMstrategy [53b] The synthesis of the β-(1rarr4)-glucopyranosyl
Scheme (45)
O
OBn
BnO
BnO
BnO
I
CrCl2-NiCl2O
OBn
OH
BnO
BnO
BnO
O
O
O
O
O
H
OBn
O
O
OBnBnO
BnO
BnO
OOBn
OBn
OAc
PMBOHOO
OBn
BnO
BnO
BnO
O
OBn
OBn
OAc
O
OH
HO
HO
HO
OH
OH
OH
O
OH
O
OBn
BnO
BnO
BnO
OBn
OBn
OAc
O
MMTr
+
1 p-TsOH2 K2CO3 MeOH3 MMTrCl pyr
1 Swern [O]2 BH3 THF
3 AcOH-H2 O4 H2 Pd(OH)2
221
222
223
1 Pd-Pb CaCO3 H22 NaH BnBr3 OsO44 Bu2 SnO5 CsF PMB-Cl6 Ac2 O 4-DMAP
1 AcOH2 TsCl pyr
3 NaH-imid4 DDQ
224225
226 227
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1419
Scheme (46)
OBnO O
OBn
OMe
OBn
XY
SMe
OBnBnO
O
OBn
OBn
OBn
OBn
O
BnO
YX
OBn
TBSO
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnOOBn
H
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnO
OBn
OHC OBn
OBn
OTBS
OMe
BnOOBn
CHO
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnOOBn
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnO
OBn
YX
OBnO O
OBn
OMe
OBn
OBn
O
BnO
O
OBn
OBn
OBn
OBn
O 1 LiHMDS
2
228
1 TBAF THF
2 MeSH BF3 OEt2
230 X = OH Y = H231 X = H Y = OH
230231 41
1 Bu3SnH AIBN2 Swern [O]
1 LiHMDS THF-TMEDA2 MgBr23
1 MsCl
2 liquid NH3
235 X = OH Y = H236 X = H Y = OH Bu3 SnH AIBN
237a and 237b
NaBH4 MeOH
238
239 X = OBn
240 X = OHH2 Pd(OH)2
229
232233
234
1420 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (47)
OH C
O
O BnAcHN
OO
O
OBn OBnOBn
Br
O
OBn OBnOBn
O
OBnA cHN
OO
O TBSO
OBn O BnO Bn
O
OBnAcHN
OO
OTBS
S2
S1
S2
OTBSS1
O H
S2
OT BSS1
O H
MgBrMgBr
S2
O TBSS1
O H
S2
OHS1
OH
S2
OTBSS1
OH
O
OHHO
O H
O
HO
H OO
OBnA cH N
HO
H O
O
O HHO
OH
O
HOHO
O
OBnA cH N
HO
H O
O
OHH O
OH
O
H O
HOO
OBnAcHN
HO
HO
O
O HH O
OH
O
H O
H O O
OBnA cHN
HO
HO
O
O HH O
O H
O
HO
H O O
OBnAcHN
HO
HO
O
OHHO
OH
O
H O
O
OBnA cHN
HO
HOHO
+
241 242
1 CrCl2-NiCl2 T HF-DMF 722 TBSOTf 2 6-lutidine 91
243 244
1 9-BBN 602 Dess-Mart in period inane 97
1 9 -BBN 552 D ess-Martin periodinane 98
245 246
1
2 T BAF 74
1
2 TBAF 88
247 248 249
250
251
250 251 1 1 252 253 1 1 254 255 1 1
252
253
254
255
1 MCPBA2 CSA CH 2Cl2 61 fo r 2 steps3 H 2 Pd (O H)2C 95
1 MCPBA2 CSA CH 2Cl2 63 fo r 2 s teps3 H 2 Pd (OH)2C 87
1 MCPBA2 CSA CH2Cl2 80 for 2 steps3 H2 Pd(O H)2C 95
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1421
Scheme (48)
O
OO
Se Ph
R
O
HO OHOH
O
OB n O B n
OB n
O B nO O
O O
R O OR
X
O
OO
R
Se Ph
O
HOOH
OH
O
OB nOB n
O Bn
OB n
O O
O O
R O O R
O H
O
O B n OB n
O B n
OB n
O
C HO
O
O O
R O OR
OAc HN
OAc
C O2NH 4HOOH
OH
O
OH O H
OH OH
O
OB n O B n
OB n
OB nO O
O O
R O OR
X
O
O
OAcOAc
C HOA cOOAc
OAc
O
OB n O B n
OB n
OB n
O
O Bn OB n
OB n
OB n
X
OH
OO
HOOH
OH
O
O
OMeOB n
OB nOB n
R
t-B uL i256 R = Li
257 R = L i
258
(R = t-B uMe 2Si )
(R = t-B uMe 2Si )
259ab (32) 79 com bine d yi eld
De ss-Ma rtin pe riodinane
260 X = O R = t-B uMe 2Si ) 95
261 X = O R = t -B uMe2S i) 62
T e bbe re age nt
TB A F THF262 X = O R = H 94
diphosge ne
C H2C l 2Pyr
263 95
T HFH2O T FAr t
264 quant it a ti ve yie ld
PhSe C l AgOT f
EtC N -80 oC
265
266
Quant it at i ve yi l ed 25 26 7 1
+
R =
1 Ac 2OPyr
2 mC PB A3 Ac 2ONa OAc
4 NaO HT HFMe OH
5 Ac2O P yr
267 90 overa ll yi e ld
ste ps
268
1422 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
glucopyranoside 280 represents an example of thischemistry The known triacetyl glucopyranoside 269 wasconverted to iodide 270 in good yield Radical allylation of271 proceeded to afford a mixture of equatorial and axialallylation products in a 61 ratio Oxidative cleavage of thedouble bond gave the corresponding aldehydes 273a and273b which were separable Pinnick oxidation of the majoraldehyde 273a then gave the C-4 equatorial acid 274 DCC-mediated coupling of alcohol 275 and acid 274 proceeded toafford ester 276 in good yield Methylenation of 276 gave277 and exposure to catalysist 278 gave a 41 yield of theC-disaccharide glycal which was exposed to an excess ofBH3
THF to give 64 yield of the β-C-disaccharide 279Removal of the benzyl groups and global peracetylation gavethe peracetylated (1rarr4)-β-C-disaccharide 281 in good yield(Scheme 49)
54 Ring Expansion-Cyclization
Nelson developed a new strategy for asymmetric andstereoselective synthesis of C-linked disaccharide mimeticsthe C58-C71 fragment of palytoxin [54] The diol (RR)-282was converted into the di-dihydropyran (DHP) template 283284 and 285 The di-DHPs were functionized in a twodirectional sense using dihydroxylation reactions The two-directional approach was often very efficient indeed forexample in the synthesis of 286 six new stereogenic centerswere introduced with almost complete stereocontrol using areduction and a dihydroxylation reaction The approach isnot restricted to the synthesis of C2-symmetricaldisaccharide mimetics Using the unsymmetrical template285 which has both a pseudo-axial and a pseudo-equatorialhydroxyl groups the unsymmetrical mimetics 289 and 290were prepared (Scheme 50)
6 RADICAL APPROACHES
The radical approach for C-C bond formation is a popularmethod within organic chemistry The use of radicalchemistry in carbohydrate synthesis has certain advantagesFirstly the reaction conditions are very mild and tolerant ofa range of functional and protecting groups Secondanomeric radicals are stable with respect to elimination andepimeration Most significantly the chemistry required toincorporate an appropriate substitute at C-1 employed in theinitial hemolytic cleavage step is common within carbo-hydrate chemistry [55] The use of such radical techniquecan be subdivided into two classes intermolecular andintramolecular approaches
61 Intermolecular Radical Approaches
Giese was the first to employ an intermolecular radical-based approach for synthesis of C-disaccharides [56]Addition of an alkene to an anomeric radical underappropriate conditions allowed exclusive entry to the α-linked C-glycoside a result which was mirrored by the workof Baldwin [57] The high α-selectivity of the reaction wasin contrast with other reports Thus radicals generated at theC-2 C-3 and C-4 centers all preferred to occupy equatorialpositions [58] When the anomeric bromide 291 was treatedwith tin hydride and AIBN resulting anomeric radical andreacted with lactone 292 in a Michael addition it afforded293 In this reaction hydrogen abstraction at the resulting
radical center occurs from axial face to selectively generatethe equatorial C-2rsquo substituent Reduction and acetylation of293 furnished C-disaccharide 294 (Scheme 51) [59]
Witczak used the facial bias of levoglucosene tostereoselectively add a carbohydrate-based radical in thepreparation of the 3-deoxy-(1rarr4)-β-C-disaccharide 299[60] Addition of the radical derived from iodide 295 to 296gave adduct 297 in 26 yield Removal of the anomerichydroxyl of 297 was achieved by treatment with triethylsilane borontrifluoride ether complex followed bystereoselective reduction of the keto function at C-2rsquo withthe formation of 298 in 89 yield Debenzylation followedby acetolysis of 16-anhydro ring produced the peracetylatedtarget C-disaccharide 299 in 19 overall yield from 295(Scheme 52)
Vogel has developed general methods to transformenantiomerically pure 7-oxabicyclo[221]heptyl derivatives(ldquonaked sugarsrdquo) into C-disaccharides Because of thesechiral bicyclic skeletons they undergo highly stereoselectivereactions with predictable diasteroselectivities An arsenal ofmethods is available that allow to substitute these ldquonakedrdquocarbon centers with a variety of functional groups with allpossible relative configurations The methods allowpreparation of both enantiomers of a given target with thesame ease Predictably high stereoselectivity of the reactionsof the bicyclic chirons adds to the flexibility of approachwhich can lead to high molecular diversity [61]
α-C-(1rarr3)-mannopyranoside of N-acetyl-galactosaminepotent β-galactosidase inhibitors was synthesized by thisapproach [61] Enone 302 was readily prepared from 300The addition of the radical derived from bromide 303 toenone 302 afforded the αminusisomer 304 The ketone was thenreduced and the selenide eliminated via the intermediacy ofthe selenoxide to give 305 Acid-promoted (CF3SO3H) 7-oxa ring opening of 305 in MeCN produced the amino-conduritol derivative 306 resulting from the quenching of theallylic cation intermediate by the solvent (Ritter reaction)Ozonolysis of the chloroalkene 306 generated an acylchloride-aldehyde intermediate that reacted with MeOH toproduce a mixture of methyl uronates The major compound307 was silylated and reduced The crude polyol obtainedwas acetylated to produce 308 Desilylated and ammonolysisafforded a mixture of α-β-pyranoses 309 and correspondingα-β-furanoses (Scheme 53)
Similar chemistry was carried out to synthesize non-protected α-C(1rarr2)-L-fucopyranoside of D-galactopyrano-side corresponding to a blood group mimetic [62] Giesersquosradical fucosidation of racemic enone 310 with α-L-bromoacetofucose 311 provided the mixture of diastereo-meric α-C-fucoside 312a and 312b in reproducible yield of78 Reduction of the mixture gave a 11 mixture of endo-alcohols 313 and 314 which were isolated pure in 40 and355 yield respectively Oxidative elimination of thebenzeneselenyl group of 313 followed by acetylation gaveendo acetate 315 in 85 yield Acid-promoted ring openingof 315 and ozonolysis of the resulted chloroalkene gavemethyl uronic ester 316 in modest yield (10) Treatment of316 with Cl3CCN and NaH followed with BF3
OEt2
furnished the totally protected C-disaccharide 317 in 79
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1423
Scheme (49)
Bu3SnO
HOAcO
OMeOAc
OAc
O
AcO
OMeOAc
OAcI
AIBN
O
AcO
OMeOBn
OBn
HO2C O
AcO
OMeOR
ORY
X
OHBnO
BnO
OBn
OBnO
BnO
OBn
O
AcO
OMeOBn
OBnX
i-Pr i-Pr
N
Mo C(Me2 Ph)((CF3)2 MeCO)2
O
RO
OMeOR
O
RO
OR
OR
RO
OR
278
I2 Ph3P
imidazole
269 270 93
271a X = CH2CH=CH2 Y = H R = Ac 64271b Y = CH2CH=CH2 X = H R = Ac 11272a X = CH2CH=CH2 Y = H R = Bn 75272b Y = CH2CH=CH2 X = H R = Bn 75273a X = CH2CHO Y = H R = Bn 79273a Y = CH2CHO X = H R = Bn 79
1 NaOMe MeOH2 NaOH BnBr DMF
OsO4 NaIO4
NaClO2 NaH2PO4
274 96
275
DCC 4-DMAP
276 X = O 82
277 X = CH2 51
TiCl4 Zn dust TMEDA CH2Br2PbCl2 (Cat )
1
2 BH3 THF H2O2 NaOH
H2 PdC EtOH
Ac2 O Pyr 4-DMAP
279 R = Bn R = H 64
280 R = R = H 99
281 R = R =Ac 97
1424 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (50)
Scheme (51)
O OOH
OH
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
286
1 VO(acac)2 t-BuOH 95
2 (MeO)3CH BF3 90
1 P-O2NC6H4 CO2H Ph3P DIAD2 K2CO3 MeOH 82 over 2 steps
1 PhCOCl Et3N DMAP 402 P-O2NC6H4 CO2H Ph3P DIAD3 KOH THF-H2O 75 over 2 steps
TMEDA OsO4
Cat OsO4 NMO 287
Cat OsO4 NMO288
TMEDA OsO4
Cat OsO4 NMO
290
289
(RR)-282283
284
285
OHO
AcO
BrOAc
OAc
BnO
O
OBn
OBnO
OHO
AcOOAc
OAc
BnO
OOBn
OBnAcO
OHO
AcOOAc
OAc
BnO
O
OBn
OBnO
+
Bu3SnH AIBN291
292
293 81
1 Na[Al(OC2H4OMe)2(OEt)H]2 Ac2O pyr
294 56 over 2 steps
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1425
Scheme (52)
Scheme (53)
OBnO
BnOOBn
OBn O
OH
O
OBnO
BnO
OHOBn
OBn O
O
O
O
O
O
OBnO
BnOOBn
OBnO
OAcOAc
OAc
OBnO
BnO
OHOBn
OBn
IBu3SnH AIBN
295 297 26
1 BF3 OEt2 Et3SiH
2 L-Selectride THF
1 Pd(OH)2C C6H10 EtOH
2 EtSiOSO2CF3 Ac2O
298 89 over 2 steps299
296
O
O
PhSeClO
O
PhSeCl
Bu3 SnH
O
O
PhSeCl
R
H
O
OAc
R
Cl
O
AcO
OAc
OAc
OAcOH
Cl
NHAc
R
OAc
AcHN
OH
O
OH OAc
OH
OHO
HO
OH
O
AcO
OAc
OAc
OAcBr
O
O
PhSeCl
O
O
PhSeCl
R
O
OTIPSAcHNR
OAc OAc
O
OHAcHN
COOMe
R
OAc
1 Bu4NF
2 NH3MeOH
1 (Me3Si)2NLi THF2 Me2N=CHI
1 Bu3 SnH AIBN2
1 NaBH42 mCPBA3 Ac2O pyr
1 H+ MeCN
2 H2 O NaHCO3
R =
1 O3MeOH
2 Me2S NaHCO3
1 TIPSOTf 26-lut idine2 LiBH43 Ac2 O pyr DMAP
furanoses +
304 56
305 68 306 84307 50
308 46
300 301 302
303
309
1426 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
The reduction of 317 and treatment with DOWEX-H+ resinprovided the desired C-fucoside 318 in 70 (Scheme 54)
62 Intramolecular Radical Approaches
One disadvantage with the intermolecular approaches isthat during such radical mediated reactions electrondeficient alkenes are required to facilitate C-C bondformation The intramolecular approach of Sinayuml overcomes
this drawback by bring two substrates together via atemporary covalent silaketal connector This enables the useof a wider range of alkenes which can include alkene-functionalized sugars thus leading to the generation of C-disaccharides [63] Based on the early work of Stork Sinayumlemployed the tether reaction in the synthesis of both α- andβ-C-disaccharides with this work subsequently beingemployed in the synthesis of biologically significant natural
Scheme (54)
O
OH
Fuc
Cl
O
O
ClPhSe
OOAc
NHAcOHFuc
O
AcOOAc
AcO
Br
O
O
PhSeCl
O
AcOOAc
AcO
O
OH
PhSe Cl
Fuc
OOAc
NHAc
OMe
Fuc
O
AcHN
OH OAc
OH
O
OH
Me
OH
O
O
Fuc
ClSePh
O
HO
Fuc
ClSePh
+
Ph3SnHAIBN
78 combined yield
Fuc
310
+
1 NaBH4 MeOHTHF2 Chromatography
313 40 314 355
1 mCPBA
2 Ac2O pyr DMAP
+
315 75
1 TfOH MeCN
2 NaHCO3 O3 -78 oC
316 10 over 2 steps
1 Cl3 CCN NaH
2 MeOH BF3 OEt2
317 79
1 LiBH4 THF
2 Dowex-H+
311
312a312b
318 70 for 2 steps
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1427
products [64] The availability of different hydroxyl groupson each monosaccharide unit allowed the fine-tuning ofstereochemical outcome by selective positioning of the silyltether [65] Development of this early stereochemical controlled to the tethering of the donor 320 with alcohol 319through a di-isopropyl silicon tether 321 Subsequent treat-ment with Bu3SnH and AIBN led to a 9-endo-trigcyclization to form the C-disaccharide 322 in an 80 yieldwith exclusive formation of the α-product The silyl tetherwas removed with Bu4NF and deprotection under standardconditions afforded the desired disaccharide 323 in excellentyield (Scheme 55)
In parallel the development of a 32rsquo silyl tether allowedaccess to the β-linked product as demonstrated in Sinayumlrsquossynthesis of methyl β-C-lactoside 328 [66] Alcohol 324 and320 were connected via the dimethylsilyl tether an 8-endo-trig cyclization followed to exclusively afford the β-
disaccharide 326 in 45 yield Removal of the tether anddeprotection of benzyl ether gave β-C-disaccharide 328(Scheme 56)
This group also selected iodosugars bearing a freehydroxyl group as progenitors of the radical donors [67] In atypical experiment the radical donor 329 was connected tothe radical acceptor 330 through a silaketal tether followingtheir procedure Tributyltinhydride mediated 8-endo-trigradical cyclization of compound 331 gave after detetheringof the non isolated intermediate 332 the protected β-C-disaccharide 333 in 37 overall yield (from startingmaterials 330 and 329) Peracetate 335 was achieved afterhydrogenolysis The C-laminaribioside 334 is of potentialbiological interest as it mimics the repeating disaccharideunit of fungal β-(1rarr3)-glucans which have antitumor andimmunomodulating properties (Scheme 57)
Scheme (55)
Scheme (56)
OO
OHSePh
OTBDPSO O
OO
SePh
OTBDPSO
OO
OBnOMe
OBn
Si
O
HOOBn
OMe
OBn
O
HOOH
OHHO
O
HOOH
OMe
OH
OTBDPSO
O
HOOBn
OMe
OBnO
OOH
1 n-BuLi THF
2 iPr2SiCl2 -78 oC
3 DMAP THF rt
1 Bu4NF THF
2 Dowex-H+
3 H2 PdC
Bu3SnH AIBN toluene
319
320
321
322323
OBnO
OHSePh
OBnBnO
OHO
OBnOMe
OBn
ROO
ROOH
OR
OHO
OROMe
OR
OBnO
O
OBnBnO
OO
OBnOMe
OBn
Si
SePh
OBnO
O
OBnBnOO
OOBn
OMe
OBn
Si
1 PhSeH Me2SiCl2
BuLi -78 oC
2 imidazole rt
Bu3SnH AIBN toluene
H2 PdC327 R = Bn
328 R = H
Bu4NF THF
324
320
325
326 45
1428 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
CONCLUSIONS
In this paper the biological importance of C-oligo-saccharides as subunits of natural products and as a newgeneration of carbohydrate based on therapeutics has beenillustrated Different methods are available for the synthesisof C-oligosaccharides As with traditional saccharidesynthesis it has been necessary to develop a number ofspecific approaches to facilitate the regioselective andstereoselective preparation of the desired targets Work inthis area continues and it is expected that many interestingnew C-oligosaccharides will be prepared using the chemistrydescribed in this review It is also likely that new chemistrywill be developed in the future for the preparation of thesebiologically important targets
ACKNOWLEDGEMENTS
The authors thank Dr Sultan Baytas for her criticalreading of this manuscript
REFERENCES
[1] Kennedy J F White C A Bioactive Carbohydrates InChemistry Biochemistry and Biology Ellis Horwood LtdChichesterUK 1983
[2] Wassarman PW Mammalian Fertilization Molecular Aspects ofGamete Adhesion xocytosion Exocytosis and Fusion Cell 199996 175-183
[3] Carbohydrate-based Drug Discovery Wong C-H EdWeinheim Cambridge Wiley-VCH 2003
[4] (a) Sharon N Lis H Lectins as Cell Recognition MoleculesScience 1987 246 227-234 (b) Dwek RA Chem Rev 1996 96683-720
[5] Postema M C-Glycoside synthesis CRC Boc Ratom 1995[6] (a) Weatherman R V Mortell K H Cheruenak MKiessling
L L Toone E J Specificity of C-Glycoside Complexation byMannoseGlucose Specific Lectins Biochem 1996 35 3619-3624(b) Ravishankar R Surolia A Vijayan M Lim S Kishi YPreferred Conformation of C-Lactose at the Free and Peanut LectinBound States J Am Chem Soc1998 120 11297-11303
[7] (a)Wong C-H Halcomb R L Ichikawa Y and Kajimoto TEnzymes in organic synthesis Application to the problems ofcarbohydrate recognition part2 Angew Chem Int Ed Engl 199534 521-546 (b)Howard S Withers SG Bromoketone C-Glycosides a New Class of βminusGlucanase Inactivators J AmChem Soc 1998 120 10326-10331(c) Wang Q Wolff MPolat T Du Y Linhardt R J C-glycoside of Neuraminic Acidsas Neura-minidase Inhibitors Bioorg Med Lett 2000 10 941-944 (d) Phili R Chang J Partis R A Mueller R A ChrestF J Passaniti A The Alpha-glucosidase I InhibitorCastanospermine Alters Endothelial cell Glycosylation PreventsAngiogenesis and Inhibits Tumor Growth Cancer Res 1995 552927-2935
[8] Ossor A Elbein A D In Carbohydrates in Chemistry andBiology Vol 3(II) WileyVCH 2000 pp 513-539
[9] (a) Sinayuml P Synthesis of oligosaccharide Mimetics Pure ApplChem 1997 69 459-463 (b) Beau J-M Gallagher TNucleophilic C-glycosyl Donors for C-glycoside Synthesis Top inCurr Chem 1997 187 1-54 (c) Nicotra F Synthesis of C-glycosides of Biological Interest Top in Curr Chem 1997 187
Scheme (57)
O
O
O
Ph
I
OMe
OHO
BnO
OH
OH
BnOOH
O
BnO
Si
O
O O
Ph
I
OMe
O
O
BnO
OR4O
R5O
OMe
OR2
OR3O
R3O
OR1
R3O
Bu3 SnH AIBN
332 R1 R2 = SiMe2 R3 = Bn R4 R5 = CHPhTBAF THF
333 R1 = R2 = H R3 = Bn R4 = R5 = CHPh 37 from 11
334 R1 = R2 = R3 = R4 = R5 = H
335 R1 = R2 = R3 = R4 = R5 = Ac
329
H2 PdC MeOH
Ac2 O pyr
1 BuLi THF -78 oC
2 Me2SiCl2
3 DMAP
330
331
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1429
55-83 (d) Du Y Linhardt R Y Recent Adv in Stereo-SelectiveC-Glycoside Synthesis Tetrahedron Lett 1998 54 9913-9959 (e)Liu L Mckee M and Postema M H D Synthesis of C-saccharides and Higher Congeners Current Org Chem 2001 51133-1167
[10] Jarosz S Fraser-Reid B Synthesis of A Higher Carbon Sugar ViaDirected Aldol Condensation Tetrahedron Lett 1989 30 2359-2362
[11] Lichtenthaler F W Lergenmiiller M Schwidetzky S C-Glycosidations of 2-Ketohexosyl With Electrophilic Radical andNudeophilic Anomeric Carbons Eur J Org Chem 2003 3094-3103
[12] Baudat A Vogel P Aza-C-disaccharides Synthesis of 6-Deoxygalactonojirimycin-β-C(1rarr3) Linked with D-Altrofuranosides and D-Galactose J Org Chem 1997 62 6252-6260
[13] Turner D Vogel P Synthesis of 4-Hydroxy-26-Bis(hydroxymethyl) tetrahydropyran-2-Carbaldehyde DerivativesSynlett 1998 304-306
[14] Zhu Y-H Vogel P Short Stereoselective Synthesis of C-(1rarr3)-Linked Disaccharides Tetrahedron Lett 1998 39 31-34
[15] Zhu Y-H Vogel P Synthesis of a (2R 6R)-2-(Hydroxymethyl)-6-Propa-1 2-Dienyl-2H-Pyran-3(6H)-One Derivative A NewEnone for The Convergent Construction of C-Glycosides of C-Disaccharides Synlett 2001 82-86
[16] Baumberger F Vasella A Deoxynitrosugars The 6th
Communication Stereolectronic Control in the reductivedenitration of tertiary nitro ethers A Synthesis of ldquoC-glycosidesrdquoHelv Chim Acta 1983 66 2210-2221
[17] Martin O R Lai W Synthesis and Conformational Studies of β-(1rarr6)- and ββ-(1rarr1)-Linked C-disaccharides J Org Chem1993 58 176-185
[18] Spak S J Martin R The synthesis of an analogue of Methyl OC-Analogue of Methyl 4rsquo-O-β-D-GlucopyranosylgentiobiosideTetrahedron 2000 56 217-224
[19] Kobertz W R Bertozzi C R Bednarski M D C-GlycosylAldehyde Synthons for C-Linked Disaccharides J Org Chem1996 61 1894-1897
[20] Gurjar M K Nagaprasad R and Ramana CV First Synthesis ofMethyl α-C-D-Arabino-furanosyl-(1rarr5)-αminusD-Arabinofuranosidethe C-Disaccharide Segment of Motif C of MycobateriumTuberculosis Tetrahedron Lett 2000 43 7577-7579
[21] Witczak Z J Synthesis of C-Glycosyl Compounds and OtherNatural Products from Levoglucosenone Pure Appl Chem 199466 2189-2192
[22] Griffin F K Paterson D Taylor R J K Ramberg-BacklundApproaches to the Synthesis of C-Linked Disaccharides AngewChem Int Engl 1999 38 2939-2942
[23] Paterson B E Griffin F K Alcaraz M-L and Taylor R J KA Ramberg-Baumlcklund Approach to the Synthesis of C-GlycosidesC-Linked Disaccharides and C-Glycosyl Amino Acids Eur JOrg Chem 2002 1323-1336
[24] McAllister G D Paterson D E Taylor R J K A SimplifiedRamberg-Bachlund Approach to Novel C-Glycosides and C-Linked Disaccharides Angew Chem Int Ed Engl 2003 42 1387-1391
[25] McCartney J L Christopher T M Cicchillo R M BernardinaM D Wagner T R and Norris P J Org Chem 2003 6810152-10155
[26] Dondoni A Zuurmond H M Bascarate A Synthesis of α-andβ-D-(1rarr6)-C-Disaccharides by Witting Olefination of Formyl C-Glycosides with Glycopyranose 6-phosphoranes J Org Chem1997 62 8114-8124
[27] Dondoni A Kleban M Zuurmond H Marra A Synthesis of(1rarr6)-C-Oligogalactosides by Interative Wittig OlefinationTetrahedron Lett 1998 39 7991-7994
[28] Dondoni A Marra A A New Synthetic Approach toMycobacterial Cell Wall α-(1rarr5)-D-Arabinofuranosyl C-Oligosaccharides Teterahedron Lett 2003 44 4067-4071
[29] Colinas P A Ponzinibbio A Lieberknecht A and Bravo R OWittig Reaction of Glycosyl Phosphonium Salts A StereoselectiveRoute to C-Disaccharides and C O-Trisaccharides TetrahedronLett 2003 44 7985-7988
[30] Schmidt R R Preuss R Synthesis of Carbon Tetrahedron Lett1989 30 3409-3412
[31] Dietrich H Schmidt R R Synthesis of Carbon-Bridged C-Lactose and Derivatives Liebigs Ann Chem 1994 975-981
[32] Rouzaud D Sinayuml P The First Synthesis of a ldquoC-DisacchariderdquoJ Chem Soc Chem Commun 1983 1353-1354
[33] Xin Y-C Zhang Y-M Mallet J-M Glaudemans C P JSinayuml P Synthesis of C-Oligosaccharides That Mimie TheirNatural O-Analogues Immunodeterminants in Binding toMonoclonal Immunoglobulins Eur J Org Chem 1999 471-476
[34] Streicher H Geyer A Schmidt R R C-Disaccharides ofKetoses Chem Eur J 1996 2 502-510
[35] Leeuwenburgh M A Timmers C M Vander Marel G A VanBoom J H Mallet J-M Sinayuml P G Stereoselective Synthesisof α-C-(Alkynyl)-Glycosides Via Ring-Opening of α-12-Anhydrous Tetrahedron Lett 1997 38 6251-6254
[36] Aslam T Fuchs M G G Le Formal A Wightman R HSynthesis of C-Disaccharide Analogue of the α-D-Arabinofuranosyl-(1rarr5)-α-Arabinofuranosyl Motif ofMycobacterial Cells Walls via Alkynyl Intermediates TetrahedronLett 2005 46 3249-3252
[37] (a) Girad P Namy J L Kagan H B Divalent LanthanideDerivative in Organic Synthesis 1 Mild Preparation of SamariumIodide and Ytterbium Iodide and Their Use as Reducing orCoupling Agents J Am Chem Soc 1980 102 2693-2698 (b)Molander G A Harris C R Sequencing Reactions withSamarium(II) Iodide Chem Rev 1996 96 307-338
[38] (a) Mazeacuteas D Skrydstrup T Doumeix O Beau J-MSamarium Iodide-Induced Intramolecular C-Glycoside FormationEfficient Radical Formation in the Absence of an Additive AngewChem Int Ed Engl 1994 33 1383-1386 (b) Mazeacuteas DSkrydstrup T Beau J-M A Highly Stereoselective Synthesis of1 2-trans-C-Glycosides Via Glycosyl Samarium(III) CompoundsAngew Chem Int Ed Engl 1995 34 909-912 (c) Jarreton OSkrydstrup T Beau J-M The Stereospecific Synthesis of Methylα-C-Mannobioside A Potential Inhibitor of M TuberculosisBinding to Human Macrophages J Chem Soc Chem Commun1996 1661-1662 (d) Jarreton O Skrydstrup T Espionosa J-FJimeacutenez-Barbero J Beau J-M Samarium Diiode Prompted C-Glycosylation An Application to The Stereospecific Synthesis ofα-(1rarr2)-C-Mannobioside and Its Derivatives Chem Eur J 19995 430-441 (e) Mipuel N Doisneau G Beau J-M ReductiveSamariation of Anomeric 2-Pyridyl Sulfones with Catalytic AnUnexpected Improvement in The Synthesis of 12-Trans-Diequatorial C-Glycosyl Compounds Angew Chem Int Ed Engl 2000 39 4111-4114
[39] Vlahov I R Vlahova P I Linhardt R J DiastereocontrolledSynthesis of Carbon Glycosides of N-Acetylneuraminic Acid ViaGlycosyl Samarium(III) Intermediates JAmChem Soc 1997 1191480-1481
[40] Kuberan B Sikkander S ATomiyama H Linhardt R JSynthesis of a C-Glycoside Analogue of sTn An HIV-and Tumor-Associated Antigen Angew Chem Int Ed Engl 2003 42 2073-2075
[41] Bazin H G Du Y Polat T Linhardt R J Synthesis of aVersatile Neuraminic Acid ldquoCrdquo-Disaccharide Precursor for theSynthesis of C-Glycoside Analogues of Gangliosides J OrgChem 1999 64 7254-7259
[42] Chen C-C Ress D K Linhardt RJ Samarium Iodide-Mediated Synthesis of Neuraminic Acid C-Glycosides InSynthesis of Glycommetics Roy R Ed ACS Syposium Series2004 896 53-80
[43] Abdallah Z Doisneau G Beau J-M Synthesis of a Carbon-Linked Mimic of The Disaccharide Component of The Tumor-Relate SialyTn Antigen Angew Chem Int Ed Engl 2003 425209-5212
[44] Lay L Nicotra F Panza L Russo G Caneva E Synthesis ofC-disaccharides through dimerization of exo-glycals J Org Chem1992 57 1304-1306
[45] Isobe M Nishizawa R Hosokawa S Nishikawa TStereocontrolled Synthesis and Reactivity of Sugar Acetylenes JChem Soc Chem Commun 1998 2665-2676
[46] Saeeng R Sirion U Sahakitpichan P Isobe M IodineCatalyzes C-Glycosidation of D-Glucal with SilylacetykeneTetrahedron Lett 2003 44 6211-6215
[47] (a) Babirad S A Wang Y Kishi Y Synthesis of C-Disaccharides J Org Chem 1987 52 1370-1372 (b) Wang YBabirad S A Kishi Y Preferred Conformation of C-Glycosides
1430 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
8 Synthesis of 14-Linked Carbon Disaccharides J Org Chem1992 57 468-481
[48] Armstrong R W Sutherlin D P Strategies for the Synthesis ofC-Disaccharides Containing D and L Sugars Tetrahedron Lett1994 35 7743-7746
[49] Wei A Kishi Y Preferred Conformation of C-Glycosides 12Synthesis and Conformational Analysis of αα- α β- and β β-Trehaloses J Org Chem 1994 59 88-96
[50] Haneda T Goekjian P G Kim S H Kishi Y PreferredConformation of C-Glycosides 10 Synthesis and ConformationAnalysis of Carbon Trisaccharides J Org Chem 1992 57 490-498
[51] Sutherlin D P Armstrong R W Synthesis of 12 Stereochemistryand Structurally Diverse C-Trisaccharides J Org Chem 1997 625267-5283
[52] Notz W Hartel C Waldscheck B Schmidt R R De NovoSynthesis of a Methylene-Bridged Neu5Ac-α-(23)-Gal C-Disaccharide J Org Chem 2001 66 4250-4260
[53] (a) Postema M H D Calimente D Liu L Behrmanm T L AnOlefin Metathesis Route for the Preparation of (1rarr6)-Linked-C-Disaccharide Glycals A Convergent and Flexible Approach to C-Saccharide Synthesis J Org Chem 2000 65 6061-6068(b) Postema M H Piper J L Liu L Faust M Andreana PSynthesis and Partial Biological Evaluation of a Small Library ofDifferentially Linked β-C-Disaccharide J Org Chem 2003 684748-4754
[54] Nelson A The Development of Strategies and Methods for TheSynthesis of Biologically Active Compounds New J Chem 200428 771-776
[55] Togo H He W Waki Y Yokoyama M C-GlycosylationTechnology With Free Radiant Reactions Synlett 1998 700-717
[56] Giese B Dupuis J Diastereoselective Synthesis of C-Glycopyranosides Angew Chem Int Ed Engl 1983 22 622-623
[57] Adlington R M Baldwin J E Basak A Kozyrod RPApplication of Radical Addition Reactions to tho Synthesis of a C-Glucoside and A Functionalized Amino Acid J Chem SocChem Commun 1983 144-145
[58] Giese B Gonzaacutelez-Goacutemez J A Witzel T The Scope of RadicalCC-Coupling by The ldquoTin Methodrdquo Angew Chem Int Ed Engl1984 23 69-70
[59] Giese B Witzel T Synthesis of ldquoC-Disaccharidesrdquo by RadicalC-C Bond Formation Angew Chem Int Ed Engl 1986 25 450-451
[60] Witczak Z J Chhabra R Chojnacki J C-Disaccharides IStereoselective Approach to β-(1rarr4)-3-Deoxy-C-Disaccharidesfrom Levoglucosenone Carb Res 1997 301 167-175
[61] Vogel P Synthesis of Rare Carbohydrates and Analogues Startingfrom Enantiomerically Pure 7-Oxabicyclo[221]heptyl Derivatives(ldquoNaked Sugarsrdquo) Current Org Chem 2000 4 455-480
[62] Viodeacute C Vogel P Synthesis of The C-Disaccharide α-C(1rarr3)-L-Fucopyranoside of N-Acetylgalactosamine J Carb Chem2001 20 733-746
[63] Xin Y C Mallet J M Sinayuml P An Expeditious Synthesis of AC-Disaccharide Using A Temporary Silaketal Connection J ChemSoc Chem Commun 1993 864-865
[64] (a) Petitou M Herault P Lormeau J-C Helmboldt A MalletJ-M Sinayuml P Herbert J-M Introducing A C-InterglycosidicBond in A Biologically Active Pentasaccharide Hardly Affects ItsBiological Properties Bioorg Med Chem 1998 6 1509-1516 (b)Sinayuml P Advances in The Synthesis of the Carbohydrate MimicsPure Appl Chem 1998 70 1495-1499
[65] Sinayuml P Chemical Synthesis of Oligosaccharide Mimetics PureAppl Chem 1998 70 407-410
[66] Sinayuml P Chemical Synthesis of Oligosaccharide Mimetics PureAppl Chem 1998 69 459-463
[67] Vauzeilles B Sinayuml P Selective Radical Synthesis of β-C-Disaccharides Tetrahedron Lett 2001 42 7269-7272
1402 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Norris et al deprotonated 88 with n-BuLi and theresulting anion was coupled with an excess lactone 89 at lowtemperature to afford the adduct 90 in 77 yield SPhgroups were removed with Raney nickel and lactol 91 wasisolated as a syrup that contained two components in
approximately a 41 ratio The two compounds were thoughtto be α- and β-lactols with the latter being major It wasstraightforward to reduce the lactols with a high degree ofstereocontrol to afford the C-disaccharide 92 with a 51isolated yield (Scheme 19) [25]
Scheme (17)
Scheme (18)
O
O O
O
O OH
O OMe
OBnBnO
SO2
P
EtO
EtO
O
OBn
O
OMe
OAc
OAc
OAcO
O O
O
O
O
OO OMe
OBnBnO
SO2
OBn
O
O O
O
O O
O
O
O
OMe
OBn
OBn
OBn
83 50 E only
80
+
NaH THF -78 oC
82 86αβ 11
KOHAl2O3
CBr2F2 CH2Cl2
tBuOH 5 oC
2 h
1 H2PdC EtOAc RT 7h
2 Ac2 O Pyr RT
84 69 over 2 st eps
81
O
O O
O
O OH POEt
OEt
O
SO2
P
EtO
EtOO
O
O
O
OO
O
O
O
O O
O
O
O O
O
O
O
O SO2
O
O
O
O
O
O O
O
OO
O
O
85 75βαββ ca 31
86 66β αββ = 141 E only
H2PdC EtOAc
87 76βαβ β = 141
21 NaH THF -78 o C
80 (2 equiv)
KOHAl2O3CBr2F2 CH2Cl2tBuOH
on majorβα is omer
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1403
24 Phosphorous Stabilized Anions
The most common type of reaction discussed in thissection is Wittig approach to C-oligosaccharide synthesisThis methodology is particularly suited for synthesis of(1rarr6)-C-saccharides since one sugar can hold the aldehydewhile the other the ylid or phosphonate anion
Dondoni has utilized this approach to prepare a variety ofβ-D-(1rarr6)-C- disaccharides The general approach is shownin Scheme 20 Coupling of β-linked galactopyranosyl ormannofuranosyl derivative (93 94 95 or 96) with ylidefrom phosphonium iodide 97 or 98 gave alkene 99 Alkenewas reduced and removal of deprotecting groups gave thecorresponding β-D-(1rarr6)-C- disaccharide 100 [26]
α-D-(1rarr6)-C-disaccharide 103 was also synthesizedusing the approach (Scheme 21)
Dondoni applied this methodology in an iterative fashionto prepare the corresponding β-(1rarr6)-C-trigalactosides andβ-(1rarr6)-C-tetragalactosides [27] Starting with coupling ofylide 104 generated in situ with aldehyde 33 gave adduct105 (EZ 19) Removal of silyl protecting group followed byoxidation led to aldehyde 106 which was coupled with theylide from 104 to give C-trisaccharide 107 in 36 yield Thesame sequence was repeated with 107 afforded the protectedC-tetrasaccharide alkene 108 Compounds 108 wasdesilylated and exposed to hydrogen over Pd(OH)2 oncarbon followed to peracetylation gave protected C-tetrasaccharide 109 (Scheme 22)
Taking advantage of their experience on the stereo-selective synthesis of C-oligosaccharides by iterative Wittigolefination this group developed new building blocks and amodified protocol for the straightforward assembly of C-α-(1rarr5)-D-oligoarabinofuranosides [28] While the twomonofunctionalized sugar moieties 110 and 111 weresuitable precursors to the head and tail of the oligo-saccharidic chain the difunctionalized compound 114 was arepeating unit (Scheme 23) Building block 114 wasdesigned to allow after the Wittig coupling for regenerationof the formyl group in a single step under conditions that donot affect the chemical and stereochemical integrity of thegrowing saccharidic chain (Scheme 24)
Colinas et al reported a method for the synthesis of C-disaccharides by a sequence involving the Wittig reaction askey step and further glycosydation of these compounds toafford new C O-trisaccharides [29] The enol ether 122a-bwere prepared by the Wittig reaction of the α β mixture of2-deoxiglycosyl phosphonium salts 120a-b with aldehyde121 Hydrogenation of the exo-glycals afforded the β-C-disaccharides with good yields The O-glycosidationemploying the exo-glycals and the glycosyl acceptor 124 isillustrated in Scheme 25
25 C-1 Vinyl Anions
Schmidt was the first to explore the addition of sulfoxide-stabilized vinyl C-1-organolithiums to carbohydrate-basedcarbonyl compounds [30] The vinyl sulfoxide 126 was
Scheme (19)
OCH3
O O
OPhS
PhS
O O
OO
OCH3
O O
OO O
O H
OCH3
O O
OPhSPhS
O O
O OH
OCH3
O O
OO O
O OH
+
n-BuLi THF -78 oC
Raney Ni EtOH H2O rt
Et3SiH BF3 OEt2
90 77
92 51 over 2 steps 91 is omers rati o βα = 41
-78 oC
88
89
1404 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
deprotonated with LDA to give 127 Addition of 127 toaldehyde 128 gave a mixture of diastereoisomers of whichthe major 129 was formed in a 101 ratio Desulfurizationhydroboration and removal of benzyl groups gave the(1rarr5)- βminusC-disaccharide 130 (Scheme 26)
Schmidt and coworkers used this methodology for ahighly efficient synthesis of an analog of C-trehalose 134Scheme 27 [31] Anion 131 was converted to aldehyde 132
and condensation of this aldehyde with the same anion gaveadduct 133 which was then converted to the target C-disaccharide 134
26 Acetylide-Based Anions
Sinayuml was the first to prepare a C-disaccharide Hisapproach involved the coupling of a C-6 alkyne with ananomeric lactone followed by reduction of the formedhemiacetal [32] Aldehyde 135 was converted to the
Scheme (20)
Scheme (21)
OO O
O
O CHO
O
BnOOBn
BnO
OBn
CHO
OBn
CHO
BnO
O
BnOBnO
O
BnOOBn
BnO OBn
CHO
PPh3I-
OO
O
OO
O
OMeOBn
OBn
OBn
PPh3I-
OCHO
O
PPh3I-
ORRO
RO
OO
ORRHO
OO
OR
+ +
+
( 93 - 96 )
( 97 - 98 )
BuLi THF-HMPA
-30 iexclaelig
99
Reduction
100
+
93 9495
96 97 98
O
OBnBnO
BnO
OO
O
OO
HO
O
O
OO
PPh3I-
O
OHHO
HO
O
HOOH OH
HO
OBnBnO
CHO
BnO
O
+
BuLi THF-HMPA
-30 oC
1 p-MeC 6H4SO2-
NH2NH2 AcONa
2 H2 Pd(OH)2 3 bar
3 Amberli te H+
+
10197
102
103
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1405
dibromoalkene 136 which was treated with n-butyllithium togive an intermediate acetylide 137 The latter uponnucleophilic addition to lactone 138 gave a mixture of lactol139 in high yield Stereoselective reduction of lactol 139 wasfollowed by hydrogenation of benzyl groups and the triplebond affording the (1rarr6)-β-C-disaccharide 140 (Scheme28)
The lactone-addition methodology was later applied bySinayuml and co-workers in an iterative fashion for the
preparation of higher homologues [33] Hydroxylmethylenein compound 141 was converted to acetylide lithium incompound 142 by a sequence of reactions Condensation ofcompound 142 with the galacto lactone 143 gave 144 asmixture of anomers The lactol were stereoselectivelyreduced to and triple bond was hydrogenated to give 145Methyl glycoside 145 was hydrolyzed to the correspondinglactols which were oxidized to lactone 146 The samesequence was then repeated twice to give C-trisaccharide147 and C-tetrasaccharide 148 (Scheme 29)
Scheme (22)
O
BnOOBn
BnO OTBDPS
PPh3I-
BnO
H
O
BnOOBn
OTBDPS
OO
O
OO
O
CHOO
O
OO
O
BnO
O
BnOOBn
BnO
OO
O
OO
H
HOBn
BnO OTBDPS
O
BnOOBn
BnO O
OO
O
OO
H
OBn
BnO OTBDPS
PPh3I-
O
BnO
O
BnOOBn
BnO OTBDPS
PPh3I-
O
AcOOAc
AcO
O
AcOOAc
AcO
OO
O
OO
O
AcOOAc
AcO OAc
O
BnOOBn
BnO
O
BnOOBn
BnO
OO
O
OO
H
H
O
BnOOBn
BnO OTBDPS
H
1 TBAF2 PCC
+107 36
+
1 TBAF2 PCC3
+
1 TBAF2 H2 Pd(OH)2 C3 Ac2 O Pyr
104
33
105
106104
104
108109
BuLi THF-HMPA
-50 o C
70EZ 19
BuLi THF-HMPA
-50 o C
1406 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
The di- tri- and tetrasaccharide derivatives (145 147 and148) were all debenzylated and tested for their bindingaffinity to three different monoclonal immunoglobulins withspecificity for different O-β-(1rarr6)-D-galactopyranosyl deter-minants These C-saccharide analogs had similar bindingproperties to the corresponding O-saccharides
Schmidt has also used acetylide-lactone condensation toassemble C-disaccharides of ketoses [34] Lithium acetylide149 was condensed with ketone 150 to give a mixture ofalcohol 151 after removal of the pivoloyl group Attemptedcyclization under Lewis acid catalysis resulted only in theremoval of the acetonide Accordingly the diol was tiedback as the carbonate and the acetylene complex as thedicobalt species 152 The isomers were then separately
cyclized to give a 11 mixture of C-disaccharide 153 Thecobalt complex on α-C-disaccharide was removed understandard conditions to give 154 and deprotection of thecarbonate was followed by hydrogenation and peracetylationto give 155 (Scheme 30) Similar chemistry was also carriedout with the corresponding β-isomer
Van Boom and co-workers used lithiated alkynylderivative 156 in presence of ZnCl2 to selectively open ringof the 12-anhydrosugar 157 affording the α-C-(alkynyl)-glycoside 158 Hydrogenolysis of the benzyl groups wasfollowed by peracetylation to give the (1rarr6)-α-C-disaccharide 159 (Scheme 31) [35]
Normally attack of the nucleophile proceeds from anequatorial direction to give the β-isomer The unexpected
Scheme (23)
Scheme (24)
BnOO
OBnCHO
OBn
O
OBn
PPh3I-
OBn
OBn
O
OBn
BnOBnO
O
OBnOBn
OBnH
O
OH
HOHO
O
OHOH
OH+
BuLi
THF-HMPA
-20 oC+
1 TBAF2 H2 Pd(OH)2C
112 65 113 100
110
111
O
OBnCHO
OBnBnO
O
OBn
BnOBnO
O
OBnCH(OiPr)2
OBnH
O
OBnCH(OiPr)2
PPh3I-
OBn
O
OBn
BnOBnO
O
OBn
OBnH
O
OBnOBn
BnOH
O
OH
HOHO
O
OH
OH
O
OHOH
HO
++
BuLi
THF-HMPA
-20 oC
BuLi
THF-HMPA
-20 oC
TFA H2 O THF rt
115 49
116 R = CH(OiPr)2
117 R = CHO
118 45
H2 Pd(OH)2C
110
114
114
119
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1407
Scheme (25)
Scheme (26)
OBn
R1
R2
PPh3BF4-O
O
OOHC
O
O
O
O
O
O
O
O
HO
O
O
O
O
O O
OBn
R1
R2
O
O
O
O
O
O
H
O
OBn
R1
R2
O
O
O
O
O
O
O
O
OBn
R1
R2
O
O
O
+
BCl3 (005 equiv)
MS 4A CH2 Cl2 0 o C
+
BuLi THF -90 oC -90 o C
to rtH2 (1 atm) PdC Et3N MeOH
R1 R2 = OBn H
120a - b
121
122a - b
123a - b
124
125a - b
OTBDPS
BnO X
SO Ph
O
BnO
OHCO
BnO
OMeOBn
OBn
O
BnO
OTBDPS
BnO
SO Ph
O
BnO
OMeOBn
OBn
O
HO
OMeOH
OHO
HOHO
OH
OH
128
229 74
1 RaNi (74)
2 BH3 DMS
NaOH H 2O2 (74)
3 H2 PdC (70)
130 74
LDA THF
-100 oC
126 X = H
127 X = Li
1408 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (27)
Scheme (28)
stereochemical outcome is rationalized by the generation ofan initial zinc acetylide species which facilitates intra-molecular delivery to the α-face (Scheme 32)
Wightman synthesized C-disaccharide analogs of the α-D-arabinofuranosyl-(1rarr5)-α-D-arabinofuranosyl motif ofmycobacterial cell walls through alkynyl intermediates [36]The lactone 164 was treated with lithio(trimethylsilyl)ethyneat low temperature to give lactol in 66 yield of 165Treatment of this with triethylsilane and BF3
Et2O gavethe separable isomers 166α (60) and 166β (13)Desilylation of the major isomer 166α gave 167 in 97yield Treatment of 167 with n-BuLi followed by addition oflactone 164 gave 85 yield of the hemiacetal 168 which onreduction with Et3SiH and BF3
Et2O gave the disubstitutedalkyne 169 (83) as the major product Reduction-
hydrogenolysis of 169 then gave the C-disaccharide 170 innear-quantitative yield (Scheme 33)
3 REDUCTIVE GLYCOSYL SAMARIUM SPECIES
The introduction of SmI2 as reducing agent can becredited to Kagan and has since been utilized in numeroussynthetic schemes [37] Sinayuml and Beau introduced SmI2
chemistry into C-glycoside synthesis through intermolecularreactions with appropriate electrophiles and intramolecularreactions of silyl tethered substrates [38] Anomericsamarium species are highly stable and not likely to undergoβ-elimination Treatment of the aryl sulfone 171 with SmI2
affords the nucleophilic intermediate 172 through two singleelectron transfer processes Introduction of a suitableelectrophile (carbonyl compounds) affords the α-C-manno-
O
BnO
OTBDPS
BnO X
SO Ph
O
BnO
OBn
BnO Li
SO Ph
DMF
OHO
HOOH
OH
O OH
OH
HO
OHOH
O
BnO
OTBDPS
BnO
SO Ph
O
OBn
OBnOBnSO
Ph
OH
131 X = Li
132 X = CHO
THF -100 oC
1 Ra-Ni
2 BH3 DMS NaOH H2O2
3 H2 PdC
131
133
134
OBnO
OBnOMe
BnO
Li
OBnO
BnOOBn
OBn
OOBn
OBnOMeBnO
OH
OBnO
BnOOBn
OBn
O
n-BuLi
BnO
OMe
BnO
BrBr
O
OBn
OHO
OH
OH
HO
OHO
OH
HO
OMe
O
BnO
OMeOBn
O
BnO
139 92
1BF3 OEt2 EtOH
2 H2 PdC AcOH
140 52 over 2 steps
135 136 137
138
CBr4 PPh3
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1409
pyrannoside 173 in good yield and with excellent stereo-selectivity (Scheme 34) [38a]
Preparation of C-glycosides of ulosonic acids using SmI2
was pioneered by Linhardt and coworkers [39] Coupling ofpyridyl sulfone 174 with aldehyde 175 in the presence ofSmI2 gave an excellent yield of the N-acetylneuraminic acidC-disaccharide 176 as single isomer This stereochemicaloutcome was rationalized on the basis of the Felkin-Anhmodel for predicting the stereochemical outcome of akinetically controlled addition of a nucleophile to a chiraladehyde (Scheme 35 A)
Reductive samarium method was utilized to synthesizesialo-antigen C-analogs by the Linhardt group A fullyprotected C-analogue of the SialylTn antigen α-D-Neu5Ac-(2rarr6)α-D-GalNAc-(1rarrO)-Ser 182 was prepared [40] C-glycosylation of the neuraminic acid sulfone donor with
aldehyde acceptor in presence of excess SmI2 afforded the α-C-glycoside 180 as an RS mixture (11) The criticalintermediate aldehyde acceptor 178 was prepared in 13steps Chemoselective resolution to compound 180 wasundertaken by oxidation with DMSOAc2O to keto-bridgedcompound 181 followed by stereoselective reduction withZn(BH4)2 to regenerate the bridge hydroxyl function gave182 in gt90 de (Scheme 36)
A common versatile N-acetylneuraminic acid C-disaccharide precursor of the C-glycoside analogs ofgangliosides GM4 and GM3 has been synthesized [41]Samarium(II) iodide coupling of N-acetylneuraminic acidsulfone 179 with a 3-formyl galactopyranoside derivative183 afforded the corresponding C-disaccharide 184 as amixture of (R) and (S) isomers at the newly formedhydroxymethylene bridge This diastereoisomeric mixturewas resolved after debenzylation of the galactoside residue
Scheme (29)
O
BnO
BnOOBn
OBn
OOBn
OBnOMe
OBnOH
O
BnO
BnO
OBn
OBn
O
O
BnOOBn
OMe
BnO
Li
OBnO
OBn
OBn
OBnO
OBn
OBn
OMe
OBnO
OBn
OBnBnO
OBnO
OBn
OBn
OBnO
OBn
OBn
OMe
OBnO
OBn
OBnOBnO
OBn
OBnBnO
O
BnO
BnO
OBn
O
OBnO
OBn
OBnBnO
OBnO
OBn
OBnBnO
OBnO
OBn
OBn
OMe
OBnO
OBn
OBnBnO
OMe
1 PCC2 CBr4 Ph3P3 n-BuLi
144 overall yield 54
1 BF3 OEt2 Et3 OH
2 H2 PtO2 EtOAc
145 76
1 H2 SO4 AcOH
2 PCC
146 62
repeat steps
repeat st eps
141 142
143
147
148
1410 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (30)
Scheme (31)
O
BnOOBn
OMe
Li
BnO
OPivBnO
OBn
OBn
BnO
O OO
BF3 OEt2
OBnO
OBn
OBn
BnO
OO
O
OMe
BnOOBn
BnO
Co(CO)3
Co(CO)3
O
CAN
OBnO
OBn
OBn
BnO
OO
OO
BnOOBn
BnO
OMe
OHBnO
OBn
OBn
BnO
OHO
O
O
OMe
BnOOBn
BnO
Co(CO)3
Co(CO)3
O
OPivBnO
OBn
OBn
BnO
OH OO
O
OMe
BnOOBn
BnO
OAcO
OAc
OAc
AcO
OAcOAc
OAcO
OAc
AcO
OMe
1
2 NaOMe MeOH
1 Lewis acid2 ClCO2CCl3 Pyr3 Co2(CO)8
with a-isomer
1 Et3N Pyr H2O
2 H2 PdC H+
3 Ac2 O Pyr
149 151
152153
154 155
150
OBn
BnO
OBnO
OBn
BnO
OBnO
BnO
MeO
OBnO
OBn
BnO
O
OMe
AcO
OAcO
OAc
OAc
AcO
OAcO
OAc
O
BnOOBn
OMe
BnO
159 74 over 2 steps
+
BuLi ZnCl2 THF
1 H2 PdC2 Ac2O Pyr
156 157
158 59
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1411
Scheme (32)
Scheme (33)
and the chirality of each isomer assigned after acetylationConversion of the p-methoxyphenyl group in the peracety-lated (S) isomer 187 into the corresponding thiophenylglycoside 188 was accomplished affording the key inter-mediate for the synthesis of C-glycoside analogs of GM4GM3 and other related gangliosides (Scheme 37)
Ganglioside GM4 is a very important cell adhesionmolecule The C-disaccharide of GM4 is currently beingsynthesized in Linhardtrsquos lab using standard O-glycosylationof C-disaccharide with protected ceramide Once theceramide has been attached it can be oxidized to afford analdehyde group for coupling to keyhole limpet hemocyanin
OBnO
OBn
BnO
O
OBnO
ClZnO
OBn
BnOCl
R
OBnO
O
OBn
BnOCl
ZnR
O
ZnR
OBnO
OBn
BnO
160 161
162163
O
OBn
OBnBnO
O
O
OBn
OBnBnO H
TMS
O
OBn
OBnBnO H
O
OBn
BnO
OBnHO
O
OBn
OBnBnO OH
TMS
OBnBnO HO
OBn
TMS
O
OR
ORRO H
O
OR
RO
OR
OBn
OBnBnO
H
TMS
O+
K2CO3 MeOH
1 n-BuLi THF -78 oC
2 164
164165 66
166α 60 166β 13167 97
BF3 Et 2O Et 3SiH -78 oC
168 85
169 R = Bn 83
170 R = H near quantitative yield
H2 (1 atm)Pd(OH) 2C
TMS-acetyl ene
n-BuLi THF -78 oC BF3 Et2O Et3SiH
-78 o C
1412 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
O
OHCOBn
OBnBnO
OMe
O
CO2MeAcO
OAcAcHN
OAc
SO2
NAcO
OBnH
H
OBn
OBn
H
O
OMeH HH
A
O
CO2MeAcO
OAcAcHN
OAc
O
OBnOMe
OBnOBn
HO
AcO
+
Nu
174175
176
SmI2 THF
Scheme (34)
Scheme (35)
Scheme (36)
O
BnO
BnO
BnO
Si lylO
O2S N
O
BnO
HO R2R1
BnOBnO
SilylO
OBnO
BnO
BnO
SilylO
Sm(III)
R1COR2 SmI2 THF
171 172
173
NHBoc
OAcO
AcO
AcHN O
O
CO2BnO
OO
OO
OH
O
CO2MeAcO
OAcAcHN
OAc
AcO
SO2Ph
R2
O
CO2Me
AcHN
OAc
AcO
R1
AcO
AcO
AcHNO CO2Bn
NHBoc
AcO
OAc
O
Zn(BH4)2
180 R1 R2 = H OH ( RS 11)
181 R1 R2 = O
182 R1 = H R2 = OH de gt 90
DMSO Ac2O
177178
179
13 steps
22 equiv SmI2 THF
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1413
Scheme (37)
Fig (2)
(KLH) by reductive amination for use as carbohydrate-basedvaccine GM3 a related trisaccharide containg gangliosideplays an important role in cell growth and differentiationFig 2 The synthesis of C-oligosaccharide GM3 is currentlyunderway following a similar route to that of C-GM4synthesis [42]
Beau also reported a sialyl C-disaccharide synthesiswhich relied on the unprecedented use of a stable andcrystalline 2-pyridyl sulfide of the N-acetylneuraminic acidderivative 189 as the anomeric precursor in a samarium-Reformastky procedure [43] The coupling procedure withsulfide 189 and aldehyde 190 afforded the carbon-linkeddimer 191 in 93 yield as a 11 diastereomeric mixture
Alcohols 191 were converted into thiocarbonates anddeoxygenated by employing triphenyltin hydride catalyticAIBN and pentafluorophenol which yielded C-disaccharide192 as a single compound in 65 yield for the 2 stepsDesilylation hydrogenolysis acetylation and finalacetolysis of the methyl glycoside provided the carbon-linked mimic 193 of the disaccharidic component of thesialylTn tumor antigen (Scheme 38)
4 CATIONIC METHODS
This section is categorized according to reactions thatinvolve the generation of anomeric ions followed by thecapture with sugar-based nucleophiles
OAcAcHN
OAc
AcO
O
OBnBnO
OBnOMP
HO
O
MeO2CAcO
O
MeO2CAcO
OAcAcHN
OAc
AcO
O
OHHO
OHOMP
HO
O
OBnOHC
OBnBnO
OMP
O
MeO2CAcO
OAcAcHN
OAc
AcO
O
OHHO
OHOMP
HO
O
CO2MeAcO
OAcAcHN
OAc
AcO
SO2Ph
O
MeO2CAcO
OAcAcHN
OAc
AcO
O
OAcAcO
OAcX
AcO
H2 PdC EtOAc CH3OHH2O
+
Ac2O Pyr
187 X = OMP
188 X = SPh 73
184 85 R and S mixture
186 90 for two i somers
+
SmI2 THF183
179
185
O
HO2 CHO
OAcAcHN
OH
HO
O
OHHO
OH
OAcO
(CH2 )12 CH3
HN
OH
(CH2)14CH3
O
O
O
OHHO
OH
O
O
HO2 CHO
OAcAcHN
OH
HO
O
OHHO
OH
O(CH2)12CH3
HN
OH
(CH2)1 4CH3
GM4
GM3
1414 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
41 Exo-glycals as Nucleophiles
Nitotra et al have found that treatment of exo-glycal 194with BF 3
OEt2 followed by a water quench afforded the C-disaccharide 195 (Scheme 39) It is noteworthy tonoteworthy that the attack of the enol ether on the anomericoxonium ion occurs with high stereoselectivity on the α-face only 195 was obtained [44]
42 Silyl-based Nucleophiles
Isobe has designed and developed alkynylation as a keyreaction for the introduction of a carbon chain onto sugarsThose alkynylated compounds are called ldquosugar acetylenesrdquo[45] The mechanism includes eliminative formation ofcation to which silylacetylene can coordinate on the α-face(Scheme 40)
Double C-glycosylation between glycal 198 and bis(silylacetylene) gave C-disaccharide ldquolikerdquo compounds 199and 200 (Scheme 41)
Silylpropargyl-sugar 201 smoothly reacted with D-glucalto furnish exclusively the α-acetylene glycoside product 202in 88 (Scheme 42) [46]
5 CYCLIZATION METHODOLOGY
This approach to C-oligosaccharide synthesis relies onthe coupling of an open chain fragment with an intact
monosaccharide to give an intermediate that is then cyclizedto deliver the C-oligosaccharide target This section isdivided by the type of chemistry used to initially assemblethe two pre-cyclization fragments
51 Wittig Reaction-Cyclization
The Kishi group was the first to use Wittig-cyclizationapproach to synthesize C-disaccharides Starting with Wittigreaction between 203 and 204 the intermediate 205 wasafforded as a single stereoisomer in 82 yield Osmylationthen gave a mixture of diols with the major one formed in a61 ratio Selective protection of the diols gave 206a and206b The mono-para-methoxybenzyl ether 206a was thentransformed into the hemiketal 207 in 75 overall yield inthree steps ie (1) Swern oxidation (2) acetonide hydro-lysis (4 N HClTHFrt) and (3) benzoylation (3 equiv ofPhCOClpyCH2Cl2rt) Silane reduction of 207 in an acidicmedium should preferentially yield the equatorially substi-tuted β-C-glycoside which was deblocked and converted tothe methyl- βminusC-disaccharide 209 Exact parallel experi-ments applied to the minor isomer gave the correspondingC-disaccharide 210 (Scheme 43) [47]
Armstrong has employed Wittig-osmylation protocol forthe preparation of a small library of α-C-(1rarr6)-disaccha-rides [48] Readily available allyl C-glycoside 211 washomologated to diene ester 212 and subjected to osmylation
Scheme (38)
O
CO2MeAcO
OAcAcHN
OAc
AcO
S(2-Py)
O
TESO
AcHNOMe
O
HO
O
CO2MeAcO
OAcAcHN
OAc
AcO
O NHAcOAc
OAc
OAc
O
CO2MeAcO
OAcAcHN
OAc
AcO
O NHAcOBn
OTES
OMe
OAc
AcO
O NHAcOBn
OTES
OMeOH
O
CO2 MeAcO
OAcAcHN
+
192 65
1 MeOHHCl2 H2 PdC EtOH3 Ac2O Pyr4 Ac2OAcOHH2SO4
193 59 overall yield
25 equiv SmI2 THF
1 11-thiocarbonyldiimidazole DMAP2 Ph3SnH cat AIBN
191 93
189
190
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1415
Scheme (39)
Scheme (40)
Scheme (41)
OBnO
OBn
OBn
OBnO
OBn
OBn
OBnO
OBn
OBn
OBnO
OBnCH3
BnO
OH
CH2
OBnO
OBn
CH3
OBn
H2 O
BF3 OEt2 MeCN
194
195 96
OOAc
OAc
AcO
R SiMe3
SnCl4
O
OAc
AcO
R
O
OAc
AcO
O
OAc
AcO
Me3Si
R
SiMe3
196
197
Me3 Si SiMe3
O
AcO
OAc
OAc
SiMe3
SiMe3
O
AcO
OAc
O
OAc
OAc
O
AcO
AcOO
OAc
OAc
SnCl4 CH2Cl2
SnCl4 CH2Cl2198
199
200
1416 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (42)
Scheme (43)
AcO
OAc
OAc
Me3 Si
BnO
OBn
BnO
OBn
AcO
OAc
BnO
OBn
BnO
OBn
+ I2 CH2Cl2
202 88
198 201
O
OBn
OBn
O
O
O
OBn
OBn
O
O
OBn
OBn O
OBn
OBn
O
OPBH2M
OH
OBnO
BnO
BnO
O
OBn
OBn
O
OHOPMB
OHO
HO
HO
O
OH
OHOH
OH
HOOMe
O
OBnOBn
O
Ph3P
O
O
OBn
OBn O
OBn
OBn
O
OPBM
OH
O O
CHO
OBn
BnO
OO
OBn
OBn
O
OHOPMB
BnO
BnO
BnO
OHO
HO
HO
O
OH
OHOH
OH
HOOMe
+ THF -78 oC
1 OsO4 pyr THF
2 NaH PMBBr
206a 206b 206a206b 61
1 Swern [O]2 4N HCl3 PhCOCl pyr
1 Swern [O]2 4N HCl3 PhCOCl pyr
1 PrSiH BF3 OEt2
2 H2 Pd(OH)2C
3 HCl MeOH 90 oC
1 PrSiH BF3 OEt2
2 H2 Pd(OH)2C
3 HCl MeOH 90 o C
203
204
205
207
209
208
210
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1417
followed by reduction to afford a 51 mixture (213214215216) of lactols that were readily separable by chromato-graphy Following a deprotection of an equimolar mixture of213 and 214 217 and the DL hybrid C-disaccharide of D-glucose-O-(1rarr6)-L-galactose 218 were obtained The DDand DL derivatives 219 and 220 of glucose-α-(1rarr6)-idosewere also obtained as a near equimolar mixture afterdeprotection of 215 and 216 (Scheme 44)
52 Anion Addition-Cyclization
Kishi developed an approach for the synthesis of theCndashtrehalo sugars which relied on nucleophilic addition ofone intact sugar fragment to a fundamental aldehyde ieKishi-Nozaki reaction [49] Coupling of monosaccharide221 and aldehyde 222 gave 223 The triple bond waspartially reduced and osmylation was followed by selectiveprotection to afford 224 The acetonide was converted toepoxide 225 by standard methods and removal of the PMBgroup Acid-catalyzed cyclization followed by aglyconichydrolysis and protection of hydroxyl group with (p-methoxyphenyl)diphenylmethyl chloride (MMTrCl) gave226 Inversion of the C-2 hydroxyl and removal of protectinggroups delivered α α-C-trehalose 227 (Scheme 44)
Kishi and co-workers also employed aldol reactions as anefficient access to the C-trisaccharide related to the type IIABO(H) blood group determinant [50] Aldol condensationof the enolate of methyl ketone 228 with aldehyde 229 gavea 41 mixture of hydroxy ketones 230 and 231 The majorketol was cyclized desulfurized and oxidized to afford thedisaccharide ketone 233 The ketone in THF was treatedwith LiHMDS (3 equiv) and TMEDA followed by theaddition of MgBr2 Addition of the aldehyde 234 led toalmost exclusive formation of the equatorial products 235and 236 in a 12 ratio Mesylation of 235 and 236 followedby treatment with liquid ammonia gave enones 237a and237b which were reduced to yield exclusively the C-2rsquo-equatorial ketone 238 Sodium borohydride reduction of theC-3rsquo carbonyl proceeded with the desired stereoselectivity toyield the protected C-trisaccharide 239 which wasdeblocked to provide the polyol 240 (Scheme 46)
Sutherlin and Amstrong cleverly applied a recursivestereochemical deconvolution (RSD) combinatorial approachfor the synthesis of a small library of C-trisaccharides aspotential inhibitors for the cell surface proteins of bacteriumHelicobactor pylori [51] The workers chose to carry outvariations in galactose ring of these trisaccharides An
Scheme (44)
OBnO
BnOOBn
OBn
P O
OEtOEtO
EtO
R H
OH
OH
OH
OH
O
R H
OH
OH
OH
OH
O
OHO
HOOH
OH
O
HO
OHOH
OH
OHO
HOOH
OH
O
HO
OH
OH
OHO
HOOH
OH
O
HO
OH
OHOH
R H
OH
OH
OH
OH
O
R
OBnO
BnOOBn
OBn
O
OHO
HOOH
OH
OO
HOHO
OH
R H
OH
OH
OH
OH
O
1 OsO4 NMO 50
2 DIBAL -32 oC 40
++ +
213 214 215 216
217 218 219 220
1 9-BBN H2O22 Swern [O]
3 t-BuOK
4 I2 C6H6212
211
1418 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
efficient Nozaki-Kishi coupling of vinyl bromide 241 withaldehyde 242 in a diasteromeric ratio of 12 followed byprotection with TBSOTf led to 243 and 244 Hydroborationfollowed by oxidation gave aldehydes 245 and 246respectively Addition of allylmagnesium bromide toaldehyde 245 followed by removal of the silyl groupafforded 247 to 246 giving 248 and 249 Epoxidation gave a11 mixture of the corresponding epoxides which werecyclized to give the C-trisaccharide 250-255 after removalof the benzyl groups (Scheme 47)
Schmidt reported a stereoselective 6-exo-trig selectiveelectrophilic cylization approach for de novo synthesis of amethylene-bridged Neu5Ac-α-(23)-Gal C-disaccharide theC-analog of an important motif in glycosphingolipids [52]The open chain precusors 259ab (a 32-mixture ofdiaseteromeric alcohols) were formed by the addition oflithiated iodide 256 to open chain aldehyde 258 Subsequent
C1 incorporation using Tebbe-reagent formation of a cycliccarbonate and deprotection of the two isopropylidene ketalsafforded tetrol 264 which upon treatment with phenylselenyltrifilate was steroselectively cyclized in a 6-exo-trigselective manner affording a diasteromeric mixture of 251and 252 in a ratio of 71 A seleno-Pummerer rearrangementto afford aldehyde 267 in 5 steps in 90 overall yieldOxidation of the aldehyde and subsequent steps led to thedesired C-disaccharide 268 (Scheme 48)
53 Esterification-Cyclization
Work from the Postema group has focused on a ringclosing metathesis (RCM) approach for the synthesis of C-saccharides [53a] The chemistry is versatile and has beenused for the synthesis of a small library of differentiallylinked β-C-disaccharides through a radical allylation-RCMstrategy [53b] The synthesis of the β-(1rarr4)-glucopyranosyl
Scheme (45)
O
OBn
BnO
BnO
BnO
I
CrCl2-NiCl2O
OBn
OH
BnO
BnO
BnO
O
O
O
O
O
H
OBn
O
O
OBnBnO
BnO
BnO
OOBn
OBn
OAc
PMBOHOO
OBn
BnO
BnO
BnO
O
OBn
OBn
OAc
O
OH
HO
HO
HO
OH
OH
OH
O
OH
O
OBn
BnO
BnO
BnO
OBn
OBn
OAc
O
MMTr
+
1 p-TsOH2 K2CO3 MeOH3 MMTrCl pyr
1 Swern [O]2 BH3 THF
3 AcOH-H2 O4 H2 Pd(OH)2
221
222
223
1 Pd-Pb CaCO3 H22 NaH BnBr3 OsO44 Bu2 SnO5 CsF PMB-Cl6 Ac2 O 4-DMAP
1 AcOH2 TsCl pyr
3 NaH-imid4 DDQ
224225
226 227
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1419
Scheme (46)
OBnO O
OBn
OMe
OBn
XY
SMe
OBnBnO
O
OBn
OBn
OBn
OBn
O
BnO
YX
OBn
TBSO
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnOOBn
H
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnO
OBn
OHC OBn
OBn
OTBS
OMe
BnOOBn
CHO
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnOOBn
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnO
OBn
YX
OBnO O
OBn
OMe
OBn
OBn
O
BnO
O
OBn
OBn
OBn
OBn
O 1 LiHMDS
2
228
1 TBAF THF
2 MeSH BF3 OEt2
230 X = OH Y = H231 X = H Y = OH
230231 41
1 Bu3SnH AIBN2 Swern [O]
1 LiHMDS THF-TMEDA2 MgBr23
1 MsCl
2 liquid NH3
235 X = OH Y = H236 X = H Y = OH Bu3 SnH AIBN
237a and 237b
NaBH4 MeOH
238
239 X = OBn
240 X = OHH2 Pd(OH)2
229
232233
234
1420 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (47)
OH C
O
O BnAcHN
OO
O
OBn OBnOBn
Br
O
OBn OBnOBn
O
OBnA cHN
OO
O TBSO
OBn O BnO Bn
O
OBnAcHN
OO
OTBS
S2
S1
S2
OTBSS1
O H
S2
OT BSS1
O H
MgBrMgBr
S2
O TBSS1
O H
S2
OHS1
OH
S2
OTBSS1
OH
O
OHHO
O H
O
HO
H OO
OBnA cH N
HO
H O
O
O HHO
OH
O
HOHO
O
OBnA cH N
HO
H O
O
OHH O
OH
O
H O
HOO
OBnAcHN
HO
HO
O
O HH O
OH
O
H O
H O O
OBnA cHN
HO
HO
O
O HH O
O H
O
HO
H O O
OBnAcHN
HO
HO
O
OHHO
OH
O
H O
O
OBnA cHN
HO
HOHO
+
241 242
1 CrCl2-NiCl2 T HF-DMF 722 TBSOTf 2 6-lutidine 91
243 244
1 9-BBN 602 Dess-Mart in period inane 97
1 9 -BBN 552 D ess-Martin periodinane 98
245 246
1
2 T BAF 74
1
2 TBAF 88
247 248 249
250
251
250 251 1 1 252 253 1 1 254 255 1 1
252
253
254
255
1 MCPBA2 CSA CH 2Cl2 61 fo r 2 steps3 H 2 Pd (O H)2C 95
1 MCPBA2 CSA CH 2Cl2 63 fo r 2 s teps3 H 2 Pd (OH)2C 87
1 MCPBA2 CSA CH2Cl2 80 for 2 steps3 H2 Pd(O H)2C 95
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1421
Scheme (48)
O
OO
Se Ph
R
O
HO OHOH
O
OB n O B n
OB n
O B nO O
O O
R O OR
X
O
OO
R
Se Ph
O
HOOH
OH
O
OB nOB n
O Bn
OB n
O O
O O
R O O R
O H
O
O B n OB n
O B n
OB n
O
C HO
O
O O
R O OR
OAc HN
OAc
C O2NH 4HOOH
OH
O
OH O H
OH OH
O
OB n O B n
OB n
OB nO O
O O
R O OR
X
O
O
OAcOAc
C HOA cOOAc
OAc
O
OB n O B n
OB n
OB n
O
O Bn OB n
OB n
OB n
X
OH
OO
HOOH
OH
O
O
OMeOB n
OB nOB n
R
t-B uL i256 R = Li
257 R = L i
258
(R = t-B uMe 2Si )
(R = t-B uMe 2Si )
259ab (32) 79 com bine d yi eld
De ss-Ma rtin pe riodinane
260 X = O R = t-B uMe 2Si ) 95
261 X = O R = t -B uMe2S i) 62
T e bbe re age nt
TB A F THF262 X = O R = H 94
diphosge ne
C H2C l 2Pyr
263 95
T HFH2O T FAr t
264 quant it a ti ve yie ld
PhSe C l AgOT f
EtC N -80 oC
265
266
Quant it at i ve yi l ed 25 26 7 1
+
R =
1 Ac 2OPyr
2 mC PB A3 Ac 2ONa OAc
4 NaO HT HFMe OH
5 Ac2O P yr
267 90 overa ll yi e ld
ste ps
268
1422 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
glucopyranoside 280 represents an example of thischemistry The known triacetyl glucopyranoside 269 wasconverted to iodide 270 in good yield Radical allylation of271 proceeded to afford a mixture of equatorial and axialallylation products in a 61 ratio Oxidative cleavage of thedouble bond gave the corresponding aldehydes 273a and273b which were separable Pinnick oxidation of the majoraldehyde 273a then gave the C-4 equatorial acid 274 DCC-mediated coupling of alcohol 275 and acid 274 proceeded toafford ester 276 in good yield Methylenation of 276 gave277 and exposure to catalysist 278 gave a 41 yield of theC-disaccharide glycal which was exposed to an excess ofBH3
THF to give 64 yield of the β-C-disaccharide 279Removal of the benzyl groups and global peracetylation gavethe peracetylated (1rarr4)-β-C-disaccharide 281 in good yield(Scheme 49)
54 Ring Expansion-Cyclization
Nelson developed a new strategy for asymmetric andstereoselective synthesis of C-linked disaccharide mimeticsthe C58-C71 fragment of palytoxin [54] The diol (RR)-282was converted into the di-dihydropyran (DHP) template 283284 and 285 The di-DHPs were functionized in a twodirectional sense using dihydroxylation reactions The two-directional approach was often very efficient indeed forexample in the synthesis of 286 six new stereogenic centerswere introduced with almost complete stereocontrol using areduction and a dihydroxylation reaction The approach isnot restricted to the synthesis of C2-symmetricaldisaccharide mimetics Using the unsymmetrical template285 which has both a pseudo-axial and a pseudo-equatorialhydroxyl groups the unsymmetrical mimetics 289 and 290were prepared (Scheme 50)
6 RADICAL APPROACHES
The radical approach for C-C bond formation is a popularmethod within organic chemistry The use of radicalchemistry in carbohydrate synthesis has certain advantagesFirstly the reaction conditions are very mild and tolerant ofa range of functional and protecting groups Secondanomeric radicals are stable with respect to elimination andepimeration Most significantly the chemistry required toincorporate an appropriate substitute at C-1 employed in theinitial hemolytic cleavage step is common within carbo-hydrate chemistry [55] The use of such radical techniquecan be subdivided into two classes intermolecular andintramolecular approaches
61 Intermolecular Radical Approaches
Giese was the first to employ an intermolecular radical-based approach for synthesis of C-disaccharides [56]Addition of an alkene to an anomeric radical underappropriate conditions allowed exclusive entry to the α-linked C-glycoside a result which was mirrored by the workof Baldwin [57] The high α-selectivity of the reaction wasin contrast with other reports Thus radicals generated at theC-2 C-3 and C-4 centers all preferred to occupy equatorialpositions [58] When the anomeric bromide 291 was treatedwith tin hydride and AIBN resulting anomeric radical andreacted with lactone 292 in a Michael addition it afforded293 In this reaction hydrogen abstraction at the resulting
radical center occurs from axial face to selectively generatethe equatorial C-2rsquo substituent Reduction and acetylation of293 furnished C-disaccharide 294 (Scheme 51) [59]
Witczak used the facial bias of levoglucosene tostereoselectively add a carbohydrate-based radical in thepreparation of the 3-deoxy-(1rarr4)-β-C-disaccharide 299[60] Addition of the radical derived from iodide 295 to 296gave adduct 297 in 26 yield Removal of the anomerichydroxyl of 297 was achieved by treatment with triethylsilane borontrifluoride ether complex followed bystereoselective reduction of the keto function at C-2rsquo withthe formation of 298 in 89 yield Debenzylation followedby acetolysis of 16-anhydro ring produced the peracetylatedtarget C-disaccharide 299 in 19 overall yield from 295(Scheme 52)
Vogel has developed general methods to transformenantiomerically pure 7-oxabicyclo[221]heptyl derivatives(ldquonaked sugarsrdquo) into C-disaccharides Because of thesechiral bicyclic skeletons they undergo highly stereoselectivereactions with predictable diasteroselectivities An arsenal ofmethods is available that allow to substitute these ldquonakedrdquocarbon centers with a variety of functional groups with allpossible relative configurations The methods allowpreparation of both enantiomers of a given target with thesame ease Predictably high stereoselectivity of the reactionsof the bicyclic chirons adds to the flexibility of approachwhich can lead to high molecular diversity [61]
α-C-(1rarr3)-mannopyranoside of N-acetyl-galactosaminepotent β-galactosidase inhibitors was synthesized by thisapproach [61] Enone 302 was readily prepared from 300The addition of the radical derived from bromide 303 toenone 302 afforded the αminusisomer 304 The ketone was thenreduced and the selenide eliminated via the intermediacy ofthe selenoxide to give 305 Acid-promoted (CF3SO3H) 7-oxa ring opening of 305 in MeCN produced the amino-conduritol derivative 306 resulting from the quenching of theallylic cation intermediate by the solvent (Ritter reaction)Ozonolysis of the chloroalkene 306 generated an acylchloride-aldehyde intermediate that reacted with MeOH toproduce a mixture of methyl uronates The major compound307 was silylated and reduced The crude polyol obtainedwas acetylated to produce 308 Desilylated and ammonolysisafforded a mixture of α-β-pyranoses 309 and correspondingα-β-furanoses (Scheme 53)
Similar chemistry was carried out to synthesize non-protected α-C(1rarr2)-L-fucopyranoside of D-galactopyrano-side corresponding to a blood group mimetic [62] Giesersquosradical fucosidation of racemic enone 310 with α-L-bromoacetofucose 311 provided the mixture of diastereo-meric α-C-fucoside 312a and 312b in reproducible yield of78 Reduction of the mixture gave a 11 mixture of endo-alcohols 313 and 314 which were isolated pure in 40 and355 yield respectively Oxidative elimination of thebenzeneselenyl group of 313 followed by acetylation gaveendo acetate 315 in 85 yield Acid-promoted ring openingof 315 and ozonolysis of the resulted chloroalkene gavemethyl uronic ester 316 in modest yield (10) Treatment of316 with Cl3CCN and NaH followed with BF3
OEt2
furnished the totally protected C-disaccharide 317 in 79
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1423
Scheme (49)
Bu3SnO
HOAcO
OMeOAc
OAc
O
AcO
OMeOAc
OAcI
AIBN
O
AcO
OMeOBn
OBn
HO2C O
AcO
OMeOR
ORY
X
OHBnO
BnO
OBn
OBnO
BnO
OBn
O
AcO
OMeOBn
OBnX
i-Pr i-Pr
N
Mo C(Me2 Ph)((CF3)2 MeCO)2
O
RO
OMeOR
O
RO
OR
OR
RO
OR
278
I2 Ph3P
imidazole
269 270 93
271a X = CH2CH=CH2 Y = H R = Ac 64271b Y = CH2CH=CH2 X = H R = Ac 11272a X = CH2CH=CH2 Y = H R = Bn 75272b Y = CH2CH=CH2 X = H R = Bn 75273a X = CH2CHO Y = H R = Bn 79273a Y = CH2CHO X = H R = Bn 79
1 NaOMe MeOH2 NaOH BnBr DMF
OsO4 NaIO4
NaClO2 NaH2PO4
274 96
275
DCC 4-DMAP
276 X = O 82
277 X = CH2 51
TiCl4 Zn dust TMEDA CH2Br2PbCl2 (Cat )
1
2 BH3 THF H2O2 NaOH
H2 PdC EtOH
Ac2 O Pyr 4-DMAP
279 R = Bn R = H 64
280 R = R = H 99
281 R = R =Ac 97
1424 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (50)
Scheme (51)
O OOH
OH
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
286
1 VO(acac)2 t-BuOH 95
2 (MeO)3CH BF3 90
1 P-O2NC6H4 CO2H Ph3P DIAD2 K2CO3 MeOH 82 over 2 steps
1 PhCOCl Et3N DMAP 402 P-O2NC6H4 CO2H Ph3P DIAD3 KOH THF-H2O 75 over 2 steps
TMEDA OsO4
Cat OsO4 NMO 287
Cat OsO4 NMO288
TMEDA OsO4
Cat OsO4 NMO
290
289
(RR)-282283
284
285
OHO
AcO
BrOAc
OAc
BnO
O
OBn
OBnO
OHO
AcOOAc
OAc
BnO
OOBn
OBnAcO
OHO
AcOOAc
OAc
BnO
O
OBn
OBnO
+
Bu3SnH AIBN291
292
293 81
1 Na[Al(OC2H4OMe)2(OEt)H]2 Ac2O pyr
294 56 over 2 steps
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1425
Scheme (52)
Scheme (53)
OBnO
BnOOBn
OBn O
OH
O
OBnO
BnO
OHOBn
OBn O
O
O
O
O
O
OBnO
BnOOBn
OBnO
OAcOAc
OAc
OBnO
BnO
OHOBn
OBn
IBu3SnH AIBN
295 297 26
1 BF3 OEt2 Et3SiH
2 L-Selectride THF
1 Pd(OH)2C C6H10 EtOH
2 EtSiOSO2CF3 Ac2O
298 89 over 2 steps299
296
O
O
PhSeClO
O
PhSeCl
Bu3 SnH
O
O
PhSeCl
R
H
O
OAc
R
Cl
O
AcO
OAc
OAc
OAcOH
Cl
NHAc
R
OAc
AcHN
OH
O
OH OAc
OH
OHO
HO
OH
O
AcO
OAc
OAc
OAcBr
O
O
PhSeCl
O
O
PhSeCl
R
O
OTIPSAcHNR
OAc OAc
O
OHAcHN
COOMe
R
OAc
1 Bu4NF
2 NH3MeOH
1 (Me3Si)2NLi THF2 Me2N=CHI
1 Bu3 SnH AIBN2
1 NaBH42 mCPBA3 Ac2O pyr
1 H+ MeCN
2 H2 O NaHCO3
R =
1 O3MeOH
2 Me2S NaHCO3
1 TIPSOTf 26-lut idine2 LiBH43 Ac2 O pyr DMAP
furanoses +
304 56
305 68 306 84307 50
308 46
300 301 302
303
309
1426 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
The reduction of 317 and treatment with DOWEX-H+ resinprovided the desired C-fucoside 318 in 70 (Scheme 54)
62 Intramolecular Radical Approaches
One disadvantage with the intermolecular approaches isthat during such radical mediated reactions electrondeficient alkenes are required to facilitate C-C bondformation The intramolecular approach of Sinayuml overcomes
this drawback by bring two substrates together via atemporary covalent silaketal connector This enables the useof a wider range of alkenes which can include alkene-functionalized sugars thus leading to the generation of C-disaccharides [63] Based on the early work of Stork Sinayumlemployed the tether reaction in the synthesis of both α- andβ-C-disaccharides with this work subsequently beingemployed in the synthesis of biologically significant natural
Scheme (54)
O
OH
Fuc
Cl
O
O
ClPhSe
OOAc
NHAcOHFuc
O
AcOOAc
AcO
Br
O
O
PhSeCl
O
AcOOAc
AcO
O
OH
PhSe Cl
Fuc
OOAc
NHAc
OMe
Fuc
O
AcHN
OH OAc
OH
O
OH
Me
OH
O
O
Fuc
ClSePh
O
HO
Fuc
ClSePh
+
Ph3SnHAIBN
78 combined yield
Fuc
310
+
1 NaBH4 MeOHTHF2 Chromatography
313 40 314 355
1 mCPBA
2 Ac2O pyr DMAP
+
315 75
1 TfOH MeCN
2 NaHCO3 O3 -78 oC
316 10 over 2 steps
1 Cl3 CCN NaH
2 MeOH BF3 OEt2
317 79
1 LiBH4 THF
2 Dowex-H+
311
312a312b
318 70 for 2 steps
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1427
products [64] The availability of different hydroxyl groupson each monosaccharide unit allowed the fine-tuning ofstereochemical outcome by selective positioning of the silyltether [65] Development of this early stereochemical controlled to the tethering of the donor 320 with alcohol 319through a di-isopropyl silicon tether 321 Subsequent treat-ment with Bu3SnH and AIBN led to a 9-endo-trigcyclization to form the C-disaccharide 322 in an 80 yieldwith exclusive formation of the α-product The silyl tetherwas removed with Bu4NF and deprotection under standardconditions afforded the desired disaccharide 323 in excellentyield (Scheme 55)
In parallel the development of a 32rsquo silyl tether allowedaccess to the β-linked product as demonstrated in Sinayumlrsquossynthesis of methyl β-C-lactoside 328 [66] Alcohol 324 and320 were connected via the dimethylsilyl tether an 8-endo-trig cyclization followed to exclusively afford the β-
disaccharide 326 in 45 yield Removal of the tether anddeprotection of benzyl ether gave β-C-disaccharide 328(Scheme 56)
This group also selected iodosugars bearing a freehydroxyl group as progenitors of the radical donors [67] In atypical experiment the radical donor 329 was connected tothe radical acceptor 330 through a silaketal tether followingtheir procedure Tributyltinhydride mediated 8-endo-trigradical cyclization of compound 331 gave after detetheringof the non isolated intermediate 332 the protected β-C-disaccharide 333 in 37 overall yield (from startingmaterials 330 and 329) Peracetate 335 was achieved afterhydrogenolysis The C-laminaribioside 334 is of potentialbiological interest as it mimics the repeating disaccharideunit of fungal β-(1rarr3)-glucans which have antitumor andimmunomodulating properties (Scheme 57)
Scheme (55)
Scheme (56)
OO
OHSePh
OTBDPSO O
OO
SePh
OTBDPSO
OO
OBnOMe
OBn
Si
O
HOOBn
OMe
OBn
O
HOOH
OHHO
O
HOOH
OMe
OH
OTBDPSO
O
HOOBn
OMe
OBnO
OOH
1 n-BuLi THF
2 iPr2SiCl2 -78 oC
3 DMAP THF rt
1 Bu4NF THF
2 Dowex-H+
3 H2 PdC
Bu3SnH AIBN toluene
319
320
321
322323
OBnO
OHSePh
OBnBnO
OHO
OBnOMe
OBn
ROO
ROOH
OR
OHO
OROMe
OR
OBnO
O
OBnBnO
OO
OBnOMe
OBn
Si
SePh
OBnO
O
OBnBnOO
OOBn
OMe
OBn
Si
1 PhSeH Me2SiCl2
BuLi -78 oC
2 imidazole rt
Bu3SnH AIBN toluene
H2 PdC327 R = Bn
328 R = H
Bu4NF THF
324
320
325
326 45
1428 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
CONCLUSIONS
In this paper the biological importance of C-oligo-saccharides as subunits of natural products and as a newgeneration of carbohydrate based on therapeutics has beenillustrated Different methods are available for the synthesisof C-oligosaccharides As with traditional saccharidesynthesis it has been necessary to develop a number ofspecific approaches to facilitate the regioselective andstereoselective preparation of the desired targets Work inthis area continues and it is expected that many interestingnew C-oligosaccharides will be prepared using the chemistrydescribed in this review It is also likely that new chemistrywill be developed in the future for the preparation of thesebiologically important targets
ACKNOWLEDGEMENTS
The authors thank Dr Sultan Baytas for her criticalreading of this manuscript
REFERENCES
[1] Kennedy J F White C A Bioactive Carbohydrates InChemistry Biochemistry and Biology Ellis Horwood LtdChichesterUK 1983
[2] Wassarman PW Mammalian Fertilization Molecular Aspects ofGamete Adhesion xocytosion Exocytosis and Fusion Cell 199996 175-183
[3] Carbohydrate-based Drug Discovery Wong C-H EdWeinheim Cambridge Wiley-VCH 2003
[4] (a) Sharon N Lis H Lectins as Cell Recognition MoleculesScience 1987 246 227-234 (b) Dwek RA Chem Rev 1996 96683-720
[5] Postema M C-Glycoside synthesis CRC Boc Ratom 1995[6] (a) Weatherman R V Mortell K H Cheruenak MKiessling
L L Toone E J Specificity of C-Glycoside Complexation byMannoseGlucose Specific Lectins Biochem 1996 35 3619-3624(b) Ravishankar R Surolia A Vijayan M Lim S Kishi YPreferred Conformation of C-Lactose at the Free and Peanut LectinBound States J Am Chem Soc1998 120 11297-11303
[7] (a)Wong C-H Halcomb R L Ichikawa Y and Kajimoto TEnzymes in organic synthesis Application to the problems ofcarbohydrate recognition part2 Angew Chem Int Ed Engl 199534 521-546 (b)Howard S Withers SG Bromoketone C-Glycosides a New Class of βminusGlucanase Inactivators J AmChem Soc 1998 120 10326-10331(c) Wang Q Wolff MPolat T Du Y Linhardt R J C-glycoside of Neuraminic Acidsas Neura-minidase Inhibitors Bioorg Med Lett 2000 10 941-944 (d) Phili R Chang J Partis R A Mueller R A ChrestF J Passaniti A The Alpha-glucosidase I InhibitorCastanospermine Alters Endothelial cell Glycosylation PreventsAngiogenesis and Inhibits Tumor Growth Cancer Res 1995 552927-2935
[8] Ossor A Elbein A D In Carbohydrates in Chemistry andBiology Vol 3(II) WileyVCH 2000 pp 513-539
[9] (a) Sinayuml P Synthesis of oligosaccharide Mimetics Pure ApplChem 1997 69 459-463 (b) Beau J-M Gallagher TNucleophilic C-glycosyl Donors for C-glycoside Synthesis Top inCurr Chem 1997 187 1-54 (c) Nicotra F Synthesis of C-glycosides of Biological Interest Top in Curr Chem 1997 187
Scheme (57)
O
O
O
Ph
I
OMe
OHO
BnO
OH
OH
BnOOH
O
BnO
Si
O
O O
Ph
I
OMe
O
O
BnO
OR4O
R5O
OMe
OR2
OR3O
R3O
OR1
R3O
Bu3 SnH AIBN
332 R1 R2 = SiMe2 R3 = Bn R4 R5 = CHPhTBAF THF
333 R1 = R2 = H R3 = Bn R4 = R5 = CHPh 37 from 11
334 R1 = R2 = R3 = R4 = R5 = H
335 R1 = R2 = R3 = R4 = R5 = Ac
329
H2 PdC MeOH
Ac2 O pyr
1 BuLi THF -78 oC
2 Me2SiCl2
3 DMAP
330
331
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1429
55-83 (d) Du Y Linhardt R Y Recent Adv in Stereo-SelectiveC-Glycoside Synthesis Tetrahedron Lett 1998 54 9913-9959 (e)Liu L Mckee M and Postema M H D Synthesis of C-saccharides and Higher Congeners Current Org Chem 2001 51133-1167
[10] Jarosz S Fraser-Reid B Synthesis of A Higher Carbon Sugar ViaDirected Aldol Condensation Tetrahedron Lett 1989 30 2359-2362
[11] Lichtenthaler F W Lergenmiiller M Schwidetzky S C-Glycosidations of 2-Ketohexosyl With Electrophilic Radical andNudeophilic Anomeric Carbons Eur J Org Chem 2003 3094-3103
[12] Baudat A Vogel P Aza-C-disaccharides Synthesis of 6-Deoxygalactonojirimycin-β-C(1rarr3) Linked with D-Altrofuranosides and D-Galactose J Org Chem 1997 62 6252-6260
[13] Turner D Vogel P Synthesis of 4-Hydroxy-26-Bis(hydroxymethyl) tetrahydropyran-2-Carbaldehyde DerivativesSynlett 1998 304-306
[14] Zhu Y-H Vogel P Short Stereoselective Synthesis of C-(1rarr3)-Linked Disaccharides Tetrahedron Lett 1998 39 31-34
[15] Zhu Y-H Vogel P Synthesis of a (2R 6R)-2-(Hydroxymethyl)-6-Propa-1 2-Dienyl-2H-Pyran-3(6H)-One Derivative A NewEnone for The Convergent Construction of C-Glycosides of C-Disaccharides Synlett 2001 82-86
[16] Baumberger F Vasella A Deoxynitrosugars The 6th
Communication Stereolectronic Control in the reductivedenitration of tertiary nitro ethers A Synthesis of ldquoC-glycosidesrdquoHelv Chim Acta 1983 66 2210-2221
[17] Martin O R Lai W Synthesis and Conformational Studies of β-(1rarr6)- and ββ-(1rarr1)-Linked C-disaccharides J Org Chem1993 58 176-185
[18] Spak S J Martin R The synthesis of an analogue of Methyl OC-Analogue of Methyl 4rsquo-O-β-D-GlucopyranosylgentiobiosideTetrahedron 2000 56 217-224
[19] Kobertz W R Bertozzi C R Bednarski M D C-GlycosylAldehyde Synthons for C-Linked Disaccharides J Org Chem1996 61 1894-1897
[20] Gurjar M K Nagaprasad R and Ramana CV First Synthesis ofMethyl α-C-D-Arabino-furanosyl-(1rarr5)-αminusD-Arabinofuranosidethe C-Disaccharide Segment of Motif C of MycobateriumTuberculosis Tetrahedron Lett 2000 43 7577-7579
[21] Witczak Z J Synthesis of C-Glycosyl Compounds and OtherNatural Products from Levoglucosenone Pure Appl Chem 199466 2189-2192
[22] Griffin F K Paterson D Taylor R J K Ramberg-BacklundApproaches to the Synthesis of C-Linked Disaccharides AngewChem Int Engl 1999 38 2939-2942
[23] Paterson B E Griffin F K Alcaraz M-L and Taylor R J KA Ramberg-Baumlcklund Approach to the Synthesis of C-GlycosidesC-Linked Disaccharides and C-Glycosyl Amino Acids Eur JOrg Chem 2002 1323-1336
[24] McAllister G D Paterson D E Taylor R J K A SimplifiedRamberg-Bachlund Approach to Novel C-Glycosides and C-Linked Disaccharides Angew Chem Int Ed Engl 2003 42 1387-1391
[25] McCartney J L Christopher T M Cicchillo R M BernardinaM D Wagner T R and Norris P J Org Chem 2003 6810152-10155
[26] Dondoni A Zuurmond H M Bascarate A Synthesis of α-andβ-D-(1rarr6)-C-Disaccharides by Witting Olefination of Formyl C-Glycosides with Glycopyranose 6-phosphoranes J Org Chem1997 62 8114-8124
[27] Dondoni A Kleban M Zuurmond H Marra A Synthesis of(1rarr6)-C-Oligogalactosides by Interative Wittig OlefinationTetrahedron Lett 1998 39 7991-7994
[28] Dondoni A Marra A A New Synthetic Approach toMycobacterial Cell Wall α-(1rarr5)-D-Arabinofuranosyl C-Oligosaccharides Teterahedron Lett 2003 44 4067-4071
[29] Colinas P A Ponzinibbio A Lieberknecht A and Bravo R OWittig Reaction of Glycosyl Phosphonium Salts A StereoselectiveRoute to C-Disaccharides and C O-Trisaccharides TetrahedronLett 2003 44 7985-7988
[30] Schmidt R R Preuss R Synthesis of Carbon Tetrahedron Lett1989 30 3409-3412
[31] Dietrich H Schmidt R R Synthesis of Carbon-Bridged C-Lactose and Derivatives Liebigs Ann Chem 1994 975-981
[32] Rouzaud D Sinayuml P The First Synthesis of a ldquoC-DisacchariderdquoJ Chem Soc Chem Commun 1983 1353-1354
[33] Xin Y-C Zhang Y-M Mallet J-M Glaudemans C P JSinayuml P Synthesis of C-Oligosaccharides That Mimie TheirNatural O-Analogues Immunodeterminants in Binding toMonoclonal Immunoglobulins Eur J Org Chem 1999 471-476
[34] Streicher H Geyer A Schmidt R R C-Disaccharides ofKetoses Chem Eur J 1996 2 502-510
[35] Leeuwenburgh M A Timmers C M Vander Marel G A VanBoom J H Mallet J-M Sinayuml P G Stereoselective Synthesisof α-C-(Alkynyl)-Glycosides Via Ring-Opening of α-12-Anhydrous Tetrahedron Lett 1997 38 6251-6254
[36] Aslam T Fuchs M G G Le Formal A Wightman R HSynthesis of C-Disaccharide Analogue of the α-D-Arabinofuranosyl-(1rarr5)-α-Arabinofuranosyl Motif ofMycobacterial Cells Walls via Alkynyl Intermediates TetrahedronLett 2005 46 3249-3252
[37] (a) Girad P Namy J L Kagan H B Divalent LanthanideDerivative in Organic Synthesis 1 Mild Preparation of SamariumIodide and Ytterbium Iodide and Their Use as Reducing orCoupling Agents J Am Chem Soc 1980 102 2693-2698 (b)Molander G A Harris C R Sequencing Reactions withSamarium(II) Iodide Chem Rev 1996 96 307-338
[38] (a) Mazeacuteas D Skrydstrup T Doumeix O Beau J-MSamarium Iodide-Induced Intramolecular C-Glycoside FormationEfficient Radical Formation in the Absence of an Additive AngewChem Int Ed Engl 1994 33 1383-1386 (b) Mazeacuteas DSkrydstrup T Beau J-M A Highly Stereoselective Synthesis of1 2-trans-C-Glycosides Via Glycosyl Samarium(III) CompoundsAngew Chem Int Ed Engl 1995 34 909-912 (c) Jarreton OSkrydstrup T Beau J-M The Stereospecific Synthesis of Methylα-C-Mannobioside A Potential Inhibitor of M TuberculosisBinding to Human Macrophages J Chem Soc Chem Commun1996 1661-1662 (d) Jarreton O Skrydstrup T Espionosa J-FJimeacutenez-Barbero J Beau J-M Samarium Diiode Prompted C-Glycosylation An Application to The Stereospecific Synthesis ofα-(1rarr2)-C-Mannobioside and Its Derivatives Chem Eur J 19995 430-441 (e) Mipuel N Doisneau G Beau J-M ReductiveSamariation of Anomeric 2-Pyridyl Sulfones with Catalytic AnUnexpected Improvement in The Synthesis of 12-Trans-Diequatorial C-Glycosyl Compounds Angew Chem Int Ed Engl 2000 39 4111-4114
[39] Vlahov I R Vlahova P I Linhardt R J DiastereocontrolledSynthesis of Carbon Glycosides of N-Acetylneuraminic Acid ViaGlycosyl Samarium(III) Intermediates JAmChem Soc 1997 1191480-1481
[40] Kuberan B Sikkander S ATomiyama H Linhardt R JSynthesis of a C-Glycoside Analogue of sTn An HIV-and Tumor-Associated Antigen Angew Chem Int Ed Engl 2003 42 2073-2075
[41] Bazin H G Du Y Polat T Linhardt R J Synthesis of aVersatile Neuraminic Acid ldquoCrdquo-Disaccharide Precursor for theSynthesis of C-Glycoside Analogues of Gangliosides J OrgChem 1999 64 7254-7259
[42] Chen C-C Ress D K Linhardt RJ Samarium Iodide-Mediated Synthesis of Neuraminic Acid C-Glycosides InSynthesis of Glycommetics Roy R Ed ACS Syposium Series2004 896 53-80
[43] Abdallah Z Doisneau G Beau J-M Synthesis of a Carbon-Linked Mimic of The Disaccharide Component of The Tumor-Relate SialyTn Antigen Angew Chem Int Ed Engl 2003 425209-5212
[44] Lay L Nicotra F Panza L Russo G Caneva E Synthesis ofC-disaccharides through dimerization of exo-glycals J Org Chem1992 57 1304-1306
[45] Isobe M Nishizawa R Hosokawa S Nishikawa TStereocontrolled Synthesis and Reactivity of Sugar Acetylenes JChem Soc Chem Commun 1998 2665-2676
[46] Saeeng R Sirion U Sahakitpichan P Isobe M IodineCatalyzes C-Glycosidation of D-Glucal with SilylacetykeneTetrahedron Lett 2003 44 6211-6215
[47] (a) Babirad S A Wang Y Kishi Y Synthesis of C-Disaccharides J Org Chem 1987 52 1370-1372 (b) Wang YBabirad S A Kishi Y Preferred Conformation of C-Glycosides
1430 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
8 Synthesis of 14-Linked Carbon Disaccharides J Org Chem1992 57 468-481
[48] Armstrong R W Sutherlin D P Strategies for the Synthesis ofC-Disaccharides Containing D and L Sugars Tetrahedron Lett1994 35 7743-7746
[49] Wei A Kishi Y Preferred Conformation of C-Glycosides 12Synthesis and Conformational Analysis of αα- α β- and β β-Trehaloses J Org Chem 1994 59 88-96
[50] Haneda T Goekjian P G Kim S H Kishi Y PreferredConformation of C-Glycosides 10 Synthesis and ConformationAnalysis of Carbon Trisaccharides J Org Chem 1992 57 490-498
[51] Sutherlin D P Armstrong R W Synthesis of 12 Stereochemistryand Structurally Diverse C-Trisaccharides J Org Chem 1997 625267-5283
[52] Notz W Hartel C Waldscheck B Schmidt R R De NovoSynthesis of a Methylene-Bridged Neu5Ac-α-(23)-Gal C-Disaccharide J Org Chem 2001 66 4250-4260
[53] (a) Postema M H D Calimente D Liu L Behrmanm T L AnOlefin Metathesis Route for the Preparation of (1rarr6)-Linked-C-Disaccharide Glycals A Convergent and Flexible Approach to C-Saccharide Synthesis J Org Chem 2000 65 6061-6068(b) Postema M H Piper J L Liu L Faust M Andreana PSynthesis and Partial Biological Evaluation of a Small Library ofDifferentially Linked β-C-Disaccharide J Org Chem 2003 684748-4754
[54] Nelson A The Development of Strategies and Methods for TheSynthesis of Biologically Active Compounds New J Chem 200428 771-776
[55] Togo H He W Waki Y Yokoyama M C-GlycosylationTechnology With Free Radiant Reactions Synlett 1998 700-717
[56] Giese B Dupuis J Diastereoselective Synthesis of C-Glycopyranosides Angew Chem Int Ed Engl 1983 22 622-623
[57] Adlington R M Baldwin J E Basak A Kozyrod RPApplication of Radical Addition Reactions to tho Synthesis of a C-Glucoside and A Functionalized Amino Acid J Chem SocChem Commun 1983 144-145
[58] Giese B Gonzaacutelez-Goacutemez J A Witzel T The Scope of RadicalCC-Coupling by The ldquoTin Methodrdquo Angew Chem Int Ed Engl1984 23 69-70
[59] Giese B Witzel T Synthesis of ldquoC-Disaccharidesrdquo by RadicalC-C Bond Formation Angew Chem Int Ed Engl 1986 25 450-451
[60] Witczak Z J Chhabra R Chojnacki J C-Disaccharides IStereoselective Approach to β-(1rarr4)-3-Deoxy-C-Disaccharidesfrom Levoglucosenone Carb Res 1997 301 167-175
[61] Vogel P Synthesis of Rare Carbohydrates and Analogues Startingfrom Enantiomerically Pure 7-Oxabicyclo[221]heptyl Derivatives(ldquoNaked Sugarsrdquo) Current Org Chem 2000 4 455-480
[62] Viodeacute C Vogel P Synthesis of The C-Disaccharide α-C(1rarr3)-L-Fucopyranoside of N-Acetylgalactosamine J Carb Chem2001 20 733-746
[63] Xin Y C Mallet J M Sinayuml P An Expeditious Synthesis of AC-Disaccharide Using A Temporary Silaketal Connection J ChemSoc Chem Commun 1993 864-865
[64] (a) Petitou M Herault P Lormeau J-C Helmboldt A MalletJ-M Sinayuml P Herbert J-M Introducing A C-InterglycosidicBond in A Biologically Active Pentasaccharide Hardly Affects ItsBiological Properties Bioorg Med Chem 1998 6 1509-1516 (b)Sinayuml P Advances in The Synthesis of the Carbohydrate MimicsPure Appl Chem 1998 70 1495-1499
[65] Sinayuml P Chemical Synthesis of Oligosaccharide Mimetics PureAppl Chem 1998 70 407-410
[66] Sinayuml P Chemical Synthesis of Oligosaccharide Mimetics PureAppl Chem 1998 69 459-463
[67] Vauzeilles B Sinayuml P Selective Radical Synthesis of β-C-Disaccharides Tetrahedron Lett 2001 42 7269-7272
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1403
24 Phosphorous Stabilized Anions
The most common type of reaction discussed in thissection is Wittig approach to C-oligosaccharide synthesisThis methodology is particularly suited for synthesis of(1rarr6)-C-saccharides since one sugar can hold the aldehydewhile the other the ylid or phosphonate anion
Dondoni has utilized this approach to prepare a variety ofβ-D-(1rarr6)-C- disaccharides The general approach is shownin Scheme 20 Coupling of β-linked galactopyranosyl ormannofuranosyl derivative (93 94 95 or 96) with ylidefrom phosphonium iodide 97 or 98 gave alkene 99 Alkenewas reduced and removal of deprotecting groups gave thecorresponding β-D-(1rarr6)-C- disaccharide 100 [26]
α-D-(1rarr6)-C-disaccharide 103 was also synthesizedusing the approach (Scheme 21)
Dondoni applied this methodology in an iterative fashionto prepare the corresponding β-(1rarr6)-C-trigalactosides andβ-(1rarr6)-C-tetragalactosides [27] Starting with coupling ofylide 104 generated in situ with aldehyde 33 gave adduct105 (EZ 19) Removal of silyl protecting group followed byoxidation led to aldehyde 106 which was coupled with theylide from 104 to give C-trisaccharide 107 in 36 yield Thesame sequence was repeated with 107 afforded the protectedC-tetrasaccharide alkene 108 Compounds 108 wasdesilylated and exposed to hydrogen over Pd(OH)2 oncarbon followed to peracetylation gave protected C-tetrasaccharide 109 (Scheme 22)
Taking advantage of their experience on the stereo-selective synthesis of C-oligosaccharides by iterative Wittigolefination this group developed new building blocks and amodified protocol for the straightforward assembly of C-α-(1rarr5)-D-oligoarabinofuranosides [28] While the twomonofunctionalized sugar moieties 110 and 111 weresuitable precursors to the head and tail of the oligo-saccharidic chain the difunctionalized compound 114 was arepeating unit (Scheme 23) Building block 114 wasdesigned to allow after the Wittig coupling for regenerationof the formyl group in a single step under conditions that donot affect the chemical and stereochemical integrity of thegrowing saccharidic chain (Scheme 24)
Colinas et al reported a method for the synthesis of C-disaccharides by a sequence involving the Wittig reaction askey step and further glycosydation of these compounds toafford new C O-trisaccharides [29] The enol ether 122a-bwere prepared by the Wittig reaction of the α β mixture of2-deoxiglycosyl phosphonium salts 120a-b with aldehyde121 Hydrogenation of the exo-glycals afforded the β-C-disaccharides with good yields The O-glycosidationemploying the exo-glycals and the glycosyl acceptor 124 isillustrated in Scheme 25
25 C-1 Vinyl Anions
Schmidt was the first to explore the addition of sulfoxide-stabilized vinyl C-1-organolithiums to carbohydrate-basedcarbonyl compounds [30] The vinyl sulfoxide 126 was
Scheme (19)
OCH3
O O
OPhS
PhS
O O
OO
OCH3
O O
OO O
O H
OCH3
O O
OPhSPhS
O O
O OH
OCH3
O O
OO O
O OH
+
n-BuLi THF -78 oC
Raney Ni EtOH H2O rt
Et3SiH BF3 OEt2
90 77
92 51 over 2 steps 91 is omers rati o βα = 41
-78 oC
88
89
1404 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
deprotonated with LDA to give 127 Addition of 127 toaldehyde 128 gave a mixture of diastereoisomers of whichthe major 129 was formed in a 101 ratio Desulfurizationhydroboration and removal of benzyl groups gave the(1rarr5)- βminusC-disaccharide 130 (Scheme 26)
Schmidt and coworkers used this methodology for ahighly efficient synthesis of an analog of C-trehalose 134Scheme 27 [31] Anion 131 was converted to aldehyde 132
and condensation of this aldehyde with the same anion gaveadduct 133 which was then converted to the target C-disaccharide 134
26 Acetylide-Based Anions
Sinayuml was the first to prepare a C-disaccharide Hisapproach involved the coupling of a C-6 alkyne with ananomeric lactone followed by reduction of the formedhemiacetal [32] Aldehyde 135 was converted to the
Scheme (20)
Scheme (21)
OO O
O
O CHO
O
BnOOBn
BnO
OBn
CHO
OBn
CHO
BnO
O
BnOBnO
O
BnOOBn
BnO OBn
CHO
PPh3I-
OO
O
OO
O
OMeOBn
OBn
OBn
PPh3I-
OCHO
O
PPh3I-
ORRO
RO
OO
ORRHO
OO
OR
+ +
+
( 93 - 96 )
( 97 - 98 )
BuLi THF-HMPA
-30 iexclaelig
99
Reduction
100
+
93 9495
96 97 98
O
OBnBnO
BnO
OO
O
OO
HO
O
O
OO
PPh3I-
O
OHHO
HO
O
HOOH OH
HO
OBnBnO
CHO
BnO
O
+
BuLi THF-HMPA
-30 oC
1 p-MeC 6H4SO2-
NH2NH2 AcONa
2 H2 Pd(OH)2 3 bar
3 Amberli te H+
+
10197
102
103
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1405
dibromoalkene 136 which was treated with n-butyllithium togive an intermediate acetylide 137 The latter uponnucleophilic addition to lactone 138 gave a mixture of lactol139 in high yield Stereoselective reduction of lactol 139 wasfollowed by hydrogenation of benzyl groups and the triplebond affording the (1rarr6)-β-C-disaccharide 140 (Scheme28)
The lactone-addition methodology was later applied bySinayuml and co-workers in an iterative fashion for the
preparation of higher homologues [33] Hydroxylmethylenein compound 141 was converted to acetylide lithium incompound 142 by a sequence of reactions Condensation ofcompound 142 with the galacto lactone 143 gave 144 asmixture of anomers The lactol were stereoselectivelyreduced to and triple bond was hydrogenated to give 145Methyl glycoside 145 was hydrolyzed to the correspondinglactols which were oxidized to lactone 146 The samesequence was then repeated twice to give C-trisaccharide147 and C-tetrasaccharide 148 (Scheme 29)
Scheme (22)
O
BnOOBn
BnO OTBDPS
PPh3I-
BnO
H
O
BnOOBn
OTBDPS
OO
O
OO
O
CHOO
O
OO
O
BnO
O
BnOOBn
BnO
OO
O
OO
H
HOBn
BnO OTBDPS
O
BnOOBn
BnO O
OO
O
OO
H
OBn
BnO OTBDPS
PPh3I-
O
BnO
O
BnOOBn
BnO OTBDPS
PPh3I-
O
AcOOAc
AcO
O
AcOOAc
AcO
OO
O
OO
O
AcOOAc
AcO OAc
O
BnOOBn
BnO
O
BnOOBn
BnO
OO
O
OO
H
H
O
BnOOBn
BnO OTBDPS
H
1 TBAF2 PCC
+107 36
+
1 TBAF2 PCC3
+
1 TBAF2 H2 Pd(OH)2 C3 Ac2 O Pyr
104
33
105
106104
104
108109
BuLi THF-HMPA
-50 o C
70EZ 19
BuLi THF-HMPA
-50 o C
1406 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
The di- tri- and tetrasaccharide derivatives (145 147 and148) were all debenzylated and tested for their bindingaffinity to three different monoclonal immunoglobulins withspecificity for different O-β-(1rarr6)-D-galactopyranosyl deter-minants These C-saccharide analogs had similar bindingproperties to the corresponding O-saccharides
Schmidt has also used acetylide-lactone condensation toassemble C-disaccharides of ketoses [34] Lithium acetylide149 was condensed with ketone 150 to give a mixture ofalcohol 151 after removal of the pivoloyl group Attemptedcyclization under Lewis acid catalysis resulted only in theremoval of the acetonide Accordingly the diol was tiedback as the carbonate and the acetylene complex as thedicobalt species 152 The isomers were then separately
cyclized to give a 11 mixture of C-disaccharide 153 Thecobalt complex on α-C-disaccharide was removed understandard conditions to give 154 and deprotection of thecarbonate was followed by hydrogenation and peracetylationto give 155 (Scheme 30) Similar chemistry was also carriedout with the corresponding β-isomer
Van Boom and co-workers used lithiated alkynylderivative 156 in presence of ZnCl2 to selectively open ringof the 12-anhydrosugar 157 affording the α-C-(alkynyl)-glycoside 158 Hydrogenolysis of the benzyl groups wasfollowed by peracetylation to give the (1rarr6)-α-C-disaccharide 159 (Scheme 31) [35]
Normally attack of the nucleophile proceeds from anequatorial direction to give the β-isomer The unexpected
Scheme (23)
Scheme (24)
BnOO
OBnCHO
OBn
O
OBn
PPh3I-
OBn
OBn
O
OBn
BnOBnO
O
OBnOBn
OBnH
O
OH
HOHO
O
OHOH
OH+
BuLi
THF-HMPA
-20 oC+
1 TBAF2 H2 Pd(OH)2C
112 65 113 100
110
111
O
OBnCHO
OBnBnO
O
OBn
BnOBnO
O
OBnCH(OiPr)2
OBnH
O
OBnCH(OiPr)2
PPh3I-
OBn
O
OBn
BnOBnO
O
OBn
OBnH
O
OBnOBn
BnOH
O
OH
HOHO
O
OH
OH
O
OHOH
HO
++
BuLi
THF-HMPA
-20 oC
BuLi
THF-HMPA
-20 oC
TFA H2 O THF rt
115 49
116 R = CH(OiPr)2
117 R = CHO
118 45
H2 Pd(OH)2C
110
114
114
119
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1407
Scheme (25)
Scheme (26)
OBn
R1
R2
PPh3BF4-O
O
OOHC
O
O
O
O
O
O
O
O
HO
O
O
O
O
O O
OBn
R1
R2
O
O
O
O
O
O
H
O
OBn
R1
R2
O
O
O
O
O
O
O
O
OBn
R1
R2
O
O
O
+
BCl3 (005 equiv)
MS 4A CH2 Cl2 0 o C
+
BuLi THF -90 oC -90 o C
to rtH2 (1 atm) PdC Et3N MeOH
R1 R2 = OBn H
120a - b
121
122a - b
123a - b
124
125a - b
OTBDPS
BnO X
SO Ph
O
BnO
OHCO
BnO
OMeOBn
OBn
O
BnO
OTBDPS
BnO
SO Ph
O
BnO
OMeOBn
OBn
O
HO
OMeOH
OHO
HOHO
OH
OH
128
229 74
1 RaNi (74)
2 BH3 DMS
NaOH H 2O2 (74)
3 H2 PdC (70)
130 74
LDA THF
-100 oC
126 X = H
127 X = Li
1408 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (27)
Scheme (28)
stereochemical outcome is rationalized by the generation ofan initial zinc acetylide species which facilitates intra-molecular delivery to the α-face (Scheme 32)
Wightman synthesized C-disaccharide analogs of the α-D-arabinofuranosyl-(1rarr5)-α-D-arabinofuranosyl motif ofmycobacterial cell walls through alkynyl intermediates [36]The lactone 164 was treated with lithio(trimethylsilyl)ethyneat low temperature to give lactol in 66 yield of 165Treatment of this with triethylsilane and BF3
Et2O gavethe separable isomers 166α (60) and 166β (13)Desilylation of the major isomer 166α gave 167 in 97yield Treatment of 167 with n-BuLi followed by addition oflactone 164 gave 85 yield of the hemiacetal 168 which onreduction with Et3SiH and BF3
Et2O gave the disubstitutedalkyne 169 (83) as the major product Reduction-
hydrogenolysis of 169 then gave the C-disaccharide 170 innear-quantitative yield (Scheme 33)
3 REDUCTIVE GLYCOSYL SAMARIUM SPECIES
The introduction of SmI2 as reducing agent can becredited to Kagan and has since been utilized in numeroussynthetic schemes [37] Sinayuml and Beau introduced SmI2
chemistry into C-glycoside synthesis through intermolecularreactions with appropriate electrophiles and intramolecularreactions of silyl tethered substrates [38] Anomericsamarium species are highly stable and not likely to undergoβ-elimination Treatment of the aryl sulfone 171 with SmI2
affords the nucleophilic intermediate 172 through two singleelectron transfer processes Introduction of a suitableelectrophile (carbonyl compounds) affords the α-C-manno-
O
BnO
OTBDPS
BnO X
SO Ph
O
BnO
OBn
BnO Li
SO Ph
DMF
OHO
HOOH
OH
O OH
OH
HO
OHOH
O
BnO
OTBDPS
BnO
SO Ph
O
OBn
OBnOBnSO
Ph
OH
131 X = Li
132 X = CHO
THF -100 oC
1 Ra-Ni
2 BH3 DMS NaOH H2O2
3 H2 PdC
131
133
134
OBnO
OBnOMe
BnO
Li
OBnO
BnOOBn
OBn
OOBn
OBnOMeBnO
OH
OBnO
BnOOBn
OBn
O
n-BuLi
BnO
OMe
BnO
BrBr
O
OBn
OHO
OH
OH
HO
OHO
OH
HO
OMe
O
BnO
OMeOBn
O
BnO
139 92
1BF3 OEt2 EtOH
2 H2 PdC AcOH
140 52 over 2 steps
135 136 137
138
CBr4 PPh3
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1409
pyrannoside 173 in good yield and with excellent stereo-selectivity (Scheme 34) [38a]
Preparation of C-glycosides of ulosonic acids using SmI2
was pioneered by Linhardt and coworkers [39] Coupling ofpyridyl sulfone 174 with aldehyde 175 in the presence ofSmI2 gave an excellent yield of the N-acetylneuraminic acidC-disaccharide 176 as single isomer This stereochemicaloutcome was rationalized on the basis of the Felkin-Anhmodel for predicting the stereochemical outcome of akinetically controlled addition of a nucleophile to a chiraladehyde (Scheme 35 A)
Reductive samarium method was utilized to synthesizesialo-antigen C-analogs by the Linhardt group A fullyprotected C-analogue of the SialylTn antigen α-D-Neu5Ac-(2rarr6)α-D-GalNAc-(1rarrO)-Ser 182 was prepared [40] C-glycosylation of the neuraminic acid sulfone donor with
aldehyde acceptor in presence of excess SmI2 afforded the α-C-glycoside 180 as an RS mixture (11) The criticalintermediate aldehyde acceptor 178 was prepared in 13steps Chemoselective resolution to compound 180 wasundertaken by oxidation with DMSOAc2O to keto-bridgedcompound 181 followed by stereoselective reduction withZn(BH4)2 to regenerate the bridge hydroxyl function gave182 in gt90 de (Scheme 36)
A common versatile N-acetylneuraminic acid C-disaccharide precursor of the C-glycoside analogs ofgangliosides GM4 and GM3 has been synthesized [41]Samarium(II) iodide coupling of N-acetylneuraminic acidsulfone 179 with a 3-formyl galactopyranoside derivative183 afforded the corresponding C-disaccharide 184 as amixture of (R) and (S) isomers at the newly formedhydroxymethylene bridge This diastereoisomeric mixturewas resolved after debenzylation of the galactoside residue
Scheme (29)
O
BnO
BnOOBn
OBn
OOBn
OBnOMe
OBnOH
O
BnO
BnO
OBn
OBn
O
O
BnOOBn
OMe
BnO
Li
OBnO
OBn
OBn
OBnO
OBn
OBn
OMe
OBnO
OBn
OBnBnO
OBnO
OBn
OBn
OBnO
OBn
OBn
OMe
OBnO
OBn
OBnOBnO
OBn
OBnBnO
O
BnO
BnO
OBn
O
OBnO
OBn
OBnBnO
OBnO
OBn
OBnBnO
OBnO
OBn
OBn
OMe
OBnO
OBn
OBnBnO
OMe
1 PCC2 CBr4 Ph3P3 n-BuLi
144 overall yield 54
1 BF3 OEt2 Et3 OH
2 H2 PtO2 EtOAc
145 76
1 H2 SO4 AcOH
2 PCC
146 62
repeat steps
repeat st eps
141 142
143
147
148
1410 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (30)
Scheme (31)
O
BnOOBn
OMe
Li
BnO
OPivBnO
OBn
OBn
BnO
O OO
BF3 OEt2
OBnO
OBn
OBn
BnO
OO
O
OMe
BnOOBn
BnO
Co(CO)3
Co(CO)3
O
CAN
OBnO
OBn
OBn
BnO
OO
OO
BnOOBn
BnO
OMe
OHBnO
OBn
OBn
BnO
OHO
O
O
OMe
BnOOBn
BnO
Co(CO)3
Co(CO)3
O
OPivBnO
OBn
OBn
BnO
OH OO
O
OMe
BnOOBn
BnO
OAcO
OAc
OAc
AcO
OAcOAc
OAcO
OAc
AcO
OMe
1
2 NaOMe MeOH
1 Lewis acid2 ClCO2CCl3 Pyr3 Co2(CO)8
with a-isomer
1 Et3N Pyr H2O
2 H2 PdC H+
3 Ac2 O Pyr
149 151
152153
154 155
150
OBn
BnO
OBnO
OBn
BnO
OBnO
BnO
MeO
OBnO
OBn
BnO
O
OMe
AcO
OAcO
OAc
OAc
AcO
OAcO
OAc
O
BnOOBn
OMe
BnO
159 74 over 2 steps
+
BuLi ZnCl2 THF
1 H2 PdC2 Ac2O Pyr
156 157
158 59
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1411
Scheme (32)
Scheme (33)
and the chirality of each isomer assigned after acetylationConversion of the p-methoxyphenyl group in the peracety-lated (S) isomer 187 into the corresponding thiophenylglycoside 188 was accomplished affording the key inter-mediate for the synthesis of C-glycoside analogs of GM4GM3 and other related gangliosides (Scheme 37)
Ganglioside GM4 is a very important cell adhesionmolecule The C-disaccharide of GM4 is currently beingsynthesized in Linhardtrsquos lab using standard O-glycosylationof C-disaccharide with protected ceramide Once theceramide has been attached it can be oxidized to afford analdehyde group for coupling to keyhole limpet hemocyanin
OBnO
OBn
BnO
O
OBnO
ClZnO
OBn
BnOCl
R
OBnO
O
OBn
BnOCl
ZnR
O
ZnR
OBnO
OBn
BnO
160 161
162163
O
OBn
OBnBnO
O
O
OBn
OBnBnO H
TMS
O
OBn
OBnBnO H
O
OBn
BnO
OBnHO
O
OBn
OBnBnO OH
TMS
OBnBnO HO
OBn
TMS
O
OR
ORRO H
O
OR
RO
OR
OBn
OBnBnO
H
TMS
O+
K2CO3 MeOH
1 n-BuLi THF -78 oC
2 164
164165 66
166α 60 166β 13167 97
BF3 Et 2O Et 3SiH -78 oC
168 85
169 R = Bn 83
170 R = H near quantitative yield
H2 (1 atm)Pd(OH) 2C
TMS-acetyl ene
n-BuLi THF -78 oC BF3 Et2O Et3SiH
-78 o C
1412 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
O
OHCOBn
OBnBnO
OMe
O
CO2MeAcO
OAcAcHN
OAc
SO2
NAcO
OBnH
H
OBn
OBn
H
O
OMeH HH
A
O
CO2MeAcO
OAcAcHN
OAc
O
OBnOMe
OBnOBn
HO
AcO
+
Nu
174175
176
SmI2 THF
Scheme (34)
Scheme (35)
Scheme (36)
O
BnO
BnO
BnO
Si lylO
O2S N
O
BnO
HO R2R1
BnOBnO
SilylO
OBnO
BnO
BnO
SilylO
Sm(III)
R1COR2 SmI2 THF
171 172
173
NHBoc
OAcO
AcO
AcHN O
O
CO2BnO
OO
OO
OH
O
CO2MeAcO
OAcAcHN
OAc
AcO
SO2Ph
R2
O
CO2Me
AcHN
OAc
AcO
R1
AcO
AcO
AcHNO CO2Bn
NHBoc
AcO
OAc
O
Zn(BH4)2
180 R1 R2 = H OH ( RS 11)
181 R1 R2 = O
182 R1 = H R2 = OH de gt 90
DMSO Ac2O
177178
179
13 steps
22 equiv SmI2 THF
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1413
Scheme (37)
Fig (2)
(KLH) by reductive amination for use as carbohydrate-basedvaccine GM3 a related trisaccharide containg gangliosideplays an important role in cell growth and differentiationFig 2 The synthesis of C-oligosaccharide GM3 is currentlyunderway following a similar route to that of C-GM4synthesis [42]
Beau also reported a sialyl C-disaccharide synthesiswhich relied on the unprecedented use of a stable andcrystalline 2-pyridyl sulfide of the N-acetylneuraminic acidderivative 189 as the anomeric precursor in a samarium-Reformastky procedure [43] The coupling procedure withsulfide 189 and aldehyde 190 afforded the carbon-linkeddimer 191 in 93 yield as a 11 diastereomeric mixture
Alcohols 191 were converted into thiocarbonates anddeoxygenated by employing triphenyltin hydride catalyticAIBN and pentafluorophenol which yielded C-disaccharide192 as a single compound in 65 yield for the 2 stepsDesilylation hydrogenolysis acetylation and finalacetolysis of the methyl glycoside provided the carbon-linked mimic 193 of the disaccharidic component of thesialylTn tumor antigen (Scheme 38)
4 CATIONIC METHODS
This section is categorized according to reactions thatinvolve the generation of anomeric ions followed by thecapture with sugar-based nucleophiles
OAcAcHN
OAc
AcO
O
OBnBnO
OBnOMP
HO
O
MeO2CAcO
O
MeO2CAcO
OAcAcHN
OAc
AcO
O
OHHO
OHOMP
HO
O
OBnOHC
OBnBnO
OMP
O
MeO2CAcO
OAcAcHN
OAc
AcO
O
OHHO
OHOMP
HO
O
CO2MeAcO
OAcAcHN
OAc
AcO
SO2Ph
O
MeO2CAcO
OAcAcHN
OAc
AcO
O
OAcAcO
OAcX
AcO
H2 PdC EtOAc CH3OHH2O
+
Ac2O Pyr
187 X = OMP
188 X = SPh 73
184 85 R and S mixture
186 90 for two i somers
+
SmI2 THF183
179
185
O
HO2 CHO
OAcAcHN
OH
HO
O
OHHO
OH
OAcO
(CH2 )12 CH3
HN
OH
(CH2)14CH3
O
O
O
OHHO
OH
O
O
HO2 CHO
OAcAcHN
OH
HO
O
OHHO
OH
O(CH2)12CH3
HN
OH
(CH2)1 4CH3
GM4
GM3
1414 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
41 Exo-glycals as Nucleophiles
Nitotra et al have found that treatment of exo-glycal 194with BF 3
OEt2 followed by a water quench afforded the C-disaccharide 195 (Scheme 39) It is noteworthy tonoteworthy that the attack of the enol ether on the anomericoxonium ion occurs with high stereoselectivity on the α-face only 195 was obtained [44]
42 Silyl-based Nucleophiles
Isobe has designed and developed alkynylation as a keyreaction for the introduction of a carbon chain onto sugarsThose alkynylated compounds are called ldquosugar acetylenesrdquo[45] The mechanism includes eliminative formation ofcation to which silylacetylene can coordinate on the α-face(Scheme 40)
Double C-glycosylation between glycal 198 and bis(silylacetylene) gave C-disaccharide ldquolikerdquo compounds 199and 200 (Scheme 41)
Silylpropargyl-sugar 201 smoothly reacted with D-glucalto furnish exclusively the α-acetylene glycoside product 202in 88 (Scheme 42) [46]
5 CYCLIZATION METHODOLOGY
This approach to C-oligosaccharide synthesis relies onthe coupling of an open chain fragment with an intact
monosaccharide to give an intermediate that is then cyclizedto deliver the C-oligosaccharide target This section isdivided by the type of chemistry used to initially assemblethe two pre-cyclization fragments
51 Wittig Reaction-Cyclization
The Kishi group was the first to use Wittig-cyclizationapproach to synthesize C-disaccharides Starting with Wittigreaction between 203 and 204 the intermediate 205 wasafforded as a single stereoisomer in 82 yield Osmylationthen gave a mixture of diols with the major one formed in a61 ratio Selective protection of the diols gave 206a and206b The mono-para-methoxybenzyl ether 206a was thentransformed into the hemiketal 207 in 75 overall yield inthree steps ie (1) Swern oxidation (2) acetonide hydro-lysis (4 N HClTHFrt) and (3) benzoylation (3 equiv ofPhCOClpyCH2Cl2rt) Silane reduction of 207 in an acidicmedium should preferentially yield the equatorially substi-tuted β-C-glycoside which was deblocked and converted tothe methyl- βminusC-disaccharide 209 Exact parallel experi-ments applied to the minor isomer gave the correspondingC-disaccharide 210 (Scheme 43) [47]
Armstrong has employed Wittig-osmylation protocol forthe preparation of a small library of α-C-(1rarr6)-disaccha-rides [48] Readily available allyl C-glycoside 211 washomologated to diene ester 212 and subjected to osmylation
Scheme (38)
O
CO2MeAcO
OAcAcHN
OAc
AcO
S(2-Py)
O
TESO
AcHNOMe
O
HO
O
CO2MeAcO
OAcAcHN
OAc
AcO
O NHAcOAc
OAc
OAc
O
CO2MeAcO
OAcAcHN
OAc
AcO
O NHAcOBn
OTES
OMe
OAc
AcO
O NHAcOBn
OTES
OMeOH
O
CO2 MeAcO
OAcAcHN
+
192 65
1 MeOHHCl2 H2 PdC EtOH3 Ac2O Pyr4 Ac2OAcOHH2SO4
193 59 overall yield
25 equiv SmI2 THF
1 11-thiocarbonyldiimidazole DMAP2 Ph3SnH cat AIBN
191 93
189
190
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1415
Scheme (39)
Scheme (40)
Scheme (41)
OBnO
OBn
OBn
OBnO
OBn
OBn
OBnO
OBn
OBn
OBnO
OBnCH3
BnO
OH
CH2
OBnO
OBn
CH3
OBn
H2 O
BF3 OEt2 MeCN
194
195 96
OOAc
OAc
AcO
R SiMe3
SnCl4
O
OAc
AcO
R
O
OAc
AcO
O
OAc
AcO
Me3Si
R
SiMe3
196
197
Me3 Si SiMe3
O
AcO
OAc
OAc
SiMe3
SiMe3
O
AcO
OAc
O
OAc
OAc
O
AcO
AcOO
OAc
OAc
SnCl4 CH2Cl2
SnCl4 CH2Cl2198
199
200
1416 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (42)
Scheme (43)
AcO
OAc
OAc
Me3 Si
BnO
OBn
BnO
OBn
AcO
OAc
BnO
OBn
BnO
OBn
+ I2 CH2Cl2
202 88
198 201
O
OBn
OBn
O
O
O
OBn
OBn
O
O
OBn
OBn O
OBn
OBn
O
OPBH2M
OH
OBnO
BnO
BnO
O
OBn
OBn
O
OHOPMB
OHO
HO
HO
O
OH
OHOH
OH
HOOMe
O
OBnOBn
O
Ph3P
O
O
OBn
OBn O
OBn
OBn
O
OPBM
OH
O O
CHO
OBn
BnO
OO
OBn
OBn
O
OHOPMB
BnO
BnO
BnO
OHO
HO
HO
O
OH
OHOH
OH
HOOMe
+ THF -78 oC
1 OsO4 pyr THF
2 NaH PMBBr
206a 206b 206a206b 61
1 Swern [O]2 4N HCl3 PhCOCl pyr
1 Swern [O]2 4N HCl3 PhCOCl pyr
1 PrSiH BF3 OEt2
2 H2 Pd(OH)2C
3 HCl MeOH 90 oC
1 PrSiH BF3 OEt2
2 H2 Pd(OH)2C
3 HCl MeOH 90 o C
203
204
205
207
209
208
210
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1417
followed by reduction to afford a 51 mixture (213214215216) of lactols that were readily separable by chromato-graphy Following a deprotection of an equimolar mixture of213 and 214 217 and the DL hybrid C-disaccharide of D-glucose-O-(1rarr6)-L-galactose 218 were obtained The DDand DL derivatives 219 and 220 of glucose-α-(1rarr6)-idosewere also obtained as a near equimolar mixture afterdeprotection of 215 and 216 (Scheme 44)
52 Anion Addition-Cyclization
Kishi developed an approach for the synthesis of theCndashtrehalo sugars which relied on nucleophilic addition ofone intact sugar fragment to a fundamental aldehyde ieKishi-Nozaki reaction [49] Coupling of monosaccharide221 and aldehyde 222 gave 223 The triple bond waspartially reduced and osmylation was followed by selectiveprotection to afford 224 The acetonide was converted toepoxide 225 by standard methods and removal of the PMBgroup Acid-catalyzed cyclization followed by aglyconichydrolysis and protection of hydroxyl group with (p-methoxyphenyl)diphenylmethyl chloride (MMTrCl) gave226 Inversion of the C-2 hydroxyl and removal of protectinggroups delivered α α-C-trehalose 227 (Scheme 44)
Kishi and co-workers also employed aldol reactions as anefficient access to the C-trisaccharide related to the type IIABO(H) blood group determinant [50] Aldol condensationof the enolate of methyl ketone 228 with aldehyde 229 gavea 41 mixture of hydroxy ketones 230 and 231 The majorketol was cyclized desulfurized and oxidized to afford thedisaccharide ketone 233 The ketone in THF was treatedwith LiHMDS (3 equiv) and TMEDA followed by theaddition of MgBr2 Addition of the aldehyde 234 led toalmost exclusive formation of the equatorial products 235and 236 in a 12 ratio Mesylation of 235 and 236 followedby treatment with liquid ammonia gave enones 237a and237b which were reduced to yield exclusively the C-2rsquo-equatorial ketone 238 Sodium borohydride reduction of theC-3rsquo carbonyl proceeded with the desired stereoselectivity toyield the protected C-trisaccharide 239 which wasdeblocked to provide the polyol 240 (Scheme 46)
Sutherlin and Amstrong cleverly applied a recursivestereochemical deconvolution (RSD) combinatorial approachfor the synthesis of a small library of C-trisaccharides aspotential inhibitors for the cell surface proteins of bacteriumHelicobactor pylori [51] The workers chose to carry outvariations in galactose ring of these trisaccharides An
Scheme (44)
OBnO
BnOOBn
OBn
P O
OEtOEtO
EtO
R H
OH
OH
OH
OH
O
R H
OH
OH
OH
OH
O
OHO
HOOH
OH
O
HO
OHOH
OH
OHO
HOOH
OH
O
HO
OH
OH
OHO
HOOH
OH
O
HO
OH
OHOH
R H
OH
OH
OH
OH
O
R
OBnO
BnOOBn
OBn
O
OHO
HOOH
OH
OO
HOHO
OH
R H
OH
OH
OH
OH
O
1 OsO4 NMO 50
2 DIBAL -32 oC 40
++ +
213 214 215 216
217 218 219 220
1 9-BBN H2O22 Swern [O]
3 t-BuOK
4 I2 C6H6212
211
1418 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
efficient Nozaki-Kishi coupling of vinyl bromide 241 withaldehyde 242 in a diasteromeric ratio of 12 followed byprotection with TBSOTf led to 243 and 244 Hydroborationfollowed by oxidation gave aldehydes 245 and 246respectively Addition of allylmagnesium bromide toaldehyde 245 followed by removal of the silyl groupafforded 247 to 246 giving 248 and 249 Epoxidation gave a11 mixture of the corresponding epoxides which werecyclized to give the C-trisaccharide 250-255 after removalof the benzyl groups (Scheme 47)
Schmidt reported a stereoselective 6-exo-trig selectiveelectrophilic cylization approach for de novo synthesis of amethylene-bridged Neu5Ac-α-(23)-Gal C-disaccharide theC-analog of an important motif in glycosphingolipids [52]The open chain precusors 259ab (a 32-mixture ofdiaseteromeric alcohols) were formed by the addition oflithiated iodide 256 to open chain aldehyde 258 Subsequent
C1 incorporation using Tebbe-reagent formation of a cycliccarbonate and deprotection of the two isopropylidene ketalsafforded tetrol 264 which upon treatment with phenylselenyltrifilate was steroselectively cyclized in a 6-exo-trigselective manner affording a diasteromeric mixture of 251and 252 in a ratio of 71 A seleno-Pummerer rearrangementto afford aldehyde 267 in 5 steps in 90 overall yieldOxidation of the aldehyde and subsequent steps led to thedesired C-disaccharide 268 (Scheme 48)
53 Esterification-Cyclization
Work from the Postema group has focused on a ringclosing metathesis (RCM) approach for the synthesis of C-saccharides [53a] The chemistry is versatile and has beenused for the synthesis of a small library of differentiallylinked β-C-disaccharides through a radical allylation-RCMstrategy [53b] The synthesis of the β-(1rarr4)-glucopyranosyl
Scheme (45)
O
OBn
BnO
BnO
BnO
I
CrCl2-NiCl2O
OBn
OH
BnO
BnO
BnO
O
O
O
O
O
H
OBn
O
O
OBnBnO
BnO
BnO
OOBn
OBn
OAc
PMBOHOO
OBn
BnO
BnO
BnO
O
OBn
OBn
OAc
O
OH
HO
HO
HO
OH
OH
OH
O
OH
O
OBn
BnO
BnO
BnO
OBn
OBn
OAc
O
MMTr
+
1 p-TsOH2 K2CO3 MeOH3 MMTrCl pyr
1 Swern [O]2 BH3 THF
3 AcOH-H2 O4 H2 Pd(OH)2
221
222
223
1 Pd-Pb CaCO3 H22 NaH BnBr3 OsO44 Bu2 SnO5 CsF PMB-Cl6 Ac2 O 4-DMAP
1 AcOH2 TsCl pyr
3 NaH-imid4 DDQ
224225
226 227
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1419
Scheme (46)
OBnO O
OBn
OMe
OBn
XY
SMe
OBnBnO
O
OBn
OBn
OBn
OBn
O
BnO
YX
OBn
TBSO
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnOOBn
H
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnO
OBn
OHC OBn
OBn
OTBS
OMe
BnOOBn
CHO
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnOOBn
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnO
OBn
YX
OBnO O
OBn
OMe
OBn
OBn
O
BnO
O
OBn
OBn
OBn
OBn
O 1 LiHMDS
2
228
1 TBAF THF
2 MeSH BF3 OEt2
230 X = OH Y = H231 X = H Y = OH
230231 41
1 Bu3SnH AIBN2 Swern [O]
1 LiHMDS THF-TMEDA2 MgBr23
1 MsCl
2 liquid NH3
235 X = OH Y = H236 X = H Y = OH Bu3 SnH AIBN
237a and 237b
NaBH4 MeOH
238
239 X = OBn
240 X = OHH2 Pd(OH)2
229
232233
234
1420 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (47)
OH C
O
O BnAcHN
OO
O
OBn OBnOBn
Br
O
OBn OBnOBn
O
OBnA cHN
OO
O TBSO
OBn O BnO Bn
O
OBnAcHN
OO
OTBS
S2
S1
S2
OTBSS1
O H
S2
OT BSS1
O H
MgBrMgBr
S2
O TBSS1
O H
S2
OHS1
OH
S2
OTBSS1
OH
O
OHHO
O H
O
HO
H OO
OBnA cH N
HO
H O
O
O HHO
OH
O
HOHO
O
OBnA cH N
HO
H O
O
OHH O
OH
O
H O
HOO
OBnAcHN
HO
HO
O
O HH O
OH
O
H O
H O O
OBnA cHN
HO
HO
O
O HH O
O H
O
HO
H O O
OBnAcHN
HO
HO
O
OHHO
OH
O
H O
O
OBnA cHN
HO
HOHO
+
241 242
1 CrCl2-NiCl2 T HF-DMF 722 TBSOTf 2 6-lutidine 91
243 244
1 9-BBN 602 Dess-Mart in period inane 97
1 9 -BBN 552 D ess-Martin periodinane 98
245 246
1
2 T BAF 74
1
2 TBAF 88
247 248 249
250
251
250 251 1 1 252 253 1 1 254 255 1 1
252
253
254
255
1 MCPBA2 CSA CH 2Cl2 61 fo r 2 steps3 H 2 Pd (O H)2C 95
1 MCPBA2 CSA CH 2Cl2 63 fo r 2 s teps3 H 2 Pd (OH)2C 87
1 MCPBA2 CSA CH2Cl2 80 for 2 steps3 H2 Pd(O H)2C 95
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1421
Scheme (48)
O
OO
Se Ph
R
O
HO OHOH
O
OB n O B n
OB n
O B nO O
O O
R O OR
X
O
OO
R
Se Ph
O
HOOH
OH
O
OB nOB n
O Bn
OB n
O O
O O
R O O R
O H
O
O B n OB n
O B n
OB n
O
C HO
O
O O
R O OR
OAc HN
OAc
C O2NH 4HOOH
OH
O
OH O H
OH OH
O
OB n O B n
OB n
OB nO O
O O
R O OR
X
O
O
OAcOAc
C HOA cOOAc
OAc
O
OB n O B n
OB n
OB n
O
O Bn OB n
OB n
OB n
X
OH
OO
HOOH
OH
O
O
OMeOB n
OB nOB n
R
t-B uL i256 R = Li
257 R = L i
258
(R = t-B uMe 2Si )
(R = t-B uMe 2Si )
259ab (32) 79 com bine d yi eld
De ss-Ma rtin pe riodinane
260 X = O R = t-B uMe 2Si ) 95
261 X = O R = t -B uMe2S i) 62
T e bbe re age nt
TB A F THF262 X = O R = H 94
diphosge ne
C H2C l 2Pyr
263 95
T HFH2O T FAr t
264 quant it a ti ve yie ld
PhSe C l AgOT f
EtC N -80 oC
265
266
Quant it at i ve yi l ed 25 26 7 1
+
R =
1 Ac 2OPyr
2 mC PB A3 Ac 2ONa OAc
4 NaO HT HFMe OH
5 Ac2O P yr
267 90 overa ll yi e ld
ste ps
268
1422 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
glucopyranoside 280 represents an example of thischemistry The known triacetyl glucopyranoside 269 wasconverted to iodide 270 in good yield Radical allylation of271 proceeded to afford a mixture of equatorial and axialallylation products in a 61 ratio Oxidative cleavage of thedouble bond gave the corresponding aldehydes 273a and273b which were separable Pinnick oxidation of the majoraldehyde 273a then gave the C-4 equatorial acid 274 DCC-mediated coupling of alcohol 275 and acid 274 proceeded toafford ester 276 in good yield Methylenation of 276 gave277 and exposure to catalysist 278 gave a 41 yield of theC-disaccharide glycal which was exposed to an excess ofBH3
THF to give 64 yield of the β-C-disaccharide 279Removal of the benzyl groups and global peracetylation gavethe peracetylated (1rarr4)-β-C-disaccharide 281 in good yield(Scheme 49)
54 Ring Expansion-Cyclization
Nelson developed a new strategy for asymmetric andstereoselective synthesis of C-linked disaccharide mimeticsthe C58-C71 fragment of palytoxin [54] The diol (RR)-282was converted into the di-dihydropyran (DHP) template 283284 and 285 The di-DHPs were functionized in a twodirectional sense using dihydroxylation reactions The two-directional approach was often very efficient indeed forexample in the synthesis of 286 six new stereogenic centerswere introduced with almost complete stereocontrol using areduction and a dihydroxylation reaction The approach isnot restricted to the synthesis of C2-symmetricaldisaccharide mimetics Using the unsymmetrical template285 which has both a pseudo-axial and a pseudo-equatorialhydroxyl groups the unsymmetrical mimetics 289 and 290were prepared (Scheme 50)
6 RADICAL APPROACHES
The radical approach for C-C bond formation is a popularmethod within organic chemistry The use of radicalchemistry in carbohydrate synthesis has certain advantagesFirstly the reaction conditions are very mild and tolerant ofa range of functional and protecting groups Secondanomeric radicals are stable with respect to elimination andepimeration Most significantly the chemistry required toincorporate an appropriate substitute at C-1 employed in theinitial hemolytic cleavage step is common within carbo-hydrate chemistry [55] The use of such radical techniquecan be subdivided into two classes intermolecular andintramolecular approaches
61 Intermolecular Radical Approaches
Giese was the first to employ an intermolecular radical-based approach for synthesis of C-disaccharides [56]Addition of an alkene to an anomeric radical underappropriate conditions allowed exclusive entry to the α-linked C-glycoside a result which was mirrored by the workof Baldwin [57] The high α-selectivity of the reaction wasin contrast with other reports Thus radicals generated at theC-2 C-3 and C-4 centers all preferred to occupy equatorialpositions [58] When the anomeric bromide 291 was treatedwith tin hydride and AIBN resulting anomeric radical andreacted with lactone 292 in a Michael addition it afforded293 In this reaction hydrogen abstraction at the resulting
radical center occurs from axial face to selectively generatethe equatorial C-2rsquo substituent Reduction and acetylation of293 furnished C-disaccharide 294 (Scheme 51) [59]
Witczak used the facial bias of levoglucosene tostereoselectively add a carbohydrate-based radical in thepreparation of the 3-deoxy-(1rarr4)-β-C-disaccharide 299[60] Addition of the radical derived from iodide 295 to 296gave adduct 297 in 26 yield Removal of the anomerichydroxyl of 297 was achieved by treatment with triethylsilane borontrifluoride ether complex followed bystereoselective reduction of the keto function at C-2rsquo withthe formation of 298 in 89 yield Debenzylation followedby acetolysis of 16-anhydro ring produced the peracetylatedtarget C-disaccharide 299 in 19 overall yield from 295(Scheme 52)
Vogel has developed general methods to transformenantiomerically pure 7-oxabicyclo[221]heptyl derivatives(ldquonaked sugarsrdquo) into C-disaccharides Because of thesechiral bicyclic skeletons they undergo highly stereoselectivereactions with predictable diasteroselectivities An arsenal ofmethods is available that allow to substitute these ldquonakedrdquocarbon centers with a variety of functional groups with allpossible relative configurations The methods allowpreparation of both enantiomers of a given target with thesame ease Predictably high stereoselectivity of the reactionsof the bicyclic chirons adds to the flexibility of approachwhich can lead to high molecular diversity [61]
α-C-(1rarr3)-mannopyranoside of N-acetyl-galactosaminepotent β-galactosidase inhibitors was synthesized by thisapproach [61] Enone 302 was readily prepared from 300The addition of the radical derived from bromide 303 toenone 302 afforded the αminusisomer 304 The ketone was thenreduced and the selenide eliminated via the intermediacy ofthe selenoxide to give 305 Acid-promoted (CF3SO3H) 7-oxa ring opening of 305 in MeCN produced the amino-conduritol derivative 306 resulting from the quenching of theallylic cation intermediate by the solvent (Ritter reaction)Ozonolysis of the chloroalkene 306 generated an acylchloride-aldehyde intermediate that reacted with MeOH toproduce a mixture of methyl uronates The major compound307 was silylated and reduced The crude polyol obtainedwas acetylated to produce 308 Desilylated and ammonolysisafforded a mixture of α-β-pyranoses 309 and correspondingα-β-furanoses (Scheme 53)
Similar chemistry was carried out to synthesize non-protected α-C(1rarr2)-L-fucopyranoside of D-galactopyrano-side corresponding to a blood group mimetic [62] Giesersquosradical fucosidation of racemic enone 310 with α-L-bromoacetofucose 311 provided the mixture of diastereo-meric α-C-fucoside 312a and 312b in reproducible yield of78 Reduction of the mixture gave a 11 mixture of endo-alcohols 313 and 314 which were isolated pure in 40 and355 yield respectively Oxidative elimination of thebenzeneselenyl group of 313 followed by acetylation gaveendo acetate 315 in 85 yield Acid-promoted ring openingof 315 and ozonolysis of the resulted chloroalkene gavemethyl uronic ester 316 in modest yield (10) Treatment of316 with Cl3CCN and NaH followed with BF3
OEt2
furnished the totally protected C-disaccharide 317 in 79
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1423
Scheme (49)
Bu3SnO
HOAcO
OMeOAc
OAc
O
AcO
OMeOAc
OAcI
AIBN
O
AcO
OMeOBn
OBn
HO2C O
AcO
OMeOR
ORY
X
OHBnO
BnO
OBn
OBnO
BnO
OBn
O
AcO
OMeOBn
OBnX
i-Pr i-Pr
N
Mo C(Me2 Ph)((CF3)2 MeCO)2
O
RO
OMeOR
O
RO
OR
OR
RO
OR
278
I2 Ph3P
imidazole
269 270 93
271a X = CH2CH=CH2 Y = H R = Ac 64271b Y = CH2CH=CH2 X = H R = Ac 11272a X = CH2CH=CH2 Y = H R = Bn 75272b Y = CH2CH=CH2 X = H R = Bn 75273a X = CH2CHO Y = H R = Bn 79273a Y = CH2CHO X = H R = Bn 79
1 NaOMe MeOH2 NaOH BnBr DMF
OsO4 NaIO4
NaClO2 NaH2PO4
274 96
275
DCC 4-DMAP
276 X = O 82
277 X = CH2 51
TiCl4 Zn dust TMEDA CH2Br2PbCl2 (Cat )
1
2 BH3 THF H2O2 NaOH
H2 PdC EtOH
Ac2 O Pyr 4-DMAP
279 R = Bn R = H 64
280 R = R = H 99
281 R = R =Ac 97
1424 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (50)
Scheme (51)
O OOH
OH
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
286
1 VO(acac)2 t-BuOH 95
2 (MeO)3CH BF3 90
1 P-O2NC6H4 CO2H Ph3P DIAD2 K2CO3 MeOH 82 over 2 steps
1 PhCOCl Et3N DMAP 402 P-O2NC6H4 CO2H Ph3P DIAD3 KOH THF-H2O 75 over 2 steps
TMEDA OsO4
Cat OsO4 NMO 287
Cat OsO4 NMO288
TMEDA OsO4
Cat OsO4 NMO
290
289
(RR)-282283
284
285
OHO
AcO
BrOAc
OAc
BnO
O
OBn
OBnO
OHO
AcOOAc
OAc
BnO
OOBn
OBnAcO
OHO
AcOOAc
OAc
BnO
O
OBn
OBnO
+
Bu3SnH AIBN291
292
293 81
1 Na[Al(OC2H4OMe)2(OEt)H]2 Ac2O pyr
294 56 over 2 steps
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1425
Scheme (52)
Scheme (53)
OBnO
BnOOBn
OBn O
OH
O
OBnO
BnO
OHOBn
OBn O
O
O
O
O
O
OBnO
BnOOBn
OBnO
OAcOAc
OAc
OBnO
BnO
OHOBn
OBn
IBu3SnH AIBN
295 297 26
1 BF3 OEt2 Et3SiH
2 L-Selectride THF
1 Pd(OH)2C C6H10 EtOH
2 EtSiOSO2CF3 Ac2O
298 89 over 2 steps299
296
O
O
PhSeClO
O
PhSeCl
Bu3 SnH
O
O
PhSeCl
R
H
O
OAc
R
Cl
O
AcO
OAc
OAc
OAcOH
Cl
NHAc
R
OAc
AcHN
OH
O
OH OAc
OH
OHO
HO
OH
O
AcO
OAc
OAc
OAcBr
O
O
PhSeCl
O
O
PhSeCl
R
O
OTIPSAcHNR
OAc OAc
O
OHAcHN
COOMe
R
OAc
1 Bu4NF
2 NH3MeOH
1 (Me3Si)2NLi THF2 Me2N=CHI
1 Bu3 SnH AIBN2
1 NaBH42 mCPBA3 Ac2O pyr
1 H+ MeCN
2 H2 O NaHCO3
R =
1 O3MeOH
2 Me2S NaHCO3
1 TIPSOTf 26-lut idine2 LiBH43 Ac2 O pyr DMAP
furanoses +
304 56
305 68 306 84307 50
308 46
300 301 302
303
309
1426 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
The reduction of 317 and treatment with DOWEX-H+ resinprovided the desired C-fucoside 318 in 70 (Scheme 54)
62 Intramolecular Radical Approaches
One disadvantage with the intermolecular approaches isthat during such radical mediated reactions electrondeficient alkenes are required to facilitate C-C bondformation The intramolecular approach of Sinayuml overcomes
this drawback by bring two substrates together via atemporary covalent silaketal connector This enables the useof a wider range of alkenes which can include alkene-functionalized sugars thus leading to the generation of C-disaccharides [63] Based on the early work of Stork Sinayumlemployed the tether reaction in the synthesis of both α- andβ-C-disaccharides with this work subsequently beingemployed in the synthesis of biologically significant natural
Scheme (54)
O
OH
Fuc
Cl
O
O
ClPhSe
OOAc
NHAcOHFuc
O
AcOOAc
AcO
Br
O
O
PhSeCl
O
AcOOAc
AcO
O
OH
PhSe Cl
Fuc
OOAc
NHAc
OMe
Fuc
O
AcHN
OH OAc
OH
O
OH
Me
OH
O
O
Fuc
ClSePh
O
HO
Fuc
ClSePh
+
Ph3SnHAIBN
78 combined yield
Fuc
310
+
1 NaBH4 MeOHTHF2 Chromatography
313 40 314 355
1 mCPBA
2 Ac2O pyr DMAP
+
315 75
1 TfOH MeCN
2 NaHCO3 O3 -78 oC
316 10 over 2 steps
1 Cl3 CCN NaH
2 MeOH BF3 OEt2
317 79
1 LiBH4 THF
2 Dowex-H+
311
312a312b
318 70 for 2 steps
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1427
products [64] The availability of different hydroxyl groupson each monosaccharide unit allowed the fine-tuning ofstereochemical outcome by selective positioning of the silyltether [65] Development of this early stereochemical controlled to the tethering of the donor 320 with alcohol 319through a di-isopropyl silicon tether 321 Subsequent treat-ment with Bu3SnH and AIBN led to a 9-endo-trigcyclization to form the C-disaccharide 322 in an 80 yieldwith exclusive formation of the α-product The silyl tetherwas removed with Bu4NF and deprotection under standardconditions afforded the desired disaccharide 323 in excellentyield (Scheme 55)
In parallel the development of a 32rsquo silyl tether allowedaccess to the β-linked product as demonstrated in Sinayumlrsquossynthesis of methyl β-C-lactoside 328 [66] Alcohol 324 and320 were connected via the dimethylsilyl tether an 8-endo-trig cyclization followed to exclusively afford the β-
disaccharide 326 in 45 yield Removal of the tether anddeprotection of benzyl ether gave β-C-disaccharide 328(Scheme 56)
This group also selected iodosugars bearing a freehydroxyl group as progenitors of the radical donors [67] In atypical experiment the radical donor 329 was connected tothe radical acceptor 330 through a silaketal tether followingtheir procedure Tributyltinhydride mediated 8-endo-trigradical cyclization of compound 331 gave after detetheringof the non isolated intermediate 332 the protected β-C-disaccharide 333 in 37 overall yield (from startingmaterials 330 and 329) Peracetate 335 was achieved afterhydrogenolysis The C-laminaribioside 334 is of potentialbiological interest as it mimics the repeating disaccharideunit of fungal β-(1rarr3)-glucans which have antitumor andimmunomodulating properties (Scheme 57)
Scheme (55)
Scheme (56)
OO
OHSePh
OTBDPSO O
OO
SePh
OTBDPSO
OO
OBnOMe
OBn
Si
O
HOOBn
OMe
OBn
O
HOOH
OHHO
O
HOOH
OMe
OH
OTBDPSO
O
HOOBn
OMe
OBnO
OOH
1 n-BuLi THF
2 iPr2SiCl2 -78 oC
3 DMAP THF rt
1 Bu4NF THF
2 Dowex-H+
3 H2 PdC
Bu3SnH AIBN toluene
319
320
321
322323
OBnO
OHSePh
OBnBnO
OHO
OBnOMe
OBn
ROO
ROOH
OR
OHO
OROMe
OR
OBnO
O
OBnBnO
OO
OBnOMe
OBn
Si
SePh
OBnO
O
OBnBnOO
OOBn
OMe
OBn
Si
1 PhSeH Me2SiCl2
BuLi -78 oC
2 imidazole rt
Bu3SnH AIBN toluene
H2 PdC327 R = Bn
328 R = H
Bu4NF THF
324
320
325
326 45
1428 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
CONCLUSIONS
In this paper the biological importance of C-oligo-saccharides as subunits of natural products and as a newgeneration of carbohydrate based on therapeutics has beenillustrated Different methods are available for the synthesisof C-oligosaccharides As with traditional saccharidesynthesis it has been necessary to develop a number ofspecific approaches to facilitate the regioselective andstereoselective preparation of the desired targets Work inthis area continues and it is expected that many interestingnew C-oligosaccharides will be prepared using the chemistrydescribed in this review It is also likely that new chemistrywill be developed in the future for the preparation of thesebiologically important targets
ACKNOWLEDGEMENTS
The authors thank Dr Sultan Baytas for her criticalreading of this manuscript
REFERENCES
[1] Kennedy J F White C A Bioactive Carbohydrates InChemistry Biochemistry and Biology Ellis Horwood LtdChichesterUK 1983
[2] Wassarman PW Mammalian Fertilization Molecular Aspects ofGamete Adhesion xocytosion Exocytosis and Fusion Cell 199996 175-183
[3] Carbohydrate-based Drug Discovery Wong C-H EdWeinheim Cambridge Wiley-VCH 2003
[4] (a) Sharon N Lis H Lectins as Cell Recognition MoleculesScience 1987 246 227-234 (b) Dwek RA Chem Rev 1996 96683-720
[5] Postema M C-Glycoside synthesis CRC Boc Ratom 1995[6] (a) Weatherman R V Mortell K H Cheruenak MKiessling
L L Toone E J Specificity of C-Glycoside Complexation byMannoseGlucose Specific Lectins Biochem 1996 35 3619-3624(b) Ravishankar R Surolia A Vijayan M Lim S Kishi YPreferred Conformation of C-Lactose at the Free and Peanut LectinBound States J Am Chem Soc1998 120 11297-11303
[7] (a)Wong C-H Halcomb R L Ichikawa Y and Kajimoto TEnzymes in organic synthesis Application to the problems ofcarbohydrate recognition part2 Angew Chem Int Ed Engl 199534 521-546 (b)Howard S Withers SG Bromoketone C-Glycosides a New Class of βminusGlucanase Inactivators J AmChem Soc 1998 120 10326-10331(c) Wang Q Wolff MPolat T Du Y Linhardt R J C-glycoside of Neuraminic Acidsas Neura-minidase Inhibitors Bioorg Med Lett 2000 10 941-944 (d) Phili R Chang J Partis R A Mueller R A ChrestF J Passaniti A The Alpha-glucosidase I InhibitorCastanospermine Alters Endothelial cell Glycosylation PreventsAngiogenesis and Inhibits Tumor Growth Cancer Res 1995 552927-2935
[8] Ossor A Elbein A D In Carbohydrates in Chemistry andBiology Vol 3(II) WileyVCH 2000 pp 513-539
[9] (a) Sinayuml P Synthesis of oligosaccharide Mimetics Pure ApplChem 1997 69 459-463 (b) Beau J-M Gallagher TNucleophilic C-glycosyl Donors for C-glycoside Synthesis Top inCurr Chem 1997 187 1-54 (c) Nicotra F Synthesis of C-glycosides of Biological Interest Top in Curr Chem 1997 187
Scheme (57)
O
O
O
Ph
I
OMe
OHO
BnO
OH
OH
BnOOH
O
BnO
Si
O
O O
Ph
I
OMe
O
O
BnO
OR4O
R5O
OMe
OR2
OR3O
R3O
OR1
R3O
Bu3 SnH AIBN
332 R1 R2 = SiMe2 R3 = Bn R4 R5 = CHPhTBAF THF
333 R1 = R2 = H R3 = Bn R4 = R5 = CHPh 37 from 11
334 R1 = R2 = R3 = R4 = R5 = H
335 R1 = R2 = R3 = R4 = R5 = Ac
329
H2 PdC MeOH
Ac2 O pyr
1 BuLi THF -78 oC
2 Me2SiCl2
3 DMAP
330
331
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1429
55-83 (d) Du Y Linhardt R Y Recent Adv in Stereo-SelectiveC-Glycoside Synthesis Tetrahedron Lett 1998 54 9913-9959 (e)Liu L Mckee M and Postema M H D Synthesis of C-saccharides and Higher Congeners Current Org Chem 2001 51133-1167
[10] Jarosz S Fraser-Reid B Synthesis of A Higher Carbon Sugar ViaDirected Aldol Condensation Tetrahedron Lett 1989 30 2359-2362
[11] Lichtenthaler F W Lergenmiiller M Schwidetzky S C-Glycosidations of 2-Ketohexosyl With Electrophilic Radical andNudeophilic Anomeric Carbons Eur J Org Chem 2003 3094-3103
[12] Baudat A Vogel P Aza-C-disaccharides Synthesis of 6-Deoxygalactonojirimycin-β-C(1rarr3) Linked with D-Altrofuranosides and D-Galactose J Org Chem 1997 62 6252-6260
[13] Turner D Vogel P Synthesis of 4-Hydroxy-26-Bis(hydroxymethyl) tetrahydropyran-2-Carbaldehyde DerivativesSynlett 1998 304-306
[14] Zhu Y-H Vogel P Short Stereoselective Synthesis of C-(1rarr3)-Linked Disaccharides Tetrahedron Lett 1998 39 31-34
[15] Zhu Y-H Vogel P Synthesis of a (2R 6R)-2-(Hydroxymethyl)-6-Propa-1 2-Dienyl-2H-Pyran-3(6H)-One Derivative A NewEnone for The Convergent Construction of C-Glycosides of C-Disaccharides Synlett 2001 82-86
[16] Baumberger F Vasella A Deoxynitrosugars The 6th
Communication Stereolectronic Control in the reductivedenitration of tertiary nitro ethers A Synthesis of ldquoC-glycosidesrdquoHelv Chim Acta 1983 66 2210-2221
[17] Martin O R Lai W Synthesis and Conformational Studies of β-(1rarr6)- and ββ-(1rarr1)-Linked C-disaccharides J Org Chem1993 58 176-185
[18] Spak S J Martin R The synthesis of an analogue of Methyl OC-Analogue of Methyl 4rsquo-O-β-D-GlucopyranosylgentiobiosideTetrahedron 2000 56 217-224
[19] Kobertz W R Bertozzi C R Bednarski M D C-GlycosylAldehyde Synthons for C-Linked Disaccharides J Org Chem1996 61 1894-1897
[20] Gurjar M K Nagaprasad R and Ramana CV First Synthesis ofMethyl α-C-D-Arabino-furanosyl-(1rarr5)-αminusD-Arabinofuranosidethe C-Disaccharide Segment of Motif C of MycobateriumTuberculosis Tetrahedron Lett 2000 43 7577-7579
[21] Witczak Z J Synthesis of C-Glycosyl Compounds and OtherNatural Products from Levoglucosenone Pure Appl Chem 199466 2189-2192
[22] Griffin F K Paterson D Taylor R J K Ramberg-BacklundApproaches to the Synthesis of C-Linked Disaccharides AngewChem Int Engl 1999 38 2939-2942
[23] Paterson B E Griffin F K Alcaraz M-L and Taylor R J KA Ramberg-Baumlcklund Approach to the Synthesis of C-GlycosidesC-Linked Disaccharides and C-Glycosyl Amino Acids Eur JOrg Chem 2002 1323-1336
[24] McAllister G D Paterson D E Taylor R J K A SimplifiedRamberg-Bachlund Approach to Novel C-Glycosides and C-Linked Disaccharides Angew Chem Int Ed Engl 2003 42 1387-1391
[25] McCartney J L Christopher T M Cicchillo R M BernardinaM D Wagner T R and Norris P J Org Chem 2003 6810152-10155
[26] Dondoni A Zuurmond H M Bascarate A Synthesis of α-andβ-D-(1rarr6)-C-Disaccharides by Witting Olefination of Formyl C-Glycosides with Glycopyranose 6-phosphoranes J Org Chem1997 62 8114-8124
[27] Dondoni A Kleban M Zuurmond H Marra A Synthesis of(1rarr6)-C-Oligogalactosides by Interative Wittig OlefinationTetrahedron Lett 1998 39 7991-7994
[28] Dondoni A Marra A A New Synthetic Approach toMycobacterial Cell Wall α-(1rarr5)-D-Arabinofuranosyl C-Oligosaccharides Teterahedron Lett 2003 44 4067-4071
[29] Colinas P A Ponzinibbio A Lieberknecht A and Bravo R OWittig Reaction of Glycosyl Phosphonium Salts A StereoselectiveRoute to C-Disaccharides and C O-Trisaccharides TetrahedronLett 2003 44 7985-7988
[30] Schmidt R R Preuss R Synthesis of Carbon Tetrahedron Lett1989 30 3409-3412
[31] Dietrich H Schmidt R R Synthesis of Carbon-Bridged C-Lactose and Derivatives Liebigs Ann Chem 1994 975-981
[32] Rouzaud D Sinayuml P The First Synthesis of a ldquoC-DisacchariderdquoJ Chem Soc Chem Commun 1983 1353-1354
[33] Xin Y-C Zhang Y-M Mallet J-M Glaudemans C P JSinayuml P Synthesis of C-Oligosaccharides That Mimie TheirNatural O-Analogues Immunodeterminants in Binding toMonoclonal Immunoglobulins Eur J Org Chem 1999 471-476
[34] Streicher H Geyer A Schmidt R R C-Disaccharides ofKetoses Chem Eur J 1996 2 502-510
[35] Leeuwenburgh M A Timmers C M Vander Marel G A VanBoom J H Mallet J-M Sinayuml P G Stereoselective Synthesisof α-C-(Alkynyl)-Glycosides Via Ring-Opening of α-12-Anhydrous Tetrahedron Lett 1997 38 6251-6254
[36] Aslam T Fuchs M G G Le Formal A Wightman R HSynthesis of C-Disaccharide Analogue of the α-D-Arabinofuranosyl-(1rarr5)-α-Arabinofuranosyl Motif ofMycobacterial Cells Walls via Alkynyl Intermediates TetrahedronLett 2005 46 3249-3252
[37] (a) Girad P Namy J L Kagan H B Divalent LanthanideDerivative in Organic Synthesis 1 Mild Preparation of SamariumIodide and Ytterbium Iodide and Their Use as Reducing orCoupling Agents J Am Chem Soc 1980 102 2693-2698 (b)Molander G A Harris C R Sequencing Reactions withSamarium(II) Iodide Chem Rev 1996 96 307-338
[38] (a) Mazeacuteas D Skrydstrup T Doumeix O Beau J-MSamarium Iodide-Induced Intramolecular C-Glycoside FormationEfficient Radical Formation in the Absence of an Additive AngewChem Int Ed Engl 1994 33 1383-1386 (b) Mazeacuteas DSkrydstrup T Beau J-M A Highly Stereoselective Synthesis of1 2-trans-C-Glycosides Via Glycosyl Samarium(III) CompoundsAngew Chem Int Ed Engl 1995 34 909-912 (c) Jarreton OSkrydstrup T Beau J-M The Stereospecific Synthesis of Methylα-C-Mannobioside A Potential Inhibitor of M TuberculosisBinding to Human Macrophages J Chem Soc Chem Commun1996 1661-1662 (d) Jarreton O Skrydstrup T Espionosa J-FJimeacutenez-Barbero J Beau J-M Samarium Diiode Prompted C-Glycosylation An Application to The Stereospecific Synthesis ofα-(1rarr2)-C-Mannobioside and Its Derivatives Chem Eur J 19995 430-441 (e) Mipuel N Doisneau G Beau J-M ReductiveSamariation of Anomeric 2-Pyridyl Sulfones with Catalytic AnUnexpected Improvement in The Synthesis of 12-Trans-Diequatorial C-Glycosyl Compounds Angew Chem Int Ed Engl 2000 39 4111-4114
[39] Vlahov I R Vlahova P I Linhardt R J DiastereocontrolledSynthesis of Carbon Glycosides of N-Acetylneuraminic Acid ViaGlycosyl Samarium(III) Intermediates JAmChem Soc 1997 1191480-1481
[40] Kuberan B Sikkander S ATomiyama H Linhardt R JSynthesis of a C-Glycoside Analogue of sTn An HIV-and Tumor-Associated Antigen Angew Chem Int Ed Engl 2003 42 2073-2075
[41] Bazin H G Du Y Polat T Linhardt R J Synthesis of aVersatile Neuraminic Acid ldquoCrdquo-Disaccharide Precursor for theSynthesis of C-Glycoside Analogues of Gangliosides J OrgChem 1999 64 7254-7259
[42] Chen C-C Ress D K Linhardt RJ Samarium Iodide-Mediated Synthesis of Neuraminic Acid C-Glycosides InSynthesis of Glycommetics Roy R Ed ACS Syposium Series2004 896 53-80
[43] Abdallah Z Doisneau G Beau J-M Synthesis of a Carbon-Linked Mimic of The Disaccharide Component of The Tumor-Relate SialyTn Antigen Angew Chem Int Ed Engl 2003 425209-5212
[44] Lay L Nicotra F Panza L Russo G Caneva E Synthesis ofC-disaccharides through dimerization of exo-glycals J Org Chem1992 57 1304-1306
[45] Isobe M Nishizawa R Hosokawa S Nishikawa TStereocontrolled Synthesis and Reactivity of Sugar Acetylenes JChem Soc Chem Commun 1998 2665-2676
[46] Saeeng R Sirion U Sahakitpichan P Isobe M IodineCatalyzes C-Glycosidation of D-Glucal with SilylacetykeneTetrahedron Lett 2003 44 6211-6215
[47] (a) Babirad S A Wang Y Kishi Y Synthesis of C-Disaccharides J Org Chem 1987 52 1370-1372 (b) Wang YBabirad S A Kishi Y Preferred Conformation of C-Glycosides
1430 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
8 Synthesis of 14-Linked Carbon Disaccharides J Org Chem1992 57 468-481
[48] Armstrong R W Sutherlin D P Strategies for the Synthesis ofC-Disaccharides Containing D and L Sugars Tetrahedron Lett1994 35 7743-7746
[49] Wei A Kishi Y Preferred Conformation of C-Glycosides 12Synthesis and Conformational Analysis of αα- α β- and β β-Trehaloses J Org Chem 1994 59 88-96
[50] Haneda T Goekjian P G Kim S H Kishi Y PreferredConformation of C-Glycosides 10 Synthesis and ConformationAnalysis of Carbon Trisaccharides J Org Chem 1992 57 490-498
[51] Sutherlin D P Armstrong R W Synthesis of 12 Stereochemistryand Structurally Diverse C-Trisaccharides J Org Chem 1997 625267-5283
[52] Notz W Hartel C Waldscheck B Schmidt R R De NovoSynthesis of a Methylene-Bridged Neu5Ac-α-(23)-Gal C-Disaccharide J Org Chem 2001 66 4250-4260
[53] (a) Postema M H D Calimente D Liu L Behrmanm T L AnOlefin Metathesis Route for the Preparation of (1rarr6)-Linked-C-Disaccharide Glycals A Convergent and Flexible Approach to C-Saccharide Synthesis J Org Chem 2000 65 6061-6068(b) Postema M H Piper J L Liu L Faust M Andreana PSynthesis and Partial Biological Evaluation of a Small Library ofDifferentially Linked β-C-Disaccharide J Org Chem 2003 684748-4754
[54] Nelson A The Development of Strategies and Methods for TheSynthesis of Biologically Active Compounds New J Chem 200428 771-776
[55] Togo H He W Waki Y Yokoyama M C-GlycosylationTechnology With Free Radiant Reactions Synlett 1998 700-717
[56] Giese B Dupuis J Diastereoselective Synthesis of C-Glycopyranosides Angew Chem Int Ed Engl 1983 22 622-623
[57] Adlington R M Baldwin J E Basak A Kozyrod RPApplication of Radical Addition Reactions to tho Synthesis of a C-Glucoside and A Functionalized Amino Acid J Chem SocChem Commun 1983 144-145
[58] Giese B Gonzaacutelez-Goacutemez J A Witzel T The Scope of RadicalCC-Coupling by The ldquoTin Methodrdquo Angew Chem Int Ed Engl1984 23 69-70
[59] Giese B Witzel T Synthesis of ldquoC-Disaccharidesrdquo by RadicalC-C Bond Formation Angew Chem Int Ed Engl 1986 25 450-451
[60] Witczak Z J Chhabra R Chojnacki J C-Disaccharides IStereoselective Approach to β-(1rarr4)-3-Deoxy-C-Disaccharidesfrom Levoglucosenone Carb Res 1997 301 167-175
[61] Vogel P Synthesis of Rare Carbohydrates and Analogues Startingfrom Enantiomerically Pure 7-Oxabicyclo[221]heptyl Derivatives(ldquoNaked Sugarsrdquo) Current Org Chem 2000 4 455-480
[62] Viodeacute C Vogel P Synthesis of The C-Disaccharide α-C(1rarr3)-L-Fucopyranoside of N-Acetylgalactosamine J Carb Chem2001 20 733-746
[63] Xin Y C Mallet J M Sinayuml P An Expeditious Synthesis of AC-Disaccharide Using A Temporary Silaketal Connection J ChemSoc Chem Commun 1993 864-865
[64] (a) Petitou M Herault P Lormeau J-C Helmboldt A MalletJ-M Sinayuml P Herbert J-M Introducing A C-InterglycosidicBond in A Biologically Active Pentasaccharide Hardly Affects ItsBiological Properties Bioorg Med Chem 1998 6 1509-1516 (b)Sinayuml P Advances in The Synthesis of the Carbohydrate MimicsPure Appl Chem 1998 70 1495-1499
[65] Sinayuml P Chemical Synthesis of Oligosaccharide Mimetics PureAppl Chem 1998 70 407-410
[66] Sinayuml P Chemical Synthesis of Oligosaccharide Mimetics PureAppl Chem 1998 69 459-463
[67] Vauzeilles B Sinayuml P Selective Radical Synthesis of β-C-Disaccharides Tetrahedron Lett 2001 42 7269-7272
1404 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
deprotonated with LDA to give 127 Addition of 127 toaldehyde 128 gave a mixture of diastereoisomers of whichthe major 129 was formed in a 101 ratio Desulfurizationhydroboration and removal of benzyl groups gave the(1rarr5)- βminusC-disaccharide 130 (Scheme 26)
Schmidt and coworkers used this methodology for ahighly efficient synthesis of an analog of C-trehalose 134Scheme 27 [31] Anion 131 was converted to aldehyde 132
and condensation of this aldehyde with the same anion gaveadduct 133 which was then converted to the target C-disaccharide 134
26 Acetylide-Based Anions
Sinayuml was the first to prepare a C-disaccharide Hisapproach involved the coupling of a C-6 alkyne with ananomeric lactone followed by reduction of the formedhemiacetal [32] Aldehyde 135 was converted to the
Scheme (20)
Scheme (21)
OO O
O
O CHO
O
BnOOBn
BnO
OBn
CHO
OBn
CHO
BnO
O
BnOBnO
O
BnOOBn
BnO OBn
CHO
PPh3I-
OO
O
OO
O
OMeOBn
OBn
OBn
PPh3I-
OCHO
O
PPh3I-
ORRO
RO
OO
ORRHO
OO
OR
+ +
+
( 93 - 96 )
( 97 - 98 )
BuLi THF-HMPA
-30 iexclaelig
99
Reduction
100
+
93 9495
96 97 98
O
OBnBnO
BnO
OO
O
OO
HO
O
O
OO
PPh3I-
O
OHHO
HO
O
HOOH OH
HO
OBnBnO
CHO
BnO
O
+
BuLi THF-HMPA
-30 oC
1 p-MeC 6H4SO2-
NH2NH2 AcONa
2 H2 Pd(OH)2 3 bar
3 Amberli te H+
+
10197
102
103
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1405
dibromoalkene 136 which was treated with n-butyllithium togive an intermediate acetylide 137 The latter uponnucleophilic addition to lactone 138 gave a mixture of lactol139 in high yield Stereoselective reduction of lactol 139 wasfollowed by hydrogenation of benzyl groups and the triplebond affording the (1rarr6)-β-C-disaccharide 140 (Scheme28)
The lactone-addition methodology was later applied bySinayuml and co-workers in an iterative fashion for the
preparation of higher homologues [33] Hydroxylmethylenein compound 141 was converted to acetylide lithium incompound 142 by a sequence of reactions Condensation ofcompound 142 with the galacto lactone 143 gave 144 asmixture of anomers The lactol were stereoselectivelyreduced to and triple bond was hydrogenated to give 145Methyl glycoside 145 was hydrolyzed to the correspondinglactols which were oxidized to lactone 146 The samesequence was then repeated twice to give C-trisaccharide147 and C-tetrasaccharide 148 (Scheme 29)
Scheme (22)
O
BnOOBn
BnO OTBDPS
PPh3I-
BnO
H
O
BnOOBn
OTBDPS
OO
O
OO
O
CHOO
O
OO
O
BnO
O
BnOOBn
BnO
OO
O
OO
H
HOBn
BnO OTBDPS
O
BnOOBn
BnO O
OO
O
OO
H
OBn
BnO OTBDPS
PPh3I-
O
BnO
O
BnOOBn
BnO OTBDPS
PPh3I-
O
AcOOAc
AcO
O
AcOOAc
AcO
OO
O
OO
O
AcOOAc
AcO OAc
O
BnOOBn
BnO
O
BnOOBn
BnO
OO
O
OO
H
H
O
BnOOBn
BnO OTBDPS
H
1 TBAF2 PCC
+107 36
+
1 TBAF2 PCC3
+
1 TBAF2 H2 Pd(OH)2 C3 Ac2 O Pyr
104
33
105
106104
104
108109
BuLi THF-HMPA
-50 o C
70EZ 19
BuLi THF-HMPA
-50 o C
1406 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
The di- tri- and tetrasaccharide derivatives (145 147 and148) were all debenzylated and tested for their bindingaffinity to three different monoclonal immunoglobulins withspecificity for different O-β-(1rarr6)-D-galactopyranosyl deter-minants These C-saccharide analogs had similar bindingproperties to the corresponding O-saccharides
Schmidt has also used acetylide-lactone condensation toassemble C-disaccharides of ketoses [34] Lithium acetylide149 was condensed with ketone 150 to give a mixture ofalcohol 151 after removal of the pivoloyl group Attemptedcyclization under Lewis acid catalysis resulted only in theremoval of the acetonide Accordingly the diol was tiedback as the carbonate and the acetylene complex as thedicobalt species 152 The isomers were then separately
cyclized to give a 11 mixture of C-disaccharide 153 Thecobalt complex on α-C-disaccharide was removed understandard conditions to give 154 and deprotection of thecarbonate was followed by hydrogenation and peracetylationto give 155 (Scheme 30) Similar chemistry was also carriedout with the corresponding β-isomer
Van Boom and co-workers used lithiated alkynylderivative 156 in presence of ZnCl2 to selectively open ringof the 12-anhydrosugar 157 affording the α-C-(alkynyl)-glycoside 158 Hydrogenolysis of the benzyl groups wasfollowed by peracetylation to give the (1rarr6)-α-C-disaccharide 159 (Scheme 31) [35]
Normally attack of the nucleophile proceeds from anequatorial direction to give the β-isomer The unexpected
Scheme (23)
Scheme (24)
BnOO
OBnCHO
OBn
O
OBn
PPh3I-
OBn
OBn
O
OBn
BnOBnO
O
OBnOBn
OBnH
O
OH
HOHO
O
OHOH
OH+
BuLi
THF-HMPA
-20 oC+
1 TBAF2 H2 Pd(OH)2C
112 65 113 100
110
111
O
OBnCHO
OBnBnO
O
OBn
BnOBnO
O
OBnCH(OiPr)2
OBnH
O
OBnCH(OiPr)2
PPh3I-
OBn
O
OBn
BnOBnO
O
OBn
OBnH
O
OBnOBn
BnOH
O
OH
HOHO
O
OH
OH
O
OHOH
HO
++
BuLi
THF-HMPA
-20 oC
BuLi
THF-HMPA
-20 oC
TFA H2 O THF rt
115 49
116 R = CH(OiPr)2
117 R = CHO
118 45
H2 Pd(OH)2C
110
114
114
119
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1407
Scheme (25)
Scheme (26)
OBn
R1
R2
PPh3BF4-O
O
OOHC
O
O
O
O
O
O
O
O
HO
O
O
O
O
O O
OBn
R1
R2
O
O
O
O
O
O
H
O
OBn
R1
R2
O
O
O
O
O
O
O
O
OBn
R1
R2
O
O
O
+
BCl3 (005 equiv)
MS 4A CH2 Cl2 0 o C
+
BuLi THF -90 oC -90 o C
to rtH2 (1 atm) PdC Et3N MeOH
R1 R2 = OBn H
120a - b
121
122a - b
123a - b
124
125a - b
OTBDPS
BnO X
SO Ph
O
BnO
OHCO
BnO
OMeOBn
OBn
O
BnO
OTBDPS
BnO
SO Ph
O
BnO
OMeOBn
OBn
O
HO
OMeOH
OHO
HOHO
OH
OH
128
229 74
1 RaNi (74)
2 BH3 DMS
NaOH H 2O2 (74)
3 H2 PdC (70)
130 74
LDA THF
-100 oC
126 X = H
127 X = Li
1408 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (27)
Scheme (28)
stereochemical outcome is rationalized by the generation ofan initial zinc acetylide species which facilitates intra-molecular delivery to the α-face (Scheme 32)
Wightman synthesized C-disaccharide analogs of the α-D-arabinofuranosyl-(1rarr5)-α-D-arabinofuranosyl motif ofmycobacterial cell walls through alkynyl intermediates [36]The lactone 164 was treated with lithio(trimethylsilyl)ethyneat low temperature to give lactol in 66 yield of 165Treatment of this with triethylsilane and BF3
Et2O gavethe separable isomers 166α (60) and 166β (13)Desilylation of the major isomer 166α gave 167 in 97yield Treatment of 167 with n-BuLi followed by addition oflactone 164 gave 85 yield of the hemiacetal 168 which onreduction with Et3SiH and BF3
Et2O gave the disubstitutedalkyne 169 (83) as the major product Reduction-
hydrogenolysis of 169 then gave the C-disaccharide 170 innear-quantitative yield (Scheme 33)
3 REDUCTIVE GLYCOSYL SAMARIUM SPECIES
The introduction of SmI2 as reducing agent can becredited to Kagan and has since been utilized in numeroussynthetic schemes [37] Sinayuml and Beau introduced SmI2
chemistry into C-glycoside synthesis through intermolecularreactions with appropriate electrophiles and intramolecularreactions of silyl tethered substrates [38] Anomericsamarium species are highly stable and not likely to undergoβ-elimination Treatment of the aryl sulfone 171 with SmI2
affords the nucleophilic intermediate 172 through two singleelectron transfer processes Introduction of a suitableelectrophile (carbonyl compounds) affords the α-C-manno-
O
BnO
OTBDPS
BnO X
SO Ph
O
BnO
OBn
BnO Li
SO Ph
DMF
OHO
HOOH
OH
O OH
OH
HO
OHOH
O
BnO
OTBDPS
BnO
SO Ph
O
OBn
OBnOBnSO
Ph
OH
131 X = Li
132 X = CHO
THF -100 oC
1 Ra-Ni
2 BH3 DMS NaOH H2O2
3 H2 PdC
131
133
134
OBnO
OBnOMe
BnO
Li
OBnO
BnOOBn
OBn
OOBn
OBnOMeBnO
OH
OBnO
BnOOBn
OBn
O
n-BuLi
BnO
OMe
BnO
BrBr
O
OBn
OHO
OH
OH
HO
OHO
OH
HO
OMe
O
BnO
OMeOBn
O
BnO
139 92
1BF3 OEt2 EtOH
2 H2 PdC AcOH
140 52 over 2 steps
135 136 137
138
CBr4 PPh3
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1409
pyrannoside 173 in good yield and with excellent stereo-selectivity (Scheme 34) [38a]
Preparation of C-glycosides of ulosonic acids using SmI2
was pioneered by Linhardt and coworkers [39] Coupling ofpyridyl sulfone 174 with aldehyde 175 in the presence ofSmI2 gave an excellent yield of the N-acetylneuraminic acidC-disaccharide 176 as single isomer This stereochemicaloutcome was rationalized on the basis of the Felkin-Anhmodel for predicting the stereochemical outcome of akinetically controlled addition of a nucleophile to a chiraladehyde (Scheme 35 A)
Reductive samarium method was utilized to synthesizesialo-antigen C-analogs by the Linhardt group A fullyprotected C-analogue of the SialylTn antigen α-D-Neu5Ac-(2rarr6)α-D-GalNAc-(1rarrO)-Ser 182 was prepared [40] C-glycosylation of the neuraminic acid sulfone donor with
aldehyde acceptor in presence of excess SmI2 afforded the α-C-glycoside 180 as an RS mixture (11) The criticalintermediate aldehyde acceptor 178 was prepared in 13steps Chemoselective resolution to compound 180 wasundertaken by oxidation with DMSOAc2O to keto-bridgedcompound 181 followed by stereoselective reduction withZn(BH4)2 to regenerate the bridge hydroxyl function gave182 in gt90 de (Scheme 36)
A common versatile N-acetylneuraminic acid C-disaccharide precursor of the C-glycoside analogs ofgangliosides GM4 and GM3 has been synthesized [41]Samarium(II) iodide coupling of N-acetylneuraminic acidsulfone 179 with a 3-formyl galactopyranoside derivative183 afforded the corresponding C-disaccharide 184 as amixture of (R) and (S) isomers at the newly formedhydroxymethylene bridge This diastereoisomeric mixturewas resolved after debenzylation of the galactoside residue
Scheme (29)
O
BnO
BnOOBn
OBn
OOBn
OBnOMe
OBnOH
O
BnO
BnO
OBn
OBn
O
O
BnOOBn
OMe
BnO
Li
OBnO
OBn
OBn
OBnO
OBn
OBn
OMe
OBnO
OBn
OBnBnO
OBnO
OBn
OBn
OBnO
OBn
OBn
OMe
OBnO
OBn
OBnOBnO
OBn
OBnBnO
O
BnO
BnO
OBn
O
OBnO
OBn
OBnBnO
OBnO
OBn
OBnBnO
OBnO
OBn
OBn
OMe
OBnO
OBn
OBnBnO
OMe
1 PCC2 CBr4 Ph3P3 n-BuLi
144 overall yield 54
1 BF3 OEt2 Et3 OH
2 H2 PtO2 EtOAc
145 76
1 H2 SO4 AcOH
2 PCC
146 62
repeat steps
repeat st eps
141 142
143
147
148
1410 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (30)
Scheme (31)
O
BnOOBn
OMe
Li
BnO
OPivBnO
OBn
OBn
BnO
O OO
BF3 OEt2
OBnO
OBn
OBn
BnO
OO
O
OMe
BnOOBn
BnO
Co(CO)3
Co(CO)3
O
CAN
OBnO
OBn
OBn
BnO
OO
OO
BnOOBn
BnO
OMe
OHBnO
OBn
OBn
BnO
OHO
O
O
OMe
BnOOBn
BnO
Co(CO)3
Co(CO)3
O
OPivBnO
OBn
OBn
BnO
OH OO
O
OMe
BnOOBn
BnO
OAcO
OAc
OAc
AcO
OAcOAc
OAcO
OAc
AcO
OMe
1
2 NaOMe MeOH
1 Lewis acid2 ClCO2CCl3 Pyr3 Co2(CO)8
with a-isomer
1 Et3N Pyr H2O
2 H2 PdC H+
3 Ac2 O Pyr
149 151
152153
154 155
150
OBn
BnO
OBnO
OBn
BnO
OBnO
BnO
MeO
OBnO
OBn
BnO
O
OMe
AcO
OAcO
OAc
OAc
AcO
OAcO
OAc
O
BnOOBn
OMe
BnO
159 74 over 2 steps
+
BuLi ZnCl2 THF
1 H2 PdC2 Ac2O Pyr
156 157
158 59
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1411
Scheme (32)
Scheme (33)
and the chirality of each isomer assigned after acetylationConversion of the p-methoxyphenyl group in the peracety-lated (S) isomer 187 into the corresponding thiophenylglycoside 188 was accomplished affording the key inter-mediate for the synthesis of C-glycoside analogs of GM4GM3 and other related gangliosides (Scheme 37)
Ganglioside GM4 is a very important cell adhesionmolecule The C-disaccharide of GM4 is currently beingsynthesized in Linhardtrsquos lab using standard O-glycosylationof C-disaccharide with protected ceramide Once theceramide has been attached it can be oxidized to afford analdehyde group for coupling to keyhole limpet hemocyanin
OBnO
OBn
BnO
O
OBnO
ClZnO
OBn
BnOCl
R
OBnO
O
OBn
BnOCl
ZnR
O
ZnR
OBnO
OBn
BnO
160 161
162163
O
OBn
OBnBnO
O
O
OBn
OBnBnO H
TMS
O
OBn
OBnBnO H
O
OBn
BnO
OBnHO
O
OBn
OBnBnO OH
TMS
OBnBnO HO
OBn
TMS
O
OR
ORRO H
O
OR
RO
OR
OBn
OBnBnO
H
TMS
O+
K2CO3 MeOH
1 n-BuLi THF -78 oC
2 164
164165 66
166α 60 166β 13167 97
BF3 Et 2O Et 3SiH -78 oC
168 85
169 R = Bn 83
170 R = H near quantitative yield
H2 (1 atm)Pd(OH) 2C
TMS-acetyl ene
n-BuLi THF -78 oC BF3 Et2O Et3SiH
-78 o C
1412 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
O
OHCOBn
OBnBnO
OMe
O
CO2MeAcO
OAcAcHN
OAc
SO2
NAcO
OBnH
H
OBn
OBn
H
O
OMeH HH
A
O
CO2MeAcO
OAcAcHN
OAc
O
OBnOMe
OBnOBn
HO
AcO
+
Nu
174175
176
SmI2 THF
Scheme (34)
Scheme (35)
Scheme (36)
O
BnO
BnO
BnO
Si lylO
O2S N
O
BnO
HO R2R1
BnOBnO
SilylO
OBnO
BnO
BnO
SilylO
Sm(III)
R1COR2 SmI2 THF
171 172
173
NHBoc
OAcO
AcO
AcHN O
O
CO2BnO
OO
OO
OH
O
CO2MeAcO
OAcAcHN
OAc
AcO
SO2Ph
R2
O
CO2Me
AcHN
OAc
AcO
R1
AcO
AcO
AcHNO CO2Bn
NHBoc
AcO
OAc
O
Zn(BH4)2
180 R1 R2 = H OH ( RS 11)
181 R1 R2 = O
182 R1 = H R2 = OH de gt 90
DMSO Ac2O
177178
179
13 steps
22 equiv SmI2 THF
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1413
Scheme (37)
Fig (2)
(KLH) by reductive amination for use as carbohydrate-basedvaccine GM3 a related trisaccharide containg gangliosideplays an important role in cell growth and differentiationFig 2 The synthesis of C-oligosaccharide GM3 is currentlyunderway following a similar route to that of C-GM4synthesis [42]
Beau also reported a sialyl C-disaccharide synthesiswhich relied on the unprecedented use of a stable andcrystalline 2-pyridyl sulfide of the N-acetylneuraminic acidderivative 189 as the anomeric precursor in a samarium-Reformastky procedure [43] The coupling procedure withsulfide 189 and aldehyde 190 afforded the carbon-linkeddimer 191 in 93 yield as a 11 diastereomeric mixture
Alcohols 191 were converted into thiocarbonates anddeoxygenated by employing triphenyltin hydride catalyticAIBN and pentafluorophenol which yielded C-disaccharide192 as a single compound in 65 yield for the 2 stepsDesilylation hydrogenolysis acetylation and finalacetolysis of the methyl glycoside provided the carbon-linked mimic 193 of the disaccharidic component of thesialylTn tumor antigen (Scheme 38)
4 CATIONIC METHODS
This section is categorized according to reactions thatinvolve the generation of anomeric ions followed by thecapture with sugar-based nucleophiles
OAcAcHN
OAc
AcO
O
OBnBnO
OBnOMP
HO
O
MeO2CAcO
O
MeO2CAcO
OAcAcHN
OAc
AcO
O
OHHO
OHOMP
HO
O
OBnOHC
OBnBnO
OMP
O
MeO2CAcO
OAcAcHN
OAc
AcO
O
OHHO
OHOMP
HO
O
CO2MeAcO
OAcAcHN
OAc
AcO
SO2Ph
O
MeO2CAcO
OAcAcHN
OAc
AcO
O
OAcAcO
OAcX
AcO
H2 PdC EtOAc CH3OHH2O
+
Ac2O Pyr
187 X = OMP
188 X = SPh 73
184 85 R and S mixture
186 90 for two i somers
+
SmI2 THF183
179
185
O
HO2 CHO
OAcAcHN
OH
HO
O
OHHO
OH
OAcO
(CH2 )12 CH3
HN
OH
(CH2)14CH3
O
O
O
OHHO
OH
O
O
HO2 CHO
OAcAcHN
OH
HO
O
OHHO
OH
O(CH2)12CH3
HN
OH
(CH2)1 4CH3
GM4
GM3
1414 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
41 Exo-glycals as Nucleophiles
Nitotra et al have found that treatment of exo-glycal 194with BF 3
OEt2 followed by a water quench afforded the C-disaccharide 195 (Scheme 39) It is noteworthy tonoteworthy that the attack of the enol ether on the anomericoxonium ion occurs with high stereoselectivity on the α-face only 195 was obtained [44]
42 Silyl-based Nucleophiles
Isobe has designed and developed alkynylation as a keyreaction for the introduction of a carbon chain onto sugarsThose alkynylated compounds are called ldquosugar acetylenesrdquo[45] The mechanism includes eliminative formation ofcation to which silylacetylene can coordinate on the α-face(Scheme 40)
Double C-glycosylation between glycal 198 and bis(silylacetylene) gave C-disaccharide ldquolikerdquo compounds 199and 200 (Scheme 41)
Silylpropargyl-sugar 201 smoothly reacted with D-glucalto furnish exclusively the α-acetylene glycoside product 202in 88 (Scheme 42) [46]
5 CYCLIZATION METHODOLOGY
This approach to C-oligosaccharide synthesis relies onthe coupling of an open chain fragment with an intact
monosaccharide to give an intermediate that is then cyclizedto deliver the C-oligosaccharide target This section isdivided by the type of chemistry used to initially assemblethe two pre-cyclization fragments
51 Wittig Reaction-Cyclization
The Kishi group was the first to use Wittig-cyclizationapproach to synthesize C-disaccharides Starting with Wittigreaction between 203 and 204 the intermediate 205 wasafforded as a single stereoisomer in 82 yield Osmylationthen gave a mixture of diols with the major one formed in a61 ratio Selective protection of the diols gave 206a and206b The mono-para-methoxybenzyl ether 206a was thentransformed into the hemiketal 207 in 75 overall yield inthree steps ie (1) Swern oxidation (2) acetonide hydro-lysis (4 N HClTHFrt) and (3) benzoylation (3 equiv ofPhCOClpyCH2Cl2rt) Silane reduction of 207 in an acidicmedium should preferentially yield the equatorially substi-tuted β-C-glycoside which was deblocked and converted tothe methyl- βminusC-disaccharide 209 Exact parallel experi-ments applied to the minor isomer gave the correspondingC-disaccharide 210 (Scheme 43) [47]
Armstrong has employed Wittig-osmylation protocol forthe preparation of a small library of α-C-(1rarr6)-disaccha-rides [48] Readily available allyl C-glycoside 211 washomologated to diene ester 212 and subjected to osmylation
Scheme (38)
O
CO2MeAcO
OAcAcHN
OAc
AcO
S(2-Py)
O
TESO
AcHNOMe
O
HO
O
CO2MeAcO
OAcAcHN
OAc
AcO
O NHAcOAc
OAc
OAc
O
CO2MeAcO
OAcAcHN
OAc
AcO
O NHAcOBn
OTES
OMe
OAc
AcO
O NHAcOBn
OTES
OMeOH
O
CO2 MeAcO
OAcAcHN
+
192 65
1 MeOHHCl2 H2 PdC EtOH3 Ac2O Pyr4 Ac2OAcOHH2SO4
193 59 overall yield
25 equiv SmI2 THF
1 11-thiocarbonyldiimidazole DMAP2 Ph3SnH cat AIBN
191 93
189
190
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1415
Scheme (39)
Scheme (40)
Scheme (41)
OBnO
OBn
OBn
OBnO
OBn
OBn
OBnO
OBn
OBn
OBnO
OBnCH3
BnO
OH
CH2
OBnO
OBn
CH3
OBn
H2 O
BF3 OEt2 MeCN
194
195 96
OOAc
OAc
AcO
R SiMe3
SnCl4
O
OAc
AcO
R
O
OAc
AcO
O
OAc
AcO
Me3Si
R
SiMe3
196
197
Me3 Si SiMe3
O
AcO
OAc
OAc
SiMe3
SiMe3
O
AcO
OAc
O
OAc
OAc
O
AcO
AcOO
OAc
OAc
SnCl4 CH2Cl2
SnCl4 CH2Cl2198
199
200
1416 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (42)
Scheme (43)
AcO
OAc
OAc
Me3 Si
BnO
OBn
BnO
OBn
AcO
OAc
BnO
OBn
BnO
OBn
+ I2 CH2Cl2
202 88
198 201
O
OBn
OBn
O
O
O
OBn
OBn
O
O
OBn
OBn O
OBn
OBn
O
OPBH2M
OH
OBnO
BnO
BnO
O
OBn
OBn
O
OHOPMB
OHO
HO
HO
O
OH
OHOH
OH
HOOMe
O
OBnOBn
O
Ph3P
O
O
OBn
OBn O
OBn
OBn
O
OPBM
OH
O O
CHO
OBn
BnO
OO
OBn
OBn
O
OHOPMB
BnO
BnO
BnO
OHO
HO
HO
O
OH
OHOH
OH
HOOMe
+ THF -78 oC
1 OsO4 pyr THF
2 NaH PMBBr
206a 206b 206a206b 61
1 Swern [O]2 4N HCl3 PhCOCl pyr
1 Swern [O]2 4N HCl3 PhCOCl pyr
1 PrSiH BF3 OEt2
2 H2 Pd(OH)2C
3 HCl MeOH 90 oC
1 PrSiH BF3 OEt2
2 H2 Pd(OH)2C
3 HCl MeOH 90 o C
203
204
205
207
209
208
210
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1417
followed by reduction to afford a 51 mixture (213214215216) of lactols that were readily separable by chromato-graphy Following a deprotection of an equimolar mixture of213 and 214 217 and the DL hybrid C-disaccharide of D-glucose-O-(1rarr6)-L-galactose 218 were obtained The DDand DL derivatives 219 and 220 of glucose-α-(1rarr6)-idosewere also obtained as a near equimolar mixture afterdeprotection of 215 and 216 (Scheme 44)
52 Anion Addition-Cyclization
Kishi developed an approach for the synthesis of theCndashtrehalo sugars which relied on nucleophilic addition ofone intact sugar fragment to a fundamental aldehyde ieKishi-Nozaki reaction [49] Coupling of monosaccharide221 and aldehyde 222 gave 223 The triple bond waspartially reduced and osmylation was followed by selectiveprotection to afford 224 The acetonide was converted toepoxide 225 by standard methods and removal of the PMBgroup Acid-catalyzed cyclization followed by aglyconichydrolysis and protection of hydroxyl group with (p-methoxyphenyl)diphenylmethyl chloride (MMTrCl) gave226 Inversion of the C-2 hydroxyl and removal of protectinggroups delivered α α-C-trehalose 227 (Scheme 44)
Kishi and co-workers also employed aldol reactions as anefficient access to the C-trisaccharide related to the type IIABO(H) blood group determinant [50] Aldol condensationof the enolate of methyl ketone 228 with aldehyde 229 gavea 41 mixture of hydroxy ketones 230 and 231 The majorketol was cyclized desulfurized and oxidized to afford thedisaccharide ketone 233 The ketone in THF was treatedwith LiHMDS (3 equiv) and TMEDA followed by theaddition of MgBr2 Addition of the aldehyde 234 led toalmost exclusive formation of the equatorial products 235and 236 in a 12 ratio Mesylation of 235 and 236 followedby treatment with liquid ammonia gave enones 237a and237b which were reduced to yield exclusively the C-2rsquo-equatorial ketone 238 Sodium borohydride reduction of theC-3rsquo carbonyl proceeded with the desired stereoselectivity toyield the protected C-trisaccharide 239 which wasdeblocked to provide the polyol 240 (Scheme 46)
Sutherlin and Amstrong cleverly applied a recursivestereochemical deconvolution (RSD) combinatorial approachfor the synthesis of a small library of C-trisaccharides aspotential inhibitors for the cell surface proteins of bacteriumHelicobactor pylori [51] The workers chose to carry outvariations in galactose ring of these trisaccharides An
Scheme (44)
OBnO
BnOOBn
OBn
P O
OEtOEtO
EtO
R H
OH
OH
OH
OH
O
R H
OH
OH
OH
OH
O
OHO
HOOH
OH
O
HO
OHOH
OH
OHO
HOOH
OH
O
HO
OH
OH
OHO
HOOH
OH
O
HO
OH
OHOH
R H
OH
OH
OH
OH
O
R
OBnO
BnOOBn
OBn
O
OHO
HOOH
OH
OO
HOHO
OH
R H
OH
OH
OH
OH
O
1 OsO4 NMO 50
2 DIBAL -32 oC 40
++ +
213 214 215 216
217 218 219 220
1 9-BBN H2O22 Swern [O]
3 t-BuOK
4 I2 C6H6212
211
1418 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
efficient Nozaki-Kishi coupling of vinyl bromide 241 withaldehyde 242 in a diasteromeric ratio of 12 followed byprotection with TBSOTf led to 243 and 244 Hydroborationfollowed by oxidation gave aldehydes 245 and 246respectively Addition of allylmagnesium bromide toaldehyde 245 followed by removal of the silyl groupafforded 247 to 246 giving 248 and 249 Epoxidation gave a11 mixture of the corresponding epoxides which werecyclized to give the C-trisaccharide 250-255 after removalof the benzyl groups (Scheme 47)
Schmidt reported a stereoselective 6-exo-trig selectiveelectrophilic cylization approach for de novo synthesis of amethylene-bridged Neu5Ac-α-(23)-Gal C-disaccharide theC-analog of an important motif in glycosphingolipids [52]The open chain precusors 259ab (a 32-mixture ofdiaseteromeric alcohols) were formed by the addition oflithiated iodide 256 to open chain aldehyde 258 Subsequent
C1 incorporation using Tebbe-reagent formation of a cycliccarbonate and deprotection of the two isopropylidene ketalsafforded tetrol 264 which upon treatment with phenylselenyltrifilate was steroselectively cyclized in a 6-exo-trigselective manner affording a diasteromeric mixture of 251and 252 in a ratio of 71 A seleno-Pummerer rearrangementto afford aldehyde 267 in 5 steps in 90 overall yieldOxidation of the aldehyde and subsequent steps led to thedesired C-disaccharide 268 (Scheme 48)
53 Esterification-Cyclization
Work from the Postema group has focused on a ringclosing metathesis (RCM) approach for the synthesis of C-saccharides [53a] The chemistry is versatile and has beenused for the synthesis of a small library of differentiallylinked β-C-disaccharides through a radical allylation-RCMstrategy [53b] The synthesis of the β-(1rarr4)-glucopyranosyl
Scheme (45)
O
OBn
BnO
BnO
BnO
I
CrCl2-NiCl2O
OBn
OH
BnO
BnO
BnO
O
O
O
O
O
H
OBn
O
O
OBnBnO
BnO
BnO
OOBn
OBn
OAc
PMBOHOO
OBn
BnO
BnO
BnO
O
OBn
OBn
OAc
O
OH
HO
HO
HO
OH
OH
OH
O
OH
O
OBn
BnO
BnO
BnO
OBn
OBn
OAc
O
MMTr
+
1 p-TsOH2 K2CO3 MeOH3 MMTrCl pyr
1 Swern [O]2 BH3 THF
3 AcOH-H2 O4 H2 Pd(OH)2
221
222
223
1 Pd-Pb CaCO3 H22 NaH BnBr3 OsO44 Bu2 SnO5 CsF PMB-Cl6 Ac2 O 4-DMAP
1 AcOH2 TsCl pyr
3 NaH-imid4 DDQ
224225
226 227
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1419
Scheme (46)
OBnO O
OBn
OMe
OBn
XY
SMe
OBnBnO
O
OBn
OBn
OBn
OBn
O
BnO
YX
OBn
TBSO
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnOOBn
H
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnO
OBn
OHC OBn
OBn
OTBS
OMe
BnOOBn
CHO
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnOOBn
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnO
OBn
YX
OBnO O
OBn
OMe
OBn
OBn
O
BnO
O
OBn
OBn
OBn
OBn
O 1 LiHMDS
2
228
1 TBAF THF
2 MeSH BF3 OEt2
230 X = OH Y = H231 X = H Y = OH
230231 41
1 Bu3SnH AIBN2 Swern [O]
1 LiHMDS THF-TMEDA2 MgBr23
1 MsCl
2 liquid NH3
235 X = OH Y = H236 X = H Y = OH Bu3 SnH AIBN
237a and 237b
NaBH4 MeOH
238
239 X = OBn
240 X = OHH2 Pd(OH)2
229
232233
234
1420 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (47)
OH C
O
O BnAcHN
OO
O
OBn OBnOBn
Br
O
OBn OBnOBn
O
OBnA cHN
OO
O TBSO
OBn O BnO Bn
O
OBnAcHN
OO
OTBS
S2
S1
S2
OTBSS1
O H
S2
OT BSS1
O H
MgBrMgBr
S2
O TBSS1
O H
S2
OHS1
OH
S2
OTBSS1
OH
O
OHHO
O H
O
HO
H OO
OBnA cH N
HO
H O
O
O HHO
OH
O
HOHO
O
OBnA cH N
HO
H O
O
OHH O
OH
O
H O
HOO
OBnAcHN
HO
HO
O
O HH O
OH
O
H O
H O O
OBnA cHN
HO
HO
O
O HH O
O H
O
HO
H O O
OBnAcHN
HO
HO
O
OHHO
OH
O
H O
O
OBnA cHN
HO
HOHO
+
241 242
1 CrCl2-NiCl2 T HF-DMF 722 TBSOTf 2 6-lutidine 91
243 244
1 9-BBN 602 Dess-Mart in period inane 97
1 9 -BBN 552 D ess-Martin periodinane 98
245 246
1
2 T BAF 74
1
2 TBAF 88
247 248 249
250
251
250 251 1 1 252 253 1 1 254 255 1 1
252
253
254
255
1 MCPBA2 CSA CH 2Cl2 61 fo r 2 steps3 H 2 Pd (O H)2C 95
1 MCPBA2 CSA CH 2Cl2 63 fo r 2 s teps3 H 2 Pd (OH)2C 87
1 MCPBA2 CSA CH2Cl2 80 for 2 steps3 H2 Pd(O H)2C 95
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1421
Scheme (48)
O
OO
Se Ph
R
O
HO OHOH
O
OB n O B n
OB n
O B nO O
O O
R O OR
X
O
OO
R
Se Ph
O
HOOH
OH
O
OB nOB n
O Bn
OB n
O O
O O
R O O R
O H
O
O B n OB n
O B n
OB n
O
C HO
O
O O
R O OR
OAc HN
OAc
C O2NH 4HOOH
OH
O
OH O H
OH OH
O
OB n O B n
OB n
OB nO O
O O
R O OR
X
O
O
OAcOAc
C HOA cOOAc
OAc
O
OB n O B n
OB n
OB n
O
O Bn OB n
OB n
OB n
X
OH
OO
HOOH
OH
O
O
OMeOB n
OB nOB n
R
t-B uL i256 R = Li
257 R = L i
258
(R = t-B uMe 2Si )
(R = t-B uMe 2Si )
259ab (32) 79 com bine d yi eld
De ss-Ma rtin pe riodinane
260 X = O R = t-B uMe 2Si ) 95
261 X = O R = t -B uMe2S i) 62
T e bbe re age nt
TB A F THF262 X = O R = H 94
diphosge ne
C H2C l 2Pyr
263 95
T HFH2O T FAr t
264 quant it a ti ve yie ld
PhSe C l AgOT f
EtC N -80 oC
265
266
Quant it at i ve yi l ed 25 26 7 1
+
R =
1 Ac 2OPyr
2 mC PB A3 Ac 2ONa OAc
4 NaO HT HFMe OH
5 Ac2O P yr
267 90 overa ll yi e ld
ste ps
268
1422 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
glucopyranoside 280 represents an example of thischemistry The known triacetyl glucopyranoside 269 wasconverted to iodide 270 in good yield Radical allylation of271 proceeded to afford a mixture of equatorial and axialallylation products in a 61 ratio Oxidative cleavage of thedouble bond gave the corresponding aldehydes 273a and273b which were separable Pinnick oxidation of the majoraldehyde 273a then gave the C-4 equatorial acid 274 DCC-mediated coupling of alcohol 275 and acid 274 proceeded toafford ester 276 in good yield Methylenation of 276 gave277 and exposure to catalysist 278 gave a 41 yield of theC-disaccharide glycal which was exposed to an excess ofBH3
THF to give 64 yield of the β-C-disaccharide 279Removal of the benzyl groups and global peracetylation gavethe peracetylated (1rarr4)-β-C-disaccharide 281 in good yield(Scheme 49)
54 Ring Expansion-Cyclization
Nelson developed a new strategy for asymmetric andstereoselective synthesis of C-linked disaccharide mimeticsthe C58-C71 fragment of palytoxin [54] The diol (RR)-282was converted into the di-dihydropyran (DHP) template 283284 and 285 The di-DHPs were functionized in a twodirectional sense using dihydroxylation reactions The two-directional approach was often very efficient indeed forexample in the synthesis of 286 six new stereogenic centerswere introduced with almost complete stereocontrol using areduction and a dihydroxylation reaction The approach isnot restricted to the synthesis of C2-symmetricaldisaccharide mimetics Using the unsymmetrical template285 which has both a pseudo-axial and a pseudo-equatorialhydroxyl groups the unsymmetrical mimetics 289 and 290were prepared (Scheme 50)
6 RADICAL APPROACHES
The radical approach for C-C bond formation is a popularmethod within organic chemistry The use of radicalchemistry in carbohydrate synthesis has certain advantagesFirstly the reaction conditions are very mild and tolerant ofa range of functional and protecting groups Secondanomeric radicals are stable with respect to elimination andepimeration Most significantly the chemistry required toincorporate an appropriate substitute at C-1 employed in theinitial hemolytic cleavage step is common within carbo-hydrate chemistry [55] The use of such radical techniquecan be subdivided into two classes intermolecular andintramolecular approaches
61 Intermolecular Radical Approaches
Giese was the first to employ an intermolecular radical-based approach for synthesis of C-disaccharides [56]Addition of an alkene to an anomeric radical underappropriate conditions allowed exclusive entry to the α-linked C-glycoside a result which was mirrored by the workof Baldwin [57] The high α-selectivity of the reaction wasin contrast with other reports Thus radicals generated at theC-2 C-3 and C-4 centers all preferred to occupy equatorialpositions [58] When the anomeric bromide 291 was treatedwith tin hydride and AIBN resulting anomeric radical andreacted with lactone 292 in a Michael addition it afforded293 In this reaction hydrogen abstraction at the resulting
radical center occurs from axial face to selectively generatethe equatorial C-2rsquo substituent Reduction and acetylation of293 furnished C-disaccharide 294 (Scheme 51) [59]
Witczak used the facial bias of levoglucosene tostereoselectively add a carbohydrate-based radical in thepreparation of the 3-deoxy-(1rarr4)-β-C-disaccharide 299[60] Addition of the radical derived from iodide 295 to 296gave adduct 297 in 26 yield Removal of the anomerichydroxyl of 297 was achieved by treatment with triethylsilane borontrifluoride ether complex followed bystereoselective reduction of the keto function at C-2rsquo withthe formation of 298 in 89 yield Debenzylation followedby acetolysis of 16-anhydro ring produced the peracetylatedtarget C-disaccharide 299 in 19 overall yield from 295(Scheme 52)
Vogel has developed general methods to transformenantiomerically pure 7-oxabicyclo[221]heptyl derivatives(ldquonaked sugarsrdquo) into C-disaccharides Because of thesechiral bicyclic skeletons they undergo highly stereoselectivereactions with predictable diasteroselectivities An arsenal ofmethods is available that allow to substitute these ldquonakedrdquocarbon centers with a variety of functional groups with allpossible relative configurations The methods allowpreparation of both enantiomers of a given target with thesame ease Predictably high stereoselectivity of the reactionsof the bicyclic chirons adds to the flexibility of approachwhich can lead to high molecular diversity [61]
α-C-(1rarr3)-mannopyranoside of N-acetyl-galactosaminepotent β-galactosidase inhibitors was synthesized by thisapproach [61] Enone 302 was readily prepared from 300The addition of the radical derived from bromide 303 toenone 302 afforded the αminusisomer 304 The ketone was thenreduced and the selenide eliminated via the intermediacy ofthe selenoxide to give 305 Acid-promoted (CF3SO3H) 7-oxa ring opening of 305 in MeCN produced the amino-conduritol derivative 306 resulting from the quenching of theallylic cation intermediate by the solvent (Ritter reaction)Ozonolysis of the chloroalkene 306 generated an acylchloride-aldehyde intermediate that reacted with MeOH toproduce a mixture of methyl uronates The major compound307 was silylated and reduced The crude polyol obtainedwas acetylated to produce 308 Desilylated and ammonolysisafforded a mixture of α-β-pyranoses 309 and correspondingα-β-furanoses (Scheme 53)
Similar chemistry was carried out to synthesize non-protected α-C(1rarr2)-L-fucopyranoside of D-galactopyrano-side corresponding to a blood group mimetic [62] Giesersquosradical fucosidation of racemic enone 310 with α-L-bromoacetofucose 311 provided the mixture of diastereo-meric α-C-fucoside 312a and 312b in reproducible yield of78 Reduction of the mixture gave a 11 mixture of endo-alcohols 313 and 314 which were isolated pure in 40 and355 yield respectively Oxidative elimination of thebenzeneselenyl group of 313 followed by acetylation gaveendo acetate 315 in 85 yield Acid-promoted ring openingof 315 and ozonolysis of the resulted chloroalkene gavemethyl uronic ester 316 in modest yield (10) Treatment of316 with Cl3CCN and NaH followed with BF3
OEt2
furnished the totally protected C-disaccharide 317 in 79
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1423
Scheme (49)
Bu3SnO
HOAcO
OMeOAc
OAc
O
AcO
OMeOAc
OAcI
AIBN
O
AcO
OMeOBn
OBn
HO2C O
AcO
OMeOR
ORY
X
OHBnO
BnO
OBn
OBnO
BnO
OBn
O
AcO
OMeOBn
OBnX
i-Pr i-Pr
N
Mo C(Me2 Ph)((CF3)2 MeCO)2
O
RO
OMeOR
O
RO
OR
OR
RO
OR
278
I2 Ph3P
imidazole
269 270 93
271a X = CH2CH=CH2 Y = H R = Ac 64271b Y = CH2CH=CH2 X = H R = Ac 11272a X = CH2CH=CH2 Y = H R = Bn 75272b Y = CH2CH=CH2 X = H R = Bn 75273a X = CH2CHO Y = H R = Bn 79273a Y = CH2CHO X = H R = Bn 79
1 NaOMe MeOH2 NaOH BnBr DMF
OsO4 NaIO4
NaClO2 NaH2PO4
274 96
275
DCC 4-DMAP
276 X = O 82
277 X = CH2 51
TiCl4 Zn dust TMEDA CH2Br2PbCl2 (Cat )
1
2 BH3 THF H2O2 NaOH
H2 PdC EtOH
Ac2 O Pyr 4-DMAP
279 R = Bn R = H 64
280 R = R = H 99
281 R = R =Ac 97
1424 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (50)
Scheme (51)
O OOH
OH
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
286
1 VO(acac)2 t-BuOH 95
2 (MeO)3CH BF3 90
1 P-O2NC6H4 CO2H Ph3P DIAD2 K2CO3 MeOH 82 over 2 steps
1 PhCOCl Et3N DMAP 402 P-O2NC6H4 CO2H Ph3P DIAD3 KOH THF-H2O 75 over 2 steps
TMEDA OsO4
Cat OsO4 NMO 287
Cat OsO4 NMO288
TMEDA OsO4
Cat OsO4 NMO
290
289
(RR)-282283
284
285
OHO
AcO
BrOAc
OAc
BnO
O
OBn
OBnO
OHO
AcOOAc
OAc
BnO
OOBn
OBnAcO
OHO
AcOOAc
OAc
BnO
O
OBn
OBnO
+
Bu3SnH AIBN291
292
293 81
1 Na[Al(OC2H4OMe)2(OEt)H]2 Ac2O pyr
294 56 over 2 steps
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1425
Scheme (52)
Scheme (53)
OBnO
BnOOBn
OBn O
OH
O
OBnO
BnO
OHOBn
OBn O
O
O
O
O
O
OBnO
BnOOBn
OBnO
OAcOAc
OAc
OBnO
BnO
OHOBn
OBn
IBu3SnH AIBN
295 297 26
1 BF3 OEt2 Et3SiH
2 L-Selectride THF
1 Pd(OH)2C C6H10 EtOH
2 EtSiOSO2CF3 Ac2O
298 89 over 2 steps299
296
O
O
PhSeClO
O
PhSeCl
Bu3 SnH
O
O
PhSeCl
R
H
O
OAc
R
Cl
O
AcO
OAc
OAc
OAcOH
Cl
NHAc
R
OAc
AcHN
OH
O
OH OAc
OH
OHO
HO
OH
O
AcO
OAc
OAc
OAcBr
O
O
PhSeCl
O
O
PhSeCl
R
O
OTIPSAcHNR
OAc OAc
O
OHAcHN
COOMe
R
OAc
1 Bu4NF
2 NH3MeOH
1 (Me3Si)2NLi THF2 Me2N=CHI
1 Bu3 SnH AIBN2
1 NaBH42 mCPBA3 Ac2O pyr
1 H+ MeCN
2 H2 O NaHCO3
R =
1 O3MeOH
2 Me2S NaHCO3
1 TIPSOTf 26-lut idine2 LiBH43 Ac2 O pyr DMAP
furanoses +
304 56
305 68 306 84307 50
308 46
300 301 302
303
309
1426 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
The reduction of 317 and treatment with DOWEX-H+ resinprovided the desired C-fucoside 318 in 70 (Scheme 54)
62 Intramolecular Radical Approaches
One disadvantage with the intermolecular approaches isthat during such radical mediated reactions electrondeficient alkenes are required to facilitate C-C bondformation The intramolecular approach of Sinayuml overcomes
this drawback by bring two substrates together via atemporary covalent silaketal connector This enables the useof a wider range of alkenes which can include alkene-functionalized sugars thus leading to the generation of C-disaccharides [63] Based on the early work of Stork Sinayumlemployed the tether reaction in the synthesis of both α- andβ-C-disaccharides with this work subsequently beingemployed in the synthesis of biologically significant natural
Scheme (54)
O
OH
Fuc
Cl
O
O
ClPhSe
OOAc
NHAcOHFuc
O
AcOOAc
AcO
Br
O
O
PhSeCl
O
AcOOAc
AcO
O
OH
PhSe Cl
Fuc
OOAc
NHAc
OMe
Fuc
O
AcHN
OH OAc
OH
O
OH
Me
OH
O
O
Fuc
ClSePh
O
HO
Fuc
ClSePh
+
Ph3SnHAIBN
78 combined yield
Fuc
310
+
1 NaBH4 MeOHTHF2 Chromatography
313 40 314 355
1 mCPBA
2 Ac2O pyr DMAP
+
315 75
1 TfOH MeCN
2 NaHCO3 O3 -78 oC
316 10 over 2 steps
1 Cl3 CCN NaH
2 MeOH BF3 OEt2
317 79
1 LiBH4 THF
2 Dowex-H+
311
312a312b
318 70 for 2 steps
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1427
products [64] The availability of different hydroxyl groupson each monosaccharide unit allowed the fine-tuning ofstereochemical outcome by selective positioning of the silyltether [65] Development of this early stereochemical controlled to the tethering of the donor 320 with alcohol 319through a di-isopropyl silicon tether 321 Subsequent treat-ment with Bu3SnH and AIBN led to a 9-endo-trigcyclization to form the C-disaccharide 322 in an 80 yieldwith exclusive formation of the α-product The silyl tetherwas removed with Bu4NF and deprotection under standardconditions afforded the desired disaccharide 323 in excellentyield (Scheme 55)
In parallel the development of a 32rsquo silyl tether allowedaccess to the β-linked product as demonstrated in Sinayumlrsquossynthesis of methyl β-C-lactoside 328 [66] Alcohol 324 and320 were connected via the dimethylsilyl tether an 8-endo-trig cyclization followed to exclusively afford the β-
disaccharide 326 in 45 yield Removal of the tether anddeprotection of benzyl ether gave β-C-disaccharide 328(Scheme 56)
This group also selected iodosugars bearing a freehydroxyl group as progenitors of the radical donors [67] In atypical experiment the radical donor 329 was connected tothe radical acceptor 330 through a silaketal tether followingtheir procedure Tributyltinhydride mediated 8-endo-trigradical cyclization of compound 331 gave after detetheringof the non isolated intermediate 332 the protected β-C-disaccharide 333 in 37 overall yield (from startingmaterials 330 and 329) Peracetate 335 was achieved afterhydrogenolysis The C-laminaribioside 334 is of potentialbiological interest as it mimics the repeating disaccharideunit of fungal β-(1rarr3)-glucans which have antitumor andimmunomodulating properties (Scheme 57)
Scheme (55)
Scheme (56)
OO
OHSePh
OTBDPSO O
OO
SePh
OTBDPSO
OO
OBnOMe
OBn
Si
O
HOOBn
OMe
OBn
O
HOOH
OHHO
O
HOOH
OMe
OH
OTBDPSO
O
HOOBn
OMe
OBnO
OOH
1 n-BuLi THF
2 iPr2SiCl2 -78 oC
3 DMAP THF rt
1 Bu4NF THF
2 Dowex-H+
3 H2 PdC
Bu3SnH AIBN toluene
319
320
321
322323
OBnO
OHSePh
OBnBnO
OHO
OBnOMe
OBn
ROO
ROOH
OR
OHO
OROMe
OR
OBnO
O
OBnBnO
OO
OBnOMe
OBn
Si
SePh
OBnO
O
OBnBnOO
OOBn
OMe
OBn
Si
1 PhSeH Me2SiCl2
BuLi -78 oC
2 imidazole rt
Bu3SnH AIBN toluene
H2 PdC327 R = Bn
328 R = H
Bu4NF THF
324
320
325
326 45
1428 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
CONCLUSIONS
In this paper the biological importance of C-oligo-saccharides as subunits of natural products and as a newgeneration of carbohydrate based on therapeutics has beenillustrated Different methods are available for the synthesisof C-oligosaccharides As with traditional saccharidesynthesis it has been necessary to develop a number ofspecific approaches to facilitate the regioselective andstereoselective preparation of the desired targets Work inthis area continues and it is expected that many interestingnew C-oligosaccharides will be prepared using the chemistrydescribed in this review It is also likely that new chemistrywill be developed in the future for the preparation of thesebiologically important targets
ACKNOWLEDGEMENTS
The authors thank Dr Sultan Baytas for her criticalreading of this manuscript
REFERENCES
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[2] Wassarman PW Mammalian Fertilization Molecular Aspects ofGamete Adhesion xocytosion Exocytosis and Fusion Cell 199996 175-183
[3] Carbohydrate-based Drug Discovery Wong C-H EdWeinheim Cambridge Wiley-VCH 2003
[4] (a) Sharon N Lis H Lectins as Cell Recognition MoleculesScience 1987 246 227-234 (b) Dwek RA Chem Rev 1996 96683-720
[5] Postema M C-Glycoside synthesis CRC Boc Ratom 1995[6] (a) Weatherman R V Mortell K H Cheruenak MKiessling
L L Toone E J Specificity of C-Glycoside Complexation byMannoseGlucose Specific Lectins Biochem 1996 35 3619-3624(b) Ravishankar R Surolia A Vijayan M Lim S Kishi YPreferred Conformation of C-Lactose at the Free and Peanut LectinBound States J Am Chem Soc1998 120 11297-11303
[7] (a)Wong C-H Halcomb R L Ichikawa Y and Kajimoto TEnzymes in organic synthesis Application to the problems ofcarbohydrate recognition part2 Angew Chem Int Ed Engl 199534 521-546 (b)Howard S Withers SG Bromoketone C-Glycosides a New Class of βminusGlucanase Inactivators J AmChem Soc 1998 120 10326-10331(c) Wang Q Wolff MPolat T Du Y Linhardt R J C-glycoside of Neuraminic Acidsas Neura-minidase Inhibitors Bioorg Med Lett 2000 10 941-944 (d) Phili R Chang J Partis R A Mueller R A ChrestF J Passaniti A The Alpha-glucosidase I InhibitorCastanospermine Alters Endothelial cell Glycosylation PreventsAngiogenesis and Inhibits Tumor Growth Cancer Res 1995 552927-2935
[8] Ossor A Elbein A D In Carbohydrates in Chemistry andBiology Vol 3(II) WileyVCH 2000 pp 513-539
[9] (a) Sinayuml P Synthesis of oligosaccharide Mimetics Pure ApplChem 1997 69 459-463 (b) Beau J-M Gallagher TNucleophilic C-glycosyl Donors for C-glycoside Synthesis Top inCurr Chem 1997 187 1-54 (c) Nicotra F Synthesis of C-glycosides of Biological Interest Top in Curr Chem 1997 187
Scheme (57)
O
O
O
Ph
I
OMe
OHO
BnO
OH
OH
BnOOH
O
BnO
Si
O
O O
Ph
I
OMe
O
O
BnO
OR4O
R5O
OMe
OR2
OR3O
R3O
OR1
R3O
Bu3 SnH AIBN
332 R1 R2 = SiMe2 R3 = Bn R4 R5 = CHPhTBAF THF
333 R1 = R2 = H R3 = Bn R4 = R5 = CHPh 37 from 11
334 R1 = R2 = R3 = R4 = R5 = H
335 R1 = R2 = R3 = R4 = R5 = Ac
329
H2 PdC MeOH
Ac2 O pyr
1 BuLi THF -78 oC
2 Me2SiCl2
3 DMAP
330
331
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1429
55-83 (d) Du Y Linhardt R Y Recent Adv in Stereo-SelectiveC-Glycoside Synthesis Tetrahedron Lett 1998 54 9913-9959 (e)Liu L Mckee M and Postema M H D Synthesis of C-saccharides and Higher Congeners Current Org Chem 2001 51133-1167
[10] Jarosz S Fraser-Reid B Synthesis of A Higher Carbon Sugar ViaDirected Aldol Condensation Tetrahedron Lett 1989 30 2359-2362
[11] Lichtenthaler F W Lergenmiiller M Schwidetzky S C-Glycosidations of 2-Ketohexosyl With Electrophilic Radical andNudeophilic Anomeric Carbons Eur J Org Chem 2003 3094-3103
[12] Baudat A Vogel P Aza-C-disaccharides Synthesis of 6-Deoxygalactonojirimycin-β-C(1rarr3) Linked with D-Altrofuranosides and D-Galactose J Org Chem 1997 62 6252-6260
[13] Turner D Vogel P Synthesis of 4-Hydroxy-26-Bis(hydroxymethyl) tetrahydropyran-2-Carbaldehyde DerivativesSynlett 1998 304-306
[14] Zhu Y-H Vogel P Short Stereoselective Synthesis of C-(1rarr3)-Linked Disaccharides Tetrahedron Lett 1998 39 31-34
[15] Zhu Y-H Vogel P Synthesis of a (2R 6R)-2-(Hydroxymethyl)-6-Propa-1 2-Dienyl-2H-Pyran-3(6H)-One Derivative A NewEnone for The Convergent Construction of C-Glycosides of C-Disaccharides Synlett 2001 82-86
[16] Baumberger F Vasella A Deoxynitrosugars The 6th
Communication Stereolectronic Control in the reductivedenitration of tertiary nitro ethers A Synthesis of ldquoC-glycosidesrdquoHelv Chim Acta 1983 66 2210-2221
[17] Martin O R Lai W Synthesis and Conformational Studies of β-(1rarr6)- and ββ-(1rarr1)-Linked C-disaccharides J Org Chem1993 58 176-185
[18] Spak S J Martin R The synthesis of an analogue of Methyl OC-Analogue of Methyl 4rsquo-O-β-D-GlucopyranosylgentiobiosideTetrahedron 2000 56 217-224
[19] Kobertz W R Bertozzi C R Bednarski M D C-GlycosylAldehyde Synthons for C-Linked Disaccharides J Org Chem1996 61 1894-1897
[20] Gurjar M K Nagaprasad R and Ramana CV First Synthesis ofMethyl α-C-D-Arabino-furanosyl-(1rarr5)-αminusD-Arabinofuranosidethe C-Disaccharide Segment of Motif C of MycobateriumTuberculosis Tetrahedron Lett 2000 43 7577-7579
[21] Witczak Z J Synthesis of C-Glycosyl Compounds and OtherNatural Products from Levoglucosenone Pure Appl Chem 199466 2189-2192
[22] Griffin F K Paterson D Taylor R J K Ramberg-BacklundApproaches to the Synthesis of C-Linked Disaccharides AngewChem Int Engl 1999 38 2939-2942
[23] Paterson B E Griffin F K Alcaraz M-L and Taylor R J KA Ramberg-Baumlcklund Approach to the Synthesis of C-GlycosidesC-Linked Disaccharides and C-Glycosyl Amino Acids Eur JOrg Chem 2002 1323-1336
[24] McAllister G D Paterson D E Taylor R J K A SimplifiedRamberg-Bachlund Approach to Novel C-Glycosides and C-Linked Disaccharides Angew Chem Int Ed Engl 2003 42 1387-1391
[25] McCartney J L Christopher T M Cicchillo R M BernardinaM D Wagner T R and Norris P J Org Chem 2003 6810152-10155
[26] Dondoni A Zuurmond H M Bascarate A Synthesis of α-andβ-D-(1rarr6)-C-Disaccharides by Witting Olefination of Formyl C-Glycosides with Glycopyranose 6-phosphoranes J Org Chem1997 62 8114-8124
[27] Dondoni A Kleban M Zuurmond H Marra A Synthesis of(1rarr6)-C-Oligogalactosides by Interative Wittig OlefinationTetrahedron Lett 1998 39 7991-7994
[28] Dondoni A Marra A A New Synthetic Approach toMycobacterial Cell Wall α-(1rarr5)-D-Arabinofuranosyl C-Oligosaccharides Teterahedron Lett 2003 44 4067-4071
[29] Colinas P A Ponzinibbio A Lieberknecht A and Bravo R OWittig Reaction of Glycosyl Phosphonium Salts A StereoselectiveRoute to C-Disaccharides and C O-Trisaccharides TetrahedronLett 2003 44 7985-7988
[30] Schmidt R R Preuss R Synthesis of Carbon Tetrahedron Lett1989 30 3409-3412
[31] Dietrich H Schmidt R R Synthesis of Carbon-Bridged C-Lactose and Derivatives Liebigs Ann Chem 1994 975-981
[32] Rouzaud D Sinayuml P The First Synthesis of a ldquoC-DisacchariderdquoJ Chem Soc Chem Commun 1983 1353-1354
[33] Xin Y-C Zhang Y-M Mallet J-M Glaudemans C P JSinayuml P Synthesis of C-Oligosaccharides That Mimie TheirNatural O-Analogues Immunodeterminants in Binding toMonoclonal Immunoglobulins Eur J Org Chem 1999 471-476
[34] Streicher H Geyer A Schmidt R R C-Disaccharides ofKetoses Chem Eur J 1996 2 502-510
[35] Leeuwenburgh M A Timmers C M Vander Marel G A VanBoom J H Mallet J-M Sinayuml P G Stereoselective Synthesisof α-C-(Alkynyl)-Glycosides Via Ring-Opening of α-12-Anhydrous Tetrahedron Lett 1997 38 6251-6254
[36] Aslam T Fuchs M G G Le Formal A Wightman R HSynthesis of C-Disaccharide Analogue of the α-D-Arabinofuranosyl-(1rarr5)-α-Arabinofuranosyl Motif ofMycobacterial Cells Walls via Alkynyl Intermediates TetrahedronLett 2005 46 3249-3252
[37] (a) Girad P Namy J L Kagan H B Divalent LanthanideDerivative in Organic Synthesis 1 Mild Preparation of SamariumIodide and Ytterbium Iodide and Their Use as Reducing orCoupling Agents J Am Chem Soc 1980 102 2693-2698 (b)Molander G A Harris C R Sequencing Reactions withSamarium(II) Iodide Chem Rev 1996 96 307-338
[38] (a) Mazeacuteas D Skrydstrup T Doumeix O Beau J-MSamarium Iodide-Induced Intramolecular C-Glycoside FormationEfficient Radical Formation in the Absence of an Additive AngewChem Int Ed Engl 1994 33 1383-1386 (b) Mazeacuteas DSkrydstrup T Beau J-M A Highly Stereoselective Synthesis of1 2-trans-C-Glycosides Via Glycosyl Samarium(III) CompoundsAngew Chem Int Ed Engl 1995 34 909-912 (c) Jarreton OSkrydstrup T Beau J-M The Stereospecific Synthesis of Methylα-C-Mannobioside A Potential Inhibitor of M TuberculosisBinding to Human Macrophages J Chem Soc Chem Commun1996 1661-1662 (d) Jarreton O Skrydstrup T Espionosa J-FJimeacutenez-Barbero J Beau J-M Samarium Diiode Prompted C-Glycosylation An Application to The Stereospecific Synthesis ofα-(1rarr2)-C-Mannobioside and Its Derivatives Chem Eur J 19995 430-441 (e) Mipuel N Doisneau G Beau J-M ReductiveSamariation of Anomeric 2-Pyridyl Sulfones with Catalytic AnUnexpected Improvement in The Synthesis of 12-Trans-Diequatorial C-Glycosyl Compounds Angew Chem Int Ed Engl 2000 39 4111-4114
[39] Vlahov I R Vlahova P I Linhardt R J DiastereocontrolledSynthesis of Carbon Glycosides of N-Acetylneuraminic Acid ViaGlycosyl Samarium(III) Intermediates JAmChem Soc 1997 1191480-1481
[40] Kuberan B Sikkander S ATomiyama H Linhardt R JSynthesis of a C-Glycoside Analogue of sTn An HIV-and Tumor-Associated Antigen Angew Chem Int Ed Engl 2003 42 2073-2075
[41] Bazin H G Du Y Polat T Linhardt R J Synthesis of aVersatile Neuraminic Acid ldquoCrdquo-Disaccharide Precursor for theSynthesis of C-Glycoside Analogues of Gangliosides J OrgChem 1999 64 7254-7259
[42] Chen C-C Ress D K Linhardt RJ Samarium Iodide-Mediated Synthesis of Neuraminic Acid C-Glycosides InSynthesis of Glycommetics Roy R Ed ACS Syposium Series2004 896 53-80
[43] Abdallah Z Doisneau G Beau J-M Synthesis of a Carbon-Linked Mimic of The Disaccharide Component of The Tumor-Relate SialyTn Antigen Angew Chem Int Ed Engl 2003 425209-5212
[44] Lay L Nicotra F Panza L Russo G Caneva E Synthesis ofC-disaccharides through dimerization of exo-glycals J Org Chem1992 57 1304-1306
[45] Isobe M Nishizawa R Hosokawa S Nishikawa TStereocontrolled Synthesis and Reactivity of Sugar Acetylenes JChem Soc Chem Commun 1998 2665-2676
[46] Saeeng R Sirion U Sahakitpichan P Isobe M IodineCatalyzes C-Glycosidation of D-Glucal with SilylacetykeneTetrahedron Lett 2003 44 6211-6215
[47] (a) Babirad S A Wang Y Kishi Y Synthesis of C-Disaccharides J Org Chem 1987 52 1370-1372 (b) Wang YBabirad S A Kishi Y Preferred Conformation of C-Glycosides
1430 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
8 Synthesis of 14-Linked Carbon Disaccharides J Org Chem1992 57 468-481
[48] Armstrong R W Sutherlin D P Strategies for the Synthesis ofC-Disaccharides Containing D and L Sugars Tetrahedron Lett1994 35 7743-7746
[49] Wei A Kishi Y Preferred Conformation of C-Glycosides 12Synthesis and Conformational Analysis of αα- α β- and β β-Trehaloses J Org Chem 1994 59 88-96
[50] Haneda T Goekjian P G Kim S H Kishi Y PreferredConformation of C-Glycosides 10 Synthesis and ConformationAnalysis of Carbon Trisaccharides J Org Chem 1992 57 490-498
[51] Sutherlin D P Armstrong R W Synthesis of 12 Stereochemistryand Structurally Diverse C-Trisaccharides J Org Chem 1997 625267-5283
[52] Notz W Hartel C Waldscheck B Schmidt R R De NovoSynthesis of a Methylene-Bridged Neu5Ac-α-(23)-Gal C-Disaccharide J Org Chem 2001 66 4250-4260
[53] (a) Postema M H D Calimente D Liu L Behrmanm T L AnOlefin Metathesis Route for the Preparation of (1rarr6)-Linked-C-Disaccharide Glycals A Convergent and Flexible Approach to C-Saccharide Synthesis J Org Chem 2000 65 6061-6068(b) Postema M H Piper J L Liu L Faust M Andreana PSynthesis and Partial Biological Evaluation of a Small Library ofDifferentially Linked β-C-Disaccharide J Org Chem 2003 684748-4754
[54] Nelson A The Development of Strategies and Methods for TheSynthesis of Biologically Active Compounds New J Chem 200428 771-776
[55] Togo H He W Waki Y Yokoyama M C-GlycosylationTechnology With Free Radiant Reactions Synlett 1998 700-717
[56] Giese B Dupuis J Diastereoselective Synthesis of C-Glycopyranosides Angew Chem Int Ed Engl 1983 22 622-623
[57] Adlington R M Baldwin J E Basak A Kozyrod RPApplication of Radical Addition Reactions to tho Synthesis of a C-Glucoside and A Functionalized Amino Acid J Chem SocChem Commun 1983 144-145
[58] Giese B Gonzaacutelez-Goacutemez J A Witzel T The Scope of RadicalCC-Coupling by The ldquoTin Methodrdquo Angew Chem Int Ed Engl1984 23 69-70
[59] Giese B Witzel T Synthesis of ldquoC-Disaccharidesrdquo by RadicalC-C Bond Formation Angew Chem Int Ed Engl 1986 25 450-451
[60] Witczak Z J Chhabra R Chojnacki J C-Disaccharides IStereoselective Approach to β-(1rarr4)-3-Deoxy-C-Disaccharidesfrom Levoglucosenone Carb Res 1997 301 167-175
[61] Vogel P Synthesis of Rare Carbohydrates and Analogues Startingfrom Enantiomerically Pure 7-Oxabicyclo[221]heptyl Derivatives(ldquoNaked Sugarsrdquo) Current Org Chem 2000 4 455-480
[62] Viodeacute C Vogel P Synthesis of The C-Disaccharide α-C(1rarr3)-L-Fucopyranoside of N-Acetylgalactosamine J Carb Chem2001 20 733-746
[63] Xin Y C Mallet J M Sinayuml P An Expeditious Synthesis of AC-Disaccharide Using A Temporary Silaketal Connection J ChemSoc Chem Commun 1993 864-865
[64] (a) Petitou M Herault P Lormeau J-C Helmboldt A MalletJ-M Sinayuml P Herbert J-M Introducing A C-InterglycosidicBond in A Biologically Active Pentasaccharide Hardly Affects ItsBiological Properties Bioorg Med Chem 1998 6 1509-1516 (b)Sinayuml P Advances in The Synthesis of the Carbohydrate MimicsPure Appl Chem 1998 70 1495-1499
[65] Sinayuml P Chemical Synthesis of Oligosaccharide Mimetics PureAppl Chem 1998 70 407-410
[66] Sinayuml P Chemical Synthesis of Oligosaccharide Mimetics PureAppl Chem 1998 69 459-463
[67] Vauzeilles B Sinayuml P Selective Radical Synthesis of β-C-Disaccharides Tetrahedron Lett 2001 42 7269-7272
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1405
dibromoalkene 136 which was treated with n-butyllithium togive an intermediate acetylide 137 The latter uponnucleophilic addition to lactone 138 gave a mixture of lactol139 in high yield Stereoselective reduction of lactol 139 wasfollowed by hydrogenation of benzyl groups and the triplebond affording the (1rarr6)-β-C-disaccharide 140 (Scheme28)
The lactone-addition methodology was later applied bySinayuml and co-workers in an iterative fashion for the
preparation of higher homologues [33] Hydroxylmethylenein compound 141 was converted to acetylide lithium incompound 142 by a sequence of reactions Condensation ofcompound 142 with the galacto lactone 143 gave 144 asmixture of anomers The lactol were stereoselectivelyreduced to and triple bond was hydrogenated to give 145Methyl glycoside 145 was hydrolyzed to the correspondinglactols which were oxidized to lactone 146 The samesequence was then repeated twice to give C-trisaccharide147 and C-tetrasaccharide 148 (Scheme 29)
Scheme (22)
O
BnOOBn
BnO OTBDPS
PPh3I-
BnO
H
O
BnOOBn
OTBDPS
OO
O
OO
O
CHOO
O
OO
O
BnO
O
BnOOBn
BnO
OO
O
OO
H
HOBn
BnO OTBDPS
O
BnOOBn
BnO O
OO
O
OO
H
OBn
BnO OTBDPS
PPh3I-
O
BnO
O
BnOOBn
BnO OTBDPS
PPh3I-
O
AcOOAc
AcO
O
AcOOAc
AcO
OO
O
OO
O
AcOOAc
AcO OAc
O
BnOOBn
BnO
O
BnOOBn
BnO
OO
O
OO
H
H
O
BnOOBn
BnO OTBDPS
H
1 TBAF2 PCC
+107 36
+
1 TBAF2 PCC3
+
1 TBAF2 H2 Pd(OH)2 C3 Ac2 O Pyr
104
33
105
106104
104
108109
BuLi THF-HMPA
-50 o C
70EZ 19
BuLi THF-HMPA
-50 o C
1406 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
The di- tri- and tetrasaccharide derivatives (145 147 and148) were all debenzylated and tested for their bindingaffinity to three different monoclonal immunoglobulins withspecificity for different O-β-(1rarr6)-D-galactopyranosyl deter-minants These C-saccharide analogs had similar bindingproperties to the corresponding O-saccharides
Schmidt has also used acetylide-lactone condensation toassemble C-disaccharides of ketoses [34] Lithium acetylide149 was condensed with ketone 150 to give a mixture ofalcohol 151 after removal of the pivoloyl group Attemptedcyclization under Lewis acid catalysis resulted only in theremoval of the acetonide Accordingly the diol was tiedback as the carbonate and the acetylene complex as thedicobalt species 152 The isomers were then separately
cyclized to give a 11 mixture of C-disaccharide 153 Thecobalt complex on α-C-disaccharide was removed understandard conditions to give 154 and deprotection of thecarbonate was followed by hydrogenation and peracetylationto give 155 (Scheme 30) Similar chemistry was also carriedout with the corresponding β-isomer
Van Boom and co-workers used lithiated alkynylderivative 156 in presence of ZnCl2 to selectively open ringof the 12-anhydrosugar 157 affording the α-C-(alkynyl)-glycoside 158 Hydrogenolysis of the benzyl groups wasfollowed by peracetylation to give the (1rarr6)-α-C-disaccharide 159 (Scheme 31) [35]
Normally attack of the nucleophile proceeds from anequatorial direction to give the β-isomer The unexpected
Scheme (23)
Scheme (24)
BnOO
OBnCHO
OBn
O
OBn
PPh3I-
OBn
OBn
O
OBn
BnOBnO
O
OBnOBn
OBnH
O
OH
HOHO
O
OHOH
OH+
BuLi
THF-HMPA
-20 oC+
1 TBAF2 H2 Pd(OH)2C
112 65 113 100
110
111
O
OBnCHO
OBnBnO
O
OBn
BnOBnO
O
OBnCH(OiPr)2
OBnH
O
OBnCH(OiPr)2
PPh3I-
OBn
O
OBn
BnOBnO
O
OBn
OBnH
O
OBnOBn
BnOH
O
OH
HOHO
O
OH
OH
O
OHOH
HO
++
BuLi
THF-HMPA
-20 oC
BuLi
THF-HMPA
-20 oC
TFA H2 O THF rt
115 49
116 R = CH(OiPr)2
117 R = CHO
118 45
H2 Pd(OH)2C
110
114
114
119
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1407
Scheme (25)
Scheme (26)
OBn
R1
R2
PPh3BF4-O
O
OOHC
O
O
O
O
O
O
O
O
HO
O
O
O
O
O O
OBn
R1
R2
O
O
O
O
O
O
H
O
OBn
R1
R2
O
O
O
O
O
O
O
O
OBn
R1
R2
O
O
O
+
BCl3 (005 equiv)
MS 4A CH2 Cl2 0 o C
+
BuLi THF -90 oC -90 o C
to rtH2 (1 atm) PdC Et3N MeOH
R1 R2 = OBn H
120a - b
121
122a - b
123a - b
124
125a - b
OTBDPS
BnO X
SO Ph
O
BnO
OHCO
BnO
OMeOBn
OBn
O
BnO
OTBDPS
BnO
SO Ph
O
BnO
OMeOBn
OBn
O
HO
OMeOH
OHO
HOHO
OH
OH
128
229 74
1 RaNi (74)
2 BH3 DMS
NaOH H 2O2 (74)
3 H2 PdC (70)
130 74
LDA THF
-100 oC
126 X = H
127 X = Li
1408 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (27)
Scheme (28)
stereochemical outcome is rationalized by the generation ofan initial zinc acetylide species which facilitates intra-molecular delivery to the α-face (Scheme 32)
Wightman synthesized C-disaccharide analogs of the α-D-arabinofuranosyl-(1rarr5)-α-D-arabinofuranosyl motif ofmycobacterial cell walls through alkynyl intermediates [36]The lactone 164 was treated with lithio(trimethylsilyl)ethyneat low temperature to give lactol in 66 yield of 165Treatment of this with triethylsilane and BF3
Et2O gavethe separable isomers 166α (60) and 166β (13)Desilylation of the major isomer 166α gave 167 in 97yield Treatment of 167 with n-BuLi followed by addition oflactone 164 gave 85 yield of the hemiacetal 168 which onreduction with Et3SiH and BF3
Et2O gave the disubstitutedalkyne 169 (83) as the major product Reduction-
hydrogenolysis of 169 then gave the C-disaccharide 170 innear-quantitative yield (Scheme 33)
3 REDUCTIVE GLYCOSYL SAMARIUM SPECIES
The introduction of SmI2 as reducing agent can becredited to Kagan and has since been utilized in numeroussynthetic schemes [37] Sinayuml and Beau introduced SmI2
chemistry into C-glycoside synthesis through intermolecularreactions with appropriate electrophiles and intramolecularreactions of silyl tethered substrates [38] Anomericsamarium species are highly stable and not likely to undergoβ-elimination Treatment of the aryl sulfone 171 with SmI2
affords the nucleophilic intermediate 172 through two singleelectron transfer processes Introduction of a suitableelectrophile (carbonyl compounds) affords the α-C-manno-
O
BnO
OTBDPS
BnO X
SO Ph
O
BnO
OBn
BnO Li
SO Ph
DMF
OHO
HOOH
OH
O OH
OH
HO
OHOH
O
BnO
OTBDPS
BnO
SO Ph
O
OBn
OBnOBnSO
Ph
OH
131 X = Li
132 X = CHO
THF -100 oC
1 Ra-Ni
2 BH3 DMS NaOH H2O2
3 H2 PdC
131
133
134
OBnO
OBnOMe
BnO
Li
OBnO
BnOOBn
OBn
OOBn
OBnOMeBnO
OH
OBnO
BnOOBn
OBn
O
n-BuLi
BnO
OMe
BnO
BrBr
O
OBn
OHO
OH
OH
HO
OHO
OH
HO
OMe
O
BnO
OMeOBn
O
BnO
139 92
1BF3 OEt2 EtOH
2 H2 PdC AcOH
140 52 over 2 steps
135 136 137
138
CBr4 PPh3
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1409
pyrannoside 173 in good yield and with excellent stereo-selectivity (Scheme 34) [38a]
Preparation of C-glycosides of ulosonic acids using SmI2
was pioneered by Linhardt and coworkers [39] Coupling ofpyridyl sulfone 174 with aldehyde 175 in the presence ofSmI2 gave an excellent yield of the N-acetylneuraminic acidC-disaccharide 176 as single isomer This stereochemicaloutcome was rationalized on the basis of the Felkin-Anhmodel for predicting the stereochemical outcome of akinetically controlled addition of a nucleophile to a chiraladehyde (Scheme 35 A)
Reductive samarium method was utilized to synthesizesialo-antigen C-analogs by the Linhardt group A fullyprotected C-analogue of the SialylTn antigen α-D-Neu5Ac-(2rarr6)α-D-GalNAc-(1rarrO)-Ser 182 was prepared [40] C-glycosylation of the neuraminic acid sulfone donor with
aldehyde acceptor in presence of excess SmI2 afforded the α-C-glycoside 180 as an RS mixture (11) The criticalintermediate aldehyde acceptor 178 was prepared in 13steps Chemoselective resolution to compound 180 wasundertaken by oxidation with DMSOAc2O to keto-bridgedcompound 181 followed by stereoselective reduction withZn(BH4)2 to regenerate the bridge hydroxyl function gave182 in gt90 de (Scheme 36)
A common versatile N-acetylneuraminic acid C-disaccharide precursor of the C-glycoside analogs ofgangliosides GM4 and GM3 has been synthesized [41]Samarium(II) iodide coupling of N-acetylneuraminic acidsulfone 179 with a 3-formyl galactopyranoside derivative183 afforded the corresponding C-disaccharide 184 as amixture of (R) and (S) isomers at the newly formedhydroxymethylene bridge This diastereoisomeric mixturewas resolved after debenzylation of the galactoside residue
Scheme (29)
O
BnO
BnOOBn
OBn
OOBn
OBnOMe
OBnOH
O
BnO
BnO
OBn
OBn
O
O
BnOOBn
OMe
BnO
Li
OBnO
OBn
OBn
OBnO
OBn
OBn
OMe
OBnO
OBn
OBnBnO
OBnO
OBn
OBn
OBnO
OBn
OBn
OMe
OBnO
OBn
OBnOBnO
OBn
OBnBnO
O
BnO
BnO
OBn
O
OBnO
OBn
OBnBnO
OBnO
OBn
OBnBnO
OBnO
OBn
OBn
OMe
OBnO
OBn
OBnBnO
OMe
1 PCC2 CBr4 Ph3P3 n-BuLi
144 overall yield 54
1 BF3 OEt2 Et3 OH
2 H2 PtO2 EtOAc
145 76
1 H2 SO4 AcOH
2 PCC
146 62
repeat steps
repeat st eps
141 142
143
147
148
1410 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (30)
Scheme (31)
O
BnOOBn
OMe
Li
BnO
OPivBnO
OBn
OBn
BnO
O OO
BF3 OEt2
OBnO
OBn
OBn
BnO
OO
O
OMe
BnOOBn
BnO
Co(CO)3
Co(CO)3
O
CAN
OBnO
OBn
OBn
BnO
OO
OO
BnOOBn
BnO
OMe
OHBnO
OBn
OBn
BnO
OHO
O
O
OMe
BnOOBn
BnO
Co(CO)3
Co(CO)3
O
OPivBnO
OBn
OBn
BnO
OH OO
O
OMe
BnOOBn
BnO
OAcO
OAc
OAc
AcO
OAcOAc
OAcO
OAc
AcO
OMe
1
2 NaOMe MeOH
1 Lewis acid2 ClCO2CCl3 Pyr3 Co2(CO)8
with a-isomer
1 Et3N Pyr H2O
2 H2 PdC H+
3 Ac2 O Pyr
149 151
152153
154 155
150
OBn
BnO
OBnO
OBn
BnO
OBnO
BnO
MeO
OBnO
OBn
BnO
O
OMe
AcO
OAcO
OAc
OAc
AcO
OAcO
OAc
O
BnOOBn
OMe
BnO
159 74 over 2 steps
+
BuLi ZnCl2 THF
1 H2 PdC2 Ac2O Pyr
156 157
158 59
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1411
Scheme (32)
Scheme (33)
and the chirality of each isomer assigned after acetylationConversion of the p-methoxyphenyl group in the peracety-lated (S) isomer 187 into the corresponding thiophenylglycoside 188 was accomplished affording the key inter-mediate for the synthesis of C-glycoside analogs of GM4GM3 and other related gangliosides (Scheme 37)
Ganglioside GM4 is a very important cell adhesionmolecule The C-disaccharide of GM4 is currently beingsynthesized in Linhardtrsquos lab using standard O-glycosylationof C-disaccharide with protected ceramide Once theceramide has been attached it can be oxidized to afford analdehyde group for coupling to keyhole limpet hemocyanin
OBnO
OBn
BnO
O
OBnO
ClZnO
OBn
BnOCl
R
OBnO
O
OBn
BnOCl
ZnR
O
ZnR
OBnO
OBn
BnO
160 161
162163
O
OBn
OBnBnO
O
O
OBn
OBnBnO H
TMS
O
OBn
OBnBnO H
O
OBn
BnO
OBnHO
O
OBn
OBnBnO OH
TMS
OBnBnO HO
OBn
TMS
O
OR
ORRO H
O
OR
RO
OR
OBn
OBnBnO
H
TMS
O+
K2CO3 MeOH
1 n-BuLi THF -78 oC
2 164
164165 66
166α 60 166β 13167 97
BF3 Et 2O Et 3SiH -78 oC
168 85
169 R = Bn 83
170 R = H near quantitative yield
H2 (1 atm)Pd(OH) 2C
TMS-acetyl ene
n-BuLi THF -78 oC BF3 Et2O Et3SiH
-78 o C
1412 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
O
OHCOBn
OBnBnO
OMe
O
CO2MeAcO
OAcAcHN
OAc
SO2
NAcO
OBnH
H
OBn
OBn
H
O
OMeH HH
A
O
CO2MeAcO
OAcAcHN
OAc
O
OBnOMe
OBnOBn
HO
AcO
+
Nu
174175
176
SmI2 THF
Scheme (34)
Scheme (35)
Scheme (36)
O
BnO
BnO
BnO
Si lylO
O2S N
O
BnO
HO R2R1
BnOBnO
SilylO
OBnO
BnO
BnO
SilylO
Sm(III)
R1COR2 SmI2 THF
171 172
173
NHBoc
OAcO
AcO
AcHN O
O
CO2BnO
OO
OO
OH
O
CO2MeAcO
OAcAcHN
OAc
AcO
SO2Ph
R2
O
CO2Me
AcHN
OAc
AcO
R1
AcO
AcO
AcHNO CO2Bn
NHBoc
AcO
OAc
O
Zn(BH4)2
180 R1 R2 = H OH ( RS 11)
181 R1 R2 = O
182 R1 = H R2 = OH de gt 90
DMSO Ac2O
177178
179
13 steps
22 equiv SmI2 THF
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1413
Scheme (37)
Fig (2)
(KLH) by reductive amination for use as carbohydrate-basedvaccine GM3 a related trisaccharide containg gangliosideplays an important role in cell growth and differentiationFig 2 The synthesis of C-oligosaccharide GM3 is currentlyunderway following a similar route to that of C-GM4synthesis [42]
Beau also reported a sialyl C-disaccharide synthesiswhich relied on the unprecedented use of a stable andcrystalline 2-pyridyl sulfide of the N-acetylneuraminic acidderivative 189 as the anomeric precursor in a samarium-Reformastky procedure [43] The coupling procedure withsulfide 189 and aldehyde 190 afforded the carbon-linkeddimer 191 in 93 yield as a 11 diastereomeric mixture
Alcohols 191 were converted into thiocarbonates anddeoxygenated by employing triphenyltin hydride catalyticAIBN and pentafluorophenol which yielded C-disaccharide192 as a single compound in 65 yield for the 2 stepsDesilylation hydrogenolysis acetylation and finalacetolysis of the methyl glycoside provided the carbon-linked mimic 193 of the disaccharidic component of thesialylTn tumor antigen (Scheme 38)
4 CATIONIC METHODS
This section is categorized according to reactions thatinvolve the generation of anomeric ions followed by thecapture with sugar-based nucleophiles
OAcAcHN
OAc
AcO
O
OBnBnO
OBnOMP
HO
O
MeO2CAcO
O
MeO2CAcO
OAcAcHN
OAc
AcO
O
OHHO
OHOMP
HO
O
OBnOHC
OBnBnO
OMP
O
MeO2CAcO
OAcAcHN
OAc
AcO
O
OHHO
OHOMP
HO
O
CO2MeAcO
OAcAcHN
OAc
AcO
SO2Ph
O
MeO2CAcO
OAcAcHN
OAc
AcO
O
OAcAcO
OAcX
AcO
H2 PdC EtOAc CH3OHH2O
+
Ac2O Pyr
187 X = OMP
188 X = SPh 73
184 85 R and S mixture
186 90 for two i somers
+
SmI2 THF183
179
185
O
HO2 CHO
OAcAcHN
OH
HO
O
OHHO
OH
OAcO
(CH2 )12 CH3
HN
OH
(CH2)14CH3
O
O
O
OHHO
OH
O
O
HO2 CHO
OAcAcHN
OH
HO
O
OHHO
OH
O(CH2)12CH3
HN
OH
(CH2)1 4CH3
GM4
GM3
1414 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
41 Exo-glycals as Nucleophiles
Nitotra et al have found that treatment of exo-glycal 194with BF 3
OEt2 followed by a water quench afforded the C-disaccharide 195 (Scheme 39) It is noteworthy tonoteworthy that the attack of the enol ether on the anomericoxonium ion occurs with high stereoselectivity on the α-face only 195 was obtained [44]
42 Silyl-based Nucleophiles
Isobe has designed and developed alkynylation as a keyreaction for the introduction of a carbon chain onto sugarsThose alkynylated compounds are called ldquosugar acetylenesrdquo[45] The mechanism includes eliminative formation ofcation to which silylacetylene can coordinate on the α-face(Scheme 40)
Double C-glycosylation between glycal 198 and bis(silylacetylene) gave C-disaccharide ldquolikerdquo compounds 199and 200 (Scheme 41)
Silylpropargyl-sugar 201 smoothly reacted with D-glucalto furnish exclusively the α-acetylene glycoside product 202in 88 (Scheme 42) [46]
5 CYCLIZATION METHODOLOGY
This approach to C-oligosaccharide synthesis relies onthe coupling of an open chain fragment with an intact
monosaccharide to give an intermediate that is then cyclizedto deliver the C-oligosaccharide target This section isdivided by the type of chemistry used to initially assemblethe two pre-cyclization fragments
51 Wittig Reaction-Cyclization
The Kishi group was the first to use Wittig-cyclizationapproach to synthesize C-disaccharides Starting with Wittigreaction between 203 and 204 the intermediate 205 wasafforded as a single stereoisomer in 82 yield Osmylationthen gave a mixture of diols with the major one formed in a61 ratio Selective protection of the diols gave 206a and206b The mono-para-methoxybenzyl ether 206a was thentransformed into the hemiketal 207 in 75 overall yield inthree steps ie (1) Swern oxidation (2) acetonide hydro-lysis (4 N HClTHFrt) and (3) benzoylation (3 equiv ofPhCOClpyCH2Cl2rt) Silane reduction of 207 in an acidicmedium should preferentially yield the equatorially substi-tuted β-C-glycoside which was deblocked and converted tothe methyl- βminusC-disaccharide 209 Exact parallel experi-ments applied to the minor isomer gave the correspondingC-disaccharide 210 (Scheme 43) [47]
Armstrong has employed Wittig-osmylation protocol forthe preparation of a small library of α-C-(1rarr6)-disaccha-rides [48] Readily available allyl C-glycoside 211 washomologated to diene ester 212 and subjected to osmylation
Scheme (38)
O
CO2MeAcO
OAcAcHN
OAc
AcO
S(2-Py)
O
TESO
AcHNOMe
O
HO
O
CO2MeAcO
OAcAcHN
OAc
AcO
O NHAcOAc
OAc
OAc
O
CO2MeAcO
OAcAcHN
OAc
AcO
O NHAcOBn
OTES
OMe
OAc
AcO
O NHAcOBn
OTES
OMeOH
O
CO2 MeAcO
OAcAcHN
+
192 65
1 MeOHHCl2 H2 PdC EtOH3 Ac2O Pyr4 Ac2OAcOHH2SO4
193 59 overall yield
25 equiv SmI2 THF
1 11-thiocarbonyldiimidazole DMAP2 Ph3SnH cat AIBN
191 93
189
190
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1415
Scheme (39)
Scheme (40)
Scheme (41)
OBnO
OBn
OBn
OBnO
OBn
OBn
OBnO
OBn
OBn
OBnO
OBnCH3
BnO
OH
CH2
OBnO
OBn
CH3
OBn
H2 O
BF3 OEt2 MeCN
194
195 96
OOAc
OAc
AcO
R SiMe3
SnCl4
O
OAc
AcO
R
O
OAc
AcO
O
OAc
AcO
Me3Si
R
SiMe3
196
197
Me3 Si SiMe3
O
AcO
OAc
OAc
SiMe3
SiMe3
O
AcO
OAc
O
OAc
OAc
O
AcO
AcOO
OAc
OAc
SnCl4 CH2Cl2
SnCl4 CH2Cl2198
199
200
1416 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (42)
Scheme (43)
AcO
OAc
OAc
Me3 Si
BnO
OBn
BnO
OBn
AcO
OAc
BnO
OBn
BnO
OBn
+ I2 CH2Cl2
202 88
198 201
O
OBn
OBn
O
O
O
OBn
OBn
O
O
OBn
OBn O
OBn
OBn
O
OPBH2M
OH
OBnO
BnO
BnO
O
OBn
OBn
O
OHOPMB
OHO
HO
HO
O
OH
OHOH
OH
HOOMe
O
OBnOBn
O
Ph3P
O
O
OBn
OBn O
OBn
OBn
O
OPBM
OH
O O
CHO
OBn
BnO
OO
OBn
OBn
O
OHOPMB
BnO
BnO
BnO
OHO
HO
HO
O
OH
OHOH
OH
HOOMe
+ THF -78 oC
1 OsO4 pyr THF
2 NaH PMBBr
206a 206b 206a206b 61
1 Swern [O]2 4N HCl3 PhCOCl pyr
1 Swern [O]2 4N HCl3 PhCOCl pyr
1 PrSiH BF3 OEt2
2 H2 Pd(OH)2C
3 HCl MeOH 90 oC
1 PrSiH BF3 OEt2
2 H2 Pd(OH)2C
3 HCl MeOH 90 o C
203
204
205
207
209
208
210
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1417
followed by reduction to afford a 51 mixture (213214215216) of lactols that were readily separable by chromato-graphy Following a deprotection of an equimolar mixture of213 and 214 217 and the DL hybrid C-disaccharide of D-glucose-O-(1rarr6)-L-galactose 218 were obtained The DDand DL derivatives 219 and 220 of glucose-α-(1rarr6)-idosewere also obtained as a near equimolar mixture afterdeprotection of 215 and 216 (Scheme 44)
52 Anion Addition-Cyclization
Kishi developed an approach for the synthesis of theCndashtrehalo sugars which relied on nucleophilic addition ofone intact sugar fragment to a fundamental aldehyde ieKishi-Nozaki reaction [49] Coupling of monosaccharide221 and aldehyde 222 gave 223 The triple bond waspartially reduced and osmylation was followed by selectiveprotection to afford 224 The acetonide was converted toepoxide 225 by standard methods and removal of the PMBgroup Acid-catalyzed cyclization followed by aglyconichydrolysis and protection of hydroxyl group with (p-methoxyphenyl)diphenylmethyl chloride (MMTrCl) gave226 Inversion of the C-2 hydroxyl and removal of protectinggroups delivered α α-C-trehalose 227 (Scheme 44)
Kishi and co-workers also employed aldol reactions as anefficient access to the C-trisaccharide related to the type IIABO(H) blood group determinant [50] Aldol condensationof the enolate of methyl ketone 228 with aldehyde 229 gavea 41 mixture of hydroxy ketones 230 and 231 The majorketol was cyclized desulfurized and oxidized to afford thedisaccharide ketone 233 The ketone in THF was treatedwith LiHMDS (3 equiv) and TMEDA followed by theaddition of MgBr2 Addition of the aldehyde 234 led toalmost exclusive formation of the equatorial products 235and 236 in a 12 ratio Mesylation of 235 and 236 followedby treatment with liquid ammonia gave enones 237a and237b which were reduced to yield exclusively the C-2rsquo-equatorial ketone 238 Sodium borohydride reduction of theC-3rsquo carbonyl proceeded with the desired stereoselectivity toyield the protected C-trisaccharide 239 which wasdeblocked to provide the polyol 240 (Scheme 46)
Sutherlin and Amstrong cleverly applied a recursivestereochemical deconvolution (RSD) combinatorial approachfor the synthesis of a small library of C-trisaccharides aspotential inhibitors for the cell surface proteins of bacteriumHelicobactor pylori [51] The workers chose to carry outvariations in galactose ring of these trisaccharides An
Scheme (44)
OBnO
BnOOBn
OBn
P O
OEtOEtO
EtO
R H
OH
OH
OH
OH
O
R H
OH
OH
OH
OH
O
OHO
HOOH
OH
O
HO
OHOH
OH
OHO
HOOH
OH
O
HO
OH
OH
OHO
HOOH
OH
O
HO
OH
OHOH
R H
OH
OH
OH
OH
O
R
OBnO
BnOOBn
OBn
O
OHO
HOOH
OH
OO
HOHO
OH
R H
OH
OH
OH
OH
O
1 OsO4 NMO 50
2 DIBAL -32 oC 40
++ +
213 214 215 216
217 218 219 220
1 9-BBN H2O22 Swern [O]
3 t-BuOK
4 I2 C6H6212
211
1418 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
efficient Nozaki-Kishi coupling of vinyl bromide 241 withaldehyde 242 in a diasteromeric ratio of 12 followed byprotection with TBSOTf led to 243 and 244 Hydroborationfollowed by oxidation gave aldehydes 245 and 246respectively Addition of allylmagnesium bromide toaldehyde 245 followed by removal of the silyl groupafforded 247 to 246 giving 248 and 249 Epoxidation gave a11 mixture of the corresponding epoxides which werecyclized to give the C-trisaccharide 250-255 after removalof the benzyl groups (Scheme 47)
Schmidt reported a stereoselective 6-exo-trig selectiveelectrophilic cylization approach for de novo synthesis of amethylene-bridged Neu5Ac-α-(23)-Gal C-disaccharide theC-analog of an important motif in glycosphingolipids [52]The open chain precusors 259ab (a 32-mixture ofdiaseteromeric alcohols) were formed by the addition oflithiated iodide 256 to open chain aldehyde 258 Subsequent
C1 incorporation using Tebbe-reagent formation of a cycliccarbonate and deprotection of the two isopropylidene ketalsafforded tetrol 264 which upon treatment with phenylselenyltrifilate was steroselectively cyclized in a 6-exo-trigselective manner affording a diasteromeric mixture of 251and 252 in a ratio of 71 A seleno-Pummerer rearrangementto afford aldehyde 267 in 5 steps in 90 overall yieldOxidation of the aldehyde and subsequent steps led to thedesired C-disaccharide 268 (Scheme 48)
53 Esterification-Cyclization
Work from the Postema group has focused on a ringclosing metathesis (RCM) approach for the synthesis of C-saccharides [53a] The chemistry is versatile and has beenused for the synthesis of a small library of differentiallylinked β-C-disaccharides through a radical allylation-RCMstrategy [53b] The synthesis of the β-(1rarr4)-glucopyranosyl
Scheme (45)
O
OBn
BnO
BnO
BnO
I
CrCl2-NiCl2O
OBn
OH
BnO
BnO
BnO
O
O
O
O
O
H
OBn
O
O
OBnBnO
BnO
BnO
OOBn
OBn
OAc
PMBOHOO
OBn
BnO
BnO
BnO
O
OBn
OBn
OAc
O
OH
HO
HO
HO
OH
OH
OH
O
OH
O
OBn
BnO
BnO
BnO
OBn
OBn
OAc
O
MMTr
+
1 p-TsOH2 K2CO3 MeOH3 MMTrCl pyr
1 Swern [O]2 BH3 THF
3 AcOH-H2 O4 H2 Pd(OH)2
221
222
223
1 Pd-Pb CaCO3 H22 NaH BnBr3 OsO44 Bu2 SnO5 CsF PMB-Cl6 Ac2 O 4-DMAP
1 AcOH2 TsCl pyr
3 NaH-imid4 DDQ
224225
226 227
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1419
Scheme (46)
OBnO O
OBn
OMe
OBn
XY
SMe
OBnBnO
O
OBn
OBn
OBn
OBn
O
BnO
YX
OBn
TBSO
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnOOBn
H
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnO
OBn
OHC OBn
OBn
OTBS
OMe
BnOOBn
CHO
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnOOBn
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnO
OBn
YX
OBnO O
OBn
OMe
OBn
OBn
O
BnO
O
OBn
OBn
OBn
OBn
O 1 LiHMDS
2
228
1 TBAF THF
2 MeSH BF3 OEt2
230 X = OH Y = H231 X = H Y = OH
230231 41
1 Bu3SnH AIBN2 Swern [O]
1 LiHMDS THF-TMEDA2 MgBr23
1 MsCl
2 liquid NH3
235 X = OH Y = H236 X = H Y = OH Bu3 SnH AIBN
237a and 237b
NaBH4 MeOH
238
239 X = OBn
240 X = OHH2 Pd(OH)2
229
232233
234
1420 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (47)
OH C
O
O BnAcHN
OO
O
OBn OBnOBn
Br
O
OBn OBnOBn
O
OBnA cHN
OO
O TBSO
OBn O BnO Bn
O
OBnAcHN
OO
OTBS
S2
S1
S2
OTBSS1
O H
S2
OT BSS1
O H
MgBrMgBr
S2
O TBSS1
O H
S2
OHS1
OH
S2
OTBSS1
OH
O
OHHO
O H
O
HO
H OO
OBnA cH N
HO
H O
O
O HHO
OH
O
HOHO
O
OBnA cH N
HO
H O
O
OHH O
OH
O
H O
HOO
OBnAcHN
HO
HO
O
O HH O
OH
O
H O
H O O
OBnA cHN
HO
HO
O
O HH O
O H
O
HO
H O O
OBnAcHN
HO
HO
O
OHHO
OH
O
H O
O
OBnA cHN
HO
HOHO
+
241 242
1 CrCl2-NiCl2 T HF-DMF 722 TBSOTf 2 6-lutidine 91
243 244
1 9-BBN 602 Dess-Mart in period inane 97
1 9 -BBN 552 D ess-Martin periodinane 98
245 246
1
2 T BAF 74
1
2 TBAF 88
247 248 249
250
251
250 251 1 1 252 253 1 1 254 255 1 1
252
253
254
255
1 MCPBA2 CSA CH 2Cl2 61 fo r 2 steps3 H 2 Pd (O H)2C 95
1 MCPBA2 CSA CH 2Cl2 63 fo r 2 s teps3 H 2 Pd (OH)2C 87
1 MCPBA2 CSA CH2Cl2 80 for 2 steps3 H2 Pd(O H)2C 95
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1421
Scheme (48)
O
OO
Se Ph
R
O
HO OHOH
O
OB n O B n
OB n
O B nO O
O O
R O OR
X
O
OO
R
Se Ph
O
HOOH
OH
O
OB nOB n
O Bn
OB n
O O
O O
R O O R
O H
O
O B n OB n
O B n
OB n
O
C HO
O
O O
R O OR
OAc HN
OAc
C O2NH 4HOOH
OH
O
OH O H
OH OH
O
OB n O B n
OB n
OB nO O
O O
R O OR
X
O
O
OAcOAc
C HOA cOOAc
OAc
O
OB n O B n
OB n
OB n
O
O Bn OB n
OB n
OB n
X
OH
OO
HOOH
OH
O
O
OMeOB n
OB nOB n
R
t-B uL i256 R = Li
257 R = L i
258
(R = t-B uMe 2Si )
(R = t-B uMe 2Si )
259ab (32) 79 com bine d yi eld
De ss-Ma rtin pe riodinane
260 X = O R = t-B uMe 2Si ) 95
261 X = O R = t -B uMe2S i) 62
T e bbe re age nt
TB A F THF262 X = O R = H 94
diphosge ne
C H2C l 2Pyr
263 95
T HFH2O T FAr t
264 quant it a ti ve yie ld
PhSe C l AgOT f
EtC N -80 oC
265
266
Quant it at i ve yi l ed 25 26 7 1
+
R =
1 Ac 2OPyr
2 mC PB A3 Ac 2ONa OAc
4 NaO HT HFMe OH
5 Ac2O P yr
267 90 overa ll yi e ld
ste ps
268
1422 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
glucopyranoside 280 represents an example of thischemistry The known triacetyl glucopyranoside 269 wasconverted to iodide 270 in good yield Radical allylation of271 proceeded to afford a mixture of equatorial and axialallylation products in a 61 ratio Oxidative cleavage of thedouble bond gave the corresponding aldehydes 273a and273b which were separable Pinnick oxidation of the majoraldehyde 273a then gave the C-4 equatorial acid 274 DCC-mediated coupling of alcohol 275 and acid 274 proceeded toafford ester 276 in good yield Methylenation of 276 gave277 and exposure to catalysist 278 gave a 41 yield of theC-disaccharide glycal which was exposed to an excess ofBH3
THF to give 64 yield of the β-C-disaccharide 279Removal of the benzyl groups and global peracetylation gavethe peracetylated (1rarr4)-β-C-disaccharide 281 in good yield(Scheme 49)
54 Ring Expansion-Cyclization
Nelson developed a new strategy for asymmetric andstereoselective synthesis of C-linked disaccharide mimeticsthe C58-C71 fragment of palytoxin [54] The diol (RR)-282was converted into the di-dihydropyran (DHP) template 283284 and 285 The di-DHPs were functionized in a twodirectional sense using dihydroxylation reactions The two-directional approach was often very efficient indeed forexample in the synthesis of 286 six new stereogenic centerswere introduced with almost complete stereocontrol using areduction and a dihydroxylation reaction The approach isnot restricted to the synthesis of C2-symmetricaldisaccharide mimetics Using the unsymmetrical template285 which has both a pseudo-axial and a pseudo-equatorialhydroxyl groups the unsymmetrical mimetics 289 and 290were prepared (Scheme 50)
6 RADICAL APPROACHES
The radical approach for C-C bond formation is a popularmethod within organic chemistry The use of radicalchemistry in carbohydrate synthesis has certain advantagesFirstly the reaction conditions are very mild and tolerant ofa range of functional and protecting groups Secondanomeric radicals are stable with respect to elimination andepimeration Most significantly the chemistry required toincorporate an appropriate substitute at C-1 employed in theinitial hemolytic cleavage step is common within carbo-hydrate chemistry [55] The use of such radical techniquecan be subdivided into two classes intermolecular andintramolecular approaches
61 Intermolecular Radical Approaches
Giese was the first to employ an intermolecular radical-based approach for synthesis of C-disaccharides [56]Addition of an alkene to an anomeric radical underappropriate conditions allowed exclusive entry to the α-linked C-glycoside a result which was mirrored by the workof Baldwin [57] The high α-selectivity of the reaction wasin contrast with other reports Thus radicals generated at theC-2 C-3 and C-4 centers all preferred to occupy equatorialpositions [58] When the anomeric bromide 291 was treatedwith tin hydride and AIBN resulting anomeric radical andreacted with lactone 292 in a Michael addition it afforded293 In this reaction hydrogen abstraction at the resulting
radical center occurs from axial face to selectively generatethe equatorial C-2rsquo substituent Reduction and acetylation of293 furnished C-disaccharide 294 (Scheme 51) [59]
Witczak used the facial bias of levoglucosene tostereoselectively add a carbohydrate-based radical in thepreparation of the 3-deoxy-(1rarr4)-β-C-disaccharide 299[60] Addition of the radical derived from iodide 295 to 296gave adduct 297 in 26 yield Removal of the anomerichydroxyl of 297 was achieved by treatment with triethylsilane borontrifluoride ether complex followed bystereoselective reduction of the keto function at C-2rsquo withthe formation of 298 in 89 yield Debenzylation followedby acetolysis of 16-anhydro ring produced the peracetylatedtarget C-disaccharide 299 in 19 overall yield from 295(Scheme 52)
Vogel has developed general methods to transformenantiomerically pure 7-oxabicyclo[221]heptyl derivatives(ldquonaked sugarsrdquo) into C-disaccharides Because of thesechiral bicyclic skeletons they undergo highly stereoselectivereactions with predictable diasteroselectivities An arsenal ofmethods is available that allow to substitute these ldquonakedrdquocarbon centers with a variety of functional groups with allpossible relative configurations The methods allowpreparation of both enantiomers of a given target with thesame ease Predictably high stereoselectivity of the reactionsof the bicyclic chirons adds to the flexibility of approachwhich can lead to high molecular diversity [61]
α-C-(1rarr3)-mannopyranoside of N-acetyl-galactosaminepotent β-galactosidase inhibitors was synthesized by thisapproach [61] Enone 302 was readily prepared from 300The addition of the radical derived from bromide 303 toenone 302 afforded the αminusisomer 304 The ketone was thenreduced and the selenide eliminated via the intermediacy ofthe selenoxide to give 305 Acid-promoted (CF3SO3H) 7-oxa ring opening of 305 in MeCN produced the amino-conduritol derivative 306 resulting from the quenching of theallylic cation intermediate by the solvent (Ritter reaction)Ozonolysis of the chloroalkene 306 generated an acylchloride-aldehyde intermediate that reacted with MeOH toproduce a mixture of methyl uronates The major compound307 was silylated and reduced The crude polyol obtainedwas acetylated to produce 308 Desilylated and ammonolysisafforded a mixture of α-β-pyranoses 309 and correspondingα-β-furanoses (Scheme 53)
Similar chemistry was carried out to synthesize non-protected α-C(1rarr2)-L-fucopyranoside of D-galactopyrano-side corresponding to a blood group mimetic [62] Giesersquosradical fucosidation of racemic enone 310 with α-L-bromoacetofucose 311 provided the mixture of diastereo-meric α-C-fucoside 312a and 312b in reproducible yield of78 Reduction of the mixture gave a 11 mixture of endo-alcohols 313 and 314 which were isolated pure in 40 and355 yield respectively Oxidative elimination of thebenzeneselenyl group of 313 followed by acetylation gaveendo acetate 315 in 85 yield Acid-promoted ring openingof 315 and ozonolysis of the resulted chloroalkene gavemethyl uronic ester 316 in modest yield (10) Treatment of316 with Cl3CCN and NaH followed with BF3
OEt2
furnished the totally protected C-disaccharide 317 in 79
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1423
Scheme (49)
Bu3SnO
HOAcO
OMeOAc
OAc
O
AcO
OMeOAc
OAcI
AIBN
O
AcO
OMeOBn
OBn
HO2C O
AcO
OMeOR
ORY
X
OHBnO
BnO
OBn
OBnO
BnO
OBn
O
AcO
OMeOBn
OBnX
i-Pr i-Pr
N
Mo C(Me2 Ph)((CF3)2 MeCO)2
O
RO
OMeOR
O
RO
OR
OR
RO
OR
278
I2 Ph3P
imidazole
269 270 93
271a X = CH2CH=CH2 Y = H R = Ac 64271b Y = CH2CH=CH2 X = H R = Ac 11272a X = CH2CH=CH2 Y = H R = Bn 75272b Y = CH2CH=CH2 X = H R = Bn 75273a X = CH2CHO Y = H R = Bn 79273a Y = CH2CHO X = H R = Bn 79
1 NaOMe MeOH2 NaOH BnBr DMF
OsO4 NaIO4
NaClO2 NaH2PO4
274 96
275
DCC 4-DMAP
276 X = O 82
277 X = CH2 51
TiCl4 Zn dust TMEDA CH2Br2PbCl2 (Cat )
1
2 BH3 THF H2O2 NaOH
H2 PdC EtOH
Ac2 O Pyr 4-DMAP
279 R = Bn R = H 64
280 R = R = H 99
281 R = R =Ac 97
1424 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (50)
Scheme (51)
O OOH
OH
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
286
1 VO(acac)2 t-BuOH 95
2 (MeO)3CH BF3 90
1 P-O2NC6H4 CO2H Ph3P DIAD2 K2CO3 MeOH 82 over 2 steps
1 PhCOCl Et3N DMAP 402 P-O2NC6H4 CO2H Ph3P DIAD3 KOH THF-H2O 75 over 2 steps
TMEDA OsO4
Cat OsO4 NMO 287
Cat OsO4 NMO288
TMEDA OsO4
Cat OsO4 NMO
290
289
(RR)-282283
284
285
OHO
AcO
BrOAc
OAc
BnO
O
OBn
OBnO
OHO
AcOOAc
OAc
BnO
OOBn
OBnAcO
OHO
AcOOAc
OAc
BnO
O
OBn
OBnO
+
Bu3SnH AIBN291
292
293 81
1 Na[Al(OC2H4OMe)2(OEt)H]2 Ac2O pyr
294 56 over 2 steps
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1425
Scheme (52)
Scheme (53)
OBnO
BnOOBn
OBn O
OH
O
OBnO
BnO
OHOBn
OBn O
O
O
O
O
O
OBnO
BnOOBn
OBnO
OAcOAc
OAc
OBnO
BnO
OHOBn
OBn
IBu3SnH AIBN
295 297 26
1 BF3 OEt2 Et3SiH
2 L-Selectride THF
1 Pd(OH)2C C6H10 EtOH
2 EtSiOSO2CF3 Ac2O
298 89 over 2 steps299
296
O
O
PhSeClO
O
PhSeCl
Bu3 SnH
O
O
PhSeCl
R
H
O
OAc
R
Cl
O
AcO
OAc
OAc
OAcOH
Cl
NHAc
R
OAc
AcHN
OH
O
OH OAc
OH
OHO
HO
OH
O
AcO
OAc
OAc
OAcBr
O
O
PhSeCl
O
O
PhSeCl
R
O
OTIPSAcHNR
OAc OAc
O
OHAcHN
COOMe
R
OAc
1 Bu4NF
2 NH3MeOH
1 (Me3Si)2NLi THF2 Me2N=CHI
1 Bu3 SnH AIBN2
1 NaBH42 mCPBA3 Ac2O pyr
1 H+ MeCN
2 H2 O NaHCO3
R =
1 O3MeOH
2 Me2S NaHCO3
1 TIPSOTf 26-lut idine2 LiBH43 Ac2 O pyr DMAP
furanoses +
304 56
305 68 306 84307 50
308 46
300 301 302
303
309
1426 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
The reduction of 317 and treatment with DOWEX-H+ resinprovided the desired C-fucoside 318 in 70 (Scheme 54)
62 Intramolecular Radical Approaches
One disadvantage with the intermolecular approaches isthat during such radical mediated reactions electrondeficient alkenes are required to facilitate C-C bondformation The intramolecular approach of Sinayuml overcomes
this drawback by bring two substrates together via atemporary covalent silaketal connector This enables the useof a wider range of alkenes which can include alkene-functionalized sugars thus leading to the generation of C-disaccharides [63] Based on the early work of Stork Sinayumlemployed the tether reaction in the synthesis of both α- andβ-C-disaccharides with this work subsequently beingemployed in the synthesis of biologically significant natural
Scheme (54)
O
OH
Fuc
Cl
O
O
ClPhSe
OOAc
NHAcOHFuc
O
AcOOAc
AcO
Br
O
O
PhSeCl
O
AcOOAc
AcO
O
OH
PhSe Cl
Fuc
OOAc
NHAc
OMe
Fuc
O
AcHN
OH OAc
OH
O
OH
Me
OH
O
O
Fuc
ClSePh
O
HO
Fuc
ClSePh
+
Ph3SnHAIBN
78 combined yield
Fuc
310
+
1 NaBH4 MeOHTHF2 Chromatography
313 40 314 355
1 mCPBA
2 Ac2O pyr DMAP
+
315 75
1 TfOH MeCN
2 NaHCO3 O3 -78 oC
316 10 over 2 steps
1 Cl3 CCN NaH
2 MeOH BF3 OEt2
317 79
1 LiBH4 THF
2 Dowex-H+
311
312a312b
318 70 for 2 steps
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1427
products [64] The availability of different hydroxyl groupson each monosaccharide unit allowed the fine-tuning ofstereochemical outcome by selective positioning of the silyltether [65] Development of this early stereochemical controlled to the tethering of the donor 320 with alcohol 319through a di-isopropyl silicon tether 321 Subsequent treat-ment with Bu3SnH and AIBN led to a 9-endo-trigcyclization to form the C-disaccharide 322 in an 80 yieldwith exclusive formation of the α-product The silyl tetherwas removed with Bu4NF and deprotection under standardconditions afforded the desired disaccharide 323 in excellentyield (Scheme 55)
In parallel the development of a 32rsquo silyl tether allowedaccess to the β-linked product as demonstrated in Sinayumlrsquossynthesis of methyl β-C-lactoside 328 [66] Alcohol 324 and320 were connected via the dimethylsilyl tether an 8-endo-trig cyclization followed to exclusively afford the β-
disaccharide 326 in 45 yield Removal of the tether anddeprotection of benzyl ether gave β-C-disaccharide 328(Scheme 56)
This group also selected iodosugars bearing a freehydroxyl group as progenitors of the radical donors [67] In atypical experiment the radical donor 329 was connected tothe radical acceptor 330 through a silaketal tether followingtheir procedure Tributyltinhydride mediated 8-endo-trigradical cyclization of compound 331 gave after detetheringof the non isolated intermediate 332 the protected β-C-disaccharide 333 in 37 overall yield (from startingmaterials 330 and 329) Peracetate 335 was achieved afterhydrogenolysis The C-laminaribioside 334 is of potentialbiological interest as it mimics the repeating disaccharideunit of fungal β-(1rarr3)-glucans which have antitumor andimmunomodulating properties (Scheme 57)
Scheme (55)
Scheme (56)
OO
OHSePh
OTBDPSO O
OO
SePh
OTBDPSO
OO
OBnOMe
OBn
Si
O
HOOBn
OMe
OBn
O
HOOH
OHHO
O
HOOH
OMe
OH
OTBDPSO
O
HOOBn
OMe
OBnO
OOH
1 n-BuLi THF
2 iPr2SiCl2 -78 oC
3 DMAP THF rt
1 Bu4NF THF
2 Dowex-H+
3 H2 PdC
Bu3SnH AIBN toluene
319
320
321
322323
OBnO
OHSePh
OBnBnO
OHO
OBnOMe
OBn
ROO
ROOH
OR
OHO
OROMe
OR
OBnO
O
OBnBnO
OO
OBnOMe
OBn
Si
SePh
OBnO
O
OBnBnOO
OOBn
OMe
OBn
Si
1 PhSeH Me2SiCl2
BuLi -78 oC
2 imidazole rt
Bu3SnH AIBN toluene
H2 PdC327 R = Bn
328 R = H
Bu4NF THF
324
320
325
326 45
1428 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
CONCLUSIONS
In this paper the biological importance of C-oligo-saccharides as subunits of natural products and as a newgeneration of carbohydrate based on therapeutics has beenillustrated Different methods are available for the synthesisof C-oligosaccharides As with traditional saccharidesynthesis it has been necessary to develop a number ofspecific approaches to facilitate the regioselective andstereoselective preparation of the desired targets Work inthis area continues and it is expected that many interestingnew C-oligosaccharides will be prepared using the chemistrydescribed in this review It is also likely that new chemistrywill be developed in the future for the preparation of thesebiologically important targets
ACKNOWLEDGEMENTS
The authors thank Dr Sultan Baytas for her criticalreading of this manuscript
REFERENCES
[1] Kennedy J F White C A Bioactive Carbohydrates InChemistry Biochemistry and Biology Ellis Horwood LtdChichesterUK 1983
[2] Wassarman PW Mammalian Fertilization Molecular Aspects ofGamete Adhesion xocytosion Exocytosis and Fusion Cell 199996 175-183
[3] Carbohydrate-based Drug Discovery Wong C-H EdWeinheim Cambridge Wiley-VCH 2003
[4] (a) Sharon N Lis H Lectins as Cell Recognition MoleculesScience 1987 246 227-234 (b) Dwek RA Chem Rev 1996 96683-720
[5] Postema M C-Glycoside synthesis CRC Boc Ratom 1995[6] (a) Weatherman R V Mortell K H Cheruenak MKiessling
L L Toone E J Specificity of C-Glycoside Complexation byMannoseGlucose Specific Lectins Biochem 1996 35 3619-3624(b) Ravishankar R Surolia A Vijayan M Lim S Kishi YPreferred Conformation of C-Lactose at the Free and Peanut LectinBound States J Am Chem Soc1998 120 11297-11303
[7] (a)Wong C-H Halcomb R L Ichikawa Y and Kajimoto TEnzymes in organic synthesis Application to the problems ofcarbohydrate recognition part2 Angew Chem Int Ed Engl 199534 521-546 (b)Howard S Withers SG Bromoketone C-Glycosides a New Class of βminusGlucanase Inactivators J AmChem Soc 1998 120 10326-10331(c) Wang Q Wolff MPolat T Du Y Linhardt R J C-glycoside of Neuraminic Acidsas Neura-minidase Inhibitors Bioorg Med Lett 2000 10 941-944 (d) Phili R Chang J Partis R A Mueller R A ChrestF J Passaniti A The Alpha-glucosidase I InhibitorCastanospermine Alters Endothelial cell Glycosylation PreventsAngiogenesis and Inhibits Tumor Growth Cancer Res 1995 552927-2935
[8] Ossor A Elbein A D In Carbohydrates in Chemistry andBiology Vol 3(II) WileyVCH 2000 pp 513-539
[9] (a) Sinayuml P Synthesis of oligosaccharide Mimetics Pure ApplChem 1997 69 459-463 (b) Beau J-M Gallagher TNucleophilic C-glycosyl Donors for C-glycoside Synthesis Top inCurr Chem 1997 187 1-54 (c) Nicotra F Synthesis of C-glycosides of Biological Interest Top in Curr Chem 1997 187
Scheme (57)
O
O
O
Ph
I
OMe
OHO
BnO
OH
OH
BnOOH
O
BnO
Si
O
O O
Ph
I
OMe
O
O
BnO
OR4O
R5O
OMe
OR2
OR3O
R3O
OR1
R3O
Bu3 SnH AIBN
332 R1 R2 = SiMe2 R3 = Bn R4 R5 = CHPhTBAF THF
333 R1 = R2 = H R3 = Bn R4 = R5 = CHPh 37 from 11
334 R1 = R2 = R3 = R4 = R5 = H
335 R1 = R2 = R3 = R4 = R5 = Ac
329
H2 PdC MeOH
Ac2 O pyr
1 BuLi THF -78 oC
2 Me2SiCl2
3 DMAP
330
331
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1429
55-83 (d) Du Y Linhardt R Y Recent Adv in Stereo-SelectiveC-Glycoside Synthesis Tetrahedron Lett 1998 54 9913-9959 (e)Liu L Mckee M and Postema M H D Synthesis of C-saccharides and Higher Congeners Current Org Chem 2001 51133-1167
[10] Jarosz S Fraser-Reid B Synthesis of A Higher Carbon Sugar ViaDirected Aldol Condensation Tetrahedron Lett 1989 30 2359-2362
[11] Lichtenthaler F W Lergenmiiller M Schwidetzky S C-Glycosidations of 2-Ketohexosyl With Electrophilic Radical andNudeophilic Anomeric Carbons Eur J Org Chem 2003 3094-3103
[12] Baudat A Vogel P Aza-C-disaccharides Synthesis of 6-Deoxygalactonojirimycin-β-C(1rarr3) Linked with D-Altrofuranosides and D-Galactose J Org Chem 1997 62 6252-6260
[13] Turner D Vogel P Synthesis of 4-Hydroxy-26-Bis(hydroxymethyl) tetrahydropyran-2-Carbaldehyde DerivativesSynlett 1998 304-306
[14] Zhu Y-H Vogel P Short Stereoselective Synthesis of C-(1rarr3)-Linked Disaccharides Tetrahedron Lett 1998 39 31-34
[15] Zhu Y-H Vogel P Synthesis of a (2R 6R)-2-(Hydroxymethyl)-6-Propa-1 2-Dienyl-2H-Pyran-3(6H)-One Derivative A NewEnone for The Convergent Construction of C-Glycosides of C-Disaccharides Synlett 2001 82-86
[16] Baumberger F Vasella A Deoxynitrosugars The 6th
Communication Stereolectronic Control in the reductivedenitration of tertiary nitro ethers A Synthesis of ldquoC-glycosidesrdquoHelv Chim Acta 1983 66 2210-2221
[17] Martin O R Lai W Synthesis and Conformational Studies of β-(1rarr6)- and ββ-(1rarr1)-Linked C-disaccharides J Org Chem1993 58 176-185
[18] Spak S J Martin R The synthesis of an analogue of Methyl OC-Analogue of Methyl 4rsquo-O-β-D-GlucopyranosylgentiobiosideTetrahedron 2000 56 217-224
[19] Kobertz W R Bertozzi C R Bednarski M D C-GlycosylAldehyde Synthons for C-Linked Disaccharides J Org Chem1996 61 1894-1897
[20] Gurjar M K Nagaprasad R and Ramana CV First Synthesis ofMethyl α-C-D-Arabino-furanosyl-(1rarr5)-αminusD-Arabinofuranosidethe C-Disaccharide Segment of Motif C of MycobateriumTuberculosis Tetrahedron Lett 2000 43 7577-7579
[21] Witczak Z J Synthesis of C-Glycosyl Compounds and OtherNatural Products from Levoglucosenone Pure Appl Chem 199466 2189-2192
[22] Griffin F K Paterson D Taylor R J K Ramberg-BacklundApproaches to the Synthesis of C-Linked Disaccharides AngewChem Int Engl 1999 38 2939-2942
[23] Paterson B E Griffin F K Alcaraz M-L and Taylor R J KA Ramberg-Baumlcklund Approach to the Synthesis of C-GlycosidesC-Linked Disaccharides and C-Glycosyl Amino Acids Eur JOrg Chem 2002 1323-1336
[24] McAllister G D Paterson D E Taylor R J K A SimplifiedRamberg-Bachlund Approach to Novel C-Glycosides and C-Linked Disaccharides Angew Chem Int Ed Engl 2003 42 1387-1391
[25] McCartney J L Christopher T M Cicchillo R M BernardinaM D Wagner T R and Norris P J Org Chem 2003 6810152-10155
[26] Dondoni A Zuurmond H M Bascarate A Synthesis of α-andβ-D-(1rarr6)-C-Disaccharides by Witting Olefination of Formyl C-Glycosides with Glycopyranose 6-phosphoranes J Org Chem1997 62 8114-8124
[27] Dondoni A Kleban M Zuurmond H Marra A Synthesis of(1rarr6)-C-Oligogalactosides by Interative Wittig OlefinationTetrahedron Lett 1998 39 7991-7994
[28] Dondoni A Marra A A New Synthetic Approach toMycobacterial Cell Wall α-(1rarr5)-D-Arabinofuranosyl C-Oligosaccharides Teterahedron Lett 2003 44 4067-4071
[29] Colinas P A Ponzinibbio A Lieberknecht A and Bravo R OWittig Reaction of Glycosyl Phosphonium Salts A StereoselectiveRoute to C-Disaccharides and C O-Trisaccharides TetrahedronLett 2003 44 7985-7988
[30] Schmidt R R Preuss R Synthesis of Carbon Tetrahedron Lett1989 30 3409-3412
[31] Dietrich H Schmidt R R Synthesis of Carbon-Bridged C-Lactose and Derivatives Liebigs Ann Chem 1994 975-981
[32] Rouzaud D Sinayuml P The First Synthesis of a ldquoC-DisacchariderdquoJ Chem Soc Chem Commun 1983 1353-1354
[33] Xin Y-C Zhang Y-M Mallet J-M Glaudemans C P JSinayuml P Synthesis of C-Oligosaccharides That Mimie TheirNatural O-Analogues Immunodeterminants in Binding toMonoclonal Immunoglobulins Eur J Org Chem 1999 471-476
[34] Streicher H Geyer A Schmidt R R C-Disaccharides ofKetoses Chem Eur J 1996 2 502-510
[35] Leeuwenburgh M A Timmers C M Vander Marel G A VanBoom J H Mallet J-M Sinayuml P G Stereoselective Synthesisof α-C-(Alkynyl)-Glycosides Via Ring-Opening of α-12-Anhydrous Tetrahedron Lett 1997 38 6251-6254
[36] Aslam T Fuchs M G G Le Formal A Wightman R HSynthesis of C-Disaccharide Analogue of the α-D-Arabinofuranosyl-(1rarr5)-α-Arabinofuranosyl Motif ofMycobacterial Cells Walls via Alkynyl Intermediates TetrahedronLett 2005 46 3249-3252
[37] (a) Girad P Namy J L Kagan H B Divalent LanthanideDerivative in Organic Synthesis 1 Mild Preparation of SamariumIodide and Ytterbium Iodide and Their Use as Reducing orCoupling Agents J Am Chem Soc 1980 102 2693-2698 (b)Molander G A Harris C R Sequencing Reactions withSamarium(II) Iodide Chem Rev 1996 96 307-338
[38] (a) Mazeacuteas D Skrydstrup T Doumeix O Beau J-MSamarium Iodide-Induced Intramolecular C-Glycoside FormationEfficient Radical Formation in the Absence of an Additive AngewChem Int Ed Engl 1994 33 1383-1386 (b) Mazeacuteas DSkrydstrup T Beau J-M A Highly Stereoselective Synthesis of1 2-trans-C-Glycosides Via Glycosyl Samarium(III) CompoundsAngew Chem Int Ed Engl 1995 34 909-912 (c) Jarreton OSkrydstrup T Beau J-M The Stereospecific Synthesis of Methylα-C-Mannobioside A Potential Inhibitor of M TuberculosisBinding to Human Macrophages J Chem Soc Chem Commun1996 1661-1662 (d) Jarreton O Skrydstrup T Espionosa J-FJimeacutenez-Barbero J Beau J-M Samarium Diiode Prompted C-Glycosylation An Application to The Stereospecific Synthesis ofα-(1rarr2)-C-Mannobioside and Its Derivatives Chem Eur J 19995 430-441 (e) Mipuel N Doisneau G Beau J-M ReductiveSamariation of Anomeric 2-Pyridyl Sulfones with Catalytic AnUnexpected Improvement in The Synthesis of 12-Trans-Diequatorial C-Glycosyl Compounds Angew Chem Int Ed Engl 2000 39 4111-4114
[39] Vlahov I R Vlahova P I Linhardt R J DiastereocontrolledSynthesis of Carbon Glycosides of N-Acetylneuraminic Acid ViaGlycosyl Samarium(III) Intermediates JAmChem Soc 1997 1191480-1481
[40] Kuberan B Sikkander S ATomiyama H Linhardt R JSynthesis of a C-Glycoside Analogue of sTn An HIV-and Tumor-Associated Antigen Angew Chem Int Ed Engl 2003 42 2073-2075
[41] Bazin H G Du Y Polat T Linhardt R J Synthesis of aVersatile Neuraminic Acid ldquoCrdquo-Disaccharide Precursor for theSynthesis of C-Glycoside Analogues of Gangliosides J OrgChem 1999 64 7254-7259
[42] Chen C-C Ress D K Linhardt RJ Samarium Iodide-Mediated Synthesis of Neuraminic Acid C-Glycosides InSynthesis of Glycommetics Roy R Ed ACS Syposium Series2004 896 53-80
[43] Abdallah Z Doisneau G Beau J-M Synthesis of a Carbon-Linked Mimic of The Disaccharide Component of The Tumor-Relate SialyTn Antigen Angew Chem Int Ed Engl 2003 425209-5212
[44] Lay L Nicotra F Panza L Russo G Caneva E Synthesis ofC-disaccharides through dimerization of exo-glycals J Org Chem1992 57 1304-1306
[45] Isobe M Nishizawa R Hosokawa S Nishikawa TStereocontrolled Synthesis and Reactivity of Sugar Acetylenes JChem Soc Chem Commun 1998 2665-2676
[46] Saeeng R Sirion U Sahakitpichan P Isobe M IodineCatalyzes C-Glycosidation of D-Glucal with SilylacetykeneTetrahedron Lett 2003 44 6211-6215
[47] (a) Babirad S A Wang Y Kishi Y Synthesis of C-Disaccharides J Org Chem 1987 52 1370-1372 (b) Wang YBabirad S A Kishi Y Preferred Conformation of C-Glycosides
1430 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
8 Synthesis of 14-Linked Carbon Disaccharides J Org Chem1992 57 468-481
[48] Armstrong R W Sutherlin D P Strategies for the Synthesis ofC-Disaccharides Containing D and L Sugars Tetrahedron Lett1994 35 7743-7746
[49] Wei A Kishi Y Preferred Conformation of C-Glycosides 12Synthesis and Conformational Analysis of αα- α β- and β β-Trehaloses J Org Chem 1994 59 88-96
[50] Haneda T Goekjian P G Kim S H Kishi Y PreferredConformation of C-Glycosides 10 Synthesis and ConformationAnalysis of Carbon Trisaccharides J Org Chem 1992 57 490-498
[51] Sutherlin D P Armstrong R W Synthesis of 12 Stereochemistryand Structurally Diverse C-Trisaccharides J Org Chem 1997 625267-5283
[52] Notz W Hartel C Waldscheck B Schmidt R R De NovoSynthesis of a Methylene-Bridged Neu5Ac-α-(23)-Gal C-Disaccharide J Org Chem 2001 66 4250-4260
[53] (a) Postema M H D Calimente D Liu L Behrmanm T L AnOlefin Metathesis Route for the Preparation of (1rarr6)-Linked-C-Disaccharide Glycals A Convergent and Flexible Approach to C-Saccharide Synthesis J Org Chem 2000 65 6061-6068(b) Postema M H Piper J L Liu L Faust M Andreana PSynthesis and Partial Biological Evaluation of a Small Library ofDifferentially Linked β-C-Disaccharide J Org Chem 2003 684748-4754
[54] Nelson A The Development of Strategies and Methods for TheSynthesis of Biologically Active Compounds New J Chem 200428 771-776
[55] Togo H He W Waki Y Yokoyama M C-GlycosylationTechnology With Free Radiant Reactions Synlett 1998 700-717
[56] Giese B Dupuis J Diastereoselective Synthesis of C-Glycopyranosides Angew Chem Int Ed Engl 1983 22 622-623
[57] Adlington R M Baldwin J E Basak A Kozyrod RPApplication of Radical Addition Reactions to tho Synthesis of a C-Glucoside and A Functionalized Amino Acid J Chem SocChem Commun 1983 144-145
[58] Giese B Gonzaacutelez-Goacutemez J A Witzel T The Scope of RadicalCC-Coupling by The ldquoTin Methodrdquo Angew Chem Int Ed Engl1984 23 69-70
[59] Giese B Witzel T Synthesis of ldquoC-Disaccharidesrdquo by RadicalC-C Bond Formation Angew Chem Int Ed Engl 1986 25 450-451
[60] Witczak Z J Chhabra R Chojnacki J C-Disaccharides IStereoselective Approach to β-(1rarr4)-3-Deoxy-C-Disaccharidesfrom Levoglucosenone Carb Res 1997 301 167-175
[61] Vogel P Synthesis of Rare Carbohydrates and Analogues Startingfrom Enantiomerically Pure 7-Oxabicyclo[221]heptyl Derivatives(ldquoNaked Sugarsrdquo) Current Org Chem 2000 4 455-480
[62] Viodeacute C Vogel P Synthesis of The C-Disaccharide α-C(1rarr3)-L-Fucopyranoside of N-Acetylgalactosamine J Carb Chem2001 20 733-746
[63] Xin Y C Mallet J M Sinayuml P An Expeditious Synthesis of AC-Disaccharide Using A Temporary Silaketal Connection J ChemSoc Chem Commun 1993 864-865
[64] (a) Petitou M Herault P Lormeau J-C Helmboldt A MalletJ-M Sinayuml P Herbert J-M Introducing A C-InterglycosidicBond in A Biologically Active Pentasaccharide Hardly Affects ItsBiological Properties Bioorg Med Chem 1998 6 1509-1516 (b)Sinayuml P Advances in The Synthesis of the Carbohydrate MimicsPure Appl Chem 1998 70 1495-1499
[65] Sinayuml P Chemical Synthesis of Oligosaccharide Mimetics PureAppl Chem 1998 70 407-410
[66] Sinayuml P Chemical Synthesis of Oligosaccharide Mimetics PureAppl Chem 1998 69 459-463
[67] Vauzeilles B Sinayuml P Selective Radical Synthesis of β-C-Disaccharides Tetrahedron Lett 2001 42 7269-7272
1406 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
The di- tri- and tetrasaccharide derivatives (145 147 and148) were all debenzylated and tested for their bindingaffinity to three different monoclonal immunoglobulins withspecificity for different O-β-(1rarr6)-D-galactopyranosyl deter-minants These C-saccharide analogs had similar bindingproperties to the corresponding O-saccharides
Schmidt has also used acetylide-lactone condensation toassemble C-disaccharides of ketoses [34] Lithium acetylide149 was condensed with ketone 150 to give a mixture ofalcohol 151 after removal of the pivoloyl group Attemptedcyclization under Lewis acid catalysis resulted only in theremoval of the acetonide Accordingly the diol was tiedback as the carbonate and the acetylene complex as thedicobalt species 152 The isomers were then separately
cyclized to give a 11 mixture of C-disaccharide 153 Thecobalt complex on α-C-disaccharide was removed understandard conditions to give 154 and deprotection of thecarbonate was followed by hydrogenation and peracetylationto give 155 (Scheme 30) Similar chemistry was also carriedout with the corresponding β-isomer
Van Boom and co-workers used lithiated alkynylderivative 156 in presence of ZnCl2 to selectively open ringof the 12-anhydrosugar 157 affording the α-C-(alkynyl)-glycoside 158 Hydrogenolysis of the benzyl groups wasfollowed by peracetylation to give the (1rarr6)-α-C-disaccharide 159 (Scheme 31) [35]
Normally attack of the nucleophile proceeds from anequatorial direction to give the β-isomer The unexpected
Scheme (23)
Scheme (24)
BnOO
OBnCHO
OBn
O
OBn
PPh3I-
OBn
OBn
O
OBn
BnOBnO
O
OBnOBn
OBnH
O
OH
HOHO
O
OHOH
OH+
BuLi
THF-HMPA
-20 oC+
1 TBAF2 H2 Pd(OH)2C
112 65 113 100
110
111
O
OBnCHO
OBnBnO
O
OBn
BnOBnO
O
OBnCH(OiPr)2
OBnH
O
OBnCH(OiPr)2
PPh3I-
OBn
O
OBn
BnOBnO
O
OBn
OBnH
O
OBnOBn
BnOH
O
OH
HOHO
O
OH
OH
O
OHOH
HO
++
BuLi
THF-HMPA
-20 oC
BuLi
THF-HMPA
-20 oC
TFA H2 O THF rt
115 49
116 R = CH(OiPr)2
117 R = CHO
118 45
H2 Pd(OH)2C
110
114
114
119
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1407
Scheme (25)
Scheme (26)
OBn
R1
R2
PPh3BF4-O
O
OOHC
O
O
O
O
O
O
O
O
HO
O
O
O
O
O O
OBn
R1
R2
O
O
O
O
O
O
H
O
OBn
R1
R2
O
O
O
O
O
O
O
O
OBn
R1
R2
O
O
O
+
BCl3 (005 equiv)
MS 4A CH2 Cl2 0 o C
+
BuLi THF -90 oC -90 o C
to rtH2 (1 atm) PdC Et3N MeOH
R1 R2 = OBn H
120a - b
121
122a - b
123a - b
124
125a - b
OTBDPS
BnO X
SO Ph
O
BnO
OHCO
BnO
OMeOBn
OBn
O
BnO
OTBDPS
BnO
SO Ph
O
BnO
OMeOBn
OBn
O
HO
OMeOH
OHO
HOHO
OH
OH
128
229 74
1 RaNi (74)
2 BH3 DMS
NaOH H 2O2 (74)
3 H2 PdC (70)
130 74
LDA THF
-100 oC
126 X = H
127 X = Li
1408 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (27)
Scheme (28)
stereochemical outcome is rationalized by the generation ofan initial zinc acetylide species which facilitates intra-molecular delivery to the α-face (Scheme 32)
Wightman synthesized C-disaccharide analogs of the α-D-arabinofuranosyl-(1rarr5)-α-D-arabinofuranosyl motif ofmycobacterial cell walls through alkynyl intermediates [36]The lactone 164 was treated with lithio(trimethylsilyl)ethyneat low temperature to give lactol in 66 yield of 165Treatment of this with triethylsilane and BF3
Et2O gavethe separable isomers 166α (60) and 166β (13)Desilylation of the major isomer 166α gave 167 in 97yield Treatment of 167 with n-BuLi followed by addition oflactone 164 gave 85 yield of the hemiacetal 168 which onreduction with Et3SiH and BF3
Et2O gave the disubstitutedalkyne 169 (83) as the major product Reduction-
hydrogenolysis of 169 then gave the C-disaccharide 170 innear-quantitative yield (Scheme 33)
3 REDUCTIVE GLYCOSYL SAMARIUM SPECIES
The introduction of SmI2 as reducing agent can becredited to Kagan and has since been utilized in numeroussynthetic schemes [37] Sinayuml and Beau introduced SmI2
chemistry into C-glycoside synthesis through intermolecularreactions with appropriate electrophiles and intramolecularreactions of silyl tethered substrates [38] Anomericsamarium species are highly stable and not likely to undergoβ-elimination Treatment of the aryl sulfone 171 with SmI2
affords the nucleophilic intermediate 172 through two singleelectron transfer processes Introduction of a suitableelectrophile (carbonyl compounds) affords the α-C-manno-
O
BnO
OTBDPS
BnO X
SO Ph
O
BnO
OBn
BnO Li
SO Ph
DMF
OHO
HOOH
OH
O OH
OH
HO
OHOH
O
BnO
OTBDPS
BnO
SO Ph
O
OBn
OBnOBnSO
Ph
OH
131 X = Li
132 X = CHO
THF -100 oC
1 Ra-Ni
2 BH3 DMS NaOH H2O2
3 H2 PdC
131
133
134
OBnO
OBnOMe
BnO
Li
OBnO
BnOOBn
OBn
OOBn
OBnOMeBnO
OH
OBnO
BnOOBn
OBn
O
n-BuLi
BnO
OMe
BnO
BrBr
O
OBn
OHO
OH
OH
HO
OHO
OH
HO
OMe
O
BnO
OMeOBn
O
BnO
139 92
1BF3 OEt2 EtOH
2 H2 PdC AcOH
140 52 over 2 steps
135 136 137
138
CBr4 PPh3
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1409
pyrannoside 173 in good yield and with excellent stereo-selectivity (Scheme 34) [38a]
Preparation of C-glycosides of ulosonic acids using SmI2
was pioneered by Linhardt and coworkers [39] Coupling ofpyridyl sulfone 174 with aldehyde 175 in the presence ofSmI2 gave an excellent yield of the N-acetylneuraminic acidC-disaccharide 176 as single isomer This stereochemicaloutcome was rationalized on the basis of the Felkin-Anhmodel for predicting the stereochemical outcome of akinetically controlled addition of a nucleophile to a chiraladehyde (Scheme 35 A)
Reductive samarium method was utilized to synthesizesialo-antigen C-analogs by the Linhardt group A fullyprotected C-analogue of the SialylTn antigen α-D-Neu5Ac-(2rarr6)α-D-GalNAc-(1rarrO)-Ser 182 was prepared [40] C-glycosylation of the neuraminic acid sulfone donor with
aldehyde acceptor in presence of excess SmI2 afforded the α-C-glycoside 180 as an RS mixture (11) The criticalintermediate aldehyde acceptor 178 was prepared in 13steps Chemoselective resolution to compound 180 wasundertaken by oxidation with DMSOAc2O to keto-bridgedcompound 181 followed by stereoselective reduction withZn(BH4)2 to regenerate the bridge hydroxyl function gave182 in gt90 de (Scheme 36)
A common versatile N-acetylneuraminic acid C-disaccharide precursor of the C-glycoside analogs ofgangliosides GM4 and GM3 has been synthesized [41]Samarium(II) iodide coupling of N-acetylneuraminic acidsulfone 179 with a 3-formyl galactopyranoside derivative183 afforded the corresponding C-disaccharide 184 as amixture of (R) and (S) isomers at the newly formedhydroxymethylene bridge This diastereoisomeric mixturewas resolved after debenzylation of the galactoside residue
Scheme (29)
O
BnO
BnOOBn
OBn
OOBn
OBnOMe
OBnOH
O
BnO
BnO
OBn
OBn
O
O
BnOOBn
OMe
BnO
Li
OBnO
OBn
OBn
OBnO
OBn
OBn
OMe
OBnO
OBn
OBnBnO
OBnO
OBn
OBn
OBnO
OBn
OBn
OMe
OBnO
OBn
OBnOBnO
OBn
OBnBnO
O
BnO
BnO
OBn
O
OBnO
OBn
OBnBnO
OBnO
OBn
OBnBnO
OBnO
OBn
OBn
OMe
OBnO
OBn
OBnBnO
OMe
1 PCC2 CBr4 Ph3P3 n-BuLi
144 overall yield 54
1 BF3 OEt2 Et3 OH
2 H2 PtO2 EtOAc
145 76
1 H2 SO4 AcOH
2 PCC
146 62
repeat steps
repeat st eps
141 142
143
147
148
1410 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (30)
Scheme (31)
O
BnOOBn
OMe
Li
BnO
OPivBnO
OBn
OBn
BnO
O OO
BF3 OEt2
OBnO
OBn
OBn
BnO
OO
O
OMe
BnOOBn
BnO
Co(CO)3
Co(CO)3
O
CAN
OBnO
OBn
OBn
BnO
OO
OO
BnOOBn
BnO
OMe
OHBnO
OBn
OBn
BnO
OHO
O
O
OMe
BnOOBn
BnO
Co(CO)3
Co(CO)3
O
OPivBnO
OBn
OBn
BnO
OH OO
O
OMe
BnOOBn
BnO
OAcO
OAc
OAc
AcO
OAcOAc
OAcO
OAc
AcO
OMe
1
2 NaOMe MeOH
1 Lewis acid2 ClCO2CCl3 Pyr3 Co2(CO)8
with a-isomer
1 Et3N Pyr H2O
2 H2 PdC H+
3 Ac2 O Pyr
149 151
152153
154 155
150
OBn
BnO
OBnO
OBn
BnO
OBnO
BnO
MeO
OBnO
OBn
BnO
O
OMe
AcO
OAcO
OAc
OAc
AcO
OAcO
OAc
O
BnOOBn
OMe
BnO
159 74 over 2 steps
+
BuLi ZnCl2 THF
1 H2 PdC2 Ac2O Pyr
156 157
158 59
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1411
Scheme (32)
Scheme (33)
and the chirality of each isomer assigned after acetylationConversion of the p-methoxyphenyl group in the peracety-lated (S) isomer 187 into the corresponding thiophenylglycoside 188 was accomplished affording the key inter-mediate for the synthesis of C-glycoside analogs of GM4GM3 and other related gangliosides (Scheme 37)
Ganglioside GM4 is a very important cell adhesionmolecule The C-disaccharide of GM4 is currently beingsynthesized in Linhardtrsquos lab using standard O-glycosylationof C-disaccharide with protected ceramide Once theceramide has been attached it can be oxidized to afford analdehyde group for coupling to keyhole limpet hemocyanin
OBnO
OBn
BnO
O
OBnO
ClZnO
OBn
BnOCl
R
OBnO
O
OBn
BnOCl
ZnR
O
ZnR
OBnO
OBn
BnO
160 161
162163
O
OBn
OBnBnO
O
O
OBn
OBnBnO H
TMS
O
OBn
OBnBnO H
O
OBn
BnO
OBnHO
O
OBn
OBnBnO OH
TMS
OBnBnO HO
OBn
TMS
O
OR
ORRO H
O
OR
RO
OR
OBn
OBnBnO
H
TMS
O+
K2CO3 MeOH
1 n-BuLi THF -78 oC
2 164
164165 66
166α 60 166β 13167 97
BF3 Et 2O Et 3SiH -78 oC
168 85
169 R = Bn 83
170 R = H near quantitative yield
H2 (1 atm)Pd(OH) 2C
TMS-acetyl ene
n-BuLi THF -78 oC BF3 Et2O Et3SiH
-78 o C
1412 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
O
OHCOBn
OBnBnO
OMe
O
CO2MeAcO
OAcAcHN
OAc
SO2
NAcO
OBnH
H
OBn
OBn
H
O
OMeH HH
A
O
CO2MeAcO
OAcAcHN
OAc
O
OBnOMe
OBnOBn
HO
AcO
+
Nu
174175
176
SmI2 THF
Scheme (34)
Scheme (35)
Scheme (36)
O
BnO
BnO
BnO
Si lylO
O2S N
O
BnO
HO R2R1
BnOBnO
SilylO
OBnO
BnO
BnO
SilylO
Sm(III)
R1COR2 SmI2 THF
171 172
173
NHBoc
OAcO
AcO
AcHN O
O
CO2BnO
OO
OO
OH
O
CO2MeAcO
OAcAcHN
OAc
AcO
SO2Ph
R2
O
CO2Me
AcHN
OAc
AcO
R1
AcO
AcO
AcHNO CO2Bn
NHBoc
AcO
OAc
O
Zn(BH4)2
180 R1 R2 = H OH ( RS 11)
181 R1 R2 = O
182 R1 = H R2 = OH de gt 90
DMSO Ac2O
177178
179
13 steps
22 equiv SmI2 THF
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1413
Scheme (37)
Fig (2)
(KLH) by reductive amination for use as carbohydrate-basedvaccine GM3 a related trisaccharide containg gangliosideplays an important role in cell growth and differentiationFig 2 The synthesis of C-oligosaccharide GM3 is currentlyunderway following a similar route to that of C-GM4synthesis [42]
Beau also reported a sialyl C-disaccharide synthesiswhich relied on the unprecedented use of a stable andcrystalline 2-pyridyl sulfide of the N-acetylneuraminic acidderivative 189 as the anomeric precursor in a samarium-Reformastky procedure [43] The coupling procedure withsulfide 189 and aldehyde 190 afforded the carbon-linkeddimer 191 in 93 yield as a 11 diastereomeric mixture
Alcohols 191 were converted into thiocarbonates anddeoxygenated by employing triphenyltin hydride catalyticAIBN and pentafluorophenol which yielded C-disaccharide192 as a single compound in 65 yield for the 2 stepsDesilylation hydrogenolysis acetylation and finalacetolysis of the methyl glycoside provided the carbon-linked mimic 193 of the disaccharidic component of thesialylTn tumor antigen (Scheme 38)
4 CATIONIC METHODS
This section is categorized according to reactions thatinvolve the generation of anomeric ions followed by thecapture with sugar-based nucleophiles
OAcAcHN
OAc
AcO
O
OBnBnO
OBnOMP
HO
O
MeO2CAcO
O
MeO2CAcO
OAcAcHN
OAc
AcO
O
OHHO
OHOMP
HO
O
OBnOHC
OBnBnO
OMP
O
MeO2CAcO
OAcAcHN
OAc
AcO
O
OHHO
OHOMP
HO
O
CO2MeAcO
OAcAcHN
OAc
AcO
SO2Ph
O
MeO2CAcO
OAcAcHN
OAc
AcO
O
OAcAcO
OAcX
AcO
H2 PdC EtOAc CH3OHH2O
+
Ac2O Pyr
187 X = OMP
188 X = SPh 73
184 85 R and S mixture
186 90 for two i somers
+
SmI2 THF183
179
185
O
HO2 CHO
OAcAcHN
OH
HO
O
OHHO
OH
OAcO
(CH2 )12 CH3
HN
OH
(CH2)14CH3
O
O
O
OHHO
OH
O
O
HO2 CHO
OAcAcHN
OH
HO
O
OHHO
OH
O(CH2)12CH3
HN
OH
(CH2)1 4CH3
GM4
GM3
1414 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
41 Exo-glycals as Nucleophiles
Nitotra et al have found that treatment of exo-glycal 194with BF 3
OEt2 followed by a water quench afforded the C-disaccharide 195 (Scheme 39) It is noteworthy tonoteworthy that the attack of the enol ether on the anomericoxonium ion occurs with high stereoselectivity on the α-face only 195 was obtained [44]
42 Silyl-based Nucleophiles
Isobe has designed and developed alkynylation as a keyreaction for the introduction of a carbon chain onto sugarsThose alkynylated compounds are called ldquosugar acetylenesrdquo[45] The mechanism includes eliminative formation ofcation to which silylacetylene can coordinate on the α-face(Scheme 40)
Double C-glycosylation between glycal 198 and bis(silylacetylene) gave C-disaccharide ldquolikerdquo compounds 199and 200 (Scheme 41)
Silylpropargyl-sugar 201 smoothly reacted with D-glucalto furnish exclusively the α-acetylene glycoside product 202in 88 (Scheme 42) [46]
5 CYCLIZATION METHODOLOGY
This approach to C-oligosaccharide synthesis relies onthe coupling of an open chain fragment with an intact
monosaccharide to give an intermediate that is then cyclizedto deliver the C-oligosaccharide target This section isdivided by the type of chemistry used to initially assemblethe two pre-cyclization fragments
51 Wittig Reaction-Cyclization
The Kishi group was the first to use Wittig-cyclizationapproach to synthesize C-disaccharides Starting with Wittigreaction between 203 and 204 the intermediate 205 wasafforded as a single stereoisomer in 82 yield Osmylationthen gave a mixture of diols with the major one formed in a61 ratio Selective protection of the diols gave 206a and206b The mono-para-methoxybenzyl ether 206a was thentransformed into the hemiketal 207 in 75 overall yield inthree steps ie (1) Swern oxidation (2) acetonide hydro-lysis (4 N HClTHFrt) and (3) benzoylation (3 equiv ofPhCOClpyCH2Cl2rt) Silane reduction of 207 in an acidicmedium should preferentially yield the equatorially substi-tuted β-C-glycoside which was deblocked and converted tothe methyl- βminusC-disaccharide 209 Exact parallel experi-ments applied to the minor isomer gave the correspondingC-disaccharide 210 (Scheme 43) [47]
Armstrong has employed Wittig-osmylation protocol forthe preparation of a small library of α-C-(1rarr6)-disaccha-rides [48] Readily available allyl C-glycoside 211 washomologated to diene ester 212 and subjected to osmylation
Scheme (38)
O
CO2MeAcO
OAcAcHN
OAc
AcO
S(2-Py)
O
TESO
AcHNOMe
O
HO
O
CO2MeAcO
OAcAcHN
OAc
AcO
O NHAcOAc
OAc
OAc
O
CO2MeAcO
OAcAcHN
OAc
AcO
O NHAcOBn
OTES
OMe
OAc
AcO
O NHAcOBn
OTES
OMeOH
O
CO2 MeAcO
OAcAcHN
+
192 65
1 MeOHHCl2 H2 PdC EtOH3 Ac2O Pyr4 Ac2OAcOHH2SO4
193 59 overall yield
25 equiv SmI2 THF
1 11-thiocarbonyldiimidazole DMAP2 Ph3SnH cat AIBN
191 93
189
190
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1415
Scheme (39)
Scheme (40)
Scheme (41)
OBnO
OBn
OBn
OBnO
OBn
OBn
OBnO
OBn
OBn
OBnO
OBnCH3
BnO
OH
CH2
OBnO
OBn
CH3
OBn
H2 O
BF3 OEt2 MeCN
194
195 96
OOAc
OAc
AcO
R SiMe3
SnCl4
O
OAc
AcO
R
O
OAc
AcO
O
OAc
AcO
Me3Si
R
SiMe3
196
197
Me3 Si SiMe3
O
AcO
OAc
OAc
SiMe3
SiMe3
O
AcO
OAc
O
OAc
OAc
O
AcO
AcOO
OAc
OAc
SnCl4 CH2Cl2
SnCl4 CH2Cl2198
199
200
1416 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (42)
Scheme (43)
AcO
OAc
OAc
Me3 Si
BnO
OBn
BnO
OBn
AcO
OAc
BnO
OBn
BnO
OBn
+ I2 CH2Cl2
202 88
198 201
O
OBn
OBn
O
O
O
OBn
OBn
O
O
OBn
OBn O
OBn
OBn
O
OPBH2M
OH
OBnO
BnO
BnO
O
OBn
OBn
O
OHOPMB
OHO
HO
HO
O
OH
OHOH
OH
HOOMe
O
OBnOBn
O
Ph3P
O
O
OBn
OBn O
OBn
OBn
O
OPBM
OH
O O
CHO
OBn
BnO
OO
OBn
OBn
O
OHOPMB
BnO
BnO
BnO
OHO
HO
HO
O
OH
OHOH
OH
HOOMe
+ THF -78 oC
1 OsO4 pyr THF
2 NaH PMBBr
206a 206b 206a206b 61
1 Swern [O]2 4N HCl3 PhCOCl pyr
1 Swern [O]2 4N HCl3 PhCOCl pyr
1 PrSiH BF3 OEt2
2 H2 Pd(OH)2C
3 HCl MeOH 90 oC
1 PrSiH BF3 OEt2
2 H2 Pd(OH)2C
3 HCl MeOH 90 o C
203
204
205
207
209
208
210
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1417
followed by reduction to afford a 51 mixture (213214215216) of lactols that were readily separable by chromato-graphy Following a deprotection of an equimolar mixture of213 and 214 217 and the DL hybrid C-disaccharide of D-glucose-O-(1rarr6)-L-galactose 218 were obtained The DDand DL derivatives 219 and 220 of glucose-α-(1rarr6)-idosewere also obtained as a near equimolar mixture afterdeprotection of 215 and 216 (Scheme 44)
52 Anion Addition-Cyclization
Kishi developed an approach for the synthesis of theCndashtrehalo sugars which relied on nucleophilic addition ofone intact sugar fragment to a fundamental aldehyde ieKishi-Nozaki reaction [49] Coupling of monosaccharide221 and aldehyde 222 gave 223 The triple bond waspartially reduced and osmylation was followed by selectiveprotection to afford 224 The acetonide was converted toepoxide 225 by standard methods and removal of the PMBgroup Acid-catalyzed cyclization followed by aglyconichydrolysis and protection of hydroxyl group with (p-methoxyphenyl)diphenylmethyl chloride (MMTrCl) gave226 Inversion of the C-2 hydroxyl and removal of protectinggroups delivered α α-C-trehalose 227 (Scheme 44)
Kishi and co-workers also employed aldol reactions as anefficient access to the C-trisaccharide related to the type IIABO(H) blood group determinant [50] Aldol condensationof the enolate of methyl ketone 228 with aldehyde 229 gavea 41 mixture of hydroxy ketones 230 and 231 The majorketol was cyclized desulfurized and oxidized to afford thedisaccharide ketone 233 The ketone in THF was treatedwith LiHMDS (3 equiv) and TMEDA followed by theaddition of MgBr2 Addition of the aldehyde 234 led toalmost exclusive formation of the equatorial products 235and 236 in a 12 ratio Mesylation of 235 and 236 followedby treatment with liquid ammonia gave enones 237a and237b which were reduced to yield exclusively the C-2rsquo-equatorial ketone 238 Sodium borohydride reduction of theC-3rsquo carbonyl proceeded with the desired stereoselectivity toyield the protected C-trisaccharide 239 which wasdeblocked to provide the polyol 240 (Scheme 46)
Sutherlin and Amstrong cleverly applied a recursivestereochemical deconvolution (RSD) combinatorial approachfor the synthesis of a small library of C-trisaccharides aspotential inhibitors for the cell surface proteins of bacteriumHelicobactor pylori [51] The workers chose to carry outvariations in galactose ring of these trisaccharides An
Scheme (44)
OBnO
BnOOBn
OBn
P O
OEtOEtO
EtO
R H
OH
OH
OH
OH
O
R H
OH
OH
OH
OH
O
OHO
HOOH
OH
O
HO
OHOH
OH
OHO
HOOH
OH
O
HO
OH
OH
OHO
HOOH
OH
O
HO
OH
OHOH
R H
OH
OH
OH
OH
O
R
OBnO
BnOOBn
OBn
O
OHO
HOOH
OH
OO
HOHO
OH
R H
OH
OH
OH
OH
O
1 OsO4 NMO 50
2 DIBAL -32 oC 40
++ +
213 214 215 216
217 218 219 220
1 9-BBN H2O22 Swern [O]
3 t-BuOK
4 I2 C6H6212
211
1418 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
efficient Nozaki-Kishi coupling of vinyl bromide 241 withaldehyde 242 in a diasteromeric ratio of 12 followed byprotection with TBSOTf led to 243 and 244 Hydroborationfollowed by oxidation gave aldehydes 245 and 246respectively Addition of allylmagnesium bromide toaldehyde 245 followed by removal of the silyl groupafforded 247 to 246 giving 248 and 249 Epoxidation gave a11 mixture of the corresponding epoxides which werecyclized to give the C-trisaccharide 250-255 after removalof the benzyl groups (Scheme 47)
Schmidt reported a stereoselective 6-exo-trig selectiveelectrophilic cylization approach for de novo synthesis of amethylene-bridged Neu5Ac-α-(23)-Gal C-disaccharide theC-analog of an important motif in glycosphingolipids [52]The open chain precusors 259ab (a 32-mixture ofdiaseteromeric alcohols) were formed by the addition oflithiated iodide 256 to open chain aldehyde 258 Subsequent
C1 incorporation using Tebbe-reagent formation of a cycliccarbonate and deprotection of the two isopropylidene ketalsafforded tetrol 264 which upon treatment with phenylselenyltrifilate was steroselectively cyclized in a 6-exo-trigselective manner affording a diasteromeric mixture of 251and 252 in a ratio of 71 A seleno-Pummerer rearrangementto afford aldehyde 267 in 5 steps in 90 overall yieldOxidation of the aldehyde and subsequent steps led to thedesired C-disaccharide 268 (Scheme 48)
53 Esterification-Cyclization
Work from the Postema group has focused on a ringclosing metathesis (RCM) approach for the synthesis of C-saccharides [53a] The chemistry is versatile and has beenused for the synthesis of a small library of differentiallylinked β-C-disaccharides through a radical allylation-RCMstrategy [53b] The synthesis of the β-(1rarr4)-glucopyranosyl
Scheme (45)
O
OBn
BnO
BnO
BnO
I
CrCl2-NiCl2O
OBn
OH
BnO
BnO
BnO
O
O
O
O
O
H
OBn
O
O
OBnBnO
BnO
BnO
OOBn
OBn
OAc
PMBOHOO
OBn
BnO
BnO
BnO
O
OBn
OBn
OAc
O
OH
HO
HO
HO
OH
OH
OH
O
OH
O
OBn
BnO
BnO
BnO
OBn
OBn
OAc
O
MMTr
+
1 p-TsOH2 K2CO3 MeOH3 MMTrCl pyr
1 Swern [O]2 BH3 THF
3 AcOH-H2 O4 H2 Pd(OH)2
221
222
223
1 Pd-Pb CaCO3 H22 NaH BnBr3 OsO44 Bu2 SnO5 CsF PMB-Cl6 Ac2 O 4-DMAP
1 AcOH2 TsCl pyr
3 NaH-imid4 DDQ
224225
226 227
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1419
Scheme (46)
OBnO O
OBn
OMe
OBn
XY
SMe
OBnBnO
O
OBn
OBn
OBn
OBn
O
BnO
YX
OBn
TBSO
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnOOBn
H
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnO
OBn
OHC OBn
OBn
OTBS
OMe
BnOOBn
CHO
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnOOBn
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnO
OBn
YX
OBnO O
OBn
OMe
OBn
OBn
O
BnO
O
OBn
OBn
OBn
OBn
O 1 LiHMDS
2
228
1 TBAF THF
2 MeSH BF3 OEt2
230 X = OH Y = H231 X = H Y = OH
230231 41
1 Bu3SnH AIBN2 Swern [O]
1 LiHMDS THF-TMEDA2 MgBr23
1 MsCl
2 liquid NH3
235 X = OH Y = H236 X = H Y = OH Bu3 SnH AIBN
237a and 237b
NaBH4 MeOH
238
239 X = OBn
240 X = OHH2 Pd(OH)2
229
232233
234
1420 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (47)
OH C
O
O BnAcHN
OO
O
OBn OBnOBn
Br
O
OBn OBnOBn
O
OBnA cHN
OO
O TBSO
OBn O BnO Bn
O
OBnAcHN
OO
OTBS
S2
S1
S2
OTBSS1
O H
S2
OT BSS1
O H
MgBrMgBr
S2
O TBSS1
O H
S2
OHS1
OH
S2
OTBSS1
OH
O
OHHO
O H
O
HO
H OO
OBnA cH N
HO
H O
O
O HHO
OH
O
HOHO
O
OBnA cH N
HO
H O
O
OHH O
OH
O
H O
HOO
OBnAcHN
HO
HO
O
O HH O
OH
O
H O
H O O
OBnA cHN
HO
HO
O
O HH O
O H
O
HO
H O O
OBnAcHN
HO
HO
O
OHHO
OH
O
H O
O
OBnA cHN
HO
HOHO
+
241 242
1 CrCl2-NiCl2 T HF-DMF 722 TBSOTf 2 6-lutidine 91
243 244
1 9-BBN 602 Dess-Mart in period inane 97
1 9 -BBN 552 D ess-Martin periodinane 98
245 246
1
2 T BAF 74
1
2 TBAF 88
247 248 249
250
251
250 251 1 1 252 253 1 1 254 255 1 1
252
253
254
255
1 MCPBA2 CSA CH 2Cl2 61 fo r 2 steps3 H 2 Pd (O H)2C 95
1 MCPBA2 CSA CH 2Cl2 63 fo r 2 s teps3 H 2 Pd (OH)2C 87
1 MCPBA2 CSA CH2Cl2 80 for 2 steps3 H2 Pd(O H)2C 95
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1421
Scheme (48)
O
OO
Se Ph
R
O
HO OHOH
O
OB n O B n
OB n
O B nO O
O O
R O OR
X
O
OO
R
Se Ph
O
HOOH
OH
O
OB nOB n
O Bn
OB n
O O
O O
R O O R
O H
O
O B n OB n
O B n
OB n
O
C HO
O
O O
R O OR
OAc HN
OAc
C O2NH 4HOOH
OH
O
OH O H
OH OH
O
OB n O B n
OB n
OB nO O
O O
R O OR
X
O
O
OAcOAc
C HOA cOOAc
OAc
O
OB n O B n
OB n
OB n
O
O Bn OB n
OB n
OB n
X
OH
OO
HOOH
OH
O
O
OMeOB n
OB nOB n
R
t-B uL i256 R = Li
257 R = L i
258
(R = t-B uMe 2Si )
(R = t-B uMe 2Si )
259ab (32) 79 com bine d yi eld
De ss-Ma rtin pe riodinane
260 X = O R = t-B uMe 2Si ) 95
261 X = O R = t -B uMe2S i) 62
T e bbe re age nt
TB A F THF262 X = O R = H 94
diphosge ne
C H2C l 2Pyr
263 95
T HFH2O T FAr t
264 quant it a ti ve yie ld
PhSe C l AgOT f
EtC N -80 oC
265
266
Quant it at i ve yi l ed 25 26 7 1
+
R =
1 Ac 2OPyr
2 mC PB A3 Ac 2ONa OAc
4 NaO HT HFMe OH
5 Ac2O P yr
267 90 overa ll yi e ld
ste ps
268
1422 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
glucopyranoside 280 represents an example of thischemistry The known triacetyl glucopyranoside 269 wasconverted to iodide 270 in good yield Radical allylation of271 proceeded to afford a mixture of equatorial and axialallylation products in a 61 ratio Oxidative cleavage of thedouble bond gave the corresponding aldehydes 273a and273b which were separable Pinnick oxidation of the majoraldehyde 273a then gave the C-4 equatorial acid 274 DCC-mediated coupling of alcohol 275 and acid 274 proceeded toafford ester 276 in good yield Methylenation of 276 gave277 and exposure to catalysist 278 gave a 41 yield of theC-disaccharide glycal which was exposed to an excess ofBH3
THF to give 64 yield of the β-C-disaccharide 279Removal of the benzyl groups and global peracetylation gavethe peracetylated (1rarr4)-β-C-disaccharide 281 in good yield(Scheme 49)
54 Ring Expansion-Cyclization
Nelson developed a new strategy for asymmetric andstereoselective synthesis of C-linked disaccharide mimeticsthe C58-C71 fragment of palytoxin [54] The diol (RR)-282was converted into the di-dihydropyran (DHP) template 283284 and 285 The di-DHPs were functionized in a twodirectional sense using dihydroxylation reactions The two-directional approach was often very efficient indeed forexample in the synthesis of 286 six new stereogenic centerswere introduced with almost complete stereocontrol using areduction and a dihydroxylation reaction The approach isnot restricted to the synthesis of C2-symmetricaldisaccharide mimetics Using the unsymmetrical template285 which has both a pseudo-axial and a pseudo-equatorialhydroxyl groups the unsymmetrical mimetics 289 and 290were prepared (Scheme 50)
6 RADICAL APPROACHES
The radical approach for C-C bond formation is a popularmethod within organic chemistry The use of radicalchemistry in carbohydrate synthesis has certain advantagesFirstly the reaction conditions are very mild and tolerant ofa range of functional and protecting groups Secondanomeric radicals are stable with respect to elimination andepimeration Most significantly the chemistry required toincorporate an appropriate substitute at C-1 employed in theinitial hemolytic cleavage step is common within carbo-hydrate chemistry [55] The use of such radical techniquecan be subdivided into two classes intermolecular andintramolecular approaches
61 Intermolecular Radical Approaches
Giese was the first to employ an intermolecular radical-based approach for synthesis of C-disaccharides [56]Addition of an alkene to an anomeric radical underappropriate conditions allowed exclusive entry to the α-linked C-glycoside a result which was mirrored by the workof Baldwin [57] The high α-selectivity of the reaction wasin contrast with other reports Thus radicals generated at theC-2 C-3 and C-4 centers all preferred to occupy equatorialpositions [58] When the anomeric bromide 291 was treatedwith tin hydride and AIBN resulting anomeric radical andreacted with lactone 292 in a Michael addition it afforded293 In this reaction hydrogen abstraction at the resulting
radical center occurs from axial face to selectively generatethe equatorial C-2rsquo substituent Reduction and acetylation of293 furnished C-disaccharide 294 (Scheme 51) [59]
Witczak used the facial bias of levoglucosene tostereoselectively add a carbohydrate-based radical in thepreparation of the 3-deoxy-(1rarr4)-β-C-disaccharide 299[60] Addition of the radical derived from iodide 295 to 296gave adduct 297 in 26 yield Removal of the anomerichydroxyl of 297 was achieved by treatment with triethylsilane borontrifluoride ether complex followed bystereoselective reduction of the keto function at C-2rsquo withthe formation of 298 in 89 yield Debenzylation followedby acetolysis of 16-anhydro ring produced the peracetylatedtarget C-disaccharide 299 in 19 overall yield from 295(Scheme 52)
Vogel has developed general methods to transformenantiomerically pure 7-oxabicyclo[221]heptyl derivatives(ldquonaked sugarsrdquo) into C-disaccharides Because of thesechiral bicyclic skeletons they undergo highly stereoselectivereactions with predictable diasteroselectivities An arsenal ofmethods is available that allow to substitute these ldquonakedrdquocarbon centers with a variety of functional groups with allpossible relative configurations The methods allowpreparation of both enantiomers of a given target with thesame ease Predictably high stereoselectivity of the reactionsof the bicyclic chirons adds to the flexibility of approachwhich can lead to high molecular diversity [61]
α-C-(1rarr3)-mannopyranoside of N-acetyl-galactosaminepotent β-galactosidase inhibitors was synthesized by thisapproach [61] Enone 302 was readily prepared from 300The addition of the radical derived from bromide 303 toenone 302 afforded the αminusisomer 304 The ketone was thenreduced and the selenide eliminated via the intermediacy ofthe selenoxide to give 305 Acid-promoted (CF3SO3H) 7-oxa ring opening of 305 in MeCN produced the amino-conduritol derivative 306 resulting from the quenching of theallylic cation intermediate by the solvent (Ritter reaction)Ozonolysis of the chloroalkene 306 generated an acylchloride-aldehyde intermediate that reacted with MeOH toproduce a mixture of methyl uronates The major compound307 was silylated and reduced The crude polyol obtainedwas acetylated to produce 308 Desilylated and ammonolysisafforded a mixture of α-β-pyranoses 309 and correspondingα-β-furanoses (Scheme 53)
Similar chemistry was carried out to synthesize non-protected α-C(1rarr2)-L-fucopyranoside of D-galactopyrano-side corresponding to a blood group mimetic [62] Giesersquosradical fucosidation of racemic enone 310 with α-L-bromoacetofucose 311 provided the mixture of diastereo-meric α-C-fucoside 312a and 312b in reproducible yield of78 Reduction of the mixture gave a 11 mixture of endo-alcohols 313 and 314 which were isolated pure in 40 and355 yield respectively Oxidative elimination of thebenzeneselenyl group of 313 followed by acetylation gaveendo acetate 315 in 85 yield Acid-promoted ring openingof 315 and ozonolysis of the resulted chloroalkene gavemethyl uronic ester 316 in modest yield (10) Treatment of316 with Cl3CCN and NaH followed with BF3
OEt2
furnished the totally protected C-disaccharide 317 in 79
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1423
Scheme (49)
Bu3SnO
HOAcO
OMeOAc
OAc
O
AcO
OMeOAc
OAcI
AIBN
O
AcO
OMeOBn
OBn
HO2C O
AcO
OMeOR
ORY
X
OHBnO
BnO
OBn
OBnO
BnO
OBn
O
AcO
OMeOBn
OBnX
i-Pr i-Pr
N
Mo C(Me2 Ph)((CF3)2 MeCO)2
O
RO
OMeOR
O
RO
OR
OR
RO
OR
278
I2 Ph3P
imidazole
269 270 93
271a X = CH2CH=CH2 Y = H R = Ac 64271b Y = CH2CH=CH2 X = H R = Ac 11272a X = CH2CH=CH2 Y = H R = Bn 75272b Y = CH2CH=CH2 X = H R = Bn 75273a X = CH2CHO Y = H R = Bn 79273a Y = CH2CHO X = H R = Bn 79
1 NaOMe MeOH2 NaOH BnBr DMF
OsO4 NaIO4
NaClO2 NaH2PO4
274 96
275
DCC 4-DMAP
276 X = O 82
277 X = CH2 51
TiCl4 Zn dust TMEDA CH2Br2PbCl2 (Cat )
1
2 BH3 THF H2O2 NaOH
H2 PdC EtOH
Ac2 O Pyr 4-DMAP
279 R = Bn R = H 64
280 R = R = H 99
281 R = R =Ac 97
1424 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (50)
Scheme (51)
O OOH
OH
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
286
1 VO(acac)2 t-BuOH 95
2 (MeO)3CH BF3 90
1 P-O2NC6H4 CO2H Ph3P DIAD2 K2CO3 MeOH 82 over 2 steps
1 PhCOCl Et3N DMAP 402 P-O2NC6H4 CO2H Ph3P DIAD3 KOH THF-H2O 75 over 2 steps
TMEDA OsO4
Cat OsO4 NMO 287
Cat OsO4 NMO288
TMEDA OsO4
Cat OsO4 NMO
290
289
(RR)-282283
284
285
OHO
AcO
BrOAc
OAc
BnO
O
OBn
OBnO
OHO
AcOOAc
OAc
BnO
OOBn
OBnAcO
OHO
AcOOAc
OAc
BnO
O
OBn
OBnO
+
Bu3SnH AIBN291
292
293 81
1 Na[Al(OC2H4OMe)2(OEt)H]2 Ac2O pyr
294 56 over 2 steps
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1425
Scheme (52)
Scheme (53)
OBnO
BnOOBn
OBn O
OH
O
OBnO
BnO
OHOBn
OBn O
O
O
O
O
O
OBnO
BnOOBn
OBnO
OAcOAc
OAc
OBnO
BnO
OHOBn
OBn
IBu3SnH AIBN
295 297 26
1 BF3 OEt2 Et3SiH
2 L-Selectride THF
1 Pd(OH)2C C6H10 EtOH
2 EtSiOSO2CF3 Ac2O
298 89 over 2 steps299
296
O
O
PhSeClO
O
PhSeCl
Bu3 SnH
O
O
PhSeCl
R
H
O
OAc
R
Cl
O
AcO
OAc
OAc
OAcOH
Cl
NHAc
R
OAc
AcHN
OH
O
OH OAc
OH
OHO
HO
OH
O
AcO
OAc
OAc
OAcBr
O
O
PhSeCl
O
O
PhSeCl
R
O
OTIPSAcHNR
OAc OAc
O
OHAcHN
COOMe
R
OAc
1 Bu4NF
2 NH3MeOH
1 (Me3Si)2NLi THF2 Me2N=CHI
1 Bu3 SnH AIBN2
1 NaBH42 mCPBA3 Ac2O pyr
1 H+ MeCN
2 H2 O NaHCO3
R =
1 O3MeOH
2 Me2S NaHCO3
1 TIPSOTf 26-lut idine2 LiBH43 Ac2 O pyr DMAP
furanoses +
304 56
305 68 306 84307 50
308 46
300 301 302
303
309
1426 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
The reduction of 317 and treatment with DOWEX-H+ resinprovided the desired C-fucoside 318 in 70 (Scheme 54)
62 Intramolecular Radical Approaches
One disadvantage with the intermolecular approaches isthat during such radical mediated reactions electrondeficient alkenes are required to facilitate C-C bondformation The intramolecular approach of Sinayuml overcomes
this drawback by bring two substrates together via atemporary covalent silaketal connector This enables the useof a wider range of alkenes which can include alkene-functionalized sugars thus leading to the generation of C-disaccharides [63] Based on the early work of Stork Sinayumlemployed the tether reaction in the synthesis of both α- andβ-C-disaccharides with this work subsequently beingemployed in the synthesis of biologically significant natural
Scheme (54)
O
OH
Fuc
Cl
O
O
ClPhSe
OOAc
NHAcOHFuc
O
AcOOAc
AcO
Br
O
O
PhSeCl
O
AcOOAc
AcO
O
OH
PhSe Cl
Fuc
OOAc
NHAc
OMe
Fuc
O
AcHN
OH OAc
OH
O
OH
Me
OH
O
O
Fuc
ClSePh
O
HO
Fuc
ClSePh
+
Ph3SnHAIBN
78 combined yield
Fuc
310
+
1 NaBH4 MeOHTHF2 Chromatography
313 40 314 355
1 mCPBA
2 Ac2O pyr DMAP
+
315 75
1 TfOH MeCN
2 NaHCO3 O3 -78 oC
316 10 over 2 steps
1 Cl3 CCN NaH
2 MeOH BF3 OEt2
317 79
1 LiBH4 THF
2 Dowex-H+
311
312a312b
318 70 for 2 steps
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1427
products [64] The availability of different hydroxyl groupson each monosaccharide unit allowed the fine-tuning ofstereochemical outcome by selective positioning of the silyltether [65] Development of this early stereochemical controlled to the tethering of the donor 320 with alcohol 319through a di-isopropyl silicon tether 321 Subsequent treat-ment with Bu3SnH and AIBN led to a 9-endo-trigcyclization to form the C-disaccharide 322 in an 80 yieldwith exclusive formation of the α-product The silyl tetherwas removed with Bu4NF and deprotection under standardconditions afforded the desired disaccharide 323 in excellentyield (Scheme 55)
In parallel the development of a 32rsquo silyl tether allowedaccess to the β-linked product as demonstrated in Sinayumlrsquossynthesis of methyl β-C-lactoside 328 [66] Alcohol 324 and320 were connected via the dimethylsilyl tether an 8-endo-trig cyclization followed to exclusively afford the β-
disaccharide 326 in 45 yield Removal of the tether anddeprotection of benzyl ether gave β-C-disaccharide 328(Scheme 56)
This group also selected iodosugars bearing a freehydroxyl group as progenitors of the radical donors [67] In atypical experiment the radical donor 329 was connected tothe radical acceptor 330 through a silaketal tether followingtheir procedure Tributyltinhydride mediated 8-endo-trigradical cyclization of compound 331 gave after detetheringof the non isolated intermediate 332 the protected β-C-disaccharide 333 in 37 overall yield (from startingmaterials 330 and 329) Peracetate 335 was achieved afterhydrogenolysis The C-laminaribioside 334 is of potentialbiological interest as it mimics the repeating disaccharideunit of fungal β-(1rarr3)-glucans which have antitumor andimmunomodulating properties (Scheme 57)
Scheme (55)
Scheme (56)
OO
OHSePh
OTBDPSO O
OO
SePh
OTBDPSO
OO
OBnOMe
OBn
Si
O
HOOBn
OMe
OBn
O
HOOH
OHHO
O
HOOH
OMe
OH
OTBDPSO
O
HOOBn
OMe
OBnO
OOH
1 n-BuLi THF
2 iPr2SiCl2 -78 oC
3 DMAP THF rt
1 Bu4NF THF
2 Dowex-H+
3 H2 PdC
Bu3SnH AIBN toluene
319
320
321
322323
OBnO
OHSePh
OBnBnO
OHO
OBnOMe
OBn
ROO
ROOH
OR
OHO
OROMe
OR
OBnO
O
OBnBnO
OO
OBnOMe
OBn
Si
SePh
OBnO
O
OBnBnOO
OOBn
OMe
OBn
Si
1 PhSeH Me2SiCl2
BuLi -78 oC
2 imidazole rt
Bu3SnH AIBN toluene
H2 PdC327 R = Bn
328 R = H
Bu4NF THF
324
320
325
326 45
1428 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
CONCLUSIONS
In this paper the biological importance of C-oligo-saccharides as subunits of natural products and as a newgeneration of carbohydrate based on therapeutics has beenillustrated Different methods are available for the synthesisof C-oligosaccharides As with traditional saccharidesynthesis it has been necessary to develop a number ofspecific approaches to facilitate the regioselective andstereoselective preparation of the desired targets Work inthis area continues and it is expected that many interestingnew C-oligosaccharides will be prepared using the chemistrydescribed in this review It is also likely that new chemistrywill be developed in the future for the preparation of thesebiologically important targets
ACKNOWLEDGEMENTS
The authors thank Dr Sultan Baytas for her criticalreading of this manuscript
REFERENCES
[1] Kennedy J F White C A Bioactive Carbohydrates InChemistry Biochemistry and Biology Ellis Horwood LtdChichesterUK 1983
[2] Wassarman PW Mammalian Fertilization Molecular Aspects ofGamete Adhesion xocytosion Exocytosis and Fusion Cell 199996 175-183
[3] Carbohydrate-based Drug Discovery Wong C-H EdWeinheim Cambridge Wiley-VCH 2003
[4] (a) Sharon N Lis H Lectins as Cell Recognition MoleculesScience 1987 246 227-234 (b) Dwek RA Chem Rev 1996 96683-720
[5] Postema M C-Glycoside synthesis CRC Boc Ratom 1995[6] (a) Weatherman R V Mortell K H Cheruenak MKiessling
L L Toone E J Specificity of C-Glycoside Complexation byMannoseGlucose Specific Lectins Biochem 1996 35 3619-3624(b) Ravishankar R Surolia A Vijayan M Lim S Kishi YPreferred Conformation of C-Lactose at the Free and Peanut LectinBound States J Am Chem Soc1998 120 11297-11303
[7] (a)Wong C-H Halcomb R L Ichikawa Y and Kajimoto TEnzymes in organic synthesis Application to the problems ofcarbohydrate recognition part2 Angew Chem Int Ed Engl 199534 521-546 (b)Howard S Withers SG Bromoketone C-Glycosides a New Class of βminusGlucanase Inactivators J AmChem Soc 1998 120 10326-10331(c) Wang Q Wolff MPolat T Du Y Linhardt R J C-glycoside of Neuraminic Acidsas Neura-minidase Inhibitors Bioorg Med Lett 2000 10 941-944 (d) Phili R Chang J Partis R A Mueller R A ChrestF J Passaniti A The Alpha-glucosidase I InhibitorCastanospermine Alters Endothelial cell Glycosylation PreventsAngiogenesis and Inhibits Tumor Growth Cancer Res 1995 552927-2935
[8] Ossor A Elbein A D In Carbohydrates in Chemistry andBiology Vol 3(II) WileyVCH 2000 pp 513-539
[9] (a) Sinayuml P Synthesis of oligosaccharide Mimetics Pure ApplChem 1997 69 459-463 (b) Beau J-M Gallagher TNucleophilic C-glycosyl Donors for C-glycoside Synthesis Top inCurr Chem 1997 187 1-54 (c) Nicotra F Synthesis of C-glycosides of Biological Interest Top in Curr Chem 1997 187
Scheme (57)
O
O
O
Ph
I
OMe
OHO
BnO
OH
OH
BnOOH
O
BnO
Si
O
O O
Ph
I
OMe
O
O
BnO
OR4O
R5O
OMe
OR2
OR3O
R3O
OR1
R3O
Bu3 SnH AIBN
332 R1 R2 = SiMe2 R3 = Bn R4 R5 = CHPhTBAF THF
333 R1 = R2 = H R3 = Bn R4 = R5 = CHPh 37 from 11
334 R1 = R2 = R3 = R4 = R5 = H
335 R1 = R2 = R3 = R4 = R5 = Ac
329
H2 PdC MeOH
Ac2 O pyr
1 BuLi THF -78 oC
2 Me2SiCl2
3 DMAP
330
331
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1429
55-83 (d) Du Y Linhardt R Y Recent Adv in Stereo-SelectiveC-Glycoside Synthesis Tetrahedron Lett 1998 54 9913-9959 (e)Liu L Mckee M and Postema M H D Synthesis of C-saccharides and Higher Congeners Current Org Chem 2001 51133-1167
[10] Jarosz S Fraser-Reid B Synthesis of A Higher Carbon Sugar ViaDirected Aldol Condensation Tetrahedron Lett 1989 30 2359-2362
[11] Lichtenthaler F W Lergenmiiller M Schwidetzky S C-Glycosidations of 2-Ketohexosyl With Electrophilic Radical andNudeophilic Anomeric Carbons Eur J Org Chem 2003 3094-3103
[12] Baudat A Vogel P Aza-C-disaccharides Synthesis of 6-Deoxygalactonojirimycin-β-C(1rarr3) Linked with D-Altrofuranosides and D-Galactose J Org Chem 1997 62 6252-6260
[13] Turner D Vogel P Synthesis of 4-Hydroxy-26-Bis(hydroxymethyl) tetrahydropyran-2-Carbaldehyde DerivativesSynlett 1998 304-306
[14] Zhu Y-H Vogel P Short Stereoselective Synthesis of C-(1rarr3)-Linked Disaccharides Tetrahedron Lett 1998 39 31-34
[15] Zhu Y-H Vogel P Synthesis of a (2R 6R)-2-(Hydroxymethyl)-6-Propa-1 2-Dienyl-2H-Pyran-3(6H)-One Derivative A NewEnone for The Convergent Construction of C-Glycosides of C-Disaccharides Synlett 2001 82-86
[16] Baumberger F Vasella A Deoxynitrosugars The 6th
Communication Stereolectronic Control in the reductivedenitration of tertiary nitro ethers A Synthesis of ldquoC-glycosidesrdquoHelv Chim Acta 1983 66 2210-2221
[17] Martin O R Lai W Synthesis and Conformational Studies of β-(1rarr6)- and ββ-(1rarr1)-Linked C-disaccharides J Org Chem1993 58 176-185
[18] Spak S J Martin R The synthesis of an analogue of Methyl OC-Analogue of Methyl 4rsquo-O-β-D-GlucopyranosylgentiobiosideTetrahedron 2000 56 217-224
[19] Kobertz W R Bertozzi C R Bednarski M D C-GlycosylAldehyde Synthons for C-Linked Disaccharides J Org Chem1996 61 1894-1897
[20] Gurjar M K Nagaprasad R and Ramana CV First Synthesis ofMethyl α-C-D-Arabino-furanosyl-(1rarr5)-αminusD-Arabinofuranosidethe C-Disaccharide Segment of Motif C of MycobateriumTuberculosis Tetrahedron Lett 2000 43 7577-7579
[21] Witczak Z J Synthesis of C-Glycosyl Compounds and OtherNatural Products from Levoglucosenone Pure Appl Chem 199466 2189-2192
[22] Griffin F K Paterson D Taylor R J K Ramberg-BacklundApproaches to the Synthesis of C-Linked Disaccharides AngewChem Int Engl 1999 38 2939-2942
[23] Paterson B E Griffin F K Alcaraz M-L and Taylor R J KA Ramberg-Baumlcklund Approach to the Synthesis of C-GlycosidesC-Linked Disaccharides and C-Glycosyl Amino Acids Eur JOrg Chem 2002 1323-1336
[24] McAllister G D Paterson D E Taylor R J K A SimplifiedRamberg-Bachlund Approach to Novel C-Glycosides and C-Linked Disaccharides Angew Chem Int Ed Engl 2003 42 1387-1391
[25] McCartney J L Christopher T M Cicchillo R M BernardinaM D Wagner T R and Norris P J Org Chem 2003 6810152-10155
[26] Dondoni A Zuurmond H M Bascarate A Synthesis of α-andβ-D-(1rarr6)-C-Disaccharides by Witting Olefination of Formyl C-Glycosides with Glycopyranose 6-phosphoranes J Org Chem1997 62 8114-8124
[27] Dondoni A Kleban M Zuurmond H Marra A Synthesis of(1rarr6)-C-Oligogalactosides by Interative Wittig OlefinationTetrahedron Lett 1998 39 7991-7994
[28] Dondoni A Marra A A New Synthetic Approach toMycobacterial Cell Wall α-(1rarr5)-D-Arabinofuranosyl C-Oligosaccharides Teterahedron Lett 2003 44 4067-4071
[29] Colinas P A Ponzinibbio A Lieberknecht A and Bravo R OWittig Reaction of Glycosyl Phosphonium Salts A StereoselectiveRoute to C-Disaccharides and C O-Trisaccharides TetrahedronLett 2003 44 7985-7988
[30] Schmidt R R Preuss R Synthesis of Carbon Tetrahedron Lett1989 30 3409-3412
[31] Dietrich H Schmidt R R Synthesis of Carbon-Bridged C-Lactose and Derivatives Liebigs Ann Chem 1994 975-981
[32] Rouzaud D Sinayuml P The First Synthesis of a ldquoC-DisacchariderdquoJ Chem Soc Chem Commun 1983 1353-1354
[33] Xin Y-C Zhang Y-M Mallet J-M Glaudemans C P JSinayuml P Synthesis of C-Oligosaccharides That Mimie TheirNatural O-Analogues Immunodeterminants in Binding toMonoclonal Immunoglobulins Eur J Org Chem 1999 471-476
[34] Streicher H Geyer A Schmidt R R C-Disaccharides ofKetoses Chem Eur J 1996 2 502-510
[35] Leeuwenburgh M A Timmers C M Vander Marel G A VanBoom J H Mallet J-M Sinayuml P G Stereoselective Synthesisof α-C-(Alkynyl)-Glycosides Via Ring-Opening of α-12-Anhydrous Tetrahedron Lett 1997 38 6251-6254
[36] Aslam T Fuchs M G G Le Formal A Wightman R HSynthesis of C-Disaccharide Analogue of the α-D-Arabinofuranosyl-(1rarr5)-α-Arabinofuranosyl Motif ofMycobacterial Cells Walls via Alkynyl Intermediates TetrahedronLett 2005 46 3249-3252
[37] (a) Girad P Namy J L Kagan H B Divalent LanthanideDerivative in Organic Synthesis 1 Mild Preparation of SamariumIodide and Ytterbium Iodide and Their Use as Reducing orCoupling Agents J Am Chem Soc 1980 102 2693-2698 (b)Molander G A Harris C R Sequencing Reactions withSamarium(II) Iodide Chem Rev 1996 96 307-338
[38] (a) Mazeacuteas D Skrydstrup T Doumeix O Beau J-MSamarium Iodide-Induced Intramolecular C-Glycoside FormationEfficient Radical Formation in the Absence of an Additive AngewChem Int Ed Engl 1994 33 1383-1386 (b) Mazeacuteas DSkrydstrup T Beau J-M A Highly Stereoselective Synthesis of1 2-trans-C-Glycosides Via Glycosyl Samarium(III) CompoundsAngew Chem Int Ed Engl 1995 34 909-912 (c) Jarreton OSkrydstrup T Beau J-M The Stereospecific Synthesis of Methylα-C-Mannobioside A Potential Inhibitor of M TuberculosisBinding to Human Macrophages J Chem Soc Chem Commun1996 1661-1662 (d) Jarreton O Skrydstrup T Espionosa J-FJimeacutenez-Barbero J Beau J-M Samarium Diiode Prompted C-Glycosylation An Application to The Stereospecific Synthesis ofα-(1rarr2)-C-Mannobioside and Its Derivatives Chem Eur J 19995 430-441 (e) Mipuel N Doisneau G Beau J-M ReductiveSamariation of Anomeric 2-Pyridyl Sulfones with Catalytic AnUnexpected Improvement in The Synthesis of 12-Trans-Diequatorial C-Glycosyl Compounds Angew Chem Int Ed Engl 2000 39 4111-4114
[39] Vlahov I R Vlahova P I Linhardt R J DiastereocontrolledSynthesis of Carbon Glycosides of N-Acetylneuraminic Acid ViaGlycosyl Samarium(III) Intermediates JAmChem Soc 1997 1191480-1481
[40] Kuberan B Sikkander S ATomiyama H Linhardt R JSynthesis of a C-Glycoside Analogue of sTn An HIV-and Tumor-Associated Antigen Angew Chem Int Ed Engl 2003 42 2073-2075
[41] Bazin H G Du Y Polat T Linhardt R J Synthesis of aVersatile Neuraminic Acid ldquoCrdquo-Disaccharide Precursor for theSynthesis of C-Glycoside Analogues of Gangliosides J OrgChem 1999 64 7254-7259
[42] Chen C-C Ress D K Linhardt RJ Samarium Iodide-Mediated Synthesis of Neuraminic Acid C-Glycosides InSynthesis of Glycommetics Roy R Ed ACS Syposium Series2004 896 53-80
[43] Abdallah Z Doisneau G Beau J-M Synthesis of a Carbon-Linked Mimic of The Disaccharide Component of The Tumor-Relate SialyTn Antigen Angew Chem Int Ed Engl 2003 425209-5212
[44] Lay L Nicotra F Panza L Russo G Caneva E Synthesis ofC-disaccharides through dimerization of exo-glycals J Org Chem1992 57 1304-1306
[45] Isobe M Nishizawa R Hosokawa S Nishikawa TStereocontrolled Synthesis and Reactivity of Sugar Acetylenes JChem Soc Chem Commun 1998 2665-2676
[46] Saeeng R Sirion U Sahakitpichan P Isobe M IodineCatalyzes C-Glycosidation of D-Glucal with SilylacetykeneTetrahedron Lett 2003 44 6211-6215
[47] (a) Babirad S A Wang Y Kishi Y Synthesis of C-Disaccharides J Org Chem 1987 52 1370-1372 (b) Wang YBabirad S A Kishi Y Preferred Conformation of C-Glycosides
1430 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
8 Synthesis of 14-Linked Carbon Disaccharides J Org Chem1992 57 468-481
[48] Armstrong R W Sutherlin D P Strategies for the Synthesis ofC-Disaccharides Containing D and L Sugars Tetrahedron Lett1994 35 7743-7746
[49] Wei A Kishi Y Preferred Conformation of C-Glycosides 12Synthesis and Conformational Analysis of αα- α β- and β β-Trehaloses J Org Chem 1994 59 88-96
[50] Haneda T Goekjian P G Kim S H Kishi Y PreferredConformation of C-Glycosides 10 Synthesis and ConformationAnalysis of Carbon Trisaccharides J Org Chem 1992 57 490-498
[51] Sutherlin D P Armstrong R W Synthesis of 12 Stereochemistryand Structurally Diverse C-Trisaccharides J Org Chem 1997 625267-5283
[52] Notz W Hartel C Waldscheck B Schmidt R R De NovoSynthesis of a Methylene-Bridged Neu5Ac-α-(23)-Gal C-Disaccharide J Org Chem 2001 66 4250-4260
[53] (a) Postema M H D Calimente D Liu L Behrmanm T L AnOlefin Metathesis Route for the Preparation of (1rarr6)-Linked-C-Disaccharide Glycals A Convergent and Flexible Approach to C-Saccharide Synthesis J Org Chem 2000 65 6061-6068(b) Postema M H Piper J L Liu L Faust M Andreana PSynthesis and Partial Biological Evaluation of a Small Library ofDifferentially Linked β-C-Disaccharide J Org Chem 2003 684748-4754
[54] Nelson A The Development of Strategies and Methods for TheSynthesis of Biologically Active Compounds New J Chem 200428 771-776
[55] Togo H He W Waki Y Yokoyama M C-GlycosylationTechnology With Free Radiant Reactions Synlett 1998 700-717
[56] Giese B Dupuis J Diastereoselective Synthesis of C-Glycopyranosides Angew Chem Int Ed Engl 1983 22 622-623
[57] Adlington R M Baldwin J E Basak A Kozyrod RPApplication of Radical Addition Reactions to tho Synthesis of a C-Glucoside and A Functionalized Amino Acid J Chem SocChem Commun 1983 144-145
[58] Giese B Gonzaacutelez-Goacutemez J A Witzel T The Scope of RadicalCC-Coupling by The ldquoTin Methodrdquo Angew Chem Int Ed Engl1984 23 69-70
[59] Giese B Witzel T Synthesis of ldquoC-Disaccharidesrdquo by RadicalC-C Bond Formation Angew Chem Int Ed Engl 1986 25 450-451
[60] Witczak Z J Chhabra R Chojnacki J C-Disaccharides IStereoselective Approach to β-(1rarr4)-3-Deoxy-C-Disaccharidesfrom Levoglucosenone Carb Res 1997 301 167-175
[61] Vogel P Synthesis of Rare Carbohydrates and Analogues Startingfrom Enantiomerically Pure 7-Oxabicyclo[221]heptyl Derivatives(ldquoNaked Sugarsrdquo) Current Org Chem 2000 4 455-480
[62] Viodeacute C Vogel P Synthesis of The C-Disaccharide α-C(1rarr3)-L-Fucopyranoside of N-Acetylgalactosamine J Carb Chem2001 20 733-746
[63] Xin Y C Mallet J M Sinayuml P An Expeditious Synthesis of AC-Disaccharide Using A Temporary Silaketal Connection J ChemSoc Chem Commun 1993 864-865
[64] (a) Petitou M Herault P Lormeau J-C Helmboldt A MalletJ-M Sinayuml P Herbert J-M Introducing A C-InterglycosidicBond in A Biologically Active Pentasaccharide Hardly Affects ItsBiological Properties Bioorg Med Chem 1998 6 1509-1516 (b)Sinayuml P Advances in The Synthesis of the Carbohydrate MimicsPure Appl Chem 1998 70 1495-1499
[65] Sinayuml P Chemical Synthesis of Oligosaccharide Mimetics PureAppl Chem 1998 70 407-410
[66] Sinayuml P Chemical Synthesis of Oligosaccharide Mimetics PureAppl Chem 1998 69 459-463
[67] Vauzeilles B Sinayuml P Selective Radical Synthesis of β-C-Disaccharides Tetrahedron Lett 2001 42 7269-7272
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1407
Scheme (25)
Scheme (26)
OBn
R1
R2
PPh3BF4-O
O
OOHC
O
O
O
O
O
O
O
O
HO
O
O
O
O
O O
OBn
R1
R2
O
O
O
O
O
O
H
O
OBn
R1
R2
O
O
O
O
O
O
O
O
OBn
R1
R2
O
O
O
+
BCl3 (005 equiv)
MS 4A CH2 Cl2 0 o C
+
BuLi THF -90 oC -90 o C
to rtH2 (1 atm) PdC Et3N MeOH
R1 R2 = OBn H
120a - b
121
122a - b
123a - b
124
125a - b
OTBDPS
BnO X
SO Ph
O
BnO
OHCO
BnO
OMeOBn
OBn
O
BnO
OTBDPS
BnO
SO Ph
O
BnO
OMeOBn
OBn
O
HO
OMeOH
OHO
HOHO
OH
OH
128
229 74
1 RaNi (74)
2 BH3 DMS
NaOH H 2O2 (74)
3 H2 PdC (70)
130 74
LDA THF
-100 oC
126 X = H
127 X = Li
1408 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (27)
Scheme (28)
stereochemical outcome is rationalized by the generation ofan initial zinc acetylide species which facilitates intra-molecular delivery to the α-face (Scheme 32)
Wightman synthesized C-disaccharide analogs of the α-D-arabinofuranosyl-(1rarr5)-α-D-arabinofuranosyl motif ofmycobacterial cell walls through alkynyl intermediates [36]The lactone 164 was treated with lithio(trimethylsilyl)ethyneat low temperature to give lactol in 66 yield of 165Treatment of this with triethylsilane and BF3
Et2O gavethe separable isomers 166α (60) and 166β (13)Desilylation of the major isomer 166α gave 167 in 97yield Treatment of 167 with n-BuLi followed by addition oflactone 164 gave 85 yield of the hemiacetal 168 which onreduction with Et3SiH and BF3
Et2O gave the disubstitutedalkyne 169 (83) as the major product Reduction-
hydrogenolysis of 169 then gave the C-disaccharide 170 innear-quantitative yield (Scheme 33)
3 REDUCTIVE GLYCOSYL SAMARIUM SPECIES
The introduction of SmI2 as reducing agent can becredited to Kagan and has since been utilized in numeroussynthetic schemes [37] Sinayuml and Beau introduced SmI2
chemistry into C-glycoside synthesis through intermolecularreactions with appropriate electrophiles and intramolecularreactions of silyl tethered substrates [38] Anomericsamarium species are highly stable and not likely to undergoβ-elimination Treatment of the aryl sulfone 171 with SmI2
affords the nucleophilic intermediate 172 through two singleelectron transfer processes Introduction of a suitableelectrophile (carbonyl compounds) affords the α-C-manno-
O
BnO
OTBDPS
BnO X
SO Ph
O
BnO
OBn
BnO Li
SO Ph
DMF
OHO
HOOH
OH
O OH
OH
HO
OHOH
O
BnO
OTBDPS
BnO
SO Ph
O
OBn
OBnOBnSO
Ph
OH
131 X = Li
132 X = CHO
THF -100 oC
1 Ra-Ni
2 BH3 DMS NaOH H2O2
3 H2 PdC
131
133
134
OBnO
OBnOMe
BnO
Li
OBnO
BnOOBn
OBn
OOBn
OBnOMeBnO
OH
OBnO
BnOOBn
OBn
O
n-BuLi
BnO
OMe
BnO
BrBr
O
OBn
OHO
OH
OH
HO
OHO
OH
HO
OMe
O
BnO
OMeOBn
O
BnO
139 92
1BF3 OEt2 EtOH
2 H2 PdC AcOH
140 52 over 2 steps
135 136 137
138
CBr4 PPh3
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1409
pyrannoside 173 in good yield and with excellent stereo-selectivity (Scheme 34) [38a]
Preparation of C-glycosides of ulosonic acids using SmI2
was pioneered by Linhardt and coworkers [39] Coupling ofpyridyl sulfone 174 with aldehyde 175 in the presence ofSmI2 gave an excellent yield of the N-acetylneuraminic acidC-disaccharide 176 as single isomer This stereochemicaloutcome was rationalized on the basis of the Felkin-Anhmodel for predicting the stereochemical outcome of akinetically controlled addition of a nucleophile to a chiraladehyde (Scheme 35 A)
Reductive samarium method was utilized to synthesizesialo-antigen C-analogs by the Linhardt group A fullyprotected C-analogue of the SialylTn antigen α-D-Neu5Ac-(2rarr6)α-D-GalNAc-(1rarrO)-Ser 182 was prepared [40] C-glycosylation of the neuraminic acid sulfone donor with
aldehyde acceptor in presence of excess SmI2 afforded the α-C-glycoside 180 as an RS mixture (11) The criticalintermediate aldehyde acceptor 178 was prepared in 13steps Chemoselective resolution to compound 180 wasundertaken by oxidation with DMSOAc2O to keto-bridgedcompound 181 followed by stereoselective reduction withZn(BH4)2 to regenerate the bridge hydroxyl function gave182 in gt90 de (Scheme 36)
A common versatile N-acetylneuraminic acid C-disaccharide precursor of the C-glycoside analogs ofgangliosides GM4 and GM3 has been synthesized [41]Samarium(II) iodide coupling of N-acetylneuraminic acidsulfone 179 with a 3-formyl galactopyranoside derivative183 afforded the corresponding C-disaccharide 184 as amixture of (R) and (S) isomers at the newly formedhydroxymethylene bridge This diastereoisomeric mixturewas resolved after debenzylation of the galactoside residue
Scheme (29)
O
BnO
BnOOBn
OBn
OOBn
OBnOMe
OBnOH
O
BnO
BnO
OBn
OBn
O
O
BnOOBn
OMe
BnO
Li
OBnO
OBn
OBn
OBnO
OBn
OBn
OMe
OBnO
OBn
OBnBnO
OBnO
OBn
OBn
OBnO
OBn
OBn
OMe
OBnO
OBn
OBnOBnO
OBn
OBnBnO
O
BnO
BnO
OBn
O
OBnO
OBn
OBnBnO
OBnO
OBn
OBnBnO
OBnO
OBn
OBn
OMe
OBnO
OBn
OBnBnO
OMe
1 PCC2 CBr4 Ph3P3 n-BuLi
144 overall yield 54
1 BF3 OEt2 Et3 OH
2 H2 PtO2 EtOAc
145 76
1 H2 SO4 AcOH
2 PCC
146 62
repeat steps
repeat st eps
141 142
143
147
148
1410 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (30)
Scheme (31)
O
BnOOBn
OMe
Li
BnO
OPivBnO
OBn
OBn
BnO
O OO
BF3 OEt2
OBnO
OBn
OBn
BnO
OO
O
OMe
BnOOBn
BnO
Co(CO)3
Co(CO)3
O
CAN
OBnO
OBn
OBn
BnO
OO
OO
BnOOBn
BnO
OMe
OHBnO
OBn
OBn
BnO
OHO
O
O
OMe
BnOOBn
BnO
Co(CO)3
Co(CO)3
O
OPivBnO
OBn
OBn
BnO
OH OO
O
OMe
BnOOBn
BnO
OAcO
OAc
OAc
AcO
OAcOAc
OAcO
OAc
AcO
OMe
1
2 NaOMe MeOH
1 Lewis acid2 ClCO2CCl3 Pyr3 Co2(CO)8
with a-isomer
1 Et3N Pyr H2O
2 H2 PdC H+
3 Ac2 O Pyr
149 151
152153
154 155
150
OBn
BnO
OBnO
OBn
BnO
OBnO
BnO
MeO
OBnO
OBn
BnO
O
OMe
AcO
OAcO
OAc
OAc
AcO
OAcO
OAc
O
BnOOBn
OMe
BnO
159 74 over 2 steps
+
BuLi ZnCl2 THF
1 H2 PdC2 Ac2O Pyr
156 157
158 59
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1411
Scheme (32)
Scheme (33)
and the chirality of each isomer assigned after acetylationConversion of the p-methoxyphenyl group in the peracety-lated (S) isomer 187 into the corresponding thiophenylglycoside 188 was accomplished affording the key inter-mediate for the synthesis of C-glycoside analogs of GM4GM3 and other related gangliosides (Scheme 37)
Ganglioside GM4 is a very important cell adhesionmolecule The C-disaccharide of GM4 is currently beingsynthesized in Linhardtrsquos lab using standard O-glycosylationof C-disaccharide with protected ceramide Once theceramide has been attached it can be oxidized to afford analdehyde group for coupling to keyhole limpet hemocyanin
OBnO
OBn
BnO
O
OBnO
ClZnO
OBn
BnOCl
R
OBnO
O
OBn
BnOCl
ZnR
O
ZnR
OBnO
OBn
BnO
160 161
162163
O
OBn
OBnBnO
O
O
OBn
OBnBnO H
TMS
O
OBn
OBnBnO H
O
OBn
BnO
OBnHO
O
OBn
OBnBnO OH
TMS
OBnBnO HO
OBn
TMS
O
OR
ORRO H
O
OR
RO
OR
OBn
OBnBnO
H
TMS
O+
K2CO3 MeOH
1 n-BuLi THF -78 oC
2 164
164165 66
166α 60 166β 13167 97
BF3 Et 2O Et 3SiH -78 oC
168 85
169 R = Bn 83
170 R = H near quantitative yield
H2 (1 atm)Pd(OH) 2C
TMS-acetyl ene
n-BuLi THF -78 oC BF3 Et2O Et3SiH
-78 o C
1412 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
O
OHCOBn
OBnBnO
OMe
O
CO2MeAcO
OAcAcHN
OAc
SO2
NAcO
OBnH
H
OBn
OBn
H
O
OMeH HH
A
O
CO2MeAcO
OAcAcHN
OAc
O
OBnOMe
OBnOBn
HO
AcO
+
Nu
174175
176
SmI2 THF
Scheme (34)
Scheme (35)
Scheme (36)
O
BnO
BnO
BnO
Si lylO
O2S N
O
BnO
HO R2R1
BnOBnO
SilylO
OBnO
BnO
BnO
SilylO
Sm(III)
R1COR2 SmI2 THF
171 172
173
NHBoc
OAcO
AcO
AcHN O
O
CO2BnO
OO
OO
OH
O
CO2MeAcO
OAcAcHN
OAc
AcO
SO2Ph
R2
O
CO2Me
AcHN
OAc
AcO
R1
AcO
AcO
AcHNO CO2Bn
NHBoc
AcO
OAc
O
Zn(BH4)2
180 R1 R2 = H OH ( RS 11)
181 R1 R2 = O
182 R1 = H R2 = OH de gt 90
DMSO Ac2O
177178
179
13 steps
22 equiv SmI2 THF
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1413
Scheme (37)
Fig (2)
(KLH) by reductive amination for use as carbohydrate-basedvaccine GM3 a related trisaccharide containg gangliosideplays an important role in cell growth and differentiationFig 2 The synthesis of C-oligosaccharide GM3 is currentlyunderway following a similar route to that of C-GM4synthesis [42]
Beau also reported a sialyl C-disaccharide synthesiswhich relied on the unprecedented use of a stable andcrystalline 2-pyridyl sulfide of the N-acetylneuraminic acidderivative 189 as the anomeric precursor in a samarium-Reformastky procedure [43] The coupling procedure withsulfide 189 and aldehyde 190 afforded the carbon-linkeddimer 191 in 93 yield as a 11 diastereomeric mixture
Alcohols 191 were converted into thiocarbonates anddeoxygenated by employing triphenyltin hydride catalyticAIBN and pentafluorophenol which yielded C-disaccharide192 as a single compound in 65 yield for the 2 stepsDesilylation hydrogenolysis acetylation and finalacetolysis of the methyl glycoside provided the carbon-linked mimic 193 of the disaccharidic component of thesialylTn tumor antigen (Scheme 38)
4 CATIONIC METHODS
This section is categorized according to reactions thatinvolve the generation of anomeric ions followed by thecapture with sugar-based nucleophiles
OAcAcHN
OAc
AcO
O
OBnBnO
OBnOMP
HO
O
MeO2CAcO
O
MeO2CAcO
OAcAcHN
OAc
AcO
O
OHHO
OHOMP
HO
O
OBnOHC
OBnBnO
OMP
O
MeO2CAcO
OAcAcHN
OAc
AcO
O
OHHO
OHOMP
HO
O
CO2MeAcO
OAcAcHN
OAc
AcO
SO2Ph
O
MeO2CAcO
OAcAcHN
OAc
AcO
O
OAcAcO
OAcX
AcO
H2 PdC EtOAc CH3OHH2O
+
Ac2O Pyr
187 X = OMP
188 X = SPh 73
184 85 R and S mixture
186 90 for two i somers
+
SmI2 THF183
179
185
O
HO2 CHO
OAcAcHN
OH
HO
O
OHHO
OH
OAcO
(CH2 )12 CH3
HN
OH
(CH2)14CH3
O
O
O
OHHO
OH
O
O
HO2 CHO
OAcAcHN
OH
HO
O
OHHO
OH
O(CH2)12CH3
HN
OH
(CH2)1 4CH3
GM4
GM3
1414 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
41 Exo-glycals as Nucleophiles
Nitotra et al have found that treatment of exo-glycal 194with BF 3
OEt2 followed by a water quench afforded the C-disaccharide 195 (Scheme 39) It is noteworthy tonoteworthy that the attack of the enol ether on the anomericoxonium ion occurs with high stereoselectivity on the α-face only 195 was obtained [44]
42 Silyl-based Nucleophiles
Isobe has designed and developed alkynylation as a keyreaction for the introduction of a carbon chain onto sugarsThose alkynylated compounds are called ldquosugar acetylenesrdquo[45] The mechanism includes eliminative formation ofcation to which silylacetylene can coordinate on the α-face(Scheme 40)
Double C-glycosylation between glycal 198 and bis(silylacetylene) gave C-disaccharide ldquolikerdquo compounds 199and 200 (Scheme 41)
Silylpropargyl-sugar 201 smoothly reacted with D-glucalto furnish exclusively the α-acetylene glycoside product 202in 88 (Scheme 42) [46]
5 CYCLIZATION METHODOLOGY
This approach to C-oligosaccharide synthesis relies onthe coupling of an open chain fragment with an intact
monosaccharide to give an intermediate that is then cyclizedto deliver the C-oligosaccharide target This section isdivided by the type of chemistry used to initially assemblethe two pre-cyclization fragments
51 Wittig Reaction-Cyclization
The Kishi group was the first to use Wittig-cyclizationapproach to synthesize C-disaccharides Starting with Wittigreaction between 203 and 204 the intermediate 205 wasafforded as a single stereoisomer in 82 yield Osmylationthen gave a mixture of diols with the major one formed in a61 ratio Selective protection of the diols gave 206a and206b The mono-para-methoxybenzyl ether 206a was thentransformed into the hemiketal 207 in 75 overall yield inthree steps ie (1) Swern oxidation (2) acetonide hydro-lysis (4 N HClTHFrt) and (3) benzoylation (3 equiv ofPhCOClpyCH2Cl2rt) Silane reduction of 207 in an acidicmedium should preferentially yield the equatorially substi-tuted β-C-glycoside which was deblocked and converted tothe methyl- βminusC-disaccharide 209 Exact parallel experi-ments applied to the minor isomer gave the correspondingC-disaccharide 210 (Scheme 43) [47]
Armstrong has employed Wittig-osmylation protocol forthe preparation of a small library of α-C-(1rarr6)-disaccha-rides [48] Readily available allyl C-glycoside 211 washomologated to diene ester 212 and subjected to osmylation
Scheme (38)
O
CO2MeAcO
OAcAcHN
OAc
AcO
S(2-Py)
O
TESO
AcHNOMe
O
HO
O
CO2MeAcO
OAcAcHN
OAc
AcO
O NHAcOAc
OAc
OAc
O
CO2MeAcO
OAcAcHN
OAc
AcO
O NHAcOBn
OTES
OMe
OAc
AcO
O NHAcOBn
OTES
OMeOH
O
CO2 MeAcO
OAcAcHN
+
192 65
1 MeOHHCl2 H2 PdC EtOH3 Ac2O Pyr4 Ac2OAcOHH2SO4
193 59 overall yield
25 equiv SmI2 THF
1 11-thiocarbonyldiimidazole DMAP2 Ph3SnH cat AIBN
191 93
189
190
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1415
Scheme (39)
Scheme (40)
Scheme (41)
OBnO
OBn
OBn
OBnO
OBn
OBn
OBnO
OBn
OBn
OBnO
OBnCH3
BnO
OH
CH2
OBnO
OBn
CH3
OBn
H2 O
BF3 OEt2 MeCN
194
195 96
OOAc
OAc
AcO
R SiMe3
SnCl4
O
OAc
AcO
R
O
OAc
AcO
O
OAc
AcO
Me3Si
R
SiMe3
196
197
Me3 Si SiMe3
O
AcO
OAc
OAc
SiMe3
SiMe3
O
AcO
OAc
O
OAc
OAc
O
AcO
AcOO
OAc
OAc
SnCl4 CH2Cl2
SnCl4 CH2Cl2198
199
200
1416 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (42)
Scheme (43)
AcO
OAc
OAc
Me3 Si
BnO
OBn
BnO
OBn
AcO
OAc
BnO
OBn
BnO
OBn
+ I2 CH2Cl2
202 88
198 201
O
OBn
OBn
O
O
O
OBn
OBn
O
O
OBn
OBn O
OBn
OBn
O
OPBH2M
OH
OBnO
BnO
BnO
O
OBn
OBn
O
OHOPMB
OHO
HO
HO
O
OH
OHOH
OH
HOOMe
O
OBnOBn
O
Ph3P
O
O
OBn
OBn O
OBn
OBn
O
OPBM
OH
O O
CHO
OBn
BnO
OO
OBn
OBn
O
OHOPMB
BnO
BnO
BnO
OHO
HO
HO
O
OH
OHOH
OH
HOOMe
+ THF -78 oC
1 OsO4 pyr THF
2 NaH PMBBr
206a 206b 206a206b 61
1 Swern [O]2 4N HCl3 PhCOCl pyr
1 Swern [O]2 4N HCl3 PhCOCl pyr
1 PrSiH BF3 OEt2
2 H2 Pd(OH)2C
3 HCl MeOH 90 oC
1 PrSiH BF3 OEt2
2 H2 Pd(OH)2C
3 HCl MeOH 90 o C
203
204
205
207
209
208
210
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1417
followed by reduction to afford a 51 mixture (213214215216) of lactols that were readily separable by chromato-graphy Following a deprotection of an equimolar mixture of213 and 214 217 and the DL hybrid C-disaccharide of D-glucose-O-(1rarr6)-L-galactose 218 were obtained The DDand DL derivatives 219 and 220 of glucose-α-(1rarr6)-idosewere also obtained as a near equimolar mixture afterdeprotection of 215 and 216 (Scheme 44)
52 Anion Addition-Cyclization
Kishi developed an approach for the synthesis of theCndashtrehalo sugars which relied on nucleophilic addition ofone intact sugar fragment to a fundamental aldehyde ieKishi-Nozaki reaction [49] Coupling of monosaccharide221 and aldehyde 222 gave 223 The triple bond waspartially reduced and osmylation was followed by selectiveprotection to afford 224 The acetonide was converted toepoxide 225 by standard methods and removal of the PMBgroup Acid-catalyzed cyclization followed by aglyconichydrolysis and protection of hydroxyl group with (p-methoxyphenyl)diphenylmethyl chloride (MMTrCl) gave226 Inversion of the C-2 hydroxyl and removal of protectinggroups delivered α α-C-trehalose 227 (Scheme 44)
Kishi and co-workers also employed aldol reactions as anefficient access to the C-trisaccharide related to the type IIABO(H) blood group determinant [50] Aldol condensationof the enolate of methyl ketone 228 with aldehyde 229 gavea 41 mixture of hydroxy ketones 230 and 231 The majorketol was cyclized desulfurized and oxidized to afford thedisaccharide ketone 233 The ketone in THF was treatedwith LiHMDS (3 equiv) and TMEDA followed by theaddition of MgBr2 Addition of the aldehyde 234 led toalmost exclusive formation of the equatorial products 235and 236 in a 12 ratio Mesylation of 235 and 236 followedby treatment with liquid ammonia gave enones 237a and237b which were reduced to yield exclusively the C-2rsquo-equatorial ketone 238 Sodium borohydride reduction of theC-3rsquo carbonyl proceeded with the desired stereoselectivity toyield the protected C-trisaccharide 239 which wasdeblocked to provide the polyol 240 (Scheme 46)
Sutherlin and Amstrong cleverly applied a recursivestereochemical deconvolution (RSD) combinatorial approachfor the synthesis of a small library of C-trisaccharides aspotential inhibitors for the cell surface proteins of bacteriumHelicobactor pylori [51] The workers chose to carry outvariations in galactose ring of these trisaccharides An
Scheme (44)
OBnO
BnOOBn
OBn
P O
OEtOEtO
EtO
R H
OH
OH
OH
OH
O
R H
OH
OH
OH
OH
O
OHO
HOOH
OH
O
HO
OHOH
OH
OHO
HOOH
OH
O
HO
OH
OH
OHO
HOOH
OH
O
HO
OH
OHOH
R H
OH
OH
OH
OH
O
R
OBnO
BnOOBn
OBn
O
OHO
HOOH
OH
OO
HOHO
OH
R H
OH
OH
OH
OH
O
1 OsO4 NMO 50
2 DIBAL -32 oC 40
++ +
213 214 215 216
217 218 219 220
1 9-BBN H2O22 Swern [O]
3 t-BuOK
4 I2 C6H6212
211
1418 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
efficient Nozaki-Kishi coupling of vinyl bromide 241 withaldehyde 242 in a diasteromeric ratio of 12 followed byprotection with TBSOTf led to 243 and 244 Hydroborationfollowed by oxidation gave aldehydes 245 and 246respectively Addition of allylmagnesium bromide toaldehyde 245 followed by removal of the silyl groupafforded 247 to 246 giving 248 and 249 Epoxidation gave a11 mixture of the corresponding epoxides which werecyclized to give the C-trisaccharide 250-255 after removalof the benzyl groups (Scheme 47)
Schmidt reported a stereoselective 6-exo-trig selectiveelectrophilic cylization approach for de novo synthesis of amethylene-bridged Neu5Ac-α-(23)-Gal C-disaccharide theC-analog of an important motif in glycosphingolipids [52]The open chain precusors 259ab (a 32-mixture ofdiaseteromeric alcohols) were formed by the addition oflithiated iodide 256 to open chain aldehyde 258 Subsequent
C1 incorporation using Tebbe-reagent formation of a cycliccarbonate and deprotection of the two isopropylidene ketalsafforded tetrol 264 which upon treatment with phenylselenyltrifilate was steroselectively cyclized in a 6-exo-trigselective manner affording a diasteromeric mixture of 251and 252 in a ratio of 71 A seleno-Pummerer rearrangementto afford aldehyde 267 in 5 steps in 90 overall yieldOxidation of the aldehyde and subsequent steps led to thedesired C-disaccharide 268 (Scheme 48)
53 Esterification-Cyclization
Work from the Postema group has focused on a ringclosing metathesis (RCM) approach for the synthesis of C-saccharides [53a] The chemistry is versatile and has beenused for the synthesis of a small library of differentiallylinked β-C-disaccharides through a radical allylation-RCMstrategy [53b] The synthesis of the β-(1rarr4)-glucopyranosyl
Scheme (45)
O
OBn
BnO
BnO
BnO
I
CrCl2-NiCl2O
OBn
OH
BnO
BnO
BnO
O
O
O
O
O
H
OBn
O
O
OBnBnO
BnO
BnO
OOBn
OBn
OAc
PMBOHOO
OBn
BnO
BnO
BnO
O
OBn
OBn
OAc
O
OH
HO
HO
HO
OH
OH
OH
O
OH
O
OBn
BnO
BnO
BnO
OBn
OBn
OAc
O
MMTr
+
1 p-TsOH2 K2CO3 MeOH3 MMTrCl pyr
1 Swern [O]2 BH3 THF
3 AcOH-H2 O4 H2 Pd(OH)2
221
222
223
1 Pd-Pb CaCO3 H22 NaH BnBr3 OsO44 Bu2 SnO5 CsF PMB-Cl6 Ac2 O 4-DMAP
1 AcOH2 TsCl pyr
3 NaH-imid4 DDQ
224225
226 227
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1419
Scheme (46)
OBnO O
OBn
OMe
OBn
XY
SMe
OBnBnO
O
OBn
OBn
OBn
OBn
O
BnO
YX
OBn
TBSO
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnOOBn
H
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnO
OBn
OHC OBn
OBn
OTBS
OMe
BnOOBn
CHO
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnOOBn
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnO
OBn
YX
OBnO O
OBn
OMe
OBn
OBn
O
BnO
O
OBn
OBn
OBn
OBn
O 1 LiHMDS
2
228
1 TBAF THF
2 MeSH BF3 OEt2
230 X = OH Y = H231 X = H Y = OH
230231 41
1 Bu3SnH AIBN2 Swern [O]
1 LiHMDS THF-TMEDA2 MgBr23
1 MsCl
2 liquid NH3
235 X = OH Y = H236 X = H Y = OH Bu3 SnH AIBN
237a and 237b
NaBH4 MeOH
238
239 X = OBn
240 X = OHH2 Pd(OH)2
229
232233
234
1420 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (47)
OH C
O
O BnAcHN
OO
O
OBn OBnOBn
Br
O
OBn OBnOBn
O
OBnA cHN
OO
O TBSO
OBn O BnO Bn
O
OBnAcHN
OO
OTBS
S2
S1
S2
OTBSS1
O H
S2
OT BSS1
O H
MgBrMgBr
S2
O TBSS1
O H
S2
OHS1
OH
S2
OTBSS1
OH
O
OHHO
O H
O
HO
H OO
OBnA cH N
HO
H O
O
O HHO
OH
O
HOHO
O
OBnA cH N
HO
H O
O
OHH O
OH
O
H O
HOO
OBnAcHN
HO
HO
O
O HH O
OH
O
H O
H O O
OBnA cHN
HO
HO
O
O HH O
O H
O
HO
H O O
OBnAcHN
HO
HO
O
OHHO
OH
O
H O
O
OBnA cHN
HO
HOHO
+
241 242
1 CrCl2-NiCl2 T HF-DMF 722 TBSOTf 2 6-lutidine 91
243 244
1 9-BBN 602 Dess-Mart in period inane 97
1 9 -BBN 552 D ess-Martin periodinane 98
245 246
1
2 T BAF 74
1
2 TBAF 88
247 248 249
250
251
250 251 1 1 252 253 1 1 254 255 1 1
252
253
254
255
1 MCPBA2 CSA CH 2Cl2 61 fo r 2 steps3 H 2 Pd (O H)2C 95
1 MCPBA2 CSA CH 2Cl2 63 fo r 2 s teps3 H 2 Pd (OH)2C 87
1 MCPBA2 CSA CH2Cl2 80 for 2 steps3 H2 Pd(O H)2C 95
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1421
Scheme (48)
O
OO
Se Ph
R
O
HO OHOH
O
OB n O B n
OB n
O B nO O
O O
R O OR
X
O
OO
R
Se Ph
O
HOOH
OH
O
OB nOB n
O Bn
OB n
O O
O O
R O O R
O H
O
O B n OB n
O B n
OB n
O
C HO
O
O O
R O OR
OAc HN
OAc
C O2NH 4HOOH
OH
O
OH O H
OH OH
O
OB n O B n
OB n
OB nO O
O O
R O OR
X
O
O
OAcOAc
C HOA cOOAc
OAc
O
OB n O B n
OB n
OB n
O
O Bn OB n
OB n
OB n
X
OH
OO
HOOH
OH
O
O
OMeOB n
OB nOB n
R
t-B uL i256 R = Li
257 R = L i
258
(R = t-B uMe 2Si )
(R = t-B uMe 2Si )
259ab (32) 79 com bine d yi eld
De ss-Ma rtin pe riodinane
260 X = O R = t-B uMe 2Si ) 95
261 X = O R = t -B uMe2S i) 62
T e bbe re age nt
TB A F THF262 X = O R = H 94
diphosge ne
C H2C l 2Pyr
263 95
T HFH2O T FAr t
264 quant it a ti ve yie ld
PhSe C l AgOT f
EtC N -80 oC
265
266
Quant it at i ve yi l ed 25 26 7 1
+
R =
1 Ac 2OPyr
2 mC PB A3 Ac 2ONa OAc
4 NaO HT HFMe OH
5 Ac2O P yr
267 90 overa ll yi e ld
ste ps
268
1422 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
glucopyranoside 280 represents an example of thischemistry The known triacetyl glucopyranoside 269 wasconverted to iodide 270 in good yield Radical allylation of271 proceeded to afford a mixture of equatorial and axialallylation products in a 61 ratio Oxidative cleavage of thedouble bond gave the corresponding aldehydes 273a and273b which were separable Pinnick oxidation of the majoraldehyde 273a then gave the C-4 equatorial acid 274 DCC-mediated coupling of alcohol 275 and acid 274 proceeded toafford ester 276 in good yield Methylenation of 276 gave277 and exposure to catalysist 278 gave a 41 yield of theC-disaccharide glycal which was exposed to an excess ofBH3
THF to give 64 yield of the β-C-disaccharide 279Removal of the benzyl groups and global peracetylation gavethe peracetylated (1rarr4)-β-C-disaccharide 281 in good yield(Scheme 49)
54 Ring Expansion-Cyclization
Nelson developed a new strategy for asymmetric andstereoselective synthesis of C-linked disaccharide mimeticsthe C58-C71 fragment of palytoxin [54] The diol (RR)-282was converted into the di-dihydropyran (DHP) template 283284 and 285 The di-DHPs were functionized in a twodirectional sense using dihydroxylation reactions The two-directional approach was often very efficient indeed forexample in the synthesis of 286 six new stereogenic centerswere introduced with almost complete stereocontrol using areduction and a dihydroxylation reaction The approach isnot restricted to the synthesis of C2-symmetricaldisaccharide mimetics Using the unsymmetrical template285 which has both a pseudo-axial and a pseudo-equatorialhydroxyl groups the unsymmetrical mimetics 289 and 290were prepared (Scheme 50)
6 RADICAL APPROACHES
The radical approach for C-C bond formation is a popularmethod within organic chemistry The use of radicalchemistry in carbohydrate synthesis has certain advantagesFirstly the reaction conditions are very mild and tolerant ofa range of functional and protecting groups Secondanomeric radicals are stable with respect to elimination andepimeration Most significantly the chemistry required toincorporate an appropriate substitute at C-1 employed in theinitial hemolytic cleavage step is common within carbo-hydrate chemistry [55] The use of such radical techniquecan be subdivided into two classes intermolecular andintramolecular approaches
61 Intermolecular Radical Approaches
Giese was the first to employ an intermolecular radical-based approach for synthesis of C-disaccharides [56]Addition of an alkene to an anomeric radical underappropriate conditions allowed exclusive entry to the α-linked C-glycoside a result which was mirrored by the workof Baldwin [57] The high α-selectivity of the reaction wasin contrast with other reports Thus radicals generated at theC-2 C-3 and C-4 centers all preferred to occupy equatorialpositions [58] When the anomeric bromide 291 was treatedwith tin hydride and AIBN resulting anomeric radical andreacted with lactone 292 in a Michael addition it afforded293 In this reaction hydrogen abstraction at the resulting
radical center occurs from axial face to selectively generatethe equatorial C-2rsquo substituent Reduction and acetylation of293 furnished C-disaccharide 294 (Scheme 51) [59]
Witczak used the facial bias of levoglucosene tostereoselectively add a carbohydrate-based radical in thepreparation of the 3-deoxy-(1rarr4)-β-C-disaccharide 299[60] Addition of the radical derived from iodide 295 to 296gave adduct 297 in 26 yield Removal of the anomerichydroxyl of 297 was achieved by treatment with triethylsilane borontrifluoride ether complex followed bystereoselective reduction of the keto function at C-2rsquo withthe formation of 298 in 89 yield Debenzylation followedby acetolysis of 16-anhydro ring produced the peracetylatedtarget C-disaccharide 299 in 19 overall yield from 295(Scheme 52)
Vogel has developed general methods to transformenantiomerically pure 7-oxabicyclo[221]heptyl derivatives(ldquonaked sugarsrdquo) into C-disaccharides Because of thesechiral bicyclic skeletons they undergo highly stereoselectivereactions with predictable diasteroselectivities An arsenal ofmethods is available that allow to substitute these ldquonakedrdquocarbon centers with a variety of functional groups with allpossible relative configurations The methods allowpreparation of both enantiomers of a given target with thesame ease Predictably high stereoselectivity of the reactionsof the bicyclic chirons adds to the flexibility of approachwhich can lead to high molecular diversity [61]
α-C-(1rarr3)-mannopyranoside of N-acetyl-galactosaminepotent β-galactosidase inhibitors was synthesized by thisapproach [61] Enone 302 was readily prepared from 300The addition of the radical derived from bromide 303 toenone 302 afforded the αminusisomer 304 The ketone was thenreduced and the selenide eliminated via the intermediacy ofthe selenoxide to give 305 Acid-promoted (CF3SO3H) 7-oxa ring opening of 305 in MeCN produced the amino-conduritol derivative 306 resulting from the quenching of theallylic cation intermediate by the solvent (Ritter reaction)Ozonolysis of the chloroalkene 306 generated an acylchloride-aldehyde intermediate that reacted with MeOH toproduce a mixture of methyl uronates The major compound307 was silylated and reduced The crude polyol obtainedwas acetylated to produce 308 Desilylated and ammonolysisafforded a mixture of α-β-pyranoses 309 and correspondingα-β-furanoses (Scheme 53)
Similar chemistry was carried out to synthesize non-protected α-C(1rarr2)-L-fucopyranoside of D-galactopyrano-side corresponding to a blood group mimetic [62] Giesersquosradical fucosidation of racemic enone 310 with α-L-bromoacetofucose 311 provided the mixture of diastereo-meric α-C-fucoside 312a and 312b in reproducible yield of78 Reduction of the mixture gave a 11 mixture of endo-alcohols 313 and 314 which were isolated pure in 40 and355 yield respectively Oxidative elimination of thebenzeneselenyl group of 313 followed by acetylation gaveendo acetate 315 in 85 yield Acid-promoted ring openingof 315 and ozonolysis of the resulted chloroalkene gavemethyl uronic ester 316 in modest yield (10) Treatment of316 with Cl3CCN and NaH followed with BF3
OEt2
furnished the totally protected C-disaccharide 317 in 79
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1423
Scheme (49)
Bu3SnO
HOAcO
OMeOAc
OAc
O
AcO
OMeOAc
OAcI
AIBN
O
AcO
OMeOBn
OBn
HO2C O
AcO
OMeOR
ORY
X
OHBnO
BnO
OBn
OBnO
BnO
OBn
O
AcO
OMeOBn
OBnX
i-Pr i-Pr
N
Mo C(Me2 Ph)((CF3)2 MeCO)2
O
RO
OMeOR
O
RO
OR
OR
RO
OR
278
I2 Ph3P
imidazole
269 270 93
271a X = CH2CH=CH2 Y = H R = Ac 64271b Y = CH2CH=CH2 X = H R = Ac 11272a X = CH2CH=CH2 Y = H R = Bn 75272b Y = CH2CH=CH2 X = H R = Bn 75273a X = CH2CHO Y = H R = Bn 79273a Y = CH2CHO X = H R = Bn 79
1 NaOMe MeOH2 NaOH BnBr DMF
OsO4 NaIO4
NaClO2 NaH2PO4
274 96
275
DCC 4-DMAP
276 X = O 82
277 X = CH2 51
TiCl4 Zn dust TMEDA CH2Br2PbCl2 (Cat )
1
2 BH3 THF H2O2 NaOH
H2 PdC EtOH
Ac2 O Pyr 4-DMAP
279 R = Bn R = H 64
280 R = R = H 99
281 R = R =Ac 97
1424 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (50)
Scheme (51)
O OOH
OH
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
286
1 VO(acac)2 t-BuOH 95
2 (MeO)3CH BF3 90
1 P-O2NC6H4 CO2H Ph3P DIAD2 K2CO3 MeOH 82 over 2 steps
1 PhCOCl Et3N DMAP 402 P-O2NC6H4 CO2H Ph3P DIAD3 KOH THF-H2O 75 over 2 steps
TMEDA OsO4
Cat OsO4 NMO 287
Cat OsO4 NMO288
TMEDA OsO4
Cat OsO4 NMO
290
289
(RR)-282283
284
285
OHO
AcO
BrOAc
OAc
BnO
O
OBn
OBnO
OHO
AcOOAc
OAc
BnO
OOBn
OBnAcO
OHO
AcOOAc
OAc
BnO
O
OBn
OBnO
+
Bu3SnH AIBN291
292
293 81
1 Na[Al(OC2H4OMe)2(OEt)H]2 Ac2O pyr
294 56 over 2 steps
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1425
Scheme (52)
Scheme (53)
OBnO
BnOOBn
OBn O
OH
O
OBnO
BnO
OHOBn
OBn O
O
O
O
O
O
OBnO
BnOOBn
OBnO
OAcOAc
OAc
OBnO
BnO
OHOBn
OBn
IBu3SnH AIBN
295 297 26
1 BF3 OEt2 Et3SiH
2 L-Selectride THF
1 Pd(OH)2C C6H10 EtOH
2 EtSiOSO2CF3 Ac2O
298 89 over 2 steps299
296
O
O
PhSeClO
O
PhSeCl
Bu3 SnH
O
O
PhSeCl
R
H
O
OAc
R
Cl
O
AcO
OAc
OAc
OAcOH
Cl
NHAc
R
OAc
AcHN
OH
O
OH OAc
OH
OHO
HO
OH
O
AcO
OAc
OAc
OAcBr
O
O
PhSeCl
O
O
PhSeCl
R
O
OTIPSAcHNR
OAc OAc
O
OHAcHN
COOMe
R
OAc
1 Bu4NF
2 NH3MeOH
1 (Me3Si)2NLi THF2 Me2N=CHI
1 Bu3 SnH AIBN2
1 NaBH42 mCPBA3 Ac2O pyr
1 H+ MeCN
2 H2 O NaHCO3
R =
1 O3MeOH
2 Me2S NaHCO3
1 TIPSOTf 26-lut idine2 LiBH43 Ac2 O pyr DMAP
furanoses +
304 56
305 68 306 84307 50
308 46
300 301 302
303
309
1426 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
The reduction of 317 and treatment with DOWEX-H+ resinprovided the desired C-fucoside 318 in 70 (Scheme 54)
62 Intramolecular Radical Approaches
One disadvantage with the intermolecular approaches isthat during such radical mediated reactions electrondeficient alkenes are required to facilitate C-C bondformation The intramolecular approach of Sinayuml overcomes
this drawback by bring two substrates together via atemporary covalent silaketal connector This enables the useof a wider range of alkenes which can include alkene-functionalized sugars thus leading to the generation of C-disaccharides [63] Based on the early work of Stork Sinayumlemployed the tether reaction in the synthesis of both α- andβ-C-disaccharides with this work subsequently beingemployed in the synthesis of biologically significant natural
Scheme (54)
O
OH
Fuc
Cl
O
O
ClPhSe
OOAc
NHAcOHFuc
O
AcOOAc
AcO
Br
O
O
PhSeCl
O
AcOOAc
AcO
O
OH
PhSe Cl
Fuc
OOAc
NHAc
OMe
Fuc
O
AcHN
OH OAc
OH
O
OH
Me
OH
O
O
Fuc
ClSePh
O
HO
Fuc
ClSePh
+
Ph3SnHAIBN
78 combined yield
Fuc
310
+
1 NaBH4 MeOHTHF2 Chromatography
313 40 314 355
1 mCPBA
2 Ac2O pyr DMAP
+
315 75
1 TfOH MeCN
2 NaHCO3 O3 -78 oC
316 10 over 2 steps
1 Cl3 CCN NaH
2 MeOH BF3 OEt2
317 79
1 LiBH4 THF
2 Dowex-H+
311
312a312b
318 70 for 2 steps
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1427
products [64] The availability of different hydroxyl groupson each monosaccharide unit allowed the fine-tuning ofstereochemical outcome by selective positioning of the silyltether [65] Development of this early stereochemical controlled to the tethering of the donor 320 with alcohol 319through a di-isopropyl silicon tether 321 Subsequent treat-ment with Bu3SnH and AIBN led to a 9-endo-trigcyclization to form the C-disaccharide 322 in an 80 yieldwith exclusive formation of the α-product The silyl tetherwas removed with Bu4NF and deprotection under standardconditions afforded the desired disaccharide 323 in excellentyield (Scheme 55)
In parallel the development of a 32rsquo silyl tether allowedaccess to the β-linked product as demonstrated in Sinayumlrsquossynthesis of methyl β-C-lactoside 328 [66] Alcohol 324 and320 were connected via the dimethylsilyl tether an 8-endo-trig cyclization followed to exclusively afford the β-
disaccharide 326 in 45 yield Removal of the tether anddeprotection of benzyl ether gave β-C-disaccharide 328(Scheme 56)
This group also selected iodosugars bearing a freehydroxyl group as progenitors of the radical donors [67] In atypical experiment the radical donor 329 was connected tothe radical acceptor 330 through a silaketal tether followingtheir procedure Tributyltinhydride mediated 8-endo-trigradical cyclization of compound 331 gave after detetheringof the non isolated intermediate 332 the protected β-C-disaccharide 333 in 37 overall yield (from startingmaterials 330 and 329) Peracetate 335 was achieved afterhydrogenolysis The C-laminaribioside 334 is of potentialbiological interest as it mimics the repeating disaccharideunit of fungal β-(1rarr3)-glucans which have antitumor andimmunomodulating properties (Scheme 57)
Scheme (55)
Scheme (56)
OO
OHSePh
OTBDPSO O
OO
SePh
OTBDPSO
OO
OBnOMe
OBn
Si
O
HOOBn
OMe
OBn
O
HOOH
OHHO
O
HOOH
OMe
OH
OTBDPSO
O
HOOBn
OMe
OBnO
OOH
1 n-BuLi THF
2 iPr2SiCl2 -78 oC
3 DMAP THF rt
1 Bu4NF THF
2 Dowex-H+
3 H2 PdC
Bu3SnH AIBN toluene
319
320
321
322323
OBnO
OHSePh
OBnBnO
OHO
OBnOMe
OBn
ROO
ROOH
OR
OHO
OROMe
OR
OBnO
O
OBnBnO
OO
OBnOMe
OBn
Si
SePh
OBnO
O
OBnBnOO
OOBn
OMe
OBn
Si
1 PhSeH Me2SiCl2
BuLi -78 oC
2 imidazole rt
Bu3SnH AIBN toluene
H2 PdC327 R = Bn
328 R = H
Bu4NF THF
324
320
325
326 45
1428 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
CONCLUSIONS
In this paper the biological importance of C-oligo-saccharides as subunits of natural products and as a newgeneration of carbohydrate based on therapeutics has beenillustrated Different methods are available for the synthesisof C-oligosaccharides As with traditional saccharidesynthesis it has been necessary to develop a number ofspecific approaches to facilitate the regioselective andstereoselective preparation of the desired targets Work inthis area continues and it is expected that many interestingnew C-oligosaccharides will be prepared using the chemistrydescribed in this review It is also likely that new chemistrywill be developed in the future for the preparation of thesebiologically important targets
ACKNOWLEDGEMENTS
The authors thank Dr Sultan Baytas for her criticalreading of this manuscript
REFERENCES
[1] Kennedy J F White C A Bioactive Carbohydrates InChemistry Biochemistry and Biology Ellis Horwood LtdChichesterUK 1983
[2] Wassarman PW Mammalian Fertilization Molecular Aspects ofGamete Adhesion xocytosion Exocytosis and Fusion Cell 199996 175-183
[3] Carbohydrate-based Drug Discovery Wong C-H EdWeinheim Cambridge Wiley-VCH 2003
[4] (a) Sharon N Lis H Lectins as Cell Recognition MoleculesScience 1987 246 227-234 (b) Dwek RA Chem Rev 1996 96683-720
[5] Postema M C-Glycoside synthesis CRC Boc Ratom 1995[6] (a) Weatherman R V Mortell K H Cheruenak MKiessling
L L Toone E J Specificity of C-Glycoside Complexation byMannoseGlucose Specific Lectins Biochem 1996 35 3619-3624(b) Ravishankar R Surolia A Vijayan M Lim S Kishi YPreferred Conformation of C-Lactose at the Free and Peanut LectinBound States J Am Chem Soc1998 120 11297-11303
[7] (a)Wong C-H Halcomb R L Ichikawa Y and Kajimoto TEnzymes in organic synthesis Application to the problems ofcarbohydrate recognition part2 Angew Chem Int Ed Engl 199534 521-546 (b)Howard S Withers SG Bromoketone C-Glycosides a New Class of βminusGlucanase Inactivators J AmChem Soc 1998 120 10326-10331(c) Wang Q Wolff MPolat T Du Y Linhardt R J C-glycoside of Neuraminic Acidsas Neura-minidase Inhibitors Bioorg Med Lett 2000 10 941-944 (d) Phili R Chang J Partis R A Mueller R A ChrestF J Passaniti A The Alpha-glucosidase I InhibitorCastanospermine Alters Endothelial cell Glycosylation PreventsAngiogenesis and Inhibits Tumor Growth Cancer Res 1995 552927-2935
[8] Ossor A Elbein A D In Carbohydrates in Chemistry andBiology Vol 3(II) WileyVCH 2000 pp 513-539
[9] (a) Sinayuml P Synthesis of oligosaccharide Mimetics Pure ApplChem 1997 69 459-463 (b) Beau J-M Gallagher TNucleophilic C-glycosyl Donors for C-glycoside Synthesis Top inCurr Chem 1997 187 1-54 (c) Nicotra F Synthesis of C-glycosides of Biological Interest Top in Curr Chem 1997 187
Scheme (57)
O
O
O
Ph
I
OMe
OHO
BnO
OH
OH
BnOOH
O
BnO
Si
O
O O
Ph
I
OMe
O
O
BnO
OR4O
R5O
OMe
OR2
OR3O
R3O
OR1
R3O
Bu3 SnH AIBN
332 R1 R2 = SiMe2 R3 = Bn R4 R5 = CHPhTBAF THF
333 R1 = R2 = H R3 = Bn R4 = R5 = CHPh 37 from 11
334 R1 = R2 = R3 = R4 = R5 = H
335 R1 = R2 = R3 = R4 = R5 = Ac
329
H2 PdC MeOH
Ac2 O pyr
1 BuLi THF -78 oC
2 Me2SiCl2
3 DMAP
330
331
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1429
55-83 (d) Du Y Linhardt R Y Recent Adv in Stereo-SelectiveC-Glycoside Synthesis Tetrahedron Lett 1998 54 9913-9959 (e)Liu L Mckee M and Postema M H D Synthesis of C-saccharides and Higher Congeners Current Org Chem 2001 51133-1167
[10] Jarosz S Fraser-Reid B Synthesis of A Higher Carbon Sugar ViaDirected Aldol Condensation Tetrahedron Lett 1989 30 2359-2362
[11] Lichtenthaler F W Lergenmiiller M Schwidetzky S C-Glycosidations of 2-Ketohexosyl With Electrophilic Radical andNudeophilic Anomeric Carbons Eur J Org Chem 2003 3094-3103
[12] Baudat A Vogel P Aza-C-disaccharides Synthesis of 6-Deoxygalactonojirimycin-β-C(1rarr3) Linked with D-Altrofuranosides and D-Galactose J Org Chem 1997 62 6252-6260
[13] Turner D Vogel P Synthesis of 4-Hydroxy-26-Bis(hydroxymethyl) tetrahydropyran-2-Carbaldehyde DerivativesSynlett 1998 304-306
[14] Zhu Y-H Vogel P Short Stereoselective Synthesis of C-(1rarr3)-Linked Disaccharides Tetrahedron Lett 1998 39 31-34
[15] Zhu Y-H Vogel P Synthesis of a (2R 6R)-2-(Hydroxymethyl)-6-Propa-1 2-Dienyl-2H-Pyran-3(6H)-One Derivative A NewEnone for The Convergent Construction of C-Glycosides of C-Disaccharides Synlett 2001 82-86
[16] Baumberger F Vasella A Deoxynitrosugars The 6th
Communication Stereolectronic Control in the reductivedenitration of tertiary nitro ethers A Synthesis of ldquoC-glycosidesrdquoHelv Chim Acta 1983 66 2210-2221
[17] Martin O R Lai W Synthesis and Conformational Studies of β-(1rarr6)- and ββ-(1rarr1)-Linked C-disaccharides J Org Chem1993 58 176-185
[18] Spak S J Martin R The synthesis of an analogue of Methyl OC-Analogue of Methyl 4rsquo-O-β-D-GlucopyranosylgentiobiosideTetrahedron 2000 56 217-224
[19] Kobertz W R Bertozzi C R Bednarski M D C-GlycosylAldehyde Synthons for C-Linked Disaccharides J Org Chem1996 61 1894-1897
[20] Gurjar M K Nagaprasad R and Ramana CV First Synthesis ofMethyl α-C-D-Arabino-furanosyl-(1rarr5)-αminusD-Arabinofuranosidethe C-Disaccharide Segment of Motif C of MycobateriumTuberculosis Tetrahedron Lett 2000 43 7577-7579
[21] Witczak Z J Synthesis of C-Glycosyl Compounds and OtherNatural Products from Levoglucosenone Pure Appl Chem 199466 2189-2192
[22] Griffin F K Paterson D Taylor R J K Ramberg-BacklundApproaches to the Synthesis of C-Linked Disaccharides AngewChem Int Engl 1999 38 2939-2942
[23] Paterson B E Griffin F K Alcaraz M-L and Taylor R J KA Ramberg-Baumlcklund Approach to the Synthesis of C-GlycosidesC-Linked Disaccharides and C-Glycosyl Amino Acids Eur JOrg Chem 2002 1323-1336
[24] McAllister G D Paterson D E Taylor R J K A SimplifiedRamberg-Bachlund Approach to Novel C-Glycosides and C-Linked Disaccharides Angew Chem Int Ed Engl 2003 42 1387-1391
[25] McCartney J L Christopher T M Cicchillo R M BernardinaM D Wagner T R and Norris P J Org Chem 2003 6810152-10155
[26] Dondoni A Zuurmond H M Bascarate A Synthesis of α-andβ-D-(1rarr6)-C-Disaccharides by Witting Olefination of Formyl C-Glycosides with Glycopyranose 6-phosphoranes J Org Chem1997 62 8114-8124
[27] Dondoni A Kleban M Zuurmond H Marra A Synthesis of(1rarr6)-C-Oligogalactosides by Interative Wittig OlefinationTetrahedron Lett 1998 39 7991-7994
[28] Dondoni A Marra A A New Synthetic Approach toMycobacterial Cell Wall α-(1rarr5)-D-Arabinofuranosyl C-Oligosaccharides Teterahedron Lett 2003 44 4067-4071
[29] Colinas P A Ponzinibbio A Lieberknecht A and Bravo R OWittig Reaction of Glycosyl Phosphonium Salts A StereoselectiveRoute to C-Disaccharides and C O-Trisaccharides TetrahedronLett 2003 44 7985-7988
[30] Schmidt R R Preuss R Synthesis of Carbon Tetrahedron Lett1989 30 3409-3412
[31] Dietrich H Schmidt R R Synthesis of Carbon-Bridged C-Lactose and Derivatives Liebigs Ann Chem 1994 975-981
[32] Rouzaud D Sinayuml P The First Synthesis of a ldquoC-DisacchariderdquoJ Chem Soc Chem Commun 1983 1353-1354
[33] Xin Y-C Zhang Y-M Mallet J-M Glaudemans C P JSinayuml P Synthesis of C-Oligosaccharides That Mimie TheirNatural O-Analogues Immunodeterminants in Binding toMonoclonal Immunoglobulins Eur J Org Chem 1999 471-476
[34] Streicher H Geyer A Schmidt R R C-Disaccharides ofKetoses Chem Eur J 1996 2 502-510
[35] Leeuwenburgh M A Timmers C M Vander Marel G A VanBoom J H Mallet J-M Sinayuml P G Stereoselective Synthesisof α-C-(Alkynyl)-Glycosides Via Ring-Opening of α-12-Anhydrous Tetrahedron Lett 1997 38 6251-6254
[36] Aslam T Fuchs M G G Le Formal A Wightman R HSynthesis of C-Disaccharide Analogue of the α-D-Arabinofuranosyl-(1rarr5)-α-Arabinofuranosyl Motif ofMycobacterial Cells Walls via Alkynyl Intermediates TetrahedronLett 2005 46 3249-3252
[37] (a) Girad P Namy J L Kagan H B Divalent LanthanideDerivative in Organic Synthesis 1 Mild Preparation of SamariumIodide and Ytterbium Iodide and Their Use as Reducing orCoupling Agents J Am Chem Soc 1980 102 2693-2698 (b)Molander G A Harris C R Sequencing Reactions withSamarium(II) Iodide Chem Rev 1996 96 307-338
[38] (a) Mazeacuteas D Skrydstrup T Doumeix O Beau J-MSamarium Iodide-Induced Intramolecular C-Glycoside FormationEfficient Radical Formation in the Absence of an Additive AngewChem Int Ed Engl 1994 33 1383-1386 (b) Mazeacuteas DSkrydstrup T Beau J-M A Highly Stereoselective Synthesis of1 2-trans-C-Glycosides Via Glycosyl Samarium(III) CompoundsAngew Chem Int Ed Engl 1995 34 909-912 (c) Jarreton OSkrydstrup T Beau J-M The Stereospecific Synthesis of Methylα-C-Mannobioside A Potential Inhibitor of M TuberculosisBinding to Human Macrophages J Chem Soc Chem Commun1996 1661-1662 (d) Jarreton O Skrydstrup T Espionosa J-FJimeacutenez-Barbero J Beau J-M Samarium Diiode Prompted C-Glycosylation An Application to The Stereospecific Synthesis ofα-(1rarr2)-C-Mannobioside and Its Derivatives Chem Eur J 19995 430-441 (e) Mipuel N Doisneau G Beau J-M ReductiveSamariation of Anomeric 2-Pyridyl Sulfones with Catalytic AnUnexpected Improvement in The Synthesis of 12-Trans-Diequatorial C-Glycosyl Compounds Angew Chem Int Ed Engl 2000 39 4111-4114
[39] Vlahov I R Vlahova P I Linhardt R J DiastereocontrolledSynthesis of Carbon Glycosides of N-Acetylneuraminic Acid ViaGlycosyl Samarium(III) Intermediates JAmChem Soc 1997 1191480-1481
[40] Kuberan B Sikkander S ATomiyama H Linhardt R JSynthesis of a C-Glycoside Analogue of sTn An HIV-and Tumor-Associated Antigen Angew Chem Int Ed Engl 2003 42 2073-2075
[41] Bazin H G Du Y Polat T Linhardt R J Synthesis of aVersatile Neuraminic Acid ldquoCrdquo-Disaccharide Precursor for theSynthesis of C-Glycoside Analogues of Gangliosides J OrgChem 1999 64 7254-7259
[42] Chen C-C Ress D K Linhardt RJ Samarium Iodide-Mediated Synthesis of Neuraminic Acid C-Glycosides InSynthesis of Glycommetics Roy R Ed ACS Syposium Series2004 896 53-80
[43] Abdallah Z Doisneau G Beau J-M Synthesis of a Carbon-Linked Mimic of The Disaccharide Component of The Tumor-Relate SialyTn Antigen Angew Chem Int Ed Engl 2003 425209-5212
[44] Lay L Nicotra F Panza L Russo G Caneva E Synthesis ofC-disaccharides through dimerization of exo-glycals J Org Chem1992 57 1304-1306
[45] Isobe M Nishizawa R Hosokawa S Nishikawa TStereocontrolled Synthesis and Reactivity of Sugar Acetylenes JChem Soc Chem Commun 1998 2665-2676
[46] Saeeng R Sirion U Sahakitpichan P Isobe M IodineCatalyzes C-Glycosidation of D-Glucal with SilylacetykeneTetrahedron Lett 2003 44 6211-6215
[47] (a) Babirad S A Wang Y Kishi Y Synthesis of C-Disaccharides J Org Chem 1987 52 1370-1372 (b) Wang YBabirad S A Kishi Y Preferred Conformation of C-Glycosides
1430 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
8 Synthesis of 14-Linked Carbon Disaccharides J Org Chem1992 57 468-481
[48] Armstrong R W Sutherlin D P Strategies for the Synthesis ofC-Disaccharides Containing D and L Sugars Tetrahedron Lett1994 35 7743-7746
[49] Wei A Kishi Y Preferred Conformation of C-Glycosides 12Synthesis and Conformational Analysis of αα- α β- and β β-Trehaloses J Org Chem 1994 59 88-96
[50] Haneda T Goekjian P G Kim S H Kishi Y PreferredConformation of C-Glycosides 10 Synthesis and ConformationAnalysis of Carbon Trisaccharides J Org Chem 1992 57 490-498
[51] Sutherlin D P Armstrong R W Synthesis of 12 Stereochemistryand Structurally Diverse C-Trisaccharides J Org Chem 1997 625267-5283
[52] Notz W Hartel C Waldscheck B Schmidt R R De NovoSynthesis of a Methylene-Bridged Neu5Ac-α-(23)-Gal C-Disaccharide J Org Chem 2001 66 4250-4260
[53] (a) Postema M H D Calimente D Liu L Behrmanm T L AnOlefin Metathesis Route for the Preparation of (1rarr6)-Linked-C-Disaccharide Glycals A Convergent and Flexible Approach to C-Saccharide Synthesis J Org Chem 2000 65 6061-6068(b) Postema M H Piper J L Liu L Faust M Andreana PSynthesis and Partial Biological Evaluation of a Small Library ofDifferentially Linked β-C-Disaccharide J Org Chem 2003 684748-4754
[54] Nelson A The Development of Strategies and Methods for TheSynthesis of Biologically Active Compounds New J Chem 200428 771-776
[55] Togo H He W Waki Y Yokoyama M C-GlycosylationTechnology With Free Radiant Reactions Synlett 1998 700-717
[56] Giese B Dupuis J Diastereoselective Synthesis of C-Glycopyranosides Angew Chem Int Ed Engl 1983 22 622-623
[57] Adlington R M Baldwin J E Basak A Kozyrod RPApplication of Radical Addition Reactions to tho Synthesis of a C-Glucoside and A Functionalized Amino Acid J Chem SocChem Commun 1983 144-145
[58] Giese B Gonzaacutelez-Goacutemez J A Witzel T The Scope of RadicalCC-Coupling by The ldquoTin Methodrdquo Angew Chem Int Ed Engl1984 23 69-70
[59] Giese B Witzel T Synthesis of ldquoC-Disaccharidesrdquo by RadicalC-C Bond Formation Angew Chem Int Ed Engl 1986 25 450-451
[60] Witczak Z J Chhabra R Chojnacki J C-Disaccharides IStereoselective Approach to β-(1rarr4)-3-Deoxy-C-Disaccharidesfrom Levoglucosenone Carb Res 1997 301 167-175
[61] Vogel P Synthesis of Rare Carbohydrates and Analogues Startingfrom Enantiomerically Pure 7-Oxabicyclo[221]heptyl Derivatives(ldquoNaked Sugarsrdquo) Current Org Chem 2000 4 455-480
[62] Viodeacute C Vogel P Synthesis of The C-Disaccharide α-C(1rarr3)-L-Fucopyranoside of N-Acetylgalactosamine J Carb Chem2001 20 733-746
[63] Xin Y C Mallet J M Sinayuml P An Expeditious Synthesis of AC-Disaccharide Using A Temporary Silaketal Connection J ChemSoc Chem Commun 1993 864-865
[64] (a) Petitou M Herault P Lormeau J-C Helmboldt A MalletJ-M Sinayuml P Herbert J-M Introducing A C-InterglycosidicBond in A Biologically Active Pentasaccharide Hardly Affects ItsBiological Properties Bioorg Med Chem 1998 6 1509-1516 (b)Sinayuml P Advances in The Synthesis of the Carbohydrate MimicsPure Appl Chem 1998 70 1495-1499
[65] Sinayuml P Chemical Synthesis of Oligosaccharide Mimetics PureAppl Chem 1998 70 407-410
[66] Sinayuml P Chemical Synthesis of Oligosaccharide Mimetics PureAppl Chem 1998 69 459-463
[67] Vauzeilles B Sinayuml P Selective Radical Synthesis of β-C-Disaccharides Tetrahedron Lett 2001 42 7269-7272
1408 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (27)
Scheme (28)
stereochemical outcome is rationalized by the generation ofan initial zinc acetylide species which facilitates intra-molecular delivery to the α-face (Scheme 32)
Wightman synthesized C-disaccharide analogs of the α-D-arabinofuranosyl-(1rarr5)-α-D-arabinofuranosyl motif ofmycobacterial cell walls through alkynyl intermediates [36]The lactone 164 was treated with lithio(trimethylsilyl)ethyneat low temperature to give lactol in 66 yield of 165Treatment of this with triethylsilane and BF3
Et2O gavethe separable isomers 166α (60) and 166β (13)Desilylation of the major isomer 166α gave 167 in 97yield Treatment of 167 with n-BuLi followed by addition oflactone 164 gave 85 yield of the hemiacetal 168 which onreduction with Et3SiH and BF3
Et2O gave the disubstitutedalkyne 169 (83) as the major product Reduction-
hydrogenolysis of 169 then gave the C-disaccharide 170 innear-quantitative yield (Scheme 33)
3 REDUCTIVE GLYCOSYL SAMARIUM SPECIES
The introduction of SmI2 as reducing agent can becredited to Kagan and has since been utilized in numeroussynthetic schemes [37] Sinayuml and Beau introduced SmI2
chemistry into C-glycoside synthesis through intermolecularreactions with appropriate electrophiles and intramolecularreactions of silyl tethered substrates [38] Anomericsamarium species are highly stable and not likely to undergoβ-elimination Treatment of the aryl sulfone 171 with SmI2
affords the nucleophilic intermediate 172 through two singleelectron transfer processes Introduction of a suitableelectrophile (carbonyl compounds) affords the α-C-manno-
O
BnO
OTBDPS
BnO X
SO Ph
O
BnO
OBn
BnO Li
SO Ph
DMF
OHO
HOOH
OH
O OH
OH
HO
OHOH
O
BnO
OTBDPS
BnO
SO Ph
O
OBn
OBnOBnSO
Ph
OH
131 X = Li
132 X = CHO
THF -100 oC
1 Ra-Ni
2 BH3 DMS NaOH H2O2
3 H2 PdC
131
133
134
OBnO
OBnOMe
BnO
Li
OBnO
BnOOBn
OBn
OOBn
OBnOMeBnO
OH
OBnO
BnOOBn
OBn
O
n-BuLi
BnO
OMe
BnO
BrBr
O
OBn
OHO
OH
OH
HO
OHO
OH
HO
OMe
O
BnO
OMeOBn
O
BnO
139 92
1BF3 OEt2 EtOH
2 H2 PdC AcOH
140 52 over 2 steps
135 136 137
138
CBr4 PPh3
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1409
pyrannoside 173 in good yield and with excellent stereo-selectivity (Scheme 34) [38a]
Preparation of C-glycosides of ulosonic acids using SmI2
was pioneered by Linhardt and coworkers [39] Coupling ofpyridyl sulfone 174 with aldehyde 175 in the presence ofSmI2 gave an excellent yield of the N-acetylneuraminic acidC-disaccharide 176 as single isomer This stereochemicaloutcome was rationalized on the basis of the Felkin-Anhmodel for predicting the stereochemical outcome of akinetically controlled addition of a nucleophile to a chiraladehyde (Scheme 35 A)
Reductive samarium method was utilized to synthesizesialo-antigen C-analogs by the Linhardt group A fullyprotected C-analogue of the SialylTn antigen α-D-Neu5Ac-(2rarr6)α-D-GalNAc-(1rarrO)-Ser 182 was prepared [40] C-glycosylation of the neuraminic acid sulfone donor with
aldehyde acceptor in presence of excess SmI2 afforded the α-C-glycoside 180 as an RS mixture (11) The criticalintermediate aldehyde acceptor 178 was prepared in 13steps Chemoselective resolution to compound 180 wasundertaken by oxidation with DMSOAc2O to keto-bridgedcompound 181 followed by stereoselective reduction withZn(BH4)2 to regenerate the bridge hydroxyl function gave182 in gt90 de (Scheme 36)
A common versatile N-acetylneuraminic acid C-disaccharide precursor of the C-glycoside analogs ofgangliosides GM4 and GM3 has been synthesized [41]Samarium(II) iodide coupling of N-acetylneuraminic acidsulfone 179 with a 3-formyl galactopyranoside derivative183 afforded the corresponding C-disaccharide 184 as amixture of (R) and (S) isomers at the newly formedhydroxymethylene bridge This diastereoisomeric mixturewas resolved after debenzylation of the galactoside residue
Scheme (29)
O
BnO
BnOOBn
OBn
OOBn
OBnOMe
OBnOH
O
BnO
BnO
OBn
OBn
O
O
BnOOBn
OMe
BnO
Li
OBnO
OBn
OBn
OBnO
OBn
OBn
OMe
OBnO
OBn
OBnBnO
OBnO
OBn
OBn
OBnO
OBn
OBn
OMe
OBnO
OBn
OBnOBnO
OBn
OBnBnO
O
BnO
BnO
OBn
O
OBnO
OBn
OBnBnO
OBnO
OBn
OBnBnO
OBnO
OBn
OBn
OMe
OBnO
OBn
OBnBnO
OMe
1 PCC2 CBr4 Ph3P3 n-BuLi
144 overall yield 54
1 BF3 OEt2 Et3 OH
2 H2 PtO2 EtOAc
145 76
1 H2 SO4 AcOH
2 PCC
146 62
repeat steps
repeat st eps
141 142
143
147
148
1410 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (30)
Scheme (31)
O
BnOOBn
OMe
Li
BnO
OPivBnO
OBn
OBn
BnO
O OO
BF3 OEt2
OBnO
OBn
OBn
BnO
OO
O
OMe
BnOOBn
BnO
Co(CO)3
Co(CO)3
O
CAN
OBnO
OBn
OBn
BnO
OO
OO
BnOOBn
BnO
OMe
OHBnO
OBn
OBn
BnO
OHO
O
O
OMe
BnOOBn
BnO
Co(CO)3
Co(CO)3
O
OPivBnO
OBn
OBn
BnO
OH OO
O
OMe
BnOOBn
BnO
OAcO
OAc
OAc
AcO
OAcOAc
OAcO
OAc
AcO
OMe
1
2 NaOMe MeOH
1 Lewis acid2 ClCO2CCl3 Pyr3 Co2(CO)8
with a-isomer
1 Et3N Pyr H2O
2 H2 PdC H+
3 Ac2 O Pyr
149 151
152153
154 155
150
OBn
BnO
OBnO
OBn
BnO
OBnO
BnO
MeO
OBnO
OBn
BnO
O
OMe
AcO
OAcO
OAc
OAc
AcO
OAcO
OAc
O
BnOOBn
OMe
BnO
159 74 over 2 steps
+
BuLi ZnCl2 THF
1 H2 PdC2 Ac2O Pyr
156 157
158 59
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1411
Scheme (32)
Scheme (33)
and the chirality of each isomer assigned after acetylationConversion of the p-methoxyphenyl group in the peracety-lated (S) isomer 187 into the corresponding thiophenylglycoside 188 was accomplished affording the key inter-mediate for the synthesis of C-glycoside analogs of GM4GM3 and other related gangliosides (Scheme 37)
Ganglioside GM4 is a very important cell adhesionmolecule The C-disaccharide of GM4 is currently beingsynthesized in Linhardtrsquos lab using standard O-glycosylationof C-disaccharide with protected ceramide Once theceramide has been attached it can be oxidized to afford analdehyde group for coupling to keyhole limpet hemocyanin
OBnO
OBn
BnO
O
OBnO
ClZnO
OBn
BnOCl
R
OBnO
O
OBn
BnOCl
ZnR
O
ZnR
OBnO
OBn
BnO
160 161
162163
O
OBn
OBnBnO
O
O
OBn
OBnBnO H
TMS
O
OBn
OBnBnO H
O
OBn
BnO
OBnHO
O
OBn
OBnBnO OH
TMS
OBnBnO HO
OBn
TMS
O
OR
ORRO H
O
OR
RO
OR
OBn
OBnBnO
H
TMS
O+
K2CO3 MeOH
1 n-BuLi THF -78 oC
2 164
164165 66
166α 60 166β 13167 97
BF3 Et 2O Et 3SiH -78 oC
168 85
169 R = Bn 83
170 R = H near quantitative yield
H2 (1 atm)Pd(OH) 2C
TMS-acetyl ene
n-BuLi THF -78 oC BF3 Et2O Et3SiH
-78 o C
1412 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
O
OHCOBn
OBnBnO
OMe
O
CO2MeAcO
OAcAcHN
OAc
SO2
NAcO
OBnH
H
OBn
OBn
H
O
OMeH HH
A
O
CO2MeAcO
OAcAcHN
OAc
O
OBnOMe
OBnOBn
HO
AcO
+
Nu
174175
176
SmI2 THF
Scheme (34)
Scheme (35)
Scheme (36)
O
BnO
BnO
BnO
Si lylO
O2S N
O
BnO
HO R2R1
BnOBnO
SilylO
OBnO
BnO
BnO
SilylO
Sm(III)
R1COR2 SmI2 THF
171 172
173
NHBoc
OAcO
AcO
AcHN O
O
CO2BnO
OO
OO
OH
O
CO2MeAcO
OAcAcHN
OAc
AcO
SO2Ph
R2
O
CO2Me
AcHN
OAc
AcO
R1
AcO
AcO
AcHNO CO2Bn
NHBoc
AcO
OAc
O
Zn(BH4)2
180 R1 R2 = H OH ( RS 11)
181 R1 R2 = O
182 R1 = H R2 = OH de gt 90
DMSO Ac2O
177178
179
13 steps
22 equiv SmI2 THF
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1413
Scheme (37)
Fig (2)
(KLH) by reductive amination for use as carbohydrate-basedvaccine GM3 a related trisaccharide containg gangliosideplays an important role in cell growth and differentiationFig 2 The synthesis of C-oligosaccharide GM3 is currentlyunderway following a similar route to that of C-GM4synthesis [42]
Beau also reported a sialyl C-disaccharide synthesiswhich relied on the unprecedented use of a stable andcrystalline 2-pyridyl sulfide of the N-acetylneuraminic acidderivative 189 as the anomeric precursor in a samarium-Reformastky procedure [43] The coupling procedure withsulfide 189 and aldehyde 190 afforded the carbon-linkeddimer 191 in 93 yield as a 11 diastereomeric mixture
Alcohols 191 were converted into thiocarbonates anddeoxygenated by employing triphenyltin hydride catalyticAIBN and pentafluorophenol which yielded C-disaccharide192 as a single compound in 65 yield for the 2 stepsDesilylation hydrogenolysis acetylation and finalacetolysis of the methyl glycoside provided the carbon-linked mimic 193 of the disaccharidic component of thesialylTn tumor antigen (Scheme 38)
4 CATIONIC METHODS
This section is categorized according to reactions thatinvolve the generation of anomeric ions followed by thecapture with sugar-based nucleophiles
OAcAcHN
OAc
AcO
O
OBnBnO
OBnOMP
HO
O
MeO2CAcO
O
MeO2CAcO
OAcAcHN
OAc
AcO
O
OHHO
OHOMP
HO
O
OBnOHC
OBnBnO
OMP
O
MeO2CAcO
OAcAcHN
OAc
AcO
O
OHHO
OHOMP
HO
O
CO2MeAcO
OAcAcHN
OAc
AcO
SO2Ph
O
MeO2CAcO
OAcAcHN
OAc
AcO
O
OAcAcO
OAcX
AcO
H2 PdC EtOAc CH3OHH2O
+
Ac2O Pyr
187 X = OMP
188 X = SPh 73
184 85 R and S mixture
186 90 for two i somers
+
SmI2 THF183
179
185
O
HO2 CHO
OAcAcHN
OH
HO
O
OHHO
OH
OAcO
(CH2 )12 CH3
HN
OH
(CH2)14CH3
O
O
O
OHHO
OH
O
O
HO2 CHO
OAcAcHN
OH
HO
O
OHHO
OH
O(CH2)12CH3
HN
OH
(CH2)1 4CH3
GM4
GM3
1414 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
41 Exo-glycals as Nucleophiles
Nitotra et al have found that treatment of exo-glycal 194with BF 3
OEt2 followed by a water quench afforded the C-disaccharide 195 (Scheme 39) It is noteworthy tonoteworthy that the attack of the enol ether on the anomericoxonium ion occurs with high stereoselectivity on the α-face only 195 was obtained [44]
42 Silyl-based Nucleophiles
Isobe has designed and developed alkynylation as a keyreaction for the introduction of a carbon chain onto sugarsThose alkynylated compounds are called ldquosugar acetylenesrdquo[45] The mechanism includes eliminative formation ofcation to which silylacetylene can coordinate on the α-face(Scheme 40)
Double C-glycosylation between glycal 198 and bis(silylacetylene) gave C-disaccharide ldquolikerdquo compounds 199and 200 (Scheme 41)
Silylpropargyl-sugar 201 smoothly reacted with D-glucalto furnish exclusively the α-acetylene glycoside product 202in 88 (Scheme 42) [46]
5 CYCLIZATION METHODOLOGY
This approach to C-oligosaccharide synthesis relies onthe coupling of an open chain fragment with an intact
monosaccharide to give an intermediate that is then cyclizedto deliver the C-oligosaccharide target This section isdivided by the type of chemistry used to initially assemblethe two pre-cyclization fragments
51 Wittig Reaction-Cyclization
The Kishi group was the first to use Wittig-cyclizationapproach to synthesize C-disaccharides Starting with Wittigreaction between 203 and 204 the intermediate 205 wasafforded as a single stereoisomer in 82 yield Osmylationthen gave a mixture of diols with the major one formed in a61 ratio Selective protection of the diols gave 206a and206b The mono-para-methoxybenzyl ether 206a was thentransformed into the hemiketal 207 in 75 overall yield inthree steps ie (1) Swern oxidation (2) acetonide hydro-lysis (4 N HClTHFrt) and (3) benzoylation (3 equiv ofPhCOClpyCH2Cl2rt) Silane reduction of 207 in an acidicmedium should preferentially yield the equatorially substi-tuted β-C-glycoside which was deblocked and converted tothe methyl- βminusC-disaccharide 209 Exact parallel experi-ments applied to the minor isomer gave the correspondingC-disaccharide 210 (Scheme 43) [47]
Armstrong has employed Wittig-osmylation protocol forthe preparation of a small library of α-C-(1rarr6)-disaccha-rides [48] Readily available allyl C-glycoside 211 washomologated to diene ester 212 and subjected to osmylation
Scheme (38)
O
CO2MeAcO
OAcAcHN
OAc
AcO
S(2-Py)
O
TESO
AcHNOMe
O
HO
O
CO2MeAcO
OAcAcHN
OAc
AcO
O NHAcOAc
OAc
OAc
O
CO2MeAcO
OAcAcHN
OAc
AcO
O NHAcOBn
OTES
OMe
OAc
AcO
O NHAcOBn
OTES
OMeOH
O
CO2 MeAcO
OAcAcHN
+
192 65
1 MeOHHCl2 H2 PdC EtOH3 Ac2O Pyr4 Ac2OAcOHH2SO4
193 59 overall yield
25 equiv SmI2 THF
1 11-thiocarbonyldiimidazole DMAP2 Ph3SnH cat AIBN
191 93
189
190
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1415
Scheme (39)
Scheme (40)
Scheme (41)
OBnO
OBn
OBn
OBnO
OBn
OBn
OBnO
OBn
OBn
OBnO
OBnCH3
BnO
OH
CH2
OBnO
OBn
CH3
OBn
H2 O
BF3 OEt2 MeCN
194
195 96
OOAc
OAc
AcO
R SiMe3
SnCl4
O
OAc
AcO
R
O
OAc
AcO
O
OAc
AcO
Me3Si
R
SiMe3
196
197
Me3 Si SiMe3
O
AcO
OAc
OAc
SiMe3
SiMe3
O
AcO
OAc
O
OAc
OAc
O
AcO
AcOO
OAc
OAc
SnCl4 CH2Cl2
SnCl4 CH2Cl2198
199
200
1416 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (42)
Scheme (43)
AcO
OAc
OAc
Me3 Si
BnO
OBn
BnO
OBn
AcO
OAc
BnO
OBn
BnO
OBn
+ I2 CH2Cl2
202 88
198 201
O
OBn
OBn
O
O
O
OBn
OBn
O
O
OBn
OBn O
OBn
OBn
O
OPBH2M
OH
OBnO
BnO
BnO
O
OBn
OBn
O
OHOPMB
OHO
HO
HO
O
OH
OHOH
OH
HOOMe
O
OBnOBn
O
Ph3P
O
O
OBn
OBn O
OBn
OBn
O
OPBM
OH
O O
CHO
OBn
BnO
OO
OBn
OBn
O
OHOPMB
BnO
BnO
BnO
OHO
HO
HO
O
OH
OHOH
OH
HOOMe
+ THF -78 oC
1 OsO4 pyr THF
2 NaH PMBBr
206a 206b 206a206b 61
1 Swern [O]2 4N HCl3 PhCOCl pyr
1 Swern [O]2 4N HCl3 PhCOCl pyr
1 PrSiH BF3 OEt2
2 H2 Pd(OH)2C
3 HCl MeOH 90 oC
1 PrSiH BF3 OEt2
2 H2 Pd(OH)2C
3 HCl MeOH 90 o C
203
204
205
207
209
208
210
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1417
followed by reduction to afford a 51 mixture (213214215216) of lactols that were readily separable by chromato-graphy Following a deprotection of an equimolar mixture of213 and 214 217 and the DL hybrid C-disaccharide of D-glucose-O-(1rarr6)-L-galactose 218 were obtained The DDand DL derivatives 219 and 220 of glucose-α-(1rarr6)-idosewere also obtained as a near equimolar mixture afterdeprotection of 215 and 216 (Scheme 44)
52 Anion Addition-Cyclization
Kishi developed an approach for the synthesis of theCndashtrehalo sugars which relied on nucleophilic addition ofone intact sugar fragment to a fundamental aldehyde ieKishi-Nozaki reaction [49] Coupling of monosaccharide221 and aldehyde 222 gave 223 The triple bond waspartially reduced and osmylation was followed by selectiveprotection to afford 224 The acetonide was converted toepoxide 225 by standard methods and removal of the PMBgroup Acid-catalyzed cyclization followed by aglyconichydrolysis and protection of hydroxyl group with (p-methoxyphenyl)diphenylmethyl chloride (MMTrCl) gave226 Inversion of the C-2 hydroxyl and removal of protectinggroups delivered α α-C-trehalose 227 (Scheme 44)
Kishi and co-workers also employed aldol reactions as anefficient access to the C-trisaccharide related to the type IIABO(H) blood group determinant [50] Aldol condensationof the enolate of methyl ketone 228 with aldehyde 229 gavea 41 mixture of hydroxy ketones 230 and 231 The majorketol was cyclized desulfurized and oxidized to afford thedisaccharide ketone 233 The ketone in THF was treatedwith LiHMDS (3 equiv) and TMEDA followed by theaddition of MgBr2 Addition of the aldehyde 234 led toalmost exclusive formation of the equatorial products 235and 236 in a 12 ratio Mesylation of 235 and 236 followedby treatment with liquid ammonia gave enones 237a and237b which were reduced to yield exclusively the C-2rsquo-equatorial ketone 238 Sodium borohydride reduction of theC-3rsquo carbonyl proceeded with the desired stereoselectivity toyield the protected C-trisaccharide 239 which wasdeblocked to provide the polyol 240 (Scheme 46)
Sutherlin and Amstrong cleverly applied a recursivestereochemical deconvolution (RSD) combinatorial approachfor the synthesis of a small library of C-trisaccharides aspotential inhibitors for the cell surface proteins of bacteriumHelicobactor pylori [51] The workers chose to carry outvariations in galactose ring of these trisaccharides An
Scheme (44)
OBnO
BnOOBn
OBn
P O
OEtOEtO
EtO
R H
OH
OH
OH
OH
O
R H
OH
OH
OH
OH
O
OHO
HOOH
OH
O
HO
OHOH
OH
OHO
HOOH
OH
O
HO
OH
OH
OHO
HOOH
OH
O
HO
OH
OHOH
R H
OH
OH
OH
OH
O
R
OBnO
BnOOBn
OBn
O
OHO
HOOH
OH
OO
HOHO
OH
R H
OH
OH
OH
OH
O
1 OsO4 NMO 50
2 DIBAL -32 oC 40
++ +
213 214 215 216
217 218 219 220
1 9-BBN H2O22 Swern [O]
3 t-BuOK
4 I2 C6H6212
211
1418 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
efficient Nozaki-Kishi coupling of vinyl bromide 241 withaldehyde 242 in a diasteromeric ratio of 12 followed byprotection with TBSOTf led to 243 and 244 Hydroborationfollowed by oxidation gave aldehydes 245 and 246respectively Addition of allylmagnesium bromide toaldehyde 245 followed by removal of the silyl groupafforded 247 to 246 giving 248 and 249 Epoxidation gave a11 mixture of the corresponding epoxides which werecyclized to give the C-trisaccharide 250-255 after removalof the benzyl groups (Scheme 47)
Schmidt reported a stereoselective 6-exo-trig selectiveelectrophilic cylization approach for de novo synthesis of amethylene-bridged Neu5Ac-α-(23)-Gal C-disaccharide theC-analog of an important motif in glycosphingolipids [52]The open chain precusors 259ab (a 32-mixture ofdiaseteromeric alcohols) were formed by the addition oflithiated iodide 256 to open chain aldehyde 258 Subsequent
C1 incorporation using Tebbe-reagent formation of a cycliccarbonate and deprotection of the two isopropylidene ketalsafforded tetrol 264 which upon treatment with phenylselenyltrifilate was steroselectively cyclized in a 6-exo-trigselective manner affording a diasteromeric mixture of 251and 252 in a ratio of 71 A seleno-Pummerer rearrangementto afford aldehyde 267 in 5 steps in 90 overall yieldOxidation of the aldehyde and subsequent steps led to thedesired C-disaccharide 268 (Scheme 48)
53 Esterification-Cyclization
Work from the Postema group has focused on a ringclosing metathesis (RCM) approach for the synthesis of C-saccharides [53a] The chemistry is versatile and has beenused for the synthesis of a small library of differentiallylinked β-C-disaccharides through a radical allylation-RCMstrategy [53b] The synthesis of the β-(1rarr4)-glucopyranosyl
Scheme (45)
O
OBn
BnO
BnO
BnO
I
CrCl2-NiCl2O
OBn
OH
BnO
BnO
BnO
O
O
O
O
O
H
OBn
O
O
OBnBnO
BnO
BnO
OOBn
OBn
OAc
PMBOHOO
OBn
BnO
BnO
BnO
O
OBn
OBn
OAc
O
OH
HO
HO
HO
OH
OH
OH
O
OH
O
OBn
BnO
BnO
BnO
OBn
OBn
OAc
O
MMTr
+
1 p-TsOH2 K2CO3 MeOH3 MMTrCl pyr
1 Swern [O]2 BH3 THF
3 AcOH-H2 O4 H2 Pd(OH)2
221
222
223
1 Pd-Pb CaCO3 H22 NaH BnBr3 OsO44 Bu2 SnO5 CsF PMB-Cl6 Ac2 O 4-DMAP
1 AcOH2 TsCl pyr
3 NaH-imid4 DDQ
224225
226 227
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1419
Scheme (46)
OBnO O
OBn
OMe
OBn
XY
SMe
OBnBnO
O
OBn
OBn
OBn
OBn
O
BnO
YX
OBn
TBSO
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnOOBn
H
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnO
OBn
OHC OBn
OBn
OTBS
OMe
BnOOBn
CHO
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnOOBn
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnO
OBn
YX
OBnO O
OBn
OMe
OBn
OBn
O
BnO
O
OBn
OBn
OBn
OBn
O 1 LiHMDS
2
228
1 TBAF THF
2 MeSH BF3 OEt2
230 X = OH Y = H231 X = H Y = OH
230231 41
1 Bu3SnH AIBN2 Swern [O]
1 LiHMDS THF-TMEDA2 MgBr23
1 MsCl
2 liquid NH3
235 X = OH Y = H236 X = H Y = OH Bu3 SnH AIBN
237a and 237b
NaBH4 MeOH
238
239 X = OBn
240 X = OHH2 Pd(OH)2
229
232233
234
1420 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (47)
OH C
O
O BnAcHN
OO
O
OBn OBnOBn
Br
O
OBn OBnOBn
O
OBnA cHN
OO
O TBSO
OBn O BnO Bn
O
OBnAcHN
OO
OTBS
S2
S1
S2
OTBSS1
O H
S2
OT BSS1
O H
MgBrMgBr
S2
O TBSS1
O H
S2
OHS1
OH
S2
OTBSS1
OH
O
OHHO
O H
O
HO
H OO
OBnA cH N
HO
H O
O
O HHO
OH
O
HOHO
O
OBnA cH N
HO
H O
O
OHH O
OH
O
H O
HOO
OBnAcHN
HO
HO
O
O HH O
OH
O
H O
H O O
OBnA cHN
HO
HO
O
O HH O
O H
O
HO
H O O
OBnAcHN
HO
HO
O
OHHO
OH
O
H O
O
OBnA cHN
HO
HOHO
+
241 242
1 CrCl2-NiCl2 T HF-DMF 722 TBSOTf 2 6-lutidine 91
243 244
1 9-BBN 602 Dess-Mart in period inane 97
1 9 -BBN 552 D ess-Martin periodinane 98
245 246
1
2 T BAF 74
1
2 TBAF 88
247 248 249
250
251
250 251 1 1 252 253 1 1 254 255 1 1
252
253
254
255
1 MCPBA2 CSA CH 2Cl2 61 fo r 2 steps3 H 2 Pd (O H)2C 95
1 MCPBA2 CSA CH 2Cl2 63 fo r 2 s teps3 H 2 Pd (OH)2C 87
1 MCPBA2 CSA CH2Cl2 80 for 2 steps3 H2 Pd(O H)2C 95
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1421
Scheme (48)
O
OO
Se Ph
R
O
HO OHOH
O
OB n O B n
OB n
O B nO O
O O
R O OR
X
O
OO
R
Se Ph
O
HOOH
OH
O
OB nOB n
O Bn
OB n
O O
O O
R O O R
O H
O
O B n OB n
O B n
OB n
O
C HO
O
O O
R O OR
OAc HN
OAc
C O2NH 4HOOH
OH
O
OH O H
OH OH
O
OB n O B n
OB n
OB nO O
O O
R O OR
X
O
O
OAcOAc
C HOA cOOAc
OAc
O
OB n O B n
OB n
OB n
O
O Bn OB n
OB n
OB n
X
OH
OO
HOOH
OH
O
O
OMeOB n
OB nOB n
R
t-B uL i256 R = Li
257 R = L i
258
(R = t-B uMe 2Si )
(R = t-B uMe 2Si )
259ab (32) 79 com bine d yi eld
De ss-Ma rtin pe riodinane
260 X = O R = t-B uMe 2Si ) 95
261 X = O R = t -B uMe2S i) 62
T e bbe re age nt
TB A F THF262 X = O R = H 94
diphosge ne
C H2C l 2Pyr
263 95
T HFH2O T FAr t
264 quant it a ti ve yie ld
PhSe C l AgOT f
EtC N -80 oC
265
266
Quant it at i ve yi l ed 25 26 7 1
+
R =
1 Ac 2OPyr
2 mC PB A3 Ac 2ONa OAc
4 NaO HT HFMe OH
5 Ac2O P yr
267 90 overa ll yi e ld
ste ps
268
1422 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
glucopyranoside 280 represents an example of thischemistry The known triacetyl glucopyranoside 269 wasconverted to iodide 270 in good yield Radical allylation of271 proceeded to afford a mixture of equatorial and axialallylation products in a 61 ratio Oxidative cleavage of thedouble bond gave the corresponding aldehydes 273a and273b which were separable Pinnick oxidation of the majoraldehyde 273a then gave the C-4 equatorial acid 274 DCC-mediated coupling of alcohol 275 and acid 274 proceeded toafford ester 276 in good yield Methylenation of 276 gave277 and exposure to catalysist 278 gave a 41 yield of theC-disaccharide glycal which was exposed to an excess ofBH3
THF to give 64 yield of the β-C-disaccharide 279Removal of the benzyl groups and global peracetylation gavethe peracetylated (1rarr4)-β-C-disaccharide 281 in good yield(Scheme 49)
54 Ring Expansion-Cyclization
Nelson developed a new strategy for asymmetric andstereoselective synthesis of C-linked disaccharide mimeticsthe C58-C71 fragment of palytoxin [54] The diol (RR)-282was converted into the di-dihydropyran (DHP) template 283284 and 285 The di-DHPs were functionized in a twodirectional sense using dihydroxylation reactions The two-directional approach was often very efficient indeed forexample in the synthesis of 286 six new stereogenic centerswere introduced with almost complete stereocontrol using areduction and a dihydroxylation reaction The approach isnot restricted to the synthesis of C2-symmetricaldisaccharide mimetics Using the unsymmetrical template285 which has both a pseudo-axial and a pseudo-equatorialhydroxyl groups the unsymmetrical mimetics 289 and 290were prepared (Scheme 50)
6 RADICAL APPROACHES
The radical approach for C-C bond formation is a popularmethod within organic chemistry The use of radicalchemistry in carbohydrate synthesis has certain advantagesFirstly the reaction conditions are very mild and tolerant ofa range of functional and protecting groups Secondanomeric radicals are stable with respect to elimination andepimeration Most significantly the chemistry required toincorporate an appropriate substitute at C-1 employed in theinitial hemolytic cleavage step is common within carbo-hydrate chemistry [55] The use of such radical techniquecan be subdivided into two classes intermolecular andintramolecular approaches
61 Intermolecular Radical Approaches
Giese was the first to employ an intermolecular radical-based approach for synthesis of C-disaccharides [56]Addition of an alkene to an anomeric radical underappropriate conditions allowed exclusive entry to the α-linked C-glycoside a result which was mirrored by the workof Baldwin [57] The high α-selectivity of the reaction wasin contrast with other reports Thus radicals generated at theC-2 C-3 and C-4 centers all preferred to occupy equatorialpositions [58] When the anomeric bromide 291 was treatedwith tin hydride and AIBN resulting anomeric radical andreacted with lactone 292 in a Michael addition it afforded293 In this reaction hydrogen abstraction at the resulting
radical center occurs from axial face to selectively generatethe equatorial C-2rsquo substituent Reduction and acetylation of293 furnished C-disaccharide 294 (Scheme 51) [59]
Witczak used the facial bias of levoglucosene tostereoselectively add a carbohydrate-based radical in thepreparation of the 3-deoxy-(1rarr4)-β-C-disaccharide 299[60] Addition of the radical derived from iodide 295 to 296gave adduct 297 in 26 yield Removal of the anomerichydroxyl of 297 was achieved by treatment with triethylsilane borontrifluoride ether complex followed bystereoselective reduction of the keto function at C-2rsquo withthe formation of 298 in 89 yield Debenzylation followedby acetolysis of 16-anhydro ring produced the peracetylatedtarget C-disaccharide 299 in 19 overall yield from 295(Scheme 52)
Vogel has developed general methods to transformenantiomerically pure 7-oxabicyclo[221]heptyl derivatives(ldquonaked sugarsrdquo) into C-disaccharides Because of thesechiral bicyclic skeletons they undergo highly stereoselectivereactions with predictable diasteroselectivities An arsenal ofmethods is available that allow to substitute these ldquonakedrdquocarbon centers with a variety of functional groups with allpossible relative configurations The methods allowpreparation of both enantiomers of a given target with thesame ease Predictably high stereoselectivity of the reactionsof the bicyclic chirons adds to the flexibility of approachwhich can lead to high molecular diversity [61]
α-C-(1rarr3)-mannopyranoside of N-acetyl-galactosaminepotent β-galactosidase inhibitors was synthesized by thisapproach [61] Enone 302 was readily prepared from 300The addition of the radical derived from bromide 303 toenone 302 afforded the αminusisomer 304 The ketone was thenreduced and the selenide eliminated via the intermediacy ofthe selenoxide to give 305 Acid-promoted (CF3SO3H) 7-oxa ring opening of 305 in MeCN produced the amino-conduritol derivative 306 resulting from the quenching of theallylic cation intermediate by the solvent (Ritter reaction)Ozonolysis of the chloroalkene 306 generated an acylchloride-aldehyde intermediate that reacted with MeOH toproduce a mixture of methyl uronates The major compound307 was silylated and reduced The crude polyol obtainedwas acetylated to produce 308 Desilylated and ammonolysisafforded a mixture of α-β-pyranoses 309 and correspondingα-β-furanoses (Scheme 53)
Similar chemistry was carried out to synthesize non-protected α-C(1rarr2)-L-fucopyranoside of D-galactopyrano-side corresponding to a blood group mimetic [62] Giesersquosradical fucosidation of racemic enone 310 with α-L-bromoacetofucose 311 provided the mixture of diastereo-meric α-C-fucoside 312a and 312b in reproducible yield of78 Reduction of the mixture gave a 11 mixture of endo-alcohols 313 and 314 which were isolated pure in 40 and355 yield respectively Oxidative elimination of thebenzeneselenyl group of 313 followed by acetylation gaveendo acetate 315 in 85 yield Acid-promoted ring openingof 315 and ozonolysis of the resulted chloroalkene gavemethyl uronic ester 316 in modest yield (10) Treatment of316 with Cl3CCN and NaH followed with BF3
OEt2
furnished the totally protected C-disaccharide 317 in 79
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1423
Scheme (49)
Bu3SnO
HOAcO
OMeOAc
OAc
O
AcO
OMeOAc
OAcI
AIBN
O
AcO
OMeOBn
OBn
HO2C O
AcO
OMeOR
ORY
X
OHBnO
BnO
OBn
OBnO
BnO
OBn
O
AcO
OMeOBn
OBnX
i-Pr i-Pr
N
Mo C(Me2 Ph)((CF3)2 MeCO)2
O
RO
OMeOR
O
RO
OR
OR
RO
OR
278
I2 Ph3P
imidazole
269 270 93
271a X = CH2CH=CH2 Y = H R = Ac 64271b Y = CH2CH=CH2 X = H R = Ac 11272a X = CH2CH=CH2 Y = H R = Bn 75272b Y = CH2CH=CH2 X = H R = Bn 75273a X = CH2CHO Y = H R = Bn 79273a Y = CH2CHO X = H R = Bn 79
1 NaOMe MeOH2 NaOH BnBr DMF
OsO4 NaIO4
NaClO2 NaH2PO4
274 96
275
DCC 4-DMAP
276 X = O 82
277 X = CH2 51
TiCl4 Zn dust TMEDA CH2Br2PbCl2 (Cat )
1
2 BH3 THF H2O2 NaOH
H2 PdC EtOH
Ac2 O Pyr 4-DMAP
279 R = Bn R = H 64
280 R = R = H 99
281 R = R =Ac 97
1424 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (50)
Scheme (51)
O OOH
OH
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
286
1 VO(acac)2 t-BuOH 95
2 (MeO)3CH BF3 90
1 P-O2NC6H4 CO2H Ph3P DIAD2 K2CO3 MeOH 82 over 2 steps
1 PhCOCl Et3N DMAP 402 P-O2NC6H4 CO2H Ph3P DIAD3 KOH THF-H2O 75 over 2 steps
TMEDA OsO4
Cat OsO4 NMO 287
Cat OsO4 NMO288
TMEDA OsO4
Cat OsO4 NMO
290
289
(RR)-282283
284
285
OHO
AcO
BrOAc
OAc
BnO
O
OBn
OBnO
OHO
AcOOAc
OAc
BnO
OOBn
OBnAcO
OHO
AcOOAc
OAc
BnO
O
OBn
OBnO
+
Bu3SnH AIBN291
292
293 81
1 Na[Al(OC2H4OMe)2(OEt)H]2 Ac2O pyr
294 56 over 2 steps
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1425
Scheme (52)
Scheme (53)
OBnO
BnOOBn
OBn O
OH
O
OBnO
BnO
OHOBn
OBn O
O
O
O
O
O
OBnO
BnOOBn
OBnO
OAcOAc
OAc
OBnO
BnO
OHOBn
OBn
IBu3SnH AIBN
295 297 26
1 BF3 OEt2 Et3SiH
2 L-Selectride THF
1 Pd(OH)2C C6H10 EtOH
2 EtSiOSO2CF3 Ac2O
298 89 over 2 steps299
296
O
O
PhSeClO
O
PhSeCl
Bu3 SnH
O
O
PhSeCl
R
H
O
OAc
R
Cl
O
AcO
OAc
OAc
OAcOH
Cl
NHAc
R
OAc
AcHN
OH
O
OH OAc
OH
OHO
HO
OH
O
AcO
OAc
OAc
OAcBr
O
O
PhSeCl
O
O
PhSeCl
R
O
OTIPSAcHNR
OAc OAc
O
OHAcHN
COOMe
R
OAc
1 Bu4NF
2 NH3MeOH
1 (Me3Si)2NLi THF2 Me2N=CHI
1 Bu3 SnH AIBN2
1 NaBH42 mCPBA3 Ac2O pyr
1 H+ MeCN
2 H2 O NaHCO3
R =
1 O3MeOH
2 Me2S NaHCO3
1 TIPSOTf 26-lut idine2 LiBH43 Ac2 O pyr DMAP
furanoses +
304 56
305 68 306 84307 50
308 46
300 301 302
303
309
1426 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
The reduction of 317 and treatment with DOWEX-H+ resinprovided the desired C-fucoside 318 in 70 (Scheme 54)
62 Intramolecular Radical Approaches
One disadvantage with the intermolecular approaches isthat during such radical mediated reactions electrondeficient alkenes are required to facilitate C-C bondformation The intramolecular approach of Sinayuml overcomes
this drawback by bring two substrates together via atemporary covalent silaketal connector This enables the useof a wider range of alkenes which can include alkene-functionalized sugars thus leading to the generation of C-disaccharides [63] Based on the early work of Stork Sinayumlemployed the tether reaction in the synthesis of both α- andβ-C-disaccharides with this work subsequently beingemployed in the synthesis of biologically significant natural
Scheme (54)
O
OH
Fuc
Cl
O
O
ClPhSe
OOAc
NHAcOHFuc
O
AcOOAc
AcO
Br
O
O
PhSeCl
O
AcOOAc
AcO
O
OH
PhSe Cl
Fuc
OOAc
NHAc
OMe
Fuc
O
AcHN
OH OAc
OH
O
OH
Me
OH
O
O
Fuc
ClSePh
O
HO
Fuc
ClSePh
+
Ph3SnHAIBN
78 combined yield
Fuc
310
+
1 NaBH4 MeOHTHF2 Chromatography
313 40 314 355
1 mCPBA
2 Ac2O pyr DMAP
+
315 75
1 TfOH MeCN
2 NaHCO3 O3 -78 oC
316 10 over 2 steps
1 Cl3 CCN NaH
2 MeOH BF3 OEt2
317 79
1 LiBH4 THF
2 Dowex-H+
311
312a312b
318 70 for 2 steps
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1427
products [64] The availability of different hydroxyl groupson each monosaccharide unit allowed the fine-tuning ofstereochemical outcome by selective positioning of the silyltether [65] Development of this early stereochemical controlled to the tethering of the donor 320 with alcohol 319through a di-isopropyl silicon tether 321 Subsequent treat-ment with Bu3SnH and AIBN led to a 9-endo-trigcyclization to form the C-disaccharide 322 in an 80 yieldwith exclusive formation of the α-product The silyl tetherwas removed with Bu4NF and deprotection under standardconditions afforded the desired disaccharide 323 in excellentyield (Scheme 55)
In parallel the development of a 32rsquo silyl tether allowedaccess to the β-linked product as demonstrated in Sinayumlrsquossynthesis of methyl β-C-lactoside 328 [66] Alcohol 324 and320 were connected via the dimethylsilyl tether an 8-endo-trig cyclization followed to exclusively afford the β-
disaccharide 326 in 45 yield Removal of the tether anddeprotection of benzyl ether gave β-C-disaccharide 328(Scheme 56)
This group also selected iodosugars bearing a freehydroxyl group as progenitors of the radical donors [67] In atypical experiment the radical donor 329 was connected tothe radical acceptor 330 through a silaketal tether followingtheir procedure Tributyltinhydride mediated 8-endo-trigradical cyclization of compound 331 gave after detetheringof the non isolated intermediate 332 the protected β-C-disaccharide 333 in 37 overall yield (from startingmaterials 330 and 329) Peracetate 335 was achieved afterhydrogenolysis The C-laminaribioside 334 is of potentialbiological interest as it mimics the repeating disaccharideunit of fungal β-(1rarr3)-glucans which have antitumor andimmunomodulating properties (Scheme 57)
Scheme (55)
Scheme (56)
OO
OHSePh
OTBDPSO O
OO
SePh
OTBDPSO
OO
OBnOMe
OBn
Si
O
HOOBn
OMe
OBn
O
HOOH
OHHO
O
HOOH
OMe
OH
OTBDPSO
O
HOOBn
OMe
OBnO
OOH
1 n-BuLi THF
2 iPr2SiCl2 -78 oC
3 DMAP THF rt
1 Bu4NF THF
2 Dowex-H+
3 H2 PdC
Bu3SnH AIBN toluene
319
320
321
322323
OBnO
OHSePh
OBnBnO
OHO
OBnOMe
OBn
ROO
ROOH
OR
OHO
OROMe
OR
OBnO
O
OBnBnO
OO
OBnOMe
OBn
Si
SePh
OBnO
O
OBnBnOO
OOBn
OMe
OBn
Si
1 PhSeH Me2SiCl2
BuLi -78 oC
2 imidazole rt
Bu3SnH AIBN toluene
H2 PdC327 R = Bn
328 R = H
Bu4NF THF
324
320
325
326 45
1428 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
CONCLUSIONS
In this paper the biological importance of C-oligo-saccharides as subunits of natural products and as a newgeneration of carbohydrate based on therapeutics has beenillustrated Different methods are available for the synthesisof C-oligosaccharides As with traditional saccharidesynthesis it has been necessary to develop a number ofspecific approaches to facilitate the regioselective andstereoselective preparation of the desired targets Work inthis area continues and it is expected that many interestingnew C-oligosaccharides will be prepared using the chemistrydescribed in this review It is also likely that new chemistrywill be developed in the future for the preparation of thesebiologically important targets
ACKNOWLEDGEMENTS
The authors thank Dr Sultan Baytas for her criticalreading of this manuscript
REFERENCES
[1] Kennedy J F White C A Bioactive Carbohydrates InChemistry Biochemistry and Biology Ellis Horwood LtdChichesterUK 1983
[2] Wassarman PW Mammalian Fertilization Molecular Aspects ofGamete Adhesion xocytosion Exocytosis and Fusion Cell 199996 175-183
[3] Carbohydrate-based Drug Discovery Wong C-H EdWeinheim Cambridge Wiley-VCH 2003
[4] (a) Sharon N Lis H Lectins as Cell Recognition MoleculesScience 1987 246 227-234 (b) Dwek RA Chem Rev 1996 96683-720
[5] Postema M C-Glycoside synthesis CRC Boc Ratom 1995[6] (a) Weatherman R V Mortell K H Cheruenak MKiessling
L L Toone E J Specificity of C-Glycoside Complexation byMannoseGlucose Specific Lectins Biochem 1996 35 3619-3624(b) Ravishankar R Surolia A Vijayan M Lim S Kishi YPreferred Conformation of C-Lactose at the Free and Peanut LectinBound States J Am Chem Soc1998 120 11297-11303
[7] (a)Wong C-H Halcomb R L Ichikawa Y and Kajimoto TEnzymes in organic synthesis Application to the problems ofcarbohydrate recognition part2 Angew Chem Int Ed Engl 199534 521-546 (b)Howard S Withers SG Bromoketone C-Glycosides a New Class of βminusGlucanase Inactivators J AmChem Soc 1998 120 10326-10331(c) Wang Q Wolff MPolat T Du Y Linhardt R J C-glycoside of Neuraminic Acidsas Neura-minidase Inhibitors Bioorg Med Lett 2000 10 941-944 (d) Phili R Chang J Partis R A Mueller R A ChrestF J Passaniti A The Alpha-glucosidase I InhibitorCastanospermine Alters Endothelial cell Glycosylation PreventsAngiogenesis and Inhibits Tumor Growth Cancer Res 1995 552927-2935
[8] Ossor A Elbein A D In Carbohydrates in Chemistry andBiology Vol 3(II) WileyVCH 2000 pp 513-539
[9] (a) Sinayuml P Synthesis of oligosaccharide Mimetics Pure ApplChem 1997 69 459-463 (b) Beau J-M Gallagher TNucleophilic C-glycosyl Donors for C-glycoside Synthesis Top inCurr Chem 1997 187 1-54 (c) Nicotra F Synthesis of C-glycosides of Biological Interest Top in Curr Chem 1997 187
Scheme (57)
O
O
O
Ph
I
OMe
OHO
BnO
OH
OH
BnOOH
O
BnO
Si
O
O O
Ph
I
OMe
O
O
BnO
OR4O
R5O
OMe
OR2
OR3O
R3O
OR1
R3O
Bu3 SnH AIBN
332 R1 R2 = SiMe2 R3 = Bn R4 R5 = CHPhTBAF THF
333 R1 = R2 = H R3 = Bn R4 = R5 = CHPh 37 from 11
334 R1 = R2 = R3 = R4 = R5 = H
335 R1 = R2 = R3 = R4 = R5 = Ac
329
H2 PdC MeOH
Ac2 O pyr
1 BuLi THF -78 oC
2 Me2SiCl2
3 DMAP
330
331
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1429
55-83 (d) Du Y Linhardt R Y Recent Adv in Stereo-SelectiveC-Glycoside Synthesis Tetrahedron Lett 1998 54 9913-9959 (e)Liu L Mckee M and Postema M H D Synthesis of C-saccharides and Higher Congeners Current Org Chem 2001 51133-1167
[10] Jarosz S Fraser-Reid B Synthesis of A Higher Carbon Sugar ViaDirected Aldol Condensation Tetrahedron Lett 1989 30 2359-2362
[11] Lichtenthaler F W Lergenmiiller M Schwidetzky S C-Glycosidations of 2-Ketohexosyl With Electrophilic Radical andNudeophilic Anomeric Carbons Eur J Org Chem 2003 3094-3103
[12] Baudat A Vogel P Aza-C-disaccharides Synthesis of 6-Deoxygalactonojirimycin-β-C(1rarr3) Linked with D-Altrofuranosides and D-Galactose J Org Chem 1997 62 6252-6260
[13] Turner D Vogel P Synthesis of 4-Hydroxy-26-Bis(hydroxymethyl) tetrahydropyran-2-Carbaldehyde DerivativesSynlett 1998 304-306
[14] Zhu Y-H Vogel P Short Stereoselective Synthesis of C-(1rarr3)-Linked Disaccharides Tetrahedron Lett 1998 39 31-34
[15] Zhu Y-H Vogel P Synthesis of a (2R 6R)-2-(Hydroxymethyl)-6-Propa-1 2-Dienyl-2H-Pyran-3(6H)-One Derivative A NewEnone for The Convergent Construction of C-Glycosides of C-Disaccharides Synlett 2001 82-86
[16] Baumberger F Vasella A Deoxynitrosugars The 6th
Communication Stereolectronic Control in the reductivedenitration of tertiary nitro ethers A Synthesis of ldquoC-glycosidesrdquoHelv Chim Acta 1983 66 2210-2221
[17] Martin O R Lai W Synthesis and Conformational Studies of β-(1rarr6)- and ββ-(1rarr1)-Linked C-disaccharides J Org Chem1993 58 176-185
[18] Spak S J Martin R The synthesis of an analogue of Methyl OC-Analogue of Methyl 4rsquo-O-β-D-GlucopyranosylgentiobiosideTetrahedron 2000 56 217-224
[19] Kobertz W R Bertozzi C R Bednarski M D C-GlycosylAldehyde Synthons for C-Linked Disaccharides J Org Chem1996 61 1894-1897
[20] Gurjar M K Nagaprasad R and Ramana CV First Synthesis ofMethyl α-C-D-Arabino-furanosyl-(1rarr5)-αminusD-Arabinofuranosidethe C-Disaccharide Segment of Motif C of MycobateriumTuberculosis Tetrahedron Lett 2000 43 7577-7579
[21] Witczak Z J Synthesis of C-Glycosyl Compounds and OtherNatural Products from Levoglucosenone Pure Appl Chem 199466 2189-2192
[22] Griffin F K Paterson D Taylor R J K Ramberg-BacklundApproaches to the Synthesis of C-Linked Disaccharides AngewChem Int Engl 1999 38 2939-2942
[23] Paterson B E Griffin F K Alcaraz M-L and Taylor R J KA Ramberg-Baumlcklund Approach to the Synthesis of C-GlycosidesC-Linked Disaccharides and C-Glycosyl Amino Acids Eur JOrg Chem 2002 1323-1336
[24] McAllister G D Paterson D E Taylor R J K A SimplifiedRamberg-Bachlund Approach to Novel C-Glycosides and C-Linked Disaccharides Angew Chem Int Ed Engl 2003 42 1387-1391
[25] McCartney J L Christopher T M Cicchillo R M BernardinaM D Wagner T R and Norris P J Org Chem 2003 6810152-10155
[26] Dondoni A Zuurmond H M Bascarate A Synthesis of α-andβ-D-(1rarr6)-C-Disaccharides by Witting Olefination of Formyl C-Glycosides with Glycopyranose 6-phosphoranes J Org Chem1997 62 8114-8124
[27] Dondoni A Kleban M Zuurmond H Marra A Synthesis of(1rarr6)-C-Oligogalactosides by Interative Wittig OlefinationTetrahedron Lett 1998 39 7991-7994
[28] Dondoni A Marra A A New Synthetic Approach toMycobacterial Cell Wall α-(1rarr5)-D-Arabinofuranosyl C-Oligosaccharides Teterahedron Lett 2003 44 4067-4071
[29] Colinas P A Ponzinibbio A Lieberknecht A and Bravo R OWittig Reaction of Glycosyl Phosphonium Salts A StereoselectiveRoute to C-Disaccharides and C O-Trisaccharides TetrahedronLett 2003 44 7985-7988
[30] Schmidt R R Preuss R Synthesis of Carbon Tetrahedron Lett1989 30 3409-3412
[31] Dietrich H Schmidt R R Synthesis of Carbon-Bridged C-Lactose and Derivatives Liebigs Ann Chem 1994 975-981
[32] Rouzaud D Sinayuml P The First Synthesis of a ldquoC-DisacchariderdquoJ Chem Soc Chem Commun 1983 1353-1354
[33] Xin Y-C Zhang Y-M Mallet J-M Glaudemans C P JSinayuml P Synthesis of C-Oligosaccharides That Mimie TheirNatural O-Analogues Immunodeterminants in Binding toMonoclonal Immunoglobulins Eur J Org Chem 1999 471-476
[34] Streicher H Geyer A Schmidt R R C-Disaccharides ofKetoses Chem Eur J 1996 2 502-510
[35] Leeuwenburgh M A Timmers C M Vander Marel G A VanBoom J H Mallet J-M Sinayuml P G Stereoselective Synthesisof α-C-(Alkynyl)-Glycosides Via Ring-Opening of α-12-Anhydrous Tetrahedron Lett 1997 38 6251-6254
[36] Aslam T Fuchs M G G Le Formal A Wightman R HSynthesis of C-Disaccharide Analogue of the α-D-Arabinofuranosyl-(1rarr5)-α-Arabinofuranosyl Motif ofMycobacterial Cells Walls via Alkynyl Intermediates TetrahedronLett 2005 46 3249-3252
[37] (a) Girad P Namy J L Kagan H B Divalent LanthanideDerivative in Organic Synthesis 1 Mild Preparation of SamariumIodide and Ytterbium Iodide and Their Use as Reducing orCoupling Agents J Am Chem Soc 1980 102 2693-2698 (b)Molander G A Harris C R Sequencing Reactions withSamarium(II) Iodide Chem Rev 1996 96 307-338
[38] (a) Mazeacuteas D Skrydstrup T Doumeix O Beau J-MSamarium Iodide-Induced Intramolecular C-Glycoside FormationEfficient Radical Formation in the Absence of an Additive AngewChem Int Ed Engl 1994 33 1383-1386 (b) Mazeacuteas DSkrydstrup T Beau J-M A Highly Stereoselective Synthesis of1 2-trans-C-Glycosides Via Glycosyl Samarium(III) CompoundsAngew Chem Int Ed Engl 1995 34 909-912 (c) Jarreton OSkrydstrup T Beau J-M The Stereospecific Synthesis of Methylα-C-Mannobioside A Potential Inhibitor of M TuberculosisBinding to Human Macrophages J Chem Soc Chem Commun1996 1661-1662 (d) Jarreton O Skrydstrup T Espionosa J-FJimeacutenez-Barbero J Beau J-M Samarium Diiode Prompted C-Glycosylation An Application to The Stereospecific Synthesis ofα-(1rarr2)-C-Mannobioside and Its Derivatives Chem Eur J 19995 430-441 (e) Mipuel N Doisneau G Beau J-M ReductiveSamariation of Anomeric 2-Pyridyl Sulfones with Catalytic AnUnexpected Improvement in The Synthesis of 12-Trans-Diequatorial C-Glycosyl Compounds Angew Chem Int Ed Engl 2000 39 4111-4114
[39] Vlahov I R Vlahova P I Linhardt R J DiastereocontrolledSynthesis of Carbon Glycosides of N-Acetylneuraminic Acid ViaGlycosyl Samarium(III) Intermediates JAmChem Soc 1997 1191480-1481
[40] Kuberan B Sikkander S ATomiyama H Linhardt R JSynthesis of a C-Glycoside Analogue of sTn An HIV-and Tumor-Associated Antigen Angew Chem Int Ed Engl 2003 42 2073-2075
[41] Bazin H G Du Y Polat T Linhardt R J Synthesis of aVersatile Neuraminic Acid ldquoCrdquo-Disaccharide Precursor for theSynthesis of C-Glycoside Analogues of Gangliosides J OrgChem 1999 64 7254-7259
[42] Chen C-C Ress D K Linhardt RJ Samarium Iodide-Mediated Synthesis of Neuraminic Acid C-Glycosides InSynthesis of Glycommetics Roy R Ed ACS Syposium Series2004 896 53-80
[43] Abdallah Z Doisneau G Beau J-M Synthesis of a Carbon-Linked Mimic of The Disaccharide Component of The Tumor-Relate SialyTn Antigen Angew Chem Int Ed Engl 2003 425209-5212
[44] Lay L Nicotra F Panza L Russo G Caneva E Synthesis ofC-disaccharides through dimerization of exo-glycals J Org Chem1992 57 1304-1306
[45] Isobe M Nishizawa R Hosokawa S Nishikawa TStereocontrolled Synthesis and Reactivity of Sugar Acetylenes JChem Soc Chem Commun 1998 2665-2676
[46] Saeeng R Sirion U Sahakitpichan P Isobe M IodineCatalyzes C-Glycosidation of D-Glucal with SilylacetykeneTetrahedron Lett 2003 44 6211-6215
[47] (a) Babirad S A Wang Y Kishi Y Synthesis of C-Disaccharides J Org Chem 1987 52 1370-1372 (b) Wang YBabirad S A Kishi Y Preferred Conformation of C-Glycosides
1430 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
8 Synthesis of 14-Linked Carbon Disaccharides J Org Chem1992 57 468-481
[48] Armstrong R W Sutherlin D P Strategies for the Synthesis ofC-Disaccharides Containing D and L Sugars Tetrahedron Lett1994 35 7743-7746
[49] Wei A Kishi Y Preferred Conformation of C-Glycosides 12Synthesis and Conformational Analysis of αα- α β- and β β-Trehaloses J Org Chem 1994 59 88-96
[50] Haneda T Goekjian P G Kim S H Kishi Y PreferredConformation of C-Glycosides 10 Synthesis and ConformationAnalysis of Carbon Trisaccharides J Org Chem 1992 57 490-498
[51] Sutherlin D P Armstrong R W Synthesis of 12 Stereochemistryand Structurally Diverse C-Trisaccharides J Org Chem 1997 625267-5283
[52] Notz W Hartel C Waldscheck B Schmidt R R De NovoSynthesis of a Methylene-Bridged Neu5Ac-α-(23)-Gal C-Disaccharide J Org Chem 2001 66 4250-4260
[53] (a) Postema M H D Calimente D Liu L Behrmanm T L AnOlefin Metathesis Route for the Preparation of (1rarr6)-Linked-C-Disaccharide Glycals A Convergent and Flexible Approach to C-Saccharide Synthesis J Org Chem 2000 65 6061-6068(b) Postema M H Piper J L Liu L Faust M Andreana PSynthesis and Partial Biological Evaluation of a Small Library ofDifferentially Linked β-C-Disaccharide J Org Chem 2003 684748-4754
[54] Nelson A The Development of Strategies and Methods for TheSynthesis of Biologically Active Compounds New J Chem 200428 771-776
[55] Togo H He W Waki Y Yokoyama M C-GlycosylationTechnology With Free Radiant Reactions Synlett 1998 700-717
[56] Giese B Dupuis J Diastereoselective Synthesis of C-Glycopyranosides Angew Chem Int Ed Engl 1983 22 622-623
[57] Adlington R M Baldwin J E Basak A Kozyrod RPApplication of Radical Addition Reactions to tho Synthesis of a C-Glucoside and A Functionalized Amino Acid J Chem SocChem Commun 1983 144-145
[58] Giese B Gonzaacutelez-Goacutemez J A Witzel T The Scope of RadicalCC-Coupling by The ldquoTin Methodrdquo Angew Chem Int Ed Engl1984 23 69-70
[59] Giese B Witzel T Synthesis of ldquoC-Disaccharidesrdquo by RadicalC-C Bond Formation Angew Chem Int Ed Engl 1986 25 450-451
[60] Witczak Z J Chhabra R Chojnacki J C-Disaccharides IStereoselective Approach to β-(1rarr4)-3-Deoxy-C-Disaccharidesfrom Levoglucosenone Carb Res 1997 301 167-175
[61] Vogel P Synthesis of Rare Carbohydrates and Analogues Startingfrom Enantiomerically Pure 7-Oxabicyclo[221]heptyl Derivatives(ldquoNaked Sugarsrdquo) Current Org Chem 2000 4 455-480
[62] Viodeacute C Vogel P Synthesis of The C-Disaccharide α-C(1rarr3)-L-Fucopyranoside of N-Acetylgalactosamine J Carb Chem2001 20 733-746
[63] Xin Y C Mallet J M Sinayuml P An Expeditious Synthesis of AC-Disaccharide Using A Temporary Silaketal Connection J ChemSoc Chem Commun 1993 864-865
[64] (a) Petitou M Herault P Lormeau J-C Helmboldt A MalletJ-M Sinayuml P Herbert J-M Introducing A C-InterglycosidicBond in A Biologically Active Pentasaccharide Hardly Affects ItsBiological Properties Bioorg Med Chem 1998 6 1509-1516 (b)Sinayuml P Advances in The Synthesis of the Carbohydrate MimicsPure Appl Chem 1998 70 1495-1499
[65] Sinayuml P Chemical Synthesis of Oligosaccharide Mimetics PureAppl Chem 1998 70 407-410
[66] Sinayuml P Chemical Synthesis of Oligosaccharide Mimetics PureAppl Chem 1998 69 459-463
[67] Vauzeilles B Sinayuml P Selective Radical Synthesis of β-C-Disaccharides Tetrahedron Lett 2001 42 7269-7272
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1409
pyrannoside 173 in good yield and with excellent stereo-selectivity (Scheme 34) [38a]
Preparation of C-glycosides of ulosonic acids using SmI2
was pioneered by Linhardt and coworkers [39] Coupling ofpyridyl sulfone 174 with aldehyde 175 in the presence ofSmI2 gave an excellent yield of the N-acetylneuraminic acidC-disaccharide 176 as single isomer This stereochemicaloutcome was rationalized on the basis of the Felkin-Anhmodel for predicting the stereochemical outcome of akinetically controlled addition of a nucleophile to a chiraladehyde (Scheme 35 A)
Reductive samarium method was utilized to synthesizesialo-antigen C-analogs by the Linhardt group A fullyprotected C-analogue of the SialylTn antigen α-D-Neu5Ac-(2rarr6)α-D-GalNAc-(1rarrO)-Ser 182 was prepared [40] C-glycosylation of the neuraminic acid sulfone donor with
aldehyde acceptor in presence of excess SmI2 afforded the α-C-glycoside 180 as an RS mixture (11) The criticalintermediate aldehyde acceptor 178 was prepared in 13steps Chemoselective resolution to compound 180 wasundertaken by oxidation with DMSOAc2O to keto-bridgedcompound 181 followed by stereoselective reduction withZn(BH4)2 to regenerate the bridge hydroxyl function gave182 in gt90 de (Scheme 36)
A common versatile N-acetylneuraminic acid C-disaccharide precursor of the C-glycoside analogs ofgangliosides GM4 and GM3 has been synthesized [41]Samarium(II) iodide coupling of N-acetylneuraminic acidsulfone 179 with a 3-formyl galactopyranoside derivative183 afforded the corresponding C-disaccharide 184 as amixture of (R) and (S) isomers at the newly formedhydroxymethylene bridge This diastereoisomeric mixturewas resolved after debenzylation of the galactoside residue
Scheme (29)
O
BnO
BnOOBn
OBn
OOBn
OBnOMe
OBnOH
O
BnO
BnO
OBn
OBn
O
O
BnOOBn
OMe
BnO
Li
OBnO
OBn
OBn
OBnO
OBn
OBn
OMe
OBnO
OBn
OBnBnO
OBnO
OBn
OBn
OBnO
OBn
OBn
OMe
OBnO
OBn
OBnOBnO
OBn
OBnBnO
O
BnO
BnO
OBn
O
OBnO
OBn
OBnBnO
OBnO
OBn
OBnBnO
OBnO
OBn
OBn
OMe
OBnO
OBn
OBnBnO
OMe
1 PCC2 CBr4 Ph3P3 n-BuLi
144 overall yield 54
1 BF3 OEt2 Et3 OH
2 H2 PtO2 EtOAc
145 76
1 H2 SO4 AcOH
2 PCC
146 62
repeat steps
repeat st eps
141 142
143
147
148
1410 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (30)
Scheme (31)
O
BnOOBn
OMe
Li
BnO
OPivBnO
OBn
OBn
BnO
O OO
BF3 OEt2
OBnO
OBn
OBn
BnO
OO
O
OMe
BnOOBn
BnO
Co(CO)3
Co(CO)3
O
CAN
OBnO
OBn
OBn
BnO
OO
OO
BnOOBn
BnO
OMe
OHBnO
OBn
OBn
BnO
OHO
O
O
OMe
BnOOBn
BnO
Co(CO)3
Co(CO)3
O
OPivBnO
OBn
OBn
BnO
OH OO
O
OMe
BnOOBn
BnO
OAcO
OAc
OAc
AcO
OAcOAc
OAcO
OAc
AcO
OMe
1
2 NaOMe MeOH
1 Lewis acid2 ClCO2CCl3 Pyr3 Co2(CO)8
with a-isomer
1 Et3N Pyr H2O
2 H2 PdC H+
3 Ac2 O Pyr
149 151
152153
154 155
150
OBn
BnO
OBnO
OBn
BnO
OBnO
BnO
MeO
OBnO
OBn
BnO
O
OMe
AcO
OAcO
OAc
OAc
AcO
OAcO
OAc
O
BnOOBn
OMe
BnO
159 74 over 2 steps
+
BuLi ZnCl2 THF
1 H2 PdC2 Ac2O Pyr
156 157
158 59
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1411
Scheme (32)
Scheme (33)
and the chirality of each isomer assigned after acetylationConversion of the p-methoxyphenyl group in the peracety-lated (S) isomer 187 into the corresponding thiophenylglycoside 188 was accomplished affording the key inter-mediate for the synthesis of C-glycoside analogs of GM4GM3 and other related gangliosides (Scheme 37)
Ganglioside GM4 is a very important cell adhesionmolecule The C-disaccharide of GM4 is currently beingsynthesized in Linhardtrsquos lab using standard O-glycosylationof C-disaccharide with protected ceramide Once theceramide has been attached it can be oxidized to afford analdehyde group for coupling to keyhole limpet hemocyanin
OBnO
OBn
BnO
O
OBnO
ClZnO
OBn
BnOCl
R
OBnO
O
OBn
BnOCl
ZnR
O
ZnR
OBnO
OBn
BnO
160 161
162163
O
OBn
OBnBnO
O
O
OBn
OBnBnO H
TMS
O
OBn
OBnBnO H
O
OBn
BnO
OBnHO
O
OBn
OBnBnO OH
TMS
OBnBnO HO
OBn
TMS
O
OR
ORRO H
O
OR
RO
OR
OBn
OBnBnO
H
TMS
O+
K2CO3 MeOH
1 n-BuLi THF -78 oC
2 164
164165 66
166α 60 166β 13167 97
BF3 Et 2O Et 3SiH -78 oC
168 85
169 R = Bn 83
170 R = H near quantitative yield
H2 (1 atm)Pd(OH) 2C
TMS-acetyl ene
n-BuLi THF -78 oC BF3 Et2O Et3SiH
-78 o C
1412 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
O
OHCOBn
OBnBnO
OMe
O
CO2MeAcO
OAcAcHN
OAc
SO2
NAcO
OBnH
H
OBn
OBn
H
O
OMeH HH
A
O
CO2MeAcO
OAcAcHN
OAc
O
OBnOMe
OBnOBn
HO
AcO
+
Nu
174175
176
SmI2 THF
Scheme (34)
Scheme (35)
Scheme (36)
O
BnO
BnO
BnO
Si lylO
O2S N
O
BnO
HO R2R1
BnOBnO
SilylO
OBnO
BnO
BnO
SilylO
Sm(III)
R1COR2 SmI2 THF
171 172
173
NHBoc
OAcO
AcO
AcHN O
O
CO2BnO
OO
OO
OH
O
CO2MeAcO
OAcAcHN
OAc
AcO
SO2Ph
R2
O
CO2Me
AcHN
OAc
AcO
R1
AcO
AcO
AcHNO CO2Bn
NHBoc
AcO
OAc
O
Zn(BH4)2
180 R1 R2 = H OH ( RS 11)
181 R1 R2 = O
182 R1 = H R2 = OH de gt 90
DMSO Ac2O
177178
179
13 steps
22 equiv SmI2 THF
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1413
Scheme (37)
Fig (2)
(KLH) by reductive amination for use as carbohydrate-basedvaccine GM3 a related trisaccharide containg gangliosideplays an important role in cell growth and differentiationFig 2 The synthesis of C-oligosaccharide GM3 is currentlyunderway following a similar route to that of C-GM4synthesis [42]
Beau also reported a sialyl C-disaccharide synthesiswhich relied on the unprecedented use of a stable andcrystalline 2-pyridyl sulfide of the N-acetylneuraminic acidderivative 189 as the anomeric precursor in a samarium-Reformastky procedure [43] The coupling procedure withsulfide 189 and aldehyde 190 afforded the carbon-linkeddimer 191 in 93 yield as a 11 diastereomeric mixture
Alcohols 191 were converted into thiocarbonates anddeoxygenated by employing triphenyltin hydride catalyticAIBN and pentafluorophenol which yielded C-disaccharide192 as a single compound in 65 yield for the 2 stepsDesilylation hydrogenolysis acetylation and finalacetolysis of the methyl glycoside provided the carbon-linked mimic 193 of the disaccharidic component of thesialylTn tumor antigen (Scheme 38)
4 CATIONIC METHODS
This section is categorized according to reactions thatinvolve the generation of anomeric ions followed by thecapture with sugar-based nucleophiles
OAcAcHN
OAc
AcO
O
OBnBnO
OBnOMP
HO
O
MeO2CAcO
O
MeO2CAcO
OAcAcHN
OAc
AcO
O
OHHO
OHOMP
HO
O
OBnOHC
OBnBnO
OMP
O
MeO2CAcO
OAcAcHN
OAc
AcO
O
OHHO
OHOMP
HO
O
CO2MeAcO
OAcAcHN
OAc
AcO
SO2Ph
O
MeO2CAcO
OAcAcHN
OAc
AcO
O
OAcAcO
OAcX
AcO
H2 PdC EtOAc CH3OHH2O
+
Ac2O Pyr
187 X = OMP
188 X = SPh 73
184 85 R and S mixture
186 90 for two i somers
+
SmI2 THF183
179
185
O
HO2 CHO
OAcAcHN
OH
HO
O
OHHO
OH
OAcO
(CH2 )12 CH3
HN
OH
(CH2)14CH3
O
O
O
OHHO
OH
O
O
HO2 CHO
OAcAcHN
OH
HO
O
OHHO
OH
O(CH2)12CH3
HN
OH
(CH2)1 4CH3
GM4
GM3
1414 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
41 Exo-glycals as Nucleophiles
Nitotra et al have found that treatment of exo-glycal 194with BF 3
OEt2 followed by a water quench afforded the C-disaccharide 195 (Scheme 39) It is noteworthy tonoteworthy that the attack of the enol ether on the anomericoxonium ion occurs with high stereoselectivity on the α-face only 195 was obtained [44]
42 Silyl-based Nucleophiles
Isobe has designed and developed alkynylation as a keyreaction for the introduction of a carbon chain onto sugarsThose alkynylated compounds are called ldquosugar acetylenesrdquo[45] The mechanism includes eliminative formation ofcation to which silylacetylene can coordinate on the α-face(Scheme 40)
Double C-glycosylation between glycal 198 and bis(silylacetylene) gave C-disaccharide ldquolikerdquo compounds 199and 200 (Scheme 41)
Silylpropargyl-sugar 201 smoothly reacted with D-glucalto furnish exclusively the α-acetylene glycoside product 202in 88 (Scheme 42) [46]
5 CYCLIZATION METHODOLOGY
This approach to C-oligosaccharide synthesis relies onthe coupling of an open chain fragment with an intact
monosaccharide to give an intermediate that is then cyclizedto deliver the C-oligosaccharide target This section isdivided by the type of chemistry used to initially assemblethe two pre-cyclization fragments
51 Wittig Reaction-Cyclization
The Kishi group was the first to use Wittig-cyclizationapproach to synthesize C-disaccharides Starting with Wittigreaction between 203 and 204 the intermediate 205 wasafforded as a single stereoisomer in 82 yield Osmylationthen gave a mixture of diols with the major one formed in a61 ratio Selective protection of the diols gave 206a and206b The mono-para-methoxybenzyl ether 206a was thentransformed into the hemiketal 207 in 75 overall yield inthree steps ie (1) Swern oxidation (2) acetonide hydro-lysis (4 N HClTHFrt) and (3) benzoylation (3 equiv ofPhCOClpyCH2Cl2rt) Silane reduction of 207 in an acidicmedium should preferentially yield the equatorially substi-tuted β-C-glycoside which was deblocked and converted tothe methyl- βminusC-disaccharide 209 Exact parallel experi-ments applied to the minor isomer gave the correspondingC-disaccharide 210 (Scheme 43) [47]
Armstrong has employed Wittig-osmylation protocol forthe preparation of a small library of α-C-(1rarr6)-disaccha-rides [48] Readily available allyl C-glycoside 211 washomologated to diene ester 212 and subjected to osmylation
Scheme (38)
O
CO2MeAcO
OAcAcHN
OAc
AcO
S(2-Py)
O
TESO
AcHNOMe
O
HO
O
CO2MeAcO
OAcAcHN
OAc
AcO
O NHAcOAc
OAc
OAc
O
CO2MeAcO
OAcAcHN
OAc
AcO
O NHAcOBn
OTES
OMe
OAc
AcO
O NHAcOBn
OTES
OMeOH
O
CO2 MeAcO
OAcAcHN
+
192 65
1 MeOHHCl2 H2 PdC EtOH3 Ac2O Pyr4 Ac2OAcOHH2SO4
193 59 overall yield
25 equiv SmI2 THF
1 11-thiocarbonyldiimidazole DMAP2 Ph3SnH cat AIBN
191 93
189
190
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1415
Scheme (39)
Scheme (40)
Scheme (41)
OBnO
OBn
OBn
OBnO
OBn
OBn
OBnO
OBn
OBn
OBnO
OBnCH3
BnO
OH
CH2
OBnO
OBn
CH3
OBn
H2 O
BF3 OEt2 MeCN
194
195 96
OOAc
OAc
AcO
R SiMe3
SnCl4
O
OAc
AcO
R
O
OAc
AcO
O
OAc
AcO
Me3Si
R
SiMe3
196
197
Me3 Si SiMe3
O
AcO
OAc
OAc
SiMe3
SiMe3
O
AcO
OAc
O
OAc
OAc
O
AcO
AcOO
OAc
OAc
SnCl4 CH2Cl2
SnCl4 CH2Cl2198
199
200
1416 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (42)
Scheme (43)
AcO
OAc
OAc
Me3 Si
BnO
OBn
BnO
OBn
AcO
OAc
BnO
OBn
BnO
OBn
+ I2 CH2Cl2
202 88
198 201
O
OBn
OBn
O
O
O
OBn
OBn
O
O
OBn
OBn O
OBn
OBn
O
OPBH2M
OH
OBnO
BnO
BnO
O
OBn
OBn
O
OHOPMB
OHO
HO
HO
O
OH
OHOH
OH
HOOMe
O
OBnOBn
O
Ph3P
O
O
OBn
OBn O
OBn
OBn
O
OPBM
OH
O O
CHO
OBn
BnO
OO
OBn
OBn
O
OHOPMB
BnO
BnO
BnO
OHO
HO
HO
O
OH
OHOH
OH
HOOMe
+ THF -78 oC
1 OsO4 pyr THF
2 NaH PMBBr
206a 206b 206a206b 61
1 Swern [O]2 4N HCl3 PhCOCl pyr
1 Swern [O]2 4N HCl3 PhCOCl pyr
1 PrSiH BF3 OEt2
2 H2 Pd(OH)2C
3 HCl MeOH 90 oC
1 PrSiH BF3 OEt2
2 H2 Pd(OH)2C
3 HCl MeOH 90 o C
203
204
205
207
209
208
210
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1417
followed by reduction to afford a 51 mixture (213214215216) of lactols that were readily separable by chromato-graphy Following a deprotection of an equimolar mixture of213 and 214 217 and the DL hybrid C-disaccharide of D-glucose-O-(1rarr6)-L-galactose 218 were obtained The DDand DL derivatives 219 and 220 of glucose-α-(1rarr6)-idosewere also obtained as a near equimolar mixture afterdeprotection of 215 and 216 (Scheme 44)
52 Anion Addition-Cyclization
Kishi developed an approach for the synthesis of theCndashtrehalo sugars which relied on nucleophilic addition ofone intact sugar fragment to a fundamental aldehyde ieKishi-Nozaki reaction [49] Coupling of monosaccharide221 and aldehyde 222 gave 223 The triple bond waspartially reduced and osmylation was followed by selectiveprotection to afford 224 The acetonide was converted toepoxide 225 by standard methods and removal of the PMBgroup Acid-catalyzed cyclization followed by aglyconichydrolysis and protection of hydroxyl group with (p-methoxyphenyl)diphenylmethyl chloride (MMTrCl) gave226 Inversion of the C-2 hydroxyl and removal of protectinggroups delivered α α-C-trehalose 227 (Scheme 44)
Kishi and co-workers also employed aldol reactions as anefficient access to the C-trisaccharide related to the type IIABO(H) blood group determinant [50] Aldol condensationof the enolate of methyl ketone 228 with aldehyde 229 gavea 41 mixture of hydroxy ketones 230 and 231 The majorketol was cyclized desulfurized and oxidized to afford thedisaccharide ketone 233 The ketone in THF was treatedwith LiHMDS (3 equiv) and TMEDA followed by theaddition of MgBr2 Addition of the aldehyde 234 led toalmost exclusive formation of the equatorial products 235and 236 in a 12 ratio Mesylation of 235 and 236 followedby treatment with liquid ammonia gave enones 237a and237b which were reduced to yield exclusively the C-2rsquo-equatorial ketone 238 Sodium borohydride reduction of theC-3rsquo carbonyl proceeded with the desired stereoselectivity toyield the protected C-trisaccharide 239 which wasdeblocked to provide the polyol 240 (Scheme 46)
Sutherlin and Amstrong cleverly applied a recursivestereochemical deconvolution (RSD) combinatorial approachfor the synthesis of a small library of C-trisaccharides aspotential inhibitors for the cell surface proteins of bacteriumHelicobactor pylori [51] The workers chose to carry outvariations in galactose ring of these trisaccharides An
Scheme (44)
OBnO
BnOOBn
OBn
P O
OEtOEtO
EtO
R H
OH
OH
OH
OH
O
R H
OH
OH
OH
OH
O
OHO
HOOH
OH
O
HO
OHOH
OH
OHO
HOOH
OH
O
HO
OH
OH
OHO
HOOH
OH
O
HO
OH
OHOH
R H
OH
OH
OH
OH
O
R
OBnO
BnOOBn
OBn
O
OHO
HOOH
OH
OO
HOHO
OH
R H
OH
OH
OH
OH
O
1 OsO4 NMO 50
2 DIBAL -32 oC 40
++ +
213 214 215 216
217 218 219 220
1 9-BBN H2O22 Swern [O]
3 t-BuOK
4 I2 C6H6212
211
1418 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
efficient Nozaki-Kishi coupling of vinyl bromide 241 withaldehyde 242 in a diasteromeric ratio of 12 followed byprotection with TBSOTf led to 243 and 244 Hydroborationfollowed by oxidation gave aldehydes 245 and 246respectively Addition of allylmagnesium bromide toaldehyde 245 followed by removal of the silyl groupafforded 247 to 246 giving 248 and 249 Epoxidation gave a11 mixture of the corresponding epoxides which werecyclized to give the C-trisaccharide 250-255 after removalof the benzyl groups (Scheme 47)
Schmidt reported a stereoselective 6-exo-trig selectiveelectrophilic cylization approach for de novo synthesis of amethylene-bridged Neu5Ac-α-(23)-Gal C-disaccharide theC-analog of an important motif in glycosphingolipids [52]The open chain precusors 259ab (a 32-mixture ofdiaseteromeric alcohols) were formed by the addition oflithiated iodide 256 to open chain aldehyde 258 Subsequent
C1 incorporation using Tebbe-reagent formation of a cycliccarbonate and deprotection of the two isopropylidene ketalsafforded tetrol 264 which upon treatment with phenylselenyltrifilate was steroselectively cyclized in a 6-exo-trigselective manner affording a diasteromeric mixture of 251and 252 in a ratio of 71 A seleno-Pummerer rearrangementto afford aldehyde 267 in 5 steps in 90 overall yieldOxidation of the aldehyde and subsequent steps led to thedesired C-disaccharide 268 (Scheme 48)
53 Esterification-Cyclization
Work from the Postema group has focused on a ringclosing metathesis (RCM) approach for the synthesis of C-saccharides [53a] The chemistry is versatile and has beenused for the synthesis of a small library of differentiallylinked β-C-disaccharides through a radical allylation-RCMstrategy [53b] The synthesis of the β-(1rarr4)-glucopyranosyl
Scheme (45)
O
OBn
BnO
BnO
BnO
I
CrCl2-NiCl2O
OBn
OH
BnO
BnO
BnO
O
O
O
O
O
H
OBn
O
O
OBnBnO
BnO
BnO
OOBn
OBn
OAc
PMBOHOO
OBn
BnO
BnO
BnO
O
OBn
OBn
OAc
O
OH
HO
HO
HO
OH
OH
OH
O
OH
O
OBn
BnO
BnO
BnO
OBn
OBn
OAc
O
MMTr
+
1 p-TsOH2 K2CO3 MeOH3 MMTrCl pyr
1 Swern [O]2 BH3 THF
3 AcOH-H2 O4 H2 Pd(OH)2
221
222
223
1 Pd-Pb CaCO3 H22 NaH BnBr3 OsO44 Bu2 SnO5 CsF PMB-Cl6 Ac2 O 4-DMAP
1 AcOH2 TsCl pyr
3 NaH-imid4 DDQ
224225
226 227
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1419
Scheme (46)
OBnO O
OBn
OMe
OBn
XY
SMe
OBnBnO
O
OBn
OBn
OBn
OBn
O
BnO
YX
OBn
TBSO
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnOOBn
H
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnO
OBn
OHC OBn
OBn
OTBS
OMe
BnOOBn
CHO
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnOOBn
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnO
OBn
YX
OBnO O
OBn
OMe
OBn
OBn
O
BnO
O
OBn
OBn
OBn
OBn
O 1 LiHMDS
2
228
1 TBAF THF
2 MeSH BF3 OEt2
230 X = OH Y = H231 X = H Y = OH
230231 41
1 Bu3SnH AIBN2 Swern [O]
1 LiHMDS THF-TMEDA2 MgBr23
1 MsCl
2 liquid NH3
235 X = OH Y = H236 X = H Y = OH Bu3 SnH AIBN
237a and 237b
NaBH4 MeOH
238
239 X = OBn
240 X = OHH2 Pd(OH)2
229
232233
234
1420 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (47)
OH C
O
O BnAcHN
OO
O
OBn OBnOBn
Br
O
OBn OBnOBn
O
OBnA cHN
OO
O TBSO
OBn O BnO Bn
O
OBnAcHN
OO
OTBS
S2
S1
S2
OTBSS1
O H
S2
OT BSS1
O H
MgBrMgBr
S2
O TBSS1
O H
S2
OHS1
OH
S2
OTBSS1
OH
O
OHHO
O H
O
HO
H OO
OBnA cH N
HO
H O
O
O HHO
OH
O
HOHO
O
OBnA cH N
HO
H O
O
OHH O
OH
O
H O
HOO
OBnAcHN
HO
HO
O
O HH O
OH
O
H O
H O O
OBnA cHN
HO
HO
O
O HH O
O H
O
HO
H O O
OBnAcHN
HO
HO
O
OHHO
OH
O
H O
O
OBnA cHN
HO
HOHO
+
241 242
1 CrCl2-NiCl2 T HF-DMF 722 TBSOTf 2 6-lutidine 91
243 244
1 9-BBN 602 Dess-Mart in period inane 97
1 9 -BBN 552 D ess-Martin periodinane 98
245 246
1
2 T BAF 74
1
2 TBAF 88
247 248 249
250
251
250 251 1 1 252 253 1 1 254 255 1 1
252
253
254
255
1 MCPBA2 CSA CH 2Cl2 61 fo r 2 steps3 H 2 Pd (O H)2C 95
1 MCPBA2 CSA CH 2Cl2 63 fo r 2 s teps3 H 2 Pd (OH)2C 87
1 MCPBA2 CSA CH2Cl2 80 for 2 steps3 H2 Pd(O H)2C 95
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1421
Scheme (48)
O
OO
Se Ph
R
O
HO OHOH
O
OB n O B n
OB n
O B nO O
O O
R O OR
X
O
OO
R
Se Ph
O
HOOH
OH
O
OB nOB n
O Bn
OB n
O O
O O
R O O R
O H
O
O B n OB n
O B n
OB n
O
C HO
O
O O
R O OR
OAc HN
OAc
C O2NH 4HOOH
OH
O
OH O H
OH OH
O
OB n O B n
OB n
OB nO O
O O
R O OR
X
O
O
OAcOAc
C HOA cOOAc
OAc
O
OB n O B n
OB n
OB n
O
O Bn OB n
OB n
OB n
X
OH
OO
HOOH
OH
O
O
OMeOB n
OB nOB n
R
t-B uL i256 R = Li
257 R = L i
258
(R = t-B uMe 2Si )
(R = t-B uMe 2Si )
259ab (32) 79 com bine d yi eld
De ss-Ma rtin pe riodinane
260 X = O R = t-B uMe 2Si ) 95
261 X = O R = t -B uMe2S i) 62
T e bbe re age nt
TB A F THF262 X = O R = H 94
diphosge ne
C H2C l 2Pyr
263 95
T HFH2O T FAr t
264 quant it a ti ve yie ld
PhSe C l AgOT f
EtC N -80 oC
265
266
Quant it at i ve yi l ed 25 26 7 1
+
R =
1 Ac 2OPyr
2 mC PB A3 Ac 2ONa OAc
4 NaO HT HFMe OH
5 Ac2O P yr
267 90 overa ll yi e ld
ste ps
268
1422 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
glucopyranoside 280 represents an example of thischemistry The known triacetyl glucopyranoside 269 wasconverted to iodide 270 in good yield Radical allylation of271 proceeded to afford a mixture of equatorial and axialallylation products in a 61 ratio Oxidative cleavage of thedouble bond gave the corresponding aldehydes 273a and273b which were separable Pinnick oxidation of the majoraldehyde 273a then gave the C-4 equatorial acid 274 DCC-mediated coupling of alcohol 275 and acid 274 proceeded toafford ester 276 in good yield Methylenation of 276 gave277 and exposure to catalysist 278 gave a 41 yield of theC-disaccharide glycal which was exposed to an excess ofBH3
THF to give 64 yield of the β-C-disaccharide 279Removal of the benzyl groups and global peracetylation gavethe peracetylated (1rarr4)-β-C-disaccharide 281 in good yield(Scheme 49)
54 Ring Expansion-Cyclization
Nelson developed a new strategy for asymmetric andstereoselective synthesis of C-linked disaccharide mimeticsthe C58-C71 fragment of palytoxin [54] The diol (RR)-282was converted into the di-dihydropyran (DHP) template 283284 and 285 The di-DHPs were functionized in a twodirectional sense using dihydroxylation reactions The two-directional approach was often very efficient indeed forexample in the synthesis of 286 six new stereogenic centerswere introduced with almost complete stereocontrol using areduction and a dihydroxylation reaction The approach isnot restricted to the synthesis of C2-symmetricaldisaccharide mimetics Using the unsymmetrical template285 which has both a pseudo-axial and a pseudo-equatorialhydroxyl groups the unsymmetrical mimetics 289 and 290were prepared (Scheme 50)
6 RADICAL APPROACHES
The radical approach for C-C bond formation is a popularmethod within organic chemistry The use of radicalchemistry in carbohydrate synthesis has certain advantagesFirstly the reaction conditions are very mild and tolerant ofa range of functional and protecting groups Secondanomeric radicals are stable with respect to elimination andepimeration Most significantly the chemistry required toincorporate an appropriate substitute at C-1 employed in theinitial hemolytic cleavage step is common within carbo-hydrate chemistry [55] The use of such radical techniquecan be subdivided into two classes intermolecular andintramolecular approaches
61 Intermolecular Radical Approaches
Giese was the first to employ an intermolecular radical-based approach for synthesis of C-disaccharides [56]Addition of an alkene to an anomeric radical underappropriate conditions allowed exclusive entry to the α-linked C-glycoside a result which was mirrored by the workof Baldwin [57] The high α-selectivity of the reaction wasin contrast with other reports Thus radicals generated at theC-2 C-3 and C-4 centers all preferred to occupy equatorialpositions [58] When the anomeric bromide 291 was treatedwith tin hydride and AIBN resulting anomeric radical andreacted with lactone 292 in a Michael addition it afforded293 In this reaction hydrogen abstraction at the resulting
radical center occurs from axial face to selectively generatethe equatorial C-2rsquo substituent Reduction and acetylation of293 furnished C-disaccharide 294 (Scheme 51) [59]
Witczak used the facial bias of levoglucosene tostereoselectively add a carbohydrate-based radical in thepreparation of the 3-deoxy-(1rarr4)-β-C-disaccharide 299[60] Addition of the radical derived from iodide 295 to 296gave adduct 297 in 26 yield Removal of the anomerichydroxyl of 297 was achieved by treatment with triethylsilane borontrifluoride ether complex followed bystereoselective reduction of the keto function at C-2rsquo withthe formation of 298 in 89 yield Debenzylation followedby acetolysis of 16-anhydro ring produced the peracetylatedtarget C-disaccharide 299 in 19 overall yield from 295(Scheme 52)
Vogel has developed general methods to transformenantiomerically pure 7-oxabicyclo[221]heptyl derivatives(ldquonaked sugarsrdquo) into C-disaccharides Because of thesechiral bicyclic skeletons they undergo highly stereoselectivereactions with predictable diasteroselectivities An arsenal ofmethods is available that allow to substitute these ldquonakedrdquocarbon centers with a variety of functional groups with allpossible relative configurations The methods allowpreparation of both enantiomers of a given target with thesame ease Predictably high stereoselectivity of the reactionsof the bicyclic chirons adds to the flexibility of approachwhich can lead to high molecular diversity [61]
α-C-(1rarr3)-mannopyranoside of N-acetyl-galactosaminepotent β-galactosidase inhibitors was synthesized by thisapproach [61] Enone 302 was readily prepared from 300The addition of the radical derived from bromide 303 toenone 302 afforded the αminusisomer 304 The ketone was thenreduced and the selenide eliminated via the intermediacy ofthe selenoxide to give 305 Acid-promoted (CF3SO3H) 7-oxa ring opening of 305 in MeCN produced the amino-conduritol derivative 306 resulting from the quenching of theallylic cation intermediate by the solvent (Ritter reaction)Ozonolysis of the chloroalkene 306 generated an acylchloride-aldehyde intermediate that reacted with MeOH toproduce a mixture of methyl uronates The major compound307 was silylated and reduced The crude polyol obtainedwas acetylated to produce 308 Desilylated and ammonolysisafforded a mixture of α-β-pyranoses 309 and correspondingα-β-furanoses (Scheme 53)
Similar chemistry was carried out to synthesize non-protected α-C(1rarr2)-L-fucopyranoside of D-galactopyrano-side corresponding to a blood group mimetic [62] Giesersquosradical fucosidation of racemic enone 310 with α-L-bromoacetofucose 311 provided the mixture of diastereo-meric α-C-fucoside 312a and 312b in reproducible yield of78 Reduction of the mixture gave a 11 mixture of endo-alcohols 313 and 314 which were isolated pure in 40 and355 yield respectively Oxidative elimination of thebenzeneselenyl group of 313 followed by acetylation gaveendo acetate 315 in 85 yield Acid-promoted ring openingof 315 and ozonolysis of the resulted chloroalkene gavemethyl uronic ester 316 in modest yield (10) Treatment of316 with Cl3CCN and NaH followed with BF3
OEt2
furnished the totally protected C-disaccharide 317 in 79
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1423
Scheme (49)
Bu3SnO
HOAcO
OMeOAc
OAc
O
AcO
OMeOAc
OAcI
AIBN
O
AcO
OMeOBn
OBn
HO2C O
AcO
OMeOR
ORY
X
OHBnO
BnO
OBn
OBnO
BnO
OBn
O
AcO
OMeOBn
OBnX
i-Pr i-Pr
N
Mo C(Me2 Ph)((CF3)2 MeCO)2
O
RO
OMeOR
O
RO
OR
OR
RO
OR
278
I2 Ph3P
imidazole
269 270 93
271a X = CH2CH=CH2 Y = H R = Ac 64271b Y = CH2CH=CH2 X = H R = Ac 11272a X = CH2CH=CH2 Y = H R = Bn 75272b Y = CH2CH=CH2 X = H R = Bn 75273a X = CH2CHO Y = H R = Bn 79273a Y = CH2CHO X = H R = Bn 79
1 NaOMe MeOH2 NaOH BnBr DMF
OsO4 NaIO4
NaClO2 NaH2PO4
274 96
275
DCC 4-DMAP
276 X = O 82
277 X = CH2 51
TiCl4 Zn dust TMEDA CH2Br2PbCl2 (Cat )
1
2 BH3 THF H2O2 NaOH
H2 PdC EtOH
Ac2 O Pyr 4-DMAP
279 R = Bn R = H 64
280 R = R = H 99
281 R = R =Ac 97
1424 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (50)
Scheme (51)
O OOH
OH
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
286
1 VO(acac)2 t-BuOH 95
2 (MeO)3CH BF3 90
1 P-O2NC6H4 CO2H Ph3P DIAD2 K2CO3 MeOH 82 over 2 steps
1 PhCOCl Et3N DMAP 402 P-O2NC6H4 CO2H Ph3P DIAD3 KOH THF-H2O 75 over 2 steps
TMEDA OsO4
Cat OsO4 NMO 287
Cat OsO4 NMO288
TMEDA OsO4
Cat OsO4 NMO
290
289
(RR)-282283
284
285
OHO
AcO
BrOAc
OAc
BnO
O
OBn
OBnO
OHO
AcOOAc
OAc
BnO
OOBn
OBnAcO
OHO
AcOOAc
OAc
BnO
O
OBn
OBnO
+
Bu3SnH AIBN291
292
293 81
1 Na[Al(OC2H4OMe)2(OEt)H]2 Ac2O pyr
294 56 over 2 steps
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1425
Scheme (52)
Scheme (53)
OBnO
BnOOBn
OBn O
OH
O
OBnO
BnO
OHOBn
OBn O
O
O
O
O
O
OBnO
BnOOBn
OBnO
OAcOAc
OAc
OBnO
BnO
OHOBn
OBn
IBu3SnH AIBN
295 297 26
1 BF3 OEt2 Et3SiH
2 L-Selectride THF
1 Pd(OH)2C C6H10 EtOH
2 EtSiOSO2CF3 Ac2O
298 89 over 2 steps299
296
O
O
PhSeClO
O
PhSeCl
Bu3 SnH
O
O
PhSeCl
R
H
O
OAc
R
Cl
O
AcO
OAc
OAc
OAcOH
Cl
NHAc
R
OAc
AcHN
OH
O
OH OAc
OH
OHO
HO
OH
O
AcO
OAc
OAc
OAcBr
O
O
PhSeCl
O
O
PhSeCl
R
O
OTIPSAcHNR
OAc OAc
O
OHAcHN
COOMe
R
OAc
1 Bu4NF
2 NH3MeOH
1 (Me3Si)2NLi THF2 Me2N=CHI
1 Bu3 SnH AIBN2
1 NaBH42 mCPBA3 Ac2O pyr
1 H+ MeCN
2 H2 O NaHCO3
R =
1 O3MeOH
2 Me2S NaHCO3
1 TIPSOTf 26-lut idine2 LiBH43 Ac2 O pyr DMAP
furanoses +
304 56
305 68 306 84307 50
308 46
300 301 302
303
309
1426 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
The reduction of 317 and treatment with DOWEX-H+ resinprovided the desired C-fucoside 318 in 70 (Scheme 54)
62 Intramolecular Radical Approaches
One disadvantage with the intermolecular approaches isthat during such radical mediated reactions electrondeficient alkenes are required to facilitate C-C bondformation The intramolecular approach of Sinayuml overcomes
this drawback by bring two substrates together via atemporary covalent silaketal connector This enables the useof a wider range of alkenes which can include alkene-functionalized sugars thus leading to the generation of C-disaccharides [63] Based on the early work of Stork Sinayumlemployed the tether reaction in the synthesis of both α- andβ-C-disaccharides with this work subsequently beingemployed in the synthesis of biologically significant natural
Scheme (54)
O
OH
Fuc
Cl
O
O
ClPhSe
OOAc
NHAcOHFuc
O
AcOOAc
AcO
Br
O
O
PhSeCl
O
AcOOAc
AcO
O
OH
PhSe Cl
Fuc
OOAc
NHAc
OMe
Fuc
O
AcHN
OH OAc
OH
O
OH
Me
OH
O
O
Fuc
ClSePh
O
HO
Fuc
ClSePh
+
Ph3SnHAIBN
78 combined yield
Fuc
310
+
1 NaBH4 MeOHTHF2 Chromatography
313 40 314 355
1 mCPBA
2 Ac2O pyr DMAP
+
315 75
1 TfOH MeCN
2 NaHCO3 O3 -78 oC
316 10 over 2 steps
1 Cl3 CCN NaH
2 MeOH BF3 OEt2
317 79
1 LiBH4 THF
2 Dowex-H+
311
312a312b
318 70 for 2 steps
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1427
products [64] The availability of different hydroxyl groupson each monosaccharide unit allowed the fine-tuning ofstereochemical outcome by selective positioning of the silyltether [65] Development of this early stereochemical controlled to the tethering of the donor 320 with alcohol 319through a di-isopropyl silicon tether 321 Subsequent treat-ment with Bu3SnH and AIBN led to a 9-endo-trigcyclization to form the C-disaccharide 322 in an 80 yieldwith exclusive formation of the α-product The silyl tetherwas removed with Bu4NF and deprotection under standardconditions afforded the desired disaccharide 323 in excellentyield (Scheme 55)
In parallel the development of a 32rsquo silyl tether allowedaccess to the β-linked product as demonstrated in Sinayumlrsquossynthesis of methyl β-C-lactoside 328 [66] Alcohol 324 and320 were connected via the dimethylsilyl tether an 8-endo-trig cyclization followed to exclusively afford the β-
disaccharide 326 in 45 yield Removal of the tether anddeprotection of benzyl ether gave β-C-disaccharide 328(Scheme 56)
This group also selected iodosugars bearing a freehydroxyl group as progenitors of the radical donors [67] In atypical experiment the radical donor 329 was connected tothe radical acceptor 330 through a silaketal tether followingtheir procedure Tributyltinhydride mediated 8-endo-trigradical cyclization of compound 331 gave after detetheringof the non isolated intermediate 332 the protected β-C-disaccharide 333 in 37 overall yield (from startingmaterials 330 and 329) Peracetate 335 was achieved afterhydrogenolysis The C-laminaribioside 334 is of potentialbiological interest as it mimics the repeating disaccharideunit of fungal β-(1rarr3)-glucans which have antitumor andimmunomodulating properties (Scheme 57)
Scheme (55)
Scheme (56)
OO
OHSePh
OTBDPSO O
OO
SePh
OTBDPSO
OO
OBnOMe
OBn
Si
O
HOOBn
OMe
OBn
O
HOOH
OHHO
O
HOOH
OMe
OH
OTBDPSO
O
HOOBn
OMe
OBnO
OOH
1 n-BuLi THF
2 iPr2SiCl2 -78 oC
3 DMAP THF rt
1 Bu4NF THF
2 Dowex-H+
3 H2 PdC
Bu3SnH AIBN toluene
319
320
321
322323
OBnO
OHSePh
OBnBnO
OHO
OBnOMe
OBn
ROO
ROOH
OR
OHO
OROMe
OR
OBnO
O
OBnBnO
OO
OBnOMe
OBn
Si
SePh
OBnO
O
OBnBnOO
OOBn
OMe
OBn
Si
1 PhSeH Me2SiCl2
BuLi -78 oC
2 imidazole rt
Bu3SnH AIBN toluene
H2 PdC327 R = Bn
328 R = H
Bu4NF THF
324
320
325
326 45
1428 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
CONCLUSIONS
In this paper the biological importance of C-oligo-saccharides as subunits of natural products and as a newgeneration of carbohydrate based on therapeutics has beenillustrated Different methods are available for the synthesisof C-oligosaccharides As with traditional saccharidesynthesis it has been necessary to develop a number ofspecific approaches to facilitate the regioselective andstereoselective preparation of the desired targets Work inthis area continues and it is expected that many interestingnew C-oligosaccharides will be prepared using the chemistrydescribed in this review It is also likely that new chemistrywill be developed in the future for the preparation of thesebiologically important targets
ACKNOWLEDGEMENTS
The authors thank Dr Sultan Baytas for her criticalreading of this manuscript
REFERENCES
[1] Kennedy J F White C A Bioactive Carbohydrates InChemistry Biochemistry and Biology Ellis Horwood LtdChichesterUK 1983
[2] Wassarman PW Mammalian Fertilization Molecular Aspects ofGamete Adhesion xocytosion Exocytosis and Fusion Cell 199996 175-183
[3] Carbohydrate-based Drug Discovery Wong C-H EdWeinheim Cambridge Wiley-VCH 2003
[4] (a) Sharon N Lis H Lectins as Cell Recognition MoleculesScience 1987 246 227-234 (b) Dwek RA Chem Rev 1996 96683-720
[5] Postema M C-Glycoside synthesis CRC Boc Ratom 1995[6] (a) Weatherman R V Mortell K H Cheruenak MKiessling
L L Toone E J Specificity of C-Glycoside Complexation byMannoseGlucose Specific Lectins Biochem 1996 35 3619-3624(b) Ravishankar R Surolia A Vijayan M Lim S Kishi YPreferred Conformation of C-Lactose at the Free and Peanut LectinBound States J Am Chem Soc1998 120 11297-11303
[7] (a)Wong C-H Halcomb R L Ichikawa Y and Kajimoto TEnzymes in organic synthesis Application to the problems ofcarbohydrate recognition part2 Angew Chem Int Ed Engl 199534 521-546 (b)Howard S Withers SG Bromoketone C-Glycosides a New Class of βminusGlucanase Inactivators J AmChem Soc 1998 120 10326-10331(c) Wang Q Wolff MPolat T Du Y Linhardt R J C-glycoside of Neuraminic Acidsas Neura-minidase Inhibitors Bioorg Med Lett 2000 10 941-944 (d) Phili R Chang J Partis R A Mueller R A ChrestF J Passaniti A The Alpha-glucosidase I InhibitorCastanospermine Alters Endothelial cell Glycosylation PreventsAngiogenesis and Inhibits Tumor Growth Cancer Res 1995 552927-2935
[8] Ossor A Elbein A D In Carbohydrates in Chemistry andBiology Vol 3(II) WileyVCH 2000 pp 513-539
[9] (a) Sinayuml P Synthesis of oligosaccharide Mimetics Pure ApplChem 1997 69 459-463 (b) Beau J-M Gallagher TNucleophilic C-glycosyl Donors for C-glycoside Synthesis Top inCurr Chem 1997 187 1-54 (c) Nicotra F Synthesis of C-glycosides of Biological Interest Top in Curr Chem 1997 187
Scheme (57)
O
O
O
Ph
I
OMe
OHO
BnO
OH
OH
BnOOH
O
BnO
Si
O
O O
Ph
I
OMe
O
O
BnO
OR4O
R5O
OMe
OR2
OR3O
R3O
OR1
R3O
Bu3 SnH AIBN
332 R1 R2 = SiMe2 R3 = Bn R4 R5 = CHPhTBAF THF
333 R1 = R2 = H R3 = Bn R4 = R5 = CHPh 37 from 11
334 R1 = R2 = R3 = R4 = R5 = H
335 R1 = R2 = R3 = R4 = R5 = Ac
329
H2 PdC MeOH
Ac2 O pyr
1 BuLi THF -78 oC
2 Me2SiCl2
3 DMAP
330
331
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1429
55-83 (d) Du Y Linhardt R Y Recent Adv in Stereo-SelectiveC-Glycoside Synthesis Tetrahedron Lett 1998 54 9913-9959 (e)Liu L Mckee M and Postema M H D Synthesis of C-saccharides and Higher Congeners Current Org Chem 2001 51133-1167
[10] Jarosz S Fraser-Reid B Synthesis of A Higher Carbon Sugar ViaDirected Aldol Condensation Tetrahedron Lett 1989 30 2359-2362
[11] Lichtenthaler F W Lergenmiiller M Schwidetzky S C-Glycosidations of 2-Ketohexosyl With Electrophilic Radical andNudeophilic Anomeric Carbons Eur J Org Chem 2003 3094-3103
[12] Baudat A Vogel P Aza-C-disaccharides Synthesis of 6-Deoxygalactonojirimycin-β-C(1rarr3) Linked with D-Altrofuranosides and D-Galactose J Org Chem 1997 62 6252-6260
[13] Turner D Vogel P Synthesis of 4-Hydroxy-26-Bis(hydroxymethyl) tetrahydropyran-2-Carbaldehyde DerivativesSynlett 1998 304-306
[14] Zhu Y-H Vogel P Short Stereoselective Synthesis of C-(1rarr3)-Linked Disaccharides Tetrahedron Lett 1998 39 31-34
[15] Zhu Y-H Vogel P Synthesis of a (2R 6R)-2-(Hydroxymethyl)-6-Propa-1 2-Dienyl-2H-Pyran-3(6H)-One Derivative A NewEnone for The Convergent Construction of C-Glycosides of C-Disaccharides Synlett 2001 82-86
[16] Baumberger F Vasella A Deoxynitrosugars The 6th
Communication Stereolectronic Control in the reductivedenitration of tertiary nitro ethers A Synthesis of ldquoC-glycosidesrdquoHelv Chim Acta 1983 66 2210-2221
[17] Martin O R Lai W Synthesis and Conformational Studies of β-(1rarr6)- and ββ-(1rarr1)-Linked C-disaccharides J Org Chem1993 58 176-185
[18] Spak S J Martin R The synthesis of an analogue of Methyl OC-Analogue of Methyl 4rsquo-O-β-D-GlucopyranosylgentiobiosideTetrahedron 2000 56 217-224
[19] Kobertz W R Bertozzi C R Bednarski M D C-GlycosylAldehyde Synthons for C-Linked Disaccharides J Org Chem1996 61 1894-1897
[20] Gurjar M K Nagaprasad R and Ramana CV First Synthesis ofMethyl α-C-D-Arabino-furanosyl-(1rarr5)-αminusD-Arabinofuranosidethe C-Disaccharide Segment of Motif C of MycobateriumTuberculosis Tetrahedron Lett 2000 43 7577-7579
[21] Witczak Z J Synthesis of C-Glycosyl Compounds and OtherNatural Products from Levoglucosenone Pure Appl Chem 199466 2189-2192
[22] Griffin F K Paterson D Taylor R J K Ramberg-BacklundApproaches to the Synthesis of C-Linked Disaccharides AngewChem Int Engl 1999 38 2939-2942
[23] Paterson B E Griffin F K Alcaraz M-L and Taylor R J KA Ramberg-Baumlcklund Approach to the Synthesis of C-GlycosidesC-Linked Disaccharides and C-Glycosyl Amino Acids Eur JOrg Chem 2002 1323-1336
[24] McAllister G D Paterson D E Taylor R J K A SimplifiedRamberg-Bachlund Approach to Novel C-Glycosides and C-Linked Disaccharides Angew Chem Int Ed Engl 2003 42 1387-1391
[25] McCartney J L Christopher T M Cicchillo R M BernardinaM D Wagner T R and Norris P J Org Chem 2003 6810152-10155
[26] Dondoni A Zuurmond H M Bascarate A Synthesis of α-andβ-D-(1rarr6)-C-Disaccharides by Witting Olefination of Formyl C-Glycosides with Glycopyranose 6-phosphoranes J Org Chem1997 62 8114-8124
[27] Dondoni A Kleban M Zuurmond H Marra A Synthesis of(1rarr6)-C-Oligogalactosides by Interative Wittig OlefinationTetrahedron Lett 1998 39 7991-7994
[28] Dondoni A Marra A A New Synthetic Approach toMycobacterial Cell Wall α-(1rarr5)-D-Arabinofuranosyl C-Oligosaccharides Teterahedron Lett 2003 44 4067-4071
[29] Colinas P A Ponzinibbio A Lieberknecht A and Bravo R OWittig Reaction of Glycosyl Phosphonium Salts A StereoselectiveRoute to C-Disaccharides and C O-Trisaccharides TetrahedronLett 2003 44 7985-7988
[30] Schmidt R R Preuss R Synthesis of Carbon Tetrahedron Lett1989 30 3409-3412
[31] Dietrich H Schmidt R R Synthesis of Carbon-Bridged C-Lactose and Derivatives Liebigs Ann Chem 1994 975-981
[32] Rouzaud D Sinayuml P The First Synthesis of a ldquoC-DisacchariderdquoJ Chem Soc Chem Commun 1983 1353-1354
[33] Xin Y-C Zhang Y-M Mallet J-M Glaudemans C P JSinayuml P Synthesis of C-Oligosaccharides That Mimie TheirNatural O-Analogues Immunodeterminants in Binding toMonoclonal Immunoglobulins Eur J Org Chem 1999 471-476
[34] Streicher H Geyer A Schmidt R R C-Disaccharides ofKetoses Chem Eur J 1996 2 502-510
[35] Leeuwenburgh M A Timmers C M Vander Marel G A VanBoom J H Mallet J-M Sinayuml P G Stereoselective Synthesisof α-C-(Alkynyl)-Glycosides Via Ring-Opening of α-12-Anhydrous Tetrahedron Lett 1997 38 6251-6254
[36] Aslam T Fuchs M G G Le Formal A Wightman R HSynthesis of C-Disaccharide Analogue of the α-D-Arabinofuranosyl-(1rarr5)-α-Arabinofuranosyl Motif ofMycobacterial Cells Walls via Alkynyl Intermediates TetrahedronLett 2005 46 3249-3252
[37] (a) Girad P Namy J L Kagan H B Divalent LanthanideDerivative in Organic Synthesis 1 Mild Preparation of SamariumIodide and Ytterbium Iodide and Their Use as Reducing orCoupling Agents J Am Chem Soc 1980 102 2693-2698 (b)Molander G A Harris C R Sequencing Reactions withSamarium(II) Iodide Chem Rev 1996 96 307-338
[38] (a) Mazeacuteas D Skrydstrup T Doumeix O Beau J-MSamarium Iodide-Induced Intramolecular C-Glycoside FormationEfficient Radical Formation in the Absence of an Additive AngewChem Int Ed Engl 1994 33 1383-1386 (b) Mazeacuteas DSkrydstrup T Beau J-M A Highly Stereoselective Synthesis of1 2-trans-C-Glycosides Via Glycosyl Samarium(III) CompoundsAngew Chem Int Ed Engl 1995 34 909-912 (c) Jarreton OSkrydstrup T Beau J-M The Stereospecific Synthesis of Methylα-C-Mannobioside A Potential Inhibitor of M TuberculosisBinding to Human Macrophages J Chem Soc Chem Commun1996 1661-1662 (d) Jarreton O Skrydstrup T Espionosa J-FJimeacutenez-Barbero J Beau J-M Samarium Diiode Prompted C-Glycosylation An Application to The Stereospecific Synthesis ofα-(1rarr2)-C-Mannobioside and Its Derivatives Chem Eur J 19995 430-441 (e) Mipuel N Doisneau G Beau J-M ReductiveSamariation of Anomeric 2-Pyridyl Sulfones with Catalytic AnUnexpected Improvement in The Synthesis of 12-Trans-Diequatorial C-Glycosyl Compounds Angew Chem Int Ed Engl 2000 39 4111-4114
[39] Vlahov I R Vlahova P I Linhardt R J DiastereocontrolledSynthesis of Carbon Glycosides of N-Acetylneuraminic Acid ViaGlycosyl Samarium(III) Intermediates JAmChem Soc 1997 1191480-1481
[40] Kuberan B Sikkander S ATomiyama H Linhardt R JSynthesis of a C-Glycoside Analogue of sTn An HIV-and Tumor-Associated Antigen Angew Chem Int Ed Engl 2003 42 2073-2075
[41] Bazin H G Du Y Polat T Linhardt R J Synthesis of aVersatile Neuraminic Acid ldquoCrdquo-Disaccharide Precursor for theSynthesis of C-Glycoside Analogues of Gangliosides J OrgChem 1999 64 7254-7259
[42] Chen C-C Ress D K Linhardt RJ Samarium Iodide-Mediated Synthesis of Neuraminic Acid C-Glycosides InSynthesis of Glycommetics Roy R Ed ACS Syposium Series2004 896 53-80
[43] Abdallah Z Doisneau G Beau J-M Synthesis of a Carbon-Linked Mimic of The Disaccharide Component of The Tumor-Relate SialyTn Antigen Angew Chem Int Ed Engl 2003 425209-5212
[44] Lay L Nicotra F Panza L Russo G Caneva E Synthesis ofC-disaccharides through dimerization of exo-glycals J Org Chem1992 57 1304-1306
[45] Isobe M Nishizawa R Hosokawa S Nishikawa TStereocontrolled Synthesis and Reactivity of Sugar Acetylenes JChem Soc Chem Commun 1998 2665-2676
[46] Saeeng R Sirion U Sahakitpichan P Isobe M IodineCatalyzes C-Glycosidation of D-Glucal with SilylacetykeneTetrahedron Lett 2003 44 6211-6215
[47] (a) Babirad S A Wang Y Kishi Y Synthesis of C-Disaccharides J Org Chem 1987 52 1370-1372 (b) Wang YBabirad S A Kishi Y Preferred Conformation of C-Glycosides
1430 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
8 Synthesis of 14-Linked Carbon Disaccharides J Org Chem1992 57 468-481
[48] Armstrong R W Sutherlin D P Strategies for the Synthesis ofC-Disaccharides Containing D and L Sugars Tetrahedron Lett1994 35 7743-7746
[49] Wei A Kishi Y Preferred Conformation of C-Glycosides 12Synthesis and Conformational Analysis of αα- α β- and β β-Trehaloses J Org Chem 1994 59 88-96
[50] Haneda T Goekjian P G Kim S H Kishi Y PreferredConformation of C-Glycosides 10 Synthesis and ConformationAnalysis of Carbon Trisaccharides J Org Chem 1992 57 490-498
[51] Sutherlin D P Armstrong R W Synthesis of 12 Stereochemistryand Structurally Diverse C-Trisaccharides J Org Chem 1997 625267-5283
[52] Notz W Hartel C Waldscheck B Schmidt R R De NovoSynthesis of a Methylene-Bridged Neu5Ac-α-(23)-Gal C-Disaccharide J Org Chem 2001 66 4250-4260
[53] (a) Postema M H D Calimente D Liu L Behrmanm T L AnOlefin Metathesis Route for the Preparation of (1rarr6)-Linked-C-Disaccharide Glycals A Convergent and Flexible Approach to C-Saccharide Synthesis J Org Chem 2000 65 6061-6068(b) Postema M H Piper J L Liu L Faust M Andreana PSynthesis and Partial Biological Evaluation of a Small Library ofDifferentially Linked β-C-Disaccharide J Org Chem 2003 684748-4754
[54] Nelson A The Development of Strategies and Methods for TheSynthesis of Biologically Active Compounds New J Chem 200428 771-776
[55] Togo H He W Waki Y Yokoyama M C-GlycosylationTechnology With Free Radiant Reactions Synlett 1998 700-717
[56] Giese B Dupuis J Diastereoselective Synthesis of C-Glycopyranosides Angew Chem Int Ed Engl 1983 22 622-623
[57] Adlington R M Baldwin J E Basak A Kozyrod RPApplication of Radical Addition Reactions to tho Synthesis of a C-Glucoside and A Functionalized Amino Acid J Chem SocChem Commun 1983 144-145
[58] Giese B Gonzaacutelez-Goacutemez J A Witzel T The Scope of RadicalCC-Coupling by The ldquoTin Methodrdquo Angew Chem Int Ed Engl1984 23 69-70
[59] Giese B Witzel T Synthesis of ldquoC-Disaccharidesrdquo by RadicalC-C Bond Formation Angew Chem Int Ed Engl 1986 25 450-451
[60] Witczak Z J Chhabra R Chojnacki J C-Disaccharides IStereoselective Approach to β-(1rarr4)-3-Deoxy-C-Disaccharidesfrom Levoglucosenone Carb Res 1997 301 167-175
[61] Vogel P Synthesis of Rare Carbohydrates and Analogues Startingfrom Enantiomerically Pure 7-Oxabicyclo[221]heptyl Derivatives(ldquoNaked Sugarsrdquo) Current Org Chem 2000 4 455-480
[62] Viodeacute C Vogel P Synthesis of The C-Disaccharide α-C(1rarr3)-L-Fucopyranoside of N-Acetylgalactosamine J Carb Chem2001 20 733-746
[63] Xin Y C Mallet J M Sinayuml P An Expeditious Synthesis of AC-Disaccharide Using A Temporary Silaketal Connection J ChemSoc Chem Commun 1993 864-865
[64] (a) Petitou M Herault P Lormeau J-C Helmboldt A MalletJ-M Sinayuml P Herbert J-M Introducing A C-InterglycosidicBond in A Biologically Active Pentasaccharide Hardly Affects ItsBiological Properties Bioorg Med Chem 1998 6 1509-1516 (b)Sinayuml P Advances in The Synthesis of the Carbohydrate MimicsPure Appl Chem 1998 70 1495-1499
[65] Sinayuml P Chemical Synthesis of Oligosaccharide Mimetics PureAppl Chem 1998 70 407-410
[66] Sinayuml P Chemical Synthesis of Oligosaccharide Mimetics PureAppl Chem 1998 69 459-463
[67] Vauzeilles B Sinayuml P Selective Radical Synthesis of β-C-Disaccharides Tetrahedron Lett 2001 42 7269-7272
1410 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (30)
Scheme (31)
O
BnOOBn
OMe
Li
BnO
OPivBnO
OBn
OBn
BnO
O OO
BF3 OEt2
OBnO
OBn
OBn
BnO
OO
O
OMe
BnOOBn
BnO
Co(CO)3
Co(CO)3
O
CAN
OBnO
OBn
OBn
BnO
OO
OO
BnOOBn
BnO
OMe
OHBnO
OBn
OBn
BnO
OHO
O
O
OMe
BnOOBn
BnO
Co(CO)3
Co(CO)3
O
OPivBnO
OBn
OBn
BnO
OH OO
O
OMe
BnOOBn
BnO
OAcO
OAc
OAc
AcO
OAcOAc
OAcO
OAc
AcO
OMe
1
2 NaOMe MeOH
1 Lewis acid2 ClCO2CCl3 Pyr3 Co2(CO)8
with a-isomer
1 Et3N Pyr H2O
2 H2 PdC H+
3 Ac2 O Pyr
149 151
152153
154 155
150
OBn
BnO
OBnO
OBn
BnO
OBnO
BnO
MeO
OBnO
OBn
BnO
O
OMe
AcO
OAcO
OAc
OAc
AcO
OAcO
OAc
O
BnOOBn
OMe
BnO
159 74 over 2 steps
+
BuLi ZnCl2 THF
1 H2 PdC2 Ac2O Pyr
156 157
158 59
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1411
Scheme (32)
Scheme (33)
and the chirality of each isomer assigned after acetylationConversion of the p-methoxyphenyl group in the peracety-lated (S) isomer 187 into the corresponding thiophenylglycoside 188 was accomplished affording the key inter-mediate for the synthesis of C-glycoside analogs of GM4GM3 and other related gangliosides (Scheme 37)
Ganglioside GM4 is a very important cell adhesionmolecule The C-disaccharide of GM4 is currently beingsynthesized in Linhardtrsquos lab using standard O-glycosylationof C-disaccharide with protected ceramide Once theceramide has been attached it can be oxidized to afford analdehyde group for coupling to keyhole limpet hemocyanin
OBnO
OBn
BnO
O
OBnO
ClZnO
OBn
BnOCl
R
OBnO
O
OBn
BnOCl
ZnR
O
ZnR
OBnO
OBn
BnO
160 161
162163
O
OBn
OBnBnO
O
O
OBn
OBnBnO H
TMS
O
OBn
OBnBnO H
O
OBn
BnO
OBnHO
O
OBn
OBnBnO OH
TMS
OBnBnO HO
OBn
TMS
O
OR
ORRO H
O
OR
RO
OR
OBn
OBnBnO
H
TMS
O+
K2CO3 MeOH
1 n-BuLi THF -78 oC
2 164
164165 66
166α 60 166β 13167 97
BF3 Et 2O Et 3SiH -78 oC
168 85
169 R = Bn 83
170 R = H near quantitative yield
H2 (1 atm)Pd(OH) 2C
TMS-acetyl ene
n-BuLi THF -78 oC BF3 Et2O Et3SiH
-78 o C
1412 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
O
OHCOBn
OBnBnO
OMe
O
CO2MeAcO
OAcAcHN
OAc
SO2
NAcO
OBnH
H
OBn
OBn
H
O
OMeH HH
A
O
CO2MeAcO
OAcAcHN
OAc
O
OBnOMe
OBnOBn
HO
AcO
+
Nu
174175
176
SmI2 THF
Scheme (34)
Scheme (35)
Scheme (36)
O
BnO
BnO
BnO
Si lylO
O2S N
O
BnO
HO R2R1
BnOBnO
SilylO
OBnO
BnO
BnO
SilylO
Sm(III)
R1COR2 SmI2 THF
171 172
173
NHBoc
OAcO
AcO
AcHN O
O
CO2BnO
OO
OO
OH
O
CO2MeAcO
OAcAcHN
OAc
AcO
SO2Ph
R2
O
CO2Me
AcHN
OAc
AcO
R1
AcO
AcO
AcHNO CO2Bn
NHBoc
AcO
OAc
O
Zn(BH4)2
180 R1 R2 = H OH ( RS 11)
181 R1 R2 = O
182 R1 = H R2 = OH de gt 90
DMSO Ac2O
177178
179
13 steps
22 equiv SmI2 THF
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1413
Scheme (37)
Fig (2)
(KLH) by reductive amination for use as carbohydrate-basedvaccine GM3 a related trisaccharide containg gangliosideplays an important role in cell growth and differentiationFig 2 The synthesis of C-oligosaccharide GM3 is currentlyunderway following a similar route to that of C-GM4synthesis [42]
Beau also reported a sialyl C-disaccharide synthesiswhich relied on the unprecedented use of a stable andcrystalline 2-pyridyl sulfide of the N-acetylneuraminic acidderivative 189 as the anomeric precursor in a samarium-Reformastky procedure [43] The coupling procedure withsulfide 189 and aldehyde 190 afforded the carbon-linkeddimer 191 in 93 yield as a 11 diastereomeric mixture
Alcohols 191 were converted into thiocarbonates anddeoxygenated by employing triphenyltin hydride catalyticAIBN and pentafluorophenol which yielded C-disaccharide192 as a single compound in 65 yield for the 2 stepsDesilylation hydrogenolysis acetylation and finalacetolysis of the methyl glycoside provided the carbon-linked mimic 193 of the disaccharidic component of thesialylTn tumor antigen (Scheme 38)
4 CATIONIC METHODS
This section is categorized according to reactions thatinvolve the generation of anomeric ions followed by thecapture with sugar-based nucleophiles
OAcAcHN
OAc
AcO
O
OBnBnO
OBnOMP
HO
O
MeO2CAcO
O
MeO2CAcO
OAcAcHN
OAc
AcO
O
OHHO
OHOMP
HO
O
OBnOHC
OBnBnO
OMP
O
MeO2CAcO
OAcAcHN
OAc
AcO
O
OHHO
OHOMP
HO
O
CO2MeAcO
OAcAcHN
OAc
AcO
SO2Ph
O
MeO2CAcO
OAcAcHN
OAc
AcO
O
OAcAcO
OAcX
AcO
H2 PdC EtOAc CH3OHH2O
+
Ac2O Pyr
187 X = OMP
188 X = SPh 73
184 85 R and S mixture
186 90 for two i somers
+
SmI2 THF183
179
185
O
HO2 CHO
OAcAcHN
OH
HO
O
OHHO
OH
OAcO
(CH2 )12 CH3
HN
OH
(CH2)14CH3
O
O
O
OHHO
OH
O
O
HO2 CHO
OAcAcHN
OH
HO
O
OHHO
OH
O(CH2)12CH3
HN
OH
(CH2)1 4CH3
GM4
GM3
1414 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
41 Exo-glycals as Nucleophiles
Nitotra et al have found that treatment of exo-glycal 194with BF 3
OEt2 followed by a water quench afforded the C-disaccharide 195 (Scheme 39) It is noteworthy tonoteworthy that the attack of the enol ether on the anomericoxonium ion occurs with high stereoselectivity on the α-face only 195 was obtained [44]
42 Silyl-based Nucleophiles
Isobe has designed and developed alkynylation as a keyreaction for the introduction of a carbon chain onto sugarsThose alkynylated compounds are called ldquosugar acetylenesrdquo[45] The mechanism includes eliminative formation ofcation to which silylacetylene can coordinate on the α-face(Scheme 40)
Double C-glycosylation between glycal 198 and bis(silylacetylene) gave C-disaccharide ldquolikerdquo compounds 199and 200 (Scheme 41)
Silylpropargyl-sugar 201 smoothly reacted with D-glucalto furnish exclusively the α-acetylene glycoside product 202in 88 (Scheme 42) [46]
5 CYCLIZATION METHODOLOGY
This approach to C-oligosaccharide synthesis relies onthe coupling of an open chain fragment with an intact
monosaccharide to give an intermediate that is then cyclizedto deliver the C-oligosaccharide target This section isdivided by the type of chemistry used to initially assemblethe two pre-cyclization fragments
51 Wittig Reaction-Cyclization
The Kishi group was the first to use Wittig-cyclizationapproach to synthesize C-disaccharides Starting with Wittigreaction between 203 and 204 the intermediate 205 wasafforded as a single stereoisomer in 82 yield Osmylationthen gave a mixture of diols with the major one formed in a61 ratio Selective protection of the diols gave 206a and206b The mono-para-methoxybenzyl ether 206a was thentransformed into the hemiketal 207 in 75 overall yield inthree steps ie (1) Swern oxidation (2) acetonide hydro-lysis (4 N HClTHFrt) and (3) benzoylation (3 equiv ofPhCOClpyCH2Cl2rt) Silane reduction of 207 in an acidicmedium should preferentially yield the equatorially substi-tuted β-C-glycoside which was deblocked and converted tothe methyl- βminusC-disaccharide 209 Exact parallel experi-ments applied to the minor isomer gave the correspondingC-disaccharide 210 (Scheme 43) [47]
Armstrong has employed Wittig-osmylation protocol forthe preparation of a small library of α-C-(1rarr6)-disaccha-rides [48] Readily available allyl C-glycoside 211 washomologated to diene ester 212 and subjected to osmylation
Scheme (38)
O
CO2MeAcO
OAcAcHN
OAc
AcO
S(2-Py)
O
TESO
AcHNOMe
O
HO
O
CO2MeAcO
OAcAcHN
OAc
AcO
O NHAcOAc
OAc
OAc
O
CO2MeAcO
OAcAcHN
OAc
AcO
O NHAcOBn
OTES
OMe
OAc
AcO
O NHAcOBn
OTES
OMeOH
O
CO2 MeAcO
OAcAcHN
+
192 65
1 MeOHHCl2 H2 PdC EtOH3 Ac2O Pyr4 Ac2OAcOHH2SO4
193 59 overall yield
25 equiv SmI2 THF
1 11-thiocarbonyldiimidazole DMAP2 Ph3SnH cat AIBN
191 93
189
190
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1415
Scheme (39)
Scheme (40)
Scheme (41)
OBnO
OBn
OBn
OBnO
OBn
OBn
OBnO
OBn
OBn
OBnO
OBnCH3
BnO
OH
CH2
OBnO
OBn
CH3
OBn
H2 O
BF3 OEt2 MeCN
194
195 96
OOAc
OAc
AcO
R SiMe3
SnCl4
O
OAc
AcO
R
O
OAc
AcO
O
OAc
AcO
Me3Si
R
SiMe3
196
197
Me3 Si SiMe3
O
AcO
OAc
OAc
SiMe3
SiMe3
O
AcO
OAc
O
OAc
OAc
O
AcO
AcOO
OAc
OAc
SnCl4 CH2Cl2
SnCl4 CH2Cl2198
199
200
1416 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (42)
Scheme (43)
AcO
OAc
OAc
Me3 Si
BnO
OBn
BnO
OBn
AcO
OAc
BnO
OBn
BnO
OBn
+ I2 CH2Cl2
202 88
198 201
O
OBn
OBn
O
O
O
OBn
OBn
O
O
OBn
OBn O
OBn
OBn
O
OPBH2M
OH
OBnO
BnO
BnO
O
OBn
OBn
O
OHOPMB
OHO
HO
HO
O
OH
OHOH
OH
HOOMe
O
OBnOBn
O
Ph3P
O
O
OBn
OBn O
OBn
OBn
O
OPBM
OH
O O
CHO
OBn
BnO
OO
OBn
OBn
O
OHOPMB
BnO
BnO
BnO
OHO
HO
HO
O
OH
OHOH
OH
HOOMe
+ THF -78 oC
1 OsO4 pyr THF
2 NaH PMBBr
206a 206b 206a206b 61
1 Swern [O]2 4N HCl3 PhCOCl pyr
1 Swern [O]2 4N HCl3 PhCOCl pyr
1 PrSiH BF3 OEt2
2 H2 Pd(OH)2C
3 HCl MeOH 90 oC
1 PrSiH BF3 OEt2
2 H2 Pd(OH)2C
3 HCl MeOH 90 o C
203
204
205
207
209
208
210
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1417
followed by reduction to afford a 51 mixture (213214215216) of lactols that were readily separable by chromato-graphy Following a deprotection of an equimolar mixture of213 and 214 217 and the DL hybrid C-disaccharide of D-glucose-O-(1rarr6)-L-galactose 218 were obtained The DDand DL derivatives 219 and 220 of glucose-α-(1rarr6)-idosewere also obtained as a near equimolar mixture afterdeprotection of 215 and 216 (Scheme 44)
52 Anion Addition-Cyclization
Kishi developed an approach for the synthesis of theCndashtrehalo sugars which relied on nucleophilic addition ofone intact sugar fragment to a fundamental aldehyde ieKishi-Nozaki reaction [49] Coupling of monosaccharide221 and aldehyde 222 gave 223 The triple bond waspartially reduced and osmylation was followed by selectiveprotection to afford 224 The acetonide was converted toepoxide 225 by standard methods and removal of the PMBgroup Acid-catalyzed cyclization followed by aglyconichydrolysis and protection of hydroxyl group with (p-methoxyphenyl)diphenylmethyl chloride (MMTrCl) gave226 Inversion of the C-2 hydroxyl and removal of protectinggroups delivered α α-C-trehalose 227 (Scheme 44)
Kishi and co-workers also employed aldol reactions as anefficient access to the C-trisaccharide related to the type IIABO(H) blood group determinant [50] Aldol condensationof the enolate of methyl ketone 228 with aldehyde 229 gavea 41 mixture of hydroxy ketones 230 and 231 The majorketol was cyclized desulfurized and oxidized to afford thedisaccharide ketone 233 The ketone in THF was treatedwith LiHMDS (3 equiv) and TMEDA followed by theaddition of MgBr2 Addition of the aldehyde 234 led toalmost exclusive formation of the equatorial products 235and 236 in a 12 ratio Mesylation of 235 and 236 followedby treatment with liquid ammonia gave enones 237a and237b which were reduced to yield exclusively the C-2rsquo-equatorial ketone 238 Sodium borohydride reduction of theC-3rsquo carbonyl proceeded with the desired stereoselectivity toyield the protected C-trisaccharide 239 which wasdeblocked to provide the polyol 240 (Scheme 46)
Sutherlin and Amstrong cleverly applied a recursivestereochemical deconvolution (RSD) combinatorial approachfor the synthesis of a small library of C-trisaccharides aspotential inhibitors for the cell surface proteins of bacteriumHelicobactor pylori [51] The workers chose to carry outvariations in galactose ring of these trisaccharides An
Scheme (44)
OBnO
BnOOBn
OBn
P O
OEtOEtO
EtO
R H
OH
OH
OH
OH
O
R H
OH
OH
OH
OH
O
OHO
HOOH
OH
O
HO
OHOH
OH
OHO
HOOH
OH
O
HO
OH
OH
OHO
HOOH
OH
O
HO
OH
OHOH
R H
OH
OH
OH
OH
O
R
OBnO
BnOOBn
OBn
O
OHO
HOOH
OH
OO
HOHO
OH
R H
OH
OH
OH
OH
O
1 OsO4 NMO 50
2 DIBAL -32 oC 40
++ +
213 214 215 216
217 218 219 220
1 9-BBN H2O22 Swern [O]
3 t-BuOK
4 I2 C6H6212
211
1418 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
efficient Nozaki-Kishi coupling of vinyl bromide 241 withaldehyde 242 in a diasteromeric ratio of 12 followed byprotection with TBSOTf led to 243 and 244 Hydroborationfollowed by oxidation gave aldehydes 245 and 246respectively Addition of allylmagnesium bromide toaldehyde 245 followed by removal of the silyl groupafforded 247 to 246 giving 248 and 249 Epoxidation gave a11 mixture of the corresponding epoxides which werecyclized to give the C-trisaccharide 250-255 after removalof the benzyl groups (Scheme 47)
Schmidt reported a stereoselective 6-exo-trig selectiveelectrophilic cylization approach for de novo synthesis of amethylene-bridged Neu5Ac-α-(23)-Gal C-disaccharide theC-analog of an important motif in glycosphingolipids [52]The open chain precusors 259ab (a 32-mixture ofdiaseteromeric alcohols) were formed by the addition oflithiated iodide 256 to open chain aldehyde 258 Subsequent
C1 incorporation using Tebbe-reagent formation of a cycliccarbonate and deprotection of the two isopropylidene ketalsafforded tetrol 264 which upon treatment with phenylselenyltrifilate was steroselectively cyclized in a 6-exo-trigselective manner affording a diasteromeric mixture of 251and 252 in a ratio of 71 A seleno-Pummerer rearrangementto afford aldehyde 267 in 5 steps in 90 overall yieldOxidation of the aldehyde and subsequent steps led to thedesired C-disaccharide 268 (Scheme 48)
53 Esterification-Cyclization
Work from the Postema group has focused on a ringclosing metathesis (RCM) approach for the synthesis of C-saccharides [53a] The chemistry is versatile and has beenused for the synthesis of a small library of differentiallylinked β-C-disaccharides through a radical allylation-RCMstrategy [53b] The synthesis of the β-(1rarr4)-glucopyranosyl
Scheme (45)
O
OBn
BnO
BnO
BnO
I
CrCl2-NiCl2O
OBn
OH
BnO
BnO
BnO
O
O
O
O
O
H
OBn
O
O
OBnBnO
BnO
BnO
OOBn
OBn
OAc
PMBOHOO
OBn
BnO
BnO
BnO
O
OBn
OBn
OAc
O
OH
HO
HO
HO
OH
OH
OH
O
OH
O
OBn
BnO
BnO
BnO
OBn
OBn
OAc
O
MMTr
+
1 p-TsOH2 K2CO3 MeOH3 MMTrCl pyr
1 Swern [O]2 BH3 THF
3 AcOH-H2 O4 H2 Pd(OH)2
221
222
223
1 Pd-Pb CaCO3 H22 NaH BnBr3 OsO44 Bu2 SnO5 CsF PMB-Cl6 Ac2 O 4-DMAP
1 AcOH2 TsCl pyr
3 NaH-imid4 DDQ
224225
226 227
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1419
Scheme (46)
OBnO O
OBn
OMe
OBn
XY
SMe
OBnBnO
O
OBn
OBn
OBn
OBn
O
BnO
YX
OBn
TBSO
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnOOBn
H
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnO
OBn
OHC OBn
OBn
OTBS
OMe
BnOOBn
CHO
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnOOBn
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnO
OBn
YX
OBnO O
OBn
OMe
OBn
OBn
O
BnO
O
OBn
OBn
OBn
OBn
O 1 LiHMDS
2
228
1 TBAF THF
2 MeSH BF3 OEt2
230 X = OH Y = H231 X = H Y = OH
230231 41
1 Bu3SnH AIBN2 Swern [O]
1 LiHMDS THF-TMEDA2 MgBr23
1 MsCl
2 liquid NH3
235 X = OH Y = H236 X = H Y = OH Bu3 SnH AIBN
237a and 237b
NaBH4 MeOH
238
239 X = OBn
240 X = OHH2 Pd(OH)2
229
232233
234
1420 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (47)
OH C
O
O BnAcHN
OO
O
OBn OBnOBn
Br
O
OBn OBnOBn
O
OBnA cHN
OO
O TBSO
OBn O BnO Bn
O
OBnAcHN
OO
OTBS
S2
S1
S2
OTBSS1
O H
S2
OT BSS1
O H
MgBrMgBr
S2
O TBSS1
O H
S2
OHS1
OH
S2
OTBSS1
OH
O
OHHO
O H
O
HO
H OO
OBnA cH N
HO
H O
O
O HHO
OH
O
HOHO
O
OBnA cH N
HO
H O
O
OHH O
OH
O
H O
HOO
OBnAcHN
HO
HO
O
O HH O
OH
O
H O
H O O
OBnA cHN
HO
HO
O
O HH O
O H
O
HO
H O O
OBnAcHN
HO
HO
O
OHHO
OH
O
H O
O
OBnA cHN
HO
HOHO
+
241 242
1 CrCl2-NiCl2 T HF-DMF 722 TBSOTf 2 6-lutidine 91
243 244
1 9-BBN 602 Dess-Mart in period inane 97
1 9 -BBN 552 D ess-Martin periodinane 98
245 246
1
2 T BAF 74
1
2 TBAF 88
247 248 249
250
251
250 251 1 1 252 253 1 1 254 255 1 1
252
253
254
255
1 MCPBA2 CSA CH 2Cl2 61 fo r 2 steps3 H 2 Pd (O H)2C 95
1 MCPBA2 CSA CH 2Cl2 63 fo r 2 s teps3 H 2 Pd (OH)2C 87
1 MCPBA2 CSA CH2Cl2 80 for 2 steps3 H2 Pd(O H)2C 95
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1421
Scheme (48)
O
OO
Se Ph
R
O
HO OHOH
O
OB n O B n
OB n
O B nO O
O O
R O OR
X
O
OO
R
Se Ph
O
HOOH
OH
O
OB nOB n
O Bn
OB n
O O
O O
R O O R
O H
O
O B n OB n
O B n
OB n
O
C HO
O
O O
R O OR
OAc HN
OAc
C O2NH 4HOOH
OH
O
OH O H
OH OH
O
OB n O B n
OB n
OB nO O
O O
R O OR
X
O
O
OAcOAc
C HOA cOOAc
OAc
O
OB n O B n
OB n
OB n
O
O Bn OB n
OB n
OB n
X
OH
OO
HOOH
OH
O
O
OMeOB n
OB nOB n
R
t-B uL i256 R = Li
257 R = L i
258
(R = t-B uMe 2Si )
(R = t-B uMe 2Si )
259ab (32) 79 com bine d yi eld
De ss-Ma rtin pe riodinane
260 X = O R = t-B uMe 2Si ) 95
261 X = O R = t -B uMe2S i) 62
T e bbe re age nt
TB A F THF262 X = O R = H 94
diphosge ne
C H2C l 2Pyr
263 95
T HFH2O T FAr t
264 quant it a ti ve yie ld
PhSe C l AgOT f
EtC N -80 oC
265
266
Quant it at i ve yi l ed 25 26 7 1
+
R =
1 Ac 2OPyr
2 mC PB A3 Ac 2ONa OAc
4 NaO HT HFMe OH
5 Ac2O P yr
267 90 overa ll yi e ld
ste ps
268
1422 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
glucopyranoside 280 represents an example of thischemistry The known triacetyl glucopyranoside 269 wasconverted to iodide 270 in good yield Radical allylation of271 proceeded to afford a mixture of equatorial and axialallylation products in a 61 ratio Oxidative cleavage of thedouble bond gave the corresponding aldehydes 273a and273b which were separable Pinnick oxidation of the majoraldehyde 273a then gave the C-4 equatorial acid 274 DCC-mediated coupling of alcohol 275 and acid 274 proceeded toafford ester 276 in good yield Methylenation of 276 gave277 and exposure to catalysist 278 gave a 41 yield of theC-disaccharide glycal which was exposed to an excess ofBH3
THF to give 64 yield of the β-C-disaccharide 279Removal of the benzyl groups and global peracetylation gavethe peracetylated (1rarr4)-β-C-disaccharide 281 in good yield(Scheme 49)
54 Ring Expansion-Cyclization
Nelson developed a new strategy for asymmetric andstereoselective synthesis of C-linked disaccharide mimeticsthe C58-C71 fragment of palytoxin [54] The diol (RR)-282was converted into the di-dihydropyran (DHP) template 283284 and 285 The di-DHPs were functionized in a twodirectional sense using dihydroxylation reactions The two-directional approach was often very efficient indeed forexample in the synthesis of 286 six new stereogenic centerswere introduced with almost complete stereocontrol using areduction and a dihydroxylation reaction The approach isnot restricted to the synthesis of C2-symmetricaldisaccharide mimetics Using the unsymmetrical template285 which has both a pseudo-axial and a pseudo-equatorialhydroxyl groups the unsymmetrical mimetics 289 and 290were prepared (Scheme 50)
6 RADICAL APPROACHES
The radical approach for C-C bond formation is a popularmethod within organic chemistry The use of radicalchemistry in carbohydrate synthesis has certain advantagesFirstly the reaction conditions are very mild and tolerant ofa range of functional and protecting groups Secondanomeric radicals are stable with respect to elimination andepimeration Most significantly the chemistry required toincorporate an appropriate substitute at C-1 employed in theinitial hemolytic cleavage step is common within carbo-hydrate chemistry [55] The use of such radical techniquecan be subdivided into two classes intermolecular andintramolecular approaches
61 Intermolecular Radical Approaches
Giese was the first to employ an intermolecular radical-based approach for synthesis of C-disaccharides [56]Addition of an alkene to an anomeric radical underappropriate conditions allowed exclusive entry to the α-linked C-glycoside a result which was mirrored by the workof Baldwin [57] The high α-selectivity of the reaction wasin contrast with other reports Thus radicals generated at theC-2 C-3 and C-4 centers all preferred to occupy equatorialpositions [58] When the anomeric bromide 291 was treatedwith tin hydride and AIBN resulting anomeric radical andreacted with lactone 292 in a Michael addition it afforded293 In this reaction hydrogen abstraction at the resulting
radical center occurs from axial face to selectively generatethe equatorial C-2rsquo substituent Reduction and acetylation of293 furnished C-disaccharide 294 (Scheme 51) [59]
Witczak used the facial bias of levoglucosene tostereoselectively add a carbohydrate-based radical in thepreparation of the 3-deoxy-(1rarr4)-β-C-disaccharide 299[60] Addition of the radical derived from iodide 295 to 296gave adduct 297 in 26 yield Removal of the anomerichydroxyl of 297 was achieved by treatment with triethylsilane borontrifluoride ether complex followed bystereoselective reduction of the keto function at C-2rsquo withthe formation of 298 in 89 yield Debenzylation followedby acetolysis of 16-anhydro ring produced the peracetylatedtarget C-disaccharide 299 in 19 overall yield from 295(Scheme 52)
Vogel has developed general methods to transformenantiomerically pure 7-oxabicyclo[221]heptyl derivatives(ldquonaked sugarsrdquo) into C-disaccharides Because of thesechiral bicyclic skeletons they undergo highly stereoselectivereactions with predictable diasteroselectivities An arsenal ofmethods is available that allow to substitute these ldquonakedrdquocarbon centers with a variety of functional groups with allpossible relative configurations The methods allowpreparation of both enantiomers of a given target with thesame ease Predictably high stereoselectivity of the reactionsof the bicyclic chirons adds to the flexibility of approachwhich can lead to high molecular diversity [61]
α-C-(1rarr3)-mannopyranoside of N-acetyl-galactosaminepotent β-galactosidase inhibitors was synthesized by thisapproach [61] Enone 302 was readily prepared from 300The addition of the radical derived from bromide 303 toenone 302 afforded the αminusisomer 304 The ketone was thenreduced and the selenide eliminated via the intermediacy ofthe selenoxide to give 305 Acid-promoted (CF3SO3H) 7-oxa ring opening of 305 in MeCN produced the amino-conduritol derivative 306 resulting from the quenching of theallylic cation intermediate by the solvent (Ritter reaction)Ozonolysis of the chloroalkene 306 generated an acylchloride-aldehyde intermediate that reacted with MeOH toproduce a mixture of methyl uronates The major compound307 was silylated and reduced The crude polyol obtainedwas acetylated to produce 308 Desilylated and ammonolysisafforded a mixture of α-β-pyranoses 309 and correspondingα-β-furanoses (Scheme 53)
Similar chemistry was carried out to synthesize non-protected α-C(1rarr2)-L-fucopyranoside of D-galactopyrano-side corresponding to a blood group mimetic [62] Giesersquosradical fucosidation of racemic enone 310 with α-L-bromoacetofucose 311 provided the mixture of diastereo-meric α-C-fucoside 312a and 312b in reproducible yield of78 Reduction of the mixture gave a 11 mixture of endo-alcohols 313 and 314 which were isolated pure in 40 and355 yield respectively Oxidative elimination of thebenzeneselenyl group of 313 followed by acetylation gaveendo acetate 315 in 85 yield Acid-promoted ring openingof 315 and ozonolysis of the resulted chloroalkene gavemethyl uronic ester 316 in modest yield (10) Treatment of316 with Cl3CCN and NaH followed with BF3
OEt2
furnished the totally protected C-disaccharide 317 in 79
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1423
Scheme (49)
Bu3SnO
HOAcO
OMeOAc
OAc
O
AcO
OMeOAc
OAcI
AIBN
O
AcO
OMeOBn
OBn
HO2C O
AcO
OMeOR
ORY
X
OHBnO
BnO
OBn
OBnO
BnO
OBn
O
AcO
OMeOBn
OBnX
i-Pr i-Pr
N
Mo C(Me2 Ph)((CF3)2 MeCO)2
O
RO
OMeOR
O
RO
OR
OR
RO
OR
278
I2 Ph3P
imidazole
269 270 93
271a X = CH2CH=CH2 Y = H R = Ac 64271b Y = CH2CH=CH2 X = H R = Ac 11272a X = CH2CH=CH2 Y = H R = Bn 75272b Y = CH2CH=CH2 X = H R = Bn 75273a X = CH2CHO Y = H R = Bn 79273a Y = CH2CHO X = H R = Bn 79
1 NaOMe MeOH2 NaOH BnBr DMF
OsO4 NaIO4
NaClO2 NaH2PO4
274 96
275
DCC 4-DMAP
276 X = O 82
277 X = CH2 51
TiCl4 Zn dust TMEDA CH2Br2PbCl2 (Cat )
1
2 BH3 THF H2O2 NaOH
H2 PdC EtOH
Ac2 O Pyr 4-DMAP
279 R = Bn R = H 64
280 R = R = H 99
281 R = R =Ac 97
1424 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (50)
Scheme (51)
O OOH
OH
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
286
1 VO(acac)2 t-BuOH 95
2 (MeO)3CH BF3 90
1 P-O2NC6H4 CO2H Ph3P DIAD2 K2CO3 MeOH 82 over 2 steps
1 PhCOCl Et3N DMAP 402 P-O2NC6H4 CO2H Ph3P DIAD3 KOH THF-H2O 75 over 2 steps
TMEDA OsO4
Cat OsO4 NMO 287
Cat OsO4 NMO288
TMEDA OsO4
Cat OsO4 NMO
290
289
(RR)-282283
284
285
OHO
AcO
BrOAc
OAc
BnO
O
OBn
OBnO
OHO
AcOOAc
OAc
BnO
OOBn
OBnAcO
OHO
AcOOAc
OAc
BnO
O
OBn
OBnO
+
Bu3SnH AIBN291
292
293 81
1 Na[Al(OC2H4OMe)2(OEt)H]2 Ac2O pyr
294 56 over 2 steps
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1425
Scheme (52)
Scheme (53)
OBnO
BnOOBn
OBn O
OH
O
OBnO
BnO
OHOBn
OBn O
O
O
O
O
O
OBnO
BnOOBn
OBnO
OAcOAc
OAc
OBnO
BnO
OHOBn
OBn
IBu3SnH AIBN
295 297 26
1 BF3 OEt2 Et3SiH
2 L-Selectride THF
1 Pd(OH)2C C6H10 EtOH
2 EtSiOSO2CF3 Ac2O
298 89 over 2 steps299
296
O
O
PhSeClO
O
PhSeCl
Bu3 SnH
O
O
PhSeCl
R
H
O
OAc
R
Cl
O
AcO
OAc
OAc
OAcOH
Cl
NHAc
R
OAc
AcHN
OH
O
OH OAc
OH
OHO
HO
OH
O
AcO
OAc
OAc
OAcBr
O
O
PhSeCl
O
O
PhSeCl
R
O
OTIPSAcHNR
OAc OAc
O
OHAcHN
COOMe
R
OAc
1 Bu4NF
2 NH3MeOH
1 (Me3Si)2NLi THF2 Me2N=CHI
1 Bu3 SnH AIBN2
1 NaBH42 mCPBA3 Ac2O pyr
1 H+ MeCN
2 H2 O NaHCO3
R =
1 O3MeOH
2 Me2S NaHCO3
1 TIPSOTf 26-lut idine2 LiBH43 Ac2 O pyr DMAP
furanoses +
304 56
305 68 306 84307 50
308 46
300 301 302
303
309
1426 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
The reduction of 317 and treatment with DOWEX-H+ resinprovided the desired C-fucoside 318 in 70 (Scheme 54)
62 Intramolecular Radical Approaches
One disadvantage with the intermolecular approaches isthat during such radical mediated reactions electrondeficient alkenes are required to facilitate C-C bondformation The intramolecular approach of Sinayuml overcomes
this drawback by bring two substrates together via atemporary covalent silaketal connector This enables the useof a wider range of alkenes which can include alkene-functionalized sugars thus leading to the generation of C-disaccharides [63] Based on the early work of Stork Sinayumlemployed the tether reaction in the synthesis of both α- andβ-C-disaccharides with this work subsequently beingemployed in the synthesis of biologically significant natural
Scheme (54)
O
OH
Fuc
Cl
O
O
ClPhSe
OOAc
NHAcOHFuc
O
AcOOAc
AcO
Br
O
O
PhSeCl
O
AcOOAc
AcO
O
OH
PhSe Cl
Fuc
OOAc
NHAc
OMe
Fuc
O
AcHN
OH OAc
OH
O
OH
Me
OH
O
O
Fuc
ClSePh
O
HO
Fuc
ClSePh
+
Ph3SnHAIBN
78 combined yield
Fuc
310
+
1 NaBH4 MeOHTHF2 Chromatography
313 40 314 355
1 mCPBA
2 Ac2O pyr DMAP
+
315 75
1 TfOH MeCN
2 NaHCO3 O3 -78 oC
316 10 over 2 steps
1 Cl3 CCN NaH
2 MeOH BF3 OEt2
317 79
1 LiBH4 THF
2 Dowex-H+
311
312a312b
318 70 for 2 steps
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1427
products [64] The availability of different hydroxyl groupson each monosaccharide unit allowed the fine-tuning ofstereochemical outcome by selective positioning of the silyltether [65] Development of this early stereochemical controlled to the tethering of the donor 320 with alcohol 319through a di-isopropyl silicon tether 321 Subsequent treat-ment with Bu3SnH and AIBN led to a 9-endo-trigcyclization to form the C-disaccharide 322 in an 80 yieldwith exclusive formation of the α-product The silyl tetherwas removed with Bu4NF and deprotection under standardconditions afforded the desired disaccharide 323 in excellentyield (Scheme 55)
In parallel the development of a 32rsquo silyl tether allowedaccess to the β-linked product as demonstrated in Sinayumlrsquossynthesis of methyl β-C-lactoside 328 [66] Alcohol 324 and320 were connected via the dimethylsilyl tether an 8-endo-trig cyclization followed to exclusively afford the β-
disaccharide 326 in 45 yield Removal of the tether anddeprotection of benzyl ether gave β-C-disaccharide 328(Scheme 56)
This group also selected iodosugars bearing a freehydroxyl group as progenitors of the radical donors [67] In atypical experiment the radical donor 329 was connected tothe radical acceptor 330 through a silaketal tether followingtheir procedure Tributyltinhydride mediated 8-endo-trigradical cyclization of compound 331 gave after detetheringof the non isolated intermediate 332 the protected β-C-disaccharide 333 in 37 overall yield (from startingmaterials 330 and 329) Peracetate 335 was achieved afterhydrogenolysis The C-laminaribioside 334 is of potentialbiological interest as it mimics the repeating disaccharideunit of fungal β-(1rarr3)-glucans which have antitumor andimmunomodulating properties (Scheme 57)
Scheme (55)
Scheme (56)
OO
OHSePh
OTBDPSO O
OO
SePh
OTBDPSO
OO
OBnOMe
OBn
Si
O
HOOBn
OMe
OBn
O
HOOH
OHHO
O
HOOH
OMe
OH
OTBDPSO
O
HOOBn
OMe
OBnO
OOH
1 n-BuLi THF
2 iPr2SiCl2 -78 oC
3 DMAP THF rt
1 Bu4NF THF
2 Dowex-H+
3 H2 PdC
Bu3SnH AIBN toluene
319
320
321
322323
OBnO
OHSePh
OBnBnO
OHO
OBnOMe
OBn
ROO
ROOH
OR
OHO
OROMe
OR
OBnO
O
OBnBnO
OO
OBnOMe
OBn
Si
SePh
OBnO
O
OBnBnOO
OOBn
OMe
OBn
Si
1 PhSeH Me2SiCl2
BuLi -78 oC
2 imidazole rt
Bu3SnH AIBN toluene
H2 PdC327 R = Bn
328 R = H
Bu4NF THF
324
320
325
326 45
1428 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
CONCLUSIONS
In this paper the biological importance of C-oligo-saccharides as subunits of natural products and as a newgeneration of carbohydrate based on therapeutics has beenillustrated Different methods are available for the synthesisof C-oligosaccharides As with traditional saccharidesynthesis it has been necessary to develop a number ofspecific approaches to facilitate the regioselective andstereoselective preparation of the desired targets Work inthis area continues and it is expected that many interestingnew C-oligosaccharides will be prepared using the chemistrydescribed in this review It is also likely that new chemistrywill be developed in the future for the preparation of thesebiologically important targets
ACKNOWLEDGEMENTS
The authors thank Dr Sultan Baytas for her criticalreading of this manuscript
REFERENCES
[1] Kennedy J F White C A Bioactive Carbohydrates InChemistry Biochemistry and Biology Ellis Horwood LtdChichesterUK 1983
[2] Wassarman PW Mammalian Fertilization Molecular Aspects ofGamete Adhesion xocytosion Exocytosis and Fusion Cell 199996 175-183
[3] Carbohydrate-based Drug Discovery Wong C-H EdWeinheim Cambridge Wiley-VCH 2003
[4] (a) Sharon N Lis H Lectins as Cell Recognition MoleculesScience 1987 246 227-234 (b) Dwek RA Chem Rev 1996 96683-720
[5] Postema M C-Glycoside synthesis CRC Boc Ratom 1995[6] (a) Weatherman R V Mortell K H Cheruenak MKiessling
L L Toone E J Specificity of C-Glycoside Complexation byMannoseGlucose Specific Lectins Biochem 1996 35 3619-3624(b) Ravishankar R Surolia A Vijayan M Lim S Kishi YPreferred Conformation of C-Lactose at the Free and Peanut LectinBound States J Am Chem Soc1998 120 11297-11303
[7] (a)Wong C-H Halcomb R L Ichikawa Y and Kajimoto TEnzymes in organic synthesis Application to the problems ofcarbohydrate recognition part2 Angew Chem Int Ed Engl 199534 521-546 (b)Howard S Withers SG Bromoketone C-Glycosides a New Class of βminusGlucanase Inactivators J AmChem Soc 1998 120 10326-10331(c) Wang Q Wolff MPolat T Du Y Linhardt R J C-glycoside of Neuraminic Acidsas Neura-minidase Inhibitors Bioorg Med Lett 2000 10 941-944 (d) Phili R Chang J Partis R A Mueller R A ChrestF J Passaniti A The Alpha-glucosidase I InhibitorCastanospermine Alters Endothelial cell Glycosylation PreventsAngiogenesis and Inhibits Tumor Growth Cancer Res 1995 552927-2935
[8] Ossor A Elbein A D In Carbohydrates in Chemistry andBiology Vol 3(II) WileyVCH 2000 pp 513-539
[9] (a) Sinayuml P Synthesis of oligosaccharide Mimetics Pure ApplChem 1997 69 459-463 (b) Beau J-M Gallagher TNucleophilic C-glycosyl Donors for C-glycoside Synthesis Top inCurr Chem 1997 187 1-54 (c) Nicotra F Synthesis of C-glycosides of Biological Interest Top in Curr Chem 1997 187
Scheme (57)
O
O
O
Ph
I
OMe
OHO
BnO
OH
OH
BnOOH
O
BnO
Si
O
O O
Ph
I
OMe
O
O
BnO
OR4O
R5O
OMe
OR2
OR3O
R3O
OR1
R3O
Bu3 SnH AIBN
332 R1 R2 = SiMe2 R3 = Bn R4 R5 = CHPhTBAF THF
333 R1 = R2 = H R3 = Bn R4 = R5 = CHPh 37 from 11
334 R1 = R2 = R3 = R4 = R5 = H
335 R1 = R2 = R3 = R4 = R5 = Ac
329
H2 PdC MeOH
Ac2 O pyr
1 BuLi THF -78 oC
2 Me2SiCl2
3 DMAP
330
331
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1429
55-83 (d) Du Y Linhardt R Y Recent Adv in Stereo-SelectiveC-Glycoside Synthesis Tetrahedron Lett 1998 54 9913-9959 (e)Liu L Mckee M and Postema M H D Synthesis of C-saccharides and Higher Congeners Current Org Chem 2001 51133-1167
[10] Jarosz S Fraser-Reid B Synthesis of A Higher Carbon Sugar ViaDirected Aldol Condensation Tetrahedron Lett 1989 30 2359-2362
[11] Lichtenthaler F W Lergenmiiller M Schwidetzky S C-Glycosidations of 2-Ketohexosyl With Electrophilic Radical andNudeophilic Anomeric Carbons Eur J Org Chem 2003 3094-3103
[12] Baudat A Vogel P Aza-C-disaccharides Synthesis of 6-Deoxygalactonojirimycin-β-C(1rarr3) Linked with D-Altrofuranosides and D-Galactose J Org Chem 1997 62 6252-6260
[13] Turner D Vogel P Synthesis of 4-Hydroxy-26-Bis(hydroxymethyl) tetrahydropyran-2-Carbaldehyde DerivativesSynlett 1998 304-306
[14] Zhu Y-H Vogel P Short Stereoselective Synthesis of C-(1rarr3)-Linked Disaccharides Tetrahedron Lett 1998 39 31-34
[15] Zhu Y-H Vogel P Synthesis of a (2R 6R)-2-(Hydroxymethyl)-6-Propa-1 2-Dienyl-2H-Pyran-3(6H)-One Derivative A NewEnone for The Convergent Construction of C-Glycosides of C-Disaccharides Synlett 2001 82-86
[16] Baumberger F Vasella A Deoxynitrosugars The 6th
Communication Stereolectronic Control in the reductivedenitration of tertiary nitro ethers A Synthesis of ldquoC-glycosidesrdquoHelv Chim Acta 1983 66 2210-2221
[17] Martin O R Lai W Synthesis and Conformational Studies of β-(1rarr6)- and ββ-(1rarr1)-Linked C-disaccharides J Org Chem1993 58 176-185
[18] Spak S J Martin R The synthesis of an analogue of Methyl OC-Analogue of Methyl 4rsquo-O-β-D-GlucopyranosylgentiobiosideTetrahedron 2000 56 217-224
[19] Kobertz W R Bertozzi C R Bednarski M D C-GlycosylAldehyde Synthons for C-Linked Disaccharides J Org Chem1996 61 1894-1897
[20] Gurjar M K Nagaprasad R and Ramana CV First Synthesis ofMethyl α-C-D-Arabino-furanosyl-(1rarr5)-αminusD-Arabinofuranosidethe C-Disaccharide Segment of Motif C of MycobateriumTuberculosis Tetrahedron Lett 2000 43 7577-7579
[21] Witczak Z J Synthesis of C-Glycosyl Compounds and OtherNatural Products from Levoglucosenone Pure Appl Chem 199466 2189-2192
[22] Griffin F K Paterson D Taylor R J K Ramberg-BacklundApproaches to the Synthesis of C-Linked Disaccharides AngewChem Int Engl 1999 38 2939-2942
[23] Paterson B E Griffin F K Alcaraz M-L and Taylor R J KA Ramberg-Baumlcklund Approach to the Synthesis of C-GlycosidesC-Linked Disaccharides and C-Glycosyl Amino Acids Eur JOrg Chem 2002 1323-1336
[24] McAllister G D Paterson D E Taylor R J K A SimplifiedRamberg-Bachlund Approach to Novel C-Glycosides and C-Linked Disaccharides Angew Chem Int Ed Engl 2003 42 1387-1391
[25] McCartney J L Christopher T M Cicchillo R M BernardinaM D Wagner T R and Norris P J Org Chem 2003 6810152-10155
[26] Dondoni A Zuurmond H M Bascarate A Synthesis of α-andβ-D-(1rarr6)-C-Disaccharides by Witting Olefination of Formyl C-Glycosides with Glycopyranose 6-phosphoranes J Org Chem1997 62 8114-8124
[27] Dondoni A Kleban M Zuurmond H Marra A Synthesis of(1rarr6)-C-Oligogalactosides by Interative Wittig OlefinationTetrahedron Lett 1998 39 7991-7994
[28] Dondoni A Marra A A New Synthetic Approach toMycobacterial Cell Wall α-(1rarr5)-D-Arabinofuranosyl C-Oligosaccharides Teterahedron Lett 2003 44 4067-4071
[29] Colinas P A Ponzinibbio A Lieberknecht A and Bravo R OWittig Reaction of Glycosyl Phosphonium Salts A StereoselectiveRoute to C-Disaccharides and C O-Trisaccharides TetrahedronLett 2003 44 7985-7988
[30] Schmidt R R Preuss R Synthesis of Carbon Tetrahedron Lett1989 30 3409-3412
[31] Dietrich H Schmidt R R Synthesis of Carbon-Bridged C-Lactose and Derivatives Liebigs Ann Chem 1994 975-981
[32] Rouzaud D Sinayuml P The First Synthesis of a ldquoC-DisacchariderdquoJ Chem Soc Chem Commun 1983 1353-1354
[33] Xin Y-C Zhang Y-M Mallet J-M Glaudemans C P JSinayuml P Synthesis of C-Oligosaccharides That Mimie TheirNatural O-Analogues Immunodeterminants in Binding toMonoclonal Immunoglobulins Eur J Org Chem 1999 471-476
[34] Streicher H Geyer A Schmidt R R C-Disaccharides ofKetoses Chem Eur J 1996 2 502-510
[35] Leeuwenburgh M A Timmers C M Vander Marel G A VanBoom J H Mallet J-M Sinayuml P G Stereoselective Synthesisof α-C-(Alkynyl)-Glycosides Via Ring-Opening of α-12-Anhydrous Tetrahedron Lett 1997 38 6251-6254
[36] Aslam T Fuchs M G G Le Formal A Wightman R HSynthesis of C-Disaccharide Analogue of the α-D-Arabinofuranosyl-(1rarr5)-α-Arabinofuranosyl Motif ofMycobacterial Cells Walls via Alkynyl Intermediates TetrahedronLett 2005 46 3249-3252
[37] (a) Girad P Namy J L Kagan H B Divalent LanthanideDerivative in Organic Synthesis 1 Mild Preparation of SamariumIodide and Ytterbium Iodide and Their Use as Reducing orCoupling Agents J Am Chem Soc 1980 102 2693-2698 (b)Molander G A Harris C R Sequencing Reactions withSamarium(II) Iodide Chem Rev 1996 96 307-338
[38] (a) Mazeacuteas D Skrydstrup T Doumeix O Beau J-MSamarium Iodide-Induced Intramolecular C-Glycoside FormationEfficient Radical Formation in the Absence of an Additive AngewChem Int Ed Engl 1994 33 1383-1386 (b) Mazeacuteas DSkrydstrup T Beau J-M A Highly Stereoselective Synthesis of1 2-trans-C-Glycosides Via Glycosyl Samarium(III) CompoundsAngew Chem Int Ed Engl 1995 34 909-912 (c) Jarreton OSkrydstrup T Beau J-M The Stereospecific Synthesis of Methylα-C-Mannobioside A Potential Inhibitor of M TuberculosisBinding to Human Macrophages J Chem Soc Chem Commun1996 1661-1662 (d) Jarreton O Skrydstrup T Espionosa J-FJimeacutenez-Barbero J Beau J-M Samarium Diiode Prompted C-Glycosylation An Application to The Stereospecific Synthesis ofα-(1rarr2)-C-Mannobioside and Its Derivatives Chem Eur J 19995 430-441 (e) Mipuel N Doisneau G Beau J-M ReductiveSamariation of Anomeric 2-Pyridyl Sulfones with Catalytic AnUnexpected Improvement in The Synthesis of 12-Trans-Diequatorial C-Glycosyl Compounds Angew Chem Int Ed Engl 2000 39 4111-4114
[39] Vlahov I R Vlahova P I Linhardt R J DiastereocontrolledSynthesis of Carbon Glycosides of N-Acetylneuraminic Acid ViaGlycosyl Samarium(III) Intermediates JAmChem Soc 1997 1191480-1481
[40] Kuberan B Sikkander S ATomiyama H Linhardt R JSynthesis of a C-Glycoside Analogue of sTn An HIV-and Tumor-Associated Antigen Angew Chem Int Ed Engl 2003 42 2073-2075
[41] Bazin H G Du Y Polat T Linhardt R J Synthesis of aVersatile Neuraminic Acid ldquoCrdquo-Disaccharide Precursor for theSynthesis of C-Glycoside Analogues of Gangliosides J OrgChem 1999 64 7254-7259
[42] Chen C-C Ress D K Linhardt RJ Samarium Iodide-Mediated Synthesis of Neuraminic Acid C-Glycosides InSynthesis of Glycommetics Roy R Ed ACS Syposium Series2004 896 53-80
[43] Abdallah Z Doisneau G Beau J-M Synthesis of a Carbon-Linked Mimic of The Disaccharide Component of The Tumor-Relate SialyTn Antigen Angew Chem Int Ed Engl 2003 425209-5212
[44] Lay L Nicotra F Panza L Russo G Caneva E Synthesis ofC-disaccharides through dimerization of exo-glycals J Org Chem1992 57 1304-1306
[45] Isobe M Nishizawa R Hosokawa S Nishikawa TStereocontrolled Synthesis and Reactivity of Sugar Acetylenes JChem Soc Chem Commun 1998 2665-2676
[46] Saeeng R Sirion U Sahakitpichan P Isobe M IodineCatalyzes C-Glycosidation of D-Glucal with SilylacetykeneTetrahedron Lett 2003 44 6211-6215
[47] (a) Babirad S A Wang Y Kishi Y Synthesis of C-Disaccharides J Org Chem 1987 52 1370-1372 (b) Wang YBabirad S A Kishi Y Preferred Conformation of C-Glycosides
1430 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
8 Synthesis of 14-Linked Carbon Disaccharides J Org Chem1992 57 468-481
[48] Armstrong R W Sutherlin D P Strategies for the Synthesis ofC-Disaccharides Containing D and L Sugars Tetrahedron Lett1994 35 7743-7746
[49] Wei A Kishi Y Preferred Conformation of C-Glycosides 12Synthesis and Conformational Analysis of αα- α β- and β β-Trehaloses J Org Chem 1994 59 88-96
[50] Haneda T Goekjian P G Kim S H Kishi Y PreferredConformation of C-Glycosides 10 Synthesis and ConformationAnalysis of Carbon Trisaccharides J Org Chem 1992 57 490-498
[51] Sutherlin D P Armstrong R W Synthesis of 12 Stereochemistryand Structurally Diverse C-Trisaccharides J Org Chem 1997 625267-5283
[52] Notz W Hartel C Waldscheck B Schmidt R R De NovoSynthesis of a Methylene-Bridged Neu5Ac-α-(23)-Gal C-Disaccharide J Org Chem 2001 66 4250-4260
[53] (a) Postema M H D Calimente D Liu L Behrmanm T L AnOlefin Metathesis Route for the Preparation of (1rarr6)-Linked-C-Disaccharide Glycals A Convergent and Flexible Approach to C-Saccharide Synthesis J Org Chem 2000 65 6061-6068(b) Postema M H Piper J L Liu L Faust M Andreana PSynthesis and Partial Biological Evaluation of a Small Library ofDifferentially Linked β-C-Disaccharide J Org Chem 2003 684748-4754
[54] Nelson A The Development of Strategies and Methods for TheSynthesis of Biologically Active Compounds New J Chem 200428 771-776
[55] Togo H He W Waki Y Yokoyama M C-GlycosylationTechnology With Free Radiant Reactions Synlett 1998 700-717
[56] Giese B Dupuis J Diastereoselective Synthesis of C-Glycopyranosides Angew Chem Int Ed Engl 1983 22 622-623
[57] Adlington R M Baldwin J E Basak A Kozyrod RPApplication of Radical Addition Reactions to tho Synthesis of a C-Glucoside and A Functionalized Amino Acid J Chem SocChem Commun 1983 144-145
[58] Giese B Gonzaacutelez-Goacutemez J A Witzel T The Scope of RadicalCC-Coupling by The ldquoTin Methodrdquo Angew Chem Int Ed Engl1984 23 69-70
[59] Giese B Witzel T Synthesis of ldquoC-Disaccharidesrdquo by RadicalC-C Bond Formation Angew Chem Int Ed Engl 1986 25 450-451
[60] Witczak Z J Chhabra R Chojnacki J C-Disaccharides IStereoselective Approach to β-(1rarr4)-3-Deoxy-C-Disaccharidesfrom Levoglucosenone Carb Res 1997 301 167-175
[61] Vogel P Synthesis of Rare Carbohydrates and Analogues Startingfrom Enantiomerically Pure 7-Oxabicyclo[221]heptyl Derivatives(ldquoNaked Sugarsrdquo) Current Org Chem 2000 4 455-480
[62] Viodeacute C Vogel P Synthesis of The C-Disaccharide α-C(1rarr3)-L-Fucopyranoside of N-Acetylgalactosamine J Carb Chem2001 20 733-746
[63] Xin Y C Mallet J M Sinayuml P An Expeditious Synthesis of AC-Disaccharide Using A Temporary Silaketal Connection J ChemSoc Chem Commun 1993 864-865
[64] (a) Petitou M Herault P Lormeau J-C Helmboldt A MalletJ-M Sinayuml P Herbert J-M Introducing A C-InterglycosidicBond in A Biologically Active Pentasaccharide Hardly Affects ItsBiological Properties Bioorg Med Chem 1998 6 1509-1516 (b)Sinayuml P Advances in The Synthesis of the Carbohydrate MimicsPure Appl Chem 1998 70 1495-1499
[65] Sinayuml P Chemical Synthesis of Oligosaccharide Mimetics PureAppl Chem 1998 70 407-410
[66] Sinayuml P Chemical Synthesis of Oligosaccharide Mimetics PureAppl Chem 1998 69 459-463
[67] Vauzeilles B Sinayuml P Selective Radical Synthesis of β-C-Disaccharides Tetrahedron Lett 2001 42 7269-7272
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1411
Scheme (32)
Scheme (33)
and the chirality of each isomer assigned after acetylationConversion of the p-methoxyphenyl group in the peracety-lated (S) isomer 187 into the corresponding thiophenylglycoside 188 was accomplished affording the key inter-mediate for the synthesis of C-glycoside analogs of GM4GM3 and other related gangliosides (Scheme 37)
Ganglioside GM4 is a very important cell adhesionmolecule The C-disaccharide of GM4 is currently beingsynthesized in Linhardtrsquos lab using standard O-glycosylationof C-disaccharide with protected ceramide Once theceramide has been attached it can be oxidized to afford analdehyde group for coupling to keyhole limpet hemocyanin
OBnO
OBn
BnO
O
OBnO
ClZnO
OBn
BnOCl
R
OBnO
O
OBn
BnOCl
ZnR
O
ZnR
OBnO
OBn
BnO
160 161
162163
O
OBn
OBnBnO
O
O
OBn
OBnBnO H
TMS
O
OBn
OBnBnO H
O
OBn
BnO
OBnHO
O
OBn
OBnBnO OH
TMS
OBnBnO HO
OBn
TMS
O
OR
ORRO H
O
OR
RO
OR
OBn
OBnBnO
H
TMS
O+
K2CO3 MeOH
1 n-BuLi THF -78 oC
2 164
164165 66
166α 60 166β 13167 97
BF3 Et 2O Et 3SiH -78 oC
168 85
169 R = Bn 83
170 R = H near quantitative yield
H2 (1 atm)Pd(OH) 2C
TMS-acetyl ene
n-BuLi THF -78 oC BF3 Et2O Et3SiH
-78 o C
1412 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
O
OHCOBn
OBnBnO
OMe
O
CO2MeAcO
OAcAcHN
OAc
SO2
NAcO
OBnH
H
OBn
OBn
H
O
OMeH HH
A
O
CO2MeAcO
OAcAcHN
OAc
O
OBnOMe
OBnOBn
HO
AcO
+
Nu
174175
176
SmI2 THF
Scheme (34)
Scheme (35)
Scheme (36)
O
BnO
BnO
BnO
Si lylO
O2S N
O
BnO
HO R2R1
BnOBnO
SilylO
OBnO
BnO
BnO
SilylO
Sm(III)
R1COR2 SmI2 THF
171 172
173
NHBoc
OAcO
AcO
AcHN O
O
CO2BnO
OO
OO
OH
O
CO2MeAcO
OAcAcHN
OAc
AcO
SO2Ph
R2
O
CO2Me
AcHN
OAc
AcO
R1
AcO
AcO
AcHNO CO2Bn
NHBoc
AcO
OAc
O
Zn(BH4)2
180 R1 R2 = H OH ( RS 11)
181 R1 R2 = O
182 R1 = H R2 = OH de gt 90
DMSO Ac2O
177178
179
13 steps
22 equiv SmI2 THF
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1413
Scheme (37)
Fig (2)
(KLH) by reductive amination for use as carbohydrate-basedvaccine GM3 a related trisaccharide containg gangliosideplays an important role in cell growth and differentiationFig 2 The synthesis of C-oligosaccharide GM3 is currentlyunderway following a similar route to that of C-GM4synthesis [42]
Beau also reported a sialyl C-disaccharide synthesiswhich relied on the unprecedented use of a stable andcrystalline 2-pyridyl sulfide of the N-acetylneuraminic acidderivative 189 as the anomeric precursor in a samarium-Reformastky procedure [43] The coupling procedure withsulfide 189 and aldehyde 190 afforded the carbon-linkeddimer 191 in 93 yield as a 11 diastereomeric mixture
Alcohols 191 were converted into thiocarbonates anddeoxygenated by employing triphenyltin hydride catalyticAIBN and pentafluorophenol which yielded C-disaccharide192 as a single compound in 65 yield for the 2 stepsDesilylation hydrogenolysis acetylation and finalacetolysis of the methyl glycoside provided the carbon-linked mimic 193 of the disaccharidic component of thesialylTn tumor antigen (Scheme 38)
4 CATIONIC METHODS
This section is categorized according to reactions thatinvolve the generation of anomeric ions followed by thecapture with sugar-based nucleophiles
OAcAcHN
OAc
AcO
O
OBnBnO
OBnOMP
HO
O
MeO2CAcO
O
MeO2CAcO
OAcAcHN
OAc
AcO
O
OHHO
OHOMP
HO
O
OBnOHC
OBnBnO
OMP
O
MeO2CAcO
OAcAcHN
OAc
AcO
O
OHHO
OHOMP
HO
O
CO2MeAcO
OAcAcHN
OAc
AcO
SO2Ph
O
MeO2CAcO
OAcAcHN
OAc
AcO
O
OAcAcO
OAcX
AcO
H2 PdC EtOAc CH3OHH2O
+
Ac2O Pyr
187 X = OMP
188 X = SPh 73
184 85 R and S mixture
186 90 for two i somers
+
SmI2 THF183
179
185
O
HO2 CHO
OAcAcHN
OH
HO
O
OHHO
OH
OAcO
(CH2 )12 CH3
HN
OH
(CH2)14CH3
O
O
O
OHHO
OH
O
O
HO2 CHO
OAcAcHN
OH
HO
O
OHHO
OH
O(CH2)12CH3
HN
OH
(CH2)1 4CH3
GM4
GM3
1414 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
41 Exo-glycals as Nucleophiles
Nitotra et al have found that treatment of exo-glycal 194with BF 3
OEt2 followed by a water quench afforded the C-disaccharide 195 (Scheme 39) It is noteworthy tonoteworthy that the attack of the enol ether on the anomericoxonium ion occurs with high stereoselectivity on the α-face only 195 was obtained [44]
42 Silyl-based Nucleophiles
Isobe has designed and developed alkynylation as a keyreaction for the introduction of a carbon chain onto sugarsThose alkynylated compounds are called ldquosugar acetylenesrdquo[45] The mechanism includes eliminative formation ofcation to which silylacetylene can coordinate on the α-face(Scheme 40)
Double C-glycosylation between glycal 198 and bis(silylacetylene) gave C-disaccharide ldquolikerdquo compounds 199and 200 (Scheme 41)
Silylpropargyl-sugar 201 smoothly reacted with D-glucalto furnish exclusively the α-acetylene glycoside product 202in 88 (Scheme 42) [46]
5 CYCLIZATION METHODOLOGY
This approach to C-oligosaccharide synthesis relies onthe coupling of an open chain fragment with an intact
monosaccharide to give an intermediate that is then cyclizedto deliver the C-oligosaccharide target This section isdivided by the type of chemistry used to initially assemblethe two pre-cyclization fragments
51 Wittig Reaction-Cyclization
The Kishi group was the first to use Wittig-cyclizationapproach to synthesize C-disaccharides Starting with Wittigreaction between 203 and 204 the intermediate 205 wasafforded as a single stereoisomer in 82 yield Osmylationthen gave a mixture of diols with the major one formed in a61 ratio Selective protection of the diols gave 206a and206b The mono-para-methoxybenzyl ether 206a was thentransformed into the hemiketal 207 in 75 overall yield inthree steps ie (1) Swern oxidation (2) acetonide hydro-lysis (4 N HClTHFrt) and (3) benzoylation (3 equiv ofPhCOClpyCH2Cl2rt) Silane reduction of 207 in an acidicmedium should preferentially yield the equatorially substi-tuted β-C-glycoside which was deblocked and converted tothe methyl- βminusC-disaccharide 209 Exact parallel experi-ments applied to the minor isomer gave the correspondingC-disaccharide 210 (Scheme 43) [47]
Armstrong has employed Wittig-osmylation protocol forthe preparation of a small library of α-C-(1rarr6)-disaccha-rides [48] Readily available allyl C-glycoside 211 washomologated to diene ester 212 and subjected to osmylation
Scheme (38)
O
CO2MeAcO
OAcAcHN
OAc
AcO
S(2-Py)
O
TESO
AcHNOMe
O
HO
O
CO2MeAcO
OAcAcHN
OAc
AcO
O NHAcOAc
OAc
OAc
O
CO2MeAcO
OAcAcHN
OAc
AcO
O NHAcOBn
OTES
OMe
OAc
AcO
O NHAcOBn
OTES
OMeOH
O
CO2 MeAcO
OAcAcHN
+
192 65
1 MeOHHCl2 H2 PdC EtOH3 Ac2O Pyr4 Ac2OAcOHH2SO4
193 59 overall yield
25 equiv SmI2 THF
1 11-thiocarbonyldiimidazole DMAP2 Ph3SnH cat AIBN
191 93
189
190
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1415
Scheme (39)
Scheme (40)
Scheme (41)
OBnO
OBn
OBn
OBnO
OBn
OBn
OBnO
OBn
OBn
OBnO
OBnCH3
BnO
OH
CH2
OBnO
OBn
CH3
OBn
H2 O
BF3 OEt2 MeCN
194
195 96
OOAc
OAc
AcO
R SiMe3
SnCl4
O
OAc
AcO
R
O
OAc
AcO
O
OAc
AcO
Me3Si
R
SiMe3
196
197
Me3 Si SiMe3
O
AcO
OAc
OAc
SiMe3
SiMe3
O
AcO
OAc
O
OAc
OAc
O
AcO
AcOO
OAc
OAc
SnCl4 CH2Cl2
SnCl4 CH2Cl2198
199
200
1416 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (42)
Scheme (43)
AcO
OAc
OAc
Me3 Si
BnO
OBn
BnO
OBn
AcO
OAc
BnO
OBn
BnO
OBn
+ I2 CH2Cl2
202 88
198 201
O
OBn
OBn
O
O
O
OBn
OBn
O
O
OBn
OBn O
OBn
OBn
O
OPBH2M
OH
OBnO
BnO
BnO
O
OBn
OBn
O
OHOPMB
OHO
HO
HO
O
OH
OHOH
OH
HOOMe
O
OBnOBn
O
Ph3P
O
O
OBn
OBn O
OBn
OBn
O
OPBM
OH
O O
CHO
OBn
BnO
OO
OBn
OBn
O
OHOPMB
BnO
BnO
BnO
OHO
HO
HO
O
OH
OHOH
OH
HOOMe
+ THF -78 oC
1 OsO4 pyr THF
2 NaH PMBBr
206a 206b 206a206b 61
1 Swern [O]2 4N HCl3 PhCOCl pyr
1 Swern [O]2 4N HCl3 PhCOCl pyr
1 PrSiH BF3 OEt2
2 H2 Pd(OH)2C
3 HCl MeOH 90 oC
1 PrSiH BF3 OEt2
2 H2 Pd(OH)2C
3 HCl MeOH 90 o C
203
204
205
207
209
208
210
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1417
followed by reduction to afford a 51 mixture (213214215216) of lactols that were readily separable by chromato-graphy Following a deprotection of an equimolar mixture of213 and 214 217 and the DL hybrid C-disaccharide of D-glucose-O-(1rarr6)-L-galactose 218 were obtained The DDand DL derivatives 219 and 220 of glucose-α-(1rarr6)-idosewere also obtained as a near equimolar mixture afterdeprotection of 215 and 216 (Scheme 44)
52 Anion Addition-Cyclization
Kishi developed an approach for the synthesis of theCndashtrehalo sugars which relied on nucleophilic addition ofone intact sugar fragment to a fundamental aldehyde ieKishi-Nozaki reaction [49] Coupling of monosaccharide221 and aldehyde 222 gave 223 The triple bond waspartially reduced and osmylation was followed by selectiveprotection to afford 224 The acetonide was converted toepoxide 225 by standard methods and removal of the PMBgroup Acid-catalyzed cyclization followed by aglyconichydrolysis and protection of hydroxyl group with (p-methoxyphenyl)diphenylmethyl chloride (MMTrCl) gave226 Inversion of the C-2 hydroxyl and removal of protectinggroups delivered α α-C-trehalose 227 (Scheme 44)
Kishi and co-workers also employed aldol reactions as anefficient access to the C-trisaccharide related to the type IIABO(H) blood group determinant [50] Aldol condensationof the enolate of methyl ketone 228 with aldehyde 229 gavea 41 mixture of hydroxy ketones 230 and 231 The majorketol was cyclized desulfurized and oxidized to afford thedisaccharide ketone 233 The ketone in THF was treatedwith LiHMDS (3 equiv) and TMEDA followed by theaddition of MgBr2 Addition of the aldehyde 234 led toalmost exclusive formation of the equatorial products 235and 236 in a 12 ratio Mesylation of 235 and 236 followedby treatment with liquid ammonia gave enones 237a and237b which were reduced to yield exclusively the C-2rsquo-equatorial ketone 238 Sodium borohydride reduction of theC-3rsquo carbonyl proceeded with the desired stereoselectivity toyield the protected C-trisaccharide 239 which wasdeblocked to provide the polyol 240 (Scheme 46)
Sutherlin and Amstrong cleverly applied a recursivestereochemical deconvolution (RSD) combinatorial approachfor the synthesis of a small library of C-trisaccharides aspotential inhibitors for the cell surface proteins of bacteriumHelicobactor pylori [51] The workers chose to carry outvariations in galactose ring of these trisaccharides An
Scheme (44)
OBnO
BnOOBn
OBn
P O
OEtOEtO
EtO
R H
OH
OH
OH
OH
O
R H
OH
OH
OH
OH
O
OHO
HOOH
OH
O
HO
OHOH
OH
OHO
HOOH
OH
O
HO
OH
OH
OHO
HOOH
OH
O
HO
OH
OHOH
R H
OH
OH
OH
OH
O
R
OBnO
BnOOBn
OBn
O
OHO
HOOH
OH
OO
HOHO
OH
R H
OH
OH
OH
OH
O
1 OsO4 NMO 50
2 DIBAL -32 oC 40
++ +
213 214 215 216
217 218 219 220
1 9-BBN H2O22 Swern [O]
3 t-BuOK
4 I2 C6H6212
211
1418 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
efficient Nozaki-Kishi coupling of vinyl bromide 241 withaldehyde 242 in a diasteromeric ratio of 12 followed byprotection with TBSOTf led to 243 and 244 Hydroborationfollowed by oxidation gave aldehydes 245 and 246respectively Addition of allylmagnesium bromide toaldehyde 245 followed by removal of the silyl groupafforded 247 to 246 giving 248 and 249 Epoxidation gave a11 mixture of the corresponding epoxides which werecyclized to give the C-trisaccharide 250-255 after removalof the benzyl groups (Scheme 47)
Schmidt reported a stereoselective 6-exo-trig selectiveelectrophilic cylization approach for de novo synthesis of amethylene-bridged Neu5Ac-α-(23)-Gal C-disaccharide theC-analog of an important motif in glycosphingolipids [52]The open chain precusors 259ab (a 32-mixture ofdiaseteromeric alcohols) were formed by the addition oflithiated iodide 256 to open chain aldehyde 258 Subsequent
C1 incorporation using Tebbe-reagent formation of a cycliccarbonate and deprotection of the two isopropylidene ketalsafforded tetrol 264 which upon treatment with phenylselenyltrifilate was steroselectively cyclized in a 6-exo-trigselective manner affording a diasteromeric mixture of 251and 252 in a ratio of 71 A seleno-Pummerer rearrangementto afford aldehyde 267 in 5 steps in 90 overall yieldOxidation of the aldehyde and subsequent steps led to thedesired C-disaccharide 268 (Scheme 48)
53 Esterification-Cyclization
Work from the Postema group has focused on a ringclosing metathesis (RCM) approach for the synthesis of C-saccharides [53a] The chemistry is versatile and has beenused for the synthesis of a small library of differentiallylinked β-C-disaccharides through a radical allylation-RCMstrategy [53b] The synthesis of the β-(1rarr4)-glucopyranosyl
Scheme (45)
O
OBn
BnO
BnO
BnO
I
CrCl2-NiCl2O
OBn
OH
BnO
BnO
BnO
O
O
O
O
O
H
OBn
O
O
OBnBnO
BnO
BnO
OOBn
OBn
OAc
PMBOHOO
OBn
BnO
BnO
BnO
O
OBn
OBn
OAc
O
OH
HO
HO
HO
OH
OH
OH
O
OH
O
OBn
BnO
BnO
BnO
OBn
OBn
OAc
O
MMTr
+
1 p-TsOH2 K2CO3 MeOH3 MMTrCl pyr
1 Swern [O]2 BH3 THF
3 AcOH-H2 O4 H2 Pd(OH)2
221
222
223
1 Pd-Pb CaCO3 H22 NaH BnBr3 OsO44 Bu2 SnO5 CsF PMB-Cl6 Ac2 O 4-DMAP
1 AcOH2 TsCl pyr
3 NaH-imid4 DDQ
224225
226 227
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1419
Scheme (46)
OBnO O
OBn
OMe
OBn
XY
SMe
OBnBnO
O
OBn
OBn
OBn
OBn
O
BnO
YX
OBn
TBSO
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnOOBn
H
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnO
OBn
OHC OBn
OBn
OTBS
OMe
BnOOBn
CHO
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnOOBn
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnO
OBn
YX
OBnO O
OBn
OMe
OBn
OBn
O
BnO
O
OBn
OBn
OBn
OBn
O 1 LiHMDS
2
228
1 TBAF THF
2 MeSH BF3 OEt2
230 X = OH Y = H231 X = H Y = OH
230231 41
1 Bu3SnH AIBN2 Swern [O]
1 LiHMDS THF-TMEDA2 MgBr23
1 MsCl
2 liquid NH3
235 X = OH Y = H236 X = H Y = OH Bu3 SnH AIBN
237a and 237b
NaBH4 MeOH
238
239 X = OBn
240 X = OHH2 Pd(OH)2
229
232233
234
1420 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (47)
OH C
O
O BnAcHN
OO
O
OBn OBnOBn
Br
O
OBn OBnOBn
O
OBnA cHN
OO
O TBSO
OBn O BnO Bn
O
OBnAcHN
OO
OTBS
S2
S1
S2
OTBSS1
O H
S2
OT BSS1
O H
MgBrMgBr
S2
O TBSS1
O H
S2
OHS1
OH
S2
OTBSS1
OH
O
OHHO
O H
O
HO
H OO
OBnA cH N
HO
H O
O
O HHO
OH
O
HOHO
O
OBnA cH N
HO
H O
O
OHH O
OH
O
H O
HOO
OBnAcHN
HO
HO
O
O HH O
OH
O
H O
H O O
OBnA cHN
HO
HO
O
O HH O
O H
O
HO
H O O
OBnAcHN
HO
HO
O
OHHO
OH
O
H O
O
OBnA cHN
HO
HOHO
+
241 242
1 CrCl2-NiCl2 T HF-DMF 722 TBSOTf 2 6-lutidine 91
243 244
1 9-BBN 602 Dess-Mart in period inane 97
1 9 -BBN 552 D ess-Martin periodinane 98
245 246
1
2 T BAF 74
1
2 TBAF 88
247 248 249
250
251
250 251 1 1 252 253 1 1 254 255 1 1
252
253
254
255
1 MCPBA2 CSA CH 2Cl2 61 fo r 2 steps3 H 2 Pd (O H)2C 95
1 MCPBA2 CSA CH 2Cl2 63 fo r 2 s teps3 H 2 Pd (OH)2C 87
1 MCPBA2 CSA CH2Cl2 80 for 2 steps3 H2 Pd(O H)2C 95
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1421
Scheme (48)
O
OO
Se Ph
R
O
HO OHOH
O
OB n O B n
OB n
O B nO O
O O
R O OR
X
O
OO
R
Se Ph
O
HOOH
OH
O
OB nOB n
O Bn
OB n
O O
O O
R O O R
O H
O
O B n OB n
O B n
OB n
O
C HO
O
O O
R O OR
OAc HN
OAc
C O2NH 4HOOH
OH
O
OH O H
OH OH
O
OB n O B n
OB n
OB nO O
O O
R O OR
X
O
O
OAcOAc
C HOA cOOAc
OAc
O
OB n O B n
OB n
OB n
O
O Bn OB n
OB n
OB n
X
OH
OO
HOOH
OH
O
O
OMeOB n
OB nOB n
R
t-B uL i256 R = Li
257 R = L i
258
(R = t-B uMe 2Si )
(R = t-B uMe 2Si )
259ab (32) 79 com bine d yi eld
De ss-Ma rtin pe riodinane
260 X = O R = t-B uMe 2Si ) 95
261 X = O R = t -B uMe2S i) 62
T e bbe re age nt
TB A F THF262 X = O R = H 94
diphosge ne
C H2C l 2Pyr
263 95
T HFH2O T FAr t
264 quant it a ti ve yie ld
PhSe C l AgOT f
EtC N -80 oC
265
266
Quant it at i ve yi l ed 25 26 7 1
+
R =
1 Ac 2OPyr
2 mC PB A3 Ac 2ONa OAc
4 NaO HT HFMe OH
5 Ac2O P yr
267 90 overa ll yi e ld
ste ps
268
1422 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
glucopyranoside 280 represents an example of thischemistry The known triacetyl glucopyranoside 269 wasconverted to iodide 270 in good yield Radical allylation of271 proceeded to afford a mixture of equatorial and axialallylation products in a 61 ratio Oxidative cleavage of thedouble bond gave the corresponding aldehydes 273a and273b which were separable Pinnick oxidation of the majoraldehyde 273a then gave the C-4 equatorial acid 274 DCC-mediated coupling of alcohol 275 and acid 274 proceeded toafford ester 276 in good yield Methylenation of 276 gave277 and exposure to catalysist 278 gave a 41 yield of theC-disaccharide glycal which was exposed to an excess ofBH3
THF to give 64 yield of the β-C-disaccharide 279Removal of the benzyl groups and global peracetylation gavethe peracetylated (1rarr4)-β-C-disaccharide 281 in good yield(Scheme 49)
54 Ring Expansion-Cyclization
Nelson developed a new strategy for asymmetric andstereoselective synthesis of C-linked disaccharide mimeticsthe C58-C71 fragment of palytoxin [54] The diol (RR)-282was converted into the di-dihydropyran (DHP) template 283284 and 285 The di-DHPs were functionized in a twodirectional sense using dihydroxylation reactions The two-directional approach was often very efficient indeed forexample in the synthesis of 286 six new stereogenic centerswere introduced with almost complete stereocontrol using areduction and a dihydroxylation reaction The approach isnot restricted to the synthesis of C2-symmetricaldisaccharide mimetics Using the unsymmetrical template285 which has both a pseudo-axial and a pseudo-equatorialhydroxyl groups the unsymmetrical mimetics 289 and 290were prepared (Scheme 50)
6 RADICAL APPROACHES
The radical approach for C-C bond formation is a popularmethod within organic chemistry The use of radicalchemistry in carbohydrate synthesis has certain advantagesFirstly the reaction conditions are very mild and tolerant ofa range of functional and protecting groups Secondanomeric radicals are stable with respect to elimination andepimeration Most significantly the chemistry required toincorporate an appropriate substitute at C-1 employed in theinitial hemolytic cleavage step is common within carbo-hydrate chemistry [55] The use of such radical techniquecan be subdivided into two classes intermolecular andintramolecular approaches
61 Intermolecular Radical Approaches
Giese was the first to employ an intermolecular radical-based approach for synthesis of C-disaccharides [56]Addition of an alkene to an anomeric radical underappropriate conditions allowed exclusive entry to the α-linked C-glycoside a result which was mirrored by the workof Baldwin [57] The high α-selectivity of the reaction wasin contrast with other reports Thus radicals generated at theC-2 C-3 and C-4 centers all preferred to occupy equatorialpositions [58] When the anomeric bromide 291 was treatedwith tin hydride and AIBN resulting anomeric radical andreacted with lactone 292 in a Michael addition it afforded293 In this reaction hydrogen abstraction at the resulting
radical center occurs from axial face to selectively generatethe equatorial C-2rsquo substituent Reduction and acetylation of293 furnished C-disaccharide 294 (Scheme 51) [59]
Witczak used the facial bias of levoglucosene tostereoselectively add a carbohydrate-based radical in thepreparation of the 3-deoxy-(1rarr4)-β-C-disaccharide 299[60] Addition of the radical derived from iodide 295 to 296gave adduct 297 in 26 yield Removal of the anomerichydroxyl of 297 was achieved by treatment with triethylsilane borontrifluoride ether complex followed bystereoselective reduction of the keto function at C-2rsquo withthe formation of 298 in 89 yield Debenzylation followedby acetolysis of 16-anhydro ring produced the peracetylatedtarget C-disaccharide 299 in 19 overall yield from 295(Scheme 52)
Vogel has developed general methods to transformenantiomerically pure 7-oxabicyclo[221]heptyl derivatives(ldquonaked sugarsrdquo) into C-disaccharides Because of thesechiral bicyclic skeletons they undergo highly stereoselectivereactions with predictable diasteroselectivities An arsenal ofmethods is available that allow to substitute these ldquonakedrdquocarbon centers with a variety of functional groups with allpossible relative configurations The methods allowpreparation of both enantiomers of a given target with thesame ease Predictably high stereoselectivity of the reactionsof the bicyclic chirons adds to the flexibility of approachwhich can lead to high molecular diversity [61]
α-C-(1rarr3)-mannopyranoside of N-acetyl-galactosaminepotent β-galactosidase inhibitors was synthesized by thisapproach [61] Enone 302 was readily prepared from 300The addition of the radical derived from bromide 303 toenone 302 afforded the αminusisomer 304 The ketone was thenreduced and the selenide eliminated via the intermediacy ofthe selenoxide to give 305 Acid-promoted (CF3SO3H) 7-oxa ring opening of 305 in MeCN produced the amino-conduritol derivative 306 resulting from the quenching of theallylic cation intermediate by the solvent (Ritter reaction)Ozonolysis of the chloroalkene 306 generated an acylchloride-aldehyde intermediate that reacted with MeOH toproduce a mixture of methyl uronates The major compound307 was silylated and reduced The crude polyol obtainedwas acetylated to produce 308 Desilylated and ammonolysisafforded a mixture of α-β-pyranoses 309 and correspondingα-β-furanoses (Scheme 53)
Similar chemistry was carried out to synthesize non-protected α-C(1rarr2)-L-fucopyranoside of D-galactopyrano-side corresponding to a blood group mimetic [62] Giesersquosradical fucosidation of racemic enone 310 with α-L-bromoacetofucose 311 provided the mixture of diastereo-meric α-C-fucoside 312a and 312b in reproducible yield of78 Reduction of the mixture gave a 11 mixture of endo-alcohols 313 and 314 which were isolated pure in 40 and355 yield respectively Oxidative elimination of thebenzeneselenyl group of 313 followed by acetylation gaveendo acetate 315 in 85 yield Acid-promoted ring openingof 315 and ozonolysis of the resulted chloroalkene gavemethyl uronic ester 316 in modest yield (10) Treatment of316 with Cl3CCN and NaH followed with BF3
OEt2
furnished the totally protected C-disaccharide 317 in 79
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1423
Scheme (49)
Bu3SnO
HOAcO
OMeOAc
OAc
O
AcO
OMeOAc
OAcI
AIBN
O
AcO
OMeOBn
OBn
HO2C O
AcO
OMeOR
ORY
X
OHBnO
BnO
OBn
OBnO
BnO
OBn
O
AcO
OMeOBn
OBnX
i-Pr i-Pr
N
Mo C(Me2 Ph)((CF3)2 MeCO)2
O
RO
OMeOR
O
RO
OR
OR
RO
OR
278
I2 Ph3P
imidazole
269 270 93
271a X = CH2CH=CH2 Y = H R = Ac 64271b Y = CH2CH=CH2 X = H R = Ac 11272a X = CH2CH=CH2 Y = H R = Bn 75272b Y = CH2CH=CH2 X = H R = Bn 75273a X = CH2CHO Y = H R = Bn 79273a Y = CH2CHO X = H R = Bn 79
1 NaOMe MeOH2 NaOH BnBr DMF
OsO4 NaIO4
NaClO2 NaH2PO4
274 96
275
DCC 4-DMAP
276 X = O 82
277 X = CH2 51
TiCl4 Zn dust TMEDA CH2Br2PbCl2 (Cat )
1
2 BH3 THF H2O2 NaOH
H2 PdC EtOH
Ac2 O Pyr 4-DMAP
279 R = Bn R = H 64
280 R = R = H 99
281 R = R =Ac 97
1424 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (50)
Scheme (51)
O OOH
OH
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
286
1 VO(acac)2 t-BuOH 95
2 (MeO)3CH BF3 90
1 P-O2NC6H4 CO2H Ph3P DIAD2 K2CO3 MeOH 82 over 2 steps
1 PhCOCl Et3N DMAP 402 P-O2NC6H4 CO2H Ph3P DIAD3 KOH THF-H2O 75 over 2 steps
TMEDA OsO4
Cat OsO4 NMO 287
Cat OsO4 NMO288
TMEDA OsO4
Cat OsO4 NMO
290
289
(RR)-282283
284
285
OHO
AcO
BrOAc
OAc
BnO
O
OBn
OBnO
OHO
AcOOAc
OAc
BnO
OOBn
OBnAcO
OHO
AcOOAc
OAc
BnO
O
OBn
OBnO
+
Bu3SnH AIBN291
292
293 81
1 Na[Al(OC2H4OMe)2(OEt)H]2 Ac2O pyr
294 56 over 2 steps
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1425
Scheme (52)
Scheme (53)
OBnO
BnOOBn
OBn O
OH
O
OBnO
BnO
OHOBn
OBn O
O
O
O
O
O
OBnO
BnOOBn
OBnO
OAcOAc
OAc
OBnO
BnO
OHOBn
OBn
IBu3SnH AIBN
295 297 26
1 BF3 OEt2 Et3SiH
2 L-Selectride THF
1 Pd(OH)2C C6H10 EtOH
2 EtSiOSO2CF3 Ac2O
298 89 over 2 steps299
296
O
O
PhSeClO
O
PhSeCl
Bu3 SnH
O
O
PhSeCl
R
H
O
OAc
R
Cl
O
AcO
OAc
OAc
OAcOH
Cl
NHAc
R
OAc
AcHN
OH
O
OH OAc
OH
OHO
HO
OH
O
AcO
OAc
OAc
OAcBr
O
O
PhSeCl
O
O
PhSeCl
R
O
OTIPSAcHNR
OAc OAc
O
OHAcHN
COOMe
R
OAc
1 Bu4NF
2 NH3MeOH
1 (Me3Si)2NLi THF2 Me2N=CHI
1 Bu3 SnH AIBN2
1 NaBH42 mCPBA3 Ac2O pyr
1 H+ MeCN
2 H2 O NaHCO3
R =
1 O3MeOH
2 Me2S NaHCO3
1 TIPSOTf 26-lut idine2 LiBH43 Ac2 O pyr DMAP
furanoses +
304 56
305 68 306 84307 50
308 46
300 301 302
303
309
1426 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
The reduction of 317 and treatment with DOWEX-H+ resinprovided the desired C-fucoside 318 in 70 (Scheme 54)
62 Intramolecular Radical Approaches
One disadvantage with the intermolecular approaches isthat during such radical mediated reactions electrondeficient alkenes are required to facilitate C-C bondformation The intramolecular approach of Sinayuml overcomes
this drawback by bring two substrates together via atemporary covalent silaketal connector This enables the useof a wider range of alkenes which can include alkene-functionalized sugars thus leading to the generation of C-disaccharides [63] Based on the early work of Stork Sinayumlemployed the tether reaction in the synthesis of both α- andβ-C-disaccharides with this work subsequently beingemployed in the synthesis of biologically significant natural
Scheme (54)
O
OH
Fuc
Cl
O
O
ClPhSe
OOAc
NHAcOHFuc
O
AcOOAc
AcO
Br
O
O
PhSeCl
O
AcOOAc
AcO
O
OH
PhSe Cl
Fuc
OOAc
NHAc
OMe
Fuc
O
AcHN
OH OAc
OH
O
OH
Me
OH
O
O
Fuc
ClSePh
O
HO
Fuc
ClSePh
+
Ph3SnHAIBN
78 combined yield
Fuc
310
+
1 NaBH4 MeOHTHF2 Chromatography
313 40 314 355
1 mCPBA
2 Ac2O pyr DMAP
+
315 75
1 TfOH MeCN
2 NaHCO3 O3 -78 oC
316 10 over 2 steps
1 Cl3 CCN NaH
2 MeOH BF3 OEt2
317 79
1 LiBH4 THF
2 Dowex-H+
311
312a312b
318 70 for 2 steps
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1427
products [64] The availability of different hydroxyl groupson each monosaccharide unit allowed the fine-tuning ofstereochemical outcome by selective positioning of the silyltether [65] Development of this early stereochemical controlled to the tethering of the donor 320 with alcohol 319through a di-isopropyl silicon tether 321 Subsequent treat-ment with Bu3SnH and AIBN led to a 9-endo-trigcyclization to form the C-disaccharide 322 in an 80 yieldwith exclusive formation of the α-product The silyl tetherwas removed with Bu4NF and deprotection under standardconditions afforded the desired disaccharide 323 in excellentyield (Scheme 55)
In parallel the development of a 32rsquo silyl tether allowedaccess to the β-linked product as demonstrated in Sinayumlrsquossynthesis of methyl β-C-lactoside 328 [66] Alcohol 324 and320 were connected via the dimethylsilyl tether an 8-endo-trig cyclization followed to exclusively afford the β-
disaccharide 326 in 45 yield Removal of the tether anddeprotection of benzyl ether gave β-C-disaccharide 328(Scheme 56)
This group also selected iodosugars bearing a freehydroxyl group as progenitors of the radical donors [67] In atypical experiment the radical donor 329 was connected tothe radical acceptor 330 through a silaketal tether followingtheir procedure Tributyltinhydride mediated 8-endo-trigradical cyclization of compound 331 gave after detetheringof the non isolated intermediate 332 the protected β-C-disaccharide 333 in 37 overall yield (from startingmaterials 330 and 329) Peracetate 335 was achieved afterhydrogenolysis The C-laminaribioside 334 is of potentialbiological interest as it mimics the repeating disaccharideunit of fungal β-(1rarr3)-glucans which have antitumor andimmunomodulating properties (Scheme 57)
Scheme (55)
Scheme (56)
OO
OHSePh
OTBDPSO O
OO
SePh
OTBDPSO
OO
OBnOMe
OBn
Si
O
HOOBn
OMe
OBn
O
HOOH
OHHO
O
HOOH
OMe
OH
OTBDPSO
O
HOOBn
OMe
OBnO
OOH
1 n-BuLi THF
2 iPr2SiCl2 -78 oC
3 DMAP THF rt
1 Bu4NF THF
2 Dowex-H+
3 H2 PdC
Bu3SnH AIBN toluene
319
320
321
322323
OBnO
OHSePh
OBnBnO
OHO
OBnOMe
OBn
ROO
ROOH
OR
OHO
OROMe
OR
OBnO
O
OBnBnO
OO
OBnOMe
OBn
Si
SePh
OBnO
O
OBnBnOO
OOBn
OMe
OBn
Si
1 PhSeH Me2SiCl2
BuLi -78 oC
2 imidazole rt
Bu3SnH AIBN toluene
H2 PdC327 R = Bn
328 R = H
Bu4NF THF
324
320
325
326 45
1428 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
CONCLUSIONS
In this paper the biological importance of C-oligo-saccharides as subunits of natural products and as a newgeneration of carbohydrate based on therapeutics has beenillustrated Different methods are available for the synthesisof C-oligosaccharides As with traditional saccharidesynthesis it has been necessary to develop a number ofspecific approaches to facilitate the regioselective andstereoselective preparation of the desired targets Work inthis area continues and it is expected that many interestingnew C-oligosaccharides will be prepared using the chemistrydescribed in this review It is also likely that new chemistrywill be developed in the future for the preparation of thesebiologically important targets
ACKNOWLEDGEMENTS
The authors thank Dr Sultan Baytas for her criticalreading of this manuscript
REFERENCES
[1] Kennedy J F White C A Bioactive Carbohydrates InChemistry Biochemistry and Biology Ellis Horwood LtdChichesterUK 1983
[2] Wassarman PW Mammalian Fertilization Molecular Aspects ofGamete Adhesion xocytosion Exocytosis and Fusion Cell 199996 175-183
[3] Carbohydrate-based Drug Discovery Wong C-H EdWeinheim Cambridge Wiley-VCH 2003
[4] (a) Sharon N Lis H Lectins as Cell Recognition MoleculesScience 1987 246 227-234 (b) Dwek RA Chem Rev 1996 96683-720
[5] Postema M C-Glycoside synthesis CRC Boc Ratom 1995[6] (a) Weatherman R V Mortell K H Cheruenak MKiessling
L L Toone E J Specificity of C-Glycoside Complexation byMannoseGlucose Specific Lectins Biochem 1996 35 3619-3624(b) Ravishankar R Surolia A Vijayan M Lim S Kishi YPreferred Conformation of C-Lactose at the Free and Peanut LectinBound States J Am Chem Soc1998 120 11297-11303
[7] (a)Wong C-H Halcomb R L Ichikawa Y and Kajimoto TEnzymes in organic synthesis Application to the problems ofcarbohydrate recognition part2 Angew Chem Int Ed Engl 199534 521-546 (b)Howard S Withers SG Bromoketone C-Glycosides a New Class of βminusGlucanase Inactivators J AmChem Soc 1998 120 10326-10331(c) Wang Q Wolff MPolat T Du Y Linhardt R J C-glycoside of Neuraminic Acidsas Neura-minidase Inhibitors Bioorg Med Lett 2000 10 941-944 (d) Phili R Chang J Partis R A Mueller R A ChrestF J Passaniti A The Alpha-glucosidase I InhibitorCastanospermine Alters Endothelial cell Glycosylation PreventsAngiogenesis and Inhibits Tumor Growth Cancer Res 1995 552927-2935
[8] Ossor A Elbein A D In Carbohydrates in Chemistry andBiology Vol 3(II) WileyVCH 2000 pp 513-539
[9] (a) Sinayuml P Synthesis of oligosaccharide Mimetics Pure ApplChem 1997 69 459-463 (b) Beau J-M Gallagher TNucleophilic C-glycosyl Donors for C-glycoside Synthesis Top inCurr Chem 1997 187 1-54 (c) Nicotra F Synthesis of C-glycosides of Biological Interest Top in Curr Chem 1997 187
Scheme (57)
O
O
O
Ph
I
OMe
OHO
BnO
OH
OH
BnOOH
O
BnO
Si
O
O O
Ph
I
OMe
O
O
BnO
OR4O
R5O
OMe
OR2
OR3O
R3O
OR1
R3O
Bu3 SnH AIBN
332 R1 R2 = SiMe2 R3 = Bn R4 R5 = CHPhTBAF THF
333 R1 = R2 = H R3 = Bn R4 = R5 = CHPh 37 from 11
334 R1 = R2 = R3 = R4 = R5 = H
335 R1 = R2 = R3 = R4 = R5 = Ac
329
H2 PdC MeOH
Ac2 O pyr
1 BuLi THF -78 oC
2 Me2SiCl2
3 DMAP
330
331
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1429
55-83 (d) Du Y Linhardt R Y Recent Adv in Stereo-SelectiveC-Glycoside Synthesis Tetrahedron Lett 1998 54 9913-9959 (e)Liu L Mckee M and Postema M H D Synthesis of C-saccharides and Higher Congeners Current Org Chem 2001 51133-1167
[10] Jarosz S Fraser-Reid B Synthesis of A Higher Carbon Sugar ViaDirected Aldol Condensation Tetrahedron Lett 1989 30 2359-2362
[11] Lichtenthaler F W Lergenmiiller M Schwidetzky S C-Glycosidations of 2-Ketohexosyl With Electrophilic Radical andNudeophilic Anomeric Carbons Eur J Org Chem 2003 3094-3103
[12] Baudat A Vogel P Aza-C-disaccharides Synthesis of 6-Deoxygalactonojirimycin-β-C(1rarr3) Linked with D-Altrofuranosides and D-Galactose J Org Chem 1997 62 6252-6260
[13] Turner D Vogel P Synthesis of 4-Hydroxy-26-Bis(hydroxymethyl) tetrahydropyran-2-Carbaldehyde DerivativesSynlett 1998 304-306
[14] Zhu Y-H Vogel P Short Stereoselective Synthesis of C-(1rarr3)-Linked Disaccharides Tetrahedron Lett 1998 39 31-34
[15] Zhu Y-H Vogel P Synthesis of a (2R 6R)-2-(Hydroxymethyl)-6-Propa-1 2-Dienyl-2H-Pyran-3(6H)-One Derivative A NewEnone for The Convergent Construction of C-Glycosides of C-Disaccharides Synlett 2001 82-86
[16] Baumberger F Vasella A Deoxynitrosugars The 6th
Communication Stereolectronic Control in the reductivedenitration of tertiary nitro ethers A Synthesis of ldquoC-glycosidesrdquoHelv Chim Acta 1983 66 2210-2221
[17] Martin O R Lai W Synthesis and Conformational Studies of β-(1rarr6)- and ββ-(1rarr1)-Linked C-disaccharides J Org Chem1993 58 176-185
[18] Spak S J Martin R The synthesis of an analogue of Methyl OC-Analogue of Methyl 4rsquo-O-β-D-GlucopyranosylgentiobiosideTetrahedron 2000 56 217-224
[19] Kobertz W R Bertozzi C R Bednarski M D C-GlycosylAldehyde Synthons for C-Linked Disaccharides J Org Chem1996 61 1894-1897
[20] Gurjar M K Nagaprasad R and Ramana CV First Synthesis ofMethyl α-C-D-Arabino-furanosyl-(1rarr5)-αminusD-Arabinofuranosidethe C-Disaccharide Segment of Motif C of MycobateriumTuberculosis Tetrahedron Lett 2000 43 7577-7579
[21] Witczak Z J Synthesis of C-Glycosyl Compounds and OtherNatural Products from Levoglucosenone Pure Appl Chem 199466 2189-2192
[22] Griffin F K Paterson D Taylor R J K Ramberg-BacklundApproaches to the Synthesis of C-Linked Disaccharides AngewChem Int Engl 1999 38 2939-2942
[23] Paterson B E Griffin F K Alcaraz M-L and Taylor R J KA Ramberg-Baumlcklund Approach to the Synthesis of C-GlycosidesC-Linked Disaccharides and C-Glycosyl Amino Acids Eur JOrg Chem 2002 1323-1336
[24] McAllister G D Paterson D E Taylor R J K A SimplifiedRamberg-Bachlund Approach to Novel C-Glycosides and C-Linked Disaccharides Angew Chem Int Ed Engl 2003 42 1387-1391
[25] McCartney J L Christopher T M Cicchillo R M BernardinaM D Wagner T R and Norris P J Org Chem 2003 6810152-10155
[26] Dondoni A Zuurmond H M Bascarate A Synthesis of α-andβ-D-(1rarr6)-C-Disaccharides by Witting Olefination of Formyl C-Glycosides with Glycopyranose 6-phosphoranes J Org Chem1997 62 8114-8124
[27] Dondoni A Kleban M Zuurmond H Marra A Synthesis of(1rarr6)-C-Oligogalactosides by Interative Wittig OlefinationTetrahedron Lett 1998 39 7991-7994
[28] Dondoni A Marra A A New Synthetic Approach toMycobacterial Cell Wall α-(1rarr5)-D-Arabinofuranosyl C-Oligosaccharides Teterahedron Lett 2003 44 4067-4071
[29] Colinas P A Ponzinibbio A Lieberknecht A and Bravo R OWittig Reaction of Glycosyl Phosphonium Salts A StereoselectiveRoute to C-Disaccharides and C O-Trisaccharides TetrahedronLett 2003 44 7985-7988
[30] Schmidt R R Preuss R Synthesis of Carbon Tetrahedron Lett1989 30 3409-3412
[31] Dietrich H Schmidt R R Synthesis of Carbon-Bridged C-Lactose and Derivatives Liebigs Ann Chem 1994 975-981
[32] Rouzaud D Sinayuml P The First Synthesis of a ldquoC-DisacchariderdquoJ Chem Soc Chem Commun 1983 1353-1354
[33] Xin Y-C Zhang Y-M Mallet J-M Glaudemans C P JSinayuml P Synthesis of C-Oligosaccharides That Mimie TheirNatural O-Analogues Immunodeterminants in Binding toMonoclonal Immunoglobulins Eur J Org Chem 1999 471-476
[34] Streicher H Geyer A Schmidt R R C-Disaccharides ofKetoses Chem Eur J 1996 2 502-510
[35] Leeuwenburgh M A Timmers C M Vander Marel G A VanBoom J H Mallet J-M Sinayuml P G Stereoselective Synthesisof α-C-(Alkynyl)-Glycosides Via Ring-Opening of α-12-Anhydrous Tetrahedron Lett 1997 38 6251-6254
[36] Aslam T Fuchs M G G Le Formal A Wightman R HSynthesis of C-Disaccharide Analogue of the α-D-Arabinofuranosyl-(1rarr5)-α-Arabinofuranosyl Motif ofMycobacterial Cells Walls via Alkynyl Intermediates TetrahedronLett 2005 46 3249-3252
[37] (a) Girad P Namy J L Kagan H B Divalent LanthanideDerivative in Organic Synthesis 1 Mild Preparation of SamariumIodide and Ytterbium Iodide and Their Use as Reducing orCoupling Agents J Am Chem Soc 1980 102 2693-2698 (b)Molander G A Harris C R Sequencing Reactions withSamarium(II) Iodide Chem Rev 1996 96 307-338
[38] (a) Mazeacuteas D Skrydstrup T Doumeix O Beau J-MSamarium Iodide-Induced Intramolecular C-Glycoside FormationEfficient Radical Formation in the Absence of an Additive AngewChem Int Ed Engl 1994 33 1383-1386 (b) Mazeacuteas DSkrydstrup T Beau J-M A Highly Stereoselective Synthesis of1 2-trans-C-Glycosides Via Glycosyl Samarium(III) CompoundsAngew Chem Int Ed Engl 1995 34 909-912 (c) Jarreton OSkrydstrup T Beau J-M The Stereospecific Synthesis of Methylα-C-Mannobioside A Potential Inhibitor of M TuberculosisBinding to Human Macrophages J Chem Soc Chem Commun1996 1661-1662 (d) Jarreton O Skrydstrup T Espionosa J-FJimeacutenez-Barbero J Beau J-M Samarium Diiode Prompted C-Glycosylation An Application to The Stereospecific Synthesis ofα-(1rarr2)-C-Mannobioside and Its Derivatives Chem Eur J 19995 430-441 (e) Mipuel N Doisneau G Beau J-M ReductiveSamariation of Anomeric 2-Pyridyl Sulfones with Catalytic AnUnexpected Improvement in The Synthesis of 12-Trans-Diequatorial C-Glycosyl Compounds Angew Chem Int Ed Engl 2000 39 4111-4114
[39] Vlahov I R Vlahova P I Linhardt R J DiastereocontrolledSynthesis of Carbon Glycosides of N-Acetylneuraminic Acid ViaGlycosyl Samarium(III) Intermediates JAmChem Soc 1997 1191480-1481
[40] Kuberan B Sikkander S ATomiyama H Linhardt R JSynthesis of a C-Glycoside Analogue of sTn An HIV-and Tumor-Associated Antigen Angew Chem Int Ed Engl 2003 42 2073-2075
[41] Bazin H G Du Y Polat T Linhardt R J Synthesis of aVersatile Neuraminic Acid ldquoCrdquo-Disaccharide Precursor for theSynthesis of C-Glycoside Analogues of Gangliosides J OrgChem 1999 64 7254-7259
[42] Chen C-C Ress D K Linhardt RJ Samarium Iodide-Mediated Synthesis of Neuraminic Acid C-Glycosides InSynthesis of Glycommetics Roy R Ed ACS Syposium Series2004 896 53-80
[43] Abdallah Z Doisneau G Beau J-M Synthesis of a Carbon-Linked Mimic of The Disaccharide Component of The Tumor-Relate SialyTn Antigen Angew Chem Int Ed Engl 2003 425209-5212
[44] Lay L Nicotra F Panza L Russo G Caneva E Synthesis ofC-disaccharides through dimerization of exo-glycals J Org Chem1992 57 1304-1306
[45] Isobe M Nishizawa R Hosokawa S Nishikawa TStereocontrolled Synthesis and Reactivity of Sugar Acetylenes JChem Soc Chem Commun 1998 2665-2676
[46] Saeeng R Sirion U Sahakitpichan P Isobe M IodineCatalyzes C-Glycosidation of D-Glucal with SilylacetykeneTetrahedron Lett 2003 44 6211-6215
[47] (a) Babirad S A Wang Y Kishi Y Synthesis of C-Disaccharides J Org Chem 1987 52 1370-1372 (b) Wang YBabirad S A Kishi Y Preferred Conformation of C-Glycosides
1430 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
8 Synthesis of 14-Linked Carbon Disaccharides J Org Chem1992 57 468-481
[48] Armstrong R W Sutherlin D P Strategies for the Synthesis ofC-Disaccharides Containing D and L Sugars Tetrahedron Lett1994 35 7743-7746
[49] Wei A Kishi Y Preferred Conformation of C-Glycosides 12Synthesis and Conformational Analysis of αα- α β- and β β-Trehaloses J Org Chem 1994 59 88-96
[50] Haneda T Goekjian P G Kim S H Kishi Y PreferredConformation of C-Glycosides 10 Synthesis and ConformationAnalysis of Carbon Trisaccharides J Org Chem 1992 57 490-498
[51] Sutherlin D P Armstrong R W Synthesis of 12 Stereochemistryand Structurally Diverse C-Trisaccharides J Org Chem 1997 625267-5283
[52] Notz W Hartel C Waldscheck B Schmidt R R De NovoSynthesis of a Methylene-Bridged Neu5Ac-α-(23)-Gal C-Disaccharide J Org Chem 2001 66 4250-4260
[53] (a) Postema M H D Calimente D Liu L Behrmanm T L AnOlefin Metathesis Route for the Preparation of (1rarr6)-Linked-C-Disaccharide Glycals A Convergent and Flexible Approach to C-Saccharide Synthesis J Org Chem 2000 65 6061-6068(b) Postema M H Piper J L Liu L Faust M Andreana PSynthesis and Partial Biological Evaluation of a Small Library ofDifferentially Linked β-C-Disaccharide J Org Chem 2003 684748-4754
[54] Nelson A The Development of Strategies and Methods for TheSynthesis of Biologically Active Compounds New J Chem 200428 771-776
[55] Togo H He W Waki Y Yokoyama M C-GlycosylationTechnology With Free Radiant Reactions Synlett 1998 700-717
[56] Giese B Dupuis J Diastereoselective Synthesis of C-Glycopyranosides Angew Chem Int Ed Engl 1983 22 622-623
[57] Adlington R M Baldwin J E Basak A Kozyrod RPApplication of Radical Addition Reactions to tho Synthesis of a C-Glucoside and A Functionalized Amino Acid J Chem SocChem Commun 1983 144-145
[58] Giese B Gonzaacutelez-Goacutemez J A Witzel T The Scope of RadicalCC-Coupling by The ldquoTin Methodrdquo Angew Chem Int Ed Engl1984 23 69-70
[59] Giese B Witzel T Synthesis of ldquoC-Disaccharidesrdquo by RadicalC-C Bond Formation Angew Chem Int Ed Engl 1986 25 450-451
[60] Witczak Z J Chhabra R Chojnacki J C-Disaccharides IStereoselective Approach to β-(1rarr4)-3-Deoxy-C-Disaccharidesfrom Levoglucosenone Carb Res 1997 301 167-175
[61] Vogel P Synthesis of Rare Carbohydrates and Analogues Startingfrom Enantiomerically Pure 7-Oxabicyclo[221]heptyl Derivatives(ldquoNaked Sugarsrdquo) Current Org Chem 2000 4 455-480
[62] Viodeacute C Vogel P Synthesis of The C-Disaccharide α-C(1rarr3)-L-Fucopyranoside of N-Acetylgalactosamine J Carb Chem2001 20 733-746
[63] Xin Y C Mallet J M Sinayuml P An Expeditious Synthesis of AC-Disaccharide Using A Temporary Silaketal Connection J ChemSoc Chem Commun 1993 864-865
[64] (a) Petitou M Herault P Lormeau J-C Helmboldt A MalletJ-M Sinayuml P Herbert J-M Introducing A C-InterglycosidicBond in A Biologically Active Pentasaccharide Hardly Affects ItsBiological Properties Bioorg Med Chem 1998 6 1509-1516 (b)Sinayuml P Advances in The Synthesis of the Carbohydrate MimicsPure Appl Chem 1998 70 1495-1499
[65] Sinayuml P Chemical Synthesis of Oligosaccharide Mimetics PureAppl Chem 1998 70 407-410
[66] Sinayuml P Chemical Synthesis of Oligosaccharide Mimetics PureAppl Chem 1998 69 459-463
[67] Vauzeilles B Sinayuml P Selective Radical Synthesis of β-C-Disaccharides Tetrahedron Lett 2001 42 7269-7272
1412 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
O
OHCOBn
OBnBnO
OMe
O
CO2MeAcO
OAcAcHN
OAc
SO2
NAcO
OBnH
H
OBn
OBn
H
O
OMeH HH
A
O
CO2MeAcO
OAcAcHN
OAc
O
OBnOMe
OBnOBn
HO
AcO
+
Nu
174175
176
SmI2 THF
Scheme (34)
Scheme (35)
Scheme (36)
O
BnO
BnO
BnO
Si lylO
O2S N
O
BnO
HO R2R1
BnOBnO
SilylO
OBnO
BnO
BnO
SilylO
Sm(III)
R1COR2 SmI2 THF
171 172
173
NHBoc
OAcO
AcO
AcHN O
O
CO2BnO
OO
OO
OH
O
CO2MeAcO
OAcAcHN
OAc
AcO
SO2Ph
R2
O
CO2Me
AcHN
OAc
AcO
R1
AcO
AcO
AcHNO CO2Bn
NHBoc
AcO
OAc
O
Zn(BH4)2
180 R1 R2 = H OH ( RS 11)
181 R1 R2 = O
182 R1 = H R2 = OH de gt 90
DMSO Ac2O
177178
179
13 steps
22 equiv SmI2 THF
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1413
Scheme (37)
Fig (2)
(KLH) by reductive amination for use as carbohydrate-basedvaccine GM3 a related trisaccharide containg gangliosideplays an important role in cell growth and differentiationFig 2 The synthesis of C-oligosaccharide GM3 is currentlyunderway following a similar route to that of C-GM4synthesis [42]
Beau also reported a sialyl C-disaccharide synthesiswhich relied on the unprecedented use of a stable andcrystalline 2-pyridyl sulfide of the N-acetylneuraminic acidderivative 189 as the anomeric precursor in a samarium-Reformastky procedure [43] The coupling procedure withsulfide 189 and aldehyde 190 afforded the carbon-linkeddimer 191 in 93 yield as a 11 diastereomeric mixture
Alcohols 191 were converted into thiocarbonates anddeoxygenated by employing triphenyltin hydride catalyticAIBN and pentafluorophenol which yielded C-disaccharide192 as a single compound in 65 yield for the 2 stepsDesilylation hydrogenolysis acetylation and finalacetolysis of the methyl glycoside provided the carbon-linked mimic 193 of the disaccharidic component of thesialylTn tumor antigen (Scheme 38)
4 CATIONIC METHODS
This section is categorized according to reactions thatinvolve the generation of anomeric ions followed by thecapture with sugar-based nucleophiles
OAcAcHN
OAc
AcO
O
OBnBnO
OBnOMP
HO
O
MeO2CAcO
O
MeO2CAcO
OAcAcHN
OAc
AcO
O
OHHO
OHOMP
HO
O
OBnOHC
OBnBnO
OMP
O
MeO2CAcO
OAcAcHN
OAc
AcO
O
OHHO
OHOMP
HO
O
CO2MeAcO
OAcAcHN
OAc
AcO
SO2Ph
O
MeO2CAcO
OAcAcHN
OAc
AcO
O
OAcAcO
OAcX
AcO
H2 PdC EtOAc CH3OHH2O
+
Ac2O Pyr
187 X = OMP
188 X = SPh 73
184 85 R and S mixture
186 90 for two i somers
+
SmI2 THF183
179
185
O
HO2 CHO
OAcAcHN
OH
HO
O
OHHO
OH
OAcO
(CH2 )12 CH3
HN
OH
(CH2)14CH3
O
O
O
OHHO
OH
O
O
HO2 CHO
OAcAcHN
OH
HO
O
OHHO
OH
O(CH2)12CH3
HN
OH
(CH2)1 4CH3
GM4
GM3
1414 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
41 Exo-glycals as Nucleophiles
Nitotra et al have found that treatment of exo-glycal 194with BF 3
OEt2 followed by a water quench afforded the C-disaccharide 195 (Scheme 39) It is noteworthy tonoteworthy that the attack of the enol ether on the anomericoxonium ion occurs with high stereoselectivity on the α-face only 195 was obtained [44]
42 Silyl-based Nucleophiles
Isobe has designed and developed alkynylation as a keyreaction for the introduction of a carbon chain onto sugarsThose alkynylated compounds are called ldquosugar acetylenesrdquo[45] The mechanism includes eliminative formation ofcation to which silylacetylene can coordinate on the α-face(Scheme 40)
Double C-glycosylation between glycal 198 and bis(silylacetylene) gave C-disaccharide ldquolikerdquo compounds 199and 200 (Scheme 41)
Silylpropargyl-sugar 201 smoothly reacted with D-glucalto furnish exclusively the α-acetylene glycoside product 202in 88 (Scheme 42) [46]
5 CYCLIZATION METHODOLOGY
This approach to C-oligosaccharide synthesis relies onthe coupling of an open chain fragment with an intact
monosaccharide to give an intermediate that is then cyclizedto deliver the C-oligosaccharide target This section isdivided by the type of chemistry used to initially assemblethe two pre-cyclization fragments
51 Wittig Reaction-Cyclization
The Kishi group was the first to use Wittig-cyclizationapproach to synthesize C-disaccharides Starting with Wittigreaction between 203 and 204 the intermediate 205 wasafforded as a single stereoisomer in 82 yield Osmylationthen gave a mixture of diols with the major one formed in a61 ratio Selective protection of the diols gave 206a and206b The mono-para-methoxybenzyl ether 206a was thentransformed into the hemiketal 207 in 75 overall yield inthree steps ie (1) Swern oxidation (2) acetonide hydro-lysis (4 N HClTHFrt) and (3) benzoylation (3 equiv ofPhCOClpyCH2Cl2rt) Silane reduction of 207 in an acidicmedium should preferentially yield the equatorially substi-tuted β-C-glycoside which was deblocked and converted tothe methyl- βminusC-disaccharide 209 Exact parallel experi-ments applied to the minor isomer gave the correspondingC-disaccharide 210 (Scheme 43) [47]
Armstrong has employed Wittig-osmylation protocol forthe preparation of a small library of α-C-(1rarr6)-disaccha-rides [48] Readily available allyl C-glycoside 211 washomologated to diene ester 212 and subjected to osmylation
Scheme (38)
O
CO2MeAcO
OAcAcHN
OAc
AcO
S(2-Py)
O
TESO
AcHNOMe
O
HO
O
CO2MeAcO
OAcAcHN
OAc
AcO
O NHAcOAc
OAc
OAc
O
CO2MeAcO
OAcAcHN
OAc
AcO
O NHAcOBn
OTES
OMe
OAc
AcO
O NHAcOBn
OTES
OMeOH
O
CO2 MeAcO
OAcAcHN
+
192 65
1 MeOHHCl2 H2 PdC EtOH3 Ac2O Pyr4 Ac2OAcOHH2SO4
193 59 overall yield
25 equiv SmI2 THF
1 11-thiocarbonyldiimidazole DMAP2 Ph3SnH cat AIBN
191 93
189
190
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1415
Scheme (39)
Scheme (40)
Scheme (41)
OBnO
OBn
OBn
OBnO
OBn
OBn
OBnO
OBn
OBn
OBnO
OBnCH3
BnO
OH
CH2
OBnO
OBn
CH3
OBn
H2 O
BF3 OEt2 MeCN
194
195 96
OOAc
OAc
AcO
R SiMe3
SnCl4
O
OAc
AcO
R
O
OAc
AcO
O
OAc
AcO
Me3Si
R
SiMe3
196
197
Me3 Si SiMe3
O
AcO
OAc
OAc
SiMe3
SiMe3
O
AcO
OAc
O
OAc
OAc
O
AcO
AcOO
OAc
OAc
SnCl4 CH2Cl2
SnCl4 CH2Cl2198
199
200
1416 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (42)
Scheme (43)
AcO
OAc
OAc
Me3 Si
BnO
OBn
BnO
OBn
AcO
OAc
BnO
OBn
BnO
OBn
+ I2 CH2Cl2
202 88
198 201
O
OBn
OBn
O
O
O
OBn
OBn
O
O
OBn
OBn O
OBn
OBn
O
OPBH2M
OH
OBnO
BnO
BnO
O
OBn
OBn
O
OHOPMB
OHO
HO
HO
O
OH
OHOH
OH
HOOMe
O
OBnOBn
O
Ph3P
O
O
OBn
OBn O
OBn
OBn
O
OPBM
OH
O O
CHO
OBn
BnO
OO
OBn
OBn
O
OHOPMB
BnO
BnO
BnO
OHO
HO
HO
O
OH
OHOH
OH
HOOMe
+ THF -78 oC
1 OsO4 pyr THF
2 NaH PMBBr
206a 206b 206a206b 61
1 Swern [O]2 4N HCl3 PhCOCl pyr
1 Swern [O]2 4N HCl3 PhCOCl pyr
1 PrSiH BF3 OEt2
2 H2 Pd(OH)2C
3 HCl MeOH 90 oC
1 PrSiH BF3 OEt2
2 H2 Pd(OH)2C
3 HCl MeOH 90 o C
203
204
205
207
209
208
210
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1417
followed by reduction to afford a 51 mixture (213214215216) of lactols that were readily separable by chromato-graphy Following a deprotection of an equimolar mixture of213 and 214 217 and the DL hybrid C-disaccharide of D-glucose-O-(1rarr6)-L-galactose 218 were obtained The DDand DL derivatives 219 and 220 of glucose-α-(1rarr6)-idosewere also obtained as a near equimolar mixture afterdeprotection of 215 and 216 (Scheme 44)
52 Anion Addition-Cyclization
Kishi developed an approach for the synthesis of theCndashtrehalo sugars which relied on nucleophilic addition ofone intact sugar fragment to a fundamental aldehyde ieKishi-Nozaki reaction [49] Coupling of monosaccharide221 and aldehyde 222 gave 223 The triple bond waspartially reduced and osmylation was followed by selectiveprotection to afford 224 The acetonide was converted toepoxide 225 by standard methods and removal of the PMBgroup Acid-catalyzed cyclization followed by aglyconichydrolysis and protection of hydroxyl group with (p-methoxyphenyl)diphenylmethyl chloride (MMTrCl) gave226 Inversion of the C-2 hydroxyl and removal of protectinggroups delivered α α-C-trehalose 227 (Scheme 44)
Kishi and co-workers also employed aldol reactions as anefficient access to the C-trisaccharide related to the type IIABO(H) blood group determinant [50] Aldol condensationof the enolate of methyl ketone 228 with aldehyde 229 gavea 41 mixture of hydroxy ketones 230 and 231 The majorketol was cyclized desulfurized and oxidized to afford thedisaccharide ketone 233 The ketone in THF was treatedwith LiHMDS (3 equiv) and TMEDA followed by theaddition of MgBr2 Addition of the aldehyde 234 led toalmost exclusive formation of the equatorial products 235and 236 in a 12 ratio Mesylation of 235 and 236 followedby treatment with liquid ammonia gave enones 237a and237b which were reduced to yield exclusively the C-2rsquo-equatorial ketone 238 Sodium borohydride reduction of theC-3rsquo carbonyl proceeded with the desired stereoselectivity toyield the protected C-trisaccharide 239 which wasdeblocked to provide the polyol 240 (Scheme 46)
Sutherlin and Amstrong cleverly applied a recursivestereochemical deconvolution (RSD) combinatorial approachfor the synthesis of a small library of C-trisaccharides aspotential inhibitors for the cell surface proteins of bacteriumHelicobactor pylori [51] The workers chose to carry outvariations in galactose ring of these trisaccharides An
Scheme (44)
OBnO
BnOOBn
OBn
P O
OEtOEtO
EtO
R H
OH
OH
OH
OH
O
R H
OH
OH
OH
OH
O
OHO
HOOH
OH
O
HO
OHOH
OH
OHO
HOOH
OH
O
HO
OH
OH
OHO
HOOH
OH
O
HO
OH
OHOH
R H
OH
OH
OH
OH
O
R
OBnO
BnOOBn
OBn
O
OHO
HOOH
OH
OO
HOHO
OH
R H
OH
OH
OH
OH
O
1 OsO4 NMO 50
2 DIBAL -32 oC 40
++ +
213 214 215 216
217 218 219 220
1 9-BBN H2O22 Swern [O]
3 t-BuOK
4 I2 C6H6212
211
1418 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
efficient Nozaki-Kishi coupling of vinyl bromide 241 withaldehyde 242 in a diasteromeric ratio of 12 followed byprotection with TBSOTf led to 243 and 244 Hydroborationfollowed by oxidation gave aldehydes 245 and 246respectively Addition of allylmagnesium bromide toaldehyde 245 followed by removal of the silyl groupafforded 247 to 246 giving 248 and 249 Epoxidation gave a11 mixture of the corresponding epoxides which werecyclized to give the C-trisaccharide 250-255 after removalof the benzyl groups (Scheme 47)
Schmidt reported a stereoselective 6-exo-trig selectiveelectrophilic cylization approach for de novo synthesis of amethylene-bridged Neu5Ac-α-(23)-Gal C-disaccharide theC-analog of an important motif in glycosphingolipids [52]The open chain precusors 259ab (a 32-mixture ofdiaseteromeric alcohols) were formed by the addition oflithiated iodide 256 to open chain aldehyde 258 Subsequent
C1 incorporation using Tebbe-reagent formation of a cycliccarbonate and deprotection of the two isopropylidene ketalsafforded tetrol 264 which upon treatment with phenylselenyltrifilate was steroselectively cyclized in a 6-exo-trigselective manner affording a diasteromeric mixture of 251and 252 in a ratio of 71 A seleno-Pummerer rearrangementto afford aldehyde 267 in 5 steps in 90 overall yieldOxidation of the aldehyde and subsequent steps led to thedesired C-disaccharide 268 (Scheme 48)
53 Esterification-Cyclization
Work from the Postema group has focused on a ringclosing metathesis (RCM) approach for the synthesis of C-saccharides [53a] The chemistry is versatile and has beenused for the synthesis of a small library of differentiallylinked β-C-disaccharides through a radical allylation-RCMstrategy [53b] The synthesis of the β-(1rarr4)-glucopyranosyl
Scheme (45)
O
OBn
BnO
BnO
BnO
I
CrCl2-NiCl2O
OBn
OH
BnO
BnO
BnO
O
O
O
O
O
H
OBn
O
O
OBnBnO
BnO
BnO
OOBn
OBn
OAc
PMBOHOO
OBn
BnO
BnO
BnO
O
OBn
OBn
OAc
O
OH
HO
HO
HO
OH
OH
OH
O
OH
O
OBn
BnO
BnO
BnO
OBn
OBn
OAc
O
MMTr
+
1 p-TsOH2 K2CO3 MeOH3 MMTrCl pyr
1 Swern [O]2 BH3 THF
3 AcOH-H2 O4 H2 Pd(OH)2
221
222
223
1 Pd-Pb CaCO3 H22 NaH BnBr3 OsO44 Bu2 SnO5 CsF PMB-Cl6 Ac2 O 4-DMAP
1 AcOH2 TsCl pyr
3 NaH-imid4 DDQ
224225
226 227
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1419
Scheme (46)
OBnO O
OBn
OMe
OBn
XY
SMe
OBnBnO
O
OBn
OBn
OBn
OBn
O
BnO
YX
OBn
TBSO
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnOOBn
H
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnO
OBn
OHC OBn
OBn
OTBS
OMe
BnOOBn
CHO
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnOOBn
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnO
OBn
YX
OBnO O
OBn
OMe
OBn
OBn
O
BnO
O
OBn
OBn
OBn
OBn
O 1 LiHMDS
2
228
1 TBAF THF
2 MeSH BF3 OEt2
230 X = OH Y = H231 X = H Y = OH
230231 41
1 Bu3SnH AIBN2 Swern [O]
1 LiHMDS THF-TMEDA2 MgBr23
1 MsCl
2 liquid NH3
235 X = OH Y = H236 X = H Y = OH Bu3 SnH AIBN
237a and 237b
NaBH4 MeOH
238
239 X = OBn
240 X = OHH2 Pd(OH)2
229
232233
234
1420 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (47)
OH C
O
O BnAcHN
OO
O
OBn OBnOBn
Br
O
OBn OBnOBn
O
OBnA cHN
OO
O TBSO
OBn O BnO Bn
O
OBnAcHN
OO
OTBS
S2
S1
S2
OTBSS1
O H
S2
OT BSS1
O H
MgBrMgBr
S2
O TBSS1
O H
S2
OHS1
OH
S2
OTBSS1
OH
O
OHHO
O H
O
HO
H OO
OBnA cH N
HO
H O
O
O HHO
OH
O
HOHO
O
OBnA cH N
HO
H O
O
OHH O
OH
O
H O
HOO
OBnAcHN
HO
HO
O
O HH O
OH
O
H O
H O O
OBnA cHN
HO
HO
O
O HH O
O H
O
HO
H O O
OBnAcHN
HO
HO
O
OHHO
OH
O
H O
O
OBnA cHN
HO
HOHO
+
241 242
1 CrCl2-NiCl2 T HF-DMF 722 TBSOTf 2 6-lutidine 91
243 244
1 9-BBN 602 Dess-Mart in period inane 97
1 9 -BBN 552 D ess-Martin periodinane 98
245 246
1
2 T BAF 74
1
2 TBAF 88
247 248 249
250
251
250 251 1 1 252 253 1 1 254 255 1 1
252
253
254
255
1 MCPBA2 CSA CH 2Cl2 61 fo r 2 steps3 H 2 Pd (O H)2C 95
1 MCPBA2 CSA CH 2Cl2 63 fo r 2 s teps3 H 2 Pd (OH)2C 87
1 MCPBA2 CSA CH2Cl2 80 for 2 steps3 H2 Pd(O H)2C 95
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1421
Scheme (48)
O
OO
Se Ph
R
O
HO OHOH
O
OB n O B n
OB n
O B nO O
O O
R O OR
X
O
OO
R
Se Ph
O
HOOH
OH
O
OB nOB n
O Bn
OB n
O O
O O
R O O R
O H
O
O B n OB n
O B n
OB n
O
C HO
O
O O
R O OR
OAc HN
OAc
C O2NH 4HOOH
OH
O
OH O H
OH OH
O
OB n O B n
OB n
OB nO O
O O
R O OR
X
O
O
OAcOAc
C HOA cOOAc
OAc
O
OB n O B n
OB n
OB n
O
O Bn OB n
OB n
OB n
X
OH
OO
HOOH
OH
O
O
OMeOB n
OB nOB n
R
t-B uL i256 R = Li
257 R = L i
258
(R = t-B uMe 2Si )
(R = t-B uMe 2Si )
259ab (32) 79 com bine d yi eld
De ss-Ma rtin pe riodinane
260 X = O R = t-B uMe 2Si ) 95
261 X = O R = t -B uMe2S i) 62
T e bbe re age nt
TB A F THF262 X = O R = H 94
diphosge ne
C H2C l 2Pyr
263 95
T HFH2O T FAr t
264 quant it a ti ve yie ld
PhSe C l AgOT f
EtC N -80 oC
265
266
Quant it at i ve yi l ed 25 26 7 1
+
R =
1 Ac 2OPyr
2 mC PB A3 Ac 2ONa OAc
4 NaO HT HFMe OH
5 Ac2O P yr
267 90 overa ll yi e ld
ste ps
268
1422 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
glucopyranoside 280 represents an example of thischemistry The known triacetyl glucopyranoside 269 wasconverted to iodide 270 in good yield Radical allylation of271 proceeded to afford a mixture of equatorial and axialallylation products in a 61 ratio Oxidative cleavage of thedouble bond gave the corresponding aldehydes 273a and273b which were separable Pinnick oxidation of the majoraldehyde 273a then gave the C-4 equatorial acid 274 DCC-mediated coupling of alcohol 275 and acid 274 proceeded toafford ester 276 in good yield Methylenation of 276 gave277 and exposure to catalysist 278 gave a 41 yield of theC-disaccharide glycal which was exposed to an excess ofBH3
THF to give 64 yield of the β-C-disaccharide 279Removal of the benzyl groups and global peracetylation gavethe peracetylated (1rarr4)-β-C-disaccharide 281 in good yield(Scheme 49)
54 Ring Expansion-Cyclization
Nelson developed a new strategy for asymmetric andstereoselective synthesis of C-linked disaccharide mimeticsthe C58-C71 fragment of palytoxin [54] The diol (RR)-282was converted into the di-dihydropyran (DHP) template 283284 and 285 The di-DHPs were functionized in a twodirectional sense using dihydroxylation reactions The two-directional approach was often very efficient indeed forexample in the synthesis of 286 six new stereogenic centerswere introduced with almost complete stereocontrol using areduction and a dihydroxylation reaction The approach isnot restricted to the synthesis of C2-symmetricaldisaccharide mimetics Using the unsymmetrical template285 which has both a pseudo-axial and a pseudo-equatorialhydroxyl groups the unsymmetrical mimetics 289 and 290were prepared (Scheme 50)
6 RADICAL APPROACHES
The radical approach for C-C bond formation is a popularmethod within organic chemistry The use of radicalchemistry in carbohydrate synthesis has certain advantagesFirstly the reaction conditions are very mild and tolerant ofa range of functional and protecting groups Secondanomeric radicals are stable with respect to elimination andepimeration Most significantly the chemistry required toincorporate an appropriate substitute at C-1 employed in theinitial hemolytic cleavage step is common within carbo-hydrate chemistry [55] The use of such radical techniquecan be subdivided into two classes intermolecular andintramolecular approaches
61 Intermolecular Radical Approaches
Giese was the first to employ an intermolecular radical-based approach for synthesis of C-disaccharides [56]Addition of an alkene to an anomeric radical underappropriate conditions allowed exclusive entry to the α-linked C-glycoside a result which was mirrored by the workof Baldwin [57] The high α-selectivity of the reaction wasin contrast with other reports Thus radicals generated at theC-2 C-3 and C-4 centers all preferred to occupy equatorialpositions [58] When the anomeric bromide 291 was treatedwith tin hydride and AIBN resulting anomeric radical andreacted with lactone 292 in a Michael addition it afforded293 In this reaction hydrogen abstraction at the resulting
radical center occurs from axial face to selectively generatethe equatorial C-2rsquo substituent Reduction and acetylation of293 furnished C-disaccharide 294 (Scheme 51) [59]
Witczak used the facial bias of levoglucosene tostereoselectively add a carbohydrate-based radical in thepreparation of the 3-deoxy-(1rarr4)-β-C-disaccharide 299[60] Addition of the radical derived from iodide 295 to 296gave adduct 297 in 26 yield Removal of the anomerichydroxyl of 297 was achieved by treatment with triethylsilane borontrifluoride ether complex followed bystereoselective reduction of the keto function at C-2rsquo withthe formation of 298 in 89 yield Debenzylation followedby acetolysis of 16-anhydro ring produced the peracetylatedtarget C-disaccharide 299 in 19 overall yield from 295(Scheme 52)
Vogel has developed general methods to transformenantiomerically pure 7-oxabicyclo[221]heptyl derivatives(ldquonaked sugarsrdquo) into C-disaccharides Because of thesechiral bicyclic skeletons they undergo highly stereoselectivereactions with predictable diasteroselectivities An arsenal ofmethods is available that allow to substitute these ldquonakedrdquocarbon centers with a variety of functional groups with allpossible relative configurations The methods allowpreparation of both enantiomers of a given target with thesame ease Predictably high stereoselectivity of the reactionsof the bicyclic chirons adds to the flexibility of approachwhich can lead to high molecular diversity [61]
α-C-(1rarr3)-mannopyranoside of N-acetyl-galactosaminepotent β-galactosidase inhibitors was synthesized by thisapproach [61] Enone 302 was readily prepared from 300The addition of the radical derived from bromide 303 toenone 302 afforded the αminusisomer 304 The ketone was thenreduced and the selenide eliminated via the intermediacy ofthe selenoxide to give 305 Acid-promoted (CF3SO3H) 7-oxa ring opening of 305 in MeCN produced the amino-conduritol derivative 306 resulting from the quenching of theallylic cation intermediate by the solvent (Ritter reaction)Ozonolysis of the chloroalkene 306 generated an acylchloride-aldehyde intermediate that reacted with MeOH toproduce a mixture of methyl uronates The major compound307 was silylated and reduced The crude polyol obtainedwas acetylated to produce 308 Desilylated and ammonolysisafforded a mixture of α-β-pyranoses 309 and correspondingα-β-furanoses (Scheme 53)
Similar chemistry was carried out to synthesize non-protected α-C(1rarr2)-L-fucopyranoside of D-galactopyrano-side corresponding to a blood group mimetic [62] Giesersquosradical fucosidation of racemic enone 310 with α-L-bromoacetofucose 311 provided the mixture of diastereo-meric α-C-fucoside 312a and 312b in reproducible yield of78 Reduction of the mixture gave a 11 mixture of endo-alcohols 313 and 314 which were isolated pure in 40 and355 yield respectively Oxidative elimination of thebenzeneselenyl group of 313 followed by acetylation gaveendo acetate 315 in 85 yield Acid-promoted ring openingof 315 and ozonolysis of the resulted chloroalkene gavemethyl uronic ester 316 in modest yield (10) Treatment of316 with Cl3CCN and NaH followed with BF3
OEt2
furnished the totally protected C-disaccharide 317 in 79
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1423
Scheme (49)
Bu3SnO
HOAcO
OMeOAc
OAc
O
AcO
OMeOAc
OAcI
AIBN
O
AcO
OMeOBn
OBn
HO2C O
AcO
OMeOR
ORY
X
OHBnO
BnO
OBn
OBnO
BnO
OBn
O
AcO
OMeOBn
OBnX
i-Pr i-Pr
N
Mo C(Me2 Ph)((CF3)2 MeCO)2
O
RO
OMeOR
O
RO
OR
OR
RO
OR
278
I2 Ph3P
imidazole
269 270 93
271a X = CH2CH=CH2 Y = H R = Ac 64271b Y = CH2CH=CH2 X = H R = Ac 11272a X = CH2CH=CH2 Y = H R = Bn 75272b Y = CH2CH=CH2 X = H R = Bn 75273a X = CH2CHO Y = H R = Bn 79273a Y = CH2CHO X = H R = Bn 79
1 NaOMe MeOH2 NaOH BnBr DMF
OsO4 NaIO4
NaClO2 NaH2PO4
274 96
275
DCC 4-DMAP
276 X = O 82
277 X = CH2 51
TiCl4 Zn dust TMEDA CH2Br2PbCl2 (Cat )
1
2 BH3 THF H2O2 NaOH
H2 PdC EtOH
Ac2 O Pyr 4-DMAP
279 R = Bn R = H 64
280 R = R = H 99
281 R = R =Ac 97
1424 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (50)
Scheme (51)
O OOH
OH
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
286
1 VO(acac)2 t-BuOH 95
2 (MeO)3CH BF3 90
1 P-O2NC6H4 CO2H Ph3P DIAD2 K2CO3 MeOH 82 over 2 steps
1 PhCOCl Et3N DMAP 402 P-O2NC6H4 CO2H Ph3P DIAD3 KOH THF-H2O 75 over 2 steps
TMEDA OsO4
Cat OsO4 NMO 287
Cat OsO4 NMO288
TMEDA OsO4
Cat OsO4 NMO
290
289
(RR)-282283
284
285
OHO
AcO
BrOAc
OAc
BnO
O
OBn
OBnO
OHO
AcOOAc
OAc
BnO
OOBn
OBnAcO
OHO
AcOOAc
OAc
BnO
O
OBn
OBnO
+
Bu3SnH AIBN291
292
293 81
1 Na[Al(OC2H4OMe)2(OEt)H]2 Ac2O pyr
294 56 over 2 steps
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1425
Scheme (52)
Scheme (53)
OBnO
BnOOBn
OBn O
OH
O
OBnO
BnO
OHOBn
OBn O
O
O
O
O
O
OBnO
BnOOBn
OBnO
OAcOAc
OAc
OBnO
BnO
OHOBn
OBn
IBu3SnH AIBN
295 297 26
1 BF3 OEt2 Et3SiH
2 L-Selectride THF
1 Pd(OH)2C C6H10 EtOH
2 EtSiOSO2CF3 Ac2O
298 89 over 2 steps299
296
O
O
PhSeClO
O
PhSeCl
Bu3 SnH
O
O
PhSeCl
R
H
O
OAc
R
Cl
O
AcO
OAc
OAc
OAcOH
Cl
NHAc
R
OAc
AcHN
OH
O
OH OAc
OH
OHO
HO
OH
O
AcO
OAc
OAc
OAcBr
O
O
PhSeCl
O
O
PhSeCl
R
O
OTIPSAcHNR
OAc OAc
O
OHAcHN
COOMe
R
OAc
1 Bu4NF
2 NH3MeOH
1 (Me3Si)2NLi THF2 Me2N=CHI
1 Bu3 SnH AIBN2
1 NaBH42 mCPBA3 Ac2O pyr
1 H+ MeCN
2 H2 O NaHCO3
R =
1 O3MeOH
2 Me2S NaHCO3
1 TIPSOTf 26-lut idine2 LiBH43 Ac2 O pyr DMAP
furanoses +
304 56
305 68 306 84307 50
308 46
300 301 302
303
309
1426 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
The reduction of 317 and treatment with DOWEX-H+ resinprovided the desired C-fucoside 318 in 70 (Scheme 54)
62 Intramolecular Radical Approaches
One disadvantage with the intermolecular approaches isthat during such radical mediated reactions electrondeficient alkenes are required to facilitate C-C bondformation The intramolecular approach of Sinayuml overcomes
this drawback by bring two substrates together via atemporary covalent silaketal connector This enables the useof a wider range of alkenes which can include alkene-functionalized sugars thus leading to the generation of C-disaccharides [63] Based on the early work of Stork Sinayumlemployed the tether reaction in the synthesis of both α- andβ-C-disaccharides with this work subsequently beingemployed in the synthesis of biologically significant natural
Scheme (54)
O
OH
Fuc
Cl
O
O
ClPhSe
OOAc
NHAcOHFuc
O
AcOOAc
AcO
Br
O
O
PhSeCl
O
AcOOAc
AcO
O
OH
PhSe Cl
Fuc
OOAc
NHAc
OMe
Fuc
O
AcHN
OH OAc
OH
O
OH
Me
OH
O
O
Fuc
ClSePh
O
HO
Fuc
ClSePh
+
Ph3SnHAIBN
78 combined yield
Fuc
310
+
1 NaBH4 MeOHTHF2 Chromatography
313 40 314 355
1 mCPBA
2 Ac2O pyr DMAP
+
315 75
1 TfOH MeCN
2 NaHCO3 O3 -78 oC
316 10 over 2 steps
1 Cl3 CCN NaH
2 MeOH BF3 OEt2
317 79
1 LiBH4 THF
2 Dowex-H+
311
312a312b
318 70 for 2 steps
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1427
products [64] The availability of different hydroxyl groupson each monosaccharide unit allowed the fine-tuning ofstereochemical outcome by selective positioning of the silyltether [65] Development of this early stereochemical controlled to the tethering of the donor 320 with alcohol 319through a di-isopropyl silicon tether 321 Subsequent treat-ment with Bu3SnH and AIBN led to a 9-endo-trigcyclization to form the C-disaccharide 322 in an 80 yieldwith exclusive formation of the α-product The silyl tetherwas removed with Bu4NF and deprotection under standardconditions afforded the desired disaccharide 323 in excellentyield (Scheme 55)
In parallel the development of a 32rsquo silyl tether allowedaccess to the β-linked product as demonstrated in Sinayumlrsquossynthesis of methyl β-C-lactoside 328 [66] Alcohol 324 and320 were connected via the dimethylsilyl tether an 8-endo-trig cyclization followed to exclusively afford the β-
disaccharide 326 in 45 yield Removal of the tether anddeprotection of benzyl ether gave β-C-disaccharide 328(Scheme 56)
This group also selected iodosugars bearing a freehydroxyl group as progenitors of the radical donors [67] In atypical experiment the radical donor 329 was connected tothe radical acceptor 330 through a silaketal tether followingtheir procedure Tributyltinhydride mediated 8-endo-trigradical cyclization of compound 331 gave after detetheringof the non isolated intermediate 332 the protected β-C-disaccharide 333 in 37 overall yield (from startingmaterials 330 and 329) Peracetate 335 was achieved afterhydrogenolysis The C-laminaribioside 334 is of potentialbiological interest as it mimics the repeating disaccharideunit of fungal β-(1rarr3)-glucans which have antitumor andimmunomodulating properties (Scheme 57)
Scheme (55)
Scheme (56)
OO
OHSePh
OTBDPSO O
OO
SePh
OTBDPSO
OO
OBnOMe
OBn
Si
O
HOOBn
OMe
OBn
O
HOOH
OHHO
O
HOOH
OMe
OH
OTBDPSO
O
HOOBn
OMe
OBnO
OOH
1 n-BuLi THF
2 iPr2SiCl2 -78 oC
3 DMAP THF rt
1 Bu4NF THF
2 Dowex-H+
3 H2 PdC
Bu3SnH AIBN toluene
319
320
321
322323
OBnO
OHSePh
OBnBnO
OHO
OBnOMe
OBn
ROO
ROOH
OR
OHO
OROMe
OR
OBnO
O
OBnBnO
OO
OBnOMe
OBn
Si
SePh
OBnO
O
OBnBnOO
OOBn
OMe
OBn
Si
1 PhSeH Me2SiCl2
BuLi -78 oC
2 imidazole rt
Bu3SnH AIBN toluene
H2 PdC327 R = Bn
328 R = H
Bu4NF THF
324
320
325
326 45
1428 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
CONCLUSIONS
In this paper the biological importance of C-oligo-saccharides as subunits of natural products and as a newgeneration of carbohydrate based on therapeutics has beenillustrated Different methods are available for the synthesisof C-oligosaccharides As with traditional saccharidesynthesis it has been necessary to develop a number ofspecific approaches to facilitate the regioselective andstereoselective preparation of the desired targets Work inthis area continues and it is expected that many interestingnew C-oligosaccharides will be prepared using the chemistrydescribed in this review It is also likely that new chemistrywill be developed in the future for the preparation of thesebiologically important targets
ACKNOWLEDGEMENTS
The authors thank Dr Sultan Baytas for her criticalreading of this manuscript
REFERENCES
[1] Kennedy J F White C A Bioactive Carbohydrates InChemistry Biochemistry and Biology Ellis Horwood LtdChichesterUK 1983
[2] Wassarman PW Mammalian Fertilization Molecular Aspects ofGamete Adhesion xocytosion Exocytosis and Fusion Cell 199996 175-183
[3] Carbohydrate-based Drug Discovery Wong C-H EdWeinheim Cambridge Wiley-VCH 2003
[4] (a) Sharon N Lis H Lectins as Cell Recognition MoleculesScience 1987 246 227-234 (b) Dwek RA Chem Rev 1996 96683-720
[5] Postema M C-Glycoside synthesis CRC Boc Ratom 1995[6] (a) Weatherman R V Mortell K H Cheruenak MKiessling
L L Toone E J Specificity of C-Glycoside Complexation byMannoseGlucose Specific Lectins Biochem 1996 35 3619-3624(b) Ravishankar R Surolia A Vijayan M Lim S Kishi YPreferred Conformation of C-Lactose at the Free and Peanut LectinBound States J Am Chem Soc1998 120 11297-11303
[7] (a)Wong C-H Halcomb R L Ichikawa Y and Kajimoto TEnzymes in organic synthesis Application to the problems ofcarbohydrate recognition part2 Angew Chem Int Ed Engl 199534 521-546 (b)Howard S Withers SG Bromoketone C-Glycosides a New Class of βminusGlucanase Inactivators J AmChem Soc 1998 120 10326-10331(c) Wang Q Wolff MPolat T Du Y Linhardt R J C-glycoside of Neuraminic Acidsas Neura-minidase Inhibitors Bioorg Med Lett 2000 10 941-944 (d) Phili R Chang J Partis R A Mueller R A ChrestF J Passaniti A The Alpha-glucosidase I InhibitorCastanospermine Alters Endothelial cell Glycosylation PreventsAngiogenesis and Inhibits Tumor Growth Cancer Res 1995 552927-2935
[8] Ossor A Elbein A D In Carbohydrates in Chemistry andBiology Vol 3(II) WileyVCH 2000 pp 513-539
[9] (a) Sinayuml P Synthesis of oligosaccharide Mimetics Pure ApplChem 1997 69 459-463 (b) Beau J-M Gallagher TNucleophilic C-glycosyl Donors for C-glycoside Synthesis Top inCurr Chem 1997 187 1-54 (c) Nicotra F Synthesis of C-glycosides of Biological Interest Top in Curr Chem 1997 187
Scheme (57)
O
O
O
Ph
I
OMe
OHO
BnO
OH
OH
BnOOH
O
BnO
Si
O
O O
Ph
I
OMe
O
O
BnO
OR4O
R5O
OMe
OR2
OR3O
R3O
OR1
R3O
Bu3 SnH AIBN
332 R1 R2 = SiMe2 R3 = Bn R4 R5 = CHPhTBAF THF
333 R1 = R2 = H R3 = Bn R4 = R5 = CHPh 37 from 11
334 R1 = R2 = R3 = R4 = R5 = H
335 R1 = R2 = R3 = R4 = R5 = Ac
329
H2 PdC MeOH
Ac2 O pyr
1 BuLi THF -78 oC
2 Me2SiCl2
3 DMAP
330
331
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1429
55-83 (d) Du Y Linhardt R Y Recent Adv in Stereo-SelectiveC-Glycoside Synthesis Tetrahedron Lett 1998 54 9913-9959 (e)Liu L Mckee M and Postema M H D Synthesis of C-saccharides and Higher Congeners Current Org Chem 2001 51133-1167
[10] Jarosz S Fraser-Reid B Synthesis of A Higher Carbon Sugar ViaDirected Aldol Condensation Tetrahedron Lett 1989 30 2359-2362
[11] Lichtenthaler F W Lergenmiiller M Schwidetzky S C-Glycosidations of 2-Ketohexosyl With Electrophilic Radical andNudeophilic Anomeric Carbons Eur J Org Chem 2003 3094-3103
[12] Baudat A Vogel P Aza-C-disaccharides Synthesis of 6-Deoxygalactonojirimycin-β-C(1rarr3) Linked with D-Altrofuranosides and D-Galactose J Org Chem 1997 62 6252-6260
[13] Turner D Vogel P Synthesis of 4-Hydroxy-26-Bis(hydroxymethyl) tetrahydropyran-2-Carbaldehyde DerivativesSynlett 1998 304-306
[14] Zhu Y-H Vogel P Short Stereoselective Synthesis of C-(1rarr3)-Linked Disaccharides Tetrahedron Lett 1998 39 31-34
[15] Zhu Y-H Vogel P Synthesis of a (2R 6R)-2-(Hydroxymethyl)-6-Propa-1 2-Dienyl-2H-Pyran-3(6H)-One Derivative A NewEnone for The Convergent Construction of C-Glycosides of C-Disaccharides Synlett 2001 82-86
[16] Baumberger F Vasella A Deoxynitrosugars The 6th
Communication Stereolectronic Control in the reductivedenitration of tertiary nitro ethers A Synthesis of ldquoC-glycosidesrdquoHelv Chim Acta 1983 66 2210-2221
[17] Martin O R Lai W Synthesis and Conformational Studies of β-(1rarr6)- and ββ-(1rarr1)-Linked C-disaccharides J Org Chem1993 58 176-185
[18] Spak S J Martin R The synthesis of an analogue of Methyl OC-Analogue of Methyl 4rsquo-O-β-D-GlucopyranosylgentiobiosideTetrahedron 2000 56 217-224
[19] Kobertz W R Bertozzi C R Bednarski M D C-GlycosylAldehyde Synthons for C-Linked Disaccharides J Org Chem1996 61 1894-1897
[20] Gurjar M K Nagaprasad R and Ramana CV First Synthesis ofMethyl α-C-D-Arabino-furanosyl-(1rarr5)-αminusD-Arabinofuranosidethe C-Disaccharide Segment of Motif C of MycobateriumTuberculosis Tetrahedron Lett 2000 43 7577-7579
[21] Witczak Z J Synthesis of C-Glycosyl Compounds and OtherNatural Products from Levoglucosenone Pure Appl Chem 199466 2189-2192
[22] Griffin F K Paterson D Taylor R J K Ramberg-BacklundApproaches to the Synthesis of C-Linked Disaccharides AngewChem Int Engl 1999 38 2939-2942
[23] Paterson B E Griffin F K Alcaraz M-L and Taylor R J KA Ramberg-Baumlcklund Approach to the Synthesis of C-GlycosidesC-Linked Disaccharides and C-Glycosyl Amino Acids Eur JOrg Chem 2002 1323-1336
[24] McAllister G D Paterson D E Taylor R J K A SimplifiedRamberg-Bachlund Approach to Novel C-Glycosides and C-Linked Disaccharides Angew Chem Int Ed Engl 2003 42 1387-1391
[25] McCartney J L Christopher T M Cicchillo R M BernardinaM D Wagner T R and Norris P J Org Chem 2003 6810152-10155
[26] Dondoni A Zuurmond H M Bascarate A Synthesis of α-andβ-D-(1rarr6)-C-Disaccharides by Witting Olefination of Formyl C-Glycosides with Glycopyranose 6-phosphoranes J Org Chem1997 62 8114-8124
[27] Dondoni A Kleban M Zuurmond H Marra A Synthesis of(1rarr6)-C-Oligogalactosides by Interative Wittig OlefinationTetrahedron Lett 1998 39 7991-7994
[28] Dondoni A Marra A A New Synthetic Approach toMycobacterial Cell Wall α-(1rarr5)-D-Arabinofuranosyl C-Oligosaccharides Teterahedron Lett 2003 44 4067-4071
[29] Colinas P A Ponzinibbio A Lieberknecht A and Bravo R OWittig Reaction of Glycosyl Phosphonium Salts A StereoselectiveRoute to C-Disaccharides and C O-Trisaccharides TetrahedronLett 2003 44 7985-7988
[30] Schmidt R R Preuss R Synthesis of Carbon Tetrahedron Lett1989 30 3409-3412
[31] Dietrich H Schmidt R R Synthesis of Carbon-Bridged C-Lactose and Derivatives Liebigs Ann Chem 1994 975-981
[32] Rouzaud D Sinayuml P The First Synthesis of a ldquoC-DisacchariderdquoJ Chem Soc Chem Commun 1983 1353-1354
[33] Xin Y-C Zhang Y-M Mallet J-M Glaudemans C P JSinayuml P Synthesis of C-Oligosaccharides That Mimie TheirNatural O-Analogues Immunodeterminants in Binding toMonoclonal Immunoglobulins Eur J Org Chem 1999 471-476
[34] Streicher H Geyer A Schmidt R R C-Disaccharides ofKetoses Chem Eur J 1996 2 502-510
[35] Leeuwenburgh M A Timmers C M Vander Marel G A VanBoom J H Mallet J-M Sinayuml P G Stereoselective Synthesisof α-C-(Alkynyl)-Glycosides Via Ring-Opening of α-12-Anhydrous Tetrahedron Lett 1997 38 6251-6254
[36] Aslam T Fuchs M G G Le Formal A Wightman R HSynthesis of C-Disaccharide Analogue of the α-D-Arabinofuranosyl-(1rarr5)-α-Arabinofuranosyl Motif ofMycobacterial Cells Walls via Alkynyl Intermediates TetrahedronLett 2005 46 3249-3252
[37] (a) Girad P Namy J L Kagan H B Divalent LanthanideDerivative in Organic Synthesis 1 Mild Preparation of SamariumIodide and Ytterbium Iodide and Their Use as Reducing orCoupling Agents J Am Chem Soc 1980 102 2693-2698 (b)Molander G A Harris C R Sequencing Reactions withSamarium(II) Iodide Chem Rev 1996 96 307-338
[38] (a) Mazeacuteas D Skrydstrup T Doumeix O Beau J-MSamarium Iodide-Induced Intramolecular C-Glycoside FormationEfficient Radical Formation in the Absence of an Additive AngewChem Int Ed Engl 1994 33 1383-1386 (b) Mazeacuteas DSkrydstrup T Beau J-M A Highly Stereoselective Synthesis of1 2-trans-C-Glycosides Via Glycosyl Samarium(III) CompoundsAngew Chem Int Ed Engl 1995 34 909-912 (c) Jarreton OSkrydstrup T Beau J-M The Stereospecific Synthesis of Methylα-C-Mannobioside A Potential Inhibitor of M TuberculosisBinding to Human Macrophages J Chem Soc Chem Commun1996 1661-1662 (d) Jarreton O Skrydstrup T Espionosa J-FJimeacutenez-Barbero J Beau J-M Samarium Diiode Prompted C-Glycosylation An Application to The Stereospecific Synthesis ofα-(1rarr2)-C-Mannobioside and Its Derivatives Chem Eur J 19995 430-441 (e) Mipuel N Doisneau G Beau J-M ReductiveSamariation of Anomeric 2-Pyridyl Sulfones with Catalytic AnUnexpected Improvement in The Synthesis of 12-Trans-Diequatorial C-Glycosyl Compounds Angew Chem Int Ed Engl 2000 39 4111-4114
[39] Vlahov I R Vlahova P I Linhardt R J DiastereocontrolledSynthesis of Carbon Glycosides of N-Acetylneuraminic Acid ViaGlycosyl Samarium(III) Intermediates JAmChem Soc 1997 1191480-1481
[40] Kuberan B Sikkander S ATomiyama H Linhardt R JSynthesis of a C-Glycoside Analogue of sTn An HIV-and Tumor-Associated Antigen Angew Chem Int Ed Engl 2003 42 2073-2075
[41] Bazin H G Du Y Polat T Linhardt R J Synthesis of aVersatile Neuraminic Acid ldquoCrdquo-Disaccharide Precursor for theSynthesis of C-Glycoside Analogues of Gangliosides J OrgChem 1999 64 7254-7259
[42] Chen C-C Ress D K Linhardt RJ Samarium Iodide-Mediated Synthesis of Neuraminic Acid C-Glycosides InSynthesis of Glycommetics Roy R Ed ACS Syposium Series2004 896 53-80
[43] Abdallah Z Doisneau G Beau J-M Synthesis of a Carbon-Linked Mimic of The Disaccharide Component of The Tumor-Relate SialyTn Antigen Angew Chem Int Ed Engl 2003 425209-5212
[44] Lay L Nicotra F Panza L Russo G Caneva E Synthesis ofC-disaccharides through dimerization of exo-glycals J Org Chem1992 57 1304-1306
[45] Isobe M Nishizawa R Hosokawa S Nishikawa TStereocontrolled Synthesis and Reactivity of Sugar Acetylenes JChem Soc Chem Commun 1998 2665-2676
[46] Saeeng R Sirion U Sahakitpichan P Isobe M IodineCatalyzes C-Glycosidation of D-Glucal with SilylacetykeneTetrahedron Lett 2003 44 6211-6215
[47] (a) Babirad S A Wang Y Kishi Y Synthesis of C-Disaccharides J Org Chem 1987 52 1370-1372 (b) Wang YBabirad S A Kishi Y Preferred Conformation of C-Glycosides
1430 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
8 Synthesis of 14-Linked Carbon Disaccharides J Org Chem1992 57 468-481
[48] Armstrong R W Sutherlin D P Strategies for the Synthesis ofC-Disaccharides Containing D and L Sugars Tetrahedron Lett1994 35 7743-7746
[49] Wei A Kishi Y Preferred Conformation of C-Glycosides 12Synthesis and Conformational Analysis of αα- α β- and β β-Trehaloses J Org Chem 1994 59 88-96
[50] Haneda T Goekjian P G Kim S H Kishi Y PreferredConformation of C-Glycosides 10 Synthesis and ConformationAnalysis of Carbon Trisaccharides J Org Chem 1992 57 490-498
[51] Sutherlin D P Armstrong R W Synthesis of 12 Stereochemistryand Structurally Diverse C-Trisaccharides J Org Chem 1997 625267-5283
[52] Notz W Hartel C Waldscheck B Schmidt R R De NovoSynthesis of a Methylene-Bridged Neu5Ac-α-(23)-Gal C-Disaccharide J Org Chem 2001 66 4250-4260
[53] (a) Postema M H D Calimente D Liu L Behrmanm T L AnOlefin Metathesis Route for the Preparation of (1rarr6)-Linked-C-Disaccharide Glycals A Convergent and Flexible Approach to C-Saccharide Synthesis J Org Chem 2000 65 6061-6068(b) Postema M H Piper J L Liu L Faust M Andreana PSynthesis and Partial Biological Evaluation of a Small Library ofDifferentially Linked β-C-Disaccharide J Org Chem 2003 684748-4754
[54] Nelson A The Development of Strategies and Methods for TheSynthesis of Biologically Active Compounds New J Chem 200428 771-776
[55] Togo H He W Waki Y Yokoyama M C-GlycosylationTechnology With Free Radiant Reactions Synlett 1998 700-717
[56] Giese B Dupuis J Diastereoselective Synthesis of C-Glycopyranosides Angew Chem Int Ed Engl 1983 22 622-623
[57] Adlington R M Baldwin J E Basak A Kozyrod RPApplication of Radical Addition Reactions to tho Synthesis of a C-Glucoside and A Functionalized Amino Acid J Chem SocChem Commun 1983 144-145
[58] Giese B Gonzaacutelez-Goacutemez J A Witzel T The Scope of RadicalCC-Coupling by The ldquoTin Methodrdquo Angew Chem Int Ed Engl1984 23 69-70
[59] Giese B Witzel T Synthesis of ldquoC-Disaccharidesrdquo by RadicalC-C Bond Formation Angew Chem Int Ed Engl 1986 25 450-451
[60] Witczak Z J Chhabra R Chojnacki J C-Disaccharides IStereoselective Approach to β-(1rarr4)-3-Deoxy-C-Disaccharidesfrom Levoglucosenone Carb Res 1997 301 167-175
[61] Vogel P Synthesis of Rare Carbohydrates and Analogues Startingfrom Enantiomerically Pure 7-Oxabicyclo[221]heptyl Derivatives(ldquoNaked Sugarsrdquo) Current Org Chem 2000 4 455-480
[62] Viodeacute C Vogel P Synthesis of The C-Disaccharide α-C(1rarr3)-L-Fucopyranoside of N-Acetylgalactosamine J Carb Chem2001 20 733-746
[63] Xin Y C Mallet J M Sinayuml P An Expeditious Synthesis of AC-Disaccharide Using A Temporary Silaketal Connection J ChemSoc Chem Commun 1993 864-865
[64] (a) Petitou M Herault P Lormeau J-C Helmboldt A MalletJ-M Sinayuml P Herbert J-M Introducing A C-InterglycosidicBond in A Biologically Active Pentasaccharide Hardly Affects ItsBiological Properties Bioorg Med Chem 1998 6 1509-1516 (b)Sinayuml P Advances in The Synthesis of the Carbohydrate MimicsPure Appl Chem 1998 70 1495-1499
[65] Sinayuml P Chemical Synthesis of Oligosaccharide Mimetics PureAppl Chem 1998 70 407-410
[66] Sinayuml P Chemical Synthesis of Oligosaccharide Mimetics PureAppl Chem 1998 69 459-463
[67] Vauzeilles B Sinayuml P Selective Radical Synthesis of β-C-Disaccharides Tetrahedron Lett 2001 42 7269-7272
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1413
Scheme (37)
Fig (2)
(KLH) by reductive amination for use as carbohydrate-basedvaccine GM3 a related trisaccharide containg gangliosideplays an important role in cell growth and differentiationFig 2 The synthesis of C-oligosaccharide GM3 is currentlyunderway following a similar route to that of C-GM4synthesis [42]
Beau also reported a sialyl C-disaccharide synthesiswhich relied on the unprecedented use of a stable andcrystalline 2-pyridyl sulfide of the N-acetylneuraminic acidderivative 189 as the anomeric precursor in a samarium-Reformastky procedure [43] The coupling procedure withsulfide 189 and aldehyde 190 afforded the carbon-linkeddimer 191 in 93 yield as a 11 diastereomeric mixture
Alcohols 191 were converted into thiocarbonates anddeoxygenated by employing triphenyltin hydride catalyticAIBN and pentafluorophenol which yielded C-disaccharide192 as a single compound in 65 yield for the 2 stepsDesilylation hydrogenolysis acetylation and finalacetolysis of the methyl glycoside provided the carbon-linked mimic 193 of the disaccharidic component of thesialylTn tumor antigen (Scheme 38)
4 CATIONIC METHODS
This section is categorized according to reactions thatinvolve the generation of anomeric ions followed by thecapture with sugar-based nucleophiles
OAcAcHN
OAc
AcO
O
OBnBnO
OBnOMP
HO
O
MeO2CAcO
O
MeO2CAcO
OAcAcHN
OAc
AcO
O
OHHO
OHOMP
HO
O
OBnOHC
OBnBnO
OMP
O
MeO2CAcO
OAcAcHN
OAc
AcO
O
OHHO
OHOMP
HO
O
CO2MeAcO
OAcAcHN
OAc
AcO
SO2Ph
O
MeO2CAcO
OAcAcHN
OAc
AcO
O
OAcAcO
OAcX
AcO
H2 PdC EtOAc CH3OHH2O
+
Ac2O Pyr
187 X = OMP
188 X = SPh 73
184 85 R and S mixture
186 90 for two i somers
+
SmI2 THF183
179
185
O
HO2 CHO
OAcAcHN
OH
HO
O
OHHO
OH
OAcO
(CH2 )12 CH3
HN
OH
(CH2)14CH3
O
O
O
OHHO
OH
O
O
HO2 CHO
OAcAcHN
OH
HO
O
OHHO
OH
O(CH2)12CH3
HN
OH
(CH2)1 4CH3
GM4
GM3
1414 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
41 Exo-glycals as Nucleophiles
Nitotra et al have found that treatment of exo-glycal 194with BF 3
OEt2 followed by a water quench afforded the C-disaccharide 195 (Scheme 39) It is noteworthy tonoteworthy that the attack of the enol ether on the anomericoxonium ion occurs with high stereoselectivity on the α-face only 195 was obtained [44]
42 Silyl-based Nucleophiles
Isobe has designed and developed alkynylation as a keyreaction for the introduction of a carbon chain onto sugarsThose alkynylated compounds are called ldquosugar acetylenesrdquo[45] The mechanism includes eliminative formation ofcation to which silylacetylene can coordinate on the α-face(Scheme 40)
Double C-glycosylation between glycal 198 and bis(silylacetylene) gave C-disaccharide ldquolikerdquo compounds 199and 200 (Scheme 41)
Silylpropargyl-sugar 201 smoothly reacted with D-glucalto furnish exclusively the α-acetylene glycoside product 202in 88 (Scheme 42) [46]
5 CYCLIZATION METHODOLOGY
This approach to C-oligosaccharide synthesis relies onthe coupling of an open chain fragment with an intact
monosaccharide to give an intermediate that is then cyclizedto deliver the C-oligosaccharide target This section isdivided by the type of chemistry used to initially assemblethe two pre-cyclization fragments
51 Wittig Reaction-Cyclization
The Kishi group was the first to use Wittig-cyclizationapproach to synthesize C-disaccharides Starting with Wittigreaction between 203 and 204 the intermediate 205 wasafforded as a single stereoisomer in 82 yield Osmylationthen gave a mixture of diols with the major one formed in a61 ratio Selective protection of the diols gave 206a and206b The mono-para-methoxybenzyl ether 206a was thentransformed into the hemiketal 207 in 75 overall yield inthree steps ie (1) Swern oxidation (2) acetonide hydro-lysis (4 N HClTHFrt) and (3) benzoylation (3 equiv ofPhCOClpyCH2Cl2rt) Silane reduction of 207 in an acidicmedium should preferentially yield the equatorially substi-tuted β-C-glycoside which was deblocked and converted tothe methyl- βminusC-disaccharide 209 Exact parallel experi-ments applied to the minor isomer gave the correspondingC-disaccharide 210 (Scheme 43) [47]
Armstrong has employed Wittig-osmylation protocol forthe preparation of a small library of α-C-(1rarr6)-disaccha-rides [48] Readily available allyl C-glycoside 211 washomologated to diene ester 212 and subjected to osmylation
Scheme (38)
O
CO2MeAcO
OAcAcHN
OAc
AcO
S(2-Py)
O
TESO
AcHNOMe
O
HO
O
CO2MeAcO
OAcAcHN
OAc
AcO
O NHAcOAc
OAc
OAc
O
CO2MeAcO
OAcAcHN
OAc
AcO
O NHAcOBn
OTES
OMe
OAc
AcO
O NHAcOBn
OTES
OMeOH
O
CO2 MeAcO
OAcAcHN
+
192 65
1 MeOHHCl2 H2 PdC EtOH3 Ac2O Pyr4 Ac2OAcOHH2SO4
193 59 overall yield
25 equiv SmI2 THF
1 11-thiocarbonyldiimidazole DMAP2 Ph3SnH cat AIBN
191 93
189
190
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1415
Scheme (39)
Scheme (40)
Scheme (41)
OBnO
OBn
OBn
OBnO
OBn
OBn
OBnO
OBn
OBn
OBnO
OBnCH3
BnO
OH
CH2
OBnO
OBn
CH3
OBn
H2 O
BF3 OEt2 MeCN
194
195 96
OOAc
OAc
AcO
R SiMe3
SnCl4
O
OAc
AcO
R
O
OAc
AcO
O
OAc
AcO
Me3Si
R
SiMe3
196
197
Me3 Si SiMe3
O
AcO
OAc
OAc
SiMe3
SiMe3
O
AcO
OAc
O
OAc
OAc
O
AcO
AcOO
OAc
OAc
SnCl4 CH2Cl2
SnCl4 CH2Cl2198
199
200
1416 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (42)
Scheme (43)
AcO
OAc
OAc
Me3 Si
BnO
OBn
BnO
OBn
AcO
OAc
BnO
OBn
BnO
OBn
+ I2 CH2Cl2
202 88
198 201
O
OBn
OBn
O
O
O
OBn
OBn
O
O
OBn
OBn O
OBn
OBn
O
OPBH2M
OH
OBnO
BnO
BnO
O
OBn
OBn
O
OHOPMB
OHO
HO
HO
O
OH
OHOH
OH
HOOMe
O
OBnOBn
O
Ph3P
O
O
OBn
OBn O
OBn
OBn
O
OPBM
OH
O O
CHO
OBn
BnO
OO
OBn
OBn
O
OHOPMB
BnO
BnO
BnO
OHO
HO
HO
O
OH
OHOH
OH
HOOMe
+ THF -78 oC
1 OsO4 pyr THF
2 NaH PMBBr
206a 206b 206a206b 61
1 Swern [O]2 4N HCl3 PhCOCl pyr
1 Swern [O]2 4N HCl3 PhCOCl pyr
1 PrSiH BF3 OEt2
2 H2 Pd(OH)2C
3 HCl MeOH 90 oC
1 PrSiH BF3 OEt2
2 H2 Pd(OH)2C
3 HCl MeOH 90 o C
203
204
205
207
209
208
210
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1417
followed by reduction to afford a 51 mixture (213214215216) of lactols that were readily separable by chromato-graphy Following a deprotection of an equimolar mixture of213 and 214 217 and the DL hybrid C-disaccharide of D-glucose-O-(1rarr6)-L-galactose 218 were obtained The DDand DL derivatives 219 and 220 of glucose-α-(1rarr6)-idosewere also obtained as a near equimolar mixture afterdeprotection of 215 and 216 (Scheme 44)
52 Anion Addition-Cyclization
Kishi developed an approach for the synthesis of theCndashtrehalo sugars which relied on nucleophilic addition ofone intact sugar fragment to a fundamental aldehyde ieKishi-Nozaki reaction [49] Coupling of monosaccharide221 and aldehyde 222 gave 223 The triple bond waspartially reduced and osmylation was followed by selectiveprotection to afford 224 The acetonide was converted toepoxide 225 by standard methods and removal of the PMBgroup Acid-catalyzed cyclization followed by aglyconichydrolysis and protection of hydroxyl group with (p-methoxyphenyl)diphenylmethyl chloride (MMTrCl) gave226 Inversion of the C-2 hydroxyl and removal of protectinggroups delivered α α-C-trehalose 227 (Scheme 44)
Kishi and co-workers also employed aldol reactions as anefficient access to the C-trisaccharide related to the type IIABO(H) blood group determinant [50] Aldol condensationof the enolate of methyl ketone 228 with aldehyde 229 gavea 41 mixture of hydroxy ketones 230 and 231 The majorketol was cyclized desulfurized and oxidized to afford thedisaccharide ketone 233 The ketone in THF was treatedwith LiHMDS (3 equiv) and TMEDA followed by theaddition of MgBr2 Addition of the aldehyde 234 led toalmost exclusive formation of the equatorial products 235and 236 in a 12 ratio Mesylation of 235 and 236 followedby treatment with liquid ammonia gave enones 237a and237b which were reduced to yield exclusively the C-2rsquo-equatorial ketone 238 Sodium borohydride reduction of theC-3rsquo carbonyl proceeded with the desired stereoselectivity toyield the protected C-trisaccharide 239 which wasdeblocked to provide the polyol 240 (Scheme 46)
Sutherlin and Amstrong cleverly applied a recursivestereochemical deconvolution (RSD) combinatorial approachfor the synthesis of a small library of C-trisaccharides aspotential inhibitors for the cell surface proteins of bacteriumHelicobactor pylori [51] The workers chose to carry outvariations in galactose ring of these trisaccharides An
Scheme (44)
OBnO
BnOOBn
OBn
P O
OEtOEtO
EtO
R H
OH
OH
OH
OH
O
R H
OH
OH
OH
OH
O
OHO
HOOH
OH
O
HO
OHOH
OH
OHO
HOOH
OH
O
HO
OH
OH
OHO
HOOH
OH
O
HO
OH
OHOH
R H
OH
OH
OH
OH
O
R
OBnO
BnOOBn
OBn
O
OHO
HOOH
OH
OO
HOHO
OH
R H
OH
OH
OH
OH
O
1 OsO4 NMO 50
2 DIBAL -32 oC 40
++ +
213 214 215 216
217 218 219 220
1 9-BBN H2O22 Swern [O]
3 t-BuOK
4 I2 C6H6212
211
1418 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
efficient Nozaki-Kishi coupling of vinyl bromide 241 withaldehyde 242 in a diasteromeric ratio of 12 followed byprotection with TBSOTf led to 243 and 244 Hydroborationfollowed by oxidation gave aldehydes 245 and 246respectively Addition of allylmagnesium bromide toaldehyde 245 followed by removal of the silyl groupafforded 247 to 246 giving 248 and 249 Epoxidation gave a11 mixture of the corresponding epoxides which werecyclized to give the C-trisaccharide 250-255 after removalof the benzyl groups (Scheme 47)
Schmidt reported a stereoselective 6-exo-trig selectiveelectrophilic cylization approach for de novo synthesis of amethylene-bridged Neu5Ac-α-(23)-Gal C-disaccharide theC-analog of an important motif in glycosphingolipids [52]The open chain precusors 259ab (a 32-mixture ofdiaseteromeric alcohols) were formed by the addition oflithiated iodide 256 to open chain aldehyde 258 Subsequent
C1 incorporation using Tebbe-reagent formation of a cycliccarbonate and deprotection of the two isopropylidene ketalsafforded tetrol 264 which upon treatment with phenylselenyltrifilate was steroselectively cyclized in a 6-exo-trigselective manner affording a diasteromeric mixture of 251and 252 in a ratio of 71 A seleno-Pummerer rearrangementto afford aldehyde 267 in 5 steps in 90 overall yieldOxidation of the aldehyde and subsequent steps led to thedesired C-disaccharide 268 (Scheme 48)
53 Esterification-Cyclization
Work from the Postema group has focused on a ringclosing metathesis (RCM) approach for the synthesis of C-saccharides [53a] The chemistry is versatile and has beenused for the synthesis of a small library of differentiallylinked β-C-disaccharides through a radical allylation-RCMstrategy [53b] The synthesis of the β-(1rarr4)-glucopyranosyl
Scheme (45)
O
OBn
BnO
BnO
BnO
I
CrCl2-NiCl2O
OBn
OH
BnO
BnO
BnO
O
O
O
O
O
H
OBn
O
O
OBnBnO
BnO
BnO
OOBn
OBn
OAc
PMBOHOO
OBn
BnO
BnO
BnO
O
OBn
OBn
OAc
O
OH
HO
HO
HO
OH
OH
OH
O
OH
O
OBn
BnO
BnO
BnO
OBn
OBn
OAc
O
MMTr
+
1 p-TsOH2 K2CO3 MeOH3 MMTrCl pyr
1 Swern [O]2 BH3 THF
3 AcOH-H2 O4 H2 Pd(OH)2
221
222
223
1 Pd-Pb CaCO3 H22 NaH BnBr3 OsO44 Bu2 SnO5 CsF PMB-Cl6 Ac2 O 4-DMAP
1 AcOH2 TsCl pyr
3 NaH-imid4 DDQ
224225
226 227
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1419
Scheme (46)
OBnO O
OBn
OMe
OBn
XY
SMe
OBnBnO
O
OBn
OBn
OBn
OBn
O
BnO
YX
OBn
TBSO
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnOOBn
H
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnO
OBn
OHC OBn
OBn
OTBS
OMe
BnOOBn
CHO
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnOOBn
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnO
OBn
YX
OBnO O
OBn
OMe
OBn
OBn
O
BnO
O
OBn
OBn
OBn
OBn
O 1 LiHMDS
2
228
1 TBAF THF
2 MeSH BF3 OEt2
230 X = OH Y = H231 X = H Y = OH
230231 41
1 Bu3SnH AIBN2 Swern [O]
1 LiHMDS THF-TMEDA2 MgBr23
1 MsCl
2 liquid NH3
235 X = OH Y = H236 X = H Y = OH Bu3 SnH AIBN
237a and 237b
NaBH4 MeOH
238
239 X = OBn
240 X = OHH2 Pd(OH)2
229
232233
234
1420 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (47)
OH C
O
O BnAcHN
OO
O
OBn OBnOBn
Br
O
OBn OBnOBn
O
OBnA cHN
OO
O TBSO
OBn O BnO Bn
O
OBnAcHN
OO
OTBS
S2
S1
S2
OTBSS1
O H
S2
OT BSS1
O H
MgBrMgBr
S2
O TBSS1
O H
S2
OHS1
OH
S2
OTBSS1
OH
O
OHHO
O H
O
HO
H OO
OBnA cH N
HO
H O
O
O HHO
OH
O
HOHO
O
OBnA cH N
HO
H O
O
OHH O
OH
O
H O
HOO
OBnAcHN
HO
HO
O
O HH O
OH
O
H O
H O O
OBnA cHN
HO
HO
O
O HH O
O H
O
HO
H O O
OBnAcHN
HO
HO
O
OHHO
OH
O
H O
O
OBnA cHN
HO
HOHO
+
241 242
1 CrCl2-NiCl2 T HF-DMF 722 TBSOTf 2 6-lutidine 91
243 244
1 9-BBN 602 Dess-Mart in period inane 97
1 9 -BBN 552 D ess-Martin periodinane 98
245 246
1
2 T BAF 74
1
2 TBAF 88
247 248 249
250
251
250 251 1 1 252 253 1 1 254 255 1 1
252
253
254
255
1 MCPBA2 CSA CH 2Cl2 61 fo r 2 steps3 H 2 Pd (O H)2C 95
1 MCPBA2 CSA CH 2Cl2 63 fo r 2 s teps3 H 2 Pd (OH)2C 87
1 MCPBA2 CSA CH2Cl2 80 for 2 steps3 H2 Pd(O H)2C 95
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1421
Scheme (48)
O
OO
Se Ph
R
O
HO OHOH
O
OB n O B n
OB n
O B nO O
O O
R O OR
X
O
OO
R
Se Ph
O
HOOH
OH
O
OB nOB n
O Bn
OB n
O O
O O
R O O R
O H
O
O B n OB n
O B n
OB n
O
C HO
O
O O
R O OR
OAc HN
OAc
C O2NH 4HOOH
OH
O
OH O H
OH OH
O
OB n O B n
OB n
OB nO O
O O
R O OR
X
O
O
OAcOAc
C HOA cOOAc
OAc
O
OB n O B n
OB n
OB n
O
O Bn OB n
OB n
OB n
X
OH
OO
HOOH
OH
O
O
OMeOB n
OB nOB n
R
t-B uL i256 R = Li
257 R = L i
258
(R = t-B uMe 2Si )
(R = t-B uMe 2Si )
259ab (32) 79 com bine d yi eld
De ss-Ma rtin pe riodinane
260 X = O R = t-B uMe 2Si ) 95
261 X = O R = t -B uMe2S i) 62
T e bbe re age nt
TB A F THF262 X = O R = H 94
diphosge ne
C H2C l 2Pyr
263 95
T HFH2O T FAr t
264 quant it a ti ve yie ld
PhSe C l AgOT f
EtC N -80 oC
265
266
Quant it at i ve yi l ed 25 26 7 1
+
R =
1 Ac 2OPyr
2 mC PB A3 Ac 2ONa OAc
4 NaO HT HFMe OH
5 Ac2O P yr
267 90 overa ll yi e ld
ste ps
268
1422 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
glucopyranoside 280 represents an example of thischemistry The known triacetyl glucopyranoside 269 wasconverted to iodide 270 in good yield Radical allylation of271 proceeded to afford a mixture of equatorial and axialallylation products in a 61 ratio Oxidative cleavage of thedouble bond gave the corresponding aldehydes 273a and273b which were separable Pinnick oxidation of the majoraldehyde 273a then gave the C-4 equatorial acid 274 DCC-mediated coupling of alcohol 275 and acid 274 proceeded toafford ester 276 in good yield Methylenation of 276 gave277 and exposure to catalysist 278 gave a 41 yield of theC-disaccharide glycal which was exposed to an excess ofBH3
THF to give 64 yield of the β-C-disaccharide 279Removal of the benzyl groups and global peracetylation gavethe peracetylated (1rarr4)-β-C-disaccharide 281 in good yield(Scheme 49)
54 Ring Expansion-Cyclization
Nelson developed a new strategy for asymmetric andstereoselective synthesis of C-linked disaccharide mimeticsthe C58-C71 fragment of palytoxin [54] The diol (RR)-282was converted into the di-dihydropyran (DHP) template 283284 and 285 The di-DHPs were functionized in a twodirectional sense using dihydroxylation reactions The two-directional approach was often very efficient indeed forexample in the synthesis of 286 six new stereogenic centerswere introduced with almost complete stereocontrol using areduction and a dihydroxylation reaction The approach isnot restricted to the synthesis of C2-symmetricaldisaccharide mimetics Using the unsymmetrical template285 which has both a pseudo-axial and a pseudo-equatorialhydroxyl groups the unsymmetrical mimetics 289 and 290were prepared (Scheme 50)
6 RADICAL APPROACHES
The radical approach for C-C bond formation is a popularmethod within organic chemistry The use of radicalchemistry in carbohydrate synthesis has certain advantagesFirstly the reaction conditions are very mild and tolerant ofa range of functional and protecting groups Secondanomeric radicals are stable with respect to elimination andepimeration Most significantly the chemistry required toincorporate an appropriate substitute at C-1 employed in theinitial hemolytic cleavage step is common within carbo-hydrate chemistry [55] The use of such radical techniquecan be subdivided into two classes intermolecular andintramolecular approaches
61 Intermolecular Radical Approaches
Giese was the first to employ an intermolecular radical-based approach for synthesis of C-disaccharides [56]Addition of an alkene to an anomeric radical underappropriate conditions allowed exclusive entry to the α-linked C-glycoside a result which was mirrored by the workof Baldwin [57] The high α-selectivity of the reaction wasin contrast with other reports Thus radicals generated at theC-2 C-3 and C-4 centers all preferred to occupy equatorialpositions [58] When the anomeric bromide 291 was treatedwith tin hydride and AIBN resulting anomeric radical andreacted with lactone 292 in a Michael addition it afforded293 In this reaction hydrogen abstraction at the resulting
radical center occurs from axial face to selectively generatethe equatorial C-2rsquo substituent Reduction and acetylation of293 furnished C-disaccharide 294 (Scheme 51) [59]
Witczak used the facial bias of levoglucosene tostereoselectively add a carbohydrate-based radical in thepreparation of the 3-deoxy-(1rarr4)-β-C-disaccharide 299[60] Addition of the radical derived from iodide 295 to 296gave adduct 297 in 26 yield Removal of the anomerichydroxyl of 297 was achieved by treatment with triethylsilane borontrifluoride ether complex followed bystereoselective reduction of the keto function at C-2rsquo withthe formation of 298 in 89 yield Debenzylation followedby acetolysis of 16-anhydro ring produced the peracetylatedtarget C-disaccharide 299 in 19 overall yield from 295(Scheme 52)
Vogel has developed general methods to transformenantiomerically pure 7-oxabicyclo[221]heptyl derivatives(ldquonaked sugarsrdquo) into C-disaccharides Because of thesechiral bicyclic skeletons they undergo highly stereoselectivereactions with predictable diasteroselectivities An arsenal ofmethods is available that allow to substitute these ldquonakedrdquocarbon centers with a variety of functional groups with allpossible relative configurations The methods allowpreparation of both enantiomers of a given target with thesame ease Predictably high stereoselectivity of the reactionsof the bicyclic chirons adds to the flexibility of approachwhich can lead to high molecular diversity [61]
α-C-(1rarr3)-mannopyranoside of N-acetyl-galactosaminepotent β-galactosidase inhibitors was synthesized by thisapproach [61] Enone 302 was readily prepared from 300The addition of the radical derived from bromide 303 toenone 302 afforded the αminusisomer 304 The ketone was thenreduced and the selenide eliminated via the intermediacy ofthe selenoxide to give 305 Acid-promoted (CF3SO3H) 7-oxa ring opening of 305 in MeCN produced the amino-conduritol derivative 306 resulting from the quenching of theallylic cation intermediate by the solvent (Ritter reaction)Ozonolysis of the chloroalkene 306 generated an acylchloride-aldehyde intermediate that reacted with MeOH toproduce a mixture of methyl uronates The major compound307 was silylated and reduced The crude polyol obtainedwas acetylated to produce 308 Desilylated and ammonolysisafforded a mixture of α-β-pyranoses 309 and correspondingα-β-furanoses (Scheme 53)
Similar chemistry was carried out to synthesize non-protected α-C(1rarr2)-L-fucopyranoside of D-galactopyrano-side corresponding to a blood group mimetic [62] Giesersquosradical fucosidation of racemic enone 310 with α-L-bromoacetofucose 311 provided the mixture of diastereo-meric α-C-fucoside 312a and 312b in reproducible yield of78 Reduction of the mixture gave a 11 mixture of endo-alcohols 313 and 314 which were isolated pure in 40 and355 yield respectively Oxidative elimination of thebenzeneselenyl group of 313 followed by acetylation gaveendo acetate 315 in 85 yield Acid-promoted ring openingof 315 and ozonolysis of the resulted chloroalkene gavemethyl uronic ester 316 in modest yield (10) Treatment of316 with Cl3CCN and NaH followed with BF3
OEt2
furnished the totally protected C-disaccharide 317 in 79
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1423
Scheme (49)
Bu3SnO
HOAcO
OMeOAc
OAc
O
AcO
OMeOAc
OAcI
AIBN
O
AcO
OMeOBn
OBn
HO2C O
AcO
OMeOR
ORY
X
OHBnO
BnO
OBn
OBnO
BnO
OBn
O
AcO
OMeOBn
OBnX
i-Pr i-Pr
N
Mo C(Me2 Ph)((CF3)2 MeCO)2
O
RO
OMeOR
O
RO
OR
OR
RO
OR
278
I2 Ph3P
imidazole
269 270 93
271a X = CH2CH=CH2 Y = H R = Ac 64271b Y = CH2CH=CH2 X = H R = Ac 11272a X = CH2CH=CH2 Y = H R = Bn 75272b Y = CH2CH=CH2 X = H R = Bn 75273a X = CH2CHO Y = H R = Bn 79273a Y = CH2CHO X = H R = Bn 79
1 NaOMe MeOH2 NaOH BnBr DMF
OsO4 NaIO4
NaClO2 NaH2PO4
274 96
275
DCC 4-DMAP
276 X = O 82
277 X = CH2 51
TiCl4 Zn dust TMEDA CH2Br2PbCl2 (Cat )
1
2 BH3 THF H2O2 NaOH
H2 PdC EtOH
Ac2 O Pyr 4-DMAP
279 R = Bn R = H 64
280 R = R = H 99
281 R = R =Ac 97
1424 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (50)
Scheme (51)
O OOH
OH
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
286
1 VO(acac)2 t-BuOH 95
2 (MeO)3CH BF3 90
1 P-O2NC6H4 CO2H Ph3P DIAD2 K2CO3 MeOH 82 over 2 steps
1 PhCOCl Et3N DMAP 402 P-O2NC6H4 CO2H Ph3P DIAD3 KOH THF-H2O 75 over 2 steps
TMEDA OsO4
Cat OsO4 NMO 287
Cat OsO4 NMO288
TMEDA OsO4
Cat OsO4 NMO
290
289
(RR)-282283
284
285
OHO
AcO
BrOAc
OAc
BnO
O
OBn
OBnO
OHO
AcOOAc
OAc
BnO
OOBn
OBnAcO
OHO
AcOOAc
OAc
BnO
O
OBn
OBnO
+
Bu3SnH AIBN291
292
293 81
1 Na[Al(OC2H4OMe)2(OEt)H]2 Ac2O pyr
294 56 over 2 steps
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1425
Scheme (52)
Scheme (53)
OBnO
BnOOBn
OBn O
OH
O
OBnO
BnO
OHOBn
OBn O
O
O
O
O
O
OBnO
BnOOBn
OBnO
OAcOAc
OAc
OBnO
BnO
OHOBn
OBn
IBu3SnH AIBN
295 297 26
1 BF3 OEt2 Et3SiH
2 L-Selectride THF
1 Pd(OH)2C C6H10 EtOH
2 EtSiOSO2CF3 Ac2O
298 89 over 2 steps299
296
O
O
PhSeClO
O
PhSeCl
Bu3 SnH
O
O
PhSeCl
R
H
O
OAc
R
Cl
O
AcO
OAc
OAc
OAcOH
Cl
NHAc
R
OAc
AcHN
OH
O
OH OAc
OH
OHO
HO
OH
O
AcO
OAc
OAc
OAcBr
O
O
PhSeCl
O
O
PhSeCl
R
O
OTIPSAcHNR
OAc OAc
O
OHAcHN
COOMe
R
OAc
1 Bu4NF
2 NH3MeOH
1 (Me3Si)2NLi THF2 Me2N=CHI
1 Bu3 SnH AIBN2
1 NaBH42 mCPBA3 Ac2O pyr
1 H+ MeCN
2 H2 O NaHCO3
R =
1 O3MeOH
2 Me2S NaHCO3
1 TIPSOTf 26-lut idine2 LiBH43 Ac2 O pyr DMAP
furanoses +
304 56
305 68 306 84307 50
308 46
300 301 302
303
309
1426 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
The reduction of 317 and treatment with DOWEX-H+ resinprovided the desired C-fucoside 318 in 70 (Scheme 54)
62 Intramolecular Radical Approaches
One disadvantage with the intermolecular approaches isthat during such radical mediated reactions electrondeficient alkenes are required to facilitate C-C bondformation The intramolecular approach of Sinayuml overcomes
this drawback by bring two substrates together via atemporary covalent silaketal connector This enables the useof a wider range of alkenes which can include alkene-functionalized sugars thus leading to the generation of C-disaccharides [63] Based on the early work of Stork Sinayumlemployed the tether reaction in the synthesis of both α- andβ-C-disaccharides with this work subsequently beingemployed in the synthesis of biologically significant natural
Scheme (54)
O
OH
Fuc
Cl
O
O
ClPhSe
OOAc
NHAcOHFuc
O
AcOOAc
AcO
Br
O
O
PhSeCl
O
AcOOAc
AcO
O
OH
PhSe Cl
Fuc
OOAc
NHAc
OMe
Fuc
O
AcHN
OH OAc
OH
O
OH
Me
OH
O
O
Fuc
ClSePh
O
HO
Fuc
ClSePh
+
Ph3SnHAIBN
78 combined yield
Fuc
310
+
1 NaBH4 MeOHTHF2 Chromatography
313 40 314 355
1 mCPBA
2 Ac2O pyr DMAP
+
315 75
1 TfOH MeCN
2 NaHCO3 O3 -78 oC
316 10 over 2 steps
1 Cl3 CCN NaH
2 MeOH BF3 OEt2
317 79
1 LiBH4 THF
2 Dowex-H+
311
312a312b
318 70 for 2 steps
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1427
products [64] The availability of different hydroxyl groupson each monosaccharide unit allowed the fine-tuning ofstereochemical outcome by selective positioning of the silyltether [65] Development of this early stereochemical controlled to the tethering of the donor 320 with alcohol 319through a di-isopropyl silicon tether 321 Subsequent treat-ment with Bu3SnH and AIBN led to a 9-endo-trigcyclization to form the C-disaccharide 322 in an 80 yieldwith exclusive formation of the α-product The silyl tetherwas removed with Bu4NF and deprotection under standardconditions afforded the desired disaccharide 323 in excellentyield (Scheme 55)
In parallel the development of a 32rsquo silyl tether allowedaccess to the β-linked product as demonstrated in Sinayumlrsquossynthesis of methyl β-C-lactoside 328 [66] Alcohol 324 and320 were connected via the dimethylsilyl tether an 8-endo-trig cyclization followed to exclusively afford the β-
disaccharide 326 in 45 yield Removal of the tether anddeprotection of benzyl ether gave β-C-disaccharide 328(Scheme 56)
This group also selected iodosugars bearing a freehydroxyl group as progenitors of the radical donors [67] In atypical experiment the radical donor 329 was connected tothe radical acceptor 330 through a silaketal tether followingtheir procedure Tributyltinhydride mediated 8-endo-trigradical cyclization of compound 331 gave after detetheringof the non isolated intermediate 332 the protected β-C-disaccharide 333 in 37 overall yield (from startingmaterials 330 and 329) Peracetate 335 was achieved afterhydrogenolysis The C-laminaribioside 334 is of potentialbiological interest as it mimics the repeating disaccharideunit of fungal β-(1rarr3)-glucans which have antitumor andimmunomodulating properties (Scheme 57)
Scheme (55)
Scheme (56)
OO
OHSePh
OTBDPSO O
OO
SePh
OTBDPSO
OO
OBnOMe
OBn
Si
O
HOOBn
OMe
OBn
O
HOOH
OHHO
O
HOOH
OMe
OH
OTBDPSO
O
HOOBn
OMe
OBnO
OOH
1 n-BuLi THF
2 iPr2SiCl2 -78 oC
3 DMAP THF rt
1 Bu4NF THF
2 Dowex-H+
3 H2 PdC
Bu3SnH AIBN toluene
319
320
321
322323
OBnO
OHSePh
OBnBnO
OHO
OBnOMe
OBn
ROO
ROOH
OR
OHO
OROMe
OR
OBnO
O
OBnBnO
OO
OBnOMe
OBn
Si
SePh
OBnO
O
OBnBnOO
OOBn
OMe
OBn
Si
1 PhSeH Me2SiCl2
BuLi -78 oC
2 imidazole rt
Bu3SnH AIBN toluene
H2 PdC327 R = Bn
328 R = H
Bu4NF THF
324
320
325
326 45
1428 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
CONCLUSIONS
In this paper the biological importance of C-oligo-saccharides as subunits of natural products and as a newgeneration of carbohydrate based on therapeutics has beenillustrated Different methods are available for the synthesisof C-oligosaccharides As with traditional saccharidesynthesis it has been necessary to develop a number ofspecific approaches to facilitate the regioselective andstereoselective preparation of the desired targets Work inthis area continues and it is expected that many interestingnew C-oligosaccharides will be prepared using the chemistrydescribed in this review It is also likely that new chemistrywill be developed in the future for the preparation of thesebiologically important targets
ACKNOWLEDGEMENTS
The authors thank Dr Sultan Baytas for her criticalreading of this manuscript
REFERENCES
[1] Kennedy J F White C A Bioactive Carbohydrates InChemistry Biochemistry and Biology Ellis Horwood LtdChichesterUK 1983
[2] Wassarman PW Mammalian Fertilization Molecular Aspects ofGamete Adhesion xocytosion Exocytosis and Fusion Cell 199996 175-183
[3] Carbohydrate-based Drug Discovery Wong C-H EdWeinheim Cambridge Wiley-VCH 2003
[4] (a) Sharon N Lis H Lectins as Cell Recognition MoleculesScience 1987 246 227-234 (b) Dwek RA Chem Rev 1996 96683-720
[5] Postema M C-Glycoside synthesis CRC Boc Ratom 1995[6] (a) Weatherman R V Mortell K H Cheruenak MKiessling
L L Toone E J Specificity of C-Glycoside Complexation byMannoseGlucose Specific Lectins Biochem 1996 35 3619-3624(b) Ravishankar R Surolia A Vijayan M Lim S Kishi YPreferred Conformation of C-Lactose at the Free and Peanut LectinBound States J Am Chem Soc1998 120 11297-11303
[7] (a)Wong C-H Halcomb R L Ichikawa Y and Kajimoto TEnzymes in organic synthesis Application to the problems ofcarbohydrate recognition part2 Angew Chem Int Ed Engl 199534 521-546 (b)Howard S Withers SG Bromoketone C-Glycosides a New Class of βminusGlucanase Inactivators J AmChem Soc 1998 120 10326-10331(c) Wang Q Wolff MPolat T Du Y Linhardt R J C-glycoside of Neuraminic Acidsas Neura-minidase Inhibitors Bioorg Med Lett 2000 10 941-944 (d) Phili R Chang J Partis R A Mueller R A ChrestF J Passaniti A The Alpha-glucosidase I InhibitorCastanospermine Alters Endothelial cell Glycosylation PreventsAngiogenesis and Inhibits Tumor Growth Cancer Res 1995 552927-2935
[8] Ossor A Elbein A D In Carbohydrates in Chemistry andBiology Vol 3(II) WileyVCH 2000 pp 513-539
[9] (a) Sinayuml P Synthesis of oligosaccharide Mimetics Pure ApplChem 1997 69 459-463 (b) Beau J-M Gallagher TNucleophilic C-glycosyl Donors for C-glycoside Synthesis Top inCurr Chem 1997 187 1-54 (c) Nicotra F Synthesis of C-glycosides of Biological Interest Top in Curr Chem 1997 187
Scheme (57)
O
O
O
Ph
I
OMe
OHO
BnO
OH
OH
BnOOH
O
BnO
Si
O
O O
Ph
I
OMe
O
O
BnO
OR4O
R5O
OMe
OR2
OR3O
R3O
OR1
R3O
Bu3 SnH AIBN
332 R1 R2 = SiMe2 R3 = Bn R4 R5 = CHPhTBAF THF
333 R1 = R2 = H R3 = Bn R4 = R5 = CHPh 37 from 11
334 R1 = R2 = R3 = R4 = R5 = H
335 R1 = R2 = R3 = R4 = R5 = Ac
329
H2 PdC MeOH
Ac2 O pyr
1 BuLi THF -78 oC
2 Me2SiCl2
3 DMAP
330
331
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1429
55-83 (d) Du Y Linhardt R Y Recent Adv in Stereo-SelectiveC-Glycoside Synthesis Tetrahedron Lett 1998 54 9913-9959 (e)Liu L Mckee M and Postema M H D Synthesis of C-saccharides and Higher Congeners Current Org Chem 2001 51133-1167
[10] Jarosz S Fraser-Reid B Synthesis of A Higher Carbon Sugar ViaDirected Aldol Condensation Tetrahedron Lett 1989 30 2359-2362
[11] Lichtenthaler F W Lergenmiiller M Schwidetzky S C-Glycosidations of 2-Ketohexosyl With Electrophilic Radical andNudeophilic Anomeric Carbons Eur J Org Chem 2003 3094-3103
[12] Baudat A Vogel P Aza-C-disaccharides Synthesis of 6-Deoxygalactonojirimycin-β-C(1rarr3) Linked with D-Altrofuranosides and D-Galactose J Org Chem 1997 62 6252-6260
[13] Turner D Vogel P Synthesis of 4-Hydroxy-26-Bis(hydroxymethyl) tetrahydropyran-2-Carbaldehyde DerivativesSynlett 1998 304-306
[14] Zhu Y-H Vogel P Short Stereoselective Synthesis of C-(1rarr3)-Linked Disaccharides Tetrahedron Lett 1998 39 31-34
[15] Zhu Y-H Vogel P Synthesis of a (2R 6R)-2-(Hydroxymethyl)-6-Propa-1 2-Dienyl-2H-Pyran-3(6H)-One Derivative A NewEnone for The Convergent Construction of C-Glycosides of C-Disaccharides Synlett 2001 82-86
[16] Baumberger F Vasella A Deoxynitrosugars The 6th
Communication Stereolectronic Control in the reductivedenitration of tertiary nitro ethers A Synthesis of ldquoC-glycosidesrdquoHelv Chim Acta 1983 66 2210-2221
[17] Martin O R Lai W Synthesis and Conformational Studies of β-(1rarr6)- and ββ-(1rarr1)-Linked C-disaccharides J Org Chem1993 58 176-185
[18] Spak S J Martin R The synthesis of an analogue of Methyl OC-Analogue of Methyl 4rsquo-O-β-D-GlucopyranosylgentiobiosideTetrahedron 2000 56 217-224
[19] Kobertz W R Bertozzi C R Bednarski M D C-GlycosylAldehyde Synthons for C-Linked Disaccharides J Org Chem1996 61 1894-1897
[20] Gurjar M K Nagaprasad R and Ramana CV First Synthesis ofMethyl α-C-D-Arabino-furanosyl-(1rarr5)-αminusD-Arabinofuranosidethe C-Disaccharide Segment of Motif C of MycobateriumTuberculosis Tetrahedron Lett 2000 43 7577-7579
[21] Witczak Z J Synthesis of C-Glycosyl Compounds and OtherNatural Products from Levoglucosenone Pure Appl Chem 199466 2189-2192
[22] Griffin F K Paterson D Taylor R J K Ramberg-BacklundApproaches to the Synthesis of C-Linked Disaccharides AngewChem Int Engl 1999 38 2939-2942
[23] Paterson B E Griffin F K Alcaraz M-L and Taylor R J KA Ramberg-Baumlcklund Approach to the Synthesis of C-GlycosidesC-Linked Disaccharides and C-Glycosyl Amino Acids Eur JOrg Chem 2002 1323-1336
[24] McAllister G D Paterson D E Taylor R J K A SimplifiedRamberg-Bachlund Approach to Novel C-Glycosides and C-Linked Disaccharides Angew Chem Int Ed Engl 2003 42 1387-1391
[25] McCartney J L Christopher T M Cicchillo R M BernardinaM D Wagner T R and Norris P J Org Chem 2003 6810152-10155
[26] Dondoni A Zuurmond H M Bascarate A Synthesis of α-andβ-D-(1rarr6)-C-Disaccharides by Witting Olefination of Formyl C-Glycosides with Glycopyranose 6-phosphoranes J Org Chem1997 62 8114-8124
[27] Dondoni A Kleban M Zuurmond H Marra A Synthesis of(1rarr6)-C-Oligogalactosides by Interative Wittig OlefinationTetrahedron Lett 1998 39 7991-7994
[28] Dondoni A Marra A A New Synthetic Approach toMycobacterial Cell Wall α-(1rarr5)-D-Arabinofuranosyl C-Oligosaccharides Teterahedron Lett 2003 44 4067-4071
[29] Colinas P A Ponzinibbio A Lieberknecht A and Bravo R OWittig Reaction of Glycosyl Phosphonium Salts A StereoselectiveRoute to C-Disaccharides and C O-Trisaccharides TetrahedronLett 2003 44 7985-7988
[30] Schmidt R R Preuss R Synthesis of Carbon Tetrahedron Lett1989 30 3409-3412
[31] Dietrich H Schmidt R R Synthesis of Carbon-Bridged C-Lactose and Derivatives Liebigs Ann Chem 1994 975-981
[32] Rouzaud D Sinayuml P The First Synthesis of a ldquoC-DisacchariderdquoJ Chem Soc Chem Commun 1983 1353-1354
[33] Xin Y-C Zhang Y-M Mallet J-M Glaudemans C P JSinayuml P Synthesis of C-Oligosaccharides That Mimie TheirNatural O-Analogues Immunodeterminants in Binding toMonoclonal Immunoglobulins Eur J Org Chem 1999 471-476
[34] Streicher H Geyer A Schmidt R R C-Disaccharides ofKetoses Chem Eur J 1996 2 502-510
[35] Leeuwenburgh M A Timmers C M Vander Marel G A VanBoom J H Mallet J-M Sinayuml P G Stereoselective Synthesisof α-C-(Alkynyl)-Glycosides Via Ring-Opening of α-12-Anhydrous Tetrahedron Lett 1997 38 6251-6254
[36] Aslam T Fuchs M G G Le Formal A Wightman R HSynthesis of C-Disaccharide Analogue of the α-D-Arabinofuranosyl-(1rarr5)-α-Arabinofuranosyl Motif ofMycobacterial Cells Walls via Alkynyl Intermediates TetrahedronLett 2005 46 3249-3252
[37] (a) Girad P Namy J L Kagan H B Divalent LanthanideDerivative in Organic Synthesis 1 Mild Preparation of SamariumIodide and Ytterbium Iodide and Their Use as Reducing orCoupling Agents J Am Chem Soc 1980 102 2693-2698 (b)Molander G A Harris C R Sequencing Reactions withSamarium(II) Iodide Chem Rev 1996 96 307-338
[38] (a) Mazeacuteas D Skrydstrup T Doumeix O Beau J-MSamarium Iodide-Induced Intramolecular C-Glycoside FormationEfficient Radical Formation in the Absence of an Additive AngewChem Int Ed Engl 1994 33 1383-1386 (b) Mazeacuteas DSkrydstrup T Beau J-M A Highly Stereoselective Synthesis of1 2-trans-C-Glycosides Via Glycosyl Samarium(III) CompoundsAngew Chem Int Ed Engl 1995 34 909-912 (c) Jarreton OSkrydstrup T Beau J-M The Stereospecific Synthesis of Methylα-C-Mannobioside A Potential Inhibitor of M TuberculosisBinding to Human Macrophages J Chem Soc Chem Commun1996 1661-1662 (d) Jarreton O Skrydstrup T Espionosa J-FJimeacutenez-Barbero J Beau J-M Samarium Diiode Prompted C-Glycosylation An Application to The Stereospecific Synthesis ofα-(1rarr2)-C-Mannobioside and Its Derivatives Chem Eur J 19995 430-441 (e) Mipuel N Doisneau G Beau J-M ReductiveSamariation of Anomeric 2-Pyridyl Sulfones with Catalytic AnUnexpected Improvement in The Synthesis of 12-Trans-Diequatorial C-Glycosyl Compounds Angew Chem Int Ed Engl 2000 39 4111-4114
[39] Vlahov I R Vlahova P I Linhardt R J DiastereocontrolledSynthesis of Carbon Glycosides of N-Acetylneuraminic Acid ViaGlycosyl Samarium(III) Intermediates JAmChem Soc 1997 1191480-1481
[40] Kuberan B Sikkander S ATomiyama H Linhardt R JSynthesis of a C-Glycoside Analogue of sTn An HIV-and Tumor-Associated Antigen Angew Chem Int Ed Engl 2003 42 2073-2075
[41] Bazin H G Du Y Polat T Linhardt R J Synthesis of aVersatile Neuraminic Acid ldquoCrdquo-Disaccharide Precursor for theSynthesis of C-Glycoside Analogues of Gangliosides J OrgChem 1999 64 7254-7259
[42] Chen C-C Ress D K Linhardt RJ Samarium Iodide-Mediated Synthesis of Neuraminic Acid C-Glycosides InSynthesis of Glycommetics Roy R Ed ACS Syposium Series2004 896 53-80
[43] Abdallah Z Doisneau G Beau J-M Synthesis of a Carbon-Linked Mimic of The Disaccharide Component of The Tumor-Relate SialyTn Antigen Angew Chem Int Ed Engl 2003 425209-5212
[44] Lay L Nicotra F Panza L Russo G Caneva E Synthesis ofC-disaccharides through dimerization of exo-glycals J Org Chem1992 57 1304-1306
[45] Isobe M Nishizawa R Hosokawa S Nishikawa TStereocontrolled Synthesis and Reactivity of Sugar Acetylenes JChem Soc Chem Commun 1998 2665-2676
[46] Saeeng R Sirion U Sahakitpichan P Isobe M IodineCatalyzes C-Glycosidation of D-Glucal with SilylacetykeneTetrahedron Lett 2003 44 6211-6215
[47] (a) Babirad S A Wang Y Kishi Y Synthesis of C-Disaccharides J Org Chem 1987 52 1370-1372 (b) Wang YBabirad S A Kishi Y Preferred Conformation of C-Glycosides
1430 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
8 Synthesis of 14-Linked Carbon Disaccharides J Org Chem1992 57 468-481
[48] Armstrong R W Sutherlin D P Strategies for the Synthesis ofC-Disaccharides Containing D and L Sugars Tetrahedron Lett1994 35 7743-7746
[49] Wei A Kishi Y Preferred Conformation of C-Glycosides 12Synthesis and Conformational Analysis of αα- α β- and β β-Trehaloses J Org Chem 1994 59 88-96
[50] Haneda T Goekjian P G Kim S H Kishi Y PreferredConformation of C-Glycosides 10 Synthesis and ConformationAnalysis of Carbon Trisaccharides J Org Chem 1992 57 490-498
[51] Sutherlin D P Armstrong R W Synthesis of 12 Stereochemistryand Structurally Diverse C-Trisaccharides J Org Chem 1997 625267-5283
[52] Notz W Hartel C Waldscheck B Schmidt R R De NovoSynthesis of a Methylene-Bridged Neu5Ac-α-(23)-Gal C-Disaccharide J Org Chem 2001 66 4250-4260
[53] (a) Postema M H D Calimente D Liu L Behrmanm T L AnOlefin Metathesis Route for the Preparation of (1rarr6)-Linked-C-Disaccharide Glycals A Convergent and Flexible Approach to C-Saccharide Synthesis J Org Chem 2000 65 6061-6068(b) Postema M H Piper J L Liu L Faust M Andreana PSynthesis and Partial Biological Evaluation of a Small Library ofDifferentially Linked β-C-Disaccharide J Org Chem 2003 684748-4754
[54] Nelson A The Development of Strategies and Methods for TheSynthesis of Biologically Active Compounds New J Chem 200428 771-776
[55] Togo H He W Waki Y Yokoyama M C-GlycosylationTechnology With Free Radiant Reactions Synlett 1998 700-717
[56] Giese B Dupuis J Diastereoselective Synthesis of C-Glycopyranosides Angew Chem Int Ed Engl 1983 22 622-623
[57] Adlington R M Baldwin J E Basak A Kozyrod RPApplication of Radical Addition Reactions to tho Synthesis of a C-Glucoside and A Functionalized Amino Acid J Chem SocChem Commun 1983 144-145
[58] Giese B Gonzaacutelez-Goacutemez J A Witzel T The Scope of RadicalCC-Coupling by The ldquoTin Methodrdquo Angew Chem Int Ed Engl1984 23 69-70
[59] Giese B Witzel T Synthesis of ldquoC-Disaccharidesrdquo by RadicalC-C Bond Formation Angew Chem Int Ed Engl 1986 25 450-451
[60] Witczak Z J Chhabra R Chojnacki J C-Disaccharides IStereoselective Approach to β-(1rarr4)-3-Deoxy-C-Disaccharidesfrom Levoglucosenone Carb Res 1997 301 167-175
[61] Vogel P Synthesis of Rare Carbohydrates and Analogues Startingfrom Enantiomerically Pure 7-Oxabicyclo[221]heptyl Derivatives(ldquoNaked Sugarsrdquo) Current Org Chem 2000 4 455-480
[62] Viodeacute C Vogel P Synthesis of The C-Disaccharide α-C(1rarr3)-L-Fucopyranoside of N-Acetylgalactosamine J Carb Chem2001 20 733-746
[63] Xin Y C Mallet J M Sinayuml P An Expeditious Synthesis of AC-Disaccharide Using A Temporary Silaketal Connection J ChemSoc Chem Commun 1993 864-865
[64] (a) Petitou M Herault P Lormeau J-C Helmboldt A MalletJ-M Sinayuml P Herbert J-M Introducing A C-InterglycosidicBond in A Biologically Active Pentasaccharide Hardly Affects ItsBiological Properties Bioorg Med Chem 1998 6 1509-1516 (b)Sinayuml P Advances in The Synthesis of the Carbohydrate MimicsPure Appl Chem 1998 70 1495-1499
[65] Sinayuml P Chemical Synthesis of Oligosaccharide Mimetics PureAppl Chem 1998 70 407-410
[66] Sinayuml P Chemical Synthesis of Oligosaccharide Mimetics PureAppl Chem 1998 69 459-463
[67] Vauzeilles B Sinayuml P Selective Radical Synthesis of β-C-Disaccharides Tetrahedron Lett 2001 42 7269-7272
1414 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
41 Exo-glycals as Nucleophiles
Nitotra et al have found that treatment of exo-glycal 194with BF 3
OEt2 followed by a water quench afforded the C-disaccharide 195 (Scheme 39) It is noteworthy tonoteworthy that the attack of the enol ether on the anomericoxonium ion occurs with high stereoselectivity on the α-face only 195 was obtained [44]
42 Silyl-based Nucleophiles
Isobe has designed and developed alkynylation as a keyreaction for the introduction of a carbon chain onto sugarsThose alkynylated compounds are called ldquosugar acetylenesrdquo[45] The mechanism includes eliminative formation ofcation to which silylacetylene can coordinate on the α-face(Scheme 40)
Double C-glycosylation between glycal 198 and bis(silylacetylene) gave C-disaccharide ldquolikerdquo compounds 199and 200 (Scheme 41)
Silylpropargyl-sugar 201 smoothly reacted with D-glucalto furnish exclusively the α-acetylene glycoside product 202in 88 (Scheme 42) [46]
5 CYCLIZATION METHODOLOGY
This approach to C-oligosaccharide synthesis relies onthe coupling of an open chain fragment with an intact
monosaccharide to give an intermediate that is then cyclizedto deliver the C-oligosaccharide target This section isdivided by the type of chemistry used to initially assemblethe two pre-cyclization fragments
51 Wittig Reaction-Cyclization
The Kishi group was the first to use Wittig-cyclizationapproach to synthesize C-disaccharides Starting with Wittigreaction between 203 and 204 the intermediate 205 wasafforded as a single stereoisomer in 82 yield Osmylationthen gave a mixture of diols with the major one formed in a61 ratio Selective protection of the diols gave 206a and206b The mono-para-methoxybenzyl ether 206a was thentransformed into the hemiketal 207 in 75 overall yield inthree steps ie (1) Swern oxidation (2) acetonide hydro-lysis (4 N HClTHFrt) and (3) benzoylation (3 equiv ofPhCOClpyCH2Cl2rt) Silane reduction of 207 in an acidicmedium should preferentially yield the equatorially substi-tuted β-C-glycoside which was deblocked and converted tothe methyl- βminusC-disaccharide 209 Exact parallel experi-ments applied to the minor isomer gave the correspondingC-disaccharide 210 (Scheme 43) [47]
Armstrong has employed Wittig-osmylation protocol forthe preparation of a small library of α-C-(1rarr6)-disaccha-rides [48] Readily available allyl C-glycoside 211 washomologated to diene ester 212 and subjected to osmylation
Scheme (38)
O
CO2MeAcO
OAcAcHN
OAc
AcO
S(2-Py)
O
TESO
AcHNOMe
O
HO
O
CO2MeAcO
OAcAcHN
OAc
AcO
O NHAcOAc
OAc
OAc
O
CO2MeAcO
OAcAcHN
OAc
AcO
O NHAcOBn
OTES
OMe
OAc
AcO
O NHAcOBn
OTES
OMeOH
O
CO2 MeAcO
OAcAcHN
+
192 65
1 MeOHHCl2 H2 PdC EtOH3 Ac2O Pyr4 Ac2OAcOHH2SO4
193 59 overall yield
25 equiv SmI2 THF
1 11-thiocarbonyldiimidazole DMAP2 Ph3SnH cat AIBN
191 93
189
190
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1415
Scheme (39)
Scheme (40)
Scheme (41)
OBnO
OBn
OBn
OBnO
OBn
OBn
OBnO
OBn
OBn
OBnO
OBnCH3
BnO
OH
CH2
OBnO
OBn
CH3
OBn
H2 O
BF3 OEt2 MeCN
194
195 96
OOAc
OAc
AcO
R SiMe3
SnCl4
O
OAc
AcO
R
O
OAc
AcO
O
OAc
AcO
Me3Si
R
SiMe3
196
197
Me3 Si SiMe3
O
AcO
OAc
OAc
SiMe3
SiMe3
O
AcO
OAc
O
OAc
OAc
O
AcO
AcOO
OAc
OAc
SnCl4 CH2Cl2
SnCl4 CH2Cl2198
199
200
1416 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (42)
Scheme (43)
AcO
OAc
OAc
Me3 Si
BnO
OBn
BnO
OBn
AcO
OAc
BnO
OBn
BnO
OBn
+ I2 CH2Cl2
202 88
198 201
O
OBn
OBn
O
O
O
OBn
OBn
O
O
OBn
OBn O
OBn
OBn
O
OPBH2M
OH
OBnO
BnO
BnO
O
OBn
OBn
O
OHOPMB
OHO
HO
HO
O
OH
OHOH
OH
HOOMe
O
OBnOBn
O
Ph3P
O
O
OBn
OBn O
OBn
OBn
O
OPBM
OH
O O
CHO
OBn
BnO
OO
OBn
OBn
O
OHOPMB
BnO
BnO
BnO
OHO
HO
HO
O
OH
OHOH
OH
HOOMe
+ THF -78 oC
1 OsO4 pyr THF
2 NaH PMBBr
206a 206b 206a206b 61
1 Swern [O]2 4N HCl3 PhCOCl pyr
1 Swern [O]2 4N HCl3 PhCOCl pyr
1 PrSiH BF3 OEt2
2 H2 Pd(OH)2C
3 HCl MeOH 90 oC
1 PrSiH BF3 OEt2
2 H2 Pd(OH)2C
3 HCl MeOH 90 o C
203
204
205
207
209
208
210
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1417
followed by reduction to afford a 51 mixture (213214215216) of lactols that were readily separable by chromato-graphy Following a deprotection of an equimolar mixture of213 and 214 217 and the DL hybrid C-disaccharide of D-glucose-O-(1rarr6)-L-galactose 218 were obtained The DDand DL derivatives 219 and 220 of glucose-α-(1rarr6)-idosewere also obtained as a near equimolar mixture afterdeprotection of 215 and 216 (Scheme 44)
52 Anion Addition-Cyclization
Kishi developed an approach for the synthesis of theCndashtrehalo sugars which relied on nucleophilic addition ofone intact sugar fragment to a fundamental aldehyde ieKishi-Nozaki reaction [49] Coupling of monosaccharide221 and aldehyde 222 gave 223 The triple bond waspartially reduced and osmylation was followed by selectiveprotection to afford 224 The acetonide was converted toepoxide 225 by standard methods and removal of the PMBgroup Acid-catalyzed cyclization followed by aglyconichydrolysis and protection of hydroxyl group with (p-methoxyphenyl)diphenylmethyl chloride (MMTrCl) gave226 Inversion of the C-2 hydroxyl and removal of protectinggroups delivered α α-C-trehalose 227 (Scheme 44)
Kishi and co-workers also employed aldol reactions as anefficient access to the C-trisaccharide related to the type IIABO(H) blood group determinant [50] Aldol condensationof the enolate of methyl ketone 228 with aldehyde 229 gavea 41 mixture of hydroxy ketones 230 and 231 The majorketol was cyclized desulfurized and oxidized to afford thedisaccharide ketone 233 The ketone in THF was treatedwith LiHMDS (3 equiv) and TMEDA followed by theaddition of MgBr2 Addition of the aldehyde 234 led toalmost exclusive formation of the equatorial products 235and 236 in a 12 ratio Mesylation of 235 and 236 followedby treatment with liquid ammonia gave enones 237a and237b which were reduced to yield exclusively the C-2rsquo-equatorial ketone 238 Sodium borohydride reduction of theC-3rsquo carbonyl proceeded with the desired stereoselectivity toyield the protected C-trisaccharide 239 which wasdeblocked to provide the polyol 240 (Scheme 46)
Sutherlin and Amstrong cleverly applied a recursivestereochemical deconvolution (RSD) combinatorial approachfor the synthesis of a small library of C-trisaccharides aspotential inhibitors for the cell surface proteins of bacteriumHelicobactor pylori [51] The workers chose to carry outvariations in galactose ring of these trisaccharides An
Scheme (44)
OBnO
BnOOBn
OBn
P O
OEtOEtO
EtO
R H
OH
OH
OH
OH
O
R H
OH
OH
OH
OH
O
OHO
HOOH
OH
O
HO
OHOH
OH
OHO
HOOH
OH
O
HO
OH
OH
OHO
HOOH
OH
O
HO
OH
OHOH
R H
OH
OH
OH
OH
O
R
OBnO
BnOOBn
OBn
O
OHO
HOOH
OH
OO
HOHO
OH
R H
OH
OH
OH
OH
O
1 OsO4 NMO 50
2 DIBAL -32 oC 40
++ +
213 214 215 216
217 218 219 220
1 9-BBN H2O22 Swern [O]
3 t-BuOK
4 I2 C6H6212
211
1418 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
efficient Nozaki-Kishi coupling of vinyl bromide 241 withaldehyde 242 in a diasteromeric ratio of 12 followed byprotection with TBSOTf led to 243 and 244 Hydroborationfollowed by oxidation gave aldehydes 245 and 246respectively Addition of allylmagnesium bromide toaldehyde 245 followed by removal of the silyl groupafforded 247 to 246 giving 248 and 249 Epoxidation gave a11 mixture of the corresponding epoxides which werecyclized to give the C-trisaccharide 250-255 after removalof the benzyl groups (Scheme 47)
Schmidt reported a stereoselective 6-exo-trig selectiveelectrophilic cylization approach for de novo synthesis of amethylene-bridged Neu5Ac-α-(23)-Gal C-disaccharide theC-analog of an important motif in glycosphingolipids [52]The open chain precusors 259ab (a 32-mixture ofdiaseteromeric alcohols) were formed by the addition oflithiated iodide 256 to open chain aldehyde 258 Subsequent
C1 incorporation using Tebbe-reagent formation of a cycliccarbonate and deprotection of the two isopropylidene ketalsafforded tetrol 264 which upon treatment with phenylselenyltrifilate was steroselectively cyclized in a 6-exo-trigselective manner affording a diasteromeric mixture of 251and 252 in a ratio of 71 A seleno-Pummerer rearrangementto afford aldehyde 267 in 5 steps in 90 overall yieldOxidation of the aldehyde and subsequent steps led to thedesired C-disaccharide 268 (Scheme 48)
53 Esterification-Cyclization
Work from the Postema group has focused on a ringclosing metathesis (RCM) approach for the synthesis of C-saccharides [53a] The chemistry is versatile and has beenused for the synthesis of a small library of differentiallylinked β-C-disaccharides through a radical allylation-RCMstrategy [53b] The synthesis of the β-(1rarr4)-glucopyranosyl
Scheme (45)
O
OBn
BnO
BnO
BnO
I
CrCl2-NiCl2O
OBn
OH
BnO
BnO
BnO
O
O
O
O
O
H
OBn
O
O
OBnBnO
BnO
BnO
OOBn
OBn
OAc
PMBOHOO
OBn
BnO
BnO
BnO
O
OBn
OBn
OAc
O
OH
HO
HO
HO
OH
OH
OH
O
OH
O
OBn
BnO
BnO
BnO
OBn
OBn
OAc
O
MMTr
+
1 p-TsOH2 K2CO3 MeOH3 MMTrCl pyr
1 Swern [O]2 BH3 THF
3 AcOH-H2 O4 H2 Pd(OH)2
221
222
223
1 Pd-Pb CaCO3 H22 NaH BnBr3 OsO44 Bu2 SnO5 CsF PMB-Cl6 Ac2 O 4-DMAP
1 AcOH2 TsCl pyr
3 NaH-imid4 DDQ
224225
226 227
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1419
Scheme (46)
OBnO O
OBn
OMe
OBn
XY
SMe
OBnBnO
O
OBn
OBn
OBn
OBn
O
BnO
YX
OBn
TBSO
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnOOBn
H
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnO
OBn
OHC OBn
OBn
OTBS
OMe
BnOOBn
CHO
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnOOBn
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnO
OBn
YX
OBnO O
OBn
OMe
OBn
OBn
O
BnO
O
OBn
OBn
OBn
OBn
O 1 LiHMDS
2
228
1 TBAF THF
2 MeSH BF3 OEt2
230 X = OH Y = H231 X = H Y = OH
230231 41
1 Bu3SnH AIBN2 Swern [O]
1 LiHMDS THF-TMEDA2 MgBr23
1 MsCl
2 liquid NH3
235 X = OH Y = H236 X = H Y = OH Bu3 SnH AIBN
237a and 237b
NaBH4 MeOH
238
239 X = OBn
240 X = OHH2 Pd(OH)2
229
232233
234
1420 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (47)
OH C
O
O BnAcHN
OO
O
OBn OBnOBn
Br
O
OBn OBnOBn
O
OBnA cHN
OO
O TBSO
OBn O BnO Bn
O
OBnAcHN
OO
OTBS
S2
S1
S2
OTBSS1
O H
S2
OT BSS1
O H
MgBrMgBr
S2
O TBSS1
O H
S2
OHS1
OH
S2
OTBSS1
OH
O
OHHO
O H
O
HO
H OO
OBnA cH N
HO
H O
O
O HHO
OH
O
HOHO
O
OBnA cH N
HO
H O
O
OHH O
OH
O
H O
HOO
OBnAcHN
HO
HO
O
O HH O
OH
O
H O
H O O
OBnA cHN
HO
HO
O
O HH O
O H
O
HO
H O O
OBnAcHN
HO
HO
O
OHHO
OH
O
H O
O
OBnA cHN
HO
HOHO
+
241 242
1 CrCl2-NiCl2 T HF-DMF 722 TBSOTf 2 6-lutidine 91
243 244
1 9-BBN 602 Dess-Mart in period inane 97
1 9 -BBN 552 D ess-Martin periodinane 98
245 246
1
2 T BAF 74
1
2 TBAF 88
247 248 249
250
251
250 251 1 1 252 253 1 1 254 255 1 1
252
253
254
255
1 MCPBA2 CSA CH 2Cl2 61 fo r 2 steps3 H 2 Pd (O H)2C 95
1 MCPBA2 CSA CH 2Cl2 63 fo r 2 s teps3 H 2 Pd (OH)2C 87
1 MCPBA2 CSA CH2Cl2 80 for 2 steps3 H2 Pd(O H)2C 95
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1421
Scheme (48)
O
OO
Se Ph
R
O
HO OHOH
O
OB n O B n
OB n
O B nO O
O O
R O OR
X
O
OO
R
Se Ph
O
HOOH
OH
O
OB nOB n
O Bn
OB n
O O
O O
R O O R
O H
O
O B n OB n
O B n
OB n
O
C HO
O
O O
R O OR
OAc HN
OAc
C O2NH 4HOOH
OH
O
OH O H
OH OH
O
OB n O B n
OB n
OB nO O
O O
R O OR
X
O
O
OAcOAc
C HOA cOOAc
OAc
O
OB n O B n
OB n
OB n
O
O Bn OB n
OB n
OB n
X
OH
OO
HOOH
OH
O
O
OMeOB n
OB nOB n
R
t-B uL i256 R = Li
257 R = L i
258
(R = t-B uMe 2Si )
(R = t-B uMe 2Si )
259ab (32) 79 com bine d yi eld
De ss-Ma rtin pe riodinane
260 X = O R = t-B uMe 2Si ) 95
261 X = O R = t -B uMe2S i) 62
T e bbe re age nt
TB A F THF262 X = O R = H 94
diphosge ne
C H2C l 2Pyr
263 95
T HFH2O T FAr t
264 quant it a ti ve yie ld
PhSe C l AgOT f
EtC N -80 oC
265
266
Quant it at i ve yi l ed 25 26 7 1
+
R =
1 Ac 2OPyr
2 mC PB A3 Ac 2ONa OAc
4 NaO HT HFMe OH
5 Ac2O P yr
267 90 overa ll yi e ld
ste ps
268
1422 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
glucopyranoside 280 represents an example of thischemistry The known triacetyl glucopyranoside 269 wasconverted to iodide 270 in good yield Radical allylation of271 proceeded to afford a mixture of equatorial and axialallylation products in a 61 ratio Oxidative cleavage of thedouble bond gave the corresponding aldehydes 273a and273b which were separable Pinnick oxidation of the majoraldehyde 273a then gave the C-4 equatorial acid 274 DCC-mediated coupling of alcohol 275 and acid 274 proceeded toafford ester 276 in good yield Methylenation of 276 gave277 and exposure to catalysist 278 gave a 41 yield of theC-disaccharide glycal which was exposed to an excess ofBH3
THF to give 64 yield of the β-C-disaccharide 279Removal of the benzyl groups and global peracetylation gavethe peracetylated (1rarr4)-β-C-disaccharide 281 in good yield(Scheme 49)
54 Ring Expansion-Cyclization
Nelson developed a new strategy for asymmetric andstereoselective synthesis of C-linked disaccharide mimeticsthe C58-C71 fragment of palytoxin [54] The diol (RR)-282was converted into the di-dihydropyran (DHP) template 283284 and 285 The di-DHPs were functionized in a twodirectional sense using dihydroxylation reactions The two-directional approach was often very efficient indeed forexample in the synthesis of 286 six new stereogenic centerswere introduced with almost complete stereocontrol using areduction and a dihydroxylation reaction The approach isnot restricted to the synthesis of C2-symmetricaldisaccharide mimetics Using the unsymmetrical template285 which has both a pseudo-axial and a pseudo-equatorialhydroxyl groups the unsymmetrical mimetics 289 and 290were prepared (Scheme 50)
6 RADICAL APPROACHES
The radical approach for C-C bond formation is a popularmethod within organic chemistry The use of radicalchemistry in carbohydrate synthesis has certain advantagesFirstly the reaction conditions are very mild and tolerant ofa range of functional and protecting groups Secondanomeric radicals are stable with respect to elimination andepimeration Most significantly the chemistry required toincorporate an appropriate substitute at C-1 employed in theinitial hemolytic cleavage step is common within carbo-hydrate chemistry [55] The use of such radical techniquecan be subdivided into two classes intermolecular andintramolecular approaches
61 Intermolecular Radical Approaches
Giese was the first to employ an intermolecular radical-based approach for synthesis of C-disaccharides [56]Addition of an alkene to an anomeric radical underappropriate conditions allowed exclusive entry to the α-linked C-glycoside a result which was mirrored by the workof Baldwin [57] The high α-selectivity of the reaction wasin contrast with other reports Thus radicals generated at theC-2 C-3 and C-4 centers all preferred to occupy equatorialpositions [58] When the anomeric bromide 291 was treatedwith tin hydride and AIBN resulting anomeric radical andreacted with lactone 292 in a Michael addition it afforded293 In this reaction hydrogen abstraction at the resulting
radical center occurs from axial face to selectively generatethe equatorial C-2rsquo substituent Reduction and acetylation of293 furnished C-disaccharide 294 (Scheme 51) [59]
Witczak used the facial bias of levoglucosene tostereoselectively add a carbohydrate-based radical in thepreparation of the 3-deoxy-(1rarr4)-β-C-disaccharide 299[60] Addition of the radical derived from iodide 295 to 296gave adduct 297 in 26 yield Removal of the anomerichydroxyl of 297 was achieved by treatment with triethylsilane borontrifluoride ether complex followed bystereoselective reduction of the keto function at C-2rsquo withthe formation of 298 in 89 yield Debenzylation followedby acetolysis of 16-anhydro ring produced the peracetylatedtarget C-disaccharide 299 in 19 overall yield from 295(Scheme 52)
Vogel has developed general methods to transformenantiomerically pure 7-oxabicyclo[221]heptyl derivatives(ldquonaked sugarsrdquo) into C-disaccharides Because of thesechiral bicyclic skeletons they undergo highly stereoselectivereactions with predictable diasteroselectivities An arsenal ofmethods is available that allow to substitute these ldquonakedrdquocarbon centers with a variety of functional groups with allpossible relative configurations The methods allowpreparation of both enantiomers of a given target with thesame ease Predictably high stereoselectivity of the reactionsof the bicyclic chirons adds to the flexibility of approachwhich can lead to high molecular diversity [61]
α-C-(1rarr3)-mannopyranoside of N-acetyl-galactosaminepotent β-galactosidase inhibitors was synthesized by thisapproach [61] Enone 302 was readily prepared from 300The addition of the radical derived from bromide 303 toenone 302 afforded the αminusisomer 304 The ketone was thenreduced and the selenide eliminated via the intermediacy ofthe selenoxide to give 305 Acid-promoted (CF3SO3H) 7-oxa ring opening of 305 in MeCN produced the amino-conduritol derivative 306 resulting from the quenching of theallylic cation intermediate by the solvent (Ritter reaction)Ozonolysis of the chloroalkene 306 generated an acylchloride-aldehyde intermediate that reacted with MeOH toproduce a mixture of methyl uronates The major compound307 was silylated and reduced The crude polyol obtainedwas acetylated to produce 308 Desilylated and ammonolysisafforded a mixture of α-β-pyranoses 309 and correspondingα-β-furanoses (Scheme 53)
Similar chemistry was carried out to synthesize non-protected α-C(1rarr2)-L-fucopyranoside of D-galactopyrano-side corresponding to a blood group mimetic [62] Giesersquosradical fucosidation of racemic enone 310 with α-L-bromoacetofucose 311 provided the mixture of diastereo-meric α-C-fucoside 312a and 312b in reproducible yield of78 Reduction of the mixture gave a 11 mixture of endo-alcohols 313 and 314 which were isolated pure in 40 and355 yield respectively Oxidative elimination of thebenzeneselenyl group of 313 followed by acetylation gaveendo acetate 315 in 85 yield Acid-promoted ring openingof 315 and ozonolysis of the resulted chloroalkene gavemethyl uronic ester 316 in modest yield (10) Treatment of316 with Cl3CCN and NaH followed with BF3
OEt2
furnished the totally protected C-disaccharide 317 in 79
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1423
Scheme (49)
Bu3SnO
HOAcO
OMeOAc
OAc
O
AcO
OMeOAc
OAcI
AIBN
O
AcO
OMeOBn
OBn
HO2C O
AcO
OMeOR
ORY
X
OHBnO
BnO
OBn
OBnO
BnO
OBn
O
AcO
OMeOBn
OBnX
i-Pr i-Pr
N
Mo C(Me2 Ph)((CF3)2 MeCO)2
O
RO
OMeOR
O
RO
OR
OR
RO
OR
278
I2 Ph3P
imidazole
269 270 93
271a X = CH2CH=CH2 Y = H R = Ac 64271b Y = CH2CH=CH2 X = H R = Ac 11272a X = CH2CH=CH2 Y = H R = Bn 75272b Y = CH2CH=CH2 X = H R = Bn 75273a X = CH2CHO Y = H R = Bn 79273a Y = CH2CHO X = H R = Bn 79
1 NaOMe MeOH2 NaOH BnBr DMF
OsO4 NaIO4
NaClO2 NaH2PO4
274 96
275
DCC 4-DMAP
276 X = O 82
277 X = CH2 51
TiCl4 Zn dust TMEDA CH2Br2PbCl2 (Cat )
1
2 BH3 THF H2O2 NaOH
H2 PdC EtOH
Ac2 O Pyr 4-DMAP
279 R = Bn R = H 64
280 R = R = H 99
281 R = R =Ac 97
1424 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (50)
Scheme (51)
O OOH
OH
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
286
1 VO(acac)2 t-BuOH 95
2 (MeO)3CH BF3 90
1 P-O2NC6H4 CO2H Ph3P DIAD2 K2CO3 MeOH 82 over 2 steps
1 PhCOCl Et3N DMAP 402 P-O2NC6H4 CO2H Ph3P DIAD3 KOH THF-H2O 75 over 2 steps
TMEDA OsO4
Cat OsO4 NMO 287
Cat OsO4 NMO288
TMEDA OsO4
Cat OsO4 NMO
290
289
(RR)-282283
284
285
OHO
AcO
BrOAc
OAc
BnO
O
OBn
OBnO
OHO
AcOOAc
OAc
BnO
OOBn
OBnAcO
OHO
AcOOAc
OAc
BnO
O
OBn
OBnO
+
Bu3SnH AIBN291
292
293 81
1 Na[Al(OC2H4OMe)2(OEt)H]2 Ac2O pyr
294 56 over 2 steps
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1425
Scheme (52)
Scheme (53)
OBnO
BnOOBn
OBn O
OH
O
OBnO
BnO
OHOBn
OBn O
O
O
O
O
O
OBnO
BnOOBn
OBnO
OAcOAc
OAc
OBnO
BnO
OHOBn
OBn
IBu3SnH AIBN
295 297 26
1 BF3 OEt2 Et3SiH
2 L-Selectride THF
1 Pd(OH)2C C6H10 EtOH
2 EtSiOSO2CF3 Ac2O
298 89 over 2 steps299
296
O
O
PhSeClO
O
PhSeCl
Bu3 SnH
O
O
PhSeCl
R
H
O
OAc
R
Cl
O
AcO
OAc
OAc
OAcOH
Cl
NHAc
R
OAc
AcHN
OH
O
OH OAc
OH
OHO
HO
OH
O
AcO
OAc
OAc
OAcBr
O
O
PhSeCl
O
O
PhSeCl
R
O
OTIPSAcHNR
OAc OAc
O
OHAcHN
COOMe
R
OAc
1 Bu4NF
2 NH3MeOH
1 (Me3Si)2NLi THF2 Me2N=CHI
1 Bu3 SnH AIBN2
1 NaBH42 mCPBA3 Ac2O pyr
1 H+ MeCN
2 H2 O NaHCO3
R =
1 O3MeOH
2 Me2S NaHCO3
1 TIPSOTf 26-lut idine2 LiBH43 Ac2 O pyr DMAP
furanoses +
304 56
305 68 306 84307 50
308 46
300 301 302
303
309
1426 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
The reduction of 317 and treatment with DOWEX-H+ resinprovided the desired C-fucoside 318 in 70 (Scheme 54)
62 Intramolecular Radical Approaches
One disadvantage with the intermolecular approaches isthat during such radical mediated reactions electrondeficient alkenes are required to facilitate C-C bondformation The intramolecular approach of Sinayuml overcomes
this drawback by bring two substrates together via atemporary covalent silaketal connector This enables the useof a wider range of alkenes which can include alkene-functionalized sugars thus leading to the generation of C-disaccharides [63] Based on the early work of Stork Sinayumlemployed the tether reaction in the synthesis of both α- andβ-C-disaccharides with this work subsequently beingemployed in the synthesis of biologically significant natural
Scheme (54)
O
OH
Fuc
Cl
O
O
ClPhSe
OOAc
NHAcOHFuc
O
AcOOAc
AcO
Br
O
O
PhSeCl
O
AcOOAc
AcO
O
OH
PhSe Cl
Fuc
OOAc
NHAc
OMe
Fuc
O
AcHN
OH OAc
OH
O
OH
Me
OH
O
O
Fuc
ClSePh
O
HO
Fuc
ClSePh
+
Ph3SnHAIBN
78 combined yield
Fuc
310
+
1 NaBH4 MeOHTHF2 Chromatography
313 40 314 355
1 mCPBA
2 Ac2O pyr DMAP
+
315 75
1 TfOH MeCN
2 NaHCO3 O3 -78 oC
316 10 over 2 steps
1 Cl3 CCN NaH
2 MeOH BF3 OEt2
317 79
1 LiBH4 THF
2 Dowex-H+
311
312a312b
318 70 for 2 steps
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1427
products [64] The availability of different hydroxyl groupson each monosaccharide unit allowed the fine-tuning ofstereochemical outcome by selective positioning of the silyltether [65] Development of this early stereochemical controlled to the tethering of the donor 320 with alcohol 319through a di-isopropyl silicon tether 321 Subsequent treat-ment with Bu3SnH and AIBN led to a 9-endo-trigcyclization to form the C-disaccharide 322 in an 80 yieldwith exclusive formation of the α-product The silyl tetherwas removed with Bu4NF and deprotection under standardconditions afforded the desired disaccharide 323 in excellentyield (Scheme 55)
In parallel the development of a 32rsquo silyl tether allowedaccess to the β-linked product as demonstrated in Sinayumlrsquossynthesis of methyl β-C-lactoside 328 [66] Alcohol 324 and320 were connected via the dimethylsilyl tether an 8-endo-trig cyclization followed to exclusively afford the β-
disaccharide 326 in 45 yield Removal of the tether anddeprotection of benzyl ether gave β-C-disaccharide 328(Scheme 56)
This group also selected iodosugars bearing a freehydroxyl group as progenitors of the radical donors [67] In atypical experiment the radical donor 329 was connected tothe radical acceptor 330 through a silaketal tether followingtheir procedure Tributyltinhydride mediated 8-endo-trigradical cyclization of compound 331 gave after detetheringof the non isolated intermediate 332 the protected β-C-disaccharide 333 in 37 overall yield (from startingmaterials 330 and 329) Peracetate 335 was achieved afterhydrogenolysis The C-laminaribioside 334 is of potentialbiological interest as it mimics the repeating disaccharideunit of fungal β-(1rarr3)-glucans which have antitumor andimmunomodulating properties (Scheme 57)
Scheme (55)
Scheme (56)
OO
OHSePh
OTBDPSO O
OO
SePh
OTBDPSO
OO
OBnOMe
OBn
Si
O
HOOBn
OMe
OBn
O
HOOH
OHHO
O
HOOH
OMe
OH
OTBDPSO
O
HOOBn
OMe
OBnO
OOH
1 n-BuLi THF
2 iPr2SiCl2 -78 oC
3 DMAP THF rt
1 Bu4NF THF
2 Dowex-H+
3 H2 PdC
Bu3SnH AIBN toluene
319
320
321
322323
OBnO
OHSePh
OBnBnO
OHO
OBnOMe
OBn
ROO
ROOH
OR
OHO
OROMe
OR
OBnO
O
OBnBnO
OO
OBnOMe
OBn
Si
SePh
OBnO
O
OBnBnOO
OOBn
OMe
OBn
Si
1 PhSeH Me2SiCl2
BuLi -78 oC
2 imidazole rt
Bu3SnH AIBN toluene
H2 PdC327 R = Bn
328 R = H
Bu4NF THF
324
320
325
326 45
1428 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
CONCLUSIONS
In this paper the biological importance of C-oligo-saccharides as subunits of natural products and as a newgeneration of carbohydrate based on therapeutics has beenillustrated Different methods are available for the synthesisof C-oligosaccharides As with traditional saccharidesynthesis it has been necessary to develop a number ofspecific approaches to facilitate the regioselective andstereoselective preparation of the desired targets Work inthis area continues and it is expected that many interestingnew C-oligosaccharides will be prepared using the chemistrydescribed in this review It is also likely that new chemistrywill be developed in the future for the preparation of thesebiologically important targets
ACKNOWLEDGEMENTS
The authors thank Dr Sultan Baytas for her criticalreading of this manuscript
REFERENCES
[1] Kennedy J F White C A Bioactive Carbohydrates InChemistry Biochemistry and Biology Ellis Horwood LtdChichesterUK 1983
[2] Wassarman PW Mammalian Fertilization Molecular Aspects ofGamete Adhesion xocytosion Exocytosis and Fusion Cell 199996 175-183
[3] Carbohydrate-based Drug Discovery Wong C-H EdWeinheim Cambridge Wiley-VCH 2003
[4] (a) Sharon N Lis H Lectins as Cell Recognition MoleculesScience 1987 246 227-234 (b) Dwek RA Chem Rev 1996 96683-720
[5] Postema M C-Glycoside synthesis CRC Boc Ratom 1995[6] (a) Weatherman R V Mortell K H Cheruenak MKiessling
L L Toone E J Specificity of C-Glycoside Complexation byMannoseGlucose Specific Lectins Biochem 1996 35 3619-3624(b) Ravishankar R Surolia A Vijayan M Lim S Kishi YPreferred Conformation of C-Lactose at the Free and Peanut LectinBound States J Am Chem Soc1998 120 11297-11303
[7] (a)Wong C-H Halcomb R L Ichikawa Y and Kajimoto TEnzymes in organic synthesis Application to the problems ofcarbohydrate recognition part2 Angew Chem Int Ed Engl 199534 521-546 (b)Howard S Withers SG Bromoketone C-Glycosides a New Class of βminusGlucanase Inactivators J AmChem Soc 1998 120 10326-10331(c) Wang Q Wolff MPolat T Du Y Linhardt R J C-glycoside of Neuraminic Acidsas Neura-minidase Inhibitors Bioorg Med Lett 2000 10 941-944 (d) Phili R Chang J Partis R A Mueller R A ChrestF J Passaniti A The Alpha-glucosidase I InhibitorCastanospermine Alters Endothelial cell Glycosylation PreventsAngiogenesis and Inhibits Tumor Growth Cancer Res 1995 552927-2935
[8] Ossor A Elbein A D In Carbohydrates in Chemistry andBiology Vol 3(II) WileyVCH 2000 pp 513-539
[9] (a) Sinayuml P Synthesis of oligosaccharide Mimetics Pure ApplChem 1997 69 459-463 (b) Beau J-M Gallagher TNucleophilic C-glycosyl Donors for C-glycoside Synthesis Top inCurr Chem 1997 187 1-54 (c) Nicotra F Synthesis of C-glycosides of Biological Interest Top in Curr Chem 1997 187
Scheme (57)
O
O
O
Ph
I
OMe
OHO
BnO
OH
OH
BnOOH
O
BnO
Si
O
O O
Ph
I
OMe
O
O
BnO
OR4O
R5O
OMe
OR2
OR3O
R3O
OR1
R3O
Bu3 SnH AIBN
332 R1 R2 = SiMe2 R3 = Bn R4 R5 = CHPhTBAF THF
333 R1 = R2 = H R3 = Bn R4 = R5 = CHPh 37 from 11
334 R1 = R2 = R3 = R4 = R5 = H
335 R1 = R2 = R3 = R4 = R5 = Ac
329
H2 PdC MeOH
Ac2 O pyr
1 BuLi THF -78 oC
2 Me2SiCl2
3 DMAP
330
331
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1429
55-83 (d) Du Y Linhardt R Y Recent Adv in Stereo-SelectiveC-Glycoside Synthesis Tetrahedron Lett 1998 54 9913-9959 (e)Liu L Mckee M and Postema M H D Synthesis of C-saccharides and Higher Congeners Current Org Chem 2001 51133-1167
[10] Jarosz S Fraser-Reid B Synthesis of A Higher Carbon Sugar ViaDirected Aldol Condensation Tetrahedron Lett 1989 30 2359-2362
[11] Lichtenthaler F W Lergenmiiller M Schwidetzky S C-Glycosidations of 2-Ketohexosyl With Electrophilic Radical andNudeophilic Anomeric Carbons Eur J Org Chem 2003 3094-3103
[12] Baudat A Vogel P Aza-C-disaccharides Synthesis of 6-Deoxygalactonojirimycin-β-C(1rarr3) Linked with D-Altrofuranosides and D-Galactose J Org Chem 1997 62 6252-6260
[13] Turner D Vogel P Synthesis of 4-Hydroxy-26-Bis(hydroxymethyl) tetrahydropyran-2-Carbaldehyde DerivativesSynlett 1998 304-306
[14] Zhu Y-H Vogel P Short Stereoselective Synthesis of C-(1rarr3)-Linked Disaccharides Tetrahedron Lett 1998 39 31-34
[15] Zhu Y-H Vogel P Synthesis of a (2R 6R)-2-(Hydroxymethyl)-6-Propa-1 2-Dienyl-2H-Pyran-3(6H)-One Derivative A NewEnone for The Convergent Construction of C-Glycosides of C-Disaccharides Synlett 2001 82-86
[16] Baumberger F Vasella A Deoxynitrosugars The 6th
Communication Stereolectronic Control in the reductivedenitration of tertiary nitro ethers A Synthesis of ldquoC-glycosidesrdquoHelv Chim Acta 1983 66 2210-2221
[17] Martin O R Lai W Synthesis and Conformational Studies of β-(1rarr6)- and ββ-(1rarr1)-Linked C-disaccharides J Org Chem1993 58 176-185
[18] Spak S J Martin R The synthesis of an analogue of Methyl OC-Analogue of Methyl 4rsquo-O-β-D-GlucopyranosylgentiobiosideTetrahedron 2000 56 217-224
[19] Kobertz W R Bertozzi C R Bednarski M D C-GlycosylAldehyde Synthons for C-Linked Disaccharides J Org Chem1996 61 1894-1897
[20] Gurjar M K Nagaprasad R and Ramana CV First Synthesis ofMethyl α-C-D-Arabino-furanosyl-(1rarr5)-αminusD-Arabinofuranosidethe C-Disaccharide Segment of Motif C of MycobateriumTuberculosis Tetrahedron Lett 2000 43 7577-7579
[21] Witczak Z J Synthesis of C-Glycosyl Compounds and OtherNatural Products from Levoglucosenone Pure Appl Chem 199466 2189-2192
[22] Griffin F K Paterson D Taylor R J K Ramberg-BacklundApproaches to the Synthesis of C-Linked Disaccharides AngewChem Int Engl 1999 38 2939-2942
[23] Paterson B E Griffin F K Alcaraz M-L and Taylor R J KA Ramberg-Baumlcklund Approach to the Synthesis of C-GlycosidesC-Linked Disaccharides and C-Glycosyl Amino Acids Eur JOrg Chem 2002 1323-1336
[24] McAllister G D Paterson D E Taylor R J K A SimplifiedRamberg-Bachlund Approach to Novel C-Glycosides and C-Linked Disaccharides Angew Chem Int Ed Engl 2003 42 1387-1391
[25] McCartney J L Christopher T M Cicchillo R M BernardinaM D Wagner T R and Norris P J Org Chem 2003 6810152-10155
[26] Dondoni A Zuurmond H M Bascarate A Synthesis of α-andβ-D-(1rarr6)-C-Disaccharides by Witting Olefination of Formyl C-Glycosides with Glycopyranose 6-phosphoranes J Org Chem1997 62 8114-8124
[27] Dondoni A Kleban M Zuurmond H Marra A Synthesis of(1rarr6)-C-Oligogalactosides by Interative Wittig OlefinationTetrahedron Lett 1998 39 7991-7994
[28] Dondoni A Marra A A New Synthetic Approach toMycobacterial Cell Wall α-(1rarr5)-D-Arabinofuranosyl C-Oligosaccharides Teterahedron Lett 2003 44 4067-4071
[29] Colinas P A Ponzinibbio A Lieberknecht A and Bravo R OWittig Reaction of Glycosyl Phosphonium Salts A StereoselectiveRoute to C-Disaccharides and C O-Trisaccharides TetrahedronLett 2003 44 7985-7988
[30] Schmidt R R Preuss R Synthesis of Carbon Tetrahedron Lett1989 30 3409-3412
[31] Dietrich H Schmidt R R Synthesis of Carbon-Bridged C-Lactose and Derivatives Liebigs Ann Chem 1994 975-981
[32] Rouzaud D Sinayuml P The First Synthesis of a ldquoC-DisacchariderdquoJ Chem Soc Chem Commun 1983 1353-1354
[33] Xin Y-C Zhang Y-M Mallet J-M Glaudemans C P JSinayuml P Synthesis of C-Oligosaccharides That Mimie TheirNatural O-Analogues Immunodeterminants in Binding toMonoclonal Immunoglobulins Eur J Org Chem 1999 471-476
[34] Streicher H Geyer A Schmidt R R C-Disaccharides ofKetoses Chem Eur J 1996 2 502-510
[35] Leeuwenburgh M A Timmers C M Vander Marel G A VanBoom J H Mallet J-M Sinayuml P G Stereoselective Synthesisof α-C-(Alkynyl)-Glycosides Via Ring-Opening of α-12-Anhydrous Tetrahedron Lett 1997 38 6251-6254
[36] Aslam T Fuchs M G G Le Formal A Wightman R HSynthesis of C-Disaccharide Analogue of the α-D-Arabinofuranosyl-(1rarr5)-α-Arabinofuranosyl Motif ofMycobacterial Cells Walls via Alkynyl Intermediates TetrahedronLett 2005 46 3249-3252
[37] (a) Girad P Namy J L Kagan H B Divalent LanthanideDerivative in Organic Synthesis 1 Mild Preparation of SamariumIodide and Ytterbium Iodide and Their Use as Reducing orCoupling Agents J Am Chem Soc 1980 102 2693-2698 (b)Molander G A Harris C R Sequencing Reactions withSamarium(II) Iodide Chem Rev 1996 96 307-338
[38] (a) Mazeacuteas D Skrydstrup T Doumeix O Beau J-MSamarium Iodide-Induced Intramolecular C-Glycoside FormationEfficient Radical Formation in the Absence of an Additive AngewChem Int Ed Engl 1994 33 1383-1386 (b) Mazeacuteas DSkrydstrup T Beau J-M A Highly Stereoselective Synthesis of1 2-trans-C-Glycosides Via Glycosyl Samarium(III) CompoundsAngew Chem Int Ed Engl 1995 34 909-912 (c) Jarreton OSkrydstrup T Beau J-M The Stereospecific Synthesis of Methylα-C-Mannobioside A Potential Inhibitor of M TuberculosisBinding to Human Macrophages J Chem Soc Chem Commun1996 1661-1662 (d) Jarreton O Skrydstrup T Espionosa J-FJimeacutenez-Barbero J Beau J-M Samarium Diiode Prompted C-Glycosylation An Application to The Stereospecific Synthesis ofα-(1rarr2)-C-Mannobioside and Its Derivatives Chem Eur J 19995 430-441 (e) Mipuel N Doisneau G Beau J-M ReductiveSamariation of Anomeric 2-Pyridyl Sulfones with Catalytic AnUnexpected Improvement in The Synthesis of 12-Trans-Diequatorial C-Glycosyl Compounds Angew Chem Int Ed Engl 2000 39 4111-4114
[39] Vlahov I R Vlahova P I Linhardt R J DiastereocontrolledSynthesis of Carbon Glycosides of N-Acetylneuraminic Acid ViaGlycosyl Samarium(III) Intermediates JAmChem Soc 1997 1191480-1481
[40] Kuberan B Sikkander S ATomiyama H Linhardt R JSynthesis of a C-Glycoside Analogue of sTn An HIV-and Tumor-Associated Antigen Angew Chem Int Ed Engl 2003 42 2073-2075
[41] Bazin H G Du Y Polat T Linhardt R J Synthesis of aVersatile Neuraminic Acid ldquoCrdquo-Disaccharide Precursor for theSynthesis of C-Glycoside Analogues of Gangliosides J OrgChem 1999 64 7254-7259
[42] Chen C-C Ress D K Linhardt RJ Samarium Iodide-Mediated Synthesis of Neuraminic Acid C-Glycosides InSynthesis of Glycommetics Roy R Ed ACS Syposium Series2004 896 53-80
[43] Abdallah Z Doisneau G Beau J-M Synthesis of a Carbon-Linked Mimic of The Disaccharide Component of The Tumor-Relate SialyTn Antigen Angew Chem Int Ed Engl 2003 425209-5212
[44] Lay L Nicotra F Panza L Russo G Caneva E Synthesis ofC-disaccharides through dimerization of exo-glycals J Org Chem1992 57 1304-1306
[45] Isobe M Nishizawa R Hosokawa S Nishikawa TStereocontrolled Synthesis and Reactivity of Sugar Acetylenes JChem Soc Chem Commun 1998 2665-2676
[46] Saeeng R Sirion U Sahakitpichan P Isobe M IodineCatalyzes C-Glycosidation of D-Glucal with SilylacetykeneTetrahedron Lett 2003 44 6211-6215
[47] (a) Babirad S A Wang Y Kishi Y Synthesis of C-Disaccharides J Org Chem 1987 52 1370-1372 (b) Wang YBabirad S A Kishi Y Preferred Conformation of C-Glycosides
1430 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
8 Synthesis of 14-Linked Carbon Disaccharides J Org Chem1992 57 468-481
[48] Armstrong R W Sutherlin D P Strategies for the Synthesis ofC-Disaccharides Containing D and L Sugars Tetrahedron Lett1994 35 7743-7746
[49] Wei A Kishi Y Preferred Conformation of C-Glycosides 12Synthesis and Conformational Analysis of αα- α β- and β β-Trehaloses J Org Chem 1994 59 88-96
[50] Haneda T Goekjian P G Kim S H Kishi Y PreferredConformation of C-Glycosides 10 Synthesis and ConformationAnalysis of Carbon Trisaccharides J Org Chem 1992 57 490-498
[51] Sutherlin D P Armstrong R W Synthesis of 12 Stereochemistryand Structurally Diverse C-Trisaccharides J Org Chem 1997 625267-5283
[52] Notz W Hartel C Waldscheck B Schmidt R R De NovoSynthesis of a Methylene-Bridged Neu5Ac-α-(23)-Gal C-Disaccharide J Org Chem 2001 66 4250-4260
[53] (a) Postema M H D Calimente D Liu L Behrmanm T L AnOlefin Metathesis Route for the Preparation of (1rarr6)-Linked-C-Disaccharide Glycals A Convergent and Flexible Approach to C-Saccharide Synthesis J Org Chem 2000 65 6061-6068(b) Postema M H Piper J L Liu L Faust M Andreana PSynthesis and Partial Biological Evaluation of a Small Library ofDifferentially Linked β-C-Disaccharide J Org Chem 2003 684748-4754
[54] Nelson A The Development of Strategies and Methods for TheSynthesis of Biologically Active Compounds New J Chem 200428 771-776
[55] Togo H He W Waki Y Yokoyama M C-GlycosylationTechnology With Free Radiant Reactions Synlett 1998 700-717
[56] Giese B Dupuis J Diastereoselective Synthesis of C-Glycopyranosides Angew Chem Int Ed Engl 1983 22 622-623
[57] Adlington R M Baldwin J E Basak A Kozyrod RPApplication of Radical Addition Reactions to tho Synthesis of a C-Glucoside and A Functionalized Amino Acid J Chem SocChem Commun 1983 144-145
[58] Giese B Gonzaacutelez-Goacutemez J A Witzel T The Scope of RadicalCC-Coupling by The ldquoTin Methodrdquo Angew Chem Int Ed Engl1984 23 69-70
[59] Giese B Witzel T Synthesis of ldquoC-Disaccharidesrdquo by RadicalC-C Bond Formation Angew Chem Int Ed Engl 1986 25 450-451
[60] Witczak Z J Chhabra R Chojnacki J C-Disaccharides IStereoselective Approach to β-(1rarr4)-3-Deoxy-C-Disaccharidesfrom Levoglucosenone Carb Res 1997 301 167-175
[61] Vogel P Synthesis of Rare Carbohydrates and Analogues Startingfrom Enantiomerically Pure 7-Oxabicyclo[221]heptyl Derivatives(ldquoNaked Sugarsrdquo) Current Org Chem 2000 4 455-480
[62] Viodeacute C Vogel P Synthesis of The C-Disaccharide α-C(1rarr3)-L-Fucopyranoside of N-Acetylgalactosamine J Carb Chem2001 20 733-746
[63] Xin Y C Mallet J M Sinayuml P An Expeditious Synthesis of AC-Disaccharide Using A Temporary Silaketal Connection J ChemSoc Chem Commun 1993 864-865
[64] (a) Petitou M Herault P Lormeau J-C Helmboldt A MalletJ-M Sinayuml P Herbert J-M Introducing A C-InterglycosidicBond in A Biologically Active Pentasaccharide Hardly Affects ItsBiological Properties Bioorg Med Chem 1998 6 1509-1516 (b)Sinayuml P Advances in The Synthesis of the Carbohydrate MimicsPure Appl Chem 1998 70 1495-1499
[65] Sinayuml P Chemical Synthesis of Oligosaccharide Mimetics PureAppl Chem 1998 70 407-410
[66] Sinayuml P Chemical Synthesis of Oligosaccharide Mimetics PureAppl Chem 1998 69 459-463
[67] Vauzeilles B Sinayuml P Selective Radical Synthesis of β-C-Disaccharides Tetrahedron Lett 2001 42 7269-7272
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1415
Scheme (39)
Scheme (40)
Scheme (41)
OBnO
OBn
OBn
OBnO
OBn
OBn
OBnO
OBn
OBn
OBnO
OBnCH3
BnO
OH
CH2
OBnO
OBn
CH3
OBn
H2 O
BF3 OEt2 MeCN
194
195 96
OOAc
OAc
AcO
R SiMe3
SnCl4
O
OAc
AcO
R
O
OAc
AcO
O
OAc
AcO
Me3Si
R
SiMe3
196
197
Me3 Si SiMe3
O
AcO
OAc
OAc
SiMe3
SiMe3
O
AcO
OAc
O
OAc
OAc
O
AcO
AcOO
OAc
OAc
SnCl4 CH2Cl2
SnCl4 CH2Cl2198
199
200
1416 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (42)
Scheme (43)
AcO
OAc
OAc
Me3 Si
BnO
OBn
BnO
OBn
AcO
OAc
BnO
OBn
BnO
OBn
+ I2 CH2Cl2
202 88
198 201
O
OBn
OBn
O
O
O
OBn
OBn
O
O
OBn
OBn O
OBn
OBn
O
OPBH2M
OH
OBnO
BnO
BnO
O
OBn
OBn
O
OHOPMB
OHO
HO
HO
O
OH
OHOH
OH
HOOMe
O
OBnOBn
O
Ph3P
O
O
OBn
OBn O
OBn
OBn
O
OPBM
OH
O O
CHO
OBn
BnO
OO
OBn
OBn
O
OHOPMB
BnO
BnO
BnO
OHO
HO
HO
O
OH
OHOH
OH
HOOMe
+ THF -78 oC
1 OsO4 pyr THF
2 NaH PMBBr
206a 206b 206a206b 61
1 Swern [O]2 4N HCl3 PhCOCl pyr
1 Swern [O]2 4N HCl3 PhCOCl pyr
1 PrSiH BF3 OEt2
2 H2 Pd(OH)2C
3 HCl MeOH 90 oC
1 PrSiH BF3 OEt2
2 H2 Pd(OH)2C
3 HCl MeOH 90 o C
203
204
205
207
209
208
210
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1417
followed by reduction to afford a 51 mixture (213214215216) of lactols that were readily separable by chromato-graphy Following a deprotection of an equimolar mixture of213 and 214 217 and the DL hybrid C-disaccharide of D-glucose-O-(1rarr6)-L-galactose 218 were obtained The DDand DL derivatives 219 and 220 of glucose-α-(1rarr6)-idosewere also obtained as a near equimolar mixture afterdeprotection of 215 and 216 (Scheme 44)
52 Anion Addition-Cyclization
Kishi developed an approach for the synthesis of theCndashtrehalo sugars which relied on nucleophilic addition ofone intact sugar fragment to a fundamental aldehyde ieKishi-Nozaki reaction [49] Coupling of monosaccharide221 and aldehyde 222 gave 223 The triple bond waspartially reduced and osmylation was followed by selectiveprotection to afford 224 The acetonide was converted toepoxide 225 by standard methods and removal of the PMBgroup Acid-catalyzed cyclization followed by aglyconichydrolysis and protection of hydroxyl group with (p-methoxyphenyl)diphenylmethyl chloride (MMTrCl) gave226 Inversion of the C-2 hydroxyl and removal of protectinggroups delivered α α-C-trehalose 227 (Scheme 44)
Kishi and co-workers also employed aldol reactions as anefficient access to the C-trisaccharide related to the type IIABO(H) blood group determinant [50] Aldol condensationof the enolate of methyl ketone 228 with aldehyde 229 gavea 41 mixture of hydroxy ketones 230 and 231 The majorketol was cyclized desulfurized and oxidized to afford thedisaccharide ketone 233 The ketone in THF was treatedwith LiHMDS (3 equiv) and TMEDA followed by theaddition of MgBr2 Addition of the aldehyde 234 led toalmost exclusive formation of the equatorial products 235and 236 in a 12 ratio Mesylation of 235 and 236 followedby treatment with liquid ammonia gave enones 237a and237b which were reduced to yield exclusively the C-2rsquo-equatorial ketone 238 Sodium borohydride reduction of theC-3rsquo carbonyl proceeded with the desired stereoselectivity toyield the protected C-trisaccharide 239 which wasdeblocked to provide the polyol 240 (Scheme 46)
Sutherlin and Amstrong cleverly applied a recursivestereochemical deconvolution (RSD) combinatorial approachfor the synthesis of a small library of C-trisaccharides aspotential inhibitors for the cell surface proteins of bacteriumHelicobactor pylori [51] The workers chose to carry outvariations in galactose ring of these trisaccharides An
Scheme (44)
OBnO
BnOOBn
OBn
P O
OEtOEtO
EtO
R H
OH
OH
OH
OH
O
R H
OH
OH
OH
OH
O
OHO
HOOH
OH
O
HO
OHOH
OH
OHO
HOOH
OH
O
HO
OH
OH
OHO
HOOH
OH
O
HO
OH
OHOH
R H
OH
OH
OH
OH
O
R
OBnO
BnOOBn
OBn
O
OHO
HOOH
OH
OO
HOHO
OH
R H
OH
OH
OH
OH
O
1 OsO4 NMO 50
2 DIBAL -32 oC 40
++ +
213 214 215 216
217 218 219 220
1 9-BBN H2O22 Swern [O]
3 t-BuOK
4 I2 C6H6212
211
1418 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
efficient Nozaki-Kishi coupling of vinyl bromide 241 withaldehyde 242 in a diasteromeric ratio of 12 followed byprotection with TBSOTf led to 243 and 244 Hydroborationfollowed by oxidation gave aldehydes 245 and 246respectively Addition of allylmagnesium bromide toaldehyde 245 followed by removal of the silyl groupafforded 247 to 246 giving 248 and 249 Epoxidation gave a11 mixture of the corresponding epoxides which werecyclized to give the C-trisaccharide 250-255 after removalof the benzyl groups (Scheme 47)
Schmidt reported a stereoselective 6-exo-trig selectiveelectrophilic cylization approach for de novo synthesis of amethylene-bridged Neu5Ac-α-(23)-Gal C-disaccharide theC-analog of an important motif in glycosphingolipids [52]The open chain precusors 259ab (a 32-mixture ofdiaseteromeric alcohols) were formed by the addition oflithiated iodide 256 to open chain aldehyde 258 Subsequent
C1 incorporation using Tebbe-reagent formation of a cycliccarbonate and deprotection of the two isopropylidene ketalsafforded tetrol 264 which upon treatment with phenylselenyltrifilate was steroselectively cyclized in a 6-exo-trigselective manner affording a diasteromeric mixture of 251and 252 in a ratio of 71 A seleno-Pummerer rearrangementto afford aldehyde 267 in 5 steps in 90 overall yieldOxidation of the aldehyde and subsequent steps led to thedesired C-disaccharide 268 (Scheme 48)
53 Esterification-Cyclization
Work from the Postema group has focused on a ringclosing metathesis (RCM) approach for the synthesis of C-saccharides [53a] The chemistry is versatile and has beenused for the synthesis of a small library of differentiallylinked β-C-disaccharides through a radical allylation-RCMstrategy [53b] The synthesis of the β-(1rarr4)-glucopyranosyl
Scheme (45)
O
OBn
BnO
BnO
BnO
I
CrCl2-NiCl2O
OBn
OH
BnO
BnO
BnO
O
O
O
O
O
H
OBn
O
O
OBnBnO
BnO
BnO
OOBn
OBn
OAc
PMBOHOO
OBn
BnO
BnO
BnO
O
OBn
OBn
OAc
O
OH
HO
HO
HO
OH
OH
OH
O
OH
O
OBn
BnO
BnO
BnO
OBn
OBn
OAc
O
MMTr
+
1 p-TsOH2 K2CO3 MeOH3 MMTrCl pyr
1 Swern [O]2 BH3 THF
3 AcOH-H2 O4 H2 Pd(OH)2
221
222
223
1 Pd-Pb CaCO3 H22 NaH BnBr3 OsO44 Bu2 SnO5 CsF PMB-Cl6 Ac2 O 4-DMAP
1 AcOH2 TsCl pyr
3 NaH-imid4 DDQ
224225
226 227
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1419
Scheme (46)
OBnO O
OBn
OMe
OBn
XY
SMe
OBnBnO
O
OBn
OBn
OBn
OBn
O
BnO
YX
OBn
TBSO
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnOOBn
H
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnO
OBn
OHC OBn
OBn
OTBS
OMe
BnOOBn
CHO
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnOOBn
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnO
OBn
YX
OBnO O
OBn
OMe
OBn
OBn
O
BnO
O
OBn
OBn
OBn
OBn
O 1 LiHMDS
2
228
1 TBAF THF
2 MeSH BF3 OEt2
230 X = OH Y = H231 X = H Y = OH
230231 41
1 Bu3SnH AIBN2 Swern [O]
1 LiHMDS THF-TMEDA2 MgBr23
1 MsCl
2 liquid NH3
235 X = OH Y = H236 X = H Y = OH Bu3 SnH AIBN
237a and 237b
NaBH4 MeOH
238
239 X = OBn
240 X = OHH2 Pd(OH)2
229
232233
234
1420 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (47)
OH C
O
O BnAcHN
OO
O
OBn OBnOBn
Br
O
OBn OBnOBn
O
OBnA cHN
OO
O TBSO
OBn O BnO Bn
O
OBnAcHN
OO
OTBS
S2
S1
S2
OTBSS1
O H
S2
OT BSS1
O H
MgBrMgBr
S2
O TBSS1
O H
S2
OHS1
OH
S2
OTBSS1
OH
O
OHHO
O H
O
HO
H OO
OBnA cH N
HO
H O
O
O HHO
OH
O
HOHO
O
OBnA cH N
HO
H O
O
OHH O
OH
O
H O
HOO
OBnAcHN
HO
HO
O
O HH O
OH
O
H O
H O O
OBnA cHN
HO
HO
O
O HH O
O H
O
HO
H O O
OBnAcHN
HO
HO
O
OHHO
OH
O
H O
O
OBnA cHN
HO
HOHO
+
241 242
1 CrCl2-NiCl2 T HF-DMF 722 TBSOTf 2 6-lutidine 91
243 244
1 9-BBN 602 Dess-Mart in period inane 97
1 9 -BBN 552 D ess-Martin periodinane 98
245 246
1
2 T BAF 74
1
2 TBAF 88
247 248 249
250
251
250 251 1 1 252 253 1 1 254 255 1 1
252
253
254
255
1 MCPBA2 CSA CH 2Cl2 61 fo r 2 steps3 H 2 Pd (O H)2C 95
1 MCPBA2 CSA CH 2Cl2 63 fo r 2 s teps3 H 2 Pd (OH)2C 87
1 MCPBA2 CSA CH2Cl2 80 for 2 steps3 H2 Pd(O H)2C 95
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1421
Scheme (48)
O
OO
Se Ph
R
O
HO OHOH
O
OB n O B n
OB n
O B nO O
O O
R O OR
X
O
OO
R
Se Ph
O
HOOH
OH
O
OB nOB n
O Bn
OB n
O O
O O
R O O R
O H
O
O B n OB n
O B n
OB n
O
C HO
O
O O
R O OR
OAc HN
OAc
C O2NH 4HOOH
OH
O
OH O H
OH OH
O
OB n O B n
OB n
OB nO O
O O
R O OR
X
O
O
OAcOAc
C HOA cOOAc
OAc
O
OB n O B n
OB n
OB n
O
O Bn OB n
OB n
OB n
X
OH
OO
HOOH
OH
O
O
OMeOB n
OB nOB n
R
t-B uL i256 R = Li
257 R = L i
258
(R = t-B uMe 2Si )
(R = t-B uMe 2Si )
259ab (32) 79 com bine d yi eld
De ss-Ma rtin pe riodinane
260 X = O R = t-B uMe 2Si ) 95
261 X = O R = t -B uMe2S i) 62
T e bbe re age nt
TB A F THF262 X = O R = H 94
diphosge ne
C H2C l 2Pyr
263 95
T HFH2O T FAr t
264 quant it a ti ve yie ld
PhSe C l AgOT f
EtC N -80 oC
265
266
Quant it at i ve yi l ed 25 26 7 1
+
R =
1 Ac 2OPyr
2 mC PB A3 Ac 2ONa OAc
4 NaO HT HFMe OH
5 Ac2O P yr
267 90 overa ll yi e ld
ste ps
268
1422 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
glucopyranoside 280 represents an example of thischemistry The known triacetyl glucopyranoside 269 wasconverted to iodide 270 in good yield Radical allylation of271 proceeded to afford a mixture of equatorial and axialallylation products in a 61 ratio Oxidative cleavage of thedouble bond gave the corresponding aldehydes 273a and273b which were separable Pinnick oxidation of the majoraldehyde 273a then gave the C-4 equatorial acid 274 DCC-mediated coupling of alcohol 275 and acid 274 proceeded toafford ester 276 in good yield Methylenation of 276 gave277 and exposure to catalysist 278 gave a 41 yield of theC-disaccharide glycal which was exposed to an excess ofBH3
THF to give 64 yield of the β-C-disaccharide 279Removal of the benzyl groups and global peracetylation gavethe peracetylated (1rarr4)-β-C-disaccharide 281 in good yield(Scheme 49)
54 Ring Expansion-Cyclization
Nelson developed a new strategy for asymmetric andstereoselective synthesis of C-linked disaccharide mimeticsthe C58-C71 fragment of palytoxin [54] The diol (RR)-282was converted into the di-dihydropyran (DHP) template 283284 and 285 The di-DHPs were functionized in a twodirectional sense using dihydroxylation reactions The two-directional approach was often very efficient indeed forexample in the synthesis of 286 six new stereogenic centerswere introduced with almost complete stereocontrol using areduction and a dihydroxylation reaction The approach isnot restricted to the synthesis of C2-symmetricaldisaccharide mimetics Using the unsymmetrical template285 which has both a pseudo-axial and a pseudo-equatorialhydroxyl groups the unsymmetrical mimetics 289 and 290were prepared (Scheme 50)
6 RADICAL APPROACHES
The radical approach for C-C bond formation is a popularmethod within organic chemistry The use of radicalchemistry in carbohydrate synthesis has certain advantagesFirstly the reaction conditions are very mild and tolerant ofa range of functional and protecting groups Secondanomeric radicals are stable with respect to elimination andepimeration Most significantly the chemistry required toincorporate an appropriate substitute at C-1 employed in theinitial hemolytic cleavage step is common within carbo-hydrate chemistry [55] The use of such radical techniquecan be subdivided into two classes intermolecular andintramolecular approaches
61 Intermolecular Radical Approaches
Giese was the first to employ an intermolecular radical-based approach for synthesis of C-disaccharides [56]Addition of an alkene to an anomeric radical underappropriate conditions allowed exclusive entry to the α-linked C-glycoside a result which was mirrored by the workof Baldwin [57] The high α-selectivity of the reaction wasin contrast with other reports Thus radicals generated at theC-2 C-3 and C-4 centers all preferred to occupy equatorialpositions [58] When the anomeric bromide 291 was treatedwith tin hydride and AIBN resulting anomeric radical andreacted with lactone 292 in a Michael addition it afforded293 In this reaction hydrogen abstraction at the resulting
radical center occurs from axial face to selectively generatethe equatorial C-2rsquo substituent Reduction and acetylation of293 furnished C-disaccharide 294 (Scheme 51) [59]
Witczak used the facial bias of levoglucosene tostereoselectively add a carbohydrate-based radical in thepreparation of the 3-deoxy-(1rarr4)-β-C-disaccharide 299[60] Addition of the radical derived from iodide 295 to 296gave adduct 297 in 26 yield Removal of the anomerichydroxyl of 297 was achieved by treatment with triethylsilane borontrifluoride ether complex followed bystereoselective reduction of the keto function at C-2rsquo withthe formation of 298 in 89 yield Debenzylation followedby acetolysis of 16-anhydro ring produced the peracetylatedtarget C-disaccharide 299 in 19 overall yield from 295(Scheme 52)
Vogel has developed general methods to transformenantiomerically pure 7-oxabicyclo[221]heptyl derivatives(ldquonaked sugarsrdquo) into C-disaccharides Because of thesechiral bicyclic skeletons they undergo highly stereoselectivereactions with predictable diasteroselectivities An arsenal ofmethods is available that allow to substitute these ldquonakedrdquocarbon centers with a variety of functional groups with allpossible relative configurations The methods allowpreparation of both enantiomers of a given target with thesame ease Predictably high stereoselectivity of the reactionsof the bicyclic chirons adds to the flexibility of approachwhich can lead to high molecular diversity [61]
α-C-(1rarr3)-mannopyranoside of N-acetyl-galactosaminepotent β-galactosidase inhibitors was synthesized by thisapproach [61] Enone 302 was readily prepared from 300The addition of the radical derived from bromide 303 toenone 302 afforded the αminusisomer 304 The ketone was thenreduced and the selenide eliminated via the intermediacy ofthe selenoxide to give 305 Acid-promoted (CF3SO3H) 7-oxa ring opening of 305 in MeCN produced the amino-conduritol derivative 306 resulting from the quenching of theallylic cation intermediate by the solvent (Ritter reaction)Ozonolysis of the chloroalkene 306 generated an acylchloride-aldehyde intermediate that reacted with MeOH toproduce a mixture of methyl uronates The major compound307 was silylated and reduced The crude polyol obtainedwas acetylated to produce 308 Desilylated and ammonolysisafforded a mixture of α-β-pyranoses 309 and correspondingα-β-furanoses (Scheme 53)
Similar chemistry was carried out to synthesize non-protected α-C(1rarr2)-L-fucopyranoside of D-galactopyrano-side corresponding to a blood group mimetic [62] Giesersquosradical fucosidation of racemic enone 310 with α-L-bromoacetofucose 311 provided the mixture of diastereo-meric α-C-fucoside 312a and 312b in reproducible yield of78 Reduction of the mixture gave a 11 mixture of endo-alcohols 313 and 314 which were isolated pure in 40 and355 yield respectively Oxidative elimination of thebenzeneselenyl group of 313 followed by acetylation gaveendo acetate 315 in 85 yield Acid-promoted ring openingof 315 and ozonolysis of the resulted chloroalkene gavemethyl uronic ester 316 in modest yield (10) Treatment of316 with Cl3CCN and NaH followed with BF3
OEt2
furnished the totally protected C-disaccharide 317 in 79
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1423
Scheme (49)
Bu3SnO
HOAcO
OMeOAc
OAc
O
AcO
OMeOAc
OAcI
AIBN
O
AcO
OMeOBn
OBn
HO2C O
AcO
OMeOR
ORY
X
OHBnO
BnO
OBn
OBnO
BnO
OBn
O
AcO
OMeOBn
OBnX
i-Pr i-Pr
N
Mo C(Me2 Ph)((CF3)2 MeCO)2
O
RO
OMeOR
O
RO
OR
OR
RO
OR
278
I2 Ph3P
imidazole
269 270 93
271a X = CH2CH=CH2 Y = H R = Ac 64271b Y = CH2CH=CH2 X = H R = Ac 11272a X = CH2CH=CH2 Y = H R = Bn 75272b Y = CH2CH=CH2 X = H R = Bn 75273a X = CH2CHO Y = H R = Bn 79273a Y = CH2CHO X = H R = Bn 79
1 NaOMe MeOH2 NaOH BnBr DMF
OsO4 NaIO4
NaClO2 NaH2PO4
274 96
275
DCC 4-DMAP
276 X = O 82
277 X = CH2 51
TiCl4 Zn dust TMEDA CH2Br2PbCl2 (Cat )
1
2 BH3 THF H2O2 NaOH
H2 PdC EtOH
Ac2 O Pyr 4-DMAP
279 R = Bn R = H 64
280 R = R = H 99
281 R = R =Ac 97
1424 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (50)
Scheme (51)
O OOH
OH
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
286
1 VO(acac)2 t-BuOH 95
2 (MeO)3CH BF3 90
1 P-O2NC6H4 CO2H Ph3P DIAD2 K2CO3 MeOH 82 over 2 steps
1 PhCOCl Et3N DMAP 402 P-O2NC6H4 CO2H Ph3P DIAD3 KOH THF-H2O 75 over 2 steps
TMEDA OsO4
Cat OsO4 NMO 287
Cat OsO4 NMO288
TMEDA OsO4
Cat OsO4 NMO
290
289
(RR)-282283
284
285
OHO
AcO
BrOAc
OAc
BnO
O
OBn
OBnO
OHO
AcOOAc
OAc
BnO
OOBn
OBnAcO
OHO
AcOOAc
OAc
BnO
O
OBn
OBnO
+
Bu3SnH AIBN291
292
293 81
1 Na[Al(OC2H4OMe)2(OEt)H]2 Ac2O pyr
294 56 over 2 steps
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1425
Scheme (52)
Scheme (53)
OBnO
BnOOBn
OBn O
OH
O
OBnO
BnO
OHOBn
OBn O
O
O
O
O
O
OBnO
BnOOBn
OBnO
OAcOAc
OAc
OBnO
BnO
OHOBn
OBn
IBu3SnH AIBN
295 297 26
1 BF3 OEt2 Et3SiH
2 L-Selectride THF
1 Pd(OH)2C C6H10 EtOH
2 EtSiOSO2CF3 Ac2O
298 89 over 2 steps299
296
O
O
PhSeClO
O
PhSeCl
Bu3 SnH
O
O
PhSeCl
R
H
O
OAc
R
Cl
O
AcO
OAc
OAc
OAcOH
Cl
NHAc
R
OAc
AcHN
OH
O
OH OAc
OH
OHO
HO
OH
O
AcO
OAc
OAc
OAcBr
O
O
PhSeCl
O
O
PhSeCl
R
O
OTIPSAcHNR
OAc OAc
O
OHAcHN
COOMe
R
OAc
1 Bu4NF
2 NH3MeOH
1 (Me3Si)2NLi THF2 Me2N=CHI
1 Bu3 SnH AIBN2
1 NaBH42 mCPBA3 Ac2O pyr
1 H+ MeCN
2 H2 O NaHCO3
R =
1 O3MeOH
2 Me2S NaHCO3
1 TIPSOTf 26-lut idine2 LiBH43 Ac2 O pyr DMAP
furanoses +
304 56
305 68 306 84307 50
308 46
300 301 302
303
309
1426 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
The reduction of 317 and treatment with DOWEX-H+ resinprovided the desired C-fucoside 318 in 70 (Scheme 54)
62 Intramolecular Radical Approaches
One disadvantage with the intermolecular approaches isthat during such radical mediated reactions electrondeficient alkenes are required to facilitate C-C bondformation The intramolecular approach of Sinayuml overcomes
this drawback by bring two substrates together via atemporary covalent silaketal connector This enables the useof a wider range of alkenes which can include alkene-functionalized sugars thus leading to the generation of C-disaccharides [63] Based on the early work of Stork Sinayumlemployed the tether reaction in the synthesis of both α- andβ-C-disaccharides with this work subsequently beingemployed in the synthesis of biologically significant natural
Scheme (54)
O
OH
Fuc
Cl
O
O
ClPhSe
OOAc
NHAcOHFuc
O
AcOOAc
AcO
Br
O
O
PhSeCl
O
AcOOAc
AcO
O
OH
PhSe Cl
Fuc
OOAc
NHAc
OMe
Fuc
O
AcHN
OH OAc
OH
O
OH
Me
OH
O
O
Fuc
ClSePh
O
HO
Fuc
ClSePh
+
Ph3SnHAIBN
78 combined yield
Fuc
310
+
1 NaBH4 MeOHTHF2 Chromatography
313 40 314 355
1 mCPBA
2 Ac2O pyr DMAP
+
315 75
1 TfOH MeCN
2 NaHCO3 O3 -78 oC
316 10 over 2 steps
1 Cl3 CCN NaH
2 MeOH BF3 OEt2
317 79
1 LiBH4 THF
2 Dowex-H+
311
312a312b
318 70 for 2 steps
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1427
products [64] The availability of different hydroxyl groupson each monosaccharide unit allowed the fine-tuning ofstereochemical outcome by selective positioning of the silyltether [65] Development of this early stereochemical controlled to the tethering of the donor 320 with alcohol 319through a di-isopropyl silicon tether 321 Subsequent treat-ment with Bu3SnH and AIBN led to a 9-endo-trigcyclization to form the C-disaccharide 322 in an 80 yieldwith exclusive formation of the α-product The silyl tetherwas removed with Bu4NF and deprotection under standardconditions afforded the desired disaccharide 323 in excellentyield (Scheme 55)
In parallel the development of a 32rsquo silyl tether allowedaccess to the β-linked product as demonstrated in Sinayumlrsquossynthesis of methyl β-C-lactoside 328 [66] Alcohol 324 and320 were connected via the dimethylsilyl tether an 8-endo-trig cyclization followed to exclusively afford the β-
disaccharide 326 in 45 yield Removal of the tether anddeprotection of benzyl ether gave β-C-disaccharide 328(Scheme 56)
This group also selected iodosugars bearing a freehydroxyl group as progenitors of the radical donors [67] In atypical experiment the radical donor 329 was connected tothe radical acceptor 330 through a silaketal tether followingtheir procedure Tributyltinhydride mediated 8-endo-trigradical cyclization of compound 331 gave after detetheringof the non isolated intermediate 332 the protected β-C-disaccharide 333 in 37 overall yield (from startingmaterials 330 and 329) Peracetate 335 was achieved afterhydrogenolysis The C-laminaribioside 334 is of potentialbiological interest as it mimics the repeating disaccharideunit of fungal β-(1rarr3)-glucans which have antitumor andimmunomodulating properties (Scheme 57)
Scheme (55)
Scheme (56)
OO
OHSePh
OTBDPSO O
OO
SePh
OTBDPSO
OO
OBnOMe
OBn
Si
O
HOOBn
OMe
OBn
O
HOOH
OHHO
O
HOOH
OMe
OH
OTBDPSO
O
HOOBn
OMe
OBnO
OOH
1 n-BuLi THF
2 iPr2SiCl2 -78 oC
3 DMAP THF rt
1 Bu4NF THF
2 Dowex-H+
3 H2 PdC
Bu3SnH AIBN toluene
319
320
321
322323
OBnO
OHSePh
OBnBnO
OHO
OBnOMe
OBn
ROO
ROOH
OR
OHO
OROMe
OR
OBnO
O
OBnBnO
OO
OBnOMe
OBn
Si
SePh
OBnO
O
OBnBnOO
OOBn
OMe
OBn
Si
1 PhSeH Me2SiCl2
BuLi -78 oC
2 imidazole rt
Bu3SnH AIBN toluene
H2 PdC327 R = Bn
328 R = H
Bu4NF THF
324
320
325
326 45
1428 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
CONCLUSIONS
In this paper the biological importance of C-oligo-saccharides as subunits of natural products and as a newgeneration of carbohydrate based on therapeutics has beenillustrated Different methods are available for the synthesisof C-oligosaccharides As with traditional saccharidesynthesis it has been necessary to develop a number ofspecific approaches to facilitate the regioselective andstereoselective preparation of the desired targets Work inthis area continues and it is expected that many interestingnew C-oligosaccharides will be prepared using the chemistrydescribed in this review It is also likely that new chemistrywill be developed in the future for the preparation of thesebiologically important targets
ACKNOWLEDGEMENTS
The authors thank Dr Sultan Baytas for her criticalreading of this manuscript
REFERENCES
[1] Kennedy J F White C A Bioactive Carbohydrates InChemistry Biochemistry and Biology Ellis Horwood LtdChichesterUK 1983
[2] Wassarman PW Mammalian Fertilization Molecular Aspects ofGamete Adhesion xocytosion Exocytosis and Fusion Cell 199996 175-183
[3] Carbohydrate-based Drug Discovery Wong C-H EdWeinheim Cambridge Wiley-VCH 2003
[4] (a) Sharon N Lis H Lectins as Cell Recognition MoleculesScience 1987 246 227-234 (b) Dwek RA Chem Rev 1996 96683-720
[5] Postema M C-Glycoside synthesis CRC Boc Ratom 1995[6] (a) Weatherman R V Mortell K H Cheruenak MKiessling
L L Toone E J Specificity of C-Glycoside Complexation byMannoseGlucose Specific Lectins Biochem 1996 35 3619-3624(b) Ravishankar R Surolia A Vijayan M Lim S Kishi YPreferred Conformation of C-Lactose at the Free and Peanut LectinBound States J Am Chem Soc1998 120 11297-11303
[7] (a)Wong C-H Halcomb R L Ichikawa Y and Kajimoto TEnzymes in organic synthesis Application to the problems ofcarbohydrate recognition part2 Angew Chem Int Ed Engl 199534 521-546 (b)Howard S Withers SG Bromoketone C-Glycosides a New Class of βminusGlucanase Inactivators J AmChem Soc 1998 120 10326-10331(c) Wang Q Wolff MPolat T Du Y Linhardt R J C-glycoside of Neuraminic Acidsas Neura-minidase Inhibitors Bioorg Med Lett 2000 10 941-944 (d) Phili R Chang J Partis R A Mueller R A ChrestF J Passaniti A The Alpha-glucosidase I InhibitorCastanospermine Alters Endothelial cell Glycosylation PreventsAngiogenesis and Inhibits Tumor Growth Cancer Res 1995 552927-2935
[8] Ossor A Elbein A D In Carbohydrates in Chemistry andBiology Vol 3(II) WileyVCH 2000 pp 513-539
[9] (a) Sinayuml P Synthesis of oligosaccharide Mimetics Pure ApplChem 1997 69 459-463 (b) Beau J-M Gallagher TNucleophilic C-glycosyl Donors for C-glycoside Synthesis Top inCurr Chem 1997 187 1-54 (c) Nicotra F Synthesis of C-glycosides of Biological Interest Top in Curr Chem 1997 187
Scheme (57)
O
O
O
Ph
I
OMe
OHO
BnO
OH
OH
BnOOH
O
BnO
Si
O
O O
Ph
I
OMe
O
O
BnO
OR4O
R5O
OMe
OR2
OR3O
R3O
OR1
R3O
Bu3 SnH AIBN
332 R1 R2 = SiMe2 R3 = Bn R4 R5 = CHPhTBAF THF
333 R1 = R2 = H R3 = Bn R4 = R5 = CHPh 37 from 11
334 R1 = R2 = R3 = R4 = R5 = H
335 R1 = R2 = R3 = R4 = R5 = Ac
329
H2 PdC MeOH
Ac2 O pyr
1 BuLi THF -78 oC
2 Me2SiCl2
3 DMAP
330
331
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1429
55-83 (d) Du Y Linhardt R Y Recent Adv in Stereo-SelectiveC-Glycoside Synthesis Tetrahedron Lett 1998 54 9913-9959 (e)Liu L Mckee M and Postema M H D Synthesis of C-saccharides and Higher Congeners Current Org Chem 2001 51133-1167
[10] Jarosz S Fraser-Reid B Synthesis of A Higher Carbon Sugar ViaDirected Aldol Condensation Tetrahedron Lett 1989 30 2359-2362
[11] Lichtenthaler F W Lergenmiiller M Schwidetzky S C-Glycosidations of 2-Ketohexosyl With Electrophilic Radical andNudeophilic Anomeric Carbons Eur J Org Chem 2003 3094-3103
[12] Baudat A Vogel P Aza-C-disaccharides Synthesis of 6-Deoxygalactonojirimycin-β-C(1rarr3) Linked with D-Altrofuranosides and D-Galactose J Org Chem 1997 62 6252-6260
[13] Turner D Vogel P Synthesis of 4-Hydroxy-26-Bis(hydroxymethyl) tetrahydropyran-2-Carbaldehyde DerivativesSynlett 1998 304-306
[14] Zhu Y-H Vogel P Short Stereoselective Synthesis of C-(1rarr3)-Linked Disaccharides Tetrahedron Lett 1998 39 31-34
[15] Zhu Y-H Vogel P Synthesis of a (2R 6R)-2-(Hydroxymethyl)-6-Propa-1 2-Dienyl-2H-Pyran-3(6H)-One Derivative A NewEnone for The Convergent Construction of C-Glycosides of C-Disaccharides Synlett 2001 82-86
[16] Baumberger F Vasella A Deoxynitrosugars The 6th
Communication Stereolectronic Control in the reductivedenitration of tertiary nitro ethers A Synthesis of ldquoC-glycosidesrdquoHelv Chim Acta 1983 66 2210-2221
[17] Martin O R Lai W Synthesis and Conformational Studies of β-(1rarr6)- and ββ-(1rarr1)-Linked C-disaccharides J Org Chem1993 58 176-185
[18] Spak S J Martin R The synthesis of an analogue of Methyl OC-Analogue of Methyl 4rsquo-O-β-D-GlucopyranosylgentiobiosideTetrahedron 2000 56 217-224
[19] Kobertz W R Bertozzi C R Bednarski M D C-GlycosylAldehyde Synthons for C-Linked Disaccharides J Org Chem1996 61 1894-1897
[20] Gurjar M K Nagaprasad R and Ramana CV First Synthesis ofMethyl α-C-D-Arabino-furanosyl-(1rarr5)-αminusD-Arabinofuranosidethe C-Disaccharide Segment of Motif C of MycobateriumTuberculosis Tetrahedron Lett 2000 43 7577-7579
[21] Witczak Z J Synthesis of C-Glycosyl Compounds and OtherNatural Products from Levoglucosenone Pure Appl Chem 199466 2189-2192
[22] Griffin F K Paterson D Taylor R J K Ramberg-BacklundApproaches to the Synthesis of C-Linked Disaccharides AngewChem Int Engl 1999 38 2939-2942
[23] Paterson B E Griffin F K Alcaraz M-L and Taylor R J KA Ramberg-Baumlcklund Approach to the Synthesis of C-GlycosidesC-Linked Disaccharides and C-Glycosyl Amino Acids Eur JOrg Chem 2002 1323-1336
[24] McAllister G D Paterson D E Taylor R J K A SimplifiedRamberg-Bachlund Approach to Novel C-Glycosides and C-Linked Disaccharides Angew Chem Int Ed Engl 2003 42 1387-1391
[25] McCartney J L Christopher T M Cicchillo R M BernardinaM D Wagner T R and Norris P J Org Chem 2003 6810152-10155
[26] Dondoni A Zuurmond H M Bascarate A Synthesis of α-andβ-D-(1rarr6)-C-Disaccharides by Witting Olefination of Formyl C-Glycosides with Glycopyranose 6-phosphoranes J Org Chem1997 62 8114-8124
[27] Dondoni A Kleban M Zuurmond H Marra A Synthesis of(1rarr6)-C-Oligogalactosides by Interative Wittig OlefinationTetrahedron Lett 1998 39 7991-7994
[28] Dondoni A Marra A A New Synthetic Approach toMycobacterial Cell Wall α-(1rarr5)-D-Arabinofuranosyl C-Oligosaccharides Teterahedron Lett 2003 44 4067-4071
[29] Colinas P A Ponzinibbio A Lieberknecht A and Bravo R OWittig Reaction of Glycosyl Phosphonium Salts A StereoselectiveRoute to C-Disaccharides and C O-Trisaccharides TetrahedronLett 2003 44 7985-7988
[30] Schmidt R R Preuss R Synthesis of Carbon Tetrahedron Lett1989 30 3409-3412
[31] Dietrich H Schmidt R R Synthesis of Carbon-Bridged C-Lactose and Derivatives Liebigs Ann Chem 1994 975-981
[32] Rouzaud D Sinayuml P The First Synthesis of a ldquoC-DisacchariderdquoJ Chem Soc Chem Commun 1983 1353-1354
[33] Xin Y-C Zhang Y-M Mallet J-M Glaudemans C P JSinayuml P Synthesis of C-Oligosaccharides That Mimie TheirNatural O-Analogues Immunodeterminants in Binding toMonoclonal Immunoglobulins Eur J Org Chem 1999 471-476
[34] Streicher H Geyer A Schmidt R R C-Disaccharides ofKetoses Chem Eur J 1996 2 502-510
[35] Leeuwenburgh M A Timmers C M Vander Marel G A VanBoom J H Mallet J-M Sinayuml P G Stereoselective Synthesisof α-C-(Alkynyl)-Glycosides Via Ring-Opening of α-12-Anhydrous Tetrahedron Lett 1997 38 6251-6254
[36] Aslam T Fuchs M G G Le Formal A Wightman R HSynthesis of C-Disaccharide Analogue of the α-D-Arabinofuranosyl-(1rarr5)-α-Arabinofuranosyl Motif ofMycobacterial Cells Walls via Alkynyl Intermediates TetrahedronLett 2005 46 3249-3252
[37] (a) Girad P Namy J L Kagan H B Divalent LanthanideDerivative in Organic Synthesis 1 Mild Preparation of SamariumIodide and Ytterbium Iodide and Their Use as Reducing orCoupling Agents J Am Chem Soc 1980 102 2693-2698 (b)Molander G A Harris C R Sequencing Reactions withSamarium(II) Iodide Chem Rev 1996 96 307-338
[38] (a) Mazeacuteas D Skrydstrup T Doumeix O Beau J-MSamarium Iodide-Induced Intramolecular C-Glycoside FormationEfficient Radical Formation in the Absence of an Additive AngewChem Int Ed Engl 1994 33 1383-1386 (b) Mazeacuteas DSkrydstrup T Beau J-M A Highly Stereoselective Synthesis of1 2-trans-C-Glycosides Via Glycosyl Samarium(III) CompoundsAngew Chem Int Ed Engl 1995 34 909-912 (c) Jarreton OSkrydstrup T Beau J-M The Stereospecific Synthesis of Methylα-C-Mannobioside A Potential Inhibitor of M TuberculosisBinding to Human Macrophages J Chem Soc Chem Commun1996 1661-1662 (d) Jarreton O Skrydstrup T Espionosa J-FJimeacutenez-Barbero J Beau J-M Samarium Diiode Prompted C-Glycosylation An Application to The Stereospecific Synthesis ofα-(1rarr2)-C-Mannobioside and Its Derivatives Chem Eur J 19995 430-441 (e) Mipuel N Doisneau G Beau J-M ReductiveSamariation of Anomeric 2-Pyridyl Sulfones with Catalytic AnUnexpected Improvement in The Synthesis of 12-Trans-Diequatorial C-Glycosyl Compounds Angew Chem Int Ed Engl 2000 39 4111-4114
[39] Vlahov I R Vlahova P I Linhardt R J DiastereocontrolledSynthesis of Carbon Glycosides of N-Acetylneuraminic Acid ViaGlycosyl Samarium(III) Intermediates JAmChem Soc 1997 1191480-1481
[40] Kuberan B Sikkander S ATomiyama H Linhardt R JSynthesis of a C-Glycoside Analogue of sTn An HIV-and Tumor-Associated Antigen Angew Chem Int Ed Engl 2003 42 2073-2075
[41] Bazin H G Du Y Polat T Linhardt R J Synthesis of aVersatile Neuraminic Acid ldquoCrdquo-Disaccharide Precursor for theSynthesis of C-Glycoside Analogues of Gangliosides J OrgChem 1999 64 7254-7259
[42] Chen C-C Ress D K Linhardt RJ Samarium Iodide-Mediated Synthesis of Neuraminic Acid C-Glycosides InSynthesis of Glycommetics Roy R Ed ACS Syposium Series2004 896 53-80
[43] Abdallah Z Doisneau G Beau J-M Synthesis of a Carbon-Linked Mimic of The Disaccharide Component of The Tumor-Relate SialyTn Antigen Angew Chem Int Ed Engl 2003 425209-5212
[44] Lay L Nicotra F Panza L Russo G Caneva E Synthesis ofC-disaccharides through dimerization of exo-glycals J Org Chem1992 57 1304-1306
[45] Isobe M Nishizawa R Hosokawa S Nishikawa TStereocontrolled Synthesis and Reactivity of Sugar Acetylenes JChem Soc Chem Commun 1998 2665-2676
[46] Saeeng R Sirion U Sahakitpichan P Isobe M IodineCatalyzes C-Glycosidation of D-Glucal with SilylacetykeneTetrahedron Lett 2003 44 6211-6215
[47] (a) Babirad S A Wang Y Kishi Y Synthesis of C-Disaccharides J Org Chem 1987 52 1370-1372 (b) Wang YBabirad S A Kishi Y Preferred Conformation of C-Glycosides
1430 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
8 Synthesis of 14-Linked Carbon Disaccharides J Org Chem1992 57 468-481
[48] Armstrong R W Sutherlin D P Strategies for the Synthesis ofC-Disaccharides Containing D and L Sugars Tetrahedron Lett1994 35 7743-7746
[49] Wei A Kishi Y Preferred Conformation of C-Glycosides 12Synthesis and Conformational Analysis of αα- α β- and β β-Trehaloses J Org Chem 1994 59 88-96
[50] Haneda T Goekjian P G Kim S H Kishi Y PreferredConformation of C-Glycosides 10 Synthesis and ConformationAnalysis of Carbon Trisaccharides J Org Chem 1992 57 490-498
[51] Sutherlin D P Armstrong R W Synthesis of 12 Stereochemistryand Structurally Diverse C-Trisaccharides J Org Chem 1997 625267-5283
[52] Notz W Hartel C Waldscheck B Schmidt R R De NovoSynthesis of a Methylene-Bridged Neu5Ac-α-(23)-Gal C-Disaccharide J Org Chem 2001 66 4250-4260
[53] (a) Postema M H D Calimente D Liu L Behrmanm T L AnOlefin Metathesis Route for the Preparation of (1rarr6)-Linked-C-Disaccharide Glycals A Convergent and Flexible Approach to C-Saccharide Synthesis J Org Chem 2000 65 6061-6068(b) Postema M H Piper J L Liu L Faust M Andreana PSynthesis and Partial Biological Evaluation of a Small Library ofDifferentially Linked β-C-Disaccharide J Org Chem 2003 684748-4754
[54] Nelson A The Development of Strategies and Methods for TheSynthesis of Biologically Active Compounds New J Chem 200428 771-776
[55] Togo H He W Waki Y Yokoyama M C-GlycosylationTechnology With Free Radiant Reactions Synlett 1998 700-717
[56] Giese B Dupuis J Diastereoselective Synthesis of C-Glycopyranosides Angew Chem Int Ed Engl 1983 22 622-623
[57] Adlington R M Baldwin J E Basak A Kozyrod RPApplication of Radical Addition Reactions to tho Synthesis of a C-Glucoside and A Functionalized Amino Acid J Chem SocChem Commun 1983 144-145
[58] Giese B Gonzaacutelez-Goacutemez J A Witzel T The Scope of RadicalCC-Coupling by The ldquoTin Methodrdquo Angew Chem Int Ed Engl1984 23 69-70
[59] Giese B Witzel T Synthesis of ldquoC-Disaccharidesrdquo by RadicalC-C Bond Formation Angew Chem Int Ed Engl 1986 25 450-451
[60] Witczak Z J Chhabra R Chojnacki J C-Disaccharides IStereoselective Approach to β-(1rarr4)-3-Deoxy-C-Disaccharidesfrom Levoglucosenone Carb Res 1997 301 167-175
[61] Vogel P Synthesis of Rare Carbohydrates and Analogues Startingfrom Enantiomerically Pure 7-Oxabicyclo[221]heptyl Derivatives(ldquoNaked Sugarsrdquo) Current Org Chem 2000 4 455-480
[62] Viodeacute C Vogel P Synthesis of The C-Disaccharide α-C(1rarr3)-L-Fucopyranoside of N-Acetylgalactosamine J Carb Chem2001 20 733-746
[63] Xin Y C Mallet J M Sinayuml P An Expeditious Synthesis of AC-Disaccharide Using A Temporary Silaketal Connection J ChemSoc Chem Commun 1993 864-865
[64] (a) Petitou M Herault P Lormeau J-C Helmboldt A MalletJ-M Sinayuml P Herbert J-M Introducing A C-InterglycosidicBond in A Biologically Active Pentasaccharide Hardly Affects ItsBiological Properties Bioorg Med Chem 1998 6 1509-1516 (b)Sinayuml P Advances in The Synthesis of the Carbohydrate MimicsPure Appl Chem 1998 70 1495-1499
[65] Sinayuml P Chemical Synthesis of Oligosaccharide Mimetics PureAppl Chem 1998 70 407-410
[66] Sinayuml P Chemical Synthesis of Oligosaccharide Mimetics PureAppl Chem 1998 69 459-463
[67] Vauzeilles B Sinayuml P Selective Radical Synthesis of β-C-Disaccharides Tetrahedron Lett 2001 42 7269-7272
1416 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (42)
Scheme (43)
AcO
OAc
OAc
Me3 Si
BnO
OBn
BnO
OBn
AcO
OAc
BnO
OBn
BnO
OBn
+ I2 CH2Cl2
202 88
198 201
O
OBn
OBn
O
O
O
OBn
OBn
O
O
OBn
OBn O
OBn
OBn
O
OPBH2M
OH
OBnO
BnO
BnO
O
OBn
OBn
O
OHOPMB
OHO
HO
HO
O
OH
OHOH
OH
HOOMe
O
OBnOBn
O
Ph3P
O
O
OBn
OBn O
OBn
OBn
O
OPBM
OH
O O
CHO
OBn
BnO
OO
OBn
OBn
O
OHOPMB
BnO
BnO
BnO
OHO
HO
HO
O
OH
OHOH
OH
HOOMe
+ THF -78 oC
1 OsO4 pyr THF
2 NaH PMBBr
206a 206b 206a206b 61
1 Swern [O]2 4N HCl3 PhCOCl pyr
1 Swern [O]2 4N HCl3 PhCOCl pyr
1 PrSiH BF3 OEt2
2 H2 Pd(OH)2C
3 HCl MeOH 90 oC
1 PrSiH BF3 OEt2
2 H2 Pd(OH)2C
3 HCl MeOH 90 o C
203
204
205
207
209
208
210
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1417
followed by reduction to afford a 51 mixture (213214215216) of lactols that were readily separable by chromato-graphy Following a deprotection of an equimolar mixture of213 and 214 217 and the DL hybrid C-disaccharide of D-glucose-O-(1rarr6)-L-galactose 218 were obtained The DDand DL derivatives 219 and 220 of glucose-α-(1rarr6)-idosewere also obtained as a near equimolar mixture afterdeprotection of 215 and 216 (Scheme 44)
52 Anion Addition-Cyclization
Kishi developed an approach for the synthesis of theCndashtrehalo sugars which relied on nucleophilic addition ofone intact sugar fragment to a fundamental aldehyde ieKishi-Nozaki reaction [49] Coupling of monosaccharide221 and aldehyde 222 gave 223 The triple bond waspartially reduced and osmylation was followed by selectiveprotection to afford 224 The acetonide was converted toepoxide 225 by standard methods and removal of the PMBgroup Acid-catalyzed cyclization followed by aglyconichydrolysis and protection of hydroxyl group with (p-methoxyphenyl)diphenylmethyl chloride (MMTrCl) gave226 Inversion of the C-2 hydroxyl and removal of protectinggroups delivered α α-C-trehalose 227 (Scheme 44)
Kishi and co-workers also employed aldol reactions as anefficient access to the C-trisaccharide related to the type IIABO(H) blood group determinant [50] Aldol condensationof the enolate of methyl ketone 228 with aldehyde 229 gavea 41 mixture of hydroxy ketones 230 and 231 The majorketol was cyclized desulfurized and oxidized to afford thedisaccharide ketone 233 The ketone in THF was treatedwith LiHMDS (3 equiv) and TMEDA followed by theaddition of MgBr2 Addition of the aldehyde 234 led toalmost exclusive formation of the equatorial products 235and 236 in a 12 ratio Mesylation of 235 and 236 followedby treatment with liquid ammonia gave enones 237a and237b which were reduced to yield exclusively the C-2rsquo-equatorial ketone 238 Sodium borohydride reduction of theC-3rsquo carbonyl proceeded with the desired stereoselectivity toyield the protected C-trisaccharide 239 which wasdeblocked to provide the polyol 240 (Scheme 46)
Sutherlin and Amstrong cleverly applied a recursivestereochemical deconvolution (RSD) combinatorial approachfor the synthesis of a small library of C-trisaccharides aspotential inhibitors for the cell surface proteins of bacteriumHelicobactor pylori [51] The workers chose to carry outvariations in galactose ring of these trisaccharides An
Scheme (44)
OBnO
BnOOBn
OBn
P O
OEtOEtO
EtO
R H
OH
OH
OH
OH
O
R H
OH
OH
OH
OH
O
OHO
HOOH
OH
O
HO
OHOH
OH
OHO
HOOH
OH
O
HO
OH
OH
OHO
HOOH
OH
O
HO
OH
OHOH
R H
OH
OH
OH
OH
O
R
OBnO
BnOOBn
OBn
O
OHO
HOOH
OH
OO
HOHO
OH
R H
OH
OH
OH
OH
O
1 OsO4 NMO 50
2 DIBAL -32 oC 40
++ +
213 214 215 216
217 218 219 220
1 9-BBN H2O22 Swern [O]
3 t-BuOK
4 I2 C6H6212
211
1418 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
efficient Nozaki-Kishi coupling of vinyl bromide 241 withaldehyde 242 in a diasteromeric ratio of 12 followed byprotection with TBSOTf led to 243 and 244 Hydroborationfollowed by oxidation gave aldehydes 245 and 246respectively Addition of allylmagnesium bromide toaldehyde 245 followed by removal of the silyl groupafforded 247 to 246 giving 248 and 249 Epoxidation gave a11 mixture of the corresponding epoxides which werecyclized to give the C-trisaccharide 250-255 after removalof the benzyl groups (Scheme 47)
Schmidt reported a stereoselective 6-exo-trig selectiveelectrophilic cylization approach for de novo synthesis of amethylene-bridged Neu5Ac-α-(23)-Gal C-disaccharide theC-analog of an important motif in glycosphingolipids [52]The open chain precusors 259ab (a 32-mixture ofdiaseteromeric alcohols) were formed by the addition oflithiated iodide 256 to open chain aldehyde 258 Subsequent
C1 incorporation using Tebbe-reagent formation of a cycliccarbonate and deprotection of the two isopropylidene ketalsafforded tetrol 264 which upon treatment with phenylselenyltrifilate was steroselectively cyclized in a 6-exo-trigselective manner affording a diasteromeric mixture of 251and 252 in a ratio of 71 A seleno-Pummerer rearrangementto afford aldehyde 267 in 5 steps in 90 overall yieldOxidation of the aldehyde and subsequent steps led to thedesired C-disaccharide 268 (Scheme 48)
53 Esterification-Cyclization
Work from the Postema group has focused on a ringclosing metathesis (RCM) approach for the synthesis of C-saccharides [53a] The chemistry is versatile and has beenused for the synthesis of a small library of differentiallylinked β-C-disaccharides through a radical allylation-RCMstrategy [53b] The synthesis of the β-(1rarr4)-glucopyranosyl
Scheme (45)
O
OBn
BnO
BnO
BnO
I
CrCl2-NiCl2O
OBn
OH
BnO
BnO
BnO
O
O
O
O
O
H
OBn
O
O
OBnBnO
BnO
BnO
OOBn
OBn
OAc
PMBOHOO
OBn
BnO
BnO
BnO
O
OBn
OBn
OAc
O
OH
HO
HO
HO
OH
OH
OH
O
OH
O
OBn
BnO
BnO
BnO
OBn
OBn
OAc
O
MMTr
+
1 p-TsOH2 K2CO3 MeOH3 MMTrCl pyr
1 Swern [O]2 BH3 THF
3 AcOH-H2 O4 H2 Pd(OH)2
221
222
223
1 Pd-Pb CaCO3 H22 NaH BnBr3 OsO44 Bu2 SnO5 CsF PMB-Cl6 Ac2 O 4-DMAP
1 AcOH2 TsCl pyr
3 NaH-imid4 DDQ
224225
226 227
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1419
Scheme (46)
OBnO O
OBn
OMe
OBn
XY
SMe
OBnBnO
O
OBn
OBn
OBn
OBn
O
BnO
YX
OBn
TBSO
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnOOBn
H
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnO
OBn
OHC OBn
OBn
OTBS
OMe
BnOOBn
CHO
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnOOBn
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnO
OBn
YX
OBnO O
OBn
OMe
OBn
OBn
O
BnO
O
OBn
OBn
OBn
OBn
O 1 LiHMDS
2
228
1 TBAF THF
2 MeSH BF3 OEt2
230 X = OH Y = H231 X = H Y = OH
230231 41
1 Bu3SnH AIBN2 Swern [O]
1 LiHMDS THF-TMEDA2 MgBr23
1 MsCl
2 liquid NH3
235 X = OH Y = H236 X = H Y = OH Bu3 SnH AIBN
237a and 237b
NaBH4 MeOH
238
239 X = OBn
240 X = OHH2 Pd(OH)2
229
232233
234
1420 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (47)
OH C
O
O BnAcHN
OO
O
OBn OBnOBn
Br
O
OBn OBnOBn
O
OBnA cHN
OO
O TBSO
OBn O BnO Bn
O
OBnAcHN
OO
OTBS
S2
S1
S2
OTBSS1
O H
S2
OT BSS1
O H
MgBrMgBr
S2
O TBSS1
O H
S2
OHS1
OH
S2
OTBSS1
OH
O
OHHO
O H
O
HO
H OO
OBnA cH N
HO
H O
O
O HHO
OH
O
HOHO
O
OBnA cH N
HO
H O
O
OHH O
OH
O
H O
HOO
OBnAcHN
HO
HO
O
O HH O
OH
O
H O
H O O
OBnA cHN
HO
HO
O
O HH O
O H
O
HO
H O O
OBnAcHN
HO
HO
O
OHHO
OH
O
H O
O
OBnA cHN
HO
HOHO
+
241 242
1 CrCl2-NiCl2 T HF-DMF 722 TBSOTf 2 6-lutidine 91
243 244
1 9-BBN 602 Dess-Mart in period inane 97
1 9 -BBN 552 D ess-Martin periodinane 98
245 246
1
2 T BAF 74
1
2 TBAF 88
247 248 249
250
251
250 251 1 1 252 253 1 1 254 255 1 1
252
253
254
255
1 MCPBA2 CSA CH 2Cl2 61 fo r 2 steps3 H 2 Pd (O H)2C 95
1 MCPBA2 CSA CH 2Cl2 63 fo r 2 s teps3 H 2 Pd (OH)2C 87
1 MCPBA2 CSA CH2Cl2 80 for 2 steps3 H2 Pd(O H)2C 95
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1421
Scheme (48)
O
OO
Se Ph
R
O
HO OHOH
O
OB n O B n
OB n
O B nO O
O O
R O OR
X
O
OO
R
Se Ph
O
HOOH
OH
O
OB nOB n
O Bn
OB n
O O
O O
R O O R
O H
O
O B n OB n
O B n
OB n
O
C HO
O
O O
R O OR
OAc HN
OAc
C O2NH 4HOOH
OH
O
OH O H
OH OH
O
OB n O B n
OB n
OB nO O
O O
R O OR
X
O
O
OAcOAc
C HOA cOOAc
OAc
O
OB n O B n
OB n
OB n
O
O Bn OB n
OB n
OB n
X
OH
OO
HOOH
OH
O
O
OMeOB n
OB nOB n
R
t-B uL i256 R = Li
257 R = L i
258
(R = t-B uMe 2Si )
(R = t-B uMe 2Si )
259ab (32) 79 com bine d yi eld
De ss-Ma rtin pe riodinane
260 X = O R = t-B uMe 2Si ) 95
261 X = O R = t -B uMe2S i) 62
T e bbe re age nt
TB A F THF262 X = O R = H 94
diphosge ne
C H2C l 2Pyr
263 95
T HFH2O T FAr t
264 quant it a ti ve yie ld
PhSe C l AgOT f
EtC N -80 oC
265
266
Quant it at i ve yi l ed 25 26 7 1
+
R =
1 Ac 2OPyr
2 mC PB A3 Ac 2ONa OAc
4 NaO HT HFMe OH
5 Ac2O P yr
267 90 overa ll yi e ld
ste ps
268
1422 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
glucopyranoside 280 represents an example of thischemistry The known triacetyl glucopyranoside 269 wasconverted to iodide 270 in good yield Radical allylation of271 proceeded to afford a mixture of equatorial and axialallylation products in a 61 ratio Oxidative cleavage of thedouble bond gave the corresponding aldehydes 273a and273b which were separable Pinnick oxidation of the majoraldehyde 273a then gave the C-4 equatorial acid 274 DCC-mediated coupling of alcohol 275 and acid 274 proceeded toafford ester 276 in good yield Methylenation of 276 gave277 and exposure to catalysist 278 gave a 41 yield of theC-disaccharide glycal which was exposed to an excess ofBH3
THF to give 64 yield of the β-C-disaccharide 279Removal of the benzyl groups and global peracetylation gavethe peracetylated (1rarr4)-β-C-disaccharide 281 in good yield(Scheme 49)
54 Ring Expansion-Cyclization
Nelson developed a new strategy for asymmetric andstereoselective synthesis of C-linked disaccharide mimeticsthe C58-C71 fragment of palytoxin [54] The diol (RR)-282was converted into the di-dihydropyran (DHP) template 283284 and 285 The di-DHPs were functionized in a twodirectional sense using dihydroxylation reactions The two-directional approach was often very efficient indeed forexample in the synthesis of 286 six new stereogenic centerswere introduced with almost complete stereocontrol using areduction and a dihydroxylation reaction The approach isnot restricted to the synthesis of C2-symmetricaldisaccharide mimetics Using the unsymmetrical template285 which has both a pseudo-axial and a pseudo-equatorialhydroxyl groups the unsymmetrical mimetics 289 and 290were prepared (Scheme 50)
6 RADICAL APPROACHES
The radical approach for C-C bond formation is a popularmethod within organic chemistry The use of radicalchemistry in carbohydrate synthesis has certain advantagesFirstly the reaction conditions are very mild and tolerant ofa range of functional and protecting groups Secondanomeric radicals are stable with respect to elimination andepimeration Most significantly the chemistry required toincorporate an appropriate substitute at C-1 employed in theinitial hemolytic cleavage step is common within carbo-hydrate chemistry [55] The use of such radical techniquecan be subdivided into two classes intermolecular andintramolecular approaches
61 Intermolecular Radical Approaches
Giese was the first to employ an intermolecular radical-based approach for synthesis of C-disaccharides [56]Addition of an alkene to an anomeric radical underappropriate conditions allowed exclusive entry to the α-linked C-glycoside a result which was mirrored by the workof Baldwin [57] The high α-selectivity of the reaction wasin contrast with other reports Thus radicals generated at theC-2 C-3 and C-4 centers all preferred to occupy equatorialpositions [58] When the anomeric bromide 291 was treatedwith tin hydride and AIBN resulting anomeric radical andreacted with lactone 292 in a Michael addition it afforded293 In this reaction hydrogen abstraction at the resulting
radical center occurs from axial face to selectively generatethe equatorial C-2rsquo substituent Reduction and acetylation of293 furnished C-disaccharide 294 (Scheme 51) [59]
Witczak used the facial bias of levoglucosene tostereoselectively add a carbohydrate-based radical in thepreparation of the 3-deoxy-(1rarr4)-β-C-disaccharide 299[60] Addition of the radical derived from iodide 295 to 296gave adduct 297 in 26 yield Removal of the anomerichydroxyl of 297 was achieved by treatment with triethylsilane borontrifluoride ether complex followed bystereoselective reduction of the keto function at C-2rsquo withthe formation of 298 in 89 yield Debenzylation followedby acetolysis of 16-anhydro ring produced the peracetylatedtarget C-disaccharide 299 in 19 overall yield from 295(Scheme 52)
Vogel has developed general methods to transformenantiomerically pure 7-oxabicyclo[221]heptyl derivatives(ldquonaked sugarsrdquo) into C-disaccharides Because of thesechiral bicyclic skeletons they undergo highly stereoselectivereactions with predictable diasteroselectivities An arsenal ofmethods is available that allow to substitute these ldquonakedrdquocarbon centers with a variety of functional groups with allpossible relative configurations The methods allowpreparation of both enantiomers of a given target with thesame ease Predictably high stereoselectivity of the reactionsof the bicyclic chirons adds to the flexibility of approachwhich can lead to high molecular diversity [61]
α-C-(1rarr3)-mannopyranoside of N-acetyl-galactosaminepotent β-galactosidase inhibitors was synthesized by thisapproach [61] Enone 302 was readily prepared from 300The addition of the radical derived from bromide 303 toenone 302 afforded the αminusisomer 304 The ketone was thenreduced and the selenide eliminated via the intermediacy ofthe selenoxide to give 305 Acid-promoted (CF3SO3H) 7-oxa ring opening of 305 in MeCN produced the amino-conduritol derivative 306 resulting from the quenching of theallylic cation intermediate by the solvent (Ritter reaction)Ozonolysis of the chloroalkene 306 generated an acylchloride-aldehyde intermediate that reacted with MeOH toproduce a mixture of methyl uronates The major compound307 was silylated and reduced The crude polyol obtainedwas acetylated to produce 308 Desilylated and ammonolysisafforded a mixture of α-β-pyranoses 309 and correspondingα-β-furanoses (Scheme 53)
Similar chemistry was carried out to synthesize non-protected α-C(1rarr2)-L-fucopyranoside of D-galactopyrano-side corresponding to a blood group mimetic [62] Giesersquosradical fucosidation of racemic enone 310 with α-L-bromoacetofucose 311 provided the mixture of diastereo-meric α-C-fucoside 312a and 312b in reproducible yield of78 Reduction of the mixture gave a 11 mixture of endo-alcohols 313 and 314 which were isolated pure in 40 and355 yield respectively Oxidative elimination of thebenzeneselenyl group of 313 followed by acetylation gaveendo acetate 315 in 85 yield Acid-promoted ring openingof 315 and ozonolysis of the resulted chloroalkene gavemethyl uronic ester 316 in modest yield (10) Treatment of316 with Cl3CCN and NaH followed with BF3
OEt2
furnished the totally protected C-disaccharide 317 in 79
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1423
Scheme (49)
Bu3SnO
HOAcO
OMeOAc
OAc
O
AcO
OMeOAc
OAcI
AIBN
O
AcO
OMeOBn
OBn
HO2C O
AcO
OMeOR
ORY
X
OHBnO
BnO
OBn
OBnO
BnO
OBn
O
AcO
OMeOBn
OBnX
i-Pr i-Pr
N
Mo C(Me2 Ph)((CF3)2 MeCO)2
O
RO
OMeOR
O
RO
OR
OR
RO
OR
278
I2 Ph3P
imidazole
269 270 93
271a X = CH2CH=CH2 Y = H R = Ac 64271b Y = CH2CH=CH2 X = H R = Ac 11272a X = CH2CH=CH2 Y = H R = Bn 75272b Y = CH2CH=CH2 X = H R = Bn 75273a X = CH2CHO Y = H R = Bn 79273a Y = CH2CHO X = H R = Bn 79
1 NaOMe MeOH2 NaOH BnBr DMF
OsO4 NaIO4
NaClO2 NaH2PO4
274 96
275
DCC 4-DMAP
276 X = O 82
277 X = CH2 51
TiCl4 Zn dust TMEDA CH2Br2PbCl2 (Cat )
1
2 BH3 THF H2O2 NaOH
H2 PdC EtOH
Ac2 O Pyr 4-DMAP
279 R = Bn R = H 64
280 R = R = H 99
281 R = R =Ac 97
1424 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (50)
Scheme (51)
O OOH
OH
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
286
1 VO(acac)2 t-BuOH 95
2 (MeO)3CH BF3 90
1 P-O2NC6H4 CO2H Ph3P DIAD2 K2CO3 MeOH 82 over 2 steps
1 PhCOCl Et3N DMAP 402 P-O2NC6H4 CO2H Ph3P DIAD3 KOH THF-H2O 75 over 2 steps
TMEDA OsO4
Cat OsO4 NMO 287
Cat OsO4 NMO288
TMEDA OsO4
Cat OsO4 NMO
290
289
(RR)-282283
284
285
OHO
AcO
BrOAc
OAc
BnO
O
OBn
OBnO
OHO
AcOOAc
OAc
BnO
OOBn
OBnAcO
OHO
AcOOAc
OAc
BnO
O
OBn
OBnO
+
Bu3SnH AIBN291
292
293 81
1 Na[Al(OC2H4OMe)2(OEt)H]2 Ac2O pyr
294 56 over 2 steps
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1425
Scheme (52)
Scheme (53)
OBnO
BnOOBn
OBn O
OH
O
OBnO
BnO
OHOBn
OBn O
O
O
O
O
O
OBnO
BnOOBn
OBnO
OAcOAc
OAc
OBnO
BnO
OHOBn
OBn
IBu3SnH AIBN
295 297 26
1 BF3 OEt2 Et3SiH
2 L-Selectride THF
1 Pd(OH)2C C6H10 EtOH
2 EtSiOSO2CF3 Ac2O
298 89 over 2 steps299
296
O
O
PhSeClO
O
PhSeCl
Bu3 SnH
O
O
PhSeCl
R
H
O
OAc
R
Cl
O
AcO
OAc
OAc
OAcOH
Cl
NHAc
R
OAc
AcHN
OH
O
OH OAc
OH
OHO
HO
OH
O
AcO
OAc
OAc
OAcBr
O
O
PhSeCl
O
O
PhSeCl
R
O
OTIPSAcHNR
OAc OAc
O
OHAcHN
COOMe
R
OAc
1 Bu4NF
2 NH3MeOH
1 (Me3Si)2NLi THF2 Me2N=CHI
1 Bu3 SnH AIBN2
1 NaBH42 mCPBA3 Ac2O pyr
1 H+ MeCN
2 H2 O NaHCO3
R =
1 O3MeOH
2 Me2S NaHCO3
1 TIPSOTf 26-lut idine2 LiBH43 Ac2 O pyr DMAP
furanoses +
304 56
305 68 306 84307 50
308 46
300 301 302
303
309
1426 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
The reduction of 317 and treatment with DOWEX-H+ resinprovided the desired C-fucoside 318 in 70 (Scheme 54)
62 Intramolecular Radical Approaches
One disadvantage with the intermolecular approaches isthat during such radical mediated reactions electrondeficient alkenes are required to facilitate C-C bondformation The intramolecular approach of Sinayuml overcomes
this drawback by bring two substrates together via atemporary covalent silaketal connector This enables the useof a wider range of alkenes which can include alkene-functionalized sugars thus leading to the generation of C-disaccharides [63] Based on the early work of Stork Sinayumlemployed the tether reaction in the synthesis of both α- andβ-C-disaccharides with this work subsequently beingemployed in the synthesis of biologically significant natural
Scheme (54)
O
OH
Fuc
Cl
O
O
ClPhSe
OOAc
NHAcOHFuc
O
AcOOAc
AcO
Br
O
O
PhSeCl
O
AcOOAc
AcO
O
OH
PhSe Cl
Fuc
OOAc
NHAc
OMe
Fuc
O
AcHN
OH OAc
OH
O
OH
Me
OH
O
O
Fuc
ClSePh
O
HO
Fuc
ClSePh
+
Ph3SnHAIBN
78 combined yield
Fuc
310
+
1 NaBH4 MeOHTHF2 Chromatography
313 40 314 355
1 mCPBA
2 Ac2O pyr DMAP
+
315 75
1 TfOH MeCN
2 NaHCO3 O3 -78 oC
316 10 over 2 steps
1 Cl3 CCN NaH
2 MeOH BF3 OEt2
317 79
1 LiBH4 THF
2 Dowex-H+
311
312a312b
318 70 for 2 steps
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1427
products [64] The availability of different hydroxyl groupson each monosaccharide unit allowed the fine-tuning ofstereochemical outcome by selective positioning of the silyltether [65] Development of this early stereochemical controlled to the tethering of the donor 320 with alcohol 319through a di-isopropyl silicon tether 321 Subsequent treat-ment with Bu3SnH and AIBN led to a 9-endo-trigcyclization to form the C-disaccharide 322 in an 80 yieldwith exclusive formation of the α-product The silyl tetherwas removed with Bu4NF and deprotection under standardconditions afforded the desired disaccharide 323 in excellentyield (Scheme 55)
In parallel the development of a 32rsquo silyl tether allowedaccess to the β-linked product as demonstrated in Sinayumlrsquossynthesis of methyl β-C-lactoside 328 [66] Alcohol 324 and320 were connected via the dimethylsilyl tether an 8-endo-trig cyclization followed to exclusively afford the β-
disaccharide 326 in 45 yield Removal of the tether anddeprotection of benzyl ether gave β-C-disaccharide 328(Scheme 56)
This group also selected iodosugars bearing a freehydroxyl group as progenitors of the radical donors [67] In atypical experiment the radical donor 329 was connected tothe radical acceptor 330 through a silaketal tether followingtheir procedure Tributyltinhydride mediated 8-endo-trigradical cyclization of compound 331 gave after detetheringof the non isolated intermediate 332 the protected β-C-disaccharide 333 in 37 overall yield (from startingmaterials 330 and 329) Peracetate 335 was achieved afterhydrogenolysis The C-laminaribioside 334 is of potentialbiological interest as it mimics the repeating disaccharideunit of fungal β-(1rarr3)-glucans which have antitumor andimmunomodulating properties (Scheme 57)
Scheme (55)
Scheme (56)
OO
OHSePh
OTBDPSO O
OO
SePh
OTBDPSO
OO
OBnOMe
OBn
Si
O
HOOBn
OMe
OBn
O
HOOH
OHHO
O
HOOH
OMe
OH
OTBDPSO
O
HOOBn
OMe
OBnO
OOH
1 n-BuLi THF
2 iPr2SiCl2 -78 oC
3 DMAP THF rt
1 Bu4NF THF
2 Dowex-H+
3 H2 PdC
Bu3SnH AIBN toluene
319
320
321
322323
OBnO
OHSePh
OBnBnO
OHO
OBnOMe
OBn
ROO
ROOH
OR
OHO
OROMe
OR
OBnO
O
OBnBnO
OO
OBnOMe
OBn
Si
SePh
OBnO
O
OBnBnOO
OOBn
OMe
OBn
Si
1 PhSeH Me2SiCl2
BuLi -78 oC
2 imidazole rt
Bu3SnH AIBN toluene
H2 PdC327 R = Bn
328 R = H
Bu4NF THF
324
320
325
326 45
1428 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
CONCLUSIONS
In this paper the biological importance of C-oligo-saccharides as subunits of natural products and as a newgeneration of carbohydrate based on therapeutics has beenillustrated Different methods are available for the synthesisof C-oligosaccharides As with traditional saccharidesynthesis it has been necessary to develop a number ofspecific approaches to facilitate the regioselective andstereoselective preparation of the desired targets Work inthis area continues and it is expected that many interestingnew C-oligosaccharides will be prepared using the chemistrydescribed in this review It is also likely that new chemistrywill be developed in the future for the preparation of thesebiologically important targets
ACKNOWLEDGEMENTS
The authors thank Dr Sultan Baytas for her criticalreading of this manuscript
REFERENCES
[1] Kennedy J F White C A Bioactive Carbohydrates InChemistry Biochemistry and Biology Ellis Horwood LtdChichesterUK 1983
[2] Wassarman PW Mammalian Fertilization Molecular Aspects ofGamete Adhesion xocytosion Exocytosis and Fusion Cell 199996 175-183
[3] Carbohydrate-based Drug Discovery Wong C-H EdWeinheim Cambridge Wiley-VCH 2003
[4] (a) Sharon N Lis H Lectins as Cell Recognition MoleculesScience 1987 246 227-234 (b) Dwek RA Chem Rev 1996 96683-720
[5] Postema M C-Glycoside synthesis CRC Boc Ratom 1995[6] (a) Weatherman R V Mortell K H Cheruenak MKiessling
L L Toone E J Specificity of C-Glycoside Complexation byMannoseGlucose Specific Lectins Biochem 1996 35 3619-3624(b) Ravishankar R Surolia A Vijayan M Lim S Kishi YPreferred Conformation of C-Lactose at the Free and Peanut LectinBound States J Am Chem Soc1998 120 11297-11303
[7] (a)Wong C-H Halcomb R L Ichikawa Y and Kajimoto TEnzymes in organic synthesis Application to the problems ofcarbohydrate recognition part2 Angew Chem Int Ed Engl 199534 521-546 (b)Howard S Withers SG Bromoketone C-Glycosides a New Class of βminusGlucanase Inactivators J AmChem Soc 1998 120 10326-10331(c) Wang Q Wolff MPolat T Du Y Linhardt R J C-glycoside of Neuraminic Acidsas Neura-minidase Inhibitors Bioorg Med Lett 2000 10 941-944 (d) Phili R Chang J Partis R A Mueller R A ChrestF J Passaniti A The Alpha-glucosidase I InhibitorCastanospermine Alters Endothelial cell Glycosylation PreventsAngiogenesis and Inhibits Tumor Growth Cancer Res 1995 552927-2935
[8] Ossor A Elbein A D In Carbohydrates in Chemistry andBiology Vol 3(II) WileyVCH 2000 pp 513-539
[9] (a) Sinayuml P Synthesis of oligosaccharide Mimetics Pure ApplChem 1997 69 459-463 (b) Beau J-M Gallagher TNucleophilic C-glycosyl Donors for C-glycoside Synthesis Top inCurr Chem 1997 187 1-54 (c) Nicotra F Synthesis of C-glycosides of Biological Interest Top in Curr Chem 1997 187
Scheme (57)
O
O
O
Ph
I
OMe
OHO
BnO
OH
OH
BnOOH
O
BnO
Si
O
O O
Ph
I
OMe
O
O
BnO
OR4O
R5O
OMe
OR2
OR3O
R3O
OR1
R3O
Bu3 SnH AIBN
332 R1 R2 = SiMe2 R3 = Bn R4 R5 = CHPhTBAF THF
333 R1 = R2 = H R3 = Bn R4 = R5 = CHPh 37 from 11
334 R1 = R2 = R3 = R4 = R5 = H
335 R1 = R2 = R3 = R4 = R5 = Ac
329
H2 PdC MeOH
Ac2 O pyr
1 BuLi THF -78 oC
2 Me2SiCl2
3 DMAP
330
331
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1429
55-83 (d) Du Y Linhardt R Y Recent Adv in Stereo-SelectiveC-Glycoside Synthesis Tetrahedron Lett 1998 54 9913-9959 (e)Liu L Mckee M and Postema M H D Synthesis of C-saccharides and Higher Congeners Current Org Chem 2001 51133-1167
[10] Jarosz S Fraser-Reid B Synthesis of A Higher Carbon Sugar ViaDirected Aldol Condensation Tetrahedron Lett 1989 30 2359-2362
[11] Lichtenthaler F W Lergenmiiller M Schwidetzky S C-Glycosidations of 2-Ketohexosyl With Electrophilic Radical andNudeophilic Anomeric Carbons Eur J Org Chem 2003 3094-3103
[12] Baudat A Vogel P Aza-C-disaccharides Synthesis of 6-Deoxygalactonojirimycin-β-C(1rarr3) Linked with D-Altrofuranosides and D-Galactose J Org Chem 1997 62 6252-6260
[13] Turner D Vogel P Synthesis of 4-Hydroxy-26-Bis(hydroxymethyl) tetrahydropyran-2-Carbaldehyde DerivativesSynlett 1998 304-306
[14] Zhu Y-H Vogel P Short Stereoselective Synthesis of C-(1rarr3)-Linked Disaccharides Tetrahedron Lett 1998 39 31-34
[15] Zhu Y-H Vogel P Synthesis of a (2R 6R)-2-(Hydroxymethyl)-6-Propa-1 2-Dienyl-2H-Pyran-3(6H)-One Derivative A NewEnone for The Convergent Construction of C-Glycosides of C-Disaccharides Synlett 2001 82-86
[16] Baumberger F Vasella A Deoxynitrosugars The 6th
Communication Stereolectronic Control in the reductivedenitration of tertiary nitro ethers A Synthesis of ldquoC-glycosidesrdquoHelv Chim Acta 1983 66 2210-2221
[17] Martin O R Lai W Synthesis and Conformational Studies of β-(1rarr6)- and ββ-(1rarr1)-Linked C-disaccharides J Org Chem1993 58 176-185
[18] Spak S J Martin R The synthesis of an analogue of Methyl OC-Analogue of Methyl 4rsquo-O-β-D-GlucopyranosylgentiobiosideTetrahedron 2000 56 217-224
[19] Kobertz W R Bertozzi C R Bednarski M D C-GlycosylAldehyde Synthons for C-Linked Disaccharides J Org Chem1996 61 1894-1897
[20] Gurjar M K Nagaprasad R and Ramana CV First Synthesis ofMethyl α-C-D-Arabino-furanosyl-(1rarr5)-αminusD-Arabinofuranosidethe C-Disaccharide Segment of Motif C of MycobateriumTuberculosis Tetrahedron Lett 2000 43 7577-7579
[21] Witczak Z J Synthesis of C-Glycosyl Compounds and OtherNatural Products from Levoglucosenone Pure Appl Chem 199466 2189-2192
[22] Griffin F K Paterson D Taylor R J K Ramberg-BacklundApproaches to the Synthesis of C-Linked Disaccharides AngewChem Int Engl 1999 38 2939-2942
[23] Paterson B E Griffin F K Alcaraz M-L and Taylor R J KA Ramberg-Baumlcklund Approach to the Synthesis of C-GlycosidesC-Linked Disaccharides and C-Glycosyl Amino Acids Eur JOrg Chem 2002 1323-1336
[24] McAllister G D Paterson D E Taylor R J K A SimplifiedRamberg-Bachlund Approach to Novel C-Glycosides and C-Linked Disaccharides Angew Chem Int Ed Engl 2003 42 1387-1391
[25] McCartney J L Christopher T M Cicchillo R M BernardinaM D Wagner T R and Norris P J Org Chem 2003 6810152-10155
[26] Dondoni A Zuurmond H M Bascarate A Synthesis of α-andβ-D-(1rarr6)-C-Disaccharides by Witting Olefination of Formyl C-Glycosides with Glycopyranose 6-phosphoranes J Org Chem1997 62 8114-8124
[27] Dondoni A Kleban M Zuurmond H Marra A Synthesis of(1rarr6)-C-Oligogalactosides by Interative Wittig OlefinationTetrahedron Lett 1998 39 7991-7994
[28] Dondoni A Marra A A New Synthetic Approach toMycobacterial Cell Wall α-(1rarr5)-D-Arabinofuranosyl C-Oligosaccharides Teterahedron Lett 2003 44 4067-4071
[29] Colinas P A Ponzinibbio A Lieberknecht A and Bravo R OWittig Reaction of Glycosyl Phosphonium Salts A StereoselectiveRoute to C-Disaccharides and C O-Trisaccharides TetrahedronLett 2003 44 7985-7988
[30] Schmidt R R Preuss R Synthesis of Carbon Tetrahedron Lett1989 30 3409-3412
[31] Dietrich H Schmidt R R Synthesis of Carbon-Bridged C-Lactose and Derivatives Liebigs Ann Chem 1994 975-981
[32] Rouzaud D Sinayuml P The First Synthesis of a ldquoC-DisacchariderdquoJ Chem Soc Chem Commun 1983 1353-1354
[33] Xin Y-C Zhang Y-M Mallet J-M Glaudemans C P JSinayuml P Synthesis of C-Oligosaccharides That Mimie TheirNatural O-Analogues Immunodeterminants in Binding toMonoclonal Immunoglobulins Eur J Org Chem 1999 471-476
[34] Streicher H Geyer A Schmidt R R C-Disaccharides ofKetoses Chem Eur J 1996 2 502-510
[35] Leeuwenburgh M A Timmers C M Vander Marel G A VanBoom J H Mallet J-M Sinayuml P G Stereoselective Synthesisof α-C-(Alkynyl)-Glycosides Via Ring-Opening of α-12-Anhydrous Tetrahedron Lett 1997 38 6251-6254
[36] Aslam T Fuchs M G G Le Formal A Wightman R HSynthesis of C-Disaccharide Analogue of the α-D-Arabinofuranosyl-(1rarr5)-α-Arabinofuranosyl Motif ofMycobacterial Cells Walls via Alkynyl Intermediates TetrahedronLett 2005 46 3249-3252
[37] (a) Girad P Namy J L Kagan H B Divalent LanthanideDerivative in Organic Synthesis 1 Mild Preparation of SamariumIodide and Ytterbium Iodide and Their Use as Reducing orCoupling Agents J Am Chem Soc 1980 102 2693-2698 (b)Molander G A Harris C R Sequencing Reactions withSamarium(II) Iodide Chem Rev 1996 96 307-338
[38] (a) Mazeacuteas D Skrydstrup T Doumeix O Beau J-MSamarium Iodide-Induced Intramolecular C-Glycoside FormationEfficient Radical Formation in the Absence of an Additive AngewChem Int Ed Engl 1994 33 1383-1386 (b) Mazeacuteas DSkrydstrup T Beau J-M A Highly Stereoselective Synthesis of1 2-trans-C-Glycosides Via Glycosyl Samarium(III) CompoundsAngew Chem Int Ed Engl 1995 34 909-912 (c) Jarreton OSkrydstrup T Beau J-M The Stereospecific Synthesis of Methylα-C-Mannobioside A Potential Inhibitor of M TuberculosisBinding to Human Macrophages J Chem Soc Chem Commun1996 1661-1662 (d) Jarreton O Skrydstrup T Espionosa J-FJimeacutenez-Barbero J Beau J-M Samarium Diiode Prompted C-Glycosylation An Application to The Stereospecific Synthesis ofα-(1rarr2)-C-Mannobioside and Its Derivatives Chem Eur J 19995 430-441 (e) Mipuel N Doisneau G Beau J-M ReductiveSamariation of Anomeric 2-Pyridyl Sulfones with Catalytic AnUnexpected Improvement in The Synthesis of 12-Trans-Diequatorial C-Glycosyl Compounds Angew Chem Int Ed Engl 2000 39 4111-4114
[39] Vlahov I R Vlahova P I Linhardt R J DiastereocontrolledSynthesis of Carbon Glycosides of N-Acetylneuraminic Acid ViaGlycosyl Samarium(III) Intermediates JAmChem Soc 1997 1191480-1481
[40] Kuberan B Sikkander S ATomiyama H Linhardt R JSynthesis of a C-Glycoside Analogue of sTn An HIV-and Tumor-Associated Antigen Angew Chem Int Ed Engl 2003 42 2073-2075
[41] Bazin H G Du Y Polat T Linhardt R J Synthesis of aVersatile Neuraminic Acid ldquoCrdquo-Disaccharide Precursor for theSynthesis of C-Glycoside Analogues of Gangliosides J OrgChem 1999 64 7254-7259
[42] Chen C-C Ress D K Linhardt RJ Samarium Iodide-Mediated Synthesis of Neuraminic Acid C-Glycosides InSynthesis of Glycommetics Roy R Ed ACS Syposium Series2004 896 53-80
[43] Abdallah Z Doisneau G Beau J-M Synthesis of a Carbon-Linked Mimic of The Disaccharide Component of The Tumor-Relate SialyTn Antigen Angew Chem Int Ed Engl 2003 425209-5212
[44] Lay L Nicotra F Panza L Russo G Caneva E Synthesis ofC-disaccharides through dimerization of exo-glycals J Org Chem1992 57 1304-1306
[45] Isobe M Nishizawa R Hosokawa S Nishikawa TStereocontrolled Synthesis and Reactivity of Sugar Acetylenes JChem Soc Chem Commun 1998 2665-2676
[46] Saeeng R Sirion U Sahakitpichan P Isobe M IodineCatalyzes C-Glycosidation of D-Glucal with SilylacetykeneTetrahedron Lett 2003 44 6211-6215
[47] (a) Babirad S A Wang Y Kishi Y Synthesis of C-Disaccharides J Org Chem 1987 52 1370-1372 (b) Wang YBabirad S A Kishi Y Preferred Conformation of C-Glycosides
1430 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
8 Synthesis of 14-Linked Carbon Disaccharides J Org Chem1992 57 468-481
[48] Armstrong R W Sutherlin D P Strategies for the Synthesis ofC-Disaccharides Containing D and L Sugars Tetrahedron Lett1994 35 7743-7746
[49] Wei A Kishi Y Preferred Conformation of C-Glycosides 12Synthesis and Conformational Analysis of αα- α β- and β β-Trehaloses J Org Chem 1994 59 88-96
[50] Haneda T Goekjian P G Kim S H Kishi Y PreferredConformation of C-Glycosides 10 Synthesis and ConformationAnalysis of Carbon Trisaccharides J Org Chem 1992 57 490-498
[51] Sutherlin D P Armstrong R W Synthesis of 12 Stereochemistryand Structurally Diverse C-Trisaccharides J Org Chem 1997 625267-5283
[52] Notz W Hartel C Waldscheck B Schmidt R R De NovoSynthesis of a Methylene-Bridged Neu5Ac-α-(23)-Gal C-Disaccharide J Org Chem 2001 66 4250-4260
[53] (a) Postema M H D Calimente D Liu L Behrmanm T L AnOlefin Metathesis Route for the Preparation of (1rarr6)-Linked-C-Disaccharide Glycals A Convergent and Flexible Approach to C-Saccharide Synthesis J Org Chem 2000 65 6061-6068(b) Postema M H Piper J L Liu L Faust M Andreana PSynthesis and Partial Biological Evaluation of a Small Library ofDifferentially Linked β-C-Disaccharide J Org Chem 2003 684748-4754
[54] Nelson A The Development of Strategies and Methods for TheSynthesis of Biologically Active Compounds New J Chem 200428 771-776
[55] Togo H He W Waki Y Yokoyama M C-GlycosylationTechnology With Free Radiant Reactions Synlett 1998 700-717
[56] Giese B Dupuis J Diastereoselective Synthesis of C-Glycopyranosides Angew Chem Int Ed Engl 1983 22 622-623
[57] Adlington R M Baldwin J E Basak A Kozyrod RPApplication of Radical Addition Reactions to tho Synthesis of a C-Glucoside and A Functionalized Amino Acid J Chem SocChem Commun 1983 144-145
[58] Giese B Gonzaacutelez-Goacutemez J A Witzel T The Scope of RadicalCC-Coupling by The ldquoTin Methodrdquo Angew Chem Int Ed Engl1984 23 69-70
[59] Giese B Witzel T Synthesis of ldquoC-Disaccharidesrdquo by RadicalC-C Bond Formation Angew Chem Int Ed Engl 1986 25 450-451
[60] Witczak Z J Chhabra R Chojnacki J C-Disaccharides IStereoselective Approach to β-(1rarr4)-3-Deoxy-C-Disaccharidesfrom Levoglucosenone Carb Res 1997 301 167-175
[61] Vogel P Synthesis of Rare Carbohydrates and Analogues Startingfrom Enantiomerically Pure 7-Oxabicyclo[221]heptyl Derivatives(ldquoNaked Sugarsrdquo) Current Org Chem 2000 4 455-480
[62] Viodeacute C Vogel P Synthesis of The C-Disaccharide α-C(1rarr3)-L-Fucopyranoside of N-Acetylgalactosamine J Carb Chem2001 20 733-746
[63] Xin Y C Mallet J M Sinayuml P An Expeditious Synthesis of AC-Disaccharide Using A Temporary Silaketal Connection J ChemSoc Chem Commun 1993 864-865
[64] (a) Petitou M Herault P Lormeau J-C Helmboldt A MalletJ-M Sinayuml P Herbert J-M Introducing A C-InterglycosidicBond in A Biologically Active Pentasaccharide Hardly Affects ItsBiological Properties Bioorg Med Chem 1998 6 1509-1516 (b)Sinayuml P Advances in The Synthesis of the Carbohydrate MimicsPure Appl Chem 1998 70 1495-1499
[65] Sinayuml P Chemical Synthesis of Oligosaccharide Mimetics PureAppl Chem 1998 70 407-410
[66] Sinayuml P Chemical Synthesis of Oligosaccharide Mimetics PureAppl Chem 1998 69 459-463
[67] Vauzeilles B Sinayuml P Selective Radical Synthesis of β-C-Disaccharides Tetrahedron Lett 2001 42 7269-7272
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1417
followed by reduction to afford a 51 mixture (213214215216) of lactols that were readily separable by chromato-graphy Following a deprotection of an equimolar mixture of213 and 214 217 and the DL hybrid C-disaccharide of D-glucose-O-(1rarr6)-L-galactose 218 were obtained The DDand DL derivatives 219 and 220 of glucose-α-(1rarr6)-idosewere also obtained as a near equimolar mixture afterdeprotection of 215 and 216 (Scheme 44)
52 Anion Addition-Cyclization
Kishi developed an approach for the synthesis of theCndashtrehalo sugars which relied on nucleophilic addition ofone intact sugar fragment to a fundamental aldehyde ieKishi-Nozaki reaction [49] Coupling of monosaccharide221 and aldehyde 222 gave 223 The triple bond waspartially reduced and osmylation was followed by selectiveprotection to afford 224 The acetonide was converted toepoxide 225 by standard methods and removal of the PMBgroup Acid-catalyzed cyclization followed by aglyconichydrolysis and protection of hydroxyl group with (p-methoxyphenyl)diphenylmethyl chloride (MMTrCl) gave226 Inversion of the C-2 hydroxyl and removal of protectinggroups delivered α α-C-trehalose 227 (Scheme 44)
Kishi and co-workers also employed aldol reactions as anefficient access to the C-trisaccharide related to the type IIABO(H) blood group determinant [50] Aldol condensationof the enolate of methyl ketone 228 with aldehyde 229 gavea 41 mixture of hydroxy ketones 230 and 231 The majorketol was cyclized desulfurized and oxidized to afford thedisaccharide ketone 233 The ketone in THF was treatedwith LiHMDS (3 equiv) and TMEDA followed by theaddition of MgBr2 Addition of the aldehyde 234 led toalmost exclusive formation of the equatorial products 235and 236 in a 12 ratio Mesylation of 235 and 236 followedby treatment with liquid ammonia gave enones 237a and237b which were reduced to yield exclusively the C-2rsquo-equatorial ketone 238 Sodium borohydride reduction of theC-3rsquo carbonyl proceeded with the desired stereoselectivity toyield the protected C-trisaccharide 239 which wasdeblocked to provide the polyol 240 (Scheme 46)
Sutherlin and Amstrong cleverly applied a recursivestereochemical deconvolution (RSD) combinatorial approachfor the synthesis of a small library of C-trisaccharides aspotential inhibitors for the cell surface proteins of bacteriumHelicobactor pylori [51] The workers chose to carry outvariations in galactose ring of these trisaccharides An
Scheme (44)
OBnO
BnOOBn
OBn
P O
OEtOEtO
EtO
R H
OH
OH
OH
OH
O
R H
OH
OH
OH
OH
O
OHO
HOOH
OH
O
HO
OHOH
OH
OHO
HOOH
OH
O
HO
OH
OH
OHO
HOOH
OH
O
HO
OH
OHOH
R H
OH
OH
OH
OH
O
R
OBnO
BnOOBn
OBn
O
OHO
HOOH
OH
OO
HOHO
OH
R H
OH
OH
OH
OH
O
1 OsO4 NMO 50
2 DIBAL -32 oC 40
++ +
213 214 215 216
217 218 219 220
1 9-BBN H2O22 Swern [O]
3 t-BuOK
4 I2 C6H6212
211
1418 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
efficient Nozaki-Kishi coupling of vinyl bromide 241 withaldehyde 242 in a diasteromeric ratio of 12 followed byprotection with TBSOTf led to 243 and 244 Hydroborationfollowed by oxidation gave aldehydes 245 and 246respectively Addition of allylmagnesium bromide toaldehyde 245 followed by removal of the silyl groupafforded 247 to 246 giving 248 and 249 Epoxidation gave a11 mixture of the corresponding epoxides which werecyclized to give the C-trisaccharide 250-255 after removalof the benzyl groups (Scheme 47)
Schmidt reported a stereoselective 6-exo-trig selectiveelectrophilic cylization approach for de novo synthesis of amethylene-bridged Neu5Ac-α-(23)-Gal C-disaccharide theC-analog of an important motif in glycosphingolipids [52]The open chain precusors 259ab (a 32-mixture ofdiaseteromeric alcohols) were formed by the addition oflithiated iodide 256 to open chain aldehyde 258 Subsequent
C1 incorporation using Tebbe-reagent formation of a cycliccarbonate and deprotection of the two isopropylidene ketalsafforded tetrol 264 which upon treatment with phenylselenyltrifilate was steroselectively cyclized in a 6-exo-trigselective manner affording a diasteromeric mixture of 251and 252 in a ratio of 71 A seleno-Pummerer rearrangementto afford aldehyde 267 in 5 steps in 90 overall yieldOxidation of the aldehyde and subsequent steps led to thedesired C-disaccharide 268 (Scheme 48)
53 Esterification-Cyclization
Work from the Postema group has focused on a ringclosing metathesis (RCM) approach for the synthesis of C-saccharides [53a] The chemistry is versatile and has beenused for the synthesis of a small library of differentiallylinked β-C-disaccharides through a radical allylation-RCMstrategy [53b] The synthesis of the β-(1rarr4)-glucopyranosyl
Scheme (45)
O
OBn
BnO
BnO
BnO
I
CrCl2-NiCl2O
OBn
OH
BnO
BnO
BnO
O
O
O
O
O
H
OBn
O
O
OBnBnO
BnO
BnO
OOBn
OBn
OAc
PMBOHOO
OBn
BnO
BnO
BnO
O
OBn
OBn
OAc
O
OH
HO
HO
HO
OH
OH
OH
O
OH
O
OBn
BnO
BnO
BnO
OBn
OBn
OAc
O
MMTr
+
1 p-TsOH2 K2CO3 MeOH3 MMTrCl pyr
1 Swern [O]2 BH3 THF
3 AcOH-H2 O4 H2 Pd(OH)2
221
222
223
1 Pd-Pb CaCO3 H22 NaH BnBr3 OsO44 Bu2 SnO5 CsF PMB-Cl6 Ac2 O 4-DMAP
1 AcOH2 TsCl pyr
3 NaH-imid4 DDQ
224225
226 227
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1419
Scheme (46)
OBnO O
OBn
OMe
OBn
XY
SMe
OBnBnO
O
OBn
OBn
OBn
OBn
O
BnO
YX
OBn
TBSO
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnOOBn
H
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnO
OBn
OHC OBn
OBn
OTBS
OMe
BnOOBn
CHO
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnOOBn
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnO
OBn
YX
OBnO O
OBn
OMe
OBn
OBn
O
BnO
O
OBn
OBn
OBn
OBn
O 1 LiHMDS
2
228
1 TBAF THF
2 MeSH BF3 OEt2
230 X = OH Y = H231 X = H Y = OH
230231 41
1 Bu3SnH AIBN2 Swern [O]
1 LiHMDS THF-TMEDA2 MgBr23
1 MsCl
2 liquid NH3
235 X = OH Y = H236 X = H Y = OH Bu3 SnH AIBN
237a and 237b
NaBH4 MeOH
238
239 X = OBn
240 X = OHH2 Pd(OH)2
229
232233
234
1420 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (47)
OH C
O
O BnAcHN
OO
O
OBn OBnOBn
Br
O
OBn OBnOBn
O
OBnA cHN
OO
O TBSO
OBn O BnO Bn
O
OBnAcHN
OO
OTBS
S2
S1
S2
OTBSS1
O H
S2
OT BSS1
O H
MgBrMgBr
S2
O TBSS1
O H
S2
OHS1
OH
S2
OTBSS1
OH
O
OHHO
O H
O
HO
H OO
OBnA cH N
HO
H O
O
O HHO
OH
O
HOHO
O
OBnA cH N
HO
H O
O
OHH O
OH
O
H O
HOO
OBnAcHN
HO
HO
O
O HH O
OH
O
H O
H O O
OBnA cHN
HO
HO
O
O HH O
O H
O
HO
H O O
OBnAcHN
HO
HO
O
OHHO
OH
O
H O
O
OBnA cHN
HO
HOHO
+
241 242
1 CrCl2-NiCl2 T HF-DMF 722 TBSOTf 2 6-lutidine 91
243 244
1 9-BBN 602 Dess-Mart in period inane 97
1 9 -BBN 552 D ess-Martin periodinane 98
245 246
1
2 T BAF 74
1
2 TBAF 88
247 248 249
250
251
250 251 1 1 252 253 1 1 254 255 1 1
252
253
254
255
1 MCPBA2 CSA CH 2Cl2 61 fo r 2 steps3 H 2 Pd (O H)2C 95
1 MCPBA2 CSA CH 2Cl2 63 fo r 2 s teps3 H 2 Pd (OH)2C 87
1 MCPBA2 CSA CH2Cl2 80 for 2 steps3 H2 Pd(O H)2C 95
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1421
Scheme (48)
O
OO
Se Ph
R
O
HO OHOH
O
OB n O B n
OB n
O B nO O
O O
R O OR
X
O
OO
R
Se Ph
O
HOOH
OH
O
OB nOB n
O Bn
OB n
O O
O O
R O O R
O H
O
O B n OB n
O B n
OB n
O
C HO
O
O O
R O OR
OAc HN
OAc
C O2NH 4HOOH
OH
O
OH O H
OH OH
O
OB n O B n
OB n
OB nO O
O O
R O OR
X
O
O
OAcOAc
C HOA cOOAc
OAc
O
OB n O B n
OB n
OB n
O
O Bn OB n
OB n
OB n
X
OH
OO
HOOH
OH
O
O
OMeOB n
OB nOB n
R
t-B uL i256 R = Li
257 R = L i
258
(R = t-B uMe 2Si )
(R = t-B uMe 2Si )
259ab (32) 79 com bine d yi eld
De ss-Ma rtin pe riodinane
260 X = O R = t-B uMe 2Si ) 95
261 X = O R = t -B uMe2S i) 62
T e bbe re age nt
TB A F THF262 X = O R = H 94
diphosge ne
C H2C l 2Pyr
263 95
T HFH2O T FAr t
264 quant it a ti ve yie ld
PhSe C l AgOT f
EtC N -80 oC
265
266
Quant it at i ve yi l ed 25 26 7 1
+
R =
1 Ac 2OPyr
2 mC PB A3 Ac 2ONa OAc
4 NaO HT HFMe OH
5 Ac2O P yr
267 90 overa ll yi e ld
ste ps
268
1422 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
glucopyranoside 280 represents an example of thischemistry The known triacetyl glucopyranoside 269 wasconverted to iodide 270 in good yield Radical allylation of271 proceeded to afford a mixture of equatorial and axialallylation products in a 61 ratio Oxidative cleavage of thedouble bond gave the corresponding aldehydes 273a and273b which were separable Pinnick oxidation of the majoraldehyde 273a then gave the C-4 equatorial acid 274 DCC-mediated coupling of alcohol 275 and acid 274 proceeded toafford ester 276 in good yield Methylenation of 276 gave277 and exposure to catalysist 278 gave a 41 yield of theC-disaccharide glycal which was exposed to an excess ofBH3
THF to give 64 yield of the β-C-disaccharide 279Removal of the benzyl groups and global peracetylation gavethe peracetylated (1rarr4)-β-C-disaccharide 281 in good yield(Scheme 49)
54 Ring Expansion-Cyclization
Nelson developed a new strategy for asymmetric andstereoselective synthesis of C-linked disaccharide mimeticsthe C58-C71 fragment of palytoxin [54] The diol (RR)-282was converted into the di-dihydropyran (DHP) template 283284 and 285 The di-DHPs were functionized in a twodirectional sense using dihydroxylation reactions The two-directional approach was often very efficient indeed forexample in the synthesis of 286 six new stereogenic centerswere introduced with almost complete stereocontrol using areduction and a dihydroxylation reaction The approach isnot restricted to the synthesis of C2-symmetricaldisaccharide mimetics Using the unsymmetrical template285 which has both a pseudo-axial and a pseudo-equatorialhydroxyl groups the unsymmetrical mimetics 289 and 290were prepared (Scheme 50)
6 RADICAL APPROACHES
The radical approach for C-C bond formation is a popularmethod within organic chemistry The use of radicalchemistry in carbohydrate synthesis has certain advantagesFirstly the reaction conditions are very mild and tolerant ofa range of functional and protecting groups Secondanomeric radicals are stable with respect to elimination andepimeration Most significantly the chemistry required toincorporate an appropriate substitute at C-1 employed in theinitial hemolytic cleavage step is common within carbo-hydrate chemistry [55] The use of such radical techniquecan be subdivided into two classes intermolecular andintramolecular approaches
61 Intermolecular Radical Approaches
Giese was the first to employ an intermolecular radical-based approach for synthesis of C-disaccharides [56]Addition of an alkene to an anomeric radical underappropriate conditions allowed exclusive entry to the α-linked C-glycoside a result which was mirrored by the workof Baldwin [57] The high α-selectivity of the reaction wasin contrast with other reports Thus radicals generated at theC-2 C-3 and C-4 centers all preferred to occupy equatorialpositions [58] When the anomeric bromide 291 was treatedwith tin hydride and AIBN resulting anomeric radical andreacted with lactone 292 in a Michael addition it afforded293 In this reaction hydrogen abstraction at the resulting
radical center occurs from axial face to selectively generatethe equatorial C-2rsquo substituent Reduction and acetylation of293 furnished C-disaccharide 294 (Scheme 51) [59]
Witczak used the facial bias of levoglucosene tostereoselectively add a carbohydrate-based radical in thepreparation of the 3-deoxy-(1rarr4)-β-C-disaccharide 299[60] Addition of the radical derived from iodide 295 to 296gave adduct 297 in 26 yield Removal of the anomerichydroxyl of 297 was achieved by treatment with triethylsilane borontrifluoride ether complex followed bystereoselective reduction of the keto function at C-2rsquo withthe formation of 298 in 89 yield Debenzylation followedby acetolysis of 16-anhydro ring produced the peracetylatedtarget C-disaccharide 299 in 19 overall yield from 295(Scheme 52)
Vogel has developed general methods to transformenantiomerically pure 7-oxabicyclo[221]heptyl derivatives(ldquonaked sugarsrdquo) into C-disaccharides Because of thesechiral bicyclic skeletons they undergo highly stereoselectivereactions with predictable diasteroselectivities An arsenal ofmethods is available that allow to substitute these ldquonakedrdquocarbon centers with a variety of functional groups with allpossible relative configurations The methods allowpreparation of both enantiomers of a given target with thesame ease Predictably high stereoselectivity of the reactionsof the bicyclic chirons adds to the flexibility of approachwhich can lead to high molecular diversity [61]
α-C-(1rarr3)-mannopyranoside of N-acetyl-galactosaminepotent β-galactosidase inhibitors was synthesized by thisapproach [61] Enone 302 was readily prepared from 300The addition of the radical derived from bromide 303 toenone 302 afforded the αminusisomer 304 The ketone was thenreduced and the selenide eliminated via the intermediacy ofthe selenoxide to give 305 Acid-promoted (CF3SO3H) 7-oxa ring opening of 305 in MeCN produced the amino-conduritol derivative 306 resulting from the quenching of theallylic cation intermediate by the solvent (Ritter reaction)Ozonolysis of the chloroalkene 306 generated an acylchloride-aldehyde intermediate that reacted with MeOH toproduce a mixture of methyl uronates The major compound307 was silylated and reduced The crude polyol obtainedwas acetylated to produce 308 Desilylated and ammonolysisafforded a mixture of α-β-pyranoses 309 and correspondingα-β-furanoses (Scheme 53)
Similar chemistry was carried out to synthesize non-protected α-C(1rarr2)-L-fucopyranoside of D-galactopyrano-side corresponding to a blood group mimetic [62] Giesersquosradical fucosidation of racemic enone 310 with α-L-bromoacetofucose 311 provided the mixture of diastereo-meric α-C-fucoside 312a and 312b in reproducible yield of78 Reduction of the mixture gave a 11 mixture of endo-alcohols 313 and 314 which were isolated pure in 40 and355 yield respectively Oxidative elimination of thebenzeneselenyl group of 313 followed by acetylation gaveendo acetate 315 in 85 yield Acid-promoted ring openingof 315 and ozonolysis of the resulted chloroalkene gavemethyl uronic ester 316 in modest yield (10) Treatment of316 with Cl3CCN and NaH followed with BF3
OEt2
furnished the totally protected C-disaccharide 317 in 79
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1423
Scheme (49)
Bu3SnO
HOAcO
OMeOAc
OAc
O
AcO
OMeOAc
OAcI
AIBN
O
AcO
OMeOBn
OBn
HO2C O
AcO
OMeOR
ORY
X
OHBnO
BnO
OBn
OBnO
BnO
OBn
O
AcO
OMeOBn
OBnX
i-Pr i-Pr
N
Mo C(Me2 Ph)((CF3)2 MeCO)2
O
RO
OMeOR
O
RO
OR
OR
RO
OR
278
I2 Ph3P
imidazole
269 270 93
271a X = CH2CH=CH2 Y = H R = Ac 64271b Y = CH2CH=CH2 X = H R = Ac 11272a X = CH2CH=CH2 Y = H R = Bn 75272b Y = CH2CH=CH2 X = H R = Bn 75273a X = CH2CHO Y = H R = Bn 79273a Y = CH2CHO X = H R = Bn 79
1 NaOMe MeOH2 NaOH BnBr DMF
OsO4 NaIO4
NaClO2 NaH2PO4
274 96
275
DCC 4-DMAP
276 X = O 82
277 X = CH2 51
TiCl4 Zn dust TMEDA CH2Br2PbCl2 (Cat )
1
2 BH3 THF H2O2 NaOH
H2 PdC EtOH
Ac2 O Pyr 4-DMAP
279 R = Bn R = H 64
280 R = R = H 99
281 R = R =Ac 97
1424 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (50)
Scheme (51)
O OOH
OH
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
286
1 VO(acac)2 t-BuOH 95
2 (MeO)3CH BF3 90
1 P-O2NC6H4 CO2H Ph3P DIAD2 K2CO3 MeOH 82 over 2 steps
1 PhCOCl Et3N DMAP 402 P-O2NC6H4 CO2H Ph3P DIAD3 KOH THF-H2O 75 over 2 steps
TMEDA OsO4
Cat OsO4 NMO 287
Cat OsO4 NMO288
TMEDA OsO4
Cat OsO4 NMO
290
289
(RR)-282283
284
285
OHO
AcO
BrOAc
OAc
BnO
O
OBn
OBnO
OHO
AcOOAc
OAc
BnO
OOBn
OBnAcO
OHO
AcOOAc
OAc
BnO
O
OBn
OBnO
+
Bu3SnH AIBN291
292
293 81
1 Na[Al(OC2H4OMe)2(OEt)H]2 Ac2O pyr
294 56 over 2 steps
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1425
Scheme (52)
Scheme (53)
OBnO
BnOOBn
OBn O
OH
O
OBnO
BnO
OHOBn
OBn O
O
O
O
O
O
OBnO
BnOOBn
OBnO
OAcOAc
OAc
OBnO
BnO
OHOBn
OBn
IBu3SnH AIBN
295 297 26
1 BF3 OEt2 Et3SiH
2 L-Selectride THF
1 Pd(OH)2C C6H10 EtOH
2 EtSiOSO2CF3 Ac2O
298 89 over 2 steps299
296
O
O
PhSeClO
O
PhSeCl
Bu3 SnH
O
O
PhSeCl
R
H
O
OAc
R
Cl
O
AcO
OAc
OAc
OAcOH
Cl
NHAc
R
OAc
AcHN
OH
O
OH OAc
OH
OHO
HO
OH
O
AcO
OAc
OAc
OAcBr
O
O
PhSeCl
O
O
PhSeCl
R
O
OTIPSAcHNR
OAc OAc
O
OHAcHN
COOMe
R
OAc
1 Bu4NF
2 NH3MeOH
1 (Me3Si)2NLi THF2 Me2N=CHI
1 Bu3 SnH AIBN2
1 NaBH42 mCPBA3 Ac2O pyr
1 H+ MeCN
2 H2 O NaHCO3
R =
1 O3MeOH
2 Me2S NaHCO3
1 TIPSOTf 26-lut idine2 LiBH43 Ac2 O pyr DMAP
furanoses +
304 56
305 68 306 84307 50
308 46
300 301 302
303
309
1426 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
The reduction of 317 and treatment with DOWEX-H+ resinprovided the desired C-fucoside 318 in 70 (Scheme 54)
62 Intramolecular Radical Approaches
One disadvantage with the intermolecular approaches isthat during such radical mediated reactions electrondeficient alkenes are required to facilitate C-C bondformation The intramolecular approach of Sinayuml overcomes
this drawback by bring two substrates together via atemporary covalent silaketal connector This enables the useof a wider range of alkenes which can include alkene-functionalized sugars thus leading to the generation of C-disaccharides [63] Based on the early work of Stork Sinayumlemployed the tether reaction in the synthesis of both α- andβ-C-disaccharides with this work subsequently beingemployed in the synthesis of biologically significant natural
Scheme (54)
O
OH
Fuc
Cl
O
O
ClPhSe
OOAc
NHAcOHFuc
O
AcOOAc
AcO
Br
O
O
PhSeCl
O
AcOOAc
AcO
O
OH
PhSe Cl
Fuc
OOAc
NHAc
OMe
Fuc
O
AcHN
OH OAc
OH
O
OH
Me
OH
O
O
Fuc
ClSePh
O
HO
Fuc
ClSePh
+
Ph3SnHAIBN
78 combined yield
Fuc
310
+
1 NaBH4 MeOHTHF2 Chromatography
313 40 314 355
1 mCPBA
2 Ac2O pyr DMAP
+
315 75
1 TfOH MeCN
2 NaHCO3 O3 -78 oC
316 10 over 2 steps
1 Cl3 CCN NaH
2 MeOH BF3 OEt2
317 79
1 LiBH4 THF
2 Dowex-H+
311
312a312b
318 70 for 2 steps
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1427
products [64] The availability of different hydroxyl groupson each monosaccharide unit allowed the fine-tuning ofstereochemical outcome by selective positioning of the silyltether [65] Development of this early stereochemical controlled to the tethering of the donor 320 with alcohol 319through a di-isopropyl silicon tether 321 Subsequent treat-ment with Bu3SnH and AIBN led to a 9-endo-trigcyclization to form the C-disaccharide 322 in an 80 yieldwith exclusive formation of the α-product The silyl tetherwas removed with Bu4NF and deprotection under standardconditions afforded the desired disaccharide 323 in excellentyield (Scheme 55)
In parallel the development of a 32rsquo silyl tether allowedaccess to the β-linked product as demonstrated in Sinayumlrsquossynthesis of methyl β-C-lactoside 328 [66] Alcohol 324 and320 were connected via the dimethylsilyl tether an 8-endo-trig cyclization followed to exclusively afford the β-
disaccharide 326 in 45 yield Removal of the tether anddeprotection of benzyl ether gave β-C-disaccharide 328(Scheme 56)
This group also selected iodosugars bearing a freehydroxyl group as progenitors of the radical donors [67] In atypical experiment the radical donor 329 was connected tothe radical acceptor 330 through a silaketal tether followingtheir procedure Tributyltinhydride mediated 8-endo-trigradical cyclization of compound 331 gave after detetheringof the non isolated intermediate 332 the protected β-C-disaccharide 333 in 37 overall yield (from startingmaterials 330 and 329) Peracetate 335 was achieved afterhydrogenolysis The C-laminaribioside 334 is of potentialbiological interest as it mimics the repeating disaccharideunit of fungal β-(1rarr3)-glucans which have antitumor andimmunomodulating properties (Scheme 57)
Scheme (55)
Scheme (56)
OO
OHSePh
OTBDPSO O
OO
SePh
OTBDPSO
OO
OBnOMe
OBn
Si
O
HOOBn
OMe
OBn
O
HOOH
OHHO
O
HOOH
OMe
OH
OTBDPSO
O
HOOBn
OMe
OBnO
OOH
1 n-BuLi THF
2 iPr2SiCl2 -78 oC
3 DMAP THF rt
1 Bu4NF THF
2 Dowex-H+
3 H2 PdC
Bu3SnH AIBN toluene
319
320
321
322323
OBnO
OHSePh
OBnBnO
OHO
OBnOMe
OBn
ROO
ROOH
OR
OHO
OROMe
OR
OBnO
O
OBnBnO
OO
OBnOMe
OBn
Si
SePh
OBnO
O
OBnBnOO
OOBn
OMe
OBn
Si
1 PhSeH Me2SiCl2
BuLi -78 oC
2 imidazole rt
Bu3SnH AIBN toluene
H2 PdC327 R = Bn
328 R = H
Bu4NF THF
324
320
325
326 45
1428 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
CONCLUSIONS
In this paper the biological importance of C-oligo-saccharides as subunits of natural products and as a newgeneration of carbohydrate based on therapeutics has beenillustrated Different methods are available for the synthesisof C-oligosaccharides As with traditional saccharidesynthesis it has been necessary to develop a number ofspecific approaches to facilitate the regioselective andstereoselective preparation of the desired targets Work inthis area continues and it is expected that many interestingnew C-oligosaccharides will be prepared using the chemistrydescribed in this review It is also likely that new chemistrywill be developed in the future for the preparation of thesebiologically important targets
ACKNOWLEDGEMENTS
The authors thank Dr Sultan Baytas for her criticalreading of this manuscript
REFERENCES
[1] Kennedy J F White C A Bioactive Carbohydrates InChemistry Biochemistry and Biology Ellis Horwood LtdChichesterUK 1983
[2] Wassarman PW Mammalian Fertilization Molecular Aspects ofGamete Adhesion xocytosion Exocytosis and Fusion Cell 199996 175-183
[3] Carbohydrate-based Drug Discovery Wong C-H EdWeinheim Cambridge Wiley-VCH 2003
[4] (a) Sharon N Lis H Lectins as Cell Recognition MoleculesScience 1987 246 227-234 (b) Dwek RA Chem Rev 1996 96683-720
[5] Postema M C-Glycoside synthesis CRC Boc Ratom 1995[6] (a) Weatherman R V Mortell K H Cheruenak MKiessling
L L Toone E J Specificity of C-Glycoside Complexation byMannoseGlucose Specific Lectins Biochem 1996 35 3619-3624(b) Ravishankar R Surolia A Vijayan M Lim S Kishi YPreferred Conformation of C-Lactose at the Free and Peanut LectinBound States J Am Chem Soc1998 120 11297-11303
[7] (a)Wong C-H Halcomb R L Ichikawa Y and Kajimoto TEnzymes in organic synthesis Application to the problems ofcarbohydrate recognition part2 Angew Chem Int Ed Engl 199534 521-546 (b)Howard S Withers SG Bromoketone C-Glycosides a New Class of βminusGlucanase Inactivators J AmChem Soc 1998 120 10326-10331(c) Wang Q Wolff MPolat T Du Y Linhardt R J C-glycoside of Neuraminic Acidsas Neura-minidase Inhibitors Bioorg Med Lett 2000 10 941-944 (d) Phili R Chang J Partis R A Mueller R A ChrestF J Passaniti A The Alpha-glucosidase I InhibitorCastanospermine Alters Endothelial cell Glycosylation PreventsAngiogenesis and Inhibits Tumor Growth Cancer Res 1995 552927-2935
[8] Ossor A Elbein A D In Carbohydrates in Chemistry andBiology Vol 3(II) WileyVCH 2000 pp 513-539
[9] (a) Sinayuml P Synthesis of oligosaccharide Mimetics Pure ApplChem 1997 69 459-463 (b) Beau J-M Gallagher TNucleophilic C-glycosyl Donors for C-glycoside Synthesis Top inCurr Chem 1997 187 1-54 (c) Nicotra F Synthesis of C-glycosides of Biological Interest Top in Curr Chem 1997 187
Scheme (57)
O
O
O
Ph
I
OMe
OHO
BnO
OH
OH
BnOOH
O
BnO
Si
O
O O
Ph
I
OMe
O
O
BnO
OR4O
R5O
OMe
OR2
OR3O
R3O
OR1
R3O
Bu3 SnH AIBN
332 R1 R2 = SiMe2 R3 = Bn R4 R5 = CHPhTBAF THF
333 R1 = R2 = H R3 = Bn R4 = R5 = CHPh 37 from 11
334 R1 = R2 = R3 = R4 = R5 = H
335 R1 = R2 = R3 = R4 = R5 = Ac
329
H2 PdC MeOH
Ac2 O pyr
1 BuLi THF -78 oC
2 Me2SiCl2
3 DMAP
330
331
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1429
55-83 (d) Du Y Linhardt R Y Recent Adv in Stereo-SelectiveC-Glycoside Synthesis Tetrahedron Lett 1998 54 9913-9959 (e)Liu L Mckee M and Postema M H D Synthesis of C-saccharides and Higher Congeners Current Org Chem 2001 51133-1167
[10] Jarosz S Fraser-Reid B Synthesis of A Higher Carbon Sugar ViaDirected Aldol Condensation Tetrahedron Lett 1989 30 2359-2362
[11] Lichtenthaler F W Lergenmiiller M Schwidetzky S C-Glycosidations of 2-Ketohexosyl With Electrophilic Radical andNudeophilic Anomeric Carbons Eur J Org Chem 2003 3094-3103
[12] Baudat A Vogel P Aza-C-disaccharides Synthesis of 6-Deoxygalactonojirimycin-β-C(1rarr3) Linked with D-Altrofuranosides and D-Galactose J Org Chem 1997 62 6252-6260
[13] Turner D Vogel P Synthesis of 4-Hydroxy-26-Bis(hydroxymethyl) tetrahydropyran-2-Carbaldehyde DerivativesSynlett 1998 304-306
[14] Zhu Y-H Vogel P Short Stereoselective Synthesis of C-(1rarr3)-Linked Disaccharides Tetrahedron Lett 1998 39 31-34
[15] Zhu Y-H Vogel P Synthesis of a (2R 6R)-2-(Hydroxymethyl)-6-Propa-1 2-Dienyl-2H-Pyran-3(6H)-One Derivative A NewEnone for The Convergent Construction of C-Glycosides of C-Disaccharides Synlett 2001 82-86
[16] Baumberger F Vasella A Deoxynitrosugars The 6th
Communication Stereolectronic Control in the reductivedenitration of tertiary nitro ethers A Synthesis of ldquoC-glycosidesrdquoHelv Chim Acta 1983 66 2210-2221
[17] Martin O R Lai W Synthesis and Conformational Studies of β-(1rarr6)- and ββ-(1rarr1)-Linked C-disaccharides J Org Chem1993 58 176-185
[18] Spak S J Martin R The synthesis of an analogue of Methyl OC-Analogue of Methyl 4rsquo-O-β-D-GlucopyranosylgentiobiosideTetrahedron 2000 56 217-224
[19] Kobertz W R Bertozzi C R Bednarski M D C-GlycosylAldehyde Synthons for C-Linked Disaccharides J Org Chem1996 61 1894-1897
[20] Gurjar M K Nagaprasad R and Ramana CV First Synthesis ofMethyl α-C-D-Arabino-furanosyl-(1rarr5)-αminusD-Arabinofuranosidethe C-Disaccharide Segment of Motif C of MycobateriumTuberculosis Tetrahedron Lett 2000 43 7577-7579
[21] Witczak Z J Synthesis of C-Glycosyl Compounds and OtherNatural Products from Levoglucosenone Pure Appl Chem 199466 2189-2192
[22] Griffin F K Paterson D Taylor R J K Ramberg-BacklundApproaches to the Synthesis of C-Linked Disaccharides AngewChem Int Engl 1999 38 2939-2942
[23] Paterson B E Griffin F K Alcaraz M-L and Taylor R J KA Ramberg-Baumlcklund Approach to the Synthesis of C-GlycosidesC-Linked Disaccharides and C-Glycosyl Amino Acids Eur JOrg Chem 2002 1323-1336
[24] McAllister G D Paterson D E Taylor R J K A SimplifiedRamberg-Bachlund Approach to Novel C-Glycosides and C-Linked Disaccharides Angew Chem Int Ed Engl 2003 42 1387-1391
[25] McCartney J L Christopher T M Cicchillo R M BernardinaM D Wagner T R and Norris P J Org Chem 2003 6810152-10155
[26] Dondoni A Zuurmond H M Bascarate A Synthesis of α-andβ-D-(1rarr6)-C-Disaccharides by Witting Olefination of Formyl C-Glycosides with Glycopyranose 6-phosphoranes J Org Chem1997 62 8114-8124
[27] Dondoni A Kleban M Zuurmond H Marra A Synthesis of(1rarr6)-C-Oligogalactosides by Interative Wittig OlefinationTetrahedron Lett 1998 39 7991-7994
[28] Dondoni A Marra A A New Synthetic Approach toMycobacterial Cell Wall α-(1rarr5)-D-Arabinofuranosyl C-Oligosaccharides Teterahedron Lett 2003 44 4067-4071
[29] Colinas P A Ponzinibbio A Lieberknecht A and Bravo R OWittig Reaction of Glycosyl Phosphonium Salts A StereoselectiveRoute to C-Disaccharides and C O-Trisaccharides TetrahedronLett 2003 44 7985-7988
[30] Schmidt R R Preuss R Synthesis of Carbon Tetrahedron Lett1989 30 3409-3412
[31] Dietrich H Schmidt R R Synthesis of Carbon-Bridged C-Lactose and Derivatives Liebigs Ann Chem 1994 975-981
[32] Rouzaud D Sinayuml P The First Synthesis of a ldquoC-DisacchariderdquoJ Chem Soc Chem Commun 1983 1353-1354
[33] Xin Y-C Zhang Y-M Mallet J-M Glaudemans C P JSinayuml P Synthesis of C-Oligosaccharides That Mimie TheirNatural O-Analogues Immunodeterminants in Binding toMonoclonal Immunoglobulins Eur J Org Chem 1999 471-476
[34] Streicher H Geyer A Schmidt R R C-Disaccharides ofKetoses Chem Eur J 1996 2 502-510
[35] Leeuwenburgh M A Timmers C M Vander Marel G A VanBoom J H Mallet J-M Sinayuml P G Stereoselective Synthesisof α-C-(Alkynyl)-Glycosides Via Ring-Opening of α-12-Anhydrous Tetrahedron Lett 1997 38 6251-6254
[36] Aslam T Fuchs M G G Le Formal A Wightman R HSynthesis of C-Disaccharide Analogue of the α-D-Arabinofuranosyl-(1rarr5)-α-Arabinofuranosyl Motif ofMycobacterial Cells Walls via Alkynyl Intermediates TetrahedronLett 2005 46 3249-3252
[37] (a) Girad P Namy J L Kagan H B Divalent LanthanideDerivative in Organic Synthesis 1 Mild Preparation of SamariumIodide and Ytterbium Iodide and Their Use as Reducing orCoupling Agents J Am Chem Soc 1980 102 2693-2698 (b)Molander G A Harris C R Sequencing Reactions withSamarium(II) Iodide Chem Rev 1996 96 307-338
[38] (a) Mazeacuteas D Skrydstrup T Doumeix O Beau J-MSamarium Iodide-Induced Intramolecular C-Glycoside FormationEfficient Radical Formation in the Absence of an Additive AngewChem Int Ed Engl 1994 33 1383-1386 (b) Mazeacuteas DSkrydstrup T Beau J-M A Highly Stereoselective Synthesis of1 2-trans-C-Glycosides Via Glycosyl Samarium(III) CompoundsAngew Chem Int Ed Engl 1995 34 909-912 (c) Jarreton OSkrydstrup T Beau J-M The Stereospecific Synthesis of Methylα-C-Mannobioside A Potential Inhibitor of M TuberculosisBinding to Human Macrophages J Chem Soc Chem Commun1996 1661-1662 (d) Jarreton O Skrydstrup T Espionosa J-FJimeacutenez-Barbero J Beau J-M Samarium Diiode Prompted C-Glycosylation An Application to The Stereospecific Synthesis ofα-(1rarr2)-C-Mannobioside and Its Derivatives Chem Eur J 19995 430-441 (e) Mipuel N Doisneau G Beau J-M ReductiveSamariation of Anomeric 2-Pyridyl Sulfones with Catalytic AnUnexpected Improvement in The Synthesis of 12-Trans-Diequatorial C-Glycosyl Compounds Angew Chem Int Ed Engl 2000 39 4111-4114
[39] Vlahov I R Vlahova P I Linhardt R J DiastereocontrolledSynthesis of Carbon Glycosides of N-Acetylneuraminic Acid ViaGlycosyl Samarium(III) Intermediates JAmChem Soc 1997 1191480-1481
[40] Kuberan B Sikkander S ATomiyama H Linhardt R JSynthesis of a C-Glycoside Analogue of sTn An HIV-and Tumor-Associated Antigen Angew Chem Int Ed Engl 2003 42 2073-2075
[41] Bazin H G Du Y Polat T Linhardt R J Synthesis of aVersatile Neuraminic Acid ldquoCrdquo-Disaccharide Precursor for theSynthesis of C-Glycoside Analogues of Gangliosides J OrgChem 1999 64 7254-7259
[42] Chen C-C Ress D K Linhardt RJ Samarium Iodide-Mediated Synthesis of Neuraminic Acid C-Glycosides InSynthesis of Glycommetics Roy R Ed ACS Syposium Series2004 896 53-80
[43] Abdallah Z Doisneau G Beau J-M Synthesis of a Carbon-Linked Mimic of The Disaccharide Component of The Tumor-Relate SialyTn Antigen Angew Chem Int Ed Engl 2003 425209-5212
[44] Lay L Nicotra F Panza L Russo G Caneva E Synthesis ofC-disaccharides through dimerization of exo-glycals J Org Chem1992 57 1304-1306
[45] Isobe M Nishizawa R Hosokawa S Nishikawa TStereocontrolled Synthesis and Reactivity of Sugar Acetylenes JChem Soc Chem Commun 1998 2665-2676
[46] Saeeng R Sirion U Sahakitpichan P Isobe M IodineCatalyzes C-Glycosidation of D-Glucal with SilylacetykeneTetrahedron Lett 2003 44 6211-6215
[47] (a) Babirad S A Wang Y Kishi Y Synthesis of C-Disaccharides J Org Chem 1987 52 1370-1372 (b) Wang YBabirad S A Kishi Y Preferred Conformation of C-Glycosides
1430 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
8 Synthesis of 14-Linked Carbon Disaccharides J Org Chem1992 57 468-481
[48] Armstrong R W Sutherlin D P Strategies for the Synthesis ofC-Disaccharides Containing D and L Sugars Tetrahedron Lett1994 35 7743-7746
[49] Wei A Kishi Y Preferred Conformation of C-Glycosides 12Synthesis and Conformational Analysis of αα- α β- and β β-Trehaloses J Org Chem 1994 59 88-96
[50] Haneda T Goekjian P G Kim S H Kishi Y PreferredConformation of C-Glycosides 10 Synthesis and ConformationAnalysis of Carbon Trisaccharides J Org Chem 1992 57 490-498
[51] Sutherlin D P Armstrong R W Synthesis of 12 Stereochemistryand Structurally Diverse C-Trisaccharides J Org Chem 1997 625267-5283
[52] Notz W Hartel C Waldscheck B Schmidt R R De NovoSynthesis of a Methylene-Bridged Neu5Ac-α-(23)-Gal C-Disaccharide J Org Chem 2001 66 4250-4260
[53] (a) Postema M H D Calimente D Liu L Behrmanm T L AnOlefin Metathesis Route for the Preparation of (1rarr6)-Linked-C-Disaccharide Glycals A Convergent and Flexible Approach to C-Saccharide Synthesis J Org Chem 2000 65 6061-6068(b) Postema M H Piper J L Liu L Faust M Andreana PSynthesis and Partial Biological Evaluation of a Small Library ofDifferentially Linked β-C-Disaccharide J Org Chem 2003 684748-4754
[54] Nelson A The Development of Strategies and Methods for TheSynthesis of Biologically Active Compounds New J Chem 200428 771-776
[55] Togo H He W Waki Y Yokoyama M C-GlycosylationTechnology With Free Radiant Reactions Synlett 1998 700-717
[56] Giese B Dupuis J Diastereoselective Synthesis of C-Glycopyranosides Angew Chem Int Ed Engl 1983 22 622-623
[57] Adlington R M Baldwin J E Basak A Kozyrod RPApplication of Radical Addition Reactions to tho Synthesis of a C-Glucoside and A Functionalized Amino Acid J Chem SocChem Commun 1983 144-145
[58] Giese B Gonzaacutelez-Goacutemez J A Witzel T The Scope of RadicalCC-Coupling by The ldquoTin Methodrdquo Angew Chem Int Ed Engl1984 23 69-70
[59] Giese B Witzel T Synthesis of ldquoC-Disaccharidesrdquo by RadicalC-C Bond Formation Angew Chem Int Ed Engl 1986 25 450-451
[60] Witczak Z J Chhabra R Chojnacki J C-Disaccharides IStereoselective Approach to β-(1rarr4)-3-Deoxy-C-Disaccharidesfrom Levoglucosenone Carb Res 1997 301 167-175
[61] Vogel P Synthesis of Rare Carbohydrates and Analogues Startingfrom Enantiomerically Pure 7-Oxabicyclo[221]heptyl Derivatives(ldquoNaked Sugarsrdquo) Current Org Chem 2000 4 455-480
[62] Viodeacute C Vogel P Synthesis of The C-Disaccharide α-C(1rarr3)-L-Fucopyranoside of N-Acetylgalactosamine J Carb Chem2001 20 733-746
[63] Xin Y C Mallet J M Sinayuml P An Expeditious Synthesis of AC-Disaccharide Using A Temporary Silaketal Connection J ChemSoc Chem Commun 1993 864-865
[64] (a) Petitou M Herault P Lormeau J-C Helmboldt A MalletJ-M Sinayuml P Herbert J-M Introducing A C-InterglycosidicBond in A Biologically Active Pentasaccharide Hardly Affects ItsBiological Properties Bioorg Med Chem 1998 6 1509-1516 (b)Sinayuml P Advances in The Synthesis of the Carbohydrate MimicsPure Appl Chem 1998 70 1495-1499
[65] Sinayuml P Chemical Synthesis of Oligosaccharide Mimetics PureAppl Chem 1998 70 407-410
[66] Sinayuml P Chemical Synthesis of Oligosaccharide Mimetics PureAppl Chem 1998 69 459-463
[67] Vauzeilles B Sinayuml P Selective Radical Synthesis of β-C-Disaccharides Tetrahedron Lett 2001 42 7269-7272
1418 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
efficient Nozaki-Kishi coupling of vinyl bromide 241 withaldehyde 242 in a diasteromeric ratio of 12 followed byprotection with TBSOTf led to 243 and 244 Hydroborationfollowed by oxidation gave aldehydes 245 and 246respectively Addition of allylmagnesium bromide toaldehyde 245 followed by removal of the silyl groupafforded 247 to 246 giving 248 and 249 Epoxidation gave a11 mixture of the corresponding epoxides which werecyclized to give the C-trisaccharide 250-255 after removalof the benzyl groups (Scheme 47)
Schmidt reported a stereoselective 6-exo-trig selectiveelectrophilic cylization approach for de novo synthesis of amethylene-bridged Neu5Ac-α-(23)-Gal C-disaccharide theC-analog of an important motif in glycosphingolipids [52]The open chain precusors 259ab (a 32-mixture ofdiaseteromeric alcohols) were formed by the addition oflithiated iodide 256 to open chain aldehyde 258 Subsequent
C1 incorporation using Tebbe-reagent formation of a cycliccarbonate and deprotection of the two isopropylidene ketalsafforded tetrol 264 which upon treatment with phenylselenyltrifilate was steroselectively cyclized in a 6-exo-trigselective manner affording a diasteromeric mixture of 251and 252 in a ratio of 71 A seleno-Pummerer rearrangementto afford aldehyde 267 in 5 steps in 90 overall yieldOxidation of the aldehyde and subsequent steps led to thedesired C-disaccharide 268 (Scheme 48)
53 Esterification-Cyclization
Work from the Postema group has focused on a ringclosing metathesis (RCM) approach for the synthesis of C-saccharides [53a] The chemistry is versatile and has beenused for the synthesis of a small library of differentiallylinked β-C-disaccharides through a radical allylation-RCMstrategy [53b] The synthesis of the β-(1rarr4)-glucopyranosyl
Scheme (45)
O
OBn
BnO
BnO
BnO
I
CrCl2-NiCl2O
OBn
OH
BnO
BnO
BnO
O
O
O
O
O
H
OBn
O
O
OBnBnO
BnO
BnO
OOBn
OBn
OAc
PMBOHOO
OBn
BnO
BnO
BnO
O
OBn
OBn
OAc
O
OH
HO
HO
HO
OH
OH
OH
O
OH
O
OBn
BnO
BnO
BnO
OBn
OBn
OAc
O
MMTr
+
1 p-TsOH2 K2CO3 MeOH3 MMTrCl pyr
1 Swern [O]2 BH3 THF
3 AcOH-H2 O4 H2 Pd(OH)2
221
222
223
1 Pd-Pb CaCO3 H22 NaH BnBr3 OsO44 Bu2 SnO5 CsF PMB-Cl6 Ac2 O 4-DMAP
1 AcOH2 TsCl pyr
3 NaH-imid4 DDQ
224225
226 227
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1419
Scheme (46)
OBnO O
OBn
OMe
OBn
XY
SMe
OBnBnO
O
OBn
OBn
OBn
OBn
O
BnO
YX
OBn
TBSO
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnOOBn
H
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnO
OBn
OHC OBn
OBn
OTBS
OMe
BnOOBn
CHO
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnOOBn
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnO
OBn
YX
OBnO O
OBn
OMe
OBn
OBn
O
BnO
O
OBn
OBn
OBn
OBn
O 1 LiHMDS
2
228
1 TBAF THF
2 MeSH BF3 OEt2
230 X = OH Y = H231 X = H Y = OH
230231 41
1 Bu3SnH AIBN2 Swern [O]
1 LiHMDS THF-TMEDA2 MgBr23
1 MsCl
2 liquid NH3
235 X = OH Y = H236 X = H Y = OH Bu3 SnH AIBN
237a and 237b
NaBH4 MeOH
238
239 X = OBn
240 X = OHH2 Pd(OH)2
229
232233
234
1420 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (47)
OH C
O
O BnAcHN
OO
O
OBn OBnOBn
Br
O
OBn OBnOBn
O
OBnA cHN
OO
O TBSO
OBn O BnO Bn
O
OBnAcHN
OO
OTBS
S2
S1
S2
OTBSS1
O H
S2
OT BSS1
O H
MgBrMgBr
S2
O TBSS1
O H
S2
OHS1
OH
S2
OTBSS1
OH
O
OHHO
O H
O
HO
H OO
OBnA cH N
HO
H O
O
O HHO
OH
O
HOHO
O
OBnA cH N
HO
H O
O
OHH O
OH
O
H O
HOO
OBnAcHN
HO
HO
O
O HH O
OH
O
H O
H O O
OBnA cHN
HO
HO
O
O HH O
O H
O
HO
H O O
OBnAcHN
HO
HO
O
OHHO
OH
O
H O
O
OBnA cHN
HO
HOHO
+
241 242
1 CrCl2-NiCl2 T HF-DMF 722 TBSOTf 2 6-lutidine 91
243 244
1 9-BBN 602 Dess-Mart in period inane 97
1 9 -BBN 552 D ess-Martin periodinane 98
245 246
1
2 T BAF 74
1
2 TBAF 88
247 248 249
250
251
250 251 1 1 252 253 1 1 254 255 1 1
252
253
254
255
1 MCPBA2 CSA CH 2Cl2 61 fo r 2 steps3 H 2 Pd (O H)2C 95
1 MCPBA2 CSA CH 2Cl2 63 fo r 2 s teps3 H 2 Pd (OH)2C 87
1 MCPBA2 CSA CH2Cl2 80 for 2 steps3 H2 Pd(O H)2C 95
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1421
Scheme (48)
O
OO
Se Ph
R
O
HO OHOH
O
OB n O B n
OB n
O B nO O
O O
R O OR
X
O
OO
R
Se Ph
O
HOOH
OH
O
OB nOB n
O Bn
OB n
O O
O O
R O O R
O H
O
O B n OB n
O B n
OB n
O
C HO
O
O O
R O OR
OAc HN
OAc
C O2NH 4HOOH
OH
O
OH O H
OH OH
O
OB n O B n
OB n
OB nO O
O O
R O OR
X
O
O
OAcOAc
C HOA cOOAc
OAc
O
OB n O B n
OB n
OB n
O
O Bn OB n
OB n
OB n
X
OH
OO
HOOH
OH
O
O
OMeOB n
OB nOB n
R
t-B uL i256 R = Li
257 R = L i
258
(R = t-B uMe 2Si )
(R = t-B uMe 2Si )
259ab (32) 79 com bine d yi eld
De ss-Ma rtin pe riodinane
260 X = O R = t-B uMe 2Si ) 95
261 X = O R = t -B uMe2S i) 62
T e bbe re age nt
TB A F THF262 X = O R = H 94
diphosge ne
C H2C l 2Pyr
263 95
T HFH2O T FAr t
264 quant it a ti ve yie ld
PhSe C l AgOT f
EtC N -80 oC
265
266
Quant it at i ve yi l ed 25 26 7 1
+
R =
1 Ac 2OPyr
2 mC PB A3 Ac 2ONa OAc
4 NaO HT HFMe OH
5 Ac2O P yr
267 90 overa ll yi e ld
ste ps
268
1422 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
glucopyranoside 280 represents an example of thischemistry The known triacetyl glucopyranoside 269 wasconverted to iodide 270 in good yield Radical allylation of271 proceeded to afford a mixture of equatorial and axialallylation products in a 61 ratio Oxidative cleavage of thedouble bond gave the corresponding aldehydes 273a and273b which were separable Pinnick oxidation of the majoraldehyde 273a then gave the C-4 equatorial acid 274 DCC-mediated coupling of alcohol 275 and acid 274 proceeded toafford ester 276 in good yield Methylenation of 276 gave277 and exposure to catalysist 278 gave a 41 yield of theC-disaccharide glycal which was exposed to an excess ofBH3
THF to give 64 yield of the β-C-disaccharide 279Removal of the benzyl groups and global peracetylation gavethe peracetylated (1rarr4)-β-C-disaccharide 281 in good yield(Scheme 49)
54 Ring Expansion-Cyclization
Nelson developed a new strategy for asymmetric andstereoselective synthesis of C-linked disaccharide mimeticsthe C58-C71 fragment of palytoxin [54] The diol (RR)-282was converted into the di-dihydropyran (DHP) template 283284 and 285 The di-DHPs were functionized in a twodirectional sense using dihydroxylation reactions The two-directional approach was often very efficient indeed forexample in the synthesis of 286 six new stereogenic centerswere introduced with almost complete stereocontrol using areduction and a dihydroxylation reaction The approach isnot restricted to the synthesis of C2-symmetricaldisaccharide mimetics Using the unsymmetrical template285 which has both a pseudo-axial and a pseudo-equatorialhydroxyl groups the unsymmetrical mimetics 289 and 290were prepared (Scheme 50)
6 RADICAL APPROACHES
The radical approach for C-C bond formation is a popularmethod within organic chemistry The use of radicalchemistry in carbohydrate synthesis has certain advantagesFirstly the reaction conditions are very mild and tolerant ofa range of functional and protecting groups Secondanomeric radicals are stable with respect to elimination andepimeration Most significantly the chemistry required toincorporate an appropriate substitute at C-1 employed in theinitial hemolytic cleavage step is common within carbo-hydrate chemistry [55] The use of such radical techniquecan be subdivided into two classes intermolecular andintramolecular approaches
61 Intermolecular Radical Approaches
Giese was the first to employ an intermolecular radical-based approach for synthesis of C-disaccharides [56]Addition of an alkene to an anomeric radical underappropriate conditions allowed exclusive entry to the α-linked C-glycoside a result which was mirrored by the workof Baldwin [57] The high α-selectivity of the reaction wasin contrast with other reports Thus radicals generated at theC-2 C-3 and C-4 centers all preferred to occupy equatorialpositions [58] When the anomeric bromide 291 was treatedwith tin hydride and AIBN resulting anomeric radical andreacted with lactone 292 in a Michael addition it afforded293 In this reaction hydrogen abstraction at the resulting
radical center occurs from axial face to selectively generatethe equatorial C-2rsquo substituent Reduction and acetylation of293 furnished C-disaccharide 294 (Scheme 51) [59]
Witczak used the facial bias of levoglucosene tostereoselectively add a carbohydrate-based radical in thepreparation of the 3-deoxy-(1rarr4)-β-C-disaccharide 299[60] Addition of the radical derived from iodide 295 to 296gave adduct 297 in 26 yield Removal of the anomerichydroxyl of 297 was achieved by treatment with triethylsilane borontrifluoride ether complex followed bystereoselective reduction of the keto function at C-2rsquo withthe formation of 298 in 89 yield Debenzylation followedby acetolysis of 16-anhydro ring produced the peracetylatedtarget C-disaccharide 299 in 19 overall yield from 295(Scheme 52)
Vogel has developed general methods to transformenantiomerically pure 7-oxabicyclo[221]heptyl derivatives(ldquonaked sugarsrdquo) into C-disaccharides Because of thesechiral bicyclic skeletons they undergo highly stereoselectivereactions with predictable diasteroselectivities An arsenal ofmethods is available that allow to substitute these ldquonakedrdquocarbon centers with a variety of functional groups with allpossible relative configurations The methods allowpreparation of both enantiomers of a given target with thesame ease Predictably high stereoselectivity of the reactionsof the bicyclic chirons adds to the flexibility of approachwhich can lead to high molecular diversity [61]
α-C-(1rarr3)-mannopyranoside of N-acetyl-galactosaminepotent β-galactosidase inhibitors was synthesized by thisapproach [61] Enone 302 was readily prepared from 300The addition of the radical derived from bromide 303 toenone 302 afforded the αminusisomer 304 The ketone was thenreduced and the selenide eliminated via the intermediacy ofthe selenoxide to give 305 Acid-promoted (CF3SO3H) 7-oxa ring opening of 305 in MeCN produced the amino-conduritol derivative 306 resulting from the quenching of theallylic cation intermediate by the solvent (Ritter reaction)Ozonolysis of the chloroalkene 306 generated an acylchloride-aldehyde intermediate that reacted with MeOH toproduce a mixture of methyl uronates The major compound307 was silylated and reduced The crude polyol obtainedwas acetylated to produce 308 Desilylated and ammonolysisafforded a mixture of α-β-pyranoses 309 and correspondingα-β-furanoses (Scheme 53)
Similar chemistry was carried out to synthesize non-protected α-C(1rarr2)-L-fucopyranoside of D-galactopyrano-side corresponding to a blood group mimetic [62] Giesersquosradical fucosidation of racemic enone 310 with α-L-bromoacetofucose 311 provided the mixture of diastereo-meric α-C-fucoside 312a and 312b in reproducible yield of78 Reduction of the mixture gave a 11 mixture of endo-alcohols 313 and 314 which were isolated pure in 40 and355 yield respectively Oxidative elimination of thebenzeneselenyl group of 313 followed by acetylation gaveendo acetate 315 in 85 yield Acid-promoted ring openingof 315 and ozonolysis of the resulted chloroalkene gavemethyl uronic ester 316 in modest yield (10) Treatment of316 with Cl3CCN and NaH followed with BF3
OEt2
furnished the totally protected C-disaccharide 317 in 79
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1423
Scheme (49)
Bu3SnO
HOAcO
OMeOAc
OAc
O
AcO
OMeOAc
OAcI
AIBN
O
AcO
OMeOBn
OBn
HO2C O
AcO
OMeOR
ORY
X
OHBnO
BnO
OBn
OBnO
BnO
OBn
O
AcO
OMeOBn
OBnX
i-Pr i-Pr
N
Mo C(Me2 Ph)((CF3)2 MeCO)2
O
RO
OMeOR
O
RO
OR
OR
RO
OR
278
I2 Ph3P
imidazole
269 270 93
271a X = CH2CH=CH2 Y = H R = Ac 64271b Y = CH2CH=CH2 X = H R = Ac 11272a X = CH2CH=CH2 Y = H R = Bn 75272b Y = CH2CH=CH2 X = H R = Bn 75273a X = CH2CHO Y = H R = Bn 79273a Y = CH2CHO X = H R = Bn 79
1 NaOMe MeOH2 NaOH BnBr DMF
OsO4 NaIO4
NaClO2 NaH2PO4
274 96
275
DCC 4-DMAP
276 X = O 82
277 X = CH2 51
TiCl4 Zn dust TMEDA CH2Br2PbCl2 (Cat )
1
2 BH3 THF H2O2 NaOH
H2 PdC EtOH
Ac2 O Pyr 4-DMAP
279 R = Bn R = H 64
280 R = R = H 99
281 R = R =Ac 97
1424 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (50)
Scheme (51)
O OOH
OH
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
286
1 VO(acac)2 t-BuOH 95
2 (MeO)3CH BF3 90
1 P-O2NC6H4 CO2H Ph3P DIAD2 K2CO3 MeOH 82 over 2 steps
1 PhCOCl Et3N DMAP 402 P-O2NC6H4 CO2H Ph3P DIAD3 KOH THF-H2O 75 over 2 steps
TMEDA OsO4
Cat OsO4 NMO 287
Cat OsO4 NMO288
TMEDA OsO4
Cat OsO4 NMO
290
289
(RR)-282283
284
285
OHO
AcO
BrOAc
OAc
BnO
O
OBn
OBnO
OHO
AcOOAc
OAc
BnO
OOBn
OBnAcO
OHO
AcOOAc
OAc
BnO
O
OBn
OBnO
+
Bu3SnH AIBN291
292
293 81
1 Na[Al(OC2H4OMe)2(OEt)H]2 Ac2O pyr
294 56 over 2 steps
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1425
Scheme (52)
Scheme (53)
OBnO
BnOOBn
OBn O
OH
O
OBnO
BnO
OHOBn
OBn O
O
O
O
O
O
OBnO
BnOOBn
OBnO
OAcOAc
OAc
OBnO
BnO
OHOBn
OBn
IBu3SnH AIBN
295 297 26
1 BF3 OEt2 Et3SiH
2 L-Selectride THF
1 Pd(OH)2C C6H10 EtOH
2 EtSiOSO2CF3 Ac2O
298 89 over 2 steps299
296
O
O
PhSeClO
O
PhSeCl
Bu3 SnH
O
O
PhSeCl
R
H
O
OAc
R
Cl
O
AcO
OAc
OAc
OAcOH
Cl
NHAc
R
OAc
AcHN
OH
O
OH OAc
OH
OHO
HO
OH
O
AcO
OAc
OAc
OAcBr
O
O
PhSeCl
O
O
PhSeCl
R
O
OTIPSAcHNR
OAc OAc
O
OHAcHN
COOMe
R
OAc
1 Bu4NF
2 NH3MeOH
1 (Me3Si)2NLi THF2 Me2N=CHI
1 Bu3 SnH AIBN2
1 NaBH42 mCPBA3 Ac2O pyr
1 H+ MeCN
2 H2 O NaHCO3
R =
1 O3MeOH
2 Me2S NaHCO3
1 TIPSOTf 26-lut idine2 LiBH43 Ac2 O pyr DMAP
furanoses +
304 56
305 68 306 84307 50
308 46
300 301 302
303
309
1426 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
The reduction of 317 and treatment with DOWEX-H+ resinprovided the desired C-fucoside 318 in 70 (Scheme 54)
62 Intramolecular Radical Approaches
One disadvantage with the intermolecular approaches isthat during such radical mediated reactions electrondeficient alkenes are required to facilitate C-C bondformation The intramolecular approach of Sinayuml overcomes
this drawback by bring two substrates together via atemporary covalent silaketal connector This enables the useof a wider range of alkenes which can include alkene-functionalized sugars thus leading to the generation of C-disaccharides [63] Based on the early work of Stork Sinayumlemployed the tether reaction in the synthesis of both α- andβ-C-disaccharides with this work subsequently beingemployed in the synthesis of biologically significant natural
Scheme (54)
O
OH
Fuc
Cl
O
O
ClPhSe
OOAc
NHAcOHFuc
O
AcOOAc
AcO
Br
O
O
PhSeCl
O
AcOOAc
AcO
O
OH
PhSe Cl
Fuc
OOAc
NHAc
OMe
Fuc
O
AcHN
OH OAc
OH
O
OH
Me
OH
O
O
Fuc
ClSePh
O
HO
Fuc
ClSePh
+
Ph3SnHAIBN
78 combined yield
Fuc
310
+
1 NaBH4 MeOHTHF2 Chromatography
313 40 314 355
1 mCPBA
2 Ac2O pyr DMAP
+
315 75
1 TfOH MeCN
2 NaHCO3 O3 -78 oC
316 10 over 2 steps
1 Cl3 CCN NaH
2 MeOH BF3 OEt2
317 79
1 LiBH4 THF
2 Dowex-H+
311
312a312b
318 70 for 2 steps
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1427
products [64] The availability of different hydroxyl groupson each monosaccharide unit allowed the fine-tuning ofstereochemical outcome by selective positioning of the silyltether [65] Development of this early stereochemical controlled to the tethering of the donor 320 with alcohol 319through a di-isopropyl silicon tether 321 Subsequent treat-ment with Bu3SnH and AIBN led to a 9-endo-trigcyclization to form the C-disaccharide 322 in an 80 yieldwith exclusive formation of the α-product The silyl tetherwas removed with Bu4NF and deprotection under standardconditions afforded the desired disaccharide 323 in excellentyield (Scheme 55)
In parallel the development of a 32rsquo silyl tether allowedaccess to the β-linked product as demonstrated in Sinayumlrsquossynthesis of methyl β-C-lactoside 328 [66] Alcohol 324 and320 were connected via the dimethylsilyl tether an 8-endo-trig cyclization followed to exclusively afford the β-
disaccharide 326 in 45 yield Removal of the tether anddeprotection of benzyl ether gave β-C-disaccharide 328(Scheme 56)
This group also selected iodosugars bearing a freehydroxyl group as progenitors of the radical donors [67] In atypical experiment the radical donor 329 was connected tothe radical acceptor 330 through a silaketal tether followingtheir procedure Tributyltinhydride mediated 8-endo-trigradical cyclization of compound 331 gave after detetheringof the non isolated intermediate 332 the protected β-C-disaccharide 333 in 37 overall yield (from startingmaterials 330 and 329) Peracetate 335 was achieved afterhydrogenolysis The C-laminaribioside 334 is of potentialbiological interest as it mimics the repeating disaccharideunit of fungal β-(1rarr3)-glucans which have antitumor andimmunomodulating properties (Scheme 57)
Scheme (55)
Scheme (56)
OO
OHSePh
OTBDPSO O
OO
SePh
OTBDPSO
OO
OBnOMe
OBn
Si
O
HOOBn
OMe
OBn
O
HOOH
OHHO
O
HOOH
OMe
OH
OTBDPSO
O
HOOBn
OMe
OBnO
OOH
1 n-BuLi THF
2 iPr2SiCl2 -78 oC
3 DMAP THF rt
1 Bu4NF THF
2 Dowex-H+
3 H2 PdC
Bu3SnH AIBN toluene
319
320
321
322323
OBnO
OHSePh
OBnBnO
OHO
OBnOMe
OBn
ROO
ROOH
OR
OHO
OROMe
OR
OBnO
O
OBnBnO
OO
OBnOMe
OBn
Si
SePh
OBnO
O
OBnBnOO
OOBn
OMe
OBn
Si
1 PhSeH Me2SiCl2
BuLi -78 oC
2 imidazole rt
Bu3SnH AIBN toluene
H2 PdC327 R = Bn
328 R = H
Bu4NF THF
324
320
325
326 45
1428 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
CONCLUSIONS
In this paper the biological importance of C-oligo-saccharides as subunits of natural products and as a newgeneration of carbohydrate based on therapeutics has beenillustrated Different methods are available for the synthesisof C-oligosaccharides As with traditional saccharidesynthesis it has been necessary to develop a number ofspecific approaches to facilitate the regioselective andstereoselective preparation of the desired targets Work inthis area continues and it is expected that many interestingnew C-oligosaccharides will be prepared using the chemistrydescribed in this review It is also likely that new chemistrywill be developed in the future for the preparation of thesebiologically important targets
ACKNOWLEDGEMENTS
The authors thank Dr Sultan Baytas for her criticalreading of this manuscript
REFERENCES
[1] Kennedy J F White C A Bioactive Carbohydrates InChemistry Biochemistry and Biology Ellis Horwood LtdChichesterUK 1983
[2] Wassarman PW Mammalian Fertilization Molecular Aspects ofGamete Adhesion xocytosion Exocytosis and Fusion Cell 199996 175-183
[3] Carbohydrate-based Drug Discovery Wong C-H EdWeinheim Cambridge Wiley-VCH 2003
[4] (a) Sharon N Lis H Lectins as Cell Recognition MoleculesScience 1987 246 227-234 (b) Dwek RA Chem Rev 1996 96683-720
[5] Postema M C-Glycoside synthesis CRC Boc Ratom 1995[6] (a) Weatherman R V Mortell K H Cheruenak MKiessling
L L Toone E J Specificity of C-Glycoside Complexation byMannoseGlucose Specific Lectins Biochem 1996 35 3619-3624(b) Ravishankar R Surolia A Vijayan M Lim S Kishi YPreferred Conformation of C-Lactose at the Free and Peanut LectinBound States J Am Chem Soc1998 120 11297-11303
[7] (a)Wong C-H Halcomb R L Ichikawa Y and Kajimoto TEnzymes in organic synthesis Application to the problems ofcarbohydrate recognition part2 Angew Chem Int Ed Engl 199534 521-546 (b)Howard S Withers SG Bromoketone C-Glycosides a New Class of βminusGlucanase Inactivators J AmChem Soc 1998 120 10326-10331(c) Wang Q Wolff MPolat T Du Y Linhardt R J C-glycoside of Neuraminic Acidsas Neura-minidase Inhibitors Bioorg Med Lett 2000 10 941-944 (d) Phili R Chang J Partis R A Mueller R A ChrestF J Passaniti A The Alpha-glucosidase I InhibitorCastanospermine Alters Endothelial cell Glycosylation PreventsAngiogenesis and Inhibits Tumor Growth Cancer Res 1995 552927-2935
[8] Ossor A Elbein A D In Carbohydrates in Chemistry andBiology Vol 3(II) WileyVCH 2000 pp 513-539
[9] (a) Sinayuml P Synthesis of oligosaccharide Mimetics Pure ApplChem 1997 69 459-463 (b) Beau J-M Gallagher TNucleophilic C-glycosyl Donors for C-glycoside Synthesis Top inCurr Chem 1997 187 1-54 (c) Nicotra F Synthesis of C-glycosides of Biological Interest Top in Curr Chem 1997 187
Scheme (57)
O
O
O
Ph
I
OMe
OHO
BnO
OH
OH
BnOOH
O
BnO
Si
O
O O
Ph
I
OMe
O
O
BnO
OR4O
R5O
OMe
OR2
OR3O
R3O
OR1
R3O
Bu3 SnH AIBN
332 R1 R2 = SiMe2 R3 = Bn R4 R5 = CHPhTBAF THF
333 R1 = R2 = H R3 = Bn R4 = R5 = CHPh 37 from 11
334 R1 = R2 = R3 = R4 = R5 = H
335 R1 = R2 = R3 = R4 = R5 = Ac
329
H2 PdC MeOH
Ac2 O pyr
1 BuLi THF -78 oC
2 Me2SiCl2
3 DMAP
330
331
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1429
55-83 (d) Du Y Linhardt R Y Recent Adv in Stereo-SelectiveC-Glycoside Synthesis Tetrahedron Lett 1998 54 9913-9959 (e)Liu L Mckee M and Postema M H D Synthesis of C-saccharides and Higher Congeners Current Org Chem 2001 51133-1167
[10] Jarosz S Fraser-Reid B Synthesis of A Higher Carbon Sugar ViaDirected Aldol Condensation Tetrahedron Lett 1989 30 2359-2362
[11] Lichtenthaler F W Lergenmiiller M Schwidetzky S C-Glycosidations of 2-Ketohexosyl With Electrophilic Radical andNudeophilic Anomeric Carbons Eur J Org Chem 2003 3094-3103
[12] Baudat A Vogel P Aza-C-disaccharides Synthesis of 6-Deoxygalactonojirimycin-β-C(1rarr3) Linked with D-Altrofuranosides and D-Galactose J Org Chem 1997 62 6252-6260
[13] Turner D Vogel P Synthesis of 4-Hydroxy-26-Bis(hydroxymethyl) tetrahydropyran-2-Carbaldehyde DerivativesSynlett 1998 304-306
[14] Zhu Y-H Vogel P Short Stereoselective Synthesis of C-(1rarr3)-Linked Disaccharides Tetrahedron Lett 1998 39 31-34
[15] Zhu Y-H Vogel P Synthesis of a (2R 6R)-2-(Hydroxymethyl)-6-Propa-1 2-Dienyl-2H-Pyran-3(6H)-One Derivative A NewEnone for The Convergent Construction of C-Glycosides of C-Disaccharides Synlett 2001 82-86
[16] Baumberger F Vasella A Deoxynitrosugars The 6th
Communication Stereolectronic Control in the reductivedenitration of tertiary nitro ethers A Synthesis of ldquoC-glycosidesrdquoHelv Chim Acta 1983 66 2210-2221
[17] Martin O R Lai W Synthesis and Conformational Studies of β-(1rarr6)- and ββ-(1rarr1)-Linked C-disaccharides J Org Chem1993 58 176-185
[18] Spak S J Martin R The synthesis of an analogue of Methyl OC-Analogue of Methyl 4rsquo-O-β-D-GlucopyranosylgentiobiosideTetrahedron 2000 56 217-224
[19] Kobertz W R Bertozzi C R Bednarski M D C-GlycosylAldehyde Synthons for C-Linked Disaccharides J Org Chem1996 61 1894-1897
[20] Gurjar M K Nagaprasad R and Ramana CV First Synthesis ofMethyl α-C-D-Arabino-furanosyl-(1rarr5)-αminusD-Arabinofuranosidethe C-Disaccharide Segment of Motif C of MycobateriumTuberculosis Tetrahedron Lett 2000 43 7577-7579
[21] Witczak Z J Synthesis of C-Glycosyl Compounds and OtherNatural Products from Levoglucosenone Pure Appl Chem 199466 2189-2192
[22] Griffin F K Paterson D Taylor R J K Ramberg-BacklundApproaches to the Synthesis of C-Linked Disaccharides AngewChem Int Engl 1999 38 2939-2942
[23] Paterson B E Griffin F K Alcaraz M-L and Taylor R J KA Ramberg-Baumlcklund Approach to the Synthesis of C-GlycosidesC-Linked Disaccharides and C-Glycosyl Amino Acids Eur JOrg Chem 2002 1323-1336
[24] McAllister G D Paterson D E Taylor R J K A SimplifiedRamberg-Bachlund Approach to Novel C-Glycosides and C-Linked Disaccharides Angew Chem Int Ed Engl 2003 42 1387-1391
[25] McCartney J L Christopher T M Cicchillo R M BernardinaM D Wagner T R and Norris P J Org Chem 2003 6810152-10155
[26] Dondoni A Zuurmond H M Bascarate A Synthesis of α-andβ-D-(1rarr6)-C-Disaccharides by Witting Olefination of Formyl C-Glycosides with Glycopyranose 6-phosphoranes J Org Chem1997 62 8114-8124
[27] Dondoni A Kleban M Zuurmond H Marra A Synthesis of(1rarr6)-C-Oligogalactosides by Interative Wittig OlefinationTetrahedron Lett 1998 39 7991-7994
[28] Dondoni A Marra A A New Synthetic Approach toMycobacterial Cell Wall α-(1rarr5)-D-Arabinofuranosyl C-Oligosaccharides Teterahedron Lett 2003 44 4067-4071
[29] Colinas P A Ponzinibbio A Lieberknecht A and Bravo R OWittig Reaction of Glycosyl Phosphonium Salts A StereoselectiveRoute to C-Disaccharides and C O-Trisaccharides TetrahedronLett 2003 44 7985-7988
[30] Schmidt R R Preuss R Synthesis of Carbon Tetrahedron Lett1989 30 3409-3412
[31] Dietrich H Schmidt R R Synthesis of Carbon-Bridged C-Lactose and Derivatives Liebigs Ann Chem 1994 975-981
[32] Rouzaud D Sinayuml P The First Synthesis of a ldquoC-DisacchariderdquoJ Chem Soc Chem Commun 1983 1353-1354
[33] Xin Y-C Zhang Y-M Mallet J-M Glaudemans C P JSinayuml P Synthesis of C-Oligosaccharides That Mimie TheirNatural O-Analogues Immunodeterminants in Binding toMonoclonal Immunoglobulins Eur J Org Chem 1999 471-476
[34] Streicher H Geyer A Schmidt R R C-Disaccharides ofKetoses Chem Eur J 1996 2 502-510
[35] Leeuwenburgh M A Timmers C M Vander Marel G A VanBoom J H Mallet J-M Sinayuml P G Stereoselective Synthesisof α-C-(Alkynyl)-Glycosides Via Ring-Opening of α-12-Anhydrous Tetrahedron Lett 1997 38 6251-6254
[36] Aslam T Fuchs M G G Le Formal A Wightman R HSynthesis of C-Disaccharide Analogue of the α-D-Arabinofuranosyl-(1rarr5)-α-Arabinofuranosyl Motif ofMycobacterial Cells Walls via Alkynyl Intermediates TetrahedronLett 2005 46 3249-3252
[37] (a) Girad P Namy J L Kagan H B Divalent LanthanideDerivative in Organic Synthesis 1 Mild Preparation of SamariumIodide and Ytterbium Iodide and Their Use as Reducing orCoupling Agents J Am Chem Soc 1980 102 2693-2698 (b)Molander G A Harris C R Sequencing Reactions withSamarium(II) Iodide Chem Rev 1996 96 307-338
[38] (a) Mazeacuteas D Skrydstrup T Doumeix O Beau J-MSamarium Iodide-Induced Intramolecular C-Glycoside FormationEfficient Radical Formation in the Absence of an Additive AngewChem Int Ed Engl 1994 33 1383-1386 (b) Mazeacuteas DSkrydstrup T Beau J-M A Highly Stereoselective Synthesis of1 2-trans-C-Glycosides Via Glycosyl Samarium(III) CompoundsAngew Chem Int Ed Engl 1995 34 909-912 (c) Jarreton OSkrydstrup T Beau J-M The Stereospecific Synthesis of Methylα-C-Mannobioside A Potential Inhibitor of M TuberculosisBinding to Human Macrophages J Chem Soc Chem Commun1996 1661-1662 (d) Jarreton O Skrydstrup T Espionosa J-FJimeacutenez-Barbero J Beau J-M Samarium Diiode Prompted C-Glycosylation An Application to The Stereospecific Synthesis ofα-(1rarr2)-C-Mannobioside and Its Derivatives Chem Eur J 19995 430-441 (e) Mipuel N Doisneau G Beau J-M ReductiveSamariation of Anomeric 2-Pyridyl Sulfones with Catalytic AnUnexpected Improvement in The Synthesis of 12-Trans-Diequatorial C-Glycosyl Compounds Angew Chem Int Ed Engl 2000 39 4111-4114
[39] Vlahov I R Vlahova P I Linhardt R J DiastereocontrolledSynthesis of Carbon Glycosides of N-Acetylneuraminic Acid ViaGlycosyl Samarium(III) Intermediates JAmChem Soc 1997 1191480-1481
[40] Kuberan B Sikkander S ATomiyama H Linhardt R JSynthesis of a C-Glycoside Analogue of sTn An HIV-and Tumor-Associated Antigen Angew Chem Int Ed Engl 2003 42 2073-2075
[41] Bazin H G Du Y Polat T Linhardt R J Synthesis of aVersatile Neuraminic Acid ldquoCrdquo-Disaccharide Precursor for theSynthesis of C-Glycoside Analogues of Gangliosides J OrgChem 1999 64 7254-7259
[42] Chen C-C Ress D K Linhardt RJ Samarium Iodide-Mediated Synthesis of Neuraminic Acid C-Glycosides InSynthesis of Glycommetics Roy R Ed ACS Syposium Series2004 896 53-80
[43] Abdallah Z Doisneau G Beau J-M Synthesis of a Carbon-Linked Mimic of The Disaccharide Component of The Tumor-Relate SialyTn Antigen Angew Chem Int Ed Engl 2003 425209-5212
[44] Lay L Nicotra F Panza L Russo G Caneva E Synthesis ofC-disaccharides through dimerization of exo-glycals J Org Chem1992 57 1304-1306
[45] Isobe M Nishizawa R Hosokawa S Nishikawa TStereocontrolled Synthesis and Reactivity of Sugar Acetylenes JChem Soc Chem Commun 1998 2665-2676
[46] Saeeng R Sirion U Sahakitpichan P Isobe M IodineCatalyzes C-Glycosidation of D-Glucal with SilylacetykeneTetrahedron Lett 2003 44 6211-6215
[47] (a) Babirad S A Wang Y Kishi Y Synthesis of C-Disaccharides J Org Chem 1987 52 1370-1372 (b) Wang YBabirad S A Kishi Y Preferred Conformation of C-Glycosides
1430 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
8 Synthesis of 14-Linked Carbon Disaccharides J Org Chem1992 57 468-481
[48] Armstrong R W Sutherlin D P Strategies for the Synthesis ofC-Disaccharides Containing D and L Sugars Tetrahedron Lett1994 35 7743-7746
[49] Wei A Kishi Y Preferred Conformation of C-Glycosides 12Synthesis and Conformational Analysis of αα- α β- and β β-Trehaloses J Org Chem 1994 59 88-96
[50] Haneda T Goekjian P G Kim S H Kishi Y PreferredConformation of C-Glycosides 10 Synthesis and ConformationAnalysis of Carbon Trisaccharides J Org Chem 1992 57 490-498
[51] Sutherlin D P Armstrong R W Synthesis of 12 Stereochemistryand Structurally Diverse C-Trisaccharides J Org Chem 1997 625267-5283
[52] Notz W Hartel C Waldscheck B Schmidt R R De NovoSynthesis of a Methylene-Bridged Neu5Ac-α-(23)-Gal C-Disaccharide J Org Chem 2001 66 4250-4260
[53] (a) Postema M H D Calimente D Liu L Behrmanm T L AnOlefin Metathesis Route for the Preparation of (1rarr6)-Linked-C-Disaccharide Glycals A Convergent and Flexible Approach to C-Saccharide Synthesis J Org Chem 2000 65 6061-6068(b) Postema M H Piper J L Liu L Faust M Andreana PSynthesis and Partial Biological Evaluation of a Small Library ofDifferentially Linked β-C-Disaccharide J Org Chem 2003 684748-4754
[54] Nelson A The Development of Strategies and Methods for TheSynthesis of Biologically Active Compounds New J Chem 200428 771-776
[55] Togo H He W Waki Y Yokoyama M C-GlycosylationTechnology With Free Radiant Reactions Synlett 1998 700-717
[56] Giese B Dupuis J Diastereoselective Synthesis of C-Glycopyranosides Angew Chem Int Ed Engl 1983 22 622-623
[57] Adlington R M Baldwin J E Basak A Kozyrod RPApplication of Radical Addition Reactions to tho Synthesis of a C-Glucoside and A Functionalized Amino Acid J Chem SocChem Commun 1983 144-145
[58] Giese B Gonzaacutelez-Goacutemez J A Witzel T The Scope of RadicalCC-Coupling by The ldquoTin Methodrdquo Angew Chem Int Ed Engl1984 23 69-70
[59] Giese B Witzel T Synthesis of ldquoC-Disaccharidesrdquo by RadicalC-C Bond Formation Angew Chem Int Ed Engl 1986 25 450-451
[60] Witczak Z J Chhabra R Chojnacki J C-Disaccharides IStereoselective Approach to β-(1rarr4)-3-Deoxy-C-Disaccharidesfrom Levoglucosenone Carb Res 1997 301 167-175
[61] Vogel P Synthesis of Rare Carbohydrates and Analogues Startingfrom Enantiomerically Pure 7-Oxabicyclo[221]heptyl Derivatives(ldquoNaked Sugarsrdquo) Current Org Chem 2000 4 455-480
[62] Viodeacute C Vogel P Synthesis of The C-Disaccharide α-C(1rarr3)-L-Fucopyranoside of N-Acetylgalactosamine J Carb Chem2001 20 733-746
[63] Xin Y C Mallet J M Sinayuml P An Expeditious Synthesis of AC-Disaccharide Using A Temporary Silaketal Connection J ChemSoc Chem Commun 1993 864-865
[64] (a) Petitou M Herault P Lormeau J-C Helmboldt A MalletJ-M Sinayuml P Herbert J-M Introducing A C-InterglycosidicBond in A Biologically Active Pentasaccharide Hardly Affects ItsBiological Properties Bioorg Med Chem 1998 6 1509-1516 (b)Sinayuml P Advances in The Synthesis of the Carbohydrate MimicsPure Appl Chem 1998 70 1495-1499
[65] Sinayuml P Chemical Synthesis of Oligosaccharide Mimetics PureAppl Chem 1998 70 407-410
[66] Sinayuml P Chemical Synthesis of Oligosaccharide Mimetics PureAppl Chem 1998 69 459-463
[67] Vauzeilles B Sinayuml P Selective Radical Synthesis of β-C-Disaccharides Tetrahedron Lett 2001 42 7269-7272
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1419
Scheme (46)
OBnO O
OBn
OMe
OBn
XY
SMe
OBnBnO
O
OBn
OBn
OBn
OBn
O
BnO
YX
OBn
TBSO
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnOOBn
H
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnO
OBn
OHC OBn
OBn
OTBS
OMe
BnOOBn
CHO
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnOOBn
OBnO O
OBn
OMe
OBn
OBn
O
BnO
OMe
BnO
OBn
YX
OBnO O
OBn
OMe
OBn
OBn
O
BnO
O
OBn
OBn
OBn
OBn
O 1 LiHMDS
2
228
1 TBAF THF
2 MeSH BF3 OEt2
230 X = OH Y = H231 X = H Y = OH
230231 41
1 Bu3SnH AIBN2 Swern [O]
1 LiHMDS THF-TMEDA2 MgBr23
1 MsCl
2 liquid NH3
235 X = OH Y = H236 X = H Y = OH Bu3 SnH AIBN
237a and 237b
NaBH4 MeOH
238
239 X = OBn
240 X = OHH2 Pd(OH)2
229
232233
234
1420 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (47)
OH C
O
O BnAcHN
OO
O
OBn OBnOBn
Br
O
OBn OBnOBn
O
OBnA cHN
OO
O TBSO
OBn O BnO Bn
O
OBnAcHN
OO
OTBS
S2
S1
S2
OTBSS1
O H
S2
OT BSS1
O H
MgBrMgBr
S2
O TBSS1
O H
S2
OHS1
OH
S2
OTBSS1
OH
O
OHHO
O H
O
HO
H OO
OBnA cH N
HO
H O
O
O HHO
OH
O
HOHO
O
OBnA cH N
HO
H O
O
OHH O
OH
O
H O
HOO
OBnAcHN
HO
HO
O
O HH O
OH
O
H O
H O O
OBnA cHN
HO
HO
O
O HH O
O H
O
HO
H O O
OBnAcHN
HO
HO
O
OHHO
OH
O
H O
O
OBnA cHN
HO
HOHO
+
241 242
1 CrCl2-NiCl2 T HF-DMF 722 TBSOTf 2 6-lutidine 91
243 244
1 9-BBN 602 Dess-Mart in period inane 97
1 9 -BBN 552 D ess-Martin periodinane 98
245 246
1
2 T BAF 74
1
2 TBAF 88
247 248 249
250
251
250 251 1 1 252 253 1 1 254 255 1 1
252
253
254
255
1 MCPBA2 CSA CH 2Cl2 61 fo r 2 steps3 H 2 Pd (O H)2C 95
1 MCPBA2 CSA CH 2Cl2 63 fo r 2 s teps3 H 2 Pd (OH)2C 87
1 MCPBA2 CSA CH2Cl2 80 for 2 steps3 H2 Pd(O H)2C 95
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1421
Scheme (48)
O
OO
Se Ph
R
O
HO OHOH
O
OB n O B n
OB n
O B nO O
O O
R O OR
X
O
OO
R
Se Ph
O
HOOH
OH
O
OB nOB n
O Bn
OB n
O O
O O
R O O R
O H
O
O B n OB n
O B n
OB n
O
C HO
O
O O
R O OR
OAc HN
OAc
C O2NH 4HOOH
OH
O
OH O H
OH OH
O
OB n O B n
OB n
OB nO O
O O
R O OR
X
O
O
OAcOAc
C HOA cOOAc
OAc
O
OB n O B n
OB n
OB n
O
O Bn OB n
OB n
OB n
X
OH
OO
HOOH
OH
O
O
OMeOB n
OB nOB n
R
t-B uL i256 R = Li
257 R = L i
258
(R = t-B uMe 2Si )
(R = t-B uMe 2Si )
259ab (32) 79 com bine d yi eld
De ss-Ma rtin pe riodinane
260 X = O R = t-B uMe 2Si ) 95
261 X = O R = t -B uMe2S i) 62
T e bbe re age nt
TB A F THF262 X = O R = H 94
diphosge ne
C H2C l 2Pyr
263 95
T HFH2O T FAr t
264 quant it a ti ve yie ld
PhSe C l AgOT f
EtC N -80 oC
265
266
Quant it at i ve yi l ed 25 26 7 1
+
R =
1 Ac 2OPyr
2 mC PB A3 Ac 2ONa OAc
4 NaO HT HFMe OH
5 Ac2O P yr
267 90 overa ll yi e ld
ste ps
268
1422 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
glucopyranoside 280 represents an example of thischemistry The known triacetyl glucopyranoside 269 wasconverted to iodide 270 in good yield Radical allylation of271 proceeded to afford a mixture of equatorial and axialallylation products in a 61 ratio Oxidative cleavage of thedouble bond gave the corresponding aldehydes 273a and273b which were separable Pinnick oxidation of the majoraldehyde 273a then gave the C-4 equatorial acid 274 DCC-mediated coupling of alcohol 275 and acid 274 proceeded toafford ester 276 in good yield Methylenation of 276 gave277 and exposure to catalysist 278 gave a 41 yield of theC-disaccharide glycal which was exposed to an excess ofBH3
THF to give 64 yield of the β-C-disaccharide 279Removal of the benzyl groups and global peracetylation gavethe peracetylated (1rarr4)-β-C-disaccharide 281 in good yield(Scheme 49)
54 Ring Expansion-Cyclization
Nelson developed a new strategy for asymmetric andstereoselective synthesis of C-linked disaccharide mimeticsthe C58-C71 fragment of palytoxin [54] The diol (RR)-282was converted into the di-dihydropyran (DHP) template 283284 and 285 The di-DHPs were functionized in a twodirectional sense using dihydroxylation reactions The two-directional approach was often very efficient indeed forexample in the synthesis of 286 six new stereogenic centerswere introduced with almost complete stereocontrol using areduction and a dihydroxylation reaction The approach isnot restricted to the synthesis of C2-symmetricaldisaccharide mimetics Using the unsymmetrical template285 which has both a pseudo-axial and a pseudo-equatorialhydroxyl groups the unsymmetrical mimetics 289 and 290were prepared (Scheme 50)
6 RADICAL APPROACHES
The radical approach for C-C bond formation is a popularmethod within organic chemistry The use of radicalchemistry in carbohydrate synthesis has certain advantagesFirstly the reaction conditions are very mild and tolerant ofa range of functional and protecting groups Secondanomeric radicals are stable with respect to elimination andepimeration Most significantly the chemistry required toincorporate an appropriate substitute at C-1 employed in theinitial hemolytic cleavage step is common within carbo-hydrate chemistry [55] The use of such radical techniquecan be subdivided into two classes intermolecular andintramolecular approaches
61 Intermolecular Radical Approaches
Giese was the first to employ an intermolecular radical-based approach for synthesis of C-disaccharides [56]Addition of an alkene to an anomeric radical underappropriate conditions allowed exclusive entry to the α-linked C-glycoside a result which was mirrored by the workof Baldwin [57] The high α-selectivity of the reaction wasin contrast with other reports Thus radicals generated at theC-2 C-3 and C-4 centers all preferred to occupy equatorialpositions [58] When the anomeric bromide 291 was treatedwith tin hydride and AIBN resulting anomeric radical andreacted with lactone 292 in a Michael addition it afforded293 In this reaction hydrogen abstraction at the resulting
radical center occurs from axial face to selectively generatethe equatorial C-2rsquo substituent Reduction and acetylation of293 furnished C-disaccharide 294 (Scheme 51) [59]
Witczak used the facial bias of levoglucosene tostereoselectively add a carbohydrate-based radical in thepreparation of the 3-deoxy-(1rarr4)-β-C-disaccharide 299[60] Addition of the radical derived from iodide 295 to 296gave adduct 297 in 26 yield Removal of the anomerichydroxyl of 297 was achieved by treatment with triethylsilane borontrifluoride ether complex followed bystereoselective reduction of the keto function at C-2rsquo withthe formation of 298 in 89 yield Debenzylation followedby acetolysis of 16-anhydro ring produced the peracetylatedtarget C-disaccharide 299 in 19 overall yield from 295(Scheme 52)
Vogel has developed general methods to transformenantiomerically pure 7-oxabicyclo[221]heptyl derivatives(ldquonaked sugarsrdquo) into C-disaccharides Because of thesechiral bicyclic skeletons they undergo highly stereoselectivereactions with predictable diasteroselectivities An arsenal ofmethods is available that allow to substitute these ldquonakedrdquocarbon centers with a variety of functional groups with allpossible relative configurations The methods allowpreparation of both enantiomers of a given target with thesame ease Predictably high stereoselectivity of the reactionsof the bicyclic chirons adds to the flexibility of approachwhich can lead to high molecular diversity [61]
α-C-(1rarr3)-mannopyranoside of N-acetyl-galactosaminepotent β-galactosidase inhibitors was synthesized by thisapproach [61] Enone 302 was readily prepared from 300The addition of the radical derived from bromide 303 toenone 302 afforded the αminusisomer 304 The ketone was thenreduced and the selenide eliminated via the intermediacy ofthe selenoxide to give 305 Acid-promoted (CF3SO3H) 7-oxa ring opening of 305 in MeCN produced the amino-conduritol derivative 306 resulting from the quenching of theallylic cation intermediate by the solvent (Ritter reaction)Ozonolysis of the chloroalkene 306 generated an acylchloride-aldehyde intermediate that reacted with MeOH toproduce a mixture of methyl uronates The major compound307 was silylated and reduced The crude polyol obtainedwas acetylated to produce 308 Desilylated and ammonolysisafforded a mixture of α-β-pyranoses 309 and correspondingα-β-furanoses (Scheme 53)
Similar chemistry was carried out to synthesize non-protected α-C(1rarr2)-L-fucopyranoside of D-galactopyrano-side corresponding to a blood group mimetic [62] Giesersquosradical fucosidation of racemic enone 310 with α-L-bromoacetofucose 311 provided the mixture of diastereo-meric α-C-fucoside 312a and 312b in reproducible yield of78 Reduction of the mixture gave a 11 mixture of endo-alcohols 313 and 314 which were isolated pure in 40 and355 yield respectively Oxidative elimination of thebenzeneselenyl group of 313 followed by acetylation gaveendo acetate 315 in 85 yield Acid-promoted ring openingof 315 and ozonolysis of the resulted chloroalkene gavemethyl uronic ester 316 in modest yield (10) Treatment of316 with Cl3CCN and NaH followed with BF3
OEt2
furnished the totally protected C-disaccharide 317 in 79
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1423
Scheme (49)
Bu3SnO
HOAcO
OMeOAc
OAc
O
AcO
OMeOAc
OAcI
AIBN
O
AcO
OMeOBn
OBn
HO2C O
AcO
OMeOR
ORY
X
OHBnO
BnO
OBn
OBnO
BnO
OBn
O
AcO
OMeOBn
OBnX
i-Pr i-Pr
N
Mo C(Me2 Ph)((CF3)2 MeCO)2
O
RO
OMeOR
O
RO
OR
OR
RO
OR
278
I2 Ph3P
imidazole
269 270 93
271a X = CH2CH=CH2 Y = H R = Ac 64271b Y = CH2CH=CH2 X = H R = Ac 11272a X = CH2CH=CH2 Y = H R = Bn 75272b Y = CH2CH=CH2 X = H R = Bn 75273a X = CH2CHO Y = H R = Bn 79273a Y = CH2CHO X = H R = Bn 79
1 NaOMe MeOH2 NaOH BnBr DMF
OsO4 NaIO4
NaClO2 NaH2PO4
274 96
275
DCC 4-DMAP
276 X = O 82
277 X = CH2 51
TiCl4 Zn dust TMEDA CH2Br2PbCl2 (Cat )
1
2 BH3 THF H2O2 NaOH
H2 PdC EtOH
Ac2 O Pyr 4-DMAP
279 R = Bn R = H 64
280 R = R = H 99
281 R = R =Ac 97
1424 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (50)
Scheme (51)
O OOH
OH
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
286
1 VO(acac)2 t-BuOH 95
2 (MeO)3CH BF3 90
1 P-O2NC6H4 CO2H Ph3P DIAD2 K2CO3 MeOH 82 over 2 steps
1 PhCOCl Et3N DMAP 402 P-O2NC6H4 CO2H Ph3P DIAD3 KOH THF-H2O 75 over 2 steps
TMEDA OsO4
Cat OsO4 NMO 287
Cat OsO4 NMO288
TMEDA OsO4
Cat OsO4 NMO
290
289
(RR)-282283
284
285
OHO
AcO
BrOAc
OAc
BnO
O
OBn
OBnO
OHO
AcOOAc
OAc
BnO
OOBn
OBnAcO
OHO
AcOOAc
OAc
BnO
O
OBn
OBnO
+
Bu3SnH AIBN291
292
293 81
1 Na[Al(OC2H4OMe)2(OEt)H]2 Ac2O pyr
294 56 over 2 steps
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1425
Scheme (52)
Scheme (53)
OBnO
BnOOBn
OBn O
OH
O
OBnO
BnO
OHOBn
OBn O
O
O
O
O
O
OBnO
BnOOBn
OBnO
OAcOAc
OAc
OBnO
BnO
OHOBn
OBn
IBu3SnH AIBN
295 297 26
1 BF3 OEt2 Et3SiH
2 L-Selectride THF
1 Pd(OH)2C C6H10 EtOH
2 EtSiOSO2CF3 Ac2O
298 89 over 2 steps299
296
O
O
PhSeClO
O
PhSeCl
Bu3 SnH
O
O
PhSeCl
R
H
O
OAc
R
Cl
O
AcO
OAc
OAc
OAcOH
Cl
NHAc
R
OAc
AcHN
OH
O
OH OAc
OH
OHO
HO
OH
O
AcO
OAc
OAc
OAcBr
O
O
PhSeCl
O
O
PhSeCl
R
O
OTIPSAcHNR
OAc OAc
O
OHAcHN
COOMe
R
OAc
1 Bu4NF
2 NH3MeOH
1 (Me3Si)2NLi THF2 Me2N=CHI
1 Bu3 SnH AIBN2
1 NaBH42 mCPBA3 Ac2O pyr
1 H+ MeCN
2 H2 O NaHCO3
R =
1 O3MeOH
2 Me2S NaHCO3
1 TIPSOTf 26-lut idine2 LiBH43 Ac2 O pyr DMAP
furanoses +
304 56
305 68 306 84307 50
308 46
300 301 302
303
309
1426 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
The reduction of 317 and treatment with DOWEX-H+ resinprovided the desired C-fucoside 318 in 70 (Scheme 54)
62 Intramolecular Radical Approaches
One disadvantage with the intermolecular approaches isthat during such radical mediated reactions electrondeficient alkenes are required to facilitate C-C bondformation The intramolecular approach of Sinayuml overcomes
this drawback by bring two substrates together via atemporary covalent silaketal connector This enables the useof a wider range of alkenes which can include alkene-functionalized sugars thus leading to the generation of C-disaccharides [63] Based on the early work of Stork Sinayumlemployed the tether reaction in the synthesis of both α- andβ-C-disaccharides with this work subsequently beingemployed in the synthesis of biologically significant natural
Scheme (54)
O
OH
Fuc
Cl
O
O
ClPhSe
OOAc
NHAcOHFuc
O
AcOOAc
AcO
Br
O
O
PhSeCl
O
AcOOAc
AcO
O
OH
PhSe Cl
Fuc
OOAc
NHAc
OMe
Fuc
O
AcHN
OH OAc
OH
O
OH
Me
OH
O
O
Fuc
ClSePh
O
HO
Fuc
ClSePh
+
Ph3SnHAIBN
78 combined yield
Fuc
310
+
1 NaBH4 MeOHTHF2 Chromatography
313 40 314 355
1 mCPBA
2 Ac2O pyr DMAP
+
315 75
1 TfOH MeCN
2 NaHCO3 O3 -78 oC
316 10 over 2 steps
1 Cl3 CCN NaH
2 MeOH BF3 OEt2
317 79
1 LiBH4 THF
2 Dowex-H+
311
312a312b
318 70 for 2 steps
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1427
products [64] The availability of different hydroxyl groupson each monosaccharide unit allowed the fine-tuning ofstereochemical outcome by selective positioning of the silyltether [65] Development of this early stereochemical controlled to the tethering of the donor 320 with alcohol 319through a di-isopropyl silicon tether 321 Subsequent treat-ment with Bu3SnH and AIBN led to a 9-endo-trigcyclization to form the C-disaccharide 322 in an 80 yieldwith exclusive formation of the α-product The silyl tetherwas removed with Bu4NF and deprotection under standardconditions afforded the desired disaccharide 323 in excellentyield (Scheme 55)
In parallel the development of a 32rsquo silyl tether allowedaccess to the β-linked product as demonstrated in Sinayumlrsquossynthesis of methyl β-C-lactoside 328 [66] Alcohol 324 and320 were connected via the dimethylsilyl tether an 8-endo-trig cyclization followed to exclusively afford the β-
disaccharide 326 in 45 yield Removal of the tether anddeprotection of benzyl ether gave β-C-disaccharide 328(Scheme 56)
This group also selected iodosugars bearing a freehydroxyl group as progenitors of the radical donors [67] In atypical experiment the radical donor 329 was connected tothe radical acceptor 330 through a silaketal tether followingtheir procedure Tributyltinhydride mediated 8-endo-trigradical cyclization of compound 331 gave after detetheringof the non isolated intermediate 332 the protected β-C-disaccharide 333 in 37 overall yield (from startingmaterials 330 and 329) Peracetate 335 was achieved afterhydrogenolysis The C-laminaribioside 334 is of potentialbiological interest as it mimics the repeating disaccharideunit of fungal β-(1rarr3)-glucans which have antitumor andimmunomodulating properties (Scheme 57)
Scheme (55)
Scheme (56)
OO
OHSePh
OTBDPSO O
OO
SePh
OTBDPSO
OO
OBnOMe
OBn
Si
O
HOOBn
OMe
OBn
O
HOOH
OHHO
O
HOOH
OMe
OH
OTBDPSO
O
HOOBn
OMe
OBnO
OOH
1 n-BuLi THF
2 iPr2SiCl2 -78 oC
3 DMAP THF rt
1 Bu4NF THF
2 Dowex-H+
3 H2 PdC
Bu3SnH AIBN toluene
319
320
321
322323
OBnO
OHSePh
OBnBnO
OHO
OBnOMe
OBn
ROO
ROOH
OR
OHO
OROMe
OR
OBnO
O
OBnBnO
OO
OBnOMe
OBn
Si
SePh
OBnO
O
OBnBnOO
OOBn
OMe
OBn
Si
1 PhSeH Me2SiCl2
BuLi -78 oC
2 imidazole rt
Bu3SnH AIBN toluene
H2 PdC327 R = Bn
328 R = H
Bu4NF THF
324
320
325
326 45
1428 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
CONCLUSIONS
In this paper the biological importance of C-oligo-saccharides as subunits of natural products and as a newgeneration of carbohydrate based on therapeutics has beenillustrated Different methods are available for the synthesisof C-oligosaccharides As with traditional saccharidesynthesis it has been necessary to develop a number ofspecific approaches to facilitate the regioselective andstereoselective preparation of the desired targets Work inthis area continues and it is expected that many interestingnew C-oligosaccharides will be prepared using the chemistrydescribed in this review It is also likely that new chemistrywill be developed in the future for the preparation of thesebiologically important targets
ACKNOWLEDGEMENTS
The authors thank Dr Sultan Baytas for her criticalreading of this manuscript
REFERENCES
[1] Kennedy J F White C A Bioactive Carbohydrates InChemistry Biochemistry and Biology Ellis Horwood LtdChichesterUK 1983
[2] Wassarman PW Mammalian Fertilization Molecular Aspects ofGamete Adhesion xocytosion Exocytosis and Fusion Cell 199996 175-183
[3] Carbohydrate-based Drug Discovery Wong C-H EdWeinheim Cambridge Wiley-VCH 2003
[4] (a) Sharon N Lis H Lectins as Cell Recognition MoleculesScience 1987 246 227-234 (b) Dwek RA Chem Rev 1996 96683-720
[5] Postema M C-Glycoside synthesis CRC Boc Ratom 1995[6] (a) Weatherman R V Mortell K H Cheruenak MKiessling
L L Toone E J Specificity of C-Glycoside Complexation byMannoseGlucose Specific Lectins Biochem 1996 35 3619-3624(b) Ravishankar R Surolia A Vijayan M Lim S Kishi YPreferred Conformation of C-Lactose at the Free and Peanut LectinBound States J Am Chem Soc1998 120 11297-11303
[7] (a)Wong C-H Halcomb R L Ichikawa Y and Kajimoto TEnzymes in organic synthesis Application to the problems ofcarbohydrate recognition part2 Angew Chem Int Ed Engl 199534 521-546 (b)Howard S Withers SG Bromoketone C-Glycosides a New Class of βminusGlucanase Inactivators J AmChem Soc 1998 120 10326-10331(c) Wang Q Wolff MPolat T Du Y Linhardt R J C-glycoside of Neuraminic Acidsas Neura-minidase Inhibitors Bioorg Med Lett 2000 10 941-944 (d) Phili R Chang J Partis R A Mueller R A ChrestF J Passaniti A The Alpha-glucosidase I InhibitorCastanospermine Alters Endothelial cell Glycosylation PreventsAngiogenesis and Inhibits Tumor Growth Cancer Res 1995 552927-2935
[8] Ossor A Elbein A D In Carbohydrates in Chemistry andBiology Vol 3(II) WileyVCH 2000 pp 513-539
[9] (a) Sinayuml P Synthesis of oligosaccharide Mimetics Pure ApplChem 1997 69 459-463 (b) Beau J-M Gallagher TNucleophilic C-glycosyl Donors for C-glycoside Synthesis Top inCurr Chem 1997 187 1-54 (c) Nicotra F Synthesis of C-glycosides of Biological Interest Top in Curr Chem 1997 187
Scheme (57)
O
O
O
Ph
I
OMe
OHO
BnO
OH
OH
BnOOH
O
BnO
Si
O
O O
Ph
I
OMe
O
O
BnO
OR4O
R5O
OMe
OR2
OR3O
R3O
OR1
R3O
Bu3 SnH AIBN
332 R1 R2 = SiMe2 R3 = Bn R4 R5 = CHPhTBAF THF
333 R1 = R2 = H R3 = Bn R4 = R5 = CHPh 37 from 11
334 R1 = R2 = R3 = R4 = R5 = H
335 R1 = R2 = R3 = R4 = R5 = Ac
329
H2 PdC MeOH
Ac2 O pyr
1 BuLi THF -78 oC
2 Me2SiCl2
3 DMAP
330
331
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1429
55-83 (d) Du Y Linhardt R Y Recent Adv in Stereo-SelectiveC-Glycoside Synthesis Tetrahedron Lett 1998 54 9913-9959 (e)Liu L Mckee M and Postema M H D Synthesis of C-saccharides and Higher Congeners Current Org Chem 2001 51133-1167
[10] Jarosz S Fraser-Reid B Synthesis of A Higher Carbon Sugar ViaDirected Aldol Condensation Tetrahedron Lett 1989 30 2359-2362
[11] Lichtenthaler F W Lergenmiiller M Schwidetzky S C-Glycosidations of 2-Ketohexosyl With Electrophilic Radical andNudeophilic Anomeric Carbons Eur J Org Chem 2003 3094-3103
[12] Baudat A Vogel P Aza-C-disaccharides Synthesis of 6-Deoxygalactonojirimycin-β-C(1rarr3) Linked with D-Altrofuranosides and D-Galactose J Org Chem 1997 62 6252-6260
[13] Turner D Vogel P Synthesis of 4-Hydroxy-26-Bis(hydroxymethyl) tetrahydropyran-2-Carbaldehyde DerivativesSynlett 1998 304-306
[14] Zhu Y-H Vogel P Short Stereoselective Synthesis of C-(1rarr3)-Linked Disaccharides Tetrahedron Lett 1998 39 31-34
[15] Zhu Y-H Vogel P Synthesis of a (2R 6R)-2-(Hydroxymethyl)-6-Propa-1 2-Dienyl-2H-Pyran-3(6H)-One Derivative A NewEnone for The Convergent Construction of C-Glycosides of C-Disaccharides Synlett 2001 82-86
[16] Baumberger F Vasella A Deoxynitrosugars The 6th
Communication Stereolectronic Control in the reductivedenitration of tertiary nitro ethers A Synthesis of ldquoC-glycosidesrdquoHelv Chim Acta 1983 66 2210-2221
[17] Martin O R Lai W Synthesis and Conformational Studies of β-(1rarr6)- and ββ-(1rarr1)-Linked C-disaccharides J Org Chem1993 58 176-185
[18] Spak S J Martin R The synthesis of an analogue of Methyl OC-Analogue of Methyl 4rsquo-O-β-D-GlucopyranosylgentiobiosideTetrahedron 2000 56 217-224
[19] Kobertz W R Bertozzi C R Bednarski M D C-GlycosylAldehyde Synthons for C-Linked Disaccharides J Org Chem1996 61 1894-1897
[20] Gurjar M K Nagaprasad R and Ramana CV First Synthesis ofMethyl α-C-D-Arabino-furanosyl-(1rarr5)-αminusD-Arabinofuranosidethe C-Disaccharide Segment of Motif C of MycobateriumTuberculosis Tetrahedron Lett 2000 43 7577-7579
[21] Witczak Z J Synthesis of C-Glycosyl Compounds and OtherNatural Products from Levoglucosenone Pure Appl Chem 199466 2189-2192
[22] Griffin F K Paterson D Taylor R J K Ramberg-BacklundApproaches to the Synthesis of C-Linked Disaccharides AngewChem Int Engl 1999 38 2939-2942
[23] Paterson B E Griffin F K Alcaraz M-L and Taylor R J KA Ramberg-Baumlcklund Approach to the Synthesis of C-GlycosidesC-Linked Disaccharides and C-Glycosyl Amino Acids Eur JOrg Chem 2002 1323-1336
[24] McAllister G D Paterson D E Taylor R J K A SimplifiedRamberg-Bachlund Approach to Novel C-Glycosides and C-Linked Disaccharides Angew Chem Int Ed Engl 2003 42 1387-1391
[25] McCartney J L Christopher T M Cicchillo R M BernardinaM D Wagner T R and Norris P J Org Chem 2003 6810152-10155
[26] Dondoni A Zuurmond H M Bascarate A Synthesis of α-andβ-D-(1rarr6)-C-Disaccharides by Witting Olefination of Formyl C-Glycosides with Glycopyranose 6-phosphoranes J Org Chem1997 62 8114-8124
[27] Dondoni A Kleban M Zuurmond H Marra A Synthesis of(1rarr6)-C-Oligogalactosides by Interative Wittig OlefinationTetrahedron Lett 1998 39 7991-7994
[28] Dondoni A Marra A A New Synthetic Approach toMycobacterial Cell Wall α-(1rarr5)-D-Arabinofuranosyl C-Oligosaccharides Teterahedron Lett 2003 44 4067-4071
[29] Colinas P A Ponzinibbio A Lieberknecht A and Bravo R OWittig Reaction of Glycosyl Phosphonium Salts A StereoselectiveRoute to C-Disaccharides and C O-Trisaccharides TetrahedronLett 2003 44 7985-7988
[30] Schmidt R R Preuss R Synthesis of Carbon Tetrahedron Lett1989 30 3409-3412
[31] Dietrich H Schmidt R R Synthesis of Carbon-Bridged C-Lactose and Derivatives Liebigs Ann Chem 1994 975-981
[32] Rouzaud D Sinayuml P The First Synthesis of a ldquoC-DisacchariderdquoJ Chem Soc Chem Commun 1983 1353-1354
[33] Xin Y-C Zhang Y-M Mallet J-M Glaudemans C P JSinayuml P Synthesis of C-Oligosaccharides That Mimie TheirNatural O-Analogues Immunodeterminants in Binding toMonoclonal Immunoglobulins Eur J Org Chem 1999 471-476
[34] Streicher H Geyer A Schmidt R R C-Disaccharides ofKetoses Chem Eur J 1996 2 502-510
[35] Leeuwenburgh M A Timmers C M Vander Marel G A VanBoom J H Mallet J-M Sinayuml P G Stereoselective Synthesisof α-C-(Alkynyl)-Glycosides Via Ring-Opening of α-12-Anhydrous Tetrahedron Lett 1997 38 6251-6254
[36] Aslam T Fuchs M G G Le Formal A Wightman R HSynthesis of C-Disaccharide Analogue of the α-D-Arabinofuranosyl-(1rarr5)-α-Arabinofuranosyl Motif ofMycobacterial Cells Walls via Alkynyl Intermediates TetrahedronLett 2005 46 3249-3252
[37] (a) Girad P Namy J L Kagan H B Divalent LanthanideDerivative in Organic Synthesis 1 Mild Preparation of SamariumIodide and Ytterbium Iodide and Their Use as Reducing orCoupling Agents J Am Chem Soc 1980 102 2693-2698 (b)Molander G A Harris C R Sequencing Reactions withSamarium(II) Iodide Chem Rev 1996 96 307-338
[38] (a) Mazeacuteas D Skrydstrup T Doumeix O Beau J-MSamarium Iodide-Induced Intramolecular C-Glycoside FormationEfficient Radical Formation in the Absence of an Additive AngewChem Int Ed Engl 1994 33 1383-1386 (b) Mazeacuteas DSkrydstrup T Beau J-M A Highly Stereoselective Synthesis of1 2-trans-C-Glycosides Via Glycosyl Samarium(III) CompoundsAngew Chem Int Ed Engl 1995 34 909-912 (c) Jarreton OSkrydstrup T Beau J-M The Stereospecific Synthesis of Methylα-C-Mannobioside A Potential Inhibitor of M TuberculosisBinding to Human Macrophages J Chem Soc Chem Commun1996 1661-1662 (d) Jarreton O Skrydstrup T Espionosa J-FJimeacutenez-Barbero J Beau J-M Samarium Diiode Prompted C-Glycosylation An Application to The Stereospecific Synthesis ofα-(1rarr2)-C-Mannobioside and Its Derivatives Chem Eur J 19995 430-441 (e) Mipuel N Doisneau G Beau J-M ReductiveSamariation of Anomeric 2-Pyridyl Sulfones with Catalytic AnUnexpected Improvement in The Synthesis of 12-Trans-Diequatorial C-Glycosyl Compounds Angew Chem Int Ed Engl 2000 39 4111-4114
[39] Vlahov I R Vlahova P I Linhardt R J DiastereocontrolledSynthesis of Carbon Glycosides of N-Acetylneuraminic Acid ViaGlycosyl Samarium(III) Intermediates JAmChem Soc 1997 1191480-1481
[40] Kuberan B Sikkander S ATomiyama H Linhardt R JSynthesis of a C-Glycoside Analogue of sTn An HIV-and Tumor-Associated Antigen Angew Chem Int Ed Engl 2003 42 2073-2075
[41] Bazin H G Du Y Polat T Linhardt R J Synthesis of aVersatile Neuraminic Acid ldquoCrdquo-Disaccharide Precursor for theSynthesis of C-Glycoside Analogues of Gangliosides J OrgChem 1999 64 7254-7259
[42] Chen C-C Ress D K Linhardt RJ Samarium Iodide-Mediated Synthesis of Neuraminic Acid C-Glycosides InSynthesis of Glycommetics Roy R Ed ACS Syposium Series2004 896 53-80
[43] Abdallah Z Doisneau G Beau J-M Synthesis of a Carbon-Linked Mimic of The Disaccharide Component of The Tumor-Relate SialyTn Antigen Angew Chem Int Ed Engl 2003 425209-5212
[44] Lay L Nicotra F Panza L Russo G Caneva E Synthesis ofC-disaccharides through dimerization of exo-glycals J Org Chem1992 57 1304-1306
[45] Isobe M Nishizawa R Hosokawa S Nishikawa TStereocontrolled Synthesis and Reactivity of Sugar Acetylenes JChem Soc Chem Commun 1998 2665-2676
[46] Saeeng R Sirion U Sahakitpichan P Isobe M IodineCatalyzes C-Glycosidation of D-Glucal with SilylacetykeneTetrahedron Lett 2003 44 6211-6215
[47] (a) Babirad S A Wang Y Kishi Y Synthesis of C-Disaccharides J Org Chem 1987 52 1370-1372 (b) Wang YBabirad S A Kishi Y Preferred Conformation of C-Glycosides
1430 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
8 Synthesis of 14-Linked Carbon Disaccharides J Org Chem1992 57 468-481
[48] Armstrong R W Sutherlin D P Strategies for the Synthesis ofC-Disaccharides Containing D and L Sugars Tetrahedron Lett1994 35 7743-7746
[49] Wei A Kishi Y Preferred Conformation of C-Glycosides 12Synthesis and Conformational Analysis of αα- α β- and β β-Trehaloses J Org Chem 1994 59 88-96
[50] Haneda T Goekjian P G Kim S H Kishi Y PreferredConformation of C-Glycosides 10 Synthesis and ConformationAnalysis of Carbon Trisaccharides J Org Chem 1992 57 490-498
[51] Sutherlin D P Armstrong R W Synthesis of 12 Stereochemistryand Structurally Diverse C-Trisaccharides J Org Chem 1997 625267-5283
[52] Notz W Hartel C Waldscheck B Schmidt R R De NovoSynthesis of a Methylene-Bridged Neu5Ac-α-(23)-Gal C-Disaccharide J Org Chem 2001 66 4250-4260
[53] (a) Postema M H D Calimente D Liu L Behrmanm T L AnOlefin Metathesis Route for the Preparation of (1rarr6)-Linked-C-Disaccharide Glycals A Convergent and Flexible Approach to C-Saccharide Synthesis J Org Chem 2000 65 6061-6068(b) Postema M H Piper J L Liu L Faust M Andreana PSynthesis and Partial Biological Evaluation of a Small Library ofDifferentially Linked β-C-Disaccharide J Org Chem 2003 684748-4754
[54] Nelson A The Development of Strategies and Methods for TheSynthesis of Biologically Active Compounds New J Chem 200428 771-776
[55] Togo H He W Waki Y Yokoyama M C-GlycosylationTechnology With Free Radiant Reactions Synlett 1998 700-717
[56] Giese B Dupuis J Diastereoselective Synthesis of C-Glycopyranosides Angew Chem Int Ed Engl 1983 22 622-623
[57] Adlington R M Baldwin J E Basak A Kozyrod RPApplication of Radical Addition Reactions to tho Synthesis of a C-Glucoside and A Functionalized Amino Acid J Chem SocChem Commun 1983 144-145
[58] Giese B Gonzaacutelez-Goacutemez J A Witzel T The Scope of RadicalCC-Coupling by The ldquoTin Methodrdquo Angew Chem Int Ed Engl1984 23 69-70
[59] Giese B Witzel T Synthesis of ldquoC-Disaccharidesrdquo by RadicalC-C Bond Formation Angew Chem Int Ed Engl 1986 25 450-451
[60] Witczak Z J Chhabra R Chojnacki J C-Disaccharides IStereoselective Approach to β-(1rarr4)-3-Deoxy-C-Disaccharidesfrom Levoglucosenone Carb Res 1997 301 167-175
[61] Vogel P Synthesis of Rare Carbohydrates and Analogues Startingfrom Enantiomerically Pure 7-Oxabicyclo[221]heptyl Derivatives(ldquoNaked Sugarsrdquo) Current Org Chem 2000 4 455-480
[62] Viodeacute C Vogel P Synthesis of The C-Disaccharide α-C(1rarr3)-L-Fucopyranoside of N-Acetylgalactosamine J Carb Chem2001 20 733-746
[63] Xin Y C Mallet J M Sinayuml P An Expeditious Synthesis of AC-Disaccharide Using A Temporary Silaketal Connection J ChemSoc Chem Commun 1993 864-865
[64] (a) Petitou M Herault P Lormeau J-C Helmboldt A MalletJ-M Sinayuml P Herbert J-M Introducing A C-InterglycosidicBond in A Biologically Active Pentasaccharide Hardly Affects ItsBiological Properties Bioorg Med Chem 1998 6 1509-1516 (b)Sinayuml P Advances in The Synthesis of the Carbohydrate MimicsPure Appl Chem 1998 70 1495-1499
[65] Sinayuml P Chemical Synthesis of Oligosaccharide Mimetics PureAppl Chem 1998 70 407-410
[66] Sinayuml P Chemical Synthesis of Oligosaccharide Mimetics PureAppl Chem 1998 69 459-463
[67] Vauzeilles B Sinayuml P Selective Radical Synthesis of β-C-Disaccharides Tetrahedron Lett 2001 42 7269-7272
1420 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (47)
OH C
O
O BnAcHN
OO
O
OBn OBnOBn
Br
O
OBn OBnOBn
O
OBnA cHN
OO
O TBSO
OBn O BnO Bn
O
OBnAcHN
OO
OTBS
S2
S1
S2
OTBSS1
O H
S2
OT BSS1
O H
MgBrMgBr
S2
O TBSS1
O H
S2
OHS1
OH
S2
OTBSS1
OH
O
OHHO
O H
O
HO
H OO
OBnA cH N
HO
H O
O
O HHO
OH
O
HOHO
O
OBnA cH N
HO
H O
O
OHH O
OH
O
H O
HOO
OBnAcHN
HO
HO
O
O HH O
OH
O
H O
H O O
OBnA cHN
HO
HO
O
O HH O
O H
O
HO
H O O
OBnAcHN
HO
HO
O
OHHO
OH
O
H O
O
OBnA cHN
HO
HOHO
+
241 242
1 CrCl2-NiCl2 T HF-DMF 722 TBSOTf 2 6-lutidine 91
243 244
1 9-BBN 602 Dess-Mart in period inane 97
1 9 -BBN 552 D ess-Martin periodinane 98
245 246
1
2 T BAF 74
1
2 TBAF 88
247 248 249
250
251
250 251 1 1 252 253 1 1 254 255 1 1
252
253
254
255
1 MCPBA2 CSA CH 2Cl2 61 fo r 2 steps3 H 2 Pd (O H)2C 95
1 MCPBA2 CSA CH 2Cl2 63 fo r 2 s teps3 H 2 Pd (OH)2C 87
1 MCPBA2 CSA CH2Cl2 80 for 2 steps3 H2 Pd(O H)2C 95
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1421
Scheme (48)
O
OO
Se Ph
R
O
HO OHOH
O
OB n O B n
OB n
O B nO O
O O
R O OR
X
O
OO
R
Se Ph
O
HOOH
OH
O
OB nOB n
O Bn
OB n
O O
O O
R O O R
O H
O
O B n OB n
O B n
OB n
O
C HO
O
O O
R O OR
OAc HN
OAc
C O2NH 4HOOH
OH
O
OH O H
OH OH
O
OB n O B n
OB n
OB nO O
O O
R O OR
X
O
O
OAcOAc
C HOA cOOAc
OAc
O
OB n O B n
OB n
OB n
O
O Bn OB n
OB n
OB n
X
OH
OO
HOOH
OH
O
O
OMeOB n
OB nOB n
R
t-B uL i256 R = Li
257 R = L i
258
(R = t-B uMe 2Si )
(R = t-B uMe 2Si )
259ab (32) 79 com bine d yi eld
De ss-Ma rtin pe riodinane
260 X = O R = t-B uMe 2Si ) 95
261 X = O R = t -B uMe2S i) 62
T e bbe re age nt
TB A F THF262 X = O R = H 94
diphosge ne
C H2C l 2Pyr
263 95
T HFH2O T FAr t
264 quant it a ti ve yie ld
PhSe C l AgOT f
EtC N -80 oC
265
266
Quant it at i ve yi l ed 25 26 7 1
+
R =
1 Ac 2OPyr
2 mC PB A3 Ac 2ONa OAc
4 NaO HT HFMe OH
5 Ac2O P yr
267 90 overa ll yi e ld
ste ps
268
1422 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
glucopyranoside 280 represents an example of thischemistry The known triacetyl glucopyranoside 269 wasconverted to iodide 270 in good yield Radical allylation of271 proceeded to afford a mixture of equatorial and axialallylation products in a 61 ratio Oxidative cleavage of thedouble bond gave the corresponding aldehydes 273a and273b which were separable Pinnick oxidation of the majoraldehyde 273a then gave the C-4 equatorial acid 274 DCC-mediated coupling of alcohol 275 and acid 274 proceeded toafford ester 276 in good yield Methylenation of 276 gave277 and exposure to catalysist 278 gave a 41 yield of theC-disaccharide glycal which was exposed to an excess ofBH3
THF to give 64 yield of the β-C-disaccharide 279Removal of the benzyl groups and global peracetylation gavethe peracetylated (1rarr4)-β-C-disaccharide 281 in good yield(Scheme 49)
54 Ring Expansion-Cyclization
Nelson developed a new strategy for asymmetric andstereoselective synthesis of C-linked disaccharide mimeticsthe C58-C71 fragment of palytoxin [54] The diol (RR)-282was converted into the di-dihydropyran (DHP) template 283284 and 285 The di-DHPs were functionized in a twodirectional sense using dihydroxylation reactions The two-directional approach was often very efficient indeed forexample in the synthesis of 286 six new stereogenic centerswere introduced with almost complete stereocontrol using areduction and a dihydroxylation reaction The approach isnot restricted to the synthesis of C2-symmetricaldisaccharide mimetics Using the unsymmetrical template285 which has both a pseudo-axial and a pseudo-equatorialhydroxyl groups the unsymmetrical mimetics 289 and 290were prepared (Scheme 50)
6 RADICAL APPROACHES
The radical approach for C-C bond formation is a popularmethod within organic chemistry The use of radicalchemistry in carbohydrate synthesis has certain advantagesFirstly the reaction conditions are very mild and tolerant ofa range of functional and protecting groups Secondanomeric radicals are stable with respect to elimination andepimeration Most significantly the chemistry required toincorporate an appropriate substitute at C-1 employed in theinitial hemolytic cleavage step is common within carbo-hydrate chemistry [55] The use of such radical techniquecan be subdivided into two classes intermolecular andintramolecular approaches
61 Intermolecular Radical Approaches
Giese was the first to employ an intermolecular radical-based approach for synthesis of C-disaccharides [56]Addition of an alkene to an anomeric radical underappropriate conditions allowed exclusive entry to the α-linked C-glycoside a result which was mirrored by the workof Baldwin [57] The high α-selectivity of the reaction wasin contrast with other reports Thus radicals generated at theC-2 C-3 and C-4 centers all preferred to occupy equatorialpositions [58] When the anomeric bromide 291 was treatedwith tin hydride and AIBN resulting anomeric radical andreacted with lactone 292 in a Michael addition it afforded293 In this reaction hydrogen abstraction at the resulting
radical center occurs from axial face to selectively generatethe equatorial C-2rsquo substituent Reduction and acetylation of293 furnished C-disaccharide 294 (Scheme 51) [59]
Witczak used the facial bias of levoglucosene tostereoselectively add a carbohydrate-based radical in thepreparation of the 3-deoxy-(1rarr4)-β-C-disaccharide 299[60] Addition of the radical derived from iodide 295 to 296gave adduct 297 in 26 yield Removal of the anomerichydroxyl of 297 was achieved by treatment with triethylsilane borontrifluoride ether complex followed bystereoselective reduction of the keto function at C-2rsquo withthe formation of 298 in 89 yield Debenzylation followedby acetolysis of 16-anhydro ring produced the peracetylatedtarget C-disaccharide 299 in 19 overall yield from 295(Scheme 52)
Vogel has developed general methods to transformenantiomerically pure 7-oxabicyclo[221]heptyl derivatives(ldquonaked sugarsrdquo) into C-disaccharides Because of thesechiral bicyclic skeletons they undergo highly stereoselectivereactions with predictable diasteroselectivities An arsenal ofmethods is available that allow to substitute these ldquonakedrdquocarbon centers with a variety of functional groups with allpossible relative configurations The methods allowpreparation of both enantiomers of a given target with thesame ease Predictably high stereoselectivity of the reactionsof the bicyclic chirons adds to the flexibility of approachwhich can lead to high molecular diversity [61]
α-C-(1rarr3)-mannopyranoside of N-acetyl-galactosaminepotent β-galactosidase inhibitors was synthesized by thisapproach [61] Enone 302 was readily prepared from 300The addition of the radical derived from bromide 303 toenone 302 afforded the αminusisomer 304 The ketone was thenreduced and the selenide eliminated via the intermediacy ofthe selenoxide to give 305 Acid-promoted (CF3SO3H) 7-oxa ring opening of 305 in MeCN produced the amino-conduritol derivative 306 resulting from the quenching of theallylic cation intermediate by the solvent (Ritter reaction)Ozonolysis of the chloroalkene 306 generated an acylchloride-aldehyde intermediate that reacted with MeOH toproduce a mixture of methyl uronates The major compound307 was silylated and reduced The crude polyol obtainedwas acetylated to produce 308 Desilylated and ammonolysisafforded a mixture of α-β-pyranoses 309 and correspondingα-β-furanoses (Scheme 53)
Similar chemistry was carried out to synthesize non-protected α-C(1rarr2)-L-fucopyranoside of D-galactopyrano-side corresponding to a blood group mimetic [62] Giesersquosradical fucosidation of racemic enone 310 with α-L-bromoacetofucose 311 provided the mixture of diastereo-meric α-C-fucoside 312a and 312b in reproducible yield of78 Reduction of the mixture gave a 11 mixture of endo-alcohols 313 and 314 which were isolated pure in 40 and355 yield respectively Oxidative elimination of thebenzeneselenyl group of 313 followed by acetylation gaveendo acetate 315 in 85 yield Acid-promoted ring openingof 315 and ozonolysis of the resulted chloroalkene gavemethyl uronic ester 316 in modest yield (10) Treatment of316 with Cl3CCN and NaH followed with BF3
OEt2
furnished the totally protected C-disaccharide 317 in 79
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1423
Scheme (49)
Bu3SnO
HOAcO
OMeOAc
OAc
O
AcO
OMeOAc
OAcI
AIBN
O
AcO
OMeOBn
OBn
HO2C O
AcO
OMeOR
ORY
X
OHBnO
BnO
OBn
OBnO
BnO
OBn
O
AcO
OMeOBn
OBnX
i-Pr i-Pr
N
Mo C(Me2 Ph)((CF3)2 MeCO)2
O
RO
OMeOR
O
RO
OR
OR
RO
OR
278
I2 Ph3P
imidazole
269 270 93
271a X = CH2CH=CH2 Y = H R = Ac 64271b Y = CH2CH=CH2 X = H R = Ac 11272a X = CH2CH=CH2 Y = H R = Bn 75272b Y = CH2CH=CH2 X = H R = Bn 75273a X = CH2CHO Y = H R = Bn 79273a Y = CH2CHO X = H R = Bn 79
1 NaOMe MeOH2 NaOH BnBr DMF
OsO4 NaIO4
NaClO2 NaH2PO4
274 96
275
DCC 4-DMAP
276 X = O 82
277 X = CH2 51
TiCl4 Zn dust TMEDA CH2Br2PbCl2 (Cat )
1
2 BH3 THF H2O2 NaOH
H2 PdC EtOH
Ac2 O Pyr 4-DMAP
279 R = Bn R = H 64
280 R = R = H 99
281 R = R =Ac 97
1424 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (50)
Scheme (51)
O OOH
OH
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
286
1 VO(acac)2 t-BuOH 95
2 (MeO)3CH BF3 90
1 P-O2NC6H4 CO2H Ph3P DIAD2 K2CO3 MeOH 82 over 2 steps
1 PhCOCl Et3N DMAP 402 P-O2NC6H4 CO2H Ph3P DIAD3 KOH THF-H2O 75 over 2 steps
TMEDA OsO4
Cat OsO4 NMO 287
Cat OsO4 NMO288
TMEDA OsO4
Cat OsO4 NMO
290
289
(RR)-282283
284
285
OHO
AcO
BrOAc
OAc
BnO
O
OBn
OBnO
OHO
AcOOAc
OAc
BnO
OOBn
OBnAcO
OHO
AcOOAc
OAc
BnO
O
OBn
OBnO
+
Bu3SnH AIBN291
292
293 81
1 Na[Al(OC2H4OMe)2(OEt)H]2 Ac2O pyr
294 56 over 2 steps
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1425
Scheme (52)
Scheme (53)
OBnO
BnOOBn
OBn O
OH
O
OBnO
BnO
OHOBn
OBn O
O
O
O
O
O
OBnO
BnOOBn
OBnO
OAcOAc
OAc
OBnO
BnO
OHOBn
OBn
IBu3SnH AIBN
295 297 26
1 BF3 OEt2 Et3SiH
2 L-Selectride THF
1 Pd(OH)2C C6H10 EtOH
2 EtSiOSO2CF3 Ac2O
298 89 over 2 steps299
296
O
O
PhSeClO
O
PhSeCl
Bu3 SnH
O
O
PhSeCl
R
H
O
OAc
R
Cl
O
AcO
OAc
OAc
OAcOH
Cl
NHAc
R
OAc
AcHN
OH
O
OH OAc
OH
OHO
HO
OH
O
AcO
OAc
OAc
OAcBr
O
O
PhSeCl
O
O
PhSeCl
R
O
OTIPSAcHNR
OAc OAc
O
OHAcHN
COOMe
R
OAc
1 Bu4NF
2 NH3MeOH
1 (Me3Si)2NLi THF2 Me2N=CHI
1 Bu3 SnH AIBN2
1 NaBH42 mCPBA3 Ac2O pyr
1 H+ MeCN
2 H2 O NaHCO3
R =
1 O3MeOH
2 Me2S NaHCO3
1 TIPSOTf 26-lut idine2 LiBH43 Ac2 O pyr DMAP
furanoses +
304 56
305 68 306 84307 50
308 46
300 301 302
303
309
1426 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
The reduction of 317 and treatment with DOWEX-H+ resinprovided the desired C-fucoside 318 in 70 (Scheme 54)
62 Intramolecular Radical Approaches
One disadvantage with the intermolecular approaches isthat during such radical mediated reactions electrondeficient alkenes are required to facilitate C-C bondformation The intramolecular approach of Sinayuml overcomes
this drawback by bring two substrates together via atemporary covalent silaketal connector This enables the useof a wider range of alkenes which can include alkene-functionalized sugars thus leading to the generation of C-disaccharides [63] Based on the early work of Stork Sinayumlemployed the tether reaction in the synthesis of both α- andβ-C-disaccharides with this work subsequently beingemployed in the synthesis of biologically significant natural
Scheme (54)
O
OH
Fuc
Cl
O
O
ClPhSe
OOAc
NHAcOHFuc
O
AcOOAc
AcO
Br
O
O
PhSeCl
O
AcOOAc
AcO
O
OH
PhSe Cl
Fuc
OOAc
NHAc
OMe
Fuc
O
AcHN
OH OAc
OH
O
OH
Me
OH
O
O
Fuc
ClSePh
O
HO
Fuc
ClSePh
+
Ph3SnHAIBN
78 combined yield
Fuc
310
+
1 NaBH4 MeOHTHF2 Chromatography
313 40 314 355
1 mCPBA
2 Ac2O pyr DMAP
+
315 75
1 TfOH MeCN
2 NaHCO3 O3 -78 oC
316 10 over 2 steps
1 Cl3 CCN NaH
2 MeOH BF3 OEt2
317 79
1 LiBH4 THF
2 Dowex-H+
311
312a312b
318 70 for 2 steps
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1427
products [64] The availability of different hydroxyl groupson each monosaccharide unit allowed the fine-tuning ofstereochemical outcome by selective positioning of the silyltether [65] Development of this early stereochemical controlled to the tethering of the donor 320 with alcohol 319through a di-isopropyl silicon tether 321 Subsequent treat-ment with Bu3SnH and AIBN led to a 9-endo-trigcyclization to form the C-disaccharide 322 in an 80 yieldwith exclusive formation of the α-product The silyl tetherwas removed with Bu4NF and deprotection under standardconditions afforded the desired disaccharide 323 in excellentyield (Scheme 55)
In parallel the development of a 32rsquo silyl tether allowedaccess to the β-linked product as demonstrated in Sinayumlrsquossynthesis of methyl β-C-lactoside 328 [66] Alcohol 324 and320 were connected via the dimethylsilyl tether an 8-endo-trig cyclization followed to exclusively afford the β-
disaccharide 326 in 45 yield Removal of the tether anddeprotection of benzyl ether gave β-C-disaccharide 328(Scheme 56)
This group also selected iodosugars bearing a freehydroxyl group as progenitors of the radical donors [67] In atypical experiment the radical donor 329 was connected tothe radical acceptor 330 through a silaketal tether followingtheir procedure Tributyltinhydride mediated 8-endo-trigradical cyclization of compound 331 gave after detetheringof the non isolated intermediate 332 the protected β-C-disaccharide 333 in 37 overall yield (from startingmaterials 330 and 329) Peracetate 335 was achieved afterhydrogenolysis The C-laminaribioside 334 is of potentialbiological interest as it mimics the repeating disaccharideunit of fungal β-(1rarr3)-glucans which have antitumor andimmunomodulating properties (Scheme 57)
Scheme (55)
Scheme (56)
OO
OHSePh
OTBDPSO O
OO
SePh
OTBDPSO
OO
OBnOMe
OBn
Si
O
HOOBn
OMe
OBn
O
HOOH
OHHO
O
HOOH
OMe
OH
OTBDPSO
O
HOOBn
OMe
OBnO
OOH
1 n-BuLi THF
2 iPr2SiCl2 -78 oC
3 DMAP THF rt
1 Bu4NF THF
2 Dowex-H+
3 H2 PdC
Bu3SnH AIBN toluene
319
320
321
322323
OBnO
OHSePh
OBnBnO
OHO
OBnOMe
OBn
ROO
ROOH
OR
OHO
OROMe
OR
OBnO
O
OBnBnO
OO
OBnOMe
OBn
Si
SePh
OBnO
O
OBnBnOO
OOBn
OMe
OBn
Si
1 PhSeH Me2SiCl2
BuLi -78 oC
2 imidazole rt
Bu3SnH AIBN toluene
H2 PdC327 R = Bn
328 R = H
Bu4NF THF
324
320
325
326 45
1428 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
CONCLUSIONS
In this paper the biological importance of C-oligo-saccharides as subunits of natural products and as a newgeneration of carbohydrate based on therapeutics has beenillustrated Different methods are available for the synthesisof C-oligosaccharides As with traditional saccharidesynthesis it has been necessary to develop a number ofspecific approaches to facilitate the regioselective andstereoselective preparation of the desired targets Work inthis area continues and it is expected that many interestingnew C-oligosaccharides will be prepared using the chemistrydescribed in this review It is also likely that new chemistrywill be developed in the future for the preparation of thesebiologically important targets
ACKNOWLEDGEMENTS
The authors thank Dr Sultan Baytas for her criticalreading of this manuscript
REFERENCES
[1] Kennedy J F White C A Bioactive Carbohydrates InChemistry Biochemistry and Biology Ellis Horwood LtdChichesterUK 1983
[2] Wassarman PW Mammalian Fertilization Molecular Aspects ofGamete Adhesion xocytosion Exocytosis and Fusion Cell 199996 175-183
[3] Carbohydrate-based Drug Discovery Wong C-H EdWeinheim Cambridge Wiley-VCH 2003
[4] (a) Sharon N Lis H Lectins as Cell Recognition MoleculesScience 1987 246 227-234 (b) Dwek RA Chem Rev 1996 96683-720
[5] Postema M C-Glycoside synthesis CRC Boc Ratom 1995[6] (a) Weatherman R V Mortell K H Cheruenak MKiessling
L L Toone E J Specificity of C-Glycoside Complexation byMannoseGlucose Specific Lectins Biochem 1996 35 3619-3624(b) Ravishankar R Surolia A Vijayan M Lim S Kishi YPreferred Conformation of C-Lactose at the Free and Peanut LectinBound States J Am Chem Soc1998 120 11297-11303
[7] (a)Wong C-H Halcomb R L Ichikawa Y and Kajimoto TEnzymes in organic synthesis Application to the problems ofcarbohydrate recognition part2 Angew Chem Int Ed Engl 199534 521-546 (b)Howard S Withers SG Bromoketone C-Glycosides a New Class of βminusGlucanase Inactivators J AmChem Soc 1998 120 10326-10331(c) Wang Q Wolff MPolat T Du Y Linhardt R J C-glycoside of Neuraminic Acidsas Neura-minidase Inhibitors Bioorg Med Lett 2000 10 941-944 (d) Phili R Chang J Partis R A Mueller R A ChrestF J Passaniti A The Alpha-glucosidase I InhibitorCastanospermine Alters Endothelial cell Glycosylation PreventsAngiogenesis and Inhibits Tumor Growth Cancer Res 1995 552927-2935
[8] Ossor A Elbein A D In Carbohydrates in Chemistry andBiology Vol 3(II) WileyVCH 2000 pp 513-539
[9] (a) Sinayuml P Synthesis of oligosaccharide Mimetics Pure ApplChem 1997 69 459-463 (b) Beau J-M Gallagher TNucleophilic C-glycosyl Donors for C-glycoside Synthesis Top inCurr Chem 1997 187 1-54 (c) Nicotra F Synthesis of C-glycosides of Biological Interest Top in Curr Chem 1997 187
Scheme (57)
O
O
O
Ph
I
OMe
OHO
BnO
OH
OH
BnOOH
O
BnO
Si
O
O O
Ph
I
OMe
O
O
BnO
OR4O
R5O
OMe
OR2
OR3O
R3O
OR1
R3O
Bu3 SnH AIBN
332 R1 R2 = SiMe2 R3 = Bn R4 R5 = CHPhTBAF THF
333 R1 = R2 = H R3 = Bn R4 = R5 = CHPh 37 from 11
334 R1 = R2 = R3 = R4 = R5 = H
335 R1 = R2 = R3 = R4 = R5 = Ac
329
H2 PdC MeOH
Ac2 O pyr
1 BuLi THF -78 oC
2 Me2SiCl2
3 DMAP
330
331
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1429
55-83 (d) Du Y Linhardt R Y Recent Adv in Stereo-SelectiveC-Glycoside Synthesis Tetrahedron Lett 1998 54 9913-9959 (e)Liu L Mckee M and Postema M H D Synthesis of C-saccharides and Higher Congeners Current Org Chem 2001 51133-1167
[10] Jarosz S Fraser-Reid B Synthesis of A Higher Carbon Sugar ViaDirected Aldol Condensation Tetrahedron Lett 1989 30 2359-2362
[11] Lichtenthaler F W Lergenmiiller M Schwidetzky S C-Glycosidations of 2-Ketohexosyl With Electrophilic Radical andNudeophilic Anomeric Carbons Eur J Org Chem 2003 3094-3103
[12] Baudat A Vogel P Aza-C-disaccharides Synthesis of 6-Deoxygalactonojirimycin-β-C(1rarr3) Linked with D-Altrofuranosides and D-Galactose J Org Chem 1997 62 6252-6260
[13] Turner D Vogel P Synthesis of 4-Hydroxy-26-Bis(hydroxymethyl) tetrahydropyran-2-Carbaldehyde DerivativesSynlett 1998 304-306
[14] Zhu Y-H Vogel P Short Stereoselective Synthesis of C-(1rarr3)-Linked Disaccharides Tetrahedron Lett 1998 39 31-34
[15] Zhu Y-H Vogel P Synthesis of a (2R 6R)-2-(Hydroxymethyl)-6-Propa-1 2-Dienyl-2H-Pyran-3(6H)-One Derivative A NewEnone for The Convergent Construction of C-Glycosides of C-Disaccharides Synlett 2001 82-86
[16] Baumberger F Vasella A Deoxynitrosugars The 6th
Communication Stereolectronic Control in the reductivedenitration of tertiary nitro ethers A Synthesis of ldquoC-glycosidesrdquoHelv Chim Acta 1983 66 2210-2221
[17] Martin O R Lai W Synthesis and Conformational Studies of β-(1rarr6)- and ββ-(1rarr1)-Linked C-disaccharides J Org Chem1993 58 176-185
[18] Spak S J Martin R The synthesis of an analogue of Methyl OC-Analogue of Methyl 4rsquo-O-β-D-GlucopyranosylgentiobiosideTetrahedron 2000 56 217-224
[19] Kobertz W R Bertozzi C R Bednarski M D C-GlycosylAldehyde Synthons for C-Linked Disaccharides J Org Chem1996 61 1894-1897
[20] Gurjar M K Nagaprasad R and Ramana CV First Synthesis ofMethyl α-C-D-Arabino-furanosyl-(1rarr5)-αminusD-Arabinofuranosidethe C-Disaccharide Segment of Motif C of MycobateriumTuberculosis Tetrahedron Lett 2000 43 7577-7579
[21] Witczak Z J Synthesis of C-Glycosyl Compounds and OtherNatural Products from Levoglucosenone Pure Appl Chem 199466 2189-2192
[22] Griffin F K Paterson D Taylor R J K Ramberg-BacklundApproaches to the Synthesis of C-Linked Disaccharides AngewChem Int Engl 1999 38 2939-2942
[23] Paterson B E Griffin F K Alcaraz M-L and Taylor R J KA Ramberg-Baumlcklund Approach to the Synthesis of C-GlycosidesC-Linked Disaccharides and C-Glycosyl Amino Acids Eur JOrg Chem 2002 1323-1336
[24] McAllister G D Paterson D E Taylor R J K A SimplifiedRamberg-Bachlund Approach to Novel C-Glycosides and C-Linked Disaccharides Angew Chem Int Ed Engl 2003 42 1387-1391
[25] McCartney J L Christopher T M Cicchillo R M BernardinaM D Wagner T R and Norris P J Org Chem 2003 6810152-10155
[26] Dondoni A Zuurmond H M Bascarate A Synthesis of α-andβ-D-(1rarr6)-C-Disaccharides by Witting Olefination of Formyl C-Glycosides with Glycopyranose 6-phosphoranes J Org Chem1997 62 8114-8124
[27] Dondoni A Kleban M Zuurmond H Marra A Synthesis of(1rarr6)-C-Oligogalactosides by Interative Wittig OlefinationTetrahedron Lett 1998 39 7991-7994
[28] Dondoni A Marra A A New Synthetic Approach toMycobacterial Cell Wall α-(1rarr5)-D-Arabinofuranosyl C-Oligosaccharides Teterahedron Lett 2003 44 4067-4071
[29] Colinas P A Ponzinibbio A Lieberknecht A and Bravo R OWittig Reaction of Glycosyl Phosphonium Salts A StereoselectiveRoute to C-Disaccharides and C O-Trisaccharides TetrahedronLett 2003 44 7985-7988
[30] Schmidt R R Preuss R Synthesis of Carbon Tetrahedron Lett1989 30 3409-3412
[31] Dietrich H Schmidt R R Synthesis of Carbon-Bridged C-Lactose and Derivatives Liebigs Ann Chem 1994 975-981
[32] Rouzaud D Sinayuml P The First Synthesis of a ldquoC-DisacchariderdquoJ Chem Soc Chem Commun 1983 1353-1354
[33] Xin Y-C Zhang Y-M Mallet J-M Glaudemans C P JSinayuml P Synthesis of C-Oligosaccharides That Mimie TheirNatural O-Analogues Immunodeterminants in Binding toMonoclonal Immunoglobulins Eur J Org Chem 1999 471-476
[34] Streicher H Geyer A Schmidt R R C-Disaccharides ofKetoses Chem Eur J 1996 2 502-510
[35] Leeuwenburgh M A Timmers C M Vander Marel G A VanBoom J H Mallet J-M Sinayuml P G Stereoselective Synthesisof α-C-(Alkynyl)-Glycosides Via Ring-Opening of α-12-Anhydrous Tetrahedron Lett 1997 38 6251-6254
[36] Aslam T Fuchs M G G Le Formal A Wightman R HSynthesis of C-Disaccharide Analogue of the α-D-Arabinofuranosyl-(1rarr5)-α-Arabinofuranosyl Motif ofMycobacterial Cells Walls via Alkynyl Intermediates TetrahedronLett 2005 46 3249-3252
[37] (a) Girad P Namy J L Kagan H B Divalent LanthanideDerivative in Organic Synthesis 1 Mild Preparation of SamariumIodide and Ytterbium Iodide and Their Use as Reducing orCoupling Agents J Am Chem Soc 1980 102 2693-2698 (b)Molander G A Harris C R Sequencing Reactions withSamarium(II) Iodide Chem Rev 1996 96 307-338
[38] (a) Mazeacuteas D Skrydstrup T Doumeix O Beau J-MSamarium Iodide-Induced Intramolecular C-Glycoside FormationEfficient Radical Formation in the Absence of an Additive AngewChem Int Ed Engl 1994 33 1383-1386 (b) Mazeacuteas DSkrydstrup T Beau J-M A Highly Stereoselective Synthesis of1 2-trans-C-Glycosides Via Glycosyl Samarium(III) CompoundsAngew Chem Int Ed Engl 1995 34 909-912 (c) Jarreton OSkrydstrup T Beau J-M The Stereospecific Synthesis of Methylα-C-Mannobioside A Potential Inhibitor of M TuberculosisBinding to Human Macrophages J Chem Soc Chem Commun1996 1661-1662 (d) Jarreton O Skrydstrup T Espionosa J-FJimeacutenez-Barbero J Beau J-M Samarium Diiode Prompted C-Glycosylation An Application to The Stereospecific Synthesis ofα-(1rarr2)-C-Mannobioside and Its Derivatives Chem Eur J 19995 430-441 (e) Mipuel N Doisneau G Beau J-M ReductiveSamariation of Anomeric 2-Pyridyl Sulfones with Catalytic AnUnexpected Improvement in The Synthesis of 12-Trans-Diequatorial C-Glycosyl Compounds Angew Chem Int Ed Engl 2000 39 4111-4114
[39] Vlahov I R Vlahova P I Linhardt R J DiastereocontrolledSynthesis of Carbon Glycosides of N-Acetylneuraminic Acid ViaGlycosyl Samarium(III) Intermediates JAmChem Soc 1997 1191480-1481
[40] Kuberan B Sikkander S ATomiyama H Linhardt R JSynthesis of a C-Glycoside Analogue of sTn An HIV-and Tumor-Associated Antigen Angew Chem Int Ed Engl 2003 42 2073-2075
[41] Bazin H G Du Y Polat T Linhardt R J Synthesis of aVersatile Neuraminic Acid ldquoCrdquo-Disaccharide Precursor for theSynthesis of C-Glycoside Analogues of Gangliosides J OrgChem 1999 64 7254-7259
[42] Chen C-C Ress D K Linhardt RJ Samarium Iodide-Mediated Synthesis of Neuraminic Acid C-Glycosides InSynthesis of Glycommetics Roy R Ed ACS Syposium Series2004 896 53-80
[43] Abdallah Z Doisneau G Beau J-M Synthesis of a Carbon-Linked Mimic of The Disaccharide Component of The Tumor-Relate SialyTn Antigen Angew Chem Int Ed Engl 2003 425209-5212
[44] Lay L Nicotra F Panza L Russo G Caneva E Synthesis ofC-disaccharides through dimerization of exo-glycals J Org Chem1992 57 1304-1306
[45] Isobe M Nishizawa R Hosokawa S Nishikawa TStereocontrolled Synthesis and Reactivity of Sugar Acetylenes JChem Soc Chem Commun 1998 2665-2676
[46] Saeeng R Sirion U Sahakitpichan P Isobe M IodineCatalyzes C-Glycosidation of D-Glucal with SilylacetykeneTetrahedron Lett 2003 44 6211-6215
[47] (a) Babirad S A Wang Y Kishi Y Synthesis of C-Disaccharides J Org Chem 1987 52 1370-1372 (b) Wang YBabirad S A Kishi Y Preferred Conformation of C-Glycosides
1430 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
8 Synthesis of 14-Linked Carbon Disaccharides J Org Chem1992 57 468-481
[48] Armstrong R W Sutherlin D P Strategies for the Synthesis ofC-Disaccharides Containing D and L Sugars Tetrahedron Lett1994 35 7743-7746
[49] Wei A Kishi Y Preferred Conformation of C-Glycosides 12Synthesis and Conformational Analysis of αα- α β- and β β-Trehaloses J Org Chem 1994 59 88-96
[50] Haneda T Goekjian P G Kim S H Kishi Y PreferredConformation of C-Glycosides 10 Synthesis and ConformationAnalysis of Carbon Trisaccharides J Org Chem 1992 57 490-498
[51] Sutherlin D P Armstrong R W Synthesis of 12 Stereochemistryand Structurally Diverse C-Trisaccharides J Org Chem 1997 625267-5283
[52] Notz W Hartel C Waldscheck B Schmidt R R De NovoSynthesis of a Methylene-Bridged Neu5Ac-α-(23)-Gal C-Disaccharide J Org Chem 2001 66 4250-4260
[53] (a) Postema M H D Calimente D Liu L Behrmanm T L AnOlefin Metathesis Route for the Preparation of (1rarr6)-Linked-C-Disaccharide Glycals A Convergent and Flexible Approach to C-Saccharide Synthesis J Org Chem 2000 65 6061-6068(b) Postema M H Piper J L Liu L Faust M Andreana PSynthesis and Partial Biological Evaluation of a Small Library ofDifferentially Linked β-C-Disaccharide J Org Chem 2003 684748-4754
[54] Nelson A The Development of Strategies and Methods for TheSynthesis of Biologically Active Compounds New J Chem 200428 771-776
[55] Togo H He W Waki Y Yokoyama M C-GlycosylationTechnology With Free Radiant Reactions Synlett 1998 700-717
[56] Giese B Dupuis J Diastereoselective Synthesis of C-Glycopyranosides Angew Chem Int Ed Engl 1983 22 622-623
[57] Adlington R M Baldwin J E Basak A Kozyrod RPApplication of Radical Addition Reactions to tho Synthesis of a C-Glucoside and A Functionalized Amino Acid J Chem SocChem Commun 1983 144-145
[58] Giese B Gonzaacutelez-Goacutemez J A Witzel T The Scope of RadicalCC-Coupling by The ldquoTin Methodrdquo Angew Chem Int Ed Engl1984 23 69-70
[59] Giese B Witzel T Synthesis of ldquoC-Disaccharidesrdquo by RadicalC-C Bond Formation Angew Chem Int Ed Engl 1986 25 450-451
[60] Witczak Z J Chhabra R Chojnacki J C-Disaccharides IStereoselective Approach to β-(1rarr4)-3-Deoxy-C-Disaccharidesfrom Levoglucosenone Carb Res 1997 301 167-175
[61] Vogel P Synthesis of Rare Carbohydrates and Analogues Startingfrom Enantiomerically Pure 7-Oxabicyclo[221]heptyl Derivatives(ldquoNaked Sugarsrdquo) Current Org Chem 2000 4 455-480
[62] Viodeacute C Vogel P Synthesis of The C-Disaccharide α-C(1rarr3)-L-Fucopyranoside of N-Acetylgalactosamine J Carb Chem2001 20 733-746
[63] Xin Y C Mallet J M Sinayuml P An Expeditious Synthesis of AC-Disaccharide Using A Temporary Silaketal Connection J ChemSoc Chem Commun 1993 864-865
[64] (a) Petitou M Herault P Lormeau J-C Helmboldt A MalletJ-M Sinayuml P Herbert J-M Introducing A C-InterglycosidicBond in A Biologically Active Pentasaccharide Hardly Affects ItsBiological Properties Bioorg Med Chem 1998 6 1509-1516 (b)Sinayuml P Advances in The Synthesis of the Carbohydrate MimicsPure Appl Chem 1998 70 1495-1499
[65] Sinayuml P Chemical Synthesis of Oligosaccharide Mimetics PureAppl Chem 1998 70 407-410
[66] Sinayuml P Chemical Synthesis of Oligosaccharide Mimetics PureAppl Chem 1998 69 459-463
[67] Vauzeilles B Sinayuml P Selective Radical Synthesis of β-C-Disaccharides Tetrahedron Lett 2001 42 7269-7272
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1421
Scheme (48)
O
OO
Se Ph
R
O
HO OHOH
O
OB n O B n
OB n
O B nO O
O O
R O OR
X
O
OO
R
Se Ph
O
HOOH
OH
O
OB nOB n
O Bn
OB n
O O
O O
R O O R
O H
O
O B n OB n
O B n
OB n
O
C HO
O
O O
R O OR
OAc HN
OAc
C O2NH 4HOOH
OH
O
OH O H
OH OH
O
OB n O B n
OB n
OB nO O
O O
R O OR
X
O
O
OAcOAc
C HOA cOOAc
OAc
O
OB n O B n
OB n
OB n
O
O Bn OB n
OB n
OB n
X
OH
OO
HOOH
OH
O
O
OMeOB n
OB nOB n
R
t-B uL i256 R = Li
257 R = L i
258
(R = t-B uMe 2Si )
(R = t-B uMe 2Si )
259ab (32) 79 com bine d yi eld
De ss-Ma rtin pe riodinane
260 X = O R = t-B uMe 2Si ) 95
261 X = O R = t -B uMe2S i) 62
T e bbe re age nt
TB A F THF262 X = O R = H 94
diphosge ne
C H2C l 2Pyr
263 95
T HFH2O T FAr t
264 quant it a ti ve yie ld
PhSe C l AgOT f
EtC N -80 oC
265
266
Quant it at i ve yi l ed 25 26 7 1
+
R =
1 Ac 2OPyr
2 mC PB A3 Ac 2ONa OAc
4 NaO HT HFMe OH
5 Ac2O P yr
267 90 overa ll yi e ld
ste ps
268
1422 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
glucopyranoside 280 represents an example of thischemistry The known triacetyl glucopyranoside 269 wasconverted to iodide 270 in good yield Radical allylation of271 proceeded to afford a mixture of equatorial and axialallylation products in a 61 ratio Oxidative cleavage of thedouble bond gave the corresponding aldehydes 273a and273b which were separable Pinnick oxidation of the majoraldehyde 273a then gave the C-4 equatorial acid 274 DCC-mediated coupling of alcohol 275 and acid 274 proceeded toafford ester 276 in good yield Methylenation of 276 gave277 and exposure to catalysist 278 gave a 41 yield of theC-disaccharide glycal which was exposed to an excess ofBH3
THF to give 64 yield of the β-C-disaccharide 279Removal of the benzyl groups and global peracetylation gavethe peracetylated (1rarr4)-β-C-disaccharide 281 in good yield(Scheme 49)
54 Ring Expansion-Cyclization
Nelson developed a new strategy for asymmetric andstereoselective synthesis of C-linked disaccharide mimeticsthe C58-C71 fragment of palytoxin [54] The diol (RR)-282was converted into the di-dihydropyran (DHP) template 283284 and 285 The di-DHPs were functionized in a twodirectional sense using dihydroxylation reactions The two-directional approach was often very efficient indeed forexample in the synthesis of 286 six new stereogenic centerswere introduced with almost complete stereocontrol using areduction and a dihydroxylation reaction The approach isnot restricted to the synthesis of C2-symmetricaldisaccharide mimetics Using the unsymmetrical template285 which has both a pseudo-axial and a pseudo-equatorialhydroxyl groups the unsymmetrical mimetics 289 and 290were prepared (Scheme 50)
6 RADICAL APPROACHES
The radical approach for C-C bond formation is a popularmethod within organic chemistry The use of radicalchemistry in carbohydrate synthesis has certain advantagesFirstly the reaction conditions are very mild and tolerant ofa range of functional and protecting groups Secondanomeric radicals are stable with respect to elimination andepimeration Most significantly the chemistry required toincorporate an appropriate substitute at C-1 employed in theinitial hemolytic cleavage step is common within carbo-hydrate chemistry [55] The use of such radical techniquecan be subdivided into two classes intermolecular andintramolecular approaches
61 Intermolecular Radical Approaches
Giese was the first to employ an intermolecular radical-based approach for synthesis of C-disaccharides [56]Addition of an alkene to an anomeric radical underappropriate conditions allowed exclusive entry to the α-linked C-glycoside a result which was mirrored by the workof Baldwin [57] The high α-selectivity of the reaction wasin contrast with other reports Thus radicals generated at theC-2 C-3 and C-4 centers all preferred to occupy equatorialpositions [58] When the anomeric bromide 291 was treatedwith tin hydride and AIBN resulting anomeric radical andreacted with lactone 292 in a Michael addition it afforded293 In this reaction hydrogen abstraction at the resulting
radical center occurs from axial face to selectively generatethe equatorial C-2rsquo substituent Reduction and acetylation of293 furnished C-disaccharide 294 (Scheme 51) [59]
Witczak used the facial bias of levoglucosene tostereoselectively add a carbohydrate-based radical in thepreparation of the 3-deoxy-(1rarr4)-β-C-disaccharide 299[60] Addition of the radical derived from iodide 295 to 296gave adduct 297 in 26 yield Removal of the anomerichydroxyl of 297 was achieved by treatment with triethylsilane borontrifluoride ether complex followed bystereoselective reduction of the keto function at C-2rsquo withthe formation of 298 in 89 yield Debenzylation followedby acetolysis of 16-anhydro ring produced the peracetylatedtarget C-disaccharide 299 in 19 overall yield from 295(Scheme 52)
Vogel has developed general methods to transformenantiomerically pure 7-oxabicyclo[221]heptyl derivatives(ldquonaked sugarsrdquo) into C-disaccharides Because of thesechiral bicyclic skeletons they undergo highly stereoselectivereactions with predictable diasteroselectivities An arsenal ofmethods is available that allow to substitute these ldquonakedrdquocarbon centers with a variety of functional groups with allpossible relative configurations The methods allowpreparation of both enantiomers of a given target with thesame ease Predictably high stereoselectivity of the reactionsof the bicyclic chirons adds to the flexibility of approachwhich can lead to high molecular diversity [61]
α-C-(1rarr3)-mannopyranoside of N-acetyl-galactosaminepotent β-galactosidase inhibitors was synthesized by thisapproach [61] Enone 302 was readily prepared from 300The addition of the radical derived from bromide 303 toenone 302 afforded the αminusisomer 304 The ketone was thenreduced and the selenide eliminated via the intermediacy ofthe selenoxide to give 305 Acid-promoted (CF3SO3H) 7-oxa ring opening of 305 in MeCN produced the amino-conduritol derivative 306 resulting from the quenching of theallylic cation intermediate by the solvent (Ritter reaction)Ozonolysis of the chloroalkene 306 generated an acylchloride-aldehyde intermediate that reacted with MeOH toproduce a mixture of methyl uronates The major compound307 was silylated and reduced The crude polyol obtainedwas acetylated to produce 308 Desilylated and ammonolysisafforded a mixture of α-β-pyranoses 309 and correspondingα-β-furanoses (Scheme 53)
Similar chemistry was carried out to synthesize non-protected α-C(1rarr2)-L-fucopyranoside of D-galactopyrano-side corresponding to a blood group mimetic [62] Giesersquosradical fucosidation of racemic enone 310 with α-L-bromoacetofucose 311 provided the mixture of diastereo-meric α-C-fucoside 312a and 312b in reproducible yield of78 Reduction of the mixture gave a 11 mixture of endo-alcohols 313 and 314 which were isolated pure in 40 and355 yield respectively Oxidative elimination of thebenzeneselenyl group of 313 followed by acetylation gaveendo acetate 315 in 85 yield Acid-promoted ring openingof 315 and ozonolysis of the resulted chloroalkene gavemethyl uronic ester 316 in modest yield (10) Treatment of316 with Cl3CCN and NaH followed with BF3
OEt2
furnished the totally protected C-disaccharide 317 in 79
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1423
Scheme (49)
Bu3SnO
HOAcO
OMeOAc
OAc
O
AcO
OMeOAc
OAcI
AIBN
O
AcO
OMeOBn
OBn
HO2C O
AcO
OMeOR
ORY
X
OHBnO
BnO
OBn
OBnO
BnO
OBn
O
AcO
OMeOBn
OBnX
i-Pr i-Pr
N
Mo C(Me2 Ph)((CF3)2 MeCO)2
O
RO
OMeOR
O
RO
OR
OR
RO
OR
278
I2 Ph3P
imidazole
269 270 93
271a X = CH2CH=CH2 Y = H R = Ac 64271b Y = CH2CH=CH2 X = H R = Ac 11272a X = CH2CH=CH2 Y = H R = Bn 75272b Y = CH2CH=CH2 X = H R = Bn 75273a X = CH2CHO Y = H R = Bn 79273a Y = CH2CHO X = H R = Bn 79
1 NaOMe MeOH2 NaOH BnBr DMF
OsO4 NaIO4
NaClO2 NaH2PO4
274 96
275
DCC 4-DMAP
276 X = O 82
277 X = CH2 51
TiCl4 Zn dust TMEDA CH2Br2PbCl2 (Cat )
1
2 BH3 THF H2O2 NaOH
H2 PdC EtOH
Ac2 O Pyr 4-DMAP
279 R = Bn R = H 64
280 R = R = H 99
281 R = R =Ac 97
1424 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (50)
Scheme (51)
O OOH
OH
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
286
1 VO(acac)2 t-BuOH 95
2 (MeO)3CH BF3 90
1 P-O2NC6H4 CO2H Ph3P DIAD2 K2CO3 MeOH 82 over 2 steps
1 PhCOCl Et3N DMAP 402 P-O2NC6H4 CO2H Ph3P DIAD3 KOH THF-H2O 75 over 2 steps
TMEDA OsO4
Cat OsO4 NMO 287
Cat OsO4 NMO288
TMEDA OsO4
Cat OsO4 NMO
290
289
(RR)-282283
284
285
OHO
AcO
BrOAc
OAc
BnO
O
OBn
OBnO
OHO
AcOOAc
OAc
BnO
OOBn
OBnAcO
OHO
AcOOAc
OAc
BnO
O
OBn
OBnO
+
Bu3SnH AIBN291
292
293 81
1 Na[Al(OC2H4OMe)2(OEt)H]2 Ac2O pyr
294 56 over 2 steps
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1425
Scheme (52)
Scheme (53)
OBnO
BnOOBn
OBn O
OH
O
OBnO
BnO
OHOBn
OBn O
O
O
O
O
O
OBnO
BnOOBn
OBnO
OAcOAc
OAc
OBnO
BnO
OHOBn
OBn
IBu3SnH AIBN
295 297 26
1 BF3 OEt2 Et3SiH
2 L-Selectride THF
1 Pd(OH)2C C6H10 EtOH
2 EtSiOSO2CF3 Ac2O
298 89 over 2 steps299
296
O
O
PhSeClO
O
PhSeCl
Bu3 SnH
O
O
PhSeCl
R
H
O
OAc
R
Cl
O
AcO
OAc
OAc
OAcOH
Cl
NHAc
R
OAc
AcHN
OH
O
OH OAc
OH
OHO
HO
OH
O
AcO
OAc
OAc
OAcBr
O
O
PhSeCl
O
O
PhSeCl
R
O
OTIPSAcHNR
OAc OAc
O
OHAcHN
COOMe
R
OAc
1 Bu4NF
2 NH3MeOH
1 (Me3Si)2NLi THF2 Me2N=CHI
1 Bu3 SnH AIBN2
1 NaBH42 mCPBA3 Ac2O pyr
1 H+ MeCN
2 H2 O NaHCO3
R =
1 O3MeOH
2 Me2S NaHCO3
1 TIPSOTf 26-lut idine2 LiBH43 Ac2 O pyr DMAP
furanoses +
304 56
305 68 306 84307 50
308 46
300 301 302
303
309
1426 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
The reduction of 317 and treatment with DOWEX-H+ resinprovided the desired C-fucoside 318 in 70 (Scheme 54)
62 Intramolecular Radical Approaches
One disadvantage with the intermolecular approaches isthat during such radical mediated reactions electrondeficient alkenes are required to facilitate C-C bondformation The intramolecular approach of Sinayuml overcomes
this drawback by bring two substrates together via atemporary covalent silaketal connector This enables the useof a wider range of alkenes which can include alkene-functionalized sugars thus leading to the generation of C-disaccharides [63] Based on the early work of Stork Sinayumlemployed the tether reaction in the synthesis of both α- andβ-C-disaccharides with this work subsequently beingemployed in the synthesis of biologically significant natural
Scheme (54)
O
OH
Fuc
Cl
O
O
ClPhSe
OOAc
NHAcOHFuc
O
AcOOAc
AcO
Br
O
O
PhSeCl
O
AcOOAc
AcO
O
OH
PhSe Cl
Fuc
OOAc
NHAc
OMe
Fuc
O
AcHN
OH OAc
OH
O
OH
Me
OH
O
O
Fuc
ClSePh
O
HO
Fuc
ClSePh
+
Ph3SnHAIBN
78 combined yield
Fuc
310
+
1 NaBH4 MeOHTHF2 Chromatography
313 40 314 355
1 mCPBA
2 Ac2O pyr DMAP
+
315 75
1 TfOH MeCN
2 NaHCO3 O3 -78 oC
316 10 over 2 steps
1 Cl3 CCN NaH
2 MeOH BF3 OEt2
317 79
1 LiBH4 THF
2 Dowex-H+
311
312a312b
318 70 for 2 steps
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1427
products [64] The availability of different hydroxyl groupson each monosaccharide unit allowed the fine-tuning ofstereochemical outcome by selective positioning of the silyltether [65] Development of this early stereochemical controlled to the tethering of the donor 320 with alcohol 319through a di-isopropyl silicon tether 321 Subsequent treat-ment with Bu3SnH and AIBN led to a 9-endo-trigcyclization to form the C-disaccharide 322 in an 80 yieldwith exclusive formation of the α-product The silyl tetherwas removed with Bu4NF and deprotection under standardconditions afforded the desired disaccharide 323 in excellentyield (Scheme 55)
In parallel the development of a 32rsquo silyl tether allowedaccess to the β-linked product as demonstrated in Sinayumlrsquossynthesis of methyl β-C-lactoside 328 [66] Alcohol 324 and320 were connected via the dimethylsilyl tether an 8-endo-trig cyclization followed to exclusively afford the β-
disaccharide 326 in 45 yield Removal of the tether anddeprotection of benzyl ether gave β-C-disaccharide 328(Scheme 56)
This group also selected iodosugars bearing a freehydroxyl group as progenitors of the radical donors [67] In atypical experiment the radical donor 329 was connected tothe radical acceptor 330 through a silaketal tether followingtheir procedure Tributyltinhydride mediated 8-endo-trigradical cyclization of compound 331 gave after detetheringof the non isolated intermediate 332 the protected β-C-disaccharide 333 in 37 overall yield (from startingmaterials 330 and 329) Peracetate 335 was achieved afterhydrogenolysis The C-laminaribioside 334 is of potentialbiological interest as it mimics the repeating disaccharideunit of fungal β-(1rarr3)-glucans which have antitumor andimmunomodulating properties (Scheme 57)
Scheme (55)
Scheme (56)
OO
OHSePh
OTBDPSO O
OO
SePh
OTBDPSO
OO
OBnOMe
OBn
Si
O
HOOBn
OMe
OBn
O
HOOH
OHHO
O
HOOH
OMe
OH
OTBDPSO
O
HOOBn
OMe
OBnO
OOH
1 n-BuLi THF
2 iPr2SiCl2 -78 oC
3 DMAP THF rt
1 Bu4NF THF
2 Dowex-H+
3 H2 PdC
Bu3SnH AIBN toluene
319
320
321
322323
OBnO
OHSePh
OBnBnO
OHO
OBnOMe
OBn
ROO
ROOH
OR
OHO
OROMe
OR
OBnO
O
OBnBnO
OO
OBnOMe
OBn
Si
SePh
OBnO
O
OBnBnOO
OOBn
OMe
OBn
Si
1 PhSeH Me2SiCl2
BuLi -78 oC
2 imidazole rt
Bu3SnH AIBN toluene
H2 PdC327 R = Bn
328 R = H
Bu4NF THF
324
320
325
326 45
1428 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
CONCLUSIONS
In this paper the biological importance of C-oligo-saccharides as subunits of natural products and as a newgeneration of carbohydrate based on therapeutics has beenillustrated Different methods are available for the synthesisof C-oligosaccharides As with traditional saccharidesynthesis it has been necessary to develop a number ofspecific approaches to facilitate the regioselective andstereoselective preparation of the desired targets Work inthis area continues and it is expected that many interestingnew C-oligosaccharides will be prepared using the chemistrydescribed in this review It is also likely that new chemistrywill be developed in the future for the preparation of thesebiologically important targets
ACKNOWLEDGEMENTS
The authors thank Dr Sultan Baytas for her criticalreading of this manuscript
REFERENCES
[1] Kennedy J F White C A Bioactive Carbohydrates InChemistry Biochemistry and Biology Ellis Horwood LtdChichesterUK 1983
[2] Wassarman PW Mammalian Fertilization Molecular Aspects ofGamete Adhesion xocytosion Exocytosis and Fusion Cell 199996 175-183
[3] Carbohydrate-based Drug Discovery Wong C-H EdWeinheim Cambridge Wiley-VCH 2003
[4] (a) Sharon N Lis H Lectins as Cell Recognition MoleculesScience 1987 246 227-234 (b) Dwek RA Chem Rev 1996 96683-720
[5] Postema M C-Glycoside synthesis CRC Boc Ratom 1995[6] (a) Weatherman R V Mortell K H Cheruenak MKiessling
L L Toone E J Specificity of C-Glycoside Complexation byMannoseGlucose Specific Lectins Biochem 1996 35 3619-3624(b) Ravishankar R Surolia A Vijayan M Lim S Kishi YPreferred Conformation of C-Lactose at the Free and Peanut LectinBound States J Am Chem Soc1998 120 11297-11303
[7] (a)Wong C-H Halcomb R L Ichikawa Y and Kajimoto TEnzymes in organic synthesis Application to the problems ofcarbohydrate recognition part2 Angew Chem Int Ed Engl 199534 521-546 (b)Howard S Withers SG Bromoketone C-Glycosides a New Class of βminusGlucanase Inactivators J AmChem Soc 1998 120 10326-10331(c) Wang Q Wolff MPolat T Du Y Linhardt R J C-glycoside of Neuraminic Acidsas Neura-minidase Inhibitors Bioorg Med Lett 2000 10 941-944 (d) Phili R Chang J Partis R A Mueller R A ChrestF J Passaniti A The Alpha-glucosidase I InhibitorCastanospermine Alters Endothelial cell Glycosylation PreventsAngiogenesis and Inhibits Tumor Growth Cancer Res 1995 552927-2935
[8] Ossor A Elbein A D In Carbohydrates in Chemistry andBiology Vol 3(II) WileyVCH 2000 pp 513-539
[9] (a) Sinayuml P Synthesis of oligosaccharide Mimetics Pure ApplChem 1997 69 459-463 (b) Beau J-M Gallagher TNucleophilic C-glycosyl Donors for C-glycoside Synthesis Top inCurr Chem 1997 187 1-54 (c) Nicotra F Synthesis of C-glycosides of Biological Interest Top in Curr Chem 1997 187
Scheme (57)
O
O
O
Ph
I
OMe
OHO
BnO
OH
OH
BnOOH
O
BnO
Si
O
O O
Ph
I
OMe
O
O
BnO
OR4O
R5O
OMe
OR2
OR3O
R3O
OR1
R3O
Bu3 SnH AIBN
332 R1 R2 = SiMe2 R3 = Bn R4 R5 = CHPhTBAF THF
333 R1 = R2 = H R3 = Bn R4 = R5 = CHPh 37 from 11
334 R1 = R2 = R3 = R4 = R5 = H
335 R1 = R2 = R3 = R4 = R5 = Ac
329
H2 PdC MeOH
Ac2 O pyr
1 BuLi THF -78 oC
2 Me2SiCl2
3 DMAP
330
331
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1429
55-83 (d) Du Y Linhardt R Y Recent Adv in Stereo-SelectiveC-Glycoside Synthesis Tetrahedron Lett 1998 54 9913-9959 (e)Liu L Mckee M and Postema M H D Synthesis of C-saccharides and Higher Congeners Current Org Chem 2001 51133-1167
[10] Jarosz S Fraser-Reid B Synthesis of A Higher Carbon Sugar ViaDirected Aldol Condensation Tetrahedron Lett 1989 30 2359-2362
[11] Lichtenthaler F W Lergenmiiller M Schwidetzky S C-Glycosidations of 2-Ketohexosyl With Electrophilic Radical andNudeophilic Anomeric Carbons Eur J Org Chem 2003 3094-3103
[12] Baudat A Vogel P Aza-C-disaccharides Synthesis of 6-Deoxygalactonojirimycin-β-C(1rarr3) Linked with D-Altrofuranosides and D-Galactose J Org Chem 1997 62 6252-6260
[13] Turner D Vogel P Synthesis of 4-Hydroxy-26-Bis(hydroxymethyl) tetrahydropyran-2-Carbaldehyde DerivativesSynlett 1998 304-306
[14] Zhu Y-H Vogel P Short Stereoselective Synthesis of C-(1rarr3)-Linked Disaccharides Tetrahedron Lett 1998 39 31-34
[15] Zhu Y-H Vogel P Synthesis of a (2R 6R)-2-(Hydroxymethyl)-6-Propa-1 2-Dienyl-2H-Pyran-3(6H)-One Derivative A NewEnone for The Convergent Construction of C-Glycosides of C-Disaccharides Synlett 2001 82-86
[16] Baumberger F Vasella A Deoxynitrosugars The 6th
Communication Stereolectronic Control in the reductivedenitration of tertiary nitro ethers A Synthesis of ldquoC-glycosidesrdquoHelv Chim Acta 1983 66 2210-2221
[17] Martin O R Lai W Synthesis and Conformational Studies of β-(1rarr6)- and ββ-(1rarr1)-Linked C-disaccharides J Org Chem1993 58 176-185
[18] Spak S J Martin R The synthesis of an analogue of Methyl OC-Analogue of Methyl 4rsquo-O-β-D-GlucopyranosylgentiobiosideTetrahedron 2000 56 217-224
[19] Kobertz W R Bertozzi C R Bednarski M D C-GlycosylAldehyde Synthons for C-Linked Disaccharides J Org Chem1996 61 1894-1897
[20] Gurjar M K Nagaprasad R and Ramana CV First Synthesis ofMethyl α-C-D-Arabino-furanosyl-(1rarr5)-αminusD-Arabinofuranosidethe C-Disaccharide Segment of Motif C of MycobateriumTuberculosis Tetrahedron Lett 2000 43 7577-7579
[21] Witczak Z J Synthesis of C-Glycosyl Compounds and OtherNatural Products from Levoglucosenone Pure Appl Chem 199466 2189-2192
[22] Griffin F K Paterson D Taylor R J K Ramberg-BacklundApproaches to the Synthesis of C-Linked Disaccharides AngewChem Int Engl 1999 38 2939-2942
[23] Paterson B E Griffin F K Alcaraz M-L and Taylor R J KA Ramberg-Baumlcklund Approach to the Synthesis of C-GlycosidesC-Linked Disaccharides and C-Glycosyl Amino Acids Eur JOrg Chem 2002 1323-1336
[24] McAllister G D Paterson D E Taylor R J K A SimplifiedRamberg-Bachlund Approach to Novel C-Glycosides and C-Linked Disaccharides Angew Chem Int Ed Engl 2003 42 1387-1391
[25] McCartney J L Christopher T M Cicchillo R M BernardinaM D Wagner T R and Norris P J Org Chem 2003 6810152-10155
[26] Dondoni A Zuurmond H M Bascarate A Synthesis of α-andβ-D-(1rarr6)-C-Disaccharides by Witting Olefination of Formyl C-Glycosides with Glycopyranose 6-phosphoranes J Org Chem1997 62 8114-8124
[27] Dondoni A Kleban M Zuurmond H Marra A Synthesis of(1rarr6)-C-Oligogalactosides by Interative Wittig OlefinationTetrahedron Lett 1998 39 7991-7994
[28] Dondoni A Marra A A New Synthetic Approach toMycobacterial Cell Wall α-(1rarr5)-D-Arabinofuranosyl C-Oligosaccharides Teterahedron Lett 2003 44 4067-4071
[29] Colinas P A Ponzinibbio A Lieberknecht A and Bravo R OWittig Reaction of Glycosyl Phosphonium Salts A StereoselectiveRoute to C-Disaccharides and C O-Trisaccharides TetrahedronLett 2003 44 7985-7988
[30] Schmidt R R Preuss R Synthesis of Carbon Tetrahedron Lett1989 30 3409-3412
[31] Dietrich H Schmidt R R Synthesis of Carbon-Bridged C-Lactose and Derivatives Liebigs Ann Chem 1994 975-981
[32] Rouzaud D Sinayuml P The First Synthesis of a ldquoC-DisacchariderdquoJ Chem Soc Chem Commun 1983 1353-1354
[33] Xin Y-C Zhang Y-M Mallet J-M Glaudemans C P JSinayuml P Synthesis of C-Oligosaccharides That Mimie TheirNatural O-Analogues Immunodeterminants in Binding toMonoclonal Immunoglobulins Eur J Org Chem 1999 471-476
[34] Streicher H Geyer A Schmidt R R C-Disaccharides ofKetoses Chem Eur J 1996 2 502-510
[35] Leeuwenburgh M A Timmers C M Vander Marel G A VanBoom J H Mallet J-M Sinayuml P G Stereoselective Synthesisof α-C-(Alkynyl)-Glycosides Via Ring-Opening of α-12-Anhydrous Tetrahedron Lett 1997 38 6251-6254
[36] Aslam T Fuchs M G G Le Formal A Wightman R HSynthesis of C-Disaccharide Analogue of the α-D-Arabinofuranosyl-(1rarr5)-α-Arabinofuranosyl Motif ofMycobacterial Cells Walls via Alkynyl Intermediates TetrahedronLett 2005 46 3249-3252
[37] (a) Girad P Namy J L Kagan H B Divalent LanthanideDerivative in Organic Synthesis 1 Mild Preparation of SamariumIodide and Ytterbium Iodide and Their Use as Reducing orCoupling Agents J Am Chem Soc 1980 102 2693-2698 (b)Molander G A Harris C R Sequencing Reactions withSamarium(II) Iodide Chem Rev 1996 96 307-338
[38] (a) Mazeacuteas D Skrydstrup T Doumeix O Beau J-MSamarium Iodide-Induced Intramolecular C-Glycoside FormationEfficient Radical Formation in the Absence of an Additive AngewChem Int Ed Engl 1994 33 1383-1386 (b) Mazeacuteas DSkrydstrup T Beau J-M A Highly Stereoselective Synthesis of1 2-trans-C-Glycosides Via Glycosyl Samarium(III) CompoundsAngew Chem Int Ed Engl 1995 34 909-912 (c) Jarreton OSkrydstrup T Beau J-M The Stereospecific Synthesis of Methylα-C-Mannobioside A Potential Inhibitor of M TuberculosisBinding to Human Macrophages J Chem Soc Chem Commun1996 1661-1662 (d) Jarreton O Skrydstrup T Espionosa J-FJimeacutenez-Barbero J Beau J-M Samarium Diiode Prompted C-Glycosylation An Application to The Stereospecific Synthesis ofα-(1rarr2)-C-Mannobioside and Its Derivatives Chem Eur J 19995 430-441 (e) Mipuel N Doisneau G Beau J-M ReductiveSamariation of Anomeric 2-Pyridyl Sulfones with Catalytic AnUnexpected Improvement in The Synthesis of 12-Trans-Diequatorial C-Glycosyl Compounds Angew Chem Int Ed Engl 2000 39 4111-4114
[39] Vlahov I R Vlahova P I Linhardt R J DiastereocontrolledSynthesis of Carbon Glycosides of N-Acetylneuraminic Acid ViaGlycosyl Samarium(III) Intermediates JAmChem Soc 1997 1191480-1481
[40] Kuberan B Sikkander S ATomiyama H Linhardt R JSynthesis of a C-Glycoside Analogue of sTn An HIV-and Tumor-Associated Antigen Angew Chem Int Ed Engl 2003 42 2073-2075
[41] Bazin H G Du Y Polat T Linhardt R J Synthesis of aVersatile Neuraminic Acid ldquoCrdquo-Disaccharide Precursor for theSynthesis of C-Glycoside Analogues of Gangliosides J OrgChem 1999 64 7254-7259
[42] Chen C-C Ress D K Linhardt RJ Samarium Iodide-Mediated Synthesis of Neuraminic Acid C-Glycosides InSynthesis of Glycommetics Roy R Ed ACS Syposium Series2004 896 53-80
[43] Abdallah Z Doisneau G Beau J-M Synthesis of a Carbon-Linked Mimic of The Disaccharide Component of The Tumor-Relate SialyTn Antigen Angew Chem Int Ed Engl 2003 425209-5212
[44] Lay L Nicotra F Panza L Russo G Caneva E Synthesis ofC-disaccharides through dimerization of exo-glycals J Org Chem1992 57 1304-1306
[45] Isobe M Nishizawa R Hosokawa S Nishikawa TStereocontrolled Synthesis and Reactivity of Sugar Acetylenes JChem Soc Chem Commun 1998 2665-2676
[46] Saeeng R Sirion U Sahakitpichan P Isobe M IodineCatalyzes C-Glycosidation of D-Glucal with SilylacetykeneTetrahedron Lett 2003 44 6211-6215
[47] (a) Babirad S A Wang Y Kishi Y Synthesis of C-Disaccharides J Org Chem 1987 52 1370-1372 (b) Wang YBabirad S A Kishi Y Preferred Conformation of C-Glycosides
1430 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
8 Synthesis of 14-Linked Carbon Disaccharides J Org Chem1992 57 468-481
[48] Armstrong R W Sutherlin D P Strategies for the Synthesis ofC-Disaccharides Containing D and L Sugars Tetrahedron Lett1994 35 7743-7746
[49] Wei A Kishi Y Preferred Conformation of C-Glycosides 12Synthesis and Conformational Analysis of αα- α β- and β β-Trehaloses J Org Chem 1994 59 88-96
[50] Haneda T Goekjian P G Kim S H Kishi Y PreferredConformation of C-Glycosides 10 Synthesis and ConformationAnalysis of Carbon Trisaccharides J Org Chem 1992 57 490-498
[51] Sutherlin D P Armstrong R W Synthesis of 12 Stereochemistryand Structurally Diverse C-Trisaccharides J Org Chem 1997 625267-5283
[52] Notz W Hartel C Waldscheck B Schmidt R R De NovoSynthesis of a Methylene-Bridged Neu5Ac-α-(23)-Gal C-Disaccharide J Org Chem 2001 66 4250-4260
[53] (a) Postema M H D Calimente D Liu L Behrmanm T L AnOlefin Metathesis Route for the Preparation of (1rarr6)-Linked-C-Disaccharide Glycals A Convergent and Flexible Approach to C-Saccharide Synthesis J Org Chem 2000 65 6061-6068(b) Postema M H Piper J L Liu L Faust M Andreana PSynthesis and Partial Biological Evaluation of a Small Library ofDifferentially Linked β-C-Disaccharide J Org Chem 2003 684748-4754
[54] Nelson A The Development of Strategies and Methods for TheSynthesis of Biologically Active Compounds New J Chem 200428 771-776
[55] Togo H He W Waki Y Yokoyama M C-GlycosylationTechnology With Free Radiant Reactions Synlett 1998 700-717
[56] Giese B Dupuis J Diastereoselective Synthesis of C-Glycopyranosides Angew Chem Int Ed Engl 1983 22 622-623
[57] Adlington R M Baldwin J E Basak A Kozyrod RPApplication of Radical Addition Reactions to tho Synthesis of a C-Glucoside and A Functionalized Amino Acid J Chem SocChem Commun 1983 144-145
[58] Giese B Gonzaacutelez-Goacutemez J A Witzel T The Scope of RadicalCC-Coupling by The ldquoTin Methodrdquo Angew Chem Int Ed Engl1984 23 69-70
[59] Giese B Witzel T Synthesis of ldquoC-Disaccharidesrdquo by RadicalC-C Bond Formation Angew Chem Int Ed Engl 1986 25 450-451
[60] Witczak Z J Chhabra R Chojnacki J C-Disaccharides IStereoselective Approach to β-(1rarr4)-3-Deoxy-C-Disaccharidesfrom Levoglucosenone Carb Res 1997 301 167-175
[61] Vogel P Synthesis of Rare Carbohydrates and Analogues Startingfrom Enantiomerically Pure 7-Oxabicyclo[221]heptyl Derivatives(ldquoNaked Sugarsrdquo) Current Org Chem 2000 4 455-480
[62] Viodeacute C Vogel P Synthesis of The C-Disaccharide α-C(1rarr3)-L-Fucopyranoside of N-Acetylgalactosamine J Carb Chem2001 20 733-746
[63] Xin Y C Mallet J M Sinayuml P An Expeditious Synthesis of AC-Disaccharide Using A Temporary Silaketal Connection J ChemSoc Chem Commun 1993 864-865
[64] (a) Petitou M Herault P Lormeau J-C Helmboldt A MalletJ-M Sinayuml P Herbert J-M Introducing A C-InterglycosidicBond in A Biologically Active Pentasaccharide Hardly Affects ItsBiological Properties Bioorg Med Chem 1998 6 1509-1516 (b)Sinayuml P Advances in The Synthesis of the Carbohydrate MimicsPure Appl Chem 1998 70 1495-1499
[65] Sinayuml P Chemical Synthesis of Oligosaccharide Mimetics PureAppl Chem 1998 70 407-410
[66] Sinayuml P Chemical Synthesis of Oligosaccharide Mimetics PureAppl Chem 1998 69 459-463
[67] Vauzeilles B Sinayuml P Selective Radical Synthesis of β-C-Disaccharides Tetrahedron Lett 2001 42 7269-7272
1422 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
glucopyranoside 280 represents an example of thischemistry The known triacetyl glucopyranoside 269 wasconverted to iodide 270 in good yield Radical allylation of271 proceeded to afford a mixture of equatorial and axialallylation products in a 61 ratio Oxidative cleavage of thedouble bond gave the corresponding aldehydes 273a and273b which were separable Pinnick oxidation of the majoraldehyde 273a then gave the C-4 equatorial acid 274 DCC-mediated coupling of alcohol 275 and acid 274 proceeded toafford ester 276 in good yield Methylenation of 276 gave277 and exposure to catalysist 278 gave a 41 yield of theC-disaccharide glycal which was exposed to an excess ofBH3
THF to give 64 yield of the β-C-disaccharide 279Removal of the benzyl groups and global peracetylation gavethe peracetylated (1rarr4)-β-C-disaccharide 281 in good yield(Scheme 49)
54 Ring Expansion-Cyclization
Nelson developed a new strategy for asymmetric andstereoselective synthesis of C-linked disaccharide mimeticsthe C58-C71 fragment of palytoxin [54] The diol (RR)-282was converted into the di-dihydropyran (DHP) template 283284 and 285 The di-DHPs were functionized in a twodirectional sense using dihydroxylation reactions The two-directional approach was often very efficient indeed forexample in the synthesis of 286 six new stereogenic centerswere introduced with almost complete stereocontrol using areduction and a dihydroxylation reaction The approach isnot restricted to the synthesis of C2-symmetricaldisaccharide mimetics Using the unsymmetrical template285 which has both a pseudo-axial and a pseudo-equatorialhydroxyl groups the unsymmetrical mimetics 289 and 290were prepared (Scheme 50)
6 RADICAL APPROACHES
The radical approach for C-C bond formation is a popularmethod within organic chemistry The use of radicalchemistry in carbohydrate synthesis has certain advantagesFirstly the reaction conditions are very mild and tolerant ofa range of functional and protecting groups Secondanomeric radicals are stable with respect to elimination andepimeration Most significantly the chemistry required toincorporate an appropriate substitute at C-1 employed in theinitial hemolytic cleavage step is common within carbo-hydrate chemistry [55] The use of such radical techniquecan be subdivided into two classes intermolecular andintramolecular approaches
61 Intermolecular Radical Approaches
Giese was the first to employ an intermolecular radical-based approach for synthesis of C-disaccharides [56]Addition of an alkene to an anomeric radical underappropriate conditions allowed exclusive entry to the α-linked C-glycoside a result which was mirrored by the workof Baldwin [57] The high α-selectivity of the reaction wasin contrast with other reports Thus radicals generated at theC-2 C-3 and C-4 centers all preferred to occupy equatorialpositions [58] When the anomeric bromide 291 was treatedwith tin hydride and AIBN resulting anomeric radical andreacted with lactone 292 in a Michael addition it afforded293 In this reaction hydrogen abstraction at the resulting
radical center occurs from axial face to selectively generatethe equatorial C-2rsquo substituent Reduction and acetylation of293 furnished C-disaccharide 294 (Scheme 51) [59]
Witczak used the facial bias of levoglucosene tostereoselectively add a carbohydrate-based radical in thepreparation of the 3-deoxy-(1rarr4)-β-C-disaccharide 299[60] Addition of the radical derived from iodide 295 to 296gave adduct 297 in 26 yield Removal of the anomerichydroxyl of 297 was achieved by treatment with triethylsilane borontrifluoride ether complex followed bystereoselective reduction of the keto function at C-2rsquo withthe formation of 298 in 89 yield Debenzylation followedby acetolysis of 16-anhydro ring produced the peracetylatedtarget C-disaccharide 299 in 19 overall yield from 295(Scheme 52)
Vogel has developed general methods to transformenantiomerically pure 7-oxabicyclo[221]heptyl derivatives(ldquonaked sugarsrdquo) into C-disaccharides Because of thesechiral bicyclic skeletons they undergo highly stereoselectivereactions with predictable diasteroselectivities An arsenal ofmethods is available that allow to substitute these ldquonakedrdquocarbon centers with a variety of functional groups with allpossible relative configurations The methods allowpreparation of both enantiomers of a given target with thesame ease Predictably high stereoselectivity of the reactionsof the bicyclic chirons adds to the flexibility of approachwhich can lead to high molecular diversity [61]
α-C-(1rarr3)-mannopyranoside of N-acetyl-galactosaminepotent β-galactosidase inhibitors was synthesized by thisapproach [61] Enone 302 was readily prepared from 300The addition of the radical derived from bromide 303 toenone 302 afforded the αminusisomer 304 The ketone was thenreduced and the selenide eliminated via the intermediacy ofthe selenoxide to give 305 Acid-promoted (CF3SO3H) 7-oxa ring opening of 305 in MeCN produced the amino-conduritol derivative 306 resulting from the quenching of theallylic cation intermediate by the solvent (Ritter reaction)Ozonolysis of the chloroalkene 306 generated an acylchloride-aldehyde intermediate that reacted with MeOH toproduce a mixture of methyl uronates The major compound307 was silylated and reduced The crude polyol obtainedwas acetylated to produce 308 Desilylated and ammonolysisafforded a mixture of α-β-pyranoses 309 and correspondingα-β-furanoses (Scheme 53)
Similar chemistry was carried out to synthesize non-protected α-C(1rarr2)-L-fucopyranoside of D-galactopyrano-side corresponding to a blood group mimetic [62] Giesersquosradical fucosidation of racemic enone 310 with α-L-bromoacetofucose 311 provided the mixture of diastereo-meric α-C-fucoside 312a and 312b in reproducible yield of78 Reduction of the mixture gave a 11 mixture of endo-alcohols 313 and 314 which were isolated pure in 40 and355 yield respectively Oxidative elimination of thebenzeneselenyl group of 313 followed by acetylation gaveendo acetate 315 in 85 yield Acid-promoted ring openingof 315 and ozonolysis of the resulted chloroalkene gavemethyl uronic ester 316 in modest yield (10) Treatment of316 with Cl3CCN and NaH followed with BF3
OEt2
furnished the totally protected C-disaccharide 317 in 79
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1423
Scheme (49)
Bu3SnO
HOAcO
OMeOAc
OAc
O
AcO
OMeOAc
OAcI
AIBN
O
AcO
OMeOBn
OBn
HO2C O
AcO
OMeOR
ORY
X
OHBnO
BnO
OBn
OBnO
BnO
OBn
O
AcO
OMeOBn
OBnX
i-Pr i-Pr
N
Mo C(Me2 Ph)((CF3)2 MeCO)2
O
RO
OMeOR
O
RO
OR
OR
RO
OR
278
I2 Ph3P
imidazole
269 270 93
271a X = CH2CH=CH2 Y = H R = Ac 64271b Y = CH2CH=CH2 X = H R = Ac 11272a X = CH2CH=CH2 Y = H R = Bn 75272b Y = CH2CH=CH2 X = H R = Bn 75273a X = CH2CHO Y = H R = Bn 79273a Y = CH2CHO X = H R = Bn 79
1 NaOMe MeOH2 NaOH BnBr DMF
OsO4 NaIO4
NaClO2 NaH2PO4
274 96
275
DCC 4-DMAP
276 X = O 82
277 X = CH2 51
TiCl4 Zn dust TMEDA CH2Br2PbCl2 (Cat )
1
2 BH3 THF H2O2 NaOH
H2 PdC EtOH
Ac2 O Pyr 4-DMAP
279 R = Bn R = H 64
280 R = R = H 99
281 R = R =Ac 97
1424 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (50)
Scheme (51)
O OOH
OH
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
286
1 VO(acac)2 t-BuOH 95
2 (MeO)3CH BF3 90
1 P-O2NC6H4 CO2H Ph3P DIAD2 K2CO3 MeOH 82 over 2 steps
1 PhCOCl Et3N DMAP 402 P-O2NC6H4 CO2H Ph3P DIAD3 KOH THF-H2O 75 over 2 steps
TMEDA OsO4
Cat OsO4 NMO 287
Cat OsO4 NMO288
TMEDA OsO4
Cat OsO4 NMO
290
289
(RR)-282283
284
285
OHO
AcO
BrOAc
OAc
BnO
O
OBn
OBnO
OHO
AcOOAc
OAc
BnO
OOBn
OBnAcO
OHO
AcOOAc
OAc
BnO
O
OBn
OBnO
+
Bu3SnH AIBN291
292
293 81
1 Na[Al(OC2H4OMe)2(OEt)H]2 Ac2O pyr
294 56 over 2 steps
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1425
Scheme (52)
Scheme (53)
OBnO
BnOOBn
OBn O
OH
O
OBnO
BnO
OHOBn
OBn O
O
O
O
O
O
OBnO
BnOOBn
OBnO
OAcOAc
OAc
OBnO
BnO
OHOBn
OBn
IBu3SnH AIBN
295 297 26
1 BF3 OEt2 Et3SiH
2 L-Selectride THF
1 Pd(OH)2C C6H10 EtOH
2 EtSiOSO2CF3 Ac2O
298 89 over 2 steps299
296
O
O
PhSeClO
O
PhSeCl
Bu3 SnH
O
O
PhSeCl
R
H
O
OAc
R
Cl
O
AcO
OAc
OAc
OAcOH
Cl
NHAc
R
OAc
AcHN
OH
O
OH OAc
OH
OHO
HO
OH
O
AcO
OAc
OAc
OAcBr
O
O
PhSeCl
O
O
PhSeCl
R
O
OTIPSAcHNR
OAc OAc
O
OHAcHN
COOMe
R
OAc
1 Bu4NF
2 NH3MeOH
1 (Me3Si)2NLi THF2 Me2N=CHI
1 Bu3 SnH AIBN2
1 NaBH42 mCPBA3 Ac2O pyr
1 H+ MeCN
2 H2 O NaHCO3
R =
1 O3MeOH
2 Me2S NaHCO3
1 TIPSOTf 26-lut idine2 LiBH43 Ac2 O pyr DMAP
furanoses +
304 56
305 68 306 84307 50
308 46
300 301 302
303
309
1426 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
The reduction of 317 and treatment with DOWEX-H+ resinprovided the desired C-fucoside 318 in 70 (Scheme 54)
62 Intramolecular Radical Approaches
One disadvantage with the intermolecular approaches isthat during such radical mediated reactions electrondeficient alkenes are required to facilitate C-C bondformation The intramolecular approach of Sinayuml overcomes
this drawback by bring two substrates together via atemporary covalent silaketal connector This enables the useof a wider range of alkenes which can include alkene-functionalized sugars thus leading to the generation of C-disaccharides [63] Based on the early work of Stork Sinayumlemployed the tether reaction in the synthesis of both α- andβ-C-disaccharides with this work subsequently beingemployed in the synthesis of biologically significant natural
Scheme (54)
O
OH
Fuc
Cl
O
O
ClPhSe
OOAc
NHAcOHFuc
O
AcOOAc
AcO
Br
O
O
PhSeCl
O
AcOOAc
AcO
O
OH
PhSe Cl
Fuc
OOAc
NHAc
OMe
Fuc
O
AcHN
OH OAc
OH
O
OH
Me
OH
O
O
Fuc
ClSePh
O
HO
Fuc
ClSePh
+
Ph3SnHAIBN
78 combined yield
Fuc
310
+
1 NaBH4 MeOHTHF2 Chromatography
313 40 314 355
1 mCPBA
2 Ac2O pyr DMAP
+
315 75
1 TfOH MeCN
2 NaHCO3 O3 -78 oC
316 10 over 2 steps
1 Cl3 CCN NaH
2 MeOH BF3 OEt2
317 79
1 LiBH4 THF
2 Dowex-H+
311
312a312b
318 70 for 2 steps
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1427
products [64] The availability of different hydroxyl groupson each monosaccharide unit allowed the fine-tuning ofstereochemical outcome by selective positioning of the silyltether [65] Development of this early stereochemical controlled to the tethering of the donor 320 with alcohol 319through a di-isopropyl silicon tether 321 Subsequent treat-ment with Bu3SnH and AIBN led to a 9-endo-trigcyclization to form the C-disaccharide 322 in an 80 yieldwith exclusive formation of the α-product The silyl tetherwas removed with Bu4NF and deprotection under standardconditions afforded the desired disaccharide 323 in excellentyield (Scheme 55)
In parallel the development of a 32rsquo silyl tether allowedaccess to the β-linked product as demonstrated in Sinayumlrsquossynthesis of methyl β-C-lactoside 328 [66] Alcohol 324 and320 were connected via the dimethylsilyl tether an 8-endo-trig cyclization followed to exclusively afford the β-
disaccharide 326 in 45 yield Removal of the tether anddeprotection of benzyl ether gave β-C-disaccharide 328(Scheme 56)
This group also selected iodosugars bearing a freehydroxyl group as progenitors of the radical donors [67] In atypical experiment the radical donor 329 was connected tothe radical acceptor 330 through a silaketal tether followingtheir procedure Tributyltinhydride mediated 8-endo-trigradical cyclization of compound 331 gave after detetheringof the non isolated intermediate 332 the protected β-C-disaccharide 333 in 37 overall yield (from startingmaterials 330 and 329) Peracetate 335 was achieved afterhydrogenolysis The C-laminaribioside 334 is of potentialbiological interest as it mimics the repeating disaccharideunit of fungal β-(1rarr3)-glucans which have antitumor andimmunomodulating properties (Scheme 57)
Scheme (55)
Scheme (56)
OO
OHSePh
OTBDPSO O
OO
SePh
OTBDPSO
OO
OBnOMe
OBn
Si
O
HOOBn
OMe
OBn
O
HOOH
OHHO
O
HOOH
OMe
OH
OTBDPSO
O
HOOBn
OMe
OBnO
OOH
1 n-BuLi THF
2 iPr2SiCl2 -78 oC
3 DMAP THF rt
1 Bu4NF THF
2 Dowex-H+
3 H2 PdC
Bu3SnH AIBN toluene
319
320
321
322323
OBnO
OHSePh
OBnBnO
OHO
OBnOMe
OBn
ROO
ROOH
OR
OHO
OROMe
OR
OBnO
O
OBnBnO
OO
OBnOMe
OBn
Si
SePh
OBnO
O
OBnBnOO
OOBn
OMe
OBn
Si
1 PhSeH Me2SiCl2
BuLi -78 oC
2 imidazole rt
Bu3SnH AIBN toluene
H2 PdC327 R = Bn
328 R = H
Bu4NF THF
324
320
325
326 45
1428 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
CONCLUSIONS
In this paper the biological importance of C-oligo-saccharides as subunits of natural products and as a newgeneration of carbohydrate based on therapeutics has beenillustrated Different methods are available for the synthesisof C-oligosaccharides As with traditional saccharidesynthesis it has been necessary to develop a number ofspecific approaches to facilitate the regioselective andstereoselective preparation of the desired targets Work inthis area continues and it is expected that many interestingnew C-oligosaccharides will be prepared using the chemistrydescribed in this review It is also likely that new chemistrywill be developed in the future for the preparation of thesebiologically important targets
ACKNOWLEDGEMENTS
The authors thank Dr Sultan Baytas for her criticalreading of this manuscript
REFERENCES
[1] Kennedy J F White C A Bioactive Carbohydrates InChemistry Biochemistry and Biology Ellis Horwood LtdChichesterUK 1983
[2] Wassarman PW Mammalian Fertilization Molecular Aspects ofGamete Adhesion xocytosion Exocytosis and Fusion Cell 199996 175-183
[3] Carbohydrate-based Drug Discovery Wong C-H EdWeinheim Cambridge Wiley-VCH 2003
[4] (a) Sharon N Lis H Lectins as Cell Recognition MoleculesScience 1987 246 227-234 (b) Dwek RA Chem Rev 1996 96683-720
[5] Postema M C-Glycoside synthesis CRC Boc Ratom 1995[6] (a) Weatherman R V Mortell K H Cheruenak MKiessling
L L Toone E J Specificity of C-Glycoside Complexation byMannoseGlucose Specific Lectins Biochem 1996 35 3619-3624(b) Ravishankar R Surolia A Vijayan M Lim S Kishi YPreferred Conformation of C-Lactose at the Free and Peanut LectinBound States J Am Chem Soc1998 120 11297-11303
[7] (a)Wong C-H Halcomb R L Ichikawa Y and Kajimoto TEnzymes in organic synthesis Application to the problems ofcarbohydrate recognition part2 Angew Chem Int Ed Engl 199534 521-546 (b)Howard S Withers SG Bromoketone C-Glycosides a New Class of βminusGlucanase Inactivators J AmChem Soc 1998 120 10326-10331(c) Wang Q Wolff MPolat T Du Y Linhardt R J C-glycoside of Neuraminic Acidsas Neura-minidase Inhibitors Bioorg Med Lett 2000 10 941-944 (d) Phili R Chang J Partis R A Mueller R A ChrestF J Passaniti A The Alpha-glucosidase I InhibitorCastanospermine Alters Endothelial cell Glycosylation PreventsAngiogenesis and Inhibits Tumor Growth Cancer Res 1995 552927-2935
[8] Ossor A Elbein A D In Carbohydrates in Chemistry andBiology Vol 3(II) WileyVCH 2000 pp 513-539
[9] (a) Sinayuml P Synthesis of oligosaccharide Mimetics Pure ApplChem 1997 69 459-463 (b) Beau J-M Gallagher TNucleophilic C-glycosyl Donors for C-glycoside Synthesis Top inCurr Chem 1997 187 1-54 (c) Nicotra F Synthesis of C-glycosides of Biological Interest Top in Curr Chem 1997 187
Scheme (57)
O
O
O
Ph
I
OMe
OHO
BnO
OH
OH
BnOOH
O
BnO
Si
O
O O
Ph
I
OMe
O
O
BnO
OR4O
R5O
OMe
OR2
OR3O
R3O
OR1
R3O
Bu3 SnH AIBN
332 R1 R2 = SiMe2 R3 = Bn R4 R5 = CHPhTBAF THF
333 R1 = R2 = H R3 = Bn R4 = R5 = CHPh 37 from 11
334 R1 = R2 = R3 = R4 = R5 = H
335 R1 = R2 = R3 = R4 = R5 = Ac
329
H2 PdC MeOH
Ac2 O pyr
1 BuLi THF -78 oC
2 Me2SiCl2
3 DMAP
330
331
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1429
55-83 (d) Du Y Linhardt R Y Recent Adv in Stereo-SelectiveC-Glycoside Synthesis Tetrahedron Lett 1998 54 9913-9959 (e)Liu L Mckee M and Postema M H D Synthesis of C-saccharides and Higher Congeners Current Org Chem 2001 51133-1167
[10] Jarosz S Fraser-Reid B Synthesis of A Higher Carbon Sugar ViaDirected Aldol Condensation Tetrahedron Lett 1989 30 2359-2362
[11] Lichtenthaler F W Lergenmiiller M Schwidetzky S C-Glycosidations of 2-Ketohexosyl With Electrophilic Radical andNudeophilic Anomeric Carbons Eur J Org Chem 2003 3094-3103
[12] Baudat A Vogel P Aza-C-disaccharides Synthesis of 6-Deoxygalactonojirimycin-β-C(1rarr3) Linked with D-Altrofuranosides and D-Galactose J Org Chem 1997 62 6252-6260
[13] Turner D Vogel P Synthesis of 4-Hydroxy-26-Bis(hydroxymethyl) tetrahydropyran-2-Carbaldehyde DerivativesSynlett 1998 304-306
[14] Zhu Y-H Vogel P Short Stereoselective Synthesis of C-(1rarr3)-Linked Disaccharides Tetrahedron Lett 1998 39 31-34
[15] Zhu Y-H Vogel P Synthesis of a (2R 6R)-2-(Hydroxymethyl)-6-Propa-1 2-Dienyl-2H-Pyran-3(6H)-One Derivative A NewEnone for The Convergent Construction of C-Glycosides of C-Disaccharides Synlett 2001 82-86
[16] Baumberger F Vasella A Deoxynitrosugars The 6th
Communication Stereolectronic Control in the reductivedenitration of tertiary nitro ethers A Synthesis of ldquoC-glycosidesrdquoHelv Chim Acta 1983 66 2210-2221
[17] Martin O R Lai W Synthesis and Conformational Studies of β-(1rarr6)- and ββ-(1rarr1)-Linked C-disaccharides J Org Chem1993 58 176-185
[18] Spak S J Martin R The synthesis of an analogue of Methyl OC-Analogue of Methyl 4rsquo-O-β-D-GlucopyranosylgentiobiosideTetrahedron 2000 56 217-224
[19] Kobertz W R Bertozzi C R Bednarski M D C-GlycosylAldehyde Synthons for C-Linked Disaccharides J Org Chem1996 61 1894-1897
[20] Gurjar M K Nagaprasad R and Ramana CV First Synthesis ofMethyl α-C-D-Arabino-furanosyl-(1rarr5)-αminusD-Arabinofuranosidethe C-Disaccharide Segment of Motif C of MycobateriumTuberculosis Tetrahedron Lett 2000 43 7577-7579
[21] Witczak Z J Synthesis of C-Glycosyl Compounds and OtherNatural Products from Levoglucosenone Pure Appl Chem 199466 2189-2192
[22] Griffin F K Paterson D Taylor R J K Ramberg-BacklundApproaches to the Synthesis of C-Linked Disaccharides AngewChem Int Engl 1999 38 2939-2942
[23] Paterson B E Griffin F K Alcaraz M-L and Taylor R J KA Ramberg-Baumlcklund Approach to the Synthesis of C-GlycosidesC-Linked Disaccharides and C-Glycosyl Amino Acids Eur JOrg Chem 2002 1323-1336
[24] McAllister G D Paterson D E Taylor R J K A SimplifiedRamberg-Bachlund Approach to Novel C-Glycosides and C-Linked Disaccharides Angew Chem Int Ed Engl 2003 42 1387-1391
[25] McCartney J L Christopher T M Cicchillo R M BernardinaM D Wagner T R and Norris P J Org Chem 2003 6810152-10155
[26] Dondoni A Zuurmond H M Bascarate A Synthesis of α-andβ-D-(1rarr6)-C-Disaccharides by Witting Olefination of Formyl C-Glycosides with Glycopyranose 6-phosphoranes J Org Chem1997 62 8114-8124
[27] Dondoni A Kleban M Zuurmond H Marra A Synthesis of(1rarr6)-C-Oligogalactosides by Interative Wittig OlefinationTetrahedron Lett 1998 39 7991-7994
[28] Dondoni A Marra A A New Synthetic Approach toMycobacterial Cell Wall α-(1rarr5)-D-Arabinofuranosyl C-Oligosaccharides Teterahedron Lett 2003 44 4067-4071
[29] Colinas P A Ponzinibbio A Lieberknecht A and Bravo R OWittig Reaction of Glycosyl Phosphonium Salts A StereoselectiveRoute to C-Disaccharides and C O-Trisaccharides TetrahedronLett 2003 44 7985-7988
[30] Schmidt R R Preuss R Synthesis of Carbon Tetrahedron Lett1989 30 3409-3412
[31] Dietrich H Schmidt R R Synthesis of Carbon-Bridged C-Lactose and Derivatives Liebigs Ann Chem 1994 975-981
[32] Rouzaud D Sinayuml P The First Synthesis of a ldquoC-DisacchariderdquoJ Chem Soc Chem Commun 1983 1353-1354
[33] Xin Y-C Zhang Y-M Mallet J-M Glaudemans C P JSinayuml P Synthesis of C-Oligosaccharides That Mimie TheirNatural O-Analogues Immunodeterminants in Binding toMonoclonal Immunoglobulins Eur J Org Chem 1999 471-476
[34] Streicher H Geyer A Schmidt R R C-Disaccharides ofKetoses Chem Eur J 1996 2 502-510
[35] Leeuwenburgh M A Timmers C M Vander Marel G A VanBoom J H Mallet J-M Sinayuml P G Stereoselective Synthesisof α-C-(Alkynyl)-Glycosides Via Ring-Opening of α-12-Anhydrous Tetrahedron Lett 1997 38 6251-6254
[36] Aslam T Fuchs M G G Le Formal A Wightman R HSynthesis of C-Disaccharide Analogue of the α-D-Arabinofuranosyl-(1rarr5)-α-Arabinofuranosyl Motif ofMycobacterial Cells Walls via Alkynyl Intermediates TetrahedronLett 2005 46 3249-3252
[37] (a) Girad P Namy J L Kagan H B Divalent LanthanideDerivative in Organic Synthesis 1 Mild Preparation of SamariumIodide and Ytterbium Iodide and Their Use as Reducing orCoupling Agents J Am Chem Soc 1980 102 2693-2698 (b)Molander G A Harris C R Sequencing Reactions withSamarium(II) Iodide Chem Rev 1996 96 307-338
[38] (a) Mazeacuteas D Skrydstrup T Doumeix O Beau J-MSamarium Iodide-Induced Intramolecular C-Glycoside FormationEfficient Radical Formation in the Absence of an Additive AngewChem Int Ed Engl 1994 33 1383-1386 (b) Mazeacuteas DSkrydstrup T Beau J-M A Highly Stereoselective Synthesis of1 2-trans-C-Glycosides Via Glycosyl Samarium(III) CompoundsAngew Chem Int Ed Engl 1995 34 909-912 (c) Jarreton OSkrydstrup T Beau J-M The Stereospecific Synthesis of Methylα-C-Mannobioside A Potential Inhibitor of M TuberculosisBinding to Human Macrophages J Chem Soc Chem Commun1996 1661-1662 (d) Jarreton O Skrydstrup T Espionosa J-FJimeacutenez-Barbero J Beau J-M Samarium Diiode Prompted C-Glycosylation An Application to The Stereospecific Synthesis ofα-(1rarr2)-C-Mannobioside and Its Derivatives Chem Eur J 19995 430-441 (e) Mipuel N Doisneau G Beau J-M ReductiveSamariation of Anomeric 2-Pyridyl Sulfones with Catalytic AnUnexpected Improvement in The Synthesis of 12-Trans-Diequatorial C-Glycosyl Compounds Angew Chem Int Ed Engl 2000 39 4111-4114
[39] Vlahov I R Vlahova P I Linhardt R J DiastereocontrolledSynthesis of Carbon Glycosides of N-Acetylneuraminic Acid ViaGlycosyl Samarium(III) Intermediates JAmChem Soc 1997 1191480-1481
[40] Kuberan B Sikkander S ATomiyama H Linhardt R JSynthesis of a C-Glycoside Analogue of sTn An HIV-and Tumor-Associated Antigen Angew Chem Int Ed Engl 2003 42 2073-2075
[41] Bazin H G Du Y Polat T Linhardt R J Synthesis of aVersatile Neuraminic Acid ldquoCrdquo-Disaccharide Precursor for theSynthesis of C-Glycoside Analogues of Gangliosides J OrgChem 1999 64 7254-7259
[42] Chen C-C Ress D K Linhardt RJ Samarium Iodide-Mediated Synthesis of Neuraminic Acid C-Glycosides InSynthesis of Glycommetics Roy R Ed ACS Syposium Series2004 896 53-80
[43] Abdallah Z Doisneau G Beau J-M Synthesis of a Carbon-Linked Mimic of The Disaccharide Component of The Tumor-Relate SialyTn Antigen Angew Chem Int Ed Engl 2003 425209-5212
[44] Lay L Nicotra F Panza L Russo G Caneva E Synthesis ofC-disaccharides through dimerization of exo-glycals J Org Chem1992 57 1304-1306
[45] Isobe M Nishizawa R Hosokawa S Nishikawa TStereocontrolled Synthesis and Reactivity of Sugar Acetylenes JChem Soc Chem Commun 1998 2665-2676
[46] Saeeng R Sirion U Sahakitpichan P Isobe M IodineCatalyzes C-Glycosidation of D-Glucal with SilylacetykeneTetrahedron Lett 2003 44 6211-6215
[47] (a) Babirad S A Wang Y Kishi Y Synthesis of C-Disaccharides J Org Chem 1987 52 1370-1372 (b) Wang YBabirad S A Kishi Y Preferred Conformation of C-Glycosides
1430 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
8 Synthesis of 14-Linked Carbon Disaccharides J Org Chem1992 57 468-481
[48] Armstrong R W Sutherlin D P Strategies for the Synthesis ofC-Disaccharides Containing D and L Sugars Tetrahedron Lett1994 35 7743-7746
[49] Wei A Kishi Y Preferred Conformation of C-Glycosides 12Synthesis and Conformational Analysis of αα- α β- and β β-Trehaloses J Org Chem 1994 59 88-96
[50] Haneda T Goekjian P G Kim S H Kishi Y PreferredConformation of C-Glycosides 10 Synthesis and ConformationAnalysis of Carbon Trisaccharides J Org Chem 1992 57 490-498
[51] Sutherlin D P Armstrong R W Synthesis of 12 Stereochemistryand Structurally Diverse C-Trisaccharides J Org Chem 1997 625267-5283
[52] Notz W Hartel C Waldscheck B Schmidt R R De NovoSynthesis of a Methylene-Bridged Neu5Ac-α-(23)-Gal C-Disaccharide J Org Chem 2001 66 4250-4260
[53] (a) Postema M H D Calimente D Liu L Behrmanm T L AnOlefin Metathesis Route for the Preparation of (1rarr6)-Linked-C-Disaccharide Glycals A Convergent and Flexible Approach to C-Saccharide Synthesis J Org Chem 2000 65 6061-6068(b) Postema M H Piper J L Liu L Faust M Andreana PSynthesis and Partial Biological Evaluation of a Small Library ofDifferentially Linked β-C-Disaccharide J Org Chem 2003 684748-4754
[54] Nelson A The Development of Strategies and Methods for TheSynthesis of Biologically Active Compounds New J Chem 200428 771-776
[55] Togo H He W Waki Y Yokoyama M C-GlycosylationTechnology With Free Radiant Reactions Synlett 1998 700-717
[56] Giese B Dupuis J Diastereoselective Synthesis of C-Glycopyranosides Angew Chem Int Ed Engl 1983 22 622-623
[57] Adlington R M Baldwin J E Basak A Kozyrod RPApplication of Radical Addition Reactions to tho Synthesis of a C-Glucoside and A Functionalized Amino Acid J Chem SocChem Commun 1983 144-145
[58] Giese B Gonzaacutelez-Goacutemez J A Witzel T The Scope of RadicalCC-Coupling by The ldquoTin Methodrdquo Angew Chem Int Ed Engl1984 23 69-70
[59] Giese B Witzel T Synthesis of ldquoC-Disaccharidesrdquo by RadicalC-C Bond Formation Angew Chem Int Ed Engl 1986 25 450-451
[60] Witczak Z J Chhabra R Chojnacki J C-Disaccharides IStereoselective Approach to β-(1rarr4)-3-Deoxy-C-Disaccharidesfrom Levoglucosenone Carb Res 1997 301 167-175
[61] Vogel P Synthesis of Rare Carbohydrates and Analogues Startingfrom Enantiomerically Pure 7-Oxabicyclo[221]heptyl Derivatives(ldquoNaked Sugarsrdquo) Current Org Chem 2000 4 455-480
[62] Viodeacute C Vogel P Synthesis of The C-Disaccharide α-C(1rarr3)-L-Fucopyranoside of N-Acetylgalactosamine J Carb Chem2001 20 733-746
[63] Xin Y C Mallet J M Sinayuml P An Expeditious Synthesis of AC-Disaccharide Using A Temporary Silaketal Connection J ChemSoc Chem Commun 1993 864-865
[64] (a) Petitou M Herault P Lormeau J-C Helmboldt A MalletJ-M Sinayuml P Herbert J-M Introducing A C-InterglycosidicBond in A Biologically Active Pentasaccharide Hardly Affects ItsBiological Properties Bioorg Med Chem 1998 6 1509-1516 (b)Sinayuml P Advances in The Synthesis of the Carbohydrate MimicsPure Appl Chem 1998 70 1495-1499
[65] Sinayuml P Chemical Synthesis of Oligosaccharide Mimetics PureAppl Chem 1998 70 407-410
[66] Sinayuml P Chemical Synthesis of Oligosaccharide Mimetics PureAppl Chem 1998 69 459-463
[67] Vauzeilles B Sinayuml P Selective Radical Synthesis of β-C-Disaccharides Tetrahedron Lett 2001 42 7269-7272
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1423
Scheme (49)
Bu3SnO
HOAcO
OMeOAc
OAc
O
AcO
OMeOAc
OAcI
AIBN
O
AcO
OMeOBn
OBn
HO2C O
AcO
OMeOR
ORY
X
OHBnO
BnO
OBn
OBnO
BnO
OBn
O
AcO
OMeOBn
OBnX
i-Pr i-Pr
N
Mo C(Me2 Ph)((CF3)2 MeCO)2
O
RO
OMeOR
O
RO
OR
OR
RO
OR
278
I2 Ph3P
imidazole
269 270 93
271a X = CH2CH=CH2 Y = H R = Ac 64271b Y = CH2CH=CH2 X = H R = Ac 11272a X = CH2CH=CH2 Y = H R = Bn 75272b Y = CH2CH=CH2 X = H R = Bn 75273a X = CH2CHO Y = H R = Bn 79273a Y = CH2CHO X = H R = Bn 79
1 NaOMe MeOH2 NaOH BnBr DMF
OsO4 NaIO4
NaClO2 NaH2PO4
274 96
275
DCC 4-DMAP
276 X = O 82
277 X = CH2 51
TiCl4 Zn dust TMEDA CH2Br2PbCl2 (Cat )
1
2 BH3 THF H2O2 NaOH
H2 PdC EtOH
Ac2 O Pyr 4-DMAP
279 R = Bn R = H 64
280 R = R = H 99
281 R = R =Ac 97
1424 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (50)
Scheme (51)
O OOH
OH
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
286
1 VO(acac)2 t-BuOH 95
2 (MeO)3CH BF3 90
1 P-O2NC6H4 CO2H Ph3P DIAD2 K2CO3 MeOH 82 over 2 steps
1 PhCOCl Et3N DMAP 402 P-O2NC6H4 CO2H Ph3P DIAD3 KOH THF-H2O 75 over 2 steps
TMEDA OsO4
Cat OsO4 NMO 287
Cat OsO4 NMO288
TMEDA OsO4
Cat OsO4 NMO
290
289
(RR)-282283
284
285
OHO
AcO
BrOAc
OAc
BnO
O
OBn
OBnO
OHO
AcOOAc
OAc
BnO
OOBn
OBnAcO
OHO
AcOOAc
OAc
BnO
O
OBn
OBnO
+
Bu3SnH AIBN291
292
293 81
1 Na[Al(OC2H4OMe)2(OEt)H]2 Ac2O pyr
294 56 over 2 steps
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1425
Scheme (52)
Scheme (53)
OBnO
BnOOBn
OBn O
OH
O
OBnO
BnO
OHOBn
OBn O
O
O
O
O
O
OBnO
BnOOBn
OBnO
OAcOAc
OAc
OBnO
BnO
OHOBn
OBn
IBu3SnH AIBN
295 297 26
1 BF3 OEt2 Et3SiH
2 L-Selectride THF
1 Pd(OH)2C C6H10 EtOH
2 EtSiOSO2CF3 Ac2O
298 89 over 2 steps299
296
O
O
PhSeClO
O
PhSeCl
Bu3 SnH
O
O
PhSeCl
R
H
O
OAc
R
Cl
O
AcO
OAc
OAc
OAcOH
Cl
NHAc
R
OAc
AcHN
OH
O
OH OAc
OH
OHO
HO
OH
O
AcO
OAc
OAc
OAcBr
O
O
PhSeCl
O
O
PhSeCl
R
O
OTIPSAcHNR
OAc OAc
O
OHAcHN
COOMe
R
OAc
1 Bu4NF
2 NH3MeOH
1 (Me3Si)2NLi THF2 Me2N=CHI
1 Bu3 SnH AIBN2
1 NaBH42 mCPBA3 Ac2O pyr
1 H+ MeCN
2 H2 O NaHCO3
R =
1 O3MeOH
2 Me2S NaHCO3
1 TIPSOTf 26-lut idine2 LiBH43 Ac2 O pyr DMAP
furanoses +
304 56
305 68 306 84307 50
308 46
300 301 302
303
309
1426 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
The reduction of 317 and treatment with DOWEX-H+ resinprovided the desired C-fucoside 318 in 70 (Scheme 54)
62 Intramolecular Radical Approaches
One disadvantage with the intermolecular approaches isthat during such radical mediated reactions electrondeficient alkenes are required to facilitate C-C bondformation The intramolecular approach of Sinayuml overcomes
this drawback by bring two substrates together via atemporary covalent silaketal connector This enables the useof a wider range of alkenes which can include alkene-functionalized sugars thus leading to the generation of C-disaccharides [63] Based on the early work of Stork Sinayumlemployed the tether reaction in the synthesis of both α- andβ-C-disaccharides with this work subsequently beingemployed in the synthesis of biologically significant natural
Scheme (54)
O
OH
Fuc
Cl
O
O
ClPhSe
OOAc
NHAcOHFuc
O
AcOOAc
AcO
Br
O
O
PhSeCl
O
AcOOAc
AcO
O
OH
PhSe Cl
Fuc
OOAc
NHAc
OMe
Fuc
O
AcHN
OH OAc
OH
O
OH
Me
OH
O
O
Fuc
ClSePh
O
HO
Fuc
ClSePh
+
Ph3SnHAIBN
78 combined yield
Fuc
310
+
1 NaBH4 MeOHTHF2 Chromatography
313 40 314 355
1 mCPBA
2 Ac2O pyr DMAP
+
315 75
1 TfOH MeCN
2 NaHCO3 O3 -78 oC
316 10 over 2 steps
1 Cl3 CCN NaH
2 MeOH BF3 OEt2
317 79
1 LiBH4 THF
2 Dowex-H+
311
312a312b
318 70 for 2 steps
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1427
products [64] The availability of different hydroxyl groupson each monosaccharide unit allowed the fine-tuning ofstereochemical outcome by selective positioning of the silyltether [65] Development of this early stereochemical controlled to the tethering of the donor 320 with alcohol 319through a di-isopropyl silicon tether 321 Subsequent treat-ment with Bu3SnH and AIBN led to a 9-endo-trigcyclization to form the C-disaccharide 322 in an 80 yieldwith exclusive formation of the α-product The silyl tetherwas removed with Bu4NF and deprotection under standardconditions afforded the desired disaccharide 323 in excellentyield (Scheme 55)
In parallel the development of a 32rsquo silyl tether allowedaccess to the β-linked product as demonstrated in Sinayumlrsquossynthesis of methyl β-C-lactoside 328 [66] Alcohol 324 and320 were connected via the dimethylsilyl tether an 8-endo-trig cyclization followed to exclusively afford the β-
disaccharide 326 in 45 yield Removal of the tether anddeprotection of benzyl ether gave β-C-disaccharide 328(Scheme 56)
This group also selected iodosugars bearing a freehydroxyl group as progenitors of the radical donors [67] In atypical experiment the radical donor 329 was connected tothe radical acceptor 330 through a silaketal tether followingtheir procedure Tributyltinhydride mediated 8-endo-trigradical cyclization of compound 331 gave after detetheringof the non isolated intermediate 332 the protected β-C-disaccharide 333 in 37 overall yield (from startingmaterials 330 and 329) Peracetate 335 was achieved afterhydrogenolysis The C-laminaribioside 334 is of potentialbiological interest as it mimics the repeating disaccharideunit of fungal β-(1rarr3)-glucans which have antitumor andimmunomodulating properties (Scheme 57)
Scheme (55)
Scheme (56)
OO
OHSePh
OTBDPSO O
OO
SePh
OTBDPSO
OO
OBnOMe
OBn
Si
O
HOOBn
OMe
OBn
O
HOOH
OHHO
O
HOOH
OMe
OH
OTBDPSO
O
HOOBn
OMe
OBnO
OOH
1 n-BuLi THF
2 iPr2SiCl2 -78 oC
3 DMAP THF rt
1 Bu4NF THF
2 Dowex-H+
3 H2 PdC
Bu3SnH AIBN toluene
319
320
321
322323
OBnO
OHSePh
OBnBnO
OHO
OBnOMe
OBn
ROO
ROOH
OR
OHO
OROMe
OR
OBnO
O
OBnBnO
OO
OBnOMe
OBn
Si
SePh
OBnO
O
OBnBnOO
OOBn
OMe
OBn
Si
1 PhSeH Me2SiCl2
BuLi -78 oC
2 imidazole rt
Bu3SnH AIBN toluene
H2 PdC327 R = Bn
328 R = H
Bu4NF THF
324
320
325
326 45
1428 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
CONCLUSIONS
In this paper the biological importance of C-oligo-saccharides as subunits of natural products and as a newgeneration of carbohydrate based on therapeutics has beenillustrated Different methods are available for the synthesisof C-oligosaccharides As with traditional saccharidesynthesis it has been necessary to develop a number ofspecific approaches to facilitate the regioselective andstereoselective preparation of the desired targets Work inthis area continues and it is expected that many interestingnew C-oligosaccharides will be prepared using the chemistrydescribed in this review It is also likely that new chemistrywill be developed in the future for the preparation of thesebiologically important targets
ACKNOWLEDGEMENTS
The authors thank Dr Sultan Baytas for her criticalreading of this manuscript
REFERENCES
[1] Kennedy J F White C A Bioactive Carbohydrates InChemistry Biochemistry and Biology Ellis Horwood LtdChichesterUK 1983
[2] Wassarman PW Mammalian Fertilization Molecular Aspects ofGamete Adhesion xocytosion Exocytosis and Fusion Cell 199996 175-183
[3] Carbohydrate-based Drug Discovery Wong C-H EdWeinheim Cambridge Wiley-VCH 2003
[4] (a) Sharon N Lis H Lectins as Cell Recognition MoleculesScience 1987 246 227-234 (b) Dwek RA Chem Rev 1996 96683-720
[5] Postema M C-Glycoside synthesis CRC Boc Ratom 1995[6] (a) Weatherman R V Mortell K H Cheruenak MKiessling
L L Toone E J Specificity of C-Glycoside Complexation byMannoseGlucose Specific Lectins Biochem 1996 35 3619-3624(b) Ravishankar R Surolia A Vijayan M Lim S Kishi YPreferred Conformation of C-Lactose at the Free and Peanut LectinBound States J Am Chem Soc1998 120 11297-11303
[7] (a)Wong C-H Halcomb R L Ichikawa Y and Kajimoto TEnzymes in organic synthesis Application to the problems ofcarbohydrate recognition part2 Angew Chem Int Ed Engl 199534 521-546 (b)Howard S Withers SG Bromoketone C-Glycosides a New Class of βminusGlucanase Inactivators J AmChem Soc 1998 120 10326-10331(c) Wang Q Wolff MPolat T Du Y Linhardt R J C-glycoside of Neuraminic Acidsas Neura-minidase Inhibitors Bioorg Med Lett 2000 10 941-944 (d) Phili R Chang J Partis R A Mueller R A ChrestF J Passaniti A The Alpha-glucosidase I InhibitorCastanospermine Alters Endothelial cell Glycosylation PreventsAngiogenesis and Inhibits Tumor Growth Cancer Res 1995 552927-2935
[8] Ossor A Elbein A D In Carbohydrates in Chemistry andBiology Vol 3(II) WileyVCH 2000 pp 513-539
[9] (a) Sinayuml P Synthesis of oligosaccharide Mimetics Pure ApplChem 1997 69 459-463 (b) Beau J-M Gallagher TNucleophilic C-glycosyl Donors for C-glycoside Synthesis Top inCurr Chem 1997 187 1-54 (c) Nicotra F Synthesis of C-glycosides of Biological Interest Top in Curr Chem 1997 187
Scheme (57)
O
O
O
Ph
I
OMe
OHO
BnO
OH
OH
BnOOH
O
BnO
Si
O
O O
Ph
I
OMe
O
O
BnO
OR4O
R5O
OMe
OR2
OR3O
R3O
OR1
R3O
Bu3 SnH AIBN
332 R1 R2 = SiMe2 R3 = Bn R4 R5 = CHPhTBAF THF
333 R1 = R2 = H R3 = Bn R4 = R5 = CHPh 37 from 11
334 R1 = R2 = R3 = R4 = R5 = H
335 R1 = R2 = R3 = R4 = R5 = Ac
329
H2 PdC MeOH
Ac2 O pyr
1 BuLi THF -78 oC
2 Me2SiCl2
3 DMAP
330
331
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1429
55-83 (d) Du Y Linhardt R Y Recent Adv in Stereo-SelectiveC-Glycoside Synthesis Tetrahedron Lett 1998 54 9913-9959 (e)Liu L Mckee M and Postema M H D Synthesis of C-saccharides and Higher Congeners Current Org Chem 2001 51133-1167
[10] Jarosz S Fraser-Reid B Synthesis of A Higher Carbon Sugar ViaDirected Aldol Condensation Tetrahedron Lett 1989 30 2359-2362
[11] Lichtenthaler F W Lergenmiiller M Schwidetzky S C-Glycosidations of 2-Ketohexosyl With Electrophilic Radical andNudeophilic Anomeric Carbons Eur J Org Chem 2003 3094-3103
[12] Baudat A Vogel P Aza-C-disaccharides Synthesis of 6-Deoxygalactonojirimycin-β-C(1rarr3) Linked with D-Altrofuranosides and D-Galactose J Org Chem 1997 62 6252-6260
[13] Turner D Vogel P Synthesis of 4-Hydroxy-26-Bis(hydroxymethyl) tetrahydropyran-2-Carbaldehyde DerivativesSynlett 1998 304-306
[14] Zhu Y-H Vogel P Short Stereoselective Synthesis of C-(1rarr3)-Linked Disaccharides Tetrahedron Lett 1998 39 31-34
[15] Zhu Y-H Vogel P Synthesis of a (2R 6R)-2-(Hydroxymethyl)-6-Propa-1 2-Dienyl-2H-Pyran-3(6H)-One Derivative A NewEnone for The Convergent Construction of C-Glycosides of C-Disaccharides Synlett 2001 82-86
[16] Baumberger F Vasella A Deoxynitrosugars The 6th
Communication Stereolectronic Control in the reductivedenitration of tertiary nitro ethers A Synthesis of ldquoC-glycosidesrdquoHelv Chim Acta 1983 66 2210-2221
[17] Martin O R Lai W Synthesis and Conformational Studies of β-(1rarr6)- and ββ-(1rarr1)-Linked C-disaccharides J Org Chem1993 58 176-185
[18] Spak S J Martin R The synthesis of an analogue of Methyl OC-Analogue of Methyl 4rsquo-O-β-D-GlucopyranosylgentiobiosideTetrahedron 2000 56 217-224
[19] Kobertz W R Bertozzi C R Bednarski M D C-GlycosylAldehyde Synthons for C-Linked Disaccharides J Org Chem1996 61 1894-1897
[20] Gurjar M K Nagaprasad R and Ramana CV First Synthesis ofMethyl α-C-D-Arabino-furanosyl-(1rarr5)-αminusD-Arabinofuranosidethe C-Disaccharide Segment of Motif C of MycobateriumTuberculosis Tetrahedron Lett 2000 43 7577-7579
[21] Witczak Z J Synthesis of C-Glycosyl Compounds and OtherNatural Products from Levoglucosenone Pure Appl Chem 199466 2189-2192
[22] Griffin F K Paterson D Taylor R J K Ramberg-BacklundApproaches to the Synthesis of C-Linked Disaccharides AngewChem Int Engl 1999 38 2939-2942
[23] Paterson B E Griffin F K Alcaraz M-L and Taylor R J KA Ramberg-Baumlcklund Approach to the Synthesis of C-GlycosidesC-Linked Disaccharides and C-Glycosyl Amino Acids Eur JOrg Chem 2002 1323-1336
[24] McAllister G D Paterson D E Taylor R J K A SimplifiedRamberg-Bachlund Approach to Novel C-Glycosides and C-Linked Disaccharides Angew Chem Int Ed Engl 2003 42 1387-1391
[25] McCartney J L Christopher T M Cicchillo R M BernardinaM D Wagner T R and Norris P J Org Chem 2003 6810152-10155
[26] Dondoni A Zuurmond H M Bascarate A Synthesis of α-andβ-D-(1rarr6)-C-Disaccharides by Witting Olefination of Formyl C-Glycosides with Glycopyranose 6-phosphoranes J Org Chem1997 62 8114-8124
[27] Dondoni A Kleban M Zuurmond H Marra A Synthesis of(1rarr6)-C-Oligogalactosides by Interative Wittig OlefinationTetrahedron Lett 1998 39 7991-7994
[28] Dondoni A Marra A A New Synthetic Approach toMycobacterial Cell Wall α-(1rarr5)-D-Arabinofuranosyl C-Oligosaccharides Teterahedron Lett 2003 44 4067-4071
[29] Colinas P A Ponzinibbio A Lieberknecht A and Bravo R OWittig Reaction of Glycosyl Phosphonium Salts A StereoselectiveRoute to C-Disaccharides and C O-Trisaccharides TetrahedronLett 2003 44 7985-7988
[30] Schmidt R R Preuss R Synthesis of Carbon Tetrahedron Lett1989 30 3409-3412
[31] Dietrich H Schmidt R R Synthesis of Carbon-Bridged C-Lactose and Derivatives Liebigs Ann Chem 1994 975-981
[32] Rouzaud D Sinayuml P The First Synthesis of a ldquoC-DisacchariderdquoJ Chem Soc Chem Commun 1983 1353-1354
[33] Xin Y-C Zhang Y-M Mallet J-M Glaudemans C P JSinayuml P Synthesis of C-Oligosaccharides That Mimie TheirNatural O-Analogues Immunodeterminants in Binding toMonoclonal Immunoglobulins Eur J Org Chem 1999 471-476
[34] Streicher H Geyer A Schmidt R R C-Disaccharides ofKetoses Chem Eur J 1996 2 502-510
[35] Leeuwenburgh M A Timmers C M Vander Marel G A VanBoom J H Mallet J-M Sinayuml P G Stereoselective Synthesisof α-C-(Alkynyl)-Glycosides Via Ring-Opening of α-12-Anhydrous Tetrahedron Lett 1997 38 6251-6254
[36] Aslam T Fuchs M G G Le Formal A Wightman R HSynthesis of C-Disaccharide Analogue of the α-D-Arabinofuranosyl-(1rarr5)-α-Arabinofuranosyl Motif ofMycobacterial Cells Walls via Alkynyl Intermediates TetrahedronLett 2005 46 3249-3252
[37] (a) Girad P Namy J L Kagan H B Divalent LanthanideDerivative in Organic Synthesis 1 Mild Preparation of SamariumIodide and Ytterbium Iodide and Their Use as Reducing orCoupling Agents J Am Chem Soc 1980 102 2693-2698 (b)Molander G A Harris C R Sequencing Reactions withSamarium(II) Iodide Chem Rev 1996 96 307-338
[38] (a) Mazeacuteas D Skrydstrup T Doumeix O Beau J-MSamarium Iodide-Induced Intramolecular C-Glycoside FormationEfficient Radical Formation in the Absence of an Additive AngewChem Int Ed Engl 1994 33 1383-1386 (b) Mazeacuteas DSkrydstrup T Beau J-M A Highly Stereoselective Synthesis of1 2-trans-C-Glycosides Via Glycosyl Samarium(III) CompoundsAngew Chem Int Ed Engl 1995 34 909-912 (c) Jarreton OSkrydstrup T Beau J-M The Stereospecific Synthesis of Methylα-C-Mannobioside A Potential Inhibitor of M TuberculosisBinding to Human Macrophages J Chem Soc Chem Commun1996 1661-1662 (d) Jarreton O Skrydstrup T Espionosa J-FJimeacutenez-Barbero J Beau J-M Samarium Diiode Prompted C-Glycosylation An Application to The Stereospecific Synthesis ofα-(1rarr2)-C-Mannobioside and Its Derivatives Chem Eur J 19995 430-441 (e) Mipuel N Doisneau G Beau J-M ReductiveSamariation of Anomeric 2-Pyridyl Sulfones with Catalytic AnUnexpected Improvement in The Synthesis of 12-Trans-Diequatorial C-Glycosyl Compounds Angew Chem Int Ed Engl 2000 39 4111-4114
[39] Vlahov I R Vlahova P I Linhardt R J DiastereocontrolledSynthesis of Carbon Glycosides of N-Acetylneuraminic Acid ViaGlycosyl Samarium(III) Intermediates JAmChem Soc 1997 1191480-1481
[40] Kuberan B Sikkander S ATomiyama H Linhardt R JSynthesis of a C-Glycoside Analogue of sTn An HIV-and Tumor-Associated Antigen Angew Chem Int Ed Engl 2003 42 2073-2075
[41] Bazin H G Du Y Polat T Linhardt R J Synthesis of aVersatile Neuraminic Acid ldquoCrdquo-Disaccharide Precursor for theSynthesis of C-Glycoside Analogues of Gangliosides J OrgChem 1999 64 7254-7259
[42] Chen C-C Ress D K Linhardt RJ Samarium Iodide-Mediated Synthesis of Neuraminic Acid C-Glycosides InSynthesis of Glycommetics Roy R Ed ACS Syposium Series2004 896 53-80
[43] Abdallah Z Doisneau G Beau J-M Synthesis of a Carbon-Linked Mimic of The Disaccharide Component of The Tumor-Relate SialyTn Antigen Angew Chem Int Ed Engl 2003 425209-5212
[44] Lay L Nicotra F Panza L Russo G Caneva E Synthesis ofC-disaccharides through dimerization of exo-glycals J Org Chem1992 57 1304-1306
[45] Isobe M Nishizawa R Hosokawa S Nishikawa TStereocontrolled Synthesis and Reactivity of Sugar Acetylenes JChem Soc Chem Commun 1998 2665-2676
[46] Saeeng R Sirion U Sahakitpichan P Isobe M IodineCatalyzes C-Glycosidation of D-Glucal with SilylacetykeneTetrahedron Lett 2003 44 6211-6215
[47] (a) Babirad S A Wang Y Kishi Y Synthesis of C-Disaccharides J Org Chem 1987 52 1370-1372 (b) Wang YBabirad S A Kishi Y Preferred Conformation of C-Glycosides
1430 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
8 Synthesis of 14-Linked Carbon Disaccharides J Org Chem1992 57 468-481
[48] Armstrong R W Sutherlin D P Strategies for the Synthesis ofC-Disaccharides Containing D and L Sugars Tetrahedron Lett1994 35 7743-7746
[49] Wei A Kishi Y Preferred Conformation of C-Glycosides 12Synthesis and Conformational Analysis of αα- α β- and β β-Trehaloses J Org Chem 1994 59 88-96
[50] Haneda T Goekjian P G Kim S H Kishi Y PreferredConformation of C-Glycosides 10 Synthesis and ConformationAnalysis of Carbon Trisaccharides J Org Chem 1992 57 490-498
[51] Sutherlin D P Armstrong R W Synthesis of 12 Stereochemistryand Structurally Diverse C-Trisaccharides J Org Chem 1997 625267-5283
[52] Notz W Hartel C Waldscheck B Schmidt R R De NovoSynthesis of a Methylene-Bridged Neu5Ac-α-(23)-Gal C-Disaccharide J Org Chem 2001 66 4250-4260
[53] (a) Postema M H D Calimente D Liu L Behrmanm T L AnOlefin Metathesis Route for the Preparation of (1rarr6)-Linked-C-Disaccharide Glycals A Convergent and Flexible Approach to C-Saccharide Synthesis J Org Chem 2000 65 6061-6068(b) Postema M H Piper J L Liu L Faust M Andreana PSynthesis and Partial Biological Evaluation of a Small Library ofDifferentially Linked β-C-Disaccharide J Org Chem 2003 684748-4754
[54] Nelson A The Development of Strategies and Methods for TheSynthesis of Biologically Active Compounds New J Chem 200428 771-776
[55] Togo H He W Waki Y Yokoyama M C-GlycosylationTechnology With Free Radiant Reactions Synlett 1998 700-717
[56] Giese B Dupuis J Diastereoselective Synthesis of C-Glycopyranosides Angew Chem Int Ed Engl 1983 22 622-623
[57] Adlington R M Baldwin J E Basak A Kozyrod RPApplication of Radical Addition Reactions to tho Synthesis of a C-Glucoside and A Functionalized Amino Acid J Chem SocChem Commun 1983 144-145
[58] Giese B Gonzaacutelez-Goacutemez J A Witzel T The Scope of RadicalCC-Coupling by The ldquoTin Methodrdquo Angew Chem Int Ed Engl1984 23 69-70
[59] Giese B Witzel T Synthesis of ldquoC-Disaccharidesrdquo by RadicalC-C Bond Formation Angew Chem Int Ed Engl 1986 25 450-451
[60] Witczak Z J Chhabra R Chojnacki J C-Disaccharides IStereoselective Approach to β-(1rarr4)-3-Deoxy-C-Disaccharidesfrom Levoglucosenone Carb Res 1997 301 167-175
[61] Vogel P Synthesis of Rare Carbohydrates and Analogues Startingfrom Enantiomerically Pure 7-Oxabicyclo[221]heptyl Derivatives(ldquoNaked Sugarsrdquo) Current Org Chem 2000 4 455-480
[62] Viodeacute C Vogel P Synthesis of The C-Disaccharide α-C(1rarr3)-L-Fucopyranoside of N-Acetylgalactosamine J Carb Chem2001 20 733-746
[63] Xin Y C Mallet J M Sinayuml P An Expeditious Synthesis of AC-Disaccharide Using A Temporary Silaketal Connection J ChemSoc Chem Commun 1993 864-865
[64] (a) Petitou M Herault P Lormeau J-C Helmboldt A MalletJ-M Sinayuml P Herbert J-M Introducing A C-InterglycosidicBond in A Biologically Active Pentasaccharide Hardly Affects ItsBiological Properties Bioorg Med Chem 1998 6 1509-1516 (b)Sinayuml P Advances in The Synthesis of the Carbohydrate MimicsPure Appl Chem 1998 70 1495-1499
[65] Sinayuml P Chemical Synthesis of Oligosaccharide Mimetics PureAppl Chem 1998 70 407-410
[66] Sinayuml P Chemical Synthesis of Oligosaccharide Mimetics PureAppl Chem 1998 69 459-463
[67] Vauzeilles B Sinayuml P Selective Radical Synthesis of β-C-Disaccharides Tetrahedron Lett 2001 42 7269-7272
1424 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
Scheme (50)
Scheme (51)
O OOH
OH
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
H
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
O
O
OMe
OHH
OH
OMe
HHO
HO
OH
OH
286
1 VO(acac)2 t-BuOH 95
2 (MeO)3CH BF3 90
1 P-O2NC6H4 CO2H Ph3P DIAD2 K2CO3 MeOH 82 over 2 steps
1 PhCOCl Et3N DMAP 402 P-O2NC6H4 CO2H Ph3P DIAD3 KOH THF-H2O 75 over 2 steps
TMEDA OsO4
Cat OsO4 NMO 287
Cat OsO4 NMO288
TMEDA OsO4
Cat OsO4 NMO
290
289
(RR)-282283
284
285
OHO
AcO
BrOAc
OAc
BnO
O
OBn
OBnO
OHO
AcOOAc
OAc
BnO
OOBn
OBnAcO
OHO
AcOOAc
OAc
BnO
O
OBn
OBnO
+
Bu3SnH AIBN291
292
293 81
1 Na[Al(OC2H4OMe)2(OEt)H]2 Ac2O pyr
294 56 over 2 steps
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1425
Scheme (52)
Scheme (53)
OBnO
BnOOBn
OBn O
OH
O
OBnO
BnO
OHOBn
OBn O
O
O
O
O
O
OBnO
BnOOBn
OBnO
OAcOAc
OAc
OBnO
BnO
OHOBn
OBn
IBu3SnH AIBN
295 297 26
1 BF3 OEt2 Et3SiH
2 L-Selectride THF
1 Pd(OH)2C C6H10 EtOH
2 EtSiOSO2CF3 Ac2O
298 89 over 2 steps299
296
O
O
PhSeClO
O
PhSeCl
Bu3 SnH
O
O
PhSeCl
R
H
O
OAc
R
Cl
O
AcO
OAc
OAc
OAcOH
Cl
NHAc
R
OAc
AcHN
OH
O
OH OAc
OH
OHO
HO
OH
O
AcO
OAc
OAc
OAcBr
O
O
PhSeCl
O
O
PhSeCl
R
O
OTIPSAcHNR
OAc OAc
O
OHAcHN
COOMe
R
OAc
1 Bu4NF
2 NH3MeOH
1 (Me3Si)2NLi THF2 Me2N=CHI
1 Bu3 SnH AIBN2
1 NaBH42 mCPBA3 Ac2O pyr
1 H+ MeCN
2 H2 O NaHCO3
R =
1 O3MeOH
2 Me2S NaHCO3
1 TIPSOTf 26-lut idine2 LiBH43 Ac2 O pyr DMAP
furanoses +
304 56
305 68 306 84307 50
308 46
300 301 302
303
309
1426 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
The reduction of 317 and treatment with DOWEX-H+ resinprovided the desired C-fucoside 318 in 70 (Scheme 54)
62 Intramolecular Radical Approaches
One disadvantage with the intermolecular approaches isthat during such radical mediated reactions electrondeficient alkenes are required to facilitate C-C bondformation The intramolecular approach of Sinayuml overcomes
this drawback by bring two substrates together via atemporary covalent silaketal connector This enables the useof a wider range of alkenes which can include alkene-functionalized sugars thus leading to the generation of C-disaccharides [63] Based on the early work of Stork Sinayumlemployed the tether reaction in the synthesis of both α- andβ-C-disaccharides with this work subsequently beingemployed in the synthesis of biologically significant natural
Scheme (54)
O
OH
Fuc
Cl
O
O
ClPhSe
OOAc
NHAcOHFuc
O
AcOOAc
AcO
Br
O
O
PhSeCl
O
AcOOAc
AcO
O
OH
PhSe Cl
Fuc
OOAc
NHAc
OMe
Fuc
O
AcHN
OH OAc
OH
O
OH
Me
OH
O
O
Fuc
ClSePh
O
HO
Fuc
ClSePh
+
Ph3SnHAIBN
78 combined yield
Fuc
310
+
1 NaBH4 MeOHTHF2 Chromatography
313 40 314 355
1 mCPBA
2 Ac2O pyr DMAP
+
315 75
1 TfOH MeCN
2 NaHCO3 O3 -78 oC
316 10 over 2 steps
1 Cl3 CCN NaH
2 MeOH BF3 OEt2
317 79
1 LiBH4 THF
2 Dowex-H+
311
312a312b
318 70 for 2 steps
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1427
products [64] The availability of different hydroxyl groupson each monosaccharide unit allowed the fine-tuning ofstereochemical outcome by selective positioning of the silyltether [65] Development of this early stereochemical controlled to the tethering of the donor 320 with alcohol 319through a di-isopropyl silicon tether 321 Subsequent treat-ment with Bu3SnH and AIBN led to a 9-endo-trigcyclization to form the C-disaccharide 322 in an 80 yieldwith exclusive formation of the α-product The silyl tetherwas removed with Bu4NF and deprotection under standardconditions afforded the desired disaccharide 323 in excellentyield (Scheme 55)
In parallel the development of a 32rsquo silyl tether allowedaccess to the β-linked product as demonstrated in Sinayumlrsquossynthesis of methyl β-C-lactoside 328 [66] Alcohol 324 and320 were connected via the dimethylsilyl tether an 8-endo-trig cyclization followed to exclusively afford the β-
disaccharide 326 in 45 yield Removal of the tether anddeprotection of benzyl ether gave β-C-disaccharide 328(Scheme 56)
This group also selected iodosugars bearing a freehydroxyl group as progenitors of the radical donors [67] In atypical experiment the radical donor 329 was connected tothe radical acceptor 330 through a silaketal tether followingtheir procedure Tributyltinhydride mediated 8-endo-trigradical cyclization of compound 331 gave after detetheringof the non isolated intermediate 332 the protected β-C-disaccharide 333 in 37 overall yield (from startingmaterials 330 and 329) Peracetate 335 was achieved afterhydrogenolysis The C-laminaribioside 334 is of potentialbiological interest as it mimics the repeating disaccharideunit of fungal β-(1rarr3)-glucans which have antitumor andimmunomodulating properties (Scheme 57)
Scheme (55)
Scheme (56)
OO
OHSePh
OTBDPSO O
OO
SePh
OTBDPSO
OO
OBnOMe
OBn
Si
O
HOOBn
OMe
OBn
O
HOOH
OHHO
O
HOOH
OMe
OH
OTBDPSO
O
HOOBn
OMe
OBnO
OOH
1 n-BuLi THF
2 iPr2SiCl2 -78 oC
3 DMAP THF rt
1 Bu4NF THF
2 Dowex-H+
3 H2 PdC
Bu3SnH AIBN toluene
319
320
321
322323
OBnO
OHSePh
OBnBnO
OHO
OBnOMe
OBn
ROO
ROOH
OR
OHO
OROMe
OR
OBnO
O
OBnBnO
OO
OBnOMe
OBn
Si
SePh
OBnO
O
OBnBnOO
OOBn
OMe
OBn
Si
1 PhSeH Me2SiCl2
BuLi -78 oC
2 imidazole rt
Bu3SnH AIBN toluene
H2 PdC327 R = Bn
328 R = H
Bu4NF THF
324
320
325
326 45
1428 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
CONCLUSIONS
In this paper the biological importance of C-oligo-saccharides as subunits of natural products and as a newgeneration of carbohydrate based on therapeutics has beenillustrated Different methods are available for the synthesisof C-oligosaccharides As with traditional saccharidesynthesis it has been necessary to develop a number ofspecific approaches to facilitate the regioselective andstereoselective preparation of the desired targets Work inthis area continues and it is expected that many interestingnew C-oligosaccharides will be prepared using the chemistrydescribed in this review It is also likely that new chemistrywill be developed in the future for the preparation of thesebiologically important targets
ACKNOWLEDGEMENTS
The authors thank Dr Sultan Baytas for her criticalreading of this manuscript
REFERENCES
[1] Kennedy J F White C A Bioactive Carbohydrates InChemistry Biochemistry and Biology Ellis Horwood LtdChichesterUK 1983
[2] Wassarman PW Mammalian Fertilization Molecular Aspects ofGamete Adhesion xocytosion Exocytosis and Fusion Cell 199996 175-183
[3] Carbohydrate-based Drug Discovery Wong C-H EdWeinheim Cambridge Wiley-VCH 2003
[4] (a) Sharon N Lis H Lectins as Cell Recognition MoleculesScience 1987 246 227-234 (b) Dwek RA Chem Rev 1996 96683-720
[5] Postema M C-Glycoside synthesis CRC Boc Ratom 1995[6] (a) Weatherman R V Mortell K H Cheruenak MKiessling
L L Toone E J Specificity of C-Glycoside Complexation byMannoseGlucose Specific Lectins Biochem 1996 35 3619-3624(b) Ravishankar R Surolia A Vijayan M Lim S Kishi YPreferred Conformation of C-Lactose at the Free and Peanut LectinBound States J Am Chem Soc1998 120 11297-11303
[7] (a)Wong C-H Halcomb R L Ichikawa Y and Kajimoto TEnzymes in organic synthesis Application to the problems ofcarbohydrate recognition part2 Angew Chem Int Ed Engl 199534 521-546 (b)Howard S Withers SG Bromoketone C-Glycosides a New Class of βminusGlucanase Inactivators J AmChem Soc 1998 120 10326-10331(c) Wang Q Wolff MPolat T Du Y Linhardt R J C-glycoside of Neuraminic Acidsas Neura-minidase Inhibitors Bioorg Med Lett 2000 10 941-944 (d) Phili R Chang J Partis R A Mueller R A ChrestF J Passaniti A The Alpha-glucosidase I InhibitorCastanospermine Alters Endothelial cell Glycosylation PreventsAngiogenesis and Inhibits Tumor Growth Cancer Res 1995 552927-2935
[8] Ossor A Elbein A D In Carbohydrates in Chemistry andBiology Vol 3(II) WileyVCH 2000 pp 513-539
[9] (a) Sinayuml P Synthesis of oligosaccharide Mimetics Pure ApplChem 1997 69 459-463 (b) Beau J-M Gallagher TNucleophilic C-glycosyl Donors for C-glycoside Synthesis Top inCurr Chem 1997 187 1-54 (c) Nicotra F Synthesis of C-glycosides of Biological Interest Top in Curr Chem 1997 187
Scheme (57)
O
O
O
Ph
I
OMe
OHO
BnO
OH
OH
BnOOH
O
BnO
Si
O
O O
Ph
I
OMe
O
O
BnO
OR4O
R5O
OMe
OR2
OR3O
R3O
OR1
R3O
Bu3 SnH AIBN
332 R1 R2 = SiMe2 R3 = Bn R4 R5 = CHPhTBAF THF
333 R1 = R2 = H R3 = Bn R4 = R5 = CHPh 37 from 11
334 R1 = R2 = R3 = R4 = R5 = H
335 R1 = R2 = R3 = R4 = R5 = Ac
329
H2 PdC MeOH
Ac2 O pyr
1 BuLi THF -78 oC
2 Me2SiCl2
3 DMAP
330
331
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1429
55-83 (d) Du Y Linhardt R Y Recent Adv in Stereo-SelectiveC-Glycoside Synthesis Tetrahedron Lett 1998 54 9913-9959 (e)Liu L Mckee M and Postema M H D Synthesis of C-saccharides and Higher Congeners Current Org Chem 2001 51133-1167
[10] Jarosz S Fraser-Reid B Synthesis of A Higher Carbon Sugar ViaDirected Aldol Condensation Tetrahedron Lett 1989 30 2359-2362
[11] Lichtenthaler F W Lergenmiiller M Schwidetzky S C-Glycosidations of 2-Ketohexosyl With Electrophilic Radical andNudeophilic Anomeric Carbons Eur J Org Chem 2003 3094-3103
[12] Baudat A Vogel P Aza-C-disaccharides Synthesis of 6-Deoxygalactonojirimycin-β-C(1rarr3) Linked with D-Altrofuranosides and D-Galactose J Org Chem 1997 62 6252-6260
[13] Turner D Vogel P Synthesis of 4-Hydroxy-26-Bis(hydroxymethyl) tetrahydropyran-2-Carbaldehyde DerivativesSynlett 1998 304-306
[14] Zhu Y-H Vogel P Short Stereoselective Synthesis of C-(1rarr3)-Linked Disaccharides Tetrahedron Lett 1998 39 31-34
[15] Zhu Y-H Vogel P Synthesis of a (2R 6R)-2-(Hydroxymethyl)-6-Propa-1 2-Dienyl-2H-Pyran-3(6H)-One Derivative A NewEnone for The Convergent Construction of C-Glycosides of C-Disaccharides Synlett 2001 82-86
[16] Baumberger F Vasella A Deoxynitrosugars The 6th
Communication Stereolectronic Control in the reductivedenitration of tertiary nitro ethers A Synthesis of ldquoC-glycosidesrdquoHelv Chim Acta 1983 66 2210-2221
[17] Martin O R Lai W Synthesis and Conformational Studies of β-(1rarr6)- and ββ-(1rarr1)-Linked C-disaccharides J Org Chem1993 58 176-185
[18] Spak S J Martin R The synthesis of an analogue of Methyl OC-Analogue of Methyl 4rsquo-O-β-D-GlucopyranosylgentiobiosideTetrahedron 2000 56 217-224
[19] Kobertz W R Bertozzi C R Bednarski M D C-GlycosylAldehyde Synthons for C-Linked Disaccharides J Org Chem1996 61 1894-1897
[20] Gurjar M K Nagaprasad R and Ramana CV First Synthesis ofMethyl α-C-D-Arabino-furanosyl-(1rarr5)-αminusD-Arabinofuranosidethe C-Disaccharide Segment of Motif C of MycobateriumTuberculosis Tetrahedron Lett 2000 43 7577-7579
[21] Witczak Z J Synthesis of C-Glycosyl Compounds and OtherNatural Products from Levoglucosenone Pure Appl Chem 199466 2189-2192
[22] Griffin F K Paterson D Taylor R J K Ramberg-BacklundApproaches to the Synthesis of C-Linked Disaccharides AngewChem Int Engl 1999 38 2939-2942
[23] Paterson B E Griffin F K Alcaraz M-L and Taylor R J KA Ramberg-Baumlcklund Approach to the Synthesis of C-GlycosidesC-Linked Disaccharides and C-Glycosyl Amino Acids Eur JOrg Chem 2002 1323-1336
[24] McAllister G D Paterson D E Taylor R J K A SimplifiedRamberg-Bachlund Approach to Novel C-Glycosides and C-Linked Disaccharides Angew Chem Int Ed Engl 2003 42 1387-1391
[25] McCartney J L Christopher T M Cicchillo R M BernardinaM D Wagner T R and Norris P J Org Chem 2003 6810152-10155
[26] Dondoni A Zuurmond H M Bascarate A Synthesis of α-andβ-D-(1rarr6)-C-Disaccharides by Witting Olefination of Formyl C-Glycosides with Glycopyranose 6-phosphoranes J Org Chem1997 62 8114-8124
[27] Dondoni A Kleban M Zuurmond H Marra A Synthesis of(1rarr6)-C-Oligogalactosides by Interative Wittig OlefinationTetrahedron Lett 1998 39 7991-7994
[28] Dondoni A Marra A A New Synthetic Approach toMycobacterial Cell Wall α-(1rarr5)-D-Arabinofuranosyl C-Oligosaccharides Teterahedron Lett 2003 44 4067-4071
[29] Colinas P A Ponzinibbio A Lieberknecht A and Bravo R OWittig Reaction of Glycosyl Phosphonium Salts A StereoselectiveRoute to C-Disaccharides and C O-Trisaccharides TetrahedronLett 2003 44 7985-7988
[30] Schmidt R R Preuss R Synthesis of Carbon Tetrahedron Lett1989 30 3409-3412
[31] Dietrich H Schmidt R R Synthesis of Carbon-Bridged C-Lactose and Derivatives Liebigs Ann Chem 1994 975-981
[32] Rouzaud D Sinayuml P The First Synthesis of a ldquoC-DisacchariderdquoJ Chem Soc Chem Commun 1983 1353-1354
[33] Xin Y-C Zhang Y-M Mallet J-M Glaudemans C P JSinayuml P Synthesis of C-Oligosaccharides That Mimie TheirNatural O-Analogues Immunodeterminants in Binding toMonoclonal Immunoglobulins Eur J Org Chem 1999 471-476
[34] Streicher H Geyer A Schmidt R R C-Disaccharides ofKetoses Chem Eur J 1996 2 502-510
[35] Leeuwenburgh M A Timmers C M Vander Marel G A VanBoom J H Mallet J-M Sinayuml P G Stereoselective Synthesisof α-C-(Alkynyl)-Glycosides Via Ring-Opening of α-12-Anhydrous Tetrahedron Lett 1997 38 6251-6254
[36] Aslam T Fuchs M G G Le Formal A Wightman R HSynthesis of C-Disaccharide Analogue of the α-D-Arabinofuranosyl-(1rarr5)-α-Arabinofuranosyl Motif ofMycobacterial Cells Walls via Alkynyl Intermediates TetrahedronLett 2005 46 3249-3252
[37] (a) Girad P Namy J L Kagan H B Divalent LanthanideDerivative in Organic Synthesis 1 Mild Preparation of SamariumIodide and Ytterbium Iodide and Their Use as Reducing orCoupling Agents J Am Chem Soc 1980 102 2693-2698 (b)Molander G A Harris C R Sequencing Reactions withSamarium(II) Iodide Chem Rev 1996 96 307-338
[38] (a) Mazeacuteas D Skrydstrup T Doumeix O Beau J-MSamarium Iodide-Induced Intramolecular C-Glycoside FormationEfficient Radical Formation in the Absence of an Additive AngewChem Int Ed Engl 1994 33 1383-1386 (b) Mazeacuteas DSkrydstrup T Beau J-M A Highly Stereoselective Synthesis of1 2-trans-C-Glycosides Via Glycosyl Samarium(III) CompoundsAngew Chem Int Ed Engl 1995 34 909-912 (c) Jarreton OSkrydstrup T Beau J-M The Stereospecific Synthesis of Methylα-C-Mannobioside A Potential Inhibitor of M TuberculosisBinding to Human Macrophages J Chem Soc Chem Commun1996 1661-1662 (d) Jarreton O Skrydstrup T Espionosa J-FJimeacutenez-Barbero J Beau J-M Samarium Diiode Prompted C-Glycosylation An Application to The Stereospecific Synthesis ofα-(1rarr2)-C-Mannobioside and Its Derivatives Chem Eur J 19995 430-441 (e) Mipuel N Doisneau G Beau J-M ReductiveSamariation of Anomeric 2-Pyridyl Sulfones with Catalytic AnUnexpected Improvement in The Synthesis of 12-Trans-Diequatorial C-Glycosyl Compounds Angew Chem Int Ed Engl 2000 39 4111-4114
[39] Vlahov I R Vlahova P I Linhardt R J DiastereocontrolledSynthesis of Carbon Glycosides of N-Acetylneuraminic Acid ViaGlycosyl Samarium(III) Intermediates JAmChem Soc 1997 1191480-1481
[40] Kuberan B Sikkander S ATomiyama H Linhardt R JSynthesis of a C-Glycoside Analogue of sTn An HIV-and Tumor-Associated Antigen Angew Chem Int Ed Engl 2003 42 2073-2075
[41] Bazin H G Du Y Polat T Linhardt R J Synthesis of aVersatile Neuraminic Acid ldquoCrdquo-Disaccharide Precursor for theSynthesis of C-Glycoside Analogues of Gangliosides J OrgChem 1999 64 7254-7259
[42] Chen C-C Ress D K Linhardt RJ Samarium Iodide-Mediated Synthesis of Neuraminic Acid C-Glycosides InSynthesis of Glycommetics Roy R Ed ACS Syposium Series2004 896 53-80
[43] Abdallah Z Doisneau G Beau J-M Synthesis of a Carbon-Linked Mimic of The Disaccharide Component of The Tumor-Relate SialyTn Antigen Angew Chem Int Ed Engl 2003 425209-5212
[44] Lay L Nicotra F Panza L Russo G Caneva E Synthesis ofC-disaccharides through dimerization of exo-glycals J Org Chem1992 57 1304-1306
[45] Isobe M Nishizawa R Hosokawa S Nishikawa TStereocontrolled Synthesis and Reactivity of Sugar Acetylenes JChem Soc Chem Commun 1998 2665-2676
[46] Saeeng R Sirion U Sahakitpichan P Isobe M IodineCatalyzes C-Glycosidation of D-Glucal with SilylacetykeneTetrahedron Lett 2003 44 6211-6215
[47] (a) Babirad S A Wang Y Kishi Y Synthesis of C-Disaccharides J Org Chem 1987 52 1370-1372 (b) Wang YBabirad S A Kishi Y Preferred Conformation of C-Glycosides
1430 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
8 Synthesis of 14-Linked Carbon Disaccharides J Org Chem1992 57 468-481
[48] Armstrong R W Sutherlin D P Strategies for the Synthesis ofC-Disaccharides Containing D and L Sugars Tetrahedron Lett1994 35 7743-7746
[49] Wei A Kishi Y Preferred Conformation of C-Glycosides 12Synthesis and Conformational Analysis of αα- α β- and β β-Trehaloses J Org Chem 1994 59 88-96
[50] Haneda T Goekjian P G Kim S H Kishi Y PreferredConformation of C-Glycosides 10 Synthesis and ConformationAnalysis of Carbon Trisaccharides J Org Chem 1992 57 490-498
[51] Sutherlin D P Armstrong R W Synthesis of 12 Stereochemistryand Structurally Diverse C-Trisaccharides J Org Chem 1997 625267-5283
[52] Notz W Hartel C Waldscheck B Schmidt R R De NovoSynthesis of a Methylene-Bridged Neu5Ac-α-(23)-Gal C-Disaccharide J Org Chem 2001 66 4250-4260
[53] (a) Postema M H D Calimente D Liu L Behrmanm T L AnOlefin Metathesis Route for the Preparation of (1rarr6)-Linked-C-Disaccharide Glycals A Convergent and Flexible Approach to C-Saccharide Synthesis J Org Chem 2000 65 6061-6068(b) Postema M H Piper J L Liu L Faust M Andreana PSynthesis and Partial Biological Evaluation of a Small Library ofDifferentially Linked β-C-Disaccharide J Org Chem 2003 684748-4754
[54] Nelson A The Development of Strategies and Methods for TheSynthesis of Biologically Active Compounds New J Chem 200428 771-776
[55] Togo H He W Waki Y Yokoyama M C-GlycosylationTechnology With Free Radiant Reactions Synlett 1998 700-717
[56] Giese B Dupuis J Diastereoselective Synthesis of C-Glycopyranosides Angew Chem Int Ed Engl 1983 22 622-623
[57] Adlington R M Baldwin J E Basak A Kozyrod RPApplication of Radical Addition Reactions to tho Synthesis of a C-Glucoside and A Functionalized Amino Acid J Chem SocChem Commun 1983 144-145
[58] Giese B Gonzaacutelez-Goacutemez J A Witzel T The Scope of RadicalCC-Coupling by The ldquoTin Methodrdquo Angew Chem Int Ed Engl1984 23 69-70
[59] Giese B Witzel T Synthesis of ldquoC-Disaccharidesrdquo by RadicalC-C Bond Formation Angew Chem Int Ed Engl 1986 25 450-451
[60] Witczak Z J Chhabra R Chojnacki J C-Disaccharides IStereoselective Approach to β-(1rarr4)-3-Deoxy-C-Disaccharidesfrom Levoglucosenone Carb Res 1997 301 167-175
[61] Vogel P Synthesis of Rare Carbohydrates and Analogues Startingfrom Enantiomerically Pure 7-Oxabicyclo[221]heptyl Derivatives(ldquoNaked Sugarsrdquo) Current Org Chem 2000 4 455-480
[62] Viodeacute C Vogel P Synthesis of The C-Disaccharide α-C(1rarr3)-L-Fucopyranoside of N-Acetylgalactosamine J Carb Chem2001 20 733-746
[63] Xin Y C Mallet J M Sinayuml P An Expeditious Synthesis of AC-Disaccharide Using A Temporary Silaketal Connection J ChemSoc Chem Commun 1993 864-865
[64] (a) Petitou M Herault P Lormeau J-C Helmboldt A MalletJ-M Sinayuml P Herbert J-M Introducing A C-InterglycosidicBond in A Biologically Active Pentasaccharide Hardly Affects ItsBiological Properties Bioorg Med Chem 1998 6 1509-1516 (b)Sinayuml P Advances in The Synthesis of the Carbohydrate MimicsPure Appl Chem 1998 70 1495-1499
[65] Sinayuml P Chemical Synthesis of Oligosaccharide Mimetics PureAppl Chem 1998 70 407-410
[66] Sinayuml P Chemical Synthesis of Oligosaccharide Mimetics PureAppl Chem 1998 69 459-463
[67] Vauzeilles B Sinayuml P Selective Radical Synthesis of β-C-Disaccharides Tetrahedron Lett 2001 42 7269-7272
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1425
Scheme (52)
Scheme (53)
OBnO
BnOOBn
OBn O
OH
O
OBnO
BnO
OHOBn
OBn O
O
O
O
O
O
OBnO
BnOOBn
OBnO
OAcOAc
OAc
OBnO
BnO
OHOBn
OBn
IBu3SnH AIBN
295 297 26
1 BF3 OEt2 Et3SiH
2 L-Selectride THF
1 Pd(OH)2C C6H10 EtOH
2 EtSiOSO2CF3 Ac2O
298 89 over 2 steps299
296
O
O
PhSeClO
O
PhSeCl
Bu3 SnH
O
O
PhSeCl
R
H
O
OAc
R
Cl
O
AcO
OAc
OAc
OAcOH
Cl
NHAc
R
OAc
AcHN
OH
O
OH OAc
OH
OHO
HO
OH
O
AcO
OAc
OAc
OAcBr
O
O
PhSeCl
O
O
PhSeCl
R
O
OTIPSAcHNR
OAc OAc
O
OHAcHN
COOMe
R
OAc
1 Bu4NF
2 NH3MeOH
1 (Me3Si)2NLi THF2 Me2N=CHI
1 Bu3 SnH AIBN2
1 NaBH42 mCPBA3 Ac2O pyr
1 H+ MeCN
2 H2 O NaHCO3
R =
1 O3MeOH
2 Me2S NaHCO3
1 TIPSOTf 26-lut idine2 LiBH43 Ac2 O pyr DMAP
furanoses +
304 56
305 68 306 84307 50
308 46
300 301 302
303
309
1426 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
The reduction of 317 and treatment with DOWEX-H+ resinprovided the desired C-fucoside 318 in 70 (Scheme 54)
62 Intramolecular Radical Approaches
One disadvantage with the intermolecular approaches isthat during such radical mediated reactions electrondeficient alkenes are required to facilitate C-C bondformation The intramolecular approach of Sinayuml overcomes
this drawback by bring two substrates together via atemporary covalent silaketal connector This enables the useof a wider range of alkenes which can include alkene-functionalized sugars thus leading to the generation of C-disaccharides [63] Based on the early work of Stork Sinayumlemployed the tether reaction in the synthesis of both α- andβ-C-disaccharides with this work subsequently beingemployed in the synthesis of biologically significant natural
Scheme (54)
O
OH
Fuc
Cl
O
O
ClPhSe
OOAc
NHAcOHFuc
O
AcOOAc
AcO
Br
O
O
PhSeCl
O
AcOOAc
AcO
O
OH
PhSe Cl
Fuc
OOAc
NHAc
OMe
Fuc
O
AcHN
OH OAc
OH
O
OH
Me
OH
O
O
Fuc
ClSePh
O
HO
Fuc
ClSePh
+
Ph3SnHAIBN
78 combined yield
Fuc
310
+
1 NaBH4 MeOHTHF2 Chromatography
313 40 314 355
1 mCPBA
2 Ac2O pyr DMAP
+
315 75
1 TfOH MeCN
2 NaHCO3 O3 -78 oC
316 10 over 2 steps
1 Cl3 CCN NaH
2 MeOH BF3 OEt2
317 79
1 LiBH4 THF
2 Dowex-H+
311
312a312b
318 70 for 2 steps
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1427
products [64] The availability of different hydroxyl groupson each monosaccharide unit allowed the fine-tuning ofstereochemical outcome by selective positioning of the silyltether [65] Development of this early stereochemical controlled to the tethering of the donor 320 with alcohol 319through a di-isopropyl silicon tether 321 Subsequent treat-ment with Bu3SnH and AIBN led to a 9-endo-trigcyclization to form the C-disaccharide 322 in an 80 yieldwith exclusive formation of the α-product The silyl tetherwas removed with Bu4NF and deprotection under standardconditions afforded the desired disaccharide 323 in excellentyield (Scheme 55)
In parallel the development of a 32rsquo silyl tether allowedaccess to the β-linked product as demonstrated in Sinayumlrsquossynthesis of methyl β-C-lactoside 328 [66] Alcohol 324 and320 were connected via the dimethylsilyl tether an 8-endo-trig cyclization followed to exclusively afford the β-
disaccharide 326 in 45 yield Removal of the tether anddeprotection of benzyl ether gave β-C-disaccharide 328(Scheme 56)
This group also selected iodosugars bearing a freehydroxyl group as progenitors of the radical donors [67] In atypical experiment the radical donor 329 was connected tothe radical acceptor 330 through a silaketal tether followingtheir procedure Tributyltinhydride mediated 8-endo-trigradical cyclization of compound 331 gave after detetheringof the non isolated intermediate 332 the protected β-C-disaccharide 333 in 37 overall yield (from startingmaterials 330 and 329) Peracetate 335 was achieved afterhydrogenolysis The C-laminaribioside 334 is of potentialbiological interest as it mimics the repeating disaccharideunit of fungal β-(1rarr3)-glucans which have antitumor andimmunomodulating properties (Scheme 57)
Scheme (55)
Scheme (56)
OO
OHSePh
OTBDPSO O
OO
SePh
OTBDPSO
OO
OBnOMe
OBn
Si
O
HOOBn
OMe
OBn
O
HOOH
OHHO
O
HOOH
OMe
OH
OTBDPSO
O
HOOBn
OMe
OBnO
OOH
1 n-BuLi THF
2 iPr2SiCl2 -78 oC
3 DMAP THF rt
1 Bu4NF THF
2 Dowex-H+
3 H2 PdC
Bu3SnH AIBN toluene
319
320
321
322323
OBnO
OHSePh
OBnBnO
OHO
OBnOMe
OBn
ROO
ROOH
OR
OHO
OROMe
OR
OBnO
O
OBnBnO
OO
OBnOMe
OBn
Si
SePh
OBnO
O
OBnBnOO
OOBn
OMe
OBn
Si
1 PhSeH Me2SiCl2
BuLi -78 oC
2 imidazole rt
Bu3SnH AIBN toluene
H2 PdC327 R = Bn
328 R = H
Bu4NF THF
324
320
325
326 45
1428 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
CONCLUSIONS
In this paper the biological importance of C-oligo-saccharides as subunits of natural products and as a newgeneration of carbohydrate based on therapeutics has beenillustrated Different methods are available for the synthesisof C-oligosaccharides As with traditional saccharidesynthesis it has been necessary to develop a number ofspecific approaches to facilitate the regioselective andstereoselective preparation of the desired targets Work inthis area continues and it is expected that many interestingnew C-oligosaccharides will be prepared using the chemistrydescribed in this review It is also likely that new chemistrywill be developed in the future for the preparation of thesebiologically important targets
ACKNOWLEDGEMENTS
The authors thank Dr Sultan Baytas for her criticalreading of this manuscript
REFERENCES
[1] Kennedy J F White C A Bioactive Carbohydrates InChemistry Biochemistry and Biology Ellis Horwood LtdChichesterUK 1983
[2] Wassarman PW Mammalian Fertilization Molecular Aspects ofGamete Adhesion xocytosion Exocytosis and Fusion Cell 199996 175-183
[3] Carbohydrate-based Drug Discovery Wong C-H EdWeinheim Cambridge Wiley-VCH 2003
[4] (a) Sharon N Lis H Lectins as Cell Recognition MoleculesScience 1987 246 227-234 (b) Dwek RA Chem Rev 1996 96683-720
[5] Postema M C-Glycoside synthesis CRC Boc Ratom 1995[6] (a) Weatherman R V Mortell K H Cheruenak MKiessling
L L Toone E J Specificity of C-Glycoside Complexation byMannoseGlucose Specific Lectins Biochem 1996 35 3619-3624(b) Ravishankar R Surolia A Vijayan M Lim S Kishi YPreferred Conformation of C-Lactose at the Free and Peanut LectinBound States J Am Chem Soc1998 120 11297-11303
[7] (a)Wong C-H Halcomb R L Ichikawa Y and Kajimoto TEnzymes in organic synthesis Application to the problems ofcarbohydrate recognition part2 Angew Chem Int Ed Engl 199534 521-546 (b)Howard S Withers SG Bromoketone C-Glycosides a New Class of βminusGlucanase Inactivators J AmChem Soc 1998 120 10326-10331(c) Wang Q Wolff MPolat T Du Y Linhardt R J C-glycoside of Neuraminic Acidsas Neura-minidase Inhibitors Bioorg Med Lett 2000 10 941-944 (d) Phili R Chang J Partis R A Mueller R A ChrestF J Passaniti A The Alpha-glucosidase I InhibitorCastanospermine Alters Endothelial cell Glycosylation PreventsAngiogenesis and Inhibits Tumor Growth Cancer Res 1995 552927-2935
[8] Ossor A Elbein A D In Carbohydrates in Chemistry andBiology Vol 3(II) WileyVCH 2000 pp 513-539
[9] (a) Sinayuml P Synthesis of oligosaccharide Mimetics Pure ApplChem 1997 69 459-463 (b) Beau J-M Gallagher TNucleophilic C-glycosyl Donors for C-glycoside Synthesis Top inCurr Chem 1997 187 1-54 (c) Nicotra F Synthesis of C-glycosides of Biological Interest Top in Curr Chem 1997 187
Scheme (57)
O
O
O
Ph
I
OMe
OHO
BnO
OH
OH
BnOOH
O
BnO
Si
O
O O
Ph
I
OMe
O
O
BnO
OR4O
R5O
OMe
OR2
OR3O
R3O
OR1
R3O
Bu3 SnH AIBN
332 R1 R2 = SiMe2 R3 = Bn R4 R5 = CHPhTBAF THF
333 R1 = R2 = H R3 = Bn R4 = R5 = CHPh 37 from 11
334 R1 = R2 = R3 = R4 = R5 = H
335 R1 = R2 = R3 = R4 = R5 = Ac
329
H2 PdC MeOH
Ac2 O pyr
1 BuLi THF -78 oC
2 Me2SiCl2
3 DMAP
330
331
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1429
55-83 (d) Du Y Linhardt R Y Recent Adv in Stereo-SelectiveC-Glycoside Synthesis Tetrahedron Lett 1998 54 9913-9959 (e)Liu L Mckee M and Postema M H D Synthesis of C-saccharides and Higher Congeners Current Org Chem 2001 51133-1167
[10] Jarosz S Fraser-Reid B Synthesis of A Higher Carbon Sugar ViaDirected Aldol Condensation Tetrahedron Lett 1989 30 2359-2362
[11] Lichtenthaler F W Lergenmiiller M Schwidetzky S C-Glycosidations of 2-Ketohexosyl With Electrophilic Radical andNudeophilic Anomeric Carbons Eur J Org Chem 2003 3094-3103
[12] Baudat A Vogel P Aza-C-disaccharides Synthesis of 6-Deoxygalactonojirimycin-β-C(1rarr3) Linked with D-Altrofuranosides and D-Galactose J Org Chem 1997 62 6252-6260
[13] Turner D Vogel P Synthesis of 4-Hydroxy-26-Bis(hydroxymethyl) tetrahydropyran-2-Carbaldehyde DerivativesSynlett 1998 304-306
[14] Zhu Y-H Vogel P Short Stereoselective Synthesis of C-(1rarr3)-Linked Disaccharides Tetrahedron Lett 1998 39 31-34
[15] Zhu Y-H Vogel P Synthesis of a (2R 6R)-2-(Hydroxymethyl)-6-Propa-1 2-Dienyl-2H-Pyran-3(6H)-One Derivative A NewEnone for The Convergent Construction of C-Glycosides of C-Disaccharides Synlett 2001 82-86
[16] Baumberger F Vasella A Deoxynitrosugars The 6th
Communication Stereolectronic Control in the reductivedenitration of tertiary nitro ethers A Synthesis of ldquoC-glycosidesrdquoHelv Chim Acta 1983 66 2210-2221
[17] Martin O R Lai W Synthesis and Conformational Studies of β-(1rarr6)- and ββ-(1rarr1)-Linked C-disaccharides J Org Chem1993 58 176-185
[18] Spak S J Martin R The synthesis of an analogue of Methyl OC-Analogue of Methyl 4rsquo-O-β-D-GlucopyranosylgentiobiosideTetrahedron 2000 56 217-224
[19] Kobertz W R Bertozzi C R Bednarski M D C-GlycosylAldehyde Synthons for C-Linked Disaccharides J Org Chem1996 61 1894-1897
[20] Gurjar M K Nagaprasad R and Ramana CV First Synthesis ofMethyl α-C-D-Arabino-furanosyl-(1rarr5)-αminusD-Arabinofuranosidethe C-Disaccharide Segment of Motif C of MycobateriumTuberculosis Tetrahedron Lett 2000 43 7577-7579
[21] Witczak Z J Synthesis of C-Glycosyl Compounds and OtherNatural Products from Levoglucosenone Pure Appl Chem 199466 2189-2192
[22] Griffin F K Paterson D Taylor R J K Ramberg-BacklundApproaches to the Synthesis of C-Linked Disaccharides AngewChem Int Engl 1999 38 2939-2942
[23] Paterson B E Griffin F K Alcaraz M-L and Taylor R J KA Ramberg-Baumlcklund Approach to the Synthesis of C-GlycosidesC-Linked Disaccharides and C-Glycosyl Amino Acids Eur JOrg Chem 2002 1323-1336
[24] McAllister G D Paterson D E Taylor R J K A SimplifiedRamberg-Bachlund Approach to Novel C-Glycosides and C-Linked Disaccharides Angew Chem Int Ed Engl 2003 42 1387-1391
[25] McCartney J L Christopher T M Cicchillo R M BernardinaM D Wagner T R and Norris P J Org Chem 2003 6810152-10155
[26] Dondoni A Zuurmond H M Bascarate A Synthesis of α-andβ-D-(1rarr6)-C-Disaccharides by Witting Olefination of Formyl C-Glycosides with Glycopyranose 6-phosphoranes J Org Chem1997 62 8114-8124
[27] Dondoni A Kleban M Zuurmond H Marra A Synthesis of(1rarr6)-C-Oligogalactosides by Interative Wittig OlefinationTetrahedron Lett 1998 39 7991-7994
[28] Dondoni A Marra A A New Synthetic Approach toMycobacterial Cell Wall α-(1rarr5)-D-Arabinofuranosyl C-Oligosaccharides Teterahedron Lett 2003 44 4067-4071
[29] Colinas P A Ponzinibbio A Lieberknecht A and Bravo R OWittig Reaction of Glycosyl Phosphonium Salts A StereoselectiveRoute to C-Disaccharides and C O-Trisaccharides TetrahedronLett 2003 44 7985-7988
[30] Schmidt R R Preuss R Synthesis of Carbon Tetrahedron Lett1989 30 3409-3412
[31] Dietrich H Schmidt R R Synthesis of Carbon-Bridged C-Lactose and Derivatives Liebigs Ann Chem 1994 975-981
[32] Rouzaud D Sinayuml P The First Synthesis of a ldquoC-DisacchariderdquoJ Chem Soc Chem Commun 1983 1353-1354
[33] Xin Y-C Zhang Y-M Mallet J-M Glaudemans C P JSinayuml P Synthesis of C-Oligosaccharides That Mimie TheirNatural O-Analogues Immunodeterminants in Binding toMonoclonal Immunoglobulins Eur J Org Chem 1999 471-476
[34] Streicher H Geyer A Schmidt R R C-Disaccharides ofKetoses Chem Eur J 1996 2 502-510
[35] Leeuwenburgh M A Timmers C M Vander Marel G A VanBoom J H Mallet J-M Sinayuml P G Stereoselective Synthesisof α-C-(Alkynyl)-Glycosides Via Ring-Opening of α-12-Anhydrous Tetrahedron Lett 1997 38 6251-6254
[36] Aslam T Fuchs M G G Le Formal A Wightman R HSynthesis of C-Disaccharide Analogue of the α-D-Arabinofuranosyl-(1rarr5)-α-Arabinofuranosyl Motif ofMycobacterial Cells Walls via Alkynyl Intermediates TetrahedronLett 2005 46 3249-3252
[37] (a) Girad P Namy J L Kagan H B Divalent LanthanideDerivative in Organic Synthesis 1 Mild Preparation of SamariumIodide and Ytterbium Iodide and Their Use as Reducing orCoupling Agents J Am Chem Soc 1980 102 2693-2698 (b)Molander G A Harris C R Sequencing Reactions withSamarium(II) Iodide Chem Rev 1996 96 307-338
[38] (a) Mazeacuteas D Skrydstrup T Doumeix O Beau J-MSamarium Iodide-Induced Intramolecular C-Glycoside FormationEfficient Radical Formation in the Absence of an Additive AngewChem Int Ed Engl 1994 33 1383-1386 (b) Mazeacuteas DSkrydstrup T Beau J-M A Highly Stereoselective Synthesis of1 2-trans-C-Glycosides Via Glycosyl Samarium(III) CompoundsAngew Chem Int Ed Engl 1995 34 909-912 (c) Jarreton OSkrydstrup T Beau J-M The Stereospecific Synthesis of Methylα-C-Mannobioside A Potential Inhibitor of M TuberculosisBinding to Human Macrophages J Chem Soc Chem Commun1996 1661-1662 (d) Jarreton O Skrydstrup T Espionosa J-FJimeacutenez-Barbero J Beau J-M Samarium Diiode Prompted C-Glycosylation An Application to The Stereospecific Synthesis ofα-(1rarr2)-C-Mannobioside and Its Derivatives Chem Eur J 19995 430-441 (e) Mipuel N Doisneau G Beau J-M ReductiveSamariation of Anomeric 2-Pyridyl Sulfones with Catalytic AnUnexpected Improvement in The Synthesis of 12-Trans-Diequatorial C-Glycosyl Compounds Angew Chem Int Ed Engl 2000 39 4111-4114
[39] Vlahov I R Vlahova P I Linhardt R J DiastereocontrolledSynthesis of Carbon Glycosides of N-Acetylneuraminic Acid ViaGlycosyl Samarium(III) Intermediates JAmChem Soc 1997 1191480-1481
[40] Kuberan B Sikkander S ATomiyama H Linhardt R JSynthesis of a C-Glycoside Analogue of sTn An HIV-and Tumor-Associated Antigen Angew Chem Int Ed Engl 2003 42 2073-2075
[41] Bazin H G Du Y Polat T Linhardt R J Synthesis of aVersatile Neuraminic Acid ldquoCrdquo-Disaccharide Precursor for theSynthesis of C-Glycoside Analogues of Gangliosides J OrgChem 1999 64 7254-7259
[42] Chen C-C Ress D K Linhardt RJ Samarium Iodide-Mediated Synthesis of Neuraminic Acid C-Glycosides InSynthesis of Glycommetics Roy R Ed ACS Syposium Series2004 896 53-80
[43] Abdallah Z Doisneau G Beau J-M Synthesis of a Carbon-Linked Mimic of The Disaccharide Component of The Tumor-Relate SialyTn Antigen Angew Chem Int Ed Engl 2003 425209-5212
[44] Lay L Nicotra F Panza L Russo G Caneva E Synthesis ofC-disaccharides through dimerization of exo-glycals J Org Chem1992 57 1304-1306
[45] Isobe M Nishizawa R Hosokawa S Nishikawa TStereocontrolled Synthesis and Reactivity of Sugar Acetylenes JChem Soc Chem Commun 1998 2665-2676
[46] Saeeng R Sirion U Sahakitpichan P Isobe M IodineCatalyzes C-Glycosidation of D-Glucal with SilylacetykeneTetrahedron Lett 2003 44 6211-6215
[47] (a) Babirad S A Wang Y Kishi Y Synthesis of C-Disaccharides J Org Chem 1987 52 1370-1372 (b) Wang YBabirad S A Kishi Y Preferred Conformation of C-Glycosides
1430 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
8 Synthesis of 14-Linked Carbon Disaccharides J Org Chem1992 57 468-481
[48] Armstrong R W Sutherlin D P Strategies for the Synthesis ofC-Disaccharides Containing D and L Sugars Tetrahedron Lett1994 35 7743-7746
[49] Wei A Kishi Y Preferred Conformation of C-Glycosides 12Synthesis and Conformational Analysis of αα- α β- and β β-Trehaloses J Org Chem 1994 59 88-96
[50] Haneda T Goekjian P G Kim S H Kishi Y PreferredConformation of C-Glycosides 10 Synthesis and ConformationAnalysis of Carbon Trisaccharides J Org Chem 1992 57 490-498
[51] Sutherlin D P Armstrong R W Synthesis of 12 Stereochemistryand Structurally Diverse C-Trisaccharides J Org Chem 1997 625267-5283
[52] Notz W Hartel C Waldscheck B Schmidt R R De NovoSynthesis of a Methylene-Bridged Neu5Ac-α-(23)-Gal C-Disaccharide J Org Chem 2001 66 4250-4260
[53] (a) Postema M H D Calimente D Liu L Behrmanm T L AnOlefin Metathesis Route for the Preparation of (1rarr6)-Linked-C-Disaccharide Glycals A Convergent and Flexible Approach to C-Saccharide Synthesis J Org Chem 2000 65 6061-6068(b) Postema M H Piper J L Liu L Faust M Andreana PSynthesis and Partial Biological Evaluation of a Small Library ofDifferentially Linked β-C-Disaccharide J Org Chem 2003 684748-4754
[54] Nelson A The Development of Strategies and Methods for TheSynthesis of Biologically Active Compounds New J Chem 200428 771-776
[55] Togo H He W Waki Y Yokoyama M C-GlycosylationTechnology With Free Radiant Reactions Synlett 1998 700-717
[56] Giese B Dupuis J Diastereoselective Synthesis of C-Glycopyranosides Angew Chem Int Ed Engl 1983 22 622-623
[57] Adlington R M Baldwin J E Basak A Kozyrod RPApplication of Radical Addition Reactions to tho Synthesis of a C-Glucoside and A Functionalized Amino Acid J Chem SocChem Commun 1983 144-145
[58] Giese B Gonzaacutelez-Goacutemez J A Witzel T The Scope of RadicalCC-Coupling by The ldquoTin Methodrdquo Angew Chem Int Ed Engl1984 23 69-70
[59] Giese B Witzel T Synthesis of ldquoC-Disaccharidesrdquo by RadicalC-C Bond Formation Angew Chem Int Ed Engl 1986 25 450-451
[60] Witczak Z J Chhabra R Chojnacki J C-Disaccharides IStereoselective Approach to β-(1rarr4)-3-Deoxy-C-Disaccharidesfrom Levoglucosenone Carb Res 1997 301 167-175
[61] Vogel P Synthesis of Rare Carbohydrates and Analogues Startingfrom Enantiomerically Pure 7-Oxabicyclo[221]heptyl Derivatives(ldquoNaked Sugarsrdquo) Current Org Chem 2000 4 455-480
[62] Viodeacute C Vogel P Synthesis of The C-Disaccharide α-C(1rarr3)-L-Fucopyranoside of N-Acetylgalactosamine J Carb Chem2001 20 733-746
[63] Xin Y C Mallet J M Sinayuml P An Expeditious Synthesis of AC-Disaccharide Using A Temporary Silaketal Connection J ChemSoc Chem Commun 1993 864-865
[64] (a) Petitou M Herault P Lormeau J-C Helmboldt A MalletJ-M Sinayuml P Herbert J-M Introducing A C-InterglycosidicBond in A Biologically Active Pentasaccharide Hardly Affects ItsBiological Properties Bioorg Med Chem 1998 6 1509-1516 (b)Sinayuml P Advances in The Synthesis of the Carbohydrate MimicsPure Appl Chem 1998 70 1495-1499
[65] Sinayuml P Chemical Synthesis of Oligosaccharide Mimetics PureAppl Chem 1998 70 407-410
[66] Sinayuml P Chemical Synthesis of Oligosaccharide Mimetics PureAppl Chem 1998 69 459-463
[67] Vauzeilles B Sinayuml P Selective Radical Synthesis of β-C-Disaccharides Tetrahedron Lett 2001 42 7269-7272
1426 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
The reduction of 317 and treatment with DOWEX-H+ resinprovided the desired C-fucoside 318 in 70 (Scheme 54)
62 Intramolecular Radical Approaches
One disadvantage with the intermolecular approaches isthat during such radical mediated reactions electrondeficient alkenes are required to facilitate C-C bondformation The intramolecular approach of Sinayuml overcomes
this drawback by bring two substrates together via atemporary covalent silaketal connector This enables the useof a wider range of alkenes which can include alkene-functionalized sugars thus leading to the generation of C-disaccharides [63] Based on the early work of Stork Sinayumlemployed the tether reaction in the synthesis of both α- andβ-C-disaccharides with this work subsequently beingemployed in the synthesis of biologically significant natural
Scheme (54)
O
OH
Fuc
Cl
O
O
ClPhSe
OOAc
NHAcOHFuc
O
AcOOAc
AcO
Br
O
O
PhSeCl
O
AcOOAc
AcO
O
OH
PhSe Cl
Fuc
OOAc
NHAc
OMe
Fuc
O
AcHN
OH OAc
OH
O
OH
Me
OH
O
O
Fuc
ClSePh
O
HO
Fuc
ClSePh
+
Ph3SnHAIBN
78 combined yield
Fuc
310
+
1 NaBH4 MeOHTHF2 Chromatography
313 40 314 355
1 mCPBA
2 Ac2O pyr DMAP
+
315 75
1 TfOH MeCN
2 NaHCO3 O3 -78 oC
316 10 over 2 steps
1 Cl3 CCN NaH
2 MeOH BF3 OEt2
317 79
1 LiBH4 THF
2 Dowex-H+
311
312a312b
318 70 for 2 steps
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1427
products [64] The availability of different hydroxyl groupson each monosaccharide unit allowed the fine-tuning ofstereochemical outcome by selective positioning of the silyltether [65] Development of this early stereochemical controlled to the tethering of the donor 320 with alcohol 319through a di-isopropyl silicon tether 321 Subsequent treat-ment with Bu3SnH and AIBN led to a 9-endo-trigcyclization to form the C-disaccharide 322 in an 80 yieldwith exclusive formation of the α-product The silyl tetherwas removed with Bu4NF and deprotection under standardconditions afforded the desired disaccharide 323 in excellentyield (Scheme 55)
In parallel the development of a 32rsquo silyl tether allowedaccess to the β-linked product as demonstrated in Sinayumlrsquossynthesis of methyl β-C-lactoside 328 [66] Alcohol 324 and320 were connected via the dimethylsilyl tether an 8-endo-trig cyclization followed to exclusively afford the β-
disaccharide 326 in 45 yield Removal of the tether anddeprotection of benzyl ether gave β-C-disaccharide 328(Scheme 56)
This group also selected iodosugars bearing a freehydroxyl group as progenitors of the radical donors [67] In atypical experiment the radical donor 329 was connected tothe radical acceptor 330 through a silaketal tether followingtheir procedure Tributyltinhydride mediated 8-endo-trigradical cyclization of compound 331 gave after detetheringof the non isolated intermediate 332 the protected β-C-disaccharide 333 in 37 overall yield (from startingmaterials 330 and 329) Peracetate 335 was achieved afterhydrogenolysis The C-laminaribioside 334 is of potentialbiological interest as it mimics the repeating disaccharideunit of fungal β-(1rarr3)-glucans which have antitumor andimmunomodulating properties (Scheme 57)
Scheme (55)
Scheme (56)
OO
OHSePh
OTBDPSO O
OO
SePh
OTBDPSO
OO
OBnOMe
OBn
Si
O
HOOBn
OMe
OBn
O
HOOH
OHHO
O
HOOH
OMe
OH
OTBDPSO
O
HOOBn
OMe
OBnO
OOH
1 n-BuLi THF
2 iPr2SiCl2 -78 oC
3 DMAP THF rt
1 Bu4NF THF
2 Dowex-H+
3 H2 PdC
Bu3SnH AIBN toluene
319
320
321
322323
OBnO
OHSePh
OBnBnO
OHO
OBnOMe
OBn
ROO
ROOH
OR
OHO
OROMe
OR
OBnO
O
OBnBnO
OO
OBnOMe
OBn
Si
SePh
OBnO
O
OBnBnOO
OOBn
OMe
OBn
Si
1 PhSeH Me2SiCl2
BuLi -78 oC
2 imidazole rt
Bu3SnH AIBN toluene
H2 PdC327 R = Bn
328 R = H
Bu4NF THF
324
320
325
326 45
1428 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
CONCLUSIONS
In this paper the biological importance of C-oligo-saccharides as subunits of natural products and as a newgeneration of carbohydrate based on therapeutics has beenillustrated Different methods are available for the synthesisof C-oligosaccharides As with traditional saccharidesynthesis it has been necessary to develop a number ofspecific approaches to facilitate the regioselective andstereoselective preparation of the desired targets Work inthis area continues and it is expected that many interestingnew C-oligosaccharides will be prepared using the chemistrydescribed in this review It is also likely that new chemistrywill be developed in the future for the preparation of thesebiologically important targets
ACKNOWLEDGEMENTS
The authors thank Dr Sultan Baytas for her criticalreading of this manuscript
REFERENCES
[1] Kennedy J F White C A Bioactive Carbohydrates InChemistry Biochemistry and Biology Ellis Horwood LtdChichesterUK 1983
[2] Wassarman PW Mammalian Fertilization Molecular Aspects ofGamete Adhesion xocytosion Exocytosis and Fusion Cell 199996 175-183
[3] Carbohydrate-based Drug Discovery Wong C-H EdWeinheim Cambridge Wiley-VCH 2003
[4] (a) Sharon N Lis H Lectins as Cell Recognition MoleculesScience 1987 246 227-234 (b) Dwek RA Chem Rev 1996 96683-720
[5] Postema M C-Glycoside synthesis CRC Boc Ratom 1995[6] (a) Weatherman R V Mortell K H Cheruenak MKiessling
L L Toone E J Specificity of C-Glycoside Complexation byMannoseGlucose Specific Lectins Biochem 1996 35 3619-3624(b) Ravishankar R Surolia A Vijayan M Lim S Kishi YPreferred Conformation of C-Lactose at the Free and Peanut LectinBound States J Am Chem Soc1998 120 11297-11303
[7] (a)Wong C-H Halcomb R L Ichikawa Y and Kajimoto TEnzymes in organic synthesis Application to the problems ofcarbohydrate recognition part2 Angew Chem Int Ed Engl 199534 521-546 (b)Howard S Withers SG Bromoketone C-Glycosides a New Class of βminusGlucanase Inactivators J AmChem Soc 1998 120 10326-10331(c) Wang Q Wolff MPolat T Du Y Linhardt R J C-glycoside of Neuraminic Acidsas Neura-minidase Inhibitors Bioorg Med Lett 2000 10 941-944 (d) Phili R Chang J Partis R A Mueller R A ChrestF J Passaniti A The Alpha-glucosidase I InhibitorCastanospermine Alters Endothelial cell Glycosylation PreventsAngiogenesis and Inhibits Tumor Growth Cancer Res 1995 552927-2935
[8] Ossor A Elbein A D In Carbohydrates in Chemistry andBiology Vol 3(II) WileyVCH 2000 pp 513-539
[9] (a) Sinayuml P Synthesis of oligosaccharide Mimetics Pure ApplChem 1997 69 459-463 (b) Beau J-M Gallagher TNucleophilic C-glycosyl Donors for C-glycoside Synthesis Top inCurr Chem 1997 187 1-54 (c) Nicotra F Synthesis of C-glycosides of Biological Interest Top in Curr Chem 1997 187
Scheme (57)
O
O
O
Ph
I
OMe
OHO
BnO
OH
OH
BnOOH
O
BnO
Si
O
O O
Ph
I
OMe
O
O
BnO
OR4O
R5O
OMe
OR2
OR3O
R3O
OR1
R3O
Bu3 SnH AIBN
332 R1 R2 = SiMe2 R3 = Bn R4 R5 = CHPhTBAF THF
333 R1 = R2 = H R3 = Bn R4 = R5 = CHPh 37 from 11
334 R1 = R2 = R3 = R4 = R5 = H
335 R1 = R2 = R3 = R4 = R5 = Ac
329
H2 PdC MeOH
Ac2 O pyr
1 BuLi THF -78 oC
2 Me2SiCl2
3 DMAP
330
331
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1429
55-83 (d) Du Y Linhardt R Y Recent Adv in Stereo-SelectiveC-Glycoside Synthesis Tetrahedron Lett 1998 54 9913-9959 (e)Liu L Mckee M and Postema M H D Synthesis of C-saccharides and Higher Congeners Current Org Chem 2001 51133-1167
[10] Jarosz S Fraser-Reid B Synthesis of A Higher Carbon Sugar ViaDirected Aldol Condensation Tetrahedron Lett 1989 30 2359-2362
[11] Lichtenthaler F W Lergenmiiller M Schwidetzky S C-Glycosidations of 2-Ketohexosyl With Electrophilic Radical andNudeophilic Anomeric Carbons Eur J Org Chem 2003 3094-3103
[12] Baudat A Vogel P Aza-C-disaccharides Synthesis of 6-Deoxygalactonojirimycin-β-C(1rarr3) Linked with D-Altrofuranosides and D-Galactose J Org Chem 1997 62 6252-6260
[13] Turner D Vogel P Synthesis of 4-Hydroxy-26-Bis(hydroxymethyl) tetrahydropyran-2-Carbaldehyde DerivativesSynlett 1998 304-306
[14] Zhu Y-H Vogel P Short Stereoselective Synthesis of C-(1rarr3)-Linked Disaccharides Tetrahedron Lett 1998 39 31-34
[15] Zhu Y-H Vogel P Synthesis of a (2R 6R)-2-(Hydroxymethyl)-6-Propa-1 2-Dienyl-2H-Pyran-3(6H)-One Derivative A NewEnone for The Convergent Construction of C-Glycosides of C-Disaccharides Synlett 2001 82-86
[16] Baumberger F Vasella A Deoxynitrosugars The 6th
Communication Stereolectronic Control in the reductivedenitration of tertiary nitro ethers A Synthesis of ldquoC-glycosidesrdquoHelv Chim Acta 1983 66 2210-2221
[17] Martin O R Lai W Synthesis and Conformational Studies of β-(1rarr6)- and ββ-(1rarr1)-Linked C-disaccharides J Org Chem1993 58 176-185
[18] Spak S J Martin R The synthesis of an analogue of Methyl OC-Analogue of Methyl 4rsquo-O-β-D-GlucopyranosylgentiobiosideTetrahedron 2000 56 217-224
[19] Kobertz W R Bertozzi C R Bednarski M D C-GlycosylAldehyde Synthons for C-Linked Disaccharides J Org Chem1996 61 1894-1897
[20] Gurjar M K Nagaprasad R and Ramana CV First Synthesis ofMethyl α-C-D-Arabino-furanosyl-(1rarr5)-αminusD-Arabinofuranosidethe C-Disaccharide Segment of Motif C of MycobateriumTuberculosis Tetrahedron Lett 2000 43 7577-7579
[21] Witczak Z J Synthesis of C-Glycosyl Compounds and OtherNatural Products from Levoglucosenone Pure Appl Chem 199466 2189-2192
[22] Griffin F K Paterson D Taylor R J K Ramberg-BacklundApproaches to the Synthesis of C-Linked Disaccharides AngewChem Int Engl 1999 38 2939-2942
[23] Paterson B E Griffin F K Alcaraz M-L and Taylor R J KA Ramberg-Baumlcklund Approach to the Synthesis of C-GlycosidesC-Linked Disaccharides and C-Glycosyl Amino Acids Eur JOrg Chem 2002 1323-1336
[24] McAllister G D Paterson D E Taylor R J K A SimplifiedRamberg-Bachlund Approach to Novel C-Glycosides and C-Linked Disaccharides Angew Chem Int Ed Engl 2003 42 1387-1391
[25] McCartney J L Christopher T M Cicchillo R M BernardinaM D Wagner T R and Norris P J Org Chem 2003 6810152-10155
[26] Dondoni A Zuurmond H M Bascarate A Synthesis of α-andβ-D-(1rarr6)-C-Disaccharides by Witting Olefination of Formyl C-Glycosides with Glycopyranose 6-phosphoranes J Org Chem1997 62 8114-8124
[27] Dondoni A Kleban M Zuurmond H Marra A Synthesis of(1rarr6)-C-Oligogalactosides by Interative Wittig OlefinationTetrahedron Lett 1998 39 7991-7994
[28] Dondoni A Marra A A New Synthetic Approach toMycobacterial Cell Wall α-(1rarr5)-D-Arabinofuranosyl C-Oligosaccharides Teterahedron Lett 2003 44 4067-4071
[29] Colinas P A Ponzinibbio A Lieberknecht A and Bravo R OWittig Reaction of Glycosyl Phosphonium Salts A StereoselectiveRoute to C-Disaccharides and C O-Trisaccharides TetrahedronLett 2003 44 7985-7988
[30] Schmidt R R Preuss R Synthesis of Carbon Tetrahedron Lett1989 30 3409-3412
[31] Dietrich H Schmidt R R Synthesis of Carbon-Bridged C-Lactose and Derivatives Liebigs Ann Chem 1994 975-981
[32] Rouzaud D Sinayuml P The First Synthesis of a ldquoC-DisacchariderdquoJ Chem Soc Chem Commun 1983 1353-1354
[33] Xin Y-C Zhang Y-M Mallet J-M Glaudemans C P JSinayuml P Synthesis of C-Oligosaccharides That Mimie TheirNatural O-Analogues Immunodeterminants in Binding toMonoclonal Immunoglobulins Eur J Org Chem 1999 471-476
[34] Streicher H Geyer A Schmidt R R C-Disaccharides ofKetoses Chem Eur J 1996 2 502-510
[35] Leeuwenburgh M A Timmers C M Vander Marel G A VanBoom J H Mallet J-M Sinayuml P G Stereoselective Synthesisof α-C-(Alkynyl)-Glycosides Via Ring-Opening of α-12-Anhydrous Tetrahedron Lett 1997 38 6251-6254
[36] Aslam T Fuchs M G G Le Formal A Wightman R HSynthesis of C-Disaccharide Analogue of the α-D-Arabinofuranosyl-(1rarr5)-α-Arabinofuranosyl Motif ofMycobacterial Cells Walls via Alkynyl Intermediates TetrahedronLett 2005 46 3249-3252
[37] (a) Girad P Namy J L Kagan H B Divalent LanthanideDerivative in Organic Synthesis 1 Mild Preparation of SamariumIodide and Ytterbium Iodide and Their Use as Reducing orCoupling Agents J Am Chem Soc 1980 102 2693-2698 (b)Molander G A Harris C R Sequencing Reactions withSamarium(II) Iodide Chem Rev 1996 96 307-338
[38] (a) Mazeacuteas D Skrydstrup T Doumeix O Beau J-MSamarium Iodide-Induced Intramolecular C-Glycoside FormationEfficient Radical Formation in the Absence of an Additive AngewChem Int Ed Engl 1994 33 1383-1386 (b) Mazeacuteas DSkrydstrup T Beau J-M A Highly Stereoselective Synthesis of1 2-trans-C-Glycosides Via Glycosyl Samarium(III) CompoundsAngew Chem Int Ed Engl 1995 34 909-912 (c) Jarreton OSkrydstrup T Beau J-M The Stereospecific Synthesis of Methylα-C-Mannobioside A Potential Inhibitor of M TuberculosisBinding to Human Macrophages J Chem Soc Chem Commun1996 1661-1662 (d) Jarreton O Skrydstrup T Espionosa J-FJimeacutenez-Barbero J Beau J-M Samarium Diiode Prompted C-Glycosylation An Application to The Stereospecific Synthesis ofα-(1rarr2)-C-Mannobioside and Its Derivatives Chem Eur J 19995 430-441 (e) Mipuel N Doisneau G Beau J-M ReductiveSamariation of Anomeric 2-Pyridyl Sulfones with Catalytic AnUnexpected Improvement in The Synthesis of 12-Trans-Diequatorial C-Glycosyl Compounds Angew Chem Int Ed Engl 2000 39 4111-4114
[39] Vlahov I R Vlahova P I Linhardt R J DiastereocontrolledSynthesis of Carbon Glycosides of N-Acetylneuraminic Acid ViaGlycosyl Samarium(III) Intermediates JAmChem Soc 1997 1191480-1481
[40] Kuberan B Sikkander S ATomiyama H Linhardt R JSynthesis of a C-Glycoside Analogue of sTn An HIV-and Tumor-Associated Antigen Angew Chem Int Ed Engl 2003 42 2073-2075
[41] Bazin H G Du Y Polat T Linhardt R J Synthesis of aVersatile Neuraminic Acid ldquoCrdquo-Disaccharide Precursor for theSynthesis of C-Glycoside Analogues of Gangliosides J OrgChem 1999 64 7254-7259
[42] Chen C-C Ress D K Linhardt RJ Samarium Iodide-Mediated Synthesis of Neuraminic Acid C-Glycosides InSynthesis of Glycommetics Roy R Ed ACS Syposium Series2004 896 53-80
[43] Abdallah Z Doisneau G Beau J-M Synthesis of a Carbon-Linked Mimic of The Disaccharide Component of The Tumor-Relate SialyTn Antigen Angew Chem Int Ed Engl 2003 425209-5212
[44] Lay L Nicotra F Panza L Russo G Caneva E Synthesis ofC-disaccharides through dimerization of exo-glycals J Org Chem1992 57 1304-1306
[45] Isobe M Nishizawa R Hosokawa S Nishikawa TStereocontrolled Synthesis and Reactivity of Sugar Acetylenes JChem Soc Chem Commun 1998 2665-2676
[46] Saeeng R Sirion U Sahakitpichan P Isobe M IodineCatalyzes C-Glycosidation of D-Glucal with SilylacetykeneTetrahedron Lett 2003 44 6211-6215
[47] (a) Babirad S A Wang Y Kishi Y Synthesis of C-Disaccharides J Org Chem 1987 52 1370-1372 (b) Wang YBabirad S A Kishi Y Preferred Conformation of C-Glycosides
1430 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
8 Synthesis of 14-Linked Carbon Disaccharides J Org Chem1992 57 468-481
[48] Armstrong R W Sutherlin D P Strategies for the Synthesis ofC-Disaccharides Containing D and L Sugars Tetrahedron Lett1994 35 7743-7746
[49] Wei A Kishi Y Preferred Conformation of C-Glycosides 12Synthesis and Conformational Analysis of αα- α β- and β β-Trehaloses J Org Chem 1994 59 88-96
[50] Haneda T Goekjian P G Kim S H Kishi Y PreferredConformation of C-Glycosides 10 Synthesis and ConformationAnalysis of Carbon Trisaccharides J Org Chem 1992 57 490-498
[51] Sutherlin D P Armstrong R W Synthesis of 12 Stereochemistryand Structurally Diverse C-Trisaccharides J Org Chem 1997 625267-5283
[52] Notz W Hartel C Waldscheck B Schmidt R R De NovoSynthesis of a Methylene-Bridged Neu5Ac-α-(23)-Gal C-Disaccharide J Org Chem 2001 66 4250-4260
[53] (a) Postema M H D Calimente D Liu L Behrmanm T L AnOlefin Metathesis Route for the Preparation of (1rarr6)-Linked-C-Disaccharide Glycals A Convergent and Flexible Approach to C-Saccharide Synthesis J Org Chem 2000 65 6061-6068(b) Postema M H Piper J L Liu L Faust M Andreana PSynthesis and Partial Biological Evaluation of a Small Library ofDifferentially Linked β-C-Disaccharide J Org Chem 2003 684748-4754
[54] Nelson A The Development of Strategies and Methods for TheSynthesis of Biologically Active Compounds New J Chem 200428 771-776
[55] Togo H He W Waki Y Yokoyama M C-GlycosylationTechnology With Free Radiant Reactions Synlett 1998 700-717
[56] Giese B Dupuis J Diastereoselective Synthesis of C-Glycopyranosides Angew Chem Int Ed Engl 1983 22 622-623
[57] Adlington R M Baldwin J E Basak A Kozyrod RPApplication of Radical Addition Reactions to tho Synthesis of a C-Glucoside and A Functionalized Amino Acid J Chem SocChem Commun 1983 144-145
[58] Giese B Gonzaacutelez-Goacutemez J A Witzel T The Scope of RadicalCC-Coupling by The ldquoTin Methodrdquo Angew Chem Int Ed Engl1984 23 69-70
[59] Giese B Witzel T Synthesis of ldquoC-Disaccharidesrdquo by RadicalC-C Bond Formation Angew Chem Int Ed Engl 1986 25 450-451
[60] Witczak Z J Chhabra R Chojnacki J C-Disaccharides IStereoselective Approach to β-(1rarr4)-3-Deoxy-C-Disaccharidesfrom Levoglucosenone Carb Res 1997 301 167-175
[61] Vogel P Synthesis of Rare Carbohydrates and Analogues Startingfrom Enantiomerically Pure 7-Oxabicyclo[221]heptyl Derivatives(ldquoNaked Sugarsrdquo) Current Org Chem 2000 4 455-480
[62] Viodeacute C Vogel P Synthesis of The C-Disaccharide α-C(1rarr3)-L-Fucopyranoside of N-Acetylgalactosamine J Carb Chem2001 20 733-746
[63] Xin Y C Mallet J M Sinayuml P An Expeditious Synthesis of AC-Disaccharide Using A Temporary Silaketal Connection J ChemSoc Chem Commun 1993 864-865
[64] (a) Petitou M Herault P Lormeau J-C Helmboldt A MalletJ-M Sinayuml P Herbert J-M Introducing A C-InterglycosidicBond in A Biologically Active Pentasaccharide Hardly Affects ItsBiological Properties Bioorg Med Chem 1998 6 1509-1516 (b)Sinayuml P Advances in The Synthesis of the Carbohydrate MimicsPure Appl Chem 1998 70 1495-1499
[65] Sinayuml P Chemical Synthesis of Oligosaccharide Mimetics PureAppl Chem 1998 70 407-410
[66] Sinayuml P Chemical Synthesis of Oligosaccharide Mimetics PureAppl Chem 1998 69 459-463
[67] Vauzeilles B Sinayuml P Selective Radical Synthesis of β-C-Disaccharides Tetrahedron Lett 2001 42 7269-7272
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1427
products [64] The availability of different hydroxyl groupson each monosaccharide unit allowed the fine-tuning ofstereochemical outcome by selective positioning of the silyltether [65] Development of this early stereochemical controlled to the tethering of the donor 320 with alcohol 319through a di-isopropyl silicon tether 321 Subsequent treat-ment with Bu3SnH and AIBN led to a 9-endo-trigcyclization to form the C-disaccharide 322 in an 80 yieldwith exclusive formation of the α-product The silyl tetherwas removed with Bu4NF and deprotection under standardconditions afforded the desired disaccharide 323 in excellentyield (Scheme 55)
In parallel the development of a 32rsquo silyl tether allowedaccess to the β-linked product as demonstrated in Sinayumlrsquossynthesis of methyl β-C-lactoside 328 [66] Alcohol 324 and320 were connected via the dimethylsilyl tether an 8-endo-trig cyclization followed to exclusively afford the β-
disaccharide 326 in 45 yield Removal of the tether anddeprotection of benzyl ether gave β-C-disaccharide 328(Scheme 56)
This group also selected iodosugars bearing a freehydroxyl group as progenitors of the radical donors [67] In atypical experiment the radical donor 329 was connected tothe radical acceptor 330 through a silaketal tether followingtheir procedure Tributyltinhydride mediated 8-endo-trigradical cyclization of compound 331 gave after detetheringof the non isolated intermediate 332 the protected β-C-disaccharide 333 in 37 overall yield (from startingmaterials 330 and 329) Peracetate 335 was achieved afterhydrogenolysis The C-laminaribioside 334 is of potentialbiological interest as it mimics the repeating disaccharideunit of fungal β-(1rarr3)-glucans which have antitumor andimmunomodulating properties (Scheme 57)
Scheme (55)
Scheme (56)
OO
OHSePh
OTBDPSO O
OO
SePh
OTBDPSO
OO
OBnOMe
OBn
Si
O
HOOBn
OMe
OBn
O
HOOH
OHHO
O
HOOH
OMe
OH
OTBDPSO
O
HOOBn
OMe
OBnO
OOH
1 n-BuLi THF
2 iPr2SiCl2 -78 oC
3 DMAP THF rt
1 Bu4NF THF
2 Dowex-H+
3 H2 PdC
Bu3SnH AIBN toluene
319
320
321
322323
OBnO
OHSePh
OBnBnO
OHO
OBnOMe
OBn
ROO
ROOH
OR
OHO
OROMe
OR
OBnO
O
OBnBnO
OO
OBnOMe
OBn
Si
SePh
OBnO
O
OBnBnOO
OOBn
OMe
OBn
Si
1 PhSeH Me2SiCl2
BuLi -78 oC
2 imidazole rt
Bu3SnH AIBN toluene
H2 PdC327 R = Bn
328 R = H
Bu4NF THF
324
320
325
326 45
1428 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
CONCLUSIONS
In this paper the biological importance of C-oligo-saccharides as subunits of natural products and as a newgeneration of carbohydrate based on therapeutics has beenillustrated Different methods are available for the synthesisof C-oligosaccharides As with traditional saccharidesynthesis it has been necessary to develop a number ofspecific approaches to facilitate the regioselective andstereoselective preparation of the desired targets Work inthis area continues and it is expected that many interestingnew C-oligosaccharides will be prepared using the chemistrydescribed in this review It is also likely that new chemistrywill be developed in the future for the preparation of thesebiologically important targets
ACKNOWLEDGEMENTS
The authors thank Dr Sultan Baytas for her criticalreading of this manuscript
REFERENCES
[1] Kennedy J F White C A Bioactive Carbohydrates InChemistry Biochemistry and Biology Ellis Horwood LtdChichesterUK 1983
[2] Wassarman PW Mammalian Fertilization Molecular Aspects ofGamete Adhesion xocytosion Exocytosis and Fusion Cell 199996 175-183
[3] Carbohydrate-based Drug Discovery Wong C-H EdWeinheim Cambridge Wiley-VCH 2003
[4] (a) Sharon N Lis H Lectins as Cell Recognition MoleculesScience 1987 246 227-234 (b) Dwek RA Chem Rev 1996 96683-720
[5] Postema M C-Glycoside synthesis CRC Boc Ratom 1995[6] (a) Weatherman R V Mortell K H Cheruenak MKiessling
L L Toone E J Specificity of C-Glycoside Complexation byMannoseGlucose Specific Lectins Biochem 1996 35 3619-3624(b) Ravishankar R Surolia A Vijayan M Lim S Kishi YPreferred Conformation of C-Lactose at the Free and Peanut LectinBound States J Am Chem Soc1998 120 11297-11303
[7] (a)Wong C-H Halcomb R L Ichikawa Y and Kajimoto TEnzymes in organic synthesis Application to the problems ofcarbohydrate recognition part2 Angew Chem Int Ed Engl 199534 521-546 (b)Howard S Withers SG Bromoketone C-Glycosides a New Class of βminusGlucanase Inactivators J AmChem Soc 1998 120 10326-10331(c) Wang Q Wolff MPolat T Du Y Linhardt R J C-glycoside of Neuraminic Acidsas Neura-minidase Inhibitors Bioorg Med Lett 2000 10 941-944 (d) Phili R Chang J Partis R A Mueller R A ChrestF J Passaniti A The Alpha-glucosidase I InhibitorCastanospermine Alters Endothelial cell Glycosylation PreventsAngiogenesis and Inhibits Tumor Growth Cancer Res 1995 552927-2935
[8] Ossor A Elbein A D In Carbohydrates in Chemistry andBiology Vol 3(II) WileyVCH 2000 pp 513-539
[9] (a) Sinayuml P Synthesis of oligosaccharide Mimetics Pure ApplChem 1997 69 459-463 (b) Beau J-M Gallagher TNucleophilic C-glycosyl Donors for C-glycoside Synthesis Top inCurr Chem 1997 187 1-54 (c) Nicotra F Synthesis of C-glycosides of Biological Interest Top in Curr Chem 1997 187
Scheme (57)
O
O
O
Ph
I
OMe
OHO
BnO
OH
OH
BnOOH
O
BnO
Si
O
O O
Ph
I
OMe
O
O
BnO
OR4O
R5O
OMe
OR2
OR3O
R3O
OR1
R3O
Bu3 SnH AIBN
332 R1 R2 = SiMe2 R3 = Bn R4 R5 = CHPhTBAF THF
333 R1 = R2 = H R3 = Bn R4 = R5 = CHPh 37 from 11
334 R1 = R2 = R3 = R4 = R5 = H
335 R1 = R2 = R3 = R4 = R5 = Ac
329
H2 PdC MeOH
Ac2 O pyr
1 BuLi THF -78 oC
2 Me2SiCl2
3 DMAP
330
331
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1429
55-83 (d) Du Y Linhardt R Y Recent Adv in Stereo-SelectiveC-Glycoside Synthesis Tetrahedron Lett 1998 54 9913-9959 (e)Liu L Mckee M and Postema M H D Synthesis of C-saccharides and Higher Congeners Current Org Chem 2001 51133-1167
[10] Jarosz S Fraser-Reid B Synthesis of A Higher Carbon Sugar ViaDirected Aldol Condensation Tetrahedron Lett 1989 30 2359-2362
[11] Lichtenthaler F W Lergenmiiller M Schwidetzky S C-Glycosidations of 2-Ketohexosyl With Electrophilic Radical andNudeophilic Anomeric Carbons Eur J Org Chem 2003 3094-3103
[12] Baudat A Vogel P Aza-C-disaccharides Synthesis of 6-Deoxygalactonojirimycin-β-C(1rarr3) Linked with D-Altrofuranosides and D-Galactose J Org Chem 1997 62 6252-6260
[13] Turner D Vogel P Synthesis of 4-Hydroxy-26-Bis(hydroxymethyl) tetrahydropyran-2-Carbaldehyde DerivativesSynlett 1998 304-306
[14] Zhu Y-H Vogel P Short Stereoselective Synthesis of C-(1rarr3)-Linked Disaccharides Tetrahedron Lett 1998 39 31-34
[15] Zhu Y-H Vogel P Synthesis of a (2R 6R)-2-(Hydroxymethyl)-6-Propa-1 2-Dienyl-2H-Pyran-3(6H)-One Derivative A NewEnone for The Convergent Construction of C-Glycosides of C-Disaccharides Synlett 2001 82-86
[16] Baumberger F Vasella A Deoxynitrosugars The 6th
Communication Stereolectronic Control in the reductivedenitration of tertiary nitro ethers A Synthesis of ldquoC-glycosidesrdquoHelv Chim Acta 1983 66 2210-2221
[17] Martin O R Lai W Synthesis and Conformational Studies of β-(1rarr6)- and ββ-(1rarr1)-Linked C-disaccharides J Org Chem1993 58 176-185
[18] Spak S J Martin R The synthesis of an analogue of Methyl OC-Analogue of Methyl 4rsquo-O-β-D-GlucopyranosylgentiobiosideTetrahedron 2000 56 217-224
[19] Kobertz W R Bertozzi C R Bednarski M D C-GlycosylAldehyde Synthons for C-Linked Disaccharides J Org Chem1996 61 1894-1897
[20] Gurjar M K Nagaprasad R and Ramana CV First Synthesis ofMethyl α-C-D-Arabino-furanosyl-(1rarr5)-αminusD-Arabinofuranosidethe C-Disaccharide Segment of Motif C of MycobateriumTuberculosis Tetrahedron Lett 2000 43 7577-7579
[21] Witczak Z J Synthesis of C-Glycosyl Compounds and OtherNatural Products from Levoglucosenone Pure Appl Chem 199466 2189-2192
[22] Griffin F K Paterson D Taylor R J K Ramberg-BacklundApproaches to the Synthesis of C-Linked Disaccharides AngewChem Int Engl 1999 38 2939-2942
[23] Paterson B E Griffin F K Alcaraz M-L and Taylor R J KA Ramberg-Baumlcklund Approach to the Synthesis of C-GlycosidesC-Linked Disaccharides and C-Glycosyl Amino Acids Eur JOrg Chem 2002 1323-1336
[24] McAllister G D Paterson D E Taylor R J K A SimplifiedRamberg-Bachlund Approach to Novel C-Glycosides and C-Linked Disaccharides Angew Chem Int Ed Engl 2003 42 1387-1391
[25] McCartney J L Christopher T M Cicchillo R M BernardinaM D Wagner T R and Norris P J Org Chem 2003 6810152-10155
[26] Dondoni A Zuurmond H M Bascarate A Synthesis of α-andβ-D-(1rarr6)-C-Disaccharides by Witting Olefination of Formyl C-Glycosides with Glycopyranose 6-phosphoranes J Org Chem1997 62 8114-8124
[27] Dondoni A Kleban M Zuurmond H Marra A Synthesis of(1rarr6)-C-Oligogalactosides by Interative Wittig OlefinationTetrahedron Lett 1998 39 7991-7994
[28] Dondoni A Marra A A New Synthetic Approach toMycobacterial Cell Wall α-(1rarr5)-D-Arabinofuranosyl C-Oligosaccharides Teterahedron Lett 2003 44 4067-4071
[29] Colinas P A Ponzinibbio A Lieberknecht A and Bravo R OWittig Reaction of Glycosyl Phosphonium Salts A StereoselectiveRoute to C-Disaccharides and C O-Trisaccharides TetrahedronLett 2003 44 7985-7988
[30] Schmidt R R Preuss R Synthesis of Carbon Tetrahedron Lett1989 30 3409-3412
[31] Dietrich H Schmidt R R Synthesis of Carbon-Bridged C-Lactose and Derivatives Liebigs Ann Chem 1994 975-981
[32] Rouzaud D Sinayuml P The First Synthesis of a ldquoC-DisacchariderdquoJ Chem Soc Chem Commun 1983 1353-1354
[33] Xin Y-C Zhang Y-M Mallet J-M Glaudemans C P JSinayuml P Synthesis of C-Oligosaccharides That Mimie TheirNatural O-Analogues Immunodeterminants in Binding toMonoclonal Immunoglobulins Eur J Org Chem 1999 471-476
[34] Streicher H Geyer A Schmidt R R C-Disaccharides ofKetoses Chem Eur J 1996 2 502-510
[35] Leeuwenburgh M A Timmers C M Vander Marel G A VanBoom J H Mallet J-M Sinayuml P G Stereoselective Synthesisof α-C-(Alkynyl)-Glycosides Via Ring-Opening of α-12-Anhydrous Tetrahedron Lett 1997 38 6251-6254
[36] Aslam T Fuchs M G G Le Formal A Wightman R HSynthesis of C-Disaccharide Analogue of the α-D-Arabinofuranosyl-(1rarr5)-α-Arabinofuranosyl Motif ofMycobacterial Cells Walls via Alkynyl Intermediates TetrahedronLett 2005 46 3249-3252
[37] (a) Girad P Namy J L Kagan H B Divalent LanthanideDerivative in Organic Synthesis 1 Mild Preparation of SamariumIodide and Ytterbium Iodide and Their Use as Reducing orCoupling Agents J Am Chem Soc 1980 102 2693-2698 (b)Molander G A Harris C R Sequencing Reactions withSamarium(II) Iodide Chem Rev 1996 96 307-338
[38] (a) Mazeacuteas D Skrydstrup T Doumeix O Beau J-MSamarium Iodide-Induced Intramolecular C-Glycoside FormationEfficient Radical Formation in the Absence of an Additive AngewChem Int Ed Engl 1994 33 1383-1386 (b) Mazeacuteas DSkrydstrup T Beau J-M A Highly Stereoselective Synthesis of1 2-trans-C-Glycosides Via Glycosyl Samarium(III) CompoundsAngew Chem Int Ed Engl 1995 34 909-912 (c) Jarreton OSkrydstrup T Beau J-M The Stereospecific Synthesis of Methylα-C-Mannobioside A Potential Inhibitor of M TuberculosisBinding to Human Macrophages J Chem Soc Chem Commun1996 1661-1662 (d) Jarreton O Skrydstrup T Espionosa J-FJimeacutenez-Barbero J Beau J-M Samarium Diiode Prompted C-Glycosylation An Application to The Stereospecific Synthesis ofα-(1rarr2)-C-Mannobioside and Its Derivatives Chem Eur J 19995 430-441 (e) Mipuel N Doisneau G Beau J-M ReductiveSamariation of Anomeric 2-Pyridyl Sulfones with Catalytic AnUnexpected Improvement in The Synthesis of 12-Trans-Diequatorial C-Glycosyl Compounds Angew Chem Int Ed Engl 2000 39 4111-4114
[39] Vlahov I R Vlahova P I Linhardt R J DiastereocontrolledSynthesis of Carbon Glycosides of N-Acetylneuraminic Acid ViaGlycosyl Samarium(III) Intermediates JAmChem Soc 1997 1191480-1481
[40] Kuberan B Sikkander S ATomiyama H Linhardt R JSynthesis of a C-Glycoside Analogue of sTn An HIV-and Tumor-Associated Antigen Angew Chem Int Ed Engl 2003 42 2073-2075
[41] Bazin H G Du Y Polat T Linhardt R J Synthesis of aVersatile Neuraminic Acid ldquoCrdquo-Disaccharide Precursor for theSynthesis of C-Glycoside Analogues of Gangliosides J OrgChem 1999 64 7254-7259
[42] Chen C-C Ress D K Linhardt RJ Samarium Iodide-Mediated Synthesis of Neuraminic Acid C-Glycosides InSynthesis of Glycommetics Roy R Ed ACS Syposium Series2004 896 53-80
[43] Abdallah Z Doisneau G Beau J-M Synthesis of a Carbon-Linked Mimic of The Disaccharide Component of The Tumor-Relate SialyTn Antigen Angew Chem Int Ed Engl 2003 425209-5212
[44] Lay L Nicotra F Panza L Russo G Caneva E Synthesis ofC-disaccharides through dimerization of exo-glycals J Org Chem1992 57 1304-1306
[45] Isobe M Nishizawa R Hosokawa S Nishikawa TStereocontrolled Synthesis and Reactivity of Sugar Acetylenes JChem Soc Chem Commun 1998 2665-2676
[46] Saeeng R Sirion U Sahakitpichan P Isobe M IodineCatalyzes C-Glycosidation of D-Glucal with SilylacetykeneTetrahedron Lett 2003 44 6211-6215
[47] (a) Babirad S A Wang Y Kishi Y Synthesis of C-Disaccharides J Org Chem 1987 52 1370-1372 (b) Wang YBabirad S A Kishi Y Preferred Conformation of C-Glycosides
1430 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
8 Synthesis of 14-Linked Carbon Disaccharides J Org Chem1992 57 468-481
[48] Armstrong R W Sutherlin D P Strategies for the Synthesis ofC-Disaccharides Containing D and L Sugars Tetrahedron Lett1994 35 7743-7746
[49] Wei A Kishi Y Preferred Conformation of C-Glycosides 12Synthesis and Conformational Analysis of αα- α β- and β β-Trehaloses J Org Chem 1994 59 88-96
[50] Haneda T Goekjian P G Kim S H Kishi Y PreferredConformation of C-Glycosides 10 Synthesis and ConformationAnalysis of Carbon Trisaccharides J Org Chem 1992 57 490-498
[51] Sutherlin D P Armstrong R W Synthesis of 12 Stereochemistryand Structurally Diverse C-Trisaccharides J Org Chem 1997 625267-5283
[52] Notz W Hartel C Waldscheck B Schmidt R R De NovoSynthesis of a Methylene-Bridged Neu5Ac-α-(23)-Gal C-Disaccharide J Org Chem 2001 66 4250-4260
[53] (a) Postema M H D Calimente D Liu L Behrmanm T L AnOlefin Metathesis Route for the Preparation of (1rarr6)-Linked-C-Disaccharide Glycals A Convergent and Flexible Approach to C-Saccharide Synthesis J Org Chem 2000 65 6061-6068(b) Postema M H Piper J L Liu L Faust M Andreana PSynthesis and Partial Biological Evaluation of a Small Library ofDifferentially Linked β-C-Disaccharide J Org Chem 2003 684748-4754
[54] Nelson A The Development of Strategies and Methods for TheSynthesis of Biologically Active Compounds New J Chem 200428 771-776
[55] Togo H He W Waki Y Yokoyama M C-GlycosylationTechnology With Free Radiant Reactions Synlett 1998 700-717
[56] Giese B Dupuis J Diastereoselective Synthesis of C-Glycopyranosides Angew Chem Int Ed Engl 1983 22 622-623
[57] Adlington R M Baldwin J E Basak A Kozyrod RPApplication of Radical Addition Reactions to tho Synthesis of a C-Glucoside and A Functionalized Amino Acid J Chem SocChem Commun 1983 144-145
[58] Giese B Gonzaacutelez-Goacutemez J A Witzel T The Scope of RadicalCC-Coupling by The ldquoTin Methodrdquo Angew Chem Int Ed Engl1984 23 69-70
[59] Giese B Witzel T Synthesis of ldquoC-Disaccharidesrdquo by RadicalC-C Bond Formation Angew Chem Int Ed Engl 1986 25 450-451
[60] Witczak Z J Chhabra R Chojnacki J C-Disaccharides IStereoselective Approach to β-(1rarr4)-3-Deoxy-C-Disaccharidesfrom Levoglucosenone Carb Res 1997 301 167-175
[61] Vogel P Synthesis of Rare Carbohydrates and Analogues Startingfrom Enantiomerically Pure 7-Oxabicyclo[221]heptyl Derivatives(ldquoNaked Sugarsrdquo) Current Org Chem 2000 4 455-480
[62] Viodeacute C Vogel P Synthesis of The C-Disaccharide α-C(1rarr3)-L-Fucopyranoside of N-Acetylgalactosamine J Carb Chem2001 20 733-746
[63] Xin Y C Mallet J M Sinayuml P An Expeditious Synthesis of AC-Disaccharide Using A Temporary Silaketal Connection J ChemSoc Chem Commun 1993 864-865
[64] (a) Petitou M Herault P Lormeau J-C Helmboldt A MalletJ-M Sinayuml P Herbert J-M Introducing A C-InterglycosidicBond in A Biologically Active Pentasaccharide Hardly Affects ItsBiological Properties Bioorg Med Chem 1998 6 1509-1516 (b)Sinayuml P Advances in The Synthesis of the Carbohydrate MimicsPure Appl Chem 1998 70 1495-1499
[65] Sinayuml P Chemical Synthesis of Oligosaccharide Mimetics PureAppl Chem 1998 70 407-410
[66] Sinayuml P Chemical Synthesis of Oligosaccharide Mimetics PureAppl Chem 1998 69 459-463
[67] Vauzeilles B Sinayuml P Selective Radical Synthesis of β-C-Disaccharides Tetrahedron Lett 2001 42 7269-7272
1428 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
CONCLUSIONS
In this paper the biological importance of C-oligo-saccharides as subunits of natural products and as a newgeneration of carbohydrate based on therapeutics has beenillustrated Different methods are available for the synthesisof C-oligosaccharides As with traditional saccharidesynthesis it has been necessary to develop a number ofspecific approaches to facilitate the regioselective andstereoselective preparation of the desired targets Work inthis area continues and it is expected that many interestingnew C-oligosaccharides will be prepared using the chemistrydescribed in this review It is also likely that new chemistrywill be developed in the future for the preparation of thesebiologically important targets
ACKNOWLEDGEMENTS
The authors thank Dr Sultan Baytas for her criticalreading of this manuscript
REFERENCES
[1] Kennedy J F White C A Bioactive Carbohydrates InChemistry Biochemistry and Biology Ellis Horwood LtdChichesterUK 1983
[2] Wassarman PW Mammalian Fertilization Molecular Aspects ofGamete Adhesion xocytosion Exocytosis and Fusion Cell 199996 175-183
[3] Carbohydrate-based Drug Discovery Wong C-H EdWeinheim Cambridge Wiley-VCH 2003
[4] (a) Sharon N Lis H Lectins as Cell Recognition MoleculesScience 1987 246 227-234 (b) Dwek RA Chem Rev 1996 96683-720
[5] Postema M C-Glycoside synthesis CRC Boc Ratom 1995[6] (a) Weatherman R V Mortell K H Cheruenak MKiessling
L L Toone E J Specificity of C-Glycoside Complexation byMannoseGlucose Specific Lectins Biochem 1996 35 3619-3624(b) Ravishankar R Surolia A Vijayan M Lim S Kishi YPreferred Conformation of C-Lactose at the Free and Peanut LectinBound States J Am Chem Soc1998 120 11297-11303
[7] (a)Wong C-H Halcomb R L Ichikawa Y and Kajimoto TEnzymes in organic synthesis Application to the problems ofcarbohydrate recognition part2 Angew Chem Int Ed Engl 199534 521-546 (b)Howard S Withers SG Bromoketone C-Glycosides a New Class of βminusGlucanase Inactivators J AmChem Soc 1998 120 10326-10331(c) Wang Q Wolff MPolat T Du Y Linhardt R J C-glycoside of Neuraminic Acidsas Neura-minidase Inhibitors Bioorg Med Lett 2000 10 941-944 (d) Phili R Chang J Partis R A Mueller R A ChrestF J Passaniti A The Alpha-glucosidase I InhibitorCastanospermine Alters Endothelial cell Glycosylation PreventsAngiogenesis and Inhibits Tumor Growth Cancer Res 1995 552927-2935
[8] Ossor A Elbein A D In Carbohydrates in Chemistry andBiology Vol 3(II) WileyVCH 2000 pp 513-539
[9] (a) Sinayuml P Synthesis of oligosaccharide Mimetics Pure ApplChem 1997 69 459-463 (b) Beau J-M Gallagher TNucleophilic C-glycosyl Donors for C-glycoside Synthesis Top inCurr Chem 1997 187 1-54 (c) Nicotra F Synthesis of C-glycosides of Biological Interest Top in Curr Chem 1997 187
Scheme (57)
O
O
O
Ph
I
OMe
OHO
BnO
OH
OH
BnOOH
O
BnO
Si
O
O O
Ph
I
OMe
O
O
BnO
OR4O
R5O
OMe
OR2
OR3O
R3O
OR1
R3O
Bu3 SnH AIBN
332 R1 R2 = SiMe2 R3 = Bn R4 R5 = CHPhTBAF THF
333 R1 = R2 = H R3 = Bn R4 = R5 = CHPh 37 from 11
334 R1 = R2 = R3 = R4 = R5 = H
335 R1 = R2 = R3 = R4 = R5 = Ac
329
H2 PdC MeOH
Ac2 O pyr
1 BuLi THF -78 oC
2 Me2SiCl2
3 DMAP
330
331
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1429
55-83 (d) Du Y Linhardt R Y Recent Adv in Stereo-SelectiveC-Glycoside Synthesis Tetrahedron Lett 1998 54 9913-9959 (e)Liu L Mckee M and Postema M H D Synthesis of C-saccharides and Higher Congeners Current Org Chem 2001 51133-1167
[10] Jarosz S Fraser-Reid B Synthesis of A Higher Carbon Sugar ViaDirected Aldol Condensation Tetrahedron Lett 1989 30 2359-2362
[11] Lichtenthaler F W Lergenmiiller M Schwidetzky S C-Glycosidations of 2-Ketohexosyl With Electrophilic Radical andNudeophilic Anomeric Carbons Eur J Org Chem 2003 3094-3103
[12] Baudat A Vogel P Aza-C-disaccharides Synthesis of 6-Deoxygalactonojirimycin-β-C(1rarr3) Linked with D-Altrofuranosides and D-Galactose J Org Chem 1997 62 6252-6260
[13] Turner D Vogel P Synthesis of 4-Hydroxy-26-Bis(hydroxymethyl) tetrahydropyran-2-Carbaldehyde DerivativesSynlett 1998 304-306
[14] Zhu Y-H Vogel P Short Stereoselective Synthesis of C-(1rarr3)-Linked Disaccharides Tetrahedron Lett 1998 39 31-34
[15] Zhu Y-H Vogel P Synthesis of a (2R 6R)-2-(Hydroxymethyl)-6-Propa-1 2-Dienyl-2H-Pyran-3(6H)-One Derivative A NewEnone for The Convergent Construction of C-Glycosides of C-Disaccharides Synlett 2001 82-86
[16] Baumberger F Vasella A Deoxynitrosugars The 6th
Communication Stereolectronic Control in the reductivedenitration of tertiary nitro ethers A Synthesis of ldquoC-glycosidesrdquoHelv Chim Acta 1983 66 2210-2221
[17] Martin O R Lai W Synthesis and Conformational Studies of β-(1rarr6)- and ββ-(1rarr1)-Linked C-disaccharides J Org Chem1993 58 176-185
[18] Spak S J Martin R The synthesis of an analogue of Methyl OC-Analogue of Methyl 4rsquo-O-β-D-GlucopyranosylgentiobiosideTetrahedron 2000 56 217-224
[19] Kobertz W R Bertozzi C R Bednarski M D C-GlycosylAldehyde Synthons for C-Linked Disaccharides J Org Chem1996 61 1894-1897
[20] Gurjar M K Nagaprasad R and Ramana CV First Synthesis ofMethyl α-C-D-Arabino-furanosyl-(1rarr5)-αminusD-Arabinofuranosidethe C-Disaccharide Segment of Motif C of MycobateriumTuberculosis Tetrahedron Lett 2000 43 7577-7579
[21] Witczak Z J Synthesis of C-Glycosyl Compounds and OtherNatural Products from Levoglucosenone Pure Appl Chem 199466 2189-2192
[22] Griffin F K Paterson D Taylor R J K Ramberg-BacklundApproaches to the Synthesis of C-Linked Disaccharides AngewChem Int Engl 1999 38 2939-2942
[23] Paterson B E Griffin F K Alcaraz M-L and Taylor R J KA Ramberg-Baumlcklund Approach to the Synthesis of C-GlycosidesC-Linked Disaccharides and C-Glycosyl Amino Acids Eur JOrg Chem 2002 1323-1336
[24] McAllister G D Paterson D E Taylor R J K A SimplifiedRamberg-Bachlund Approach to Novel C-Glycosides and C-Linked Disaccharides Angew Chem Int Ed Engl 2003 42 1387-1391
[25] McCartney J L Christopher T M Cicchillo R M BernardinaM D Wagner T R and Norris P J Org Chem 2003 6810152-10155
[26] Dondoni A Zuurmond H M Bascarate A Synthesis of α-andβ-D-(1rarr6)-C-Disaccharides by Witting Olefination of Formyl C-Glycosides with Glycopyranose 6-phosphoranes J Org Chem1997 62 8114-8124
[27] Dondoni A Kleban M Zuurmond H Marra A Synthesis of(1rarr6)-C-Oligogalactosides by Interative Wittig OlefinationTetrahedron Lett 1998 39 7991-7994
[28] Dondoni A Marra A A New Synthetic Approach toMycobacterial Cell Wall α-(1rarr5)-D-Arabinofuranosyl C-Oligosaccharides Teterahedron Lett 2003 44 4067-4071
[29] Colinas P A Ponzinibbio A Lieberknecht A and Bravo R OWittig Reaction of Glycosyl Phosphonium Salts A StereoselectiveRoute to C-Disaccharides and C O-Trisaccharides TetrahedronLett 2003 44 7985-7988
[30] Schmidt R R Preuss R Synthesis of Carbon Tetrahedron Lett1989 30 3409-3412
[31] Dietrich H Schmidt R R Synthesis of Carbon-Bridged C-Lactose and Derivatives Liebigs Ann Chem 1994 975-981
[32] Rouzaud D Sinayuml P The First Synthesis of a ldquoC-DisacchariderdquoJ Chem Soc Chem Commun 1983 1353-1354
[33] Xin Y-C Zhang Y-M Mallet J-M Glaudemans C P JSinayuml P Synthesis of C-Oligosaccharides That Mimie TheirNatural O-Analogues Immunodeterminants in Binding toMonoclonal Immunoglobulins Eur J Org Chem 1999 471-476
[34] Streicher H Geyer A Schmidt R R C-Disaccharides ofKetoses Chem Eur J 1996 2 502-510
[35] Leeuwenburgh M A Timmers C M Vander Marel G A VanBoom J H Mallet J-M Sinayuml P G Stereoselective Synthesisof α-C-(Alkynyl)-Glycosides Via Ring-Opening of α-12-Anhydrous Tetrahedron Lett 1997 38 6251-6254
[36] Aslam T Fuchs M G G Le Formal A Wightman R HSynthesis of C-Disaccharide Analogue of the α-D-Arabinofuranosyl-(1rarr5)-α-Arabinofuranosyl Motif ofMycobacterial Cells Walls via Alkynyl Intermediates TetrahedronLett 2005 46 3249-3252
[37] (a) Girad P Namy J L Kagan H B Divalent LanthanideDerivative in Organic Synthesis 1 Mild Preparation of SamariumIodide and Ytterbium Iodide and Their Use as Reducing orCoupling Agents J Am Chem Soc 1980 102 2693-2698 (b)Molander G A Harris C R Sequencing Reactions withSamarium(II) Iodide Chem Rev 1996 96 307-338
[38] (a) Mazeacuteas D Skrydstrup T Doumeix O Beau J-MSamarium Iodide-Induced Intramolecular C-Glycoside FormationEfficient Radical Formation in the Absence of an Additive AngewChem Int Ed Engl 1994 33 1383-1386 (b) Mazeacuteas DSkrydstrup T Beau J-M A Highly Stereoselective Synthesis of1 2-trans-C-Glycosides Via Glycosyl Samarium(III) CompoundsAngew Chem Int Ed Engl 1995 34 909-912 (c) Jarreton OSkrydstrup T Beau J-M The Stereospecific Synthesis of Methylα-C-Mannobioside A Potential Inhibitor of M TuberculosisBinding to Human Macrophages J Chem Soc Chem Commun1996 1661-1662 (d) Jarreton O Skrydstrup T Espionosa J-FJimeacutenez-Barbero J Beau J-M Samarium Diiode Prompted C-Glycosylation An Application to The Stereospecific Synthesis ofα-(1rarr2)-C-Mannobioside and Its Derivatives Chem Eur J 19995 430-441 (e) Mipuel N Doisneau G Beau J-M ReductiveSamariation of Anomeric 2-Pyridyl Sulfones with Catalytic AnUnexpected Improvement in The Synthesis of 12-Trans-Diequatorial C-Glycosyl Compounds Angew Chem Int Ed Engl 2000 39 4111-4114
[39] Vlahov I R Vlahova P I Linhardt R J DiastereocontrolledSynthesis of Carbon Glycosides of N-Acetylneuraminic Acid ViaGlycosyl Samarium(III) Intermediates JAmChem Soc 1997 1191480-1481
[40] Kuberan B Sikkander S ATomiyama H Linhardt R JSynthesis of a C-Glycoside Analogue of sTn An HIV-and Tumor-Associated Antigen Angew Chem Int Ed Engl 2003 42 2073-2075
[41] Bazin H G Du Y Polat T Linhardt R J Synthesis of aVersatile Neuraminic Acid ldquoCrdquo-Disaccharide Precursor for theSynthesis of C-Glycoside Analogues of Gangliosides J OrgChem 1999 64 7254-7259
[42] Chen C-C Ress D K Linhardt RJ Samarium Iodide-Mediated Synthesis of Neuraminic Acid C-Glycosides InSynthesis of Glycommetics Roy R Ed ACS Syposium Series2004 896 53-80
[43] Abdallah Z Doisneau G Beau J-M Synthesis of a Carbon-Linked Mimic of The Disaccharide Component of The Tumor-Relate SialyTn Antigen Angew Chem Int Ed Engl 2003 425209-5212
[44] Lay L Nicotra F Panza L Russo G Caneva E Synthesis ofC-disaccharides through dimerization of exo-glycals J Org Chem1992 57 1304-1306
[45] Isobe M Nishizawa R Hosokawa S Nishikawa TStereocontrolled Synthesis and Reactivity of Sugar Acetylenes JChem Soc Chem Commun 1998 2665-2676
[46] Saeeng R Sirion U Sahakitpichan P Isobe M IodineCatalyzes C-Glycosidation of D-Glucal with SilylacetykeneTetrahedron Lett 2003 44 6211-6215
[47] (a) Babirad S A Wang Y Kishi Y Synthesis of C-Disaccharides J Org Chem 1987 52 1370-1372 (b) Wang YBabirad S A Kishi Y Preferred Conformation of C-Glycosides
1430 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
8 Synthesis of 14-Linked Carbon Disaccharides J Org Chem1992 57 468-481
[48] Armstrong R W Sutherlin D P Strategies for the Synthesis ofC-Disaccharides Containing D and L Sugars Tetrahedron Lett1994 35 7743-7746
[49] Wei A Kishi Y Preferred Conformation of C-Glycosides 12Synthesis and Conformational Analysis of αα- α β- and β β-Trehaloses J Org Chem 1994 59 88-96
[50] Haneda T Goekjian P G Kim S H Kishi Y PreferredConformation of C-Glycosides 10 Synthesis and ConformationAnalysis of Carbon Trisaccharides J Org Chem 1992 57 490-498
[51] Sutherlin D P Armstrong R W Synthesis of 12 Stereochemistryand Structurally Diverse C-Trisaccharides J Org Chem 1997 625267-5283
[52] Notz W Hartel C Waldscheck B Schmidt R R De NovoSynthesis of a Methylene-Bridged Neu5Ac-α-(23)-Gal C-Disaccharide J Org Chem 2001 66 4250-4260
[53] (a) Postema M H D Calimente D Liu L Behrmanm T L AnOlefin Metathesis Route for the Preparation of (1rarr6)-Linked-C-Disaccharide Glycals A Convergent and Flexible Approach to C-Saccharide Synthesis J Org Chem 2000 65 6061-6068(b) Postema M H Piper J L Liu L Faust M Andreana PSynthesis and Partial Biological Evaluation of a Small Library ofDifferentially Linked β-C-Disaccharide J Org Chem 2003 684748-4754
[54] Nelson A The Development of Strategies and Methods for TheSynthesis of Biologically Active Compounds New J Chem 200428 771-776
[55] Togo H He W Waki Y Yokoyama M C-GlycosylationTechnology With Free Radiant Reactions Synlett 1998 700-717
[56] Giese B Dupuis J Diastereoselective Synthesis of C-Glycopyranosides Angew Chem Int Ed Engl 1983 22 622-623
[57] Adlington R M Baldwin J E Basak A Kozyrod RPApplication of Radical Addition Reactions to tho Synthesis of a C-Glucoside and A Functionalized Amino Acid J Chem SocChem Commun 1983 144-145
[58] Giese B Gonzaacutelez-Goacutemez J A Witzel T The Scope of RadicalCC-Coupling by The ldquoTin Methodrdquo Angew Chem Int Ed Engl1984 23 69-70
[59] Giese B Witzel T Synthesis of ldquoC-Disaccharidesrdquo by RadicalC-C Bond Formation Angew Chem Int Ed Engl 1986 25 450-451
[60] Witczak Z J Chhabra R Chojnacki J C-Disaccharides IStereoselective Approach to β-(1rarr4)-3-Deoxy-C-Disaccharidesfrom Levoglucosenone Carb Res 1997 301 167-175
[61] Vogel P Synthesis of Rare Carbohydrates and Analogues Startingfrom Enantiomerically Pure 7-Oxabicyclo[221]heptyl Derivatives(ldquoNaked Sugarsrdquo) Current Org Chem 2000 4 455-480
[62] Viodeacute C Vogel P Synthesis of The C-Disaccharide α-C(1rarr3)-L-Fucopyranoside of N-Acetylgalactosamine J Carb Chem2001 20 733-746
[63] Xin Y C Mallet J M Sinayuml P An Expeditious Synthesis of AC-Disaccharide Using A Temporary Silaketal Connection J ChemSoc Chem Commun 1993 864-865
[64] (a) Petitou M Herault P Lormeau J-C Helmboldt A MalletJ-M Sinayuml P Herbert J-M Introducing A C-InterglycosidicBond in A Biologically Active Pentasaccharide Hardly Affects ItsBiological Properties Bioorg Med Chem 1998 6 1509-1516 (b)Sinayuml P Advances in The Synthesis of the Carbohydrate MimicsPure Appl Chem 1998 70 1495-1499
[65] Sinayuml P Chemical Synthesis of Oligosaccharide Mimetics PureAppl Chem 1998 70 407-410
[66] Sinayuml P Chemical Synthesis of Oligosaccharide Mimetics PureAppl Chem 1998 69 459-463
[67] Vauzeilles B Sinayuml P Selective Radical Synthesis of β-C-Disaccharides Tetrahedron Lett 2001 42 7269-7272
Recent Advances in the Synthesis of C-oligosaccharides Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 1429
55-83 (d) Du Y Linhardt R Y Recent Adv in Stereo-SelectiveC-Glycoside Synthesis Tetrahedron Lett 1998 54 9913-9959 (e)Liu L Mckee M and Postema M H D Synthesis of C-saccharides and Higher Congeners Current Org Chem 2001 51133-1167
[10] Jarosz S Fraser-Reid B Synthesis of A Higher Carbon Sugar ViaDirected Aldol Condensation Tetrahedron Lett 1989 30 2359-2362
[11] Lichtenthaler F W Lergenmiiller M Schwidetzky S C-Glycosidations of 2-Ketohexosyl With Electrophilic Radical andNudeophilic Anomeric Carbons Eur J Org Chem 2003 3094-3103
[12] Baudat A Vogel P Aza-C-disaccharides Synthesis of 6-Deoxygalactonojirimycin-β-C(1rarr3) Linked with D-Altrofuranosides and D-Galactose J Org Chem 1997 62 6252-6260
[13] Turner D Vogel P Synthesis of 4-Hydroxy-26-Bis(hydroxymethyl) tetrahydropyran-2-Carbaldehyde DerivativesSynlett 1998 304-306
[14] Zhu Y-H Vogel P Short Stereoselective Synthesis of C-(1rarr3)-Linked Disaccharides Tetrahedron Lett 1998 39 31-34
[15] Zhu Y-H Vogel P Synthesis of a (2R 6R)-2-(Hydroxymethyl)-6-Propa-1 2-Dienyl-2H-Pyran-3(6H)-One Derivative A NewEnone for The Convergent Construction of C-Glycosides of C-Disaccharides Synlett 2001 82-86
[16] Baumberger F Vasella A Deoxynitrosugars The 6th
Communication Stereolectronic Control in the reductivedenitration of tertiary nitro ethers A Synthesis of ldquoC-glycosidesrdquoHelv Chim Acta 1983 66 2210-2221
[17] Martin O R Lai W Synthesis and Conformational Studies of β-(1rarr6)- and ββ-(1rarr1)-Linked C-disaccharides J Org Chem1993 58 176-185
[18] Spak S J Martin R The synthesis of an analogue of Methyl OC-Analogue of Methyl 4rsquo-O-β-D-GlucopyranosylgentiobiosideTetrahedron 2000 56 217-224
[19] Kobertz W R Bertozzi C R Bednarski M D C-GlycosylAldehyde Synthons for C-Linked Disaccharides J Org Chem1996 61 1894-1897
[20] Gurjar M K Nagaprasad R and Ramana CV First Synthesis ofMethyl α-C-D-Arabino-furanosyl-(1rarr5)-αminusD-Arabinofuranosidethe C-Disaccharide Segment of Motif C of MycobateriumTuberculosis Tetrahedron Lett 2000 43 7577-7579
[21] Witczak Z J Synthesis of C-Glycosyl Compounds and OtherNatural Products from Levoglucosenone Pure Appl Chem 199466 2189-2192
[22] Griffin F K Paterson D Taylor R J K Ramberg-BacklundApproaches to the Synthesis of C-Linked Disaccharides AngewChem Int Engl 1999 38 2939-2942
[23] Paterson B E Griffin F K Alcaraz M-L and Taylor R J KA Ramberg-Baumlcklund Approach to the Synthesis of C-GlycosidesC-Linked Disaccharides and C-Glycosyl Amino Acids Eur JOrg Chem 2002 1323-1336
[24] McAllister G D Paterson D E Taylor R J K A SimplifiedRamberg-Bachlund Approach to Novel C-Glycosides and C-Linked Disaccharides Angew Chem Int Ed Engl 2003 42 1387-1391
[25] McCartney J L Christopher T M Cicchillo R M BernardinaM D Wagner T R and Norris P J Org Chem 2003 6810152-10155
[26] Dondoni A Zuurmond H M Bascarate A Synthesis of α-andβ-D-(1rarr6)-C-Disaccharides by Witting Olefination of Formyl C-Glycosides with Glycopyranose 6-phosphoranes J Org Chem1997 62 8114-8124
[27] Dondoni A Kleban M Zuurmond H Marra A Synthesis of(1rarr6)-C-Oligogalactosides by Interative Wittig OlefinationTetrahedron Lett 1998 39 7991-7994
[28] Dondoni A Marra A A New Synthetic Approach toMycobacterial Cell Wall α-(1rarr5)-D-Arabinofuranosyl C-Oligosaccharides Teterahedron Lett 2003 44 4067-4071
[29] Colinas P A Ponzinibbio A Lieberknecht A and Bravo R OWittig Reaction of Glycosyl Phosphonium Salts A StereoselectiveRoute to C-Disaccharides and C O-Trisaccharides TetrahedronLett 2003 44 7985-7988
[30] Schmidt R R Preuss R Synthesis of Carbon Tetrahedron Lett1989 30 3409-3412
[31] Dietrich H Schmidt R R Synthesis of Carbon-Bridged C-Lactose and Derivatives Liebigs Ann Chem 1994 975-981
[32] Rouzaud D Sinayuml P The First Synthesis of a ldquoC-DisacchariderdquoJ Chem Soc Chem Commun 1983 1353-1354
[33] Xin Y-C Zhang Y-M Mallet J-M Glaudemans C P JSinayuml P Synthesis of C-Oligosaccharides That Mimie TheirNatural O-Analogues Immunodeterminants in Binding toMonoclonal Immunoglobulins Eur J Org Chem 1999 471-476
[34] Streicher H Geyer A Schmidt R R C-Disaccharides ofKetoses Chem Eur J 1996 2 502-510
[35] Leeuwenburgh M A Timmers C M Vander Marel G A VanBoom J H Mallet J-M Sinayuml P G Stereoselective Synthesisof α-C-(Alkynyl)-Glycosides Via Ring-Opening of α-12-Anhydrous Tetrahedron Lett 1997 38 6251-6254
[36] Aslam T Fuchs M G G Le Formal A Wightman R HSynthesis of C-Disaccharide Analogue of the α-D-Arabinofuranosyl-(1rarr5)-α-Arabinofuranosyl Motif ofMycobacterial Cells Walls via Alkynyl Intermediates TetrahedronLett 2005 46 3249-3252
[37] (a) Girad P Namy J L Kagan H B Divalent LanthanideDerivative in Organic Synthesis 1 Mild Preparation of SamariumIodide and Ytterbium Iodide and Their Use as Reducing orCoupling Agents J Am Chem Soc 1980 102 2693-2698 (b)Molander G A Harris C R Sequencing Reactions withSamarium(II) Iodide Chem Rev 1996 96 307-338
[38] (a) Mazeacuteas D Skrydstrup T Doumeix O Beau J-MSamarium Iodide-Induced Intramolecular C-Glycoside FormationEfficient Radical Formation in the Absence of an Additive AngewChem Int Ed Engl 1994 33 1383-1386 (b) Mazeacuteas DSkrydstrup T Beau J-M A Highly Stereoselective Synthesis of1 2-trans-C-Glycosides Via Glycosyl Samarium(III) CompoundsAngew Chem Int Ed Engl 1995 34 909-912 (c) Jarreton OSkrydstrup T Beau J-M The Stereospecific Synthesis of Methylα-C-Mannobioside A Potential Inhibitor of M TuberculosisBinding to Human Macrophages J Chem Soc Chem Commun1996 1661-1662 (d) Jarreton O Skrydstrup T Espionosa J-FJimeacutenez-Barbero J Beau J-M Samarium Diiode Prompted C-Glycosylation An Application to The Stereospecific Synthesis ofα-(1rarr2)-C-Mannobioside and Its Derivatives Chem Eur J 19995 430-441 (e) Mipuel N Doisneau G Beau J-M ReductiveSamariation of Anomeric 2-Pyridyl Sulfones with Catalytic AnUnexpected Improvement in The Synthesis of 12-Trans-Diequatorial C-Glycosyl Compounds Angew Chem Int Ed Engl 2000 39 4111-4114
[39] Vlahov I R Vlahova P I Linhardt R J DiastereocontrolledSynthesis of Carbon Glycosides of N-Acetylneuraminic Acid ViaGlycosyl Samarium(III) Intermediates JAmChem Soc 1997 1191480-1481
[40] Kuberan B Sikkander S ATomiyama H Linhardt R JSynthesis of a C-Glycoside Analogue of sTn An HIV-and Tumor-Associated Antigen Angew Chem Int Ed Engl 2003 42 2073-2075
[41] Bazin H G Du Y Polat T Linhardt R J Synthesis of aVersatile Neuraminic Acid ldquoCrdquo-Disaccharide Precursor for theSynthesis of C-Glycoside Analogues of Gangliosides J OrgChem 1999 64 7254-7259
[42] Chen C-C Ress D K Linhardt RJ Samarium Iodide-Mediated Synthesis of Neuraminic Acid C-Glycosides InSynthesis of Glycommetics Roy R Ed ACS Syposium Series2004 896 53-80
[43] Abdallah Z Doisneau G Beau J-M Synthesis of a Carbon-Linked Mimic of The Disaccharide Component of The Tumor-Relate SialyTn Antigen Angew Chem Int Ed Engl 2003 425209-5212
[44] Lay L Nicotra F Panza L Russo G Caneva E Synthesis ofC-disaccharides through dimerization of exo-glycals J Org Chem1992 57 1304-1306
[45] Isobe M Nishizawa R Hosokawa S Nishikawa TStereocontrolled Synthesis and Reactivity of Sugar Acetylenes JChem Soc Chem Commun 1998 2665-2676
[46] Saeeng R Sirion U Sahakitpichan P Isobe M IodineCatalyzes C-Glycosidation of D-Glucal with SilylacetykeneTetrahedron Lett 2003 44 6211-6215
[47] (a) Babirad S A Wang Y Kishi Y Synthesis of C-Disaccharides J Org Chem 1987 52 1370-1372 (b) Wang YBabirad S A Kishi Y Preferred Conformation of C-Glycosides
1430 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
8 Synthesis of 14-Linked Carbon Disaccharides J Org Chem1992 57 468-481
[48] Armstrong R W Sutherlin D P Strategies for the Synthesis ofC-Disaccharides Containing D and L Sugars Tetrahedron Lett1994 35 7743-7746
[49] Wei A Kishi Y Preferred Conformation of C-Glycosides 12Synthesis and Conformational Analysis of αα- α β- and β β-Trehaloses J Org Chem 1994 59 88-96
[50] Haneda T Goekjian P G Kim S H Kishi Y PreferredConformation of C-Glycosides 10 Synthesis and ConformationAnalysis of Carbon Trisaccharides J Org Chem 1992 57 490-498
[51] Sutherlin D P Armstrong R W Synthesis of 12 Stereochemistryand Structurally Diverse C-Trisaccharides J Org Chem 1997 625267-5283
[52] Notz W Hartel C Waldscheck B Schmidt R R De NovoSynthesis of a Methylene-Bridged Neu5Ac-α-(23)-Gal C-Disaccharide J Org Chem 2001 66 4250-4260
[53] (a) Postema M H D Calimente D Liu L Behrmanm T L AnOlefin Metathesis Route for the Preparation of (1rarr6)-Linked-C-Disaccharide Glycals A Convergent and Flexible Approach to C-Saccharide Synthesis J Org Chem 2000 65 6061-6068(b) Postema M H Piper J L Liu L Faust M Andreana PSynthesis and Partial Biological Evaluation of a Small Library ofDifferentially Linked β-C-Disaccharide J Org Chem 2003 684748-4754
[54] Nelson A The Development of Strategies and Methods for TheSynthesis of Biologically Active Compounds New J Chem 200428 771-776
[55] Togo H He W Waki Y Yokoyama M C-GlycosylationTechnology With Free Radiant Reactions Synlett 1998 700-717
[56] Giese B Dupuis J Diastereoselective Synthesis of C-Glycopyranosides Angew Chem Int Ed Engl 1983 22 622-623
[57] Adlington R M Baldwin J E Basak A Kozyrod RPApplication of Radical Addition Reactions to tho Synthesis of a C-Glucoside and A Functionalized Amino Acid J Chem SocChem Commun 1983 144-145
[58] Giese B Gonzaacutelez-Goacutemez J A Witzel T The Scope of RadicalCC-Coupling by The ldquoTin Methodrdquo Angew Chem Int Ed Engl1984 23 69-70
[59] Giese B Witzel T Synthesis of ldquoC-Disaccharidesrdquo by RadicalC-C Bond Formation Angew Chem Int Ed Engl 1986 25 450-451
[60] Witczak Z J Chhabra R Chojnacki J C-Disaccharides IStereoselective Approach to β-(1rarr4)-3-Deoxy-C-Disaccharidesfrom Levoglucosenone Carb Res 1997 301 167-175
[61] Vogel P Synthesis of Rare Carbohydrates and Analogues Startingfrom Enantiomerically Pure 7-Oxabicyclo[221]heptyl Derivatives(ldquoNaked Sugarsrdquo) Current Org Chem 2000 4 455-480
[62] Viodeacute C Vogel P Synthesis of The C-Disaccharide α-C(1rarr3)-L-Fucopyranoside of N-Acetylgalactosamine J Carb Chem2001 20 733-746
[63] Xin Y C Mallet J M Sinayuml P An Expeditious Synthesis of AC-Disaccharide Using A Temporary Silaketal Connection J ChemSoc Chem Commun 1993 864-865
[64] (a) Petitou M Herault P Lormeau J-C Helmboldt A MalletJ-M Sinayuml P Herbert J-M Introducing A C-InterglycosidicBond in A Biologically Active Pentasaccharide Hardly Affects ItsBiological Properties Bioorg Med Chem 1998 6 1509-1516 (b)Sinayuml P Advances in The Synthesis of the Carbohydrate MimicsPure Appl Chem 1998 70 1495-1499
[65] Sinayuml P Chemical Synthesis of Oligosaccharide Mimetics PureAppl Chem 1998 70 407-410
[66] Sinayuml P Chemical Synthesis of Oligosaccharide Mimetics PureAppl Chem 1998 69 459-463
[67] Vauzeilles B Sinayuml P Selective Radical Synthesis of β-C-Disaccharides Tetrahedron Lett 2001 42 7269-7272
1430 Current Topics in Medicinal Chemistry 2005 Vol 5 No 14 Yuan and Linhardt
8 Synthesis of 14-Linked Carbon Disaccharides J Org Chem1992 57 468-481
[48] Armstrong R W Sutherlin D P Strategies for the Synthesis ofC-Disaccharides Containing D and L Sugars Tetrahedron Lett1994 35 7743-7746
[49] Wei A Kishi Y Preferred Conformation of C-Glycosides 12Synthesis and Conformational Analysis of αα- α β- and β β-Trehaloses J Org Chem 1994 59 88-96
[50] Haneda T Goekjian P G Kim S H Kishi Y PreferredConformation of C-Glycosides 10 Synthesis and ConformationAnalysis of Carbon Trisaccharides J Org Chem 1992 57 490-498
[51] Sutherlin D P Armstrong R W Synthesis of 12 Stereochemistryand Structurally Diverse C-Trisaccharides J Org Chem 1997 625267-5283
[52] Notz W Hartel C Waldscheck B Schmidt R R De NovoSynthesis of a Methylene-Bridged Neu5Ac-α-(23)-Gal C-Disaccharide J Org Chem 2001 66 4250-4260
[53] (a) Postema M H D Calimente D Liu L Behrmanm T L AnOlefin Metathesis Route for the Preparation of (1rarr6)-Linked-C-Disaccharide Glycals A Convergent and Flexible Approach to C-Saccharide Synthesis J Org Chem 2000 65 6061-6068(b) Postema M H Piper J L Liu L Faust M Andreana PSynthesis and Partial Biological Evaluation of a Small Library ofDifferentially Linked β-C-Disaccharide J Org Chem 2003 684748-4754
[54] Nelson A The Development of Strategies and Methods for TheSynthesis of Biologically Active Compounds New J Chem 200428 771-776
[55] Togo H He W Waki Y Yokoyama M C-GlycosylationTechnology With Free Radiant Reactions Synlett 1998 700-717
[56] Giese B Dupuis J Diastereoselective Synthesis of C-Glycopyranosides Angew Chem Int Ed Engl 1983 22 622-623
[57] Adlington R M Baldwin J E Basak A Kozyrod RPApplication of Radical Addition Reactions to tho Synthesis of a C-Glucoside and A Functionalized Amino Acid J Chem SocChem Commun 1983 144-145
[58] Giese B Gonzaacutelez-Goacutemez J A Witzel T The Scope of RadicalCC-Coupling by The ldquoTin Methodrdquo Angew Chem Int Ed Engl1984 23 69-70
[59] Giese B Witzel T Synthesis of ldquoC-Disaccharidesrdquo by RadicalC-C Bond Formation Angew Chem Int Ed Engl 1986 25 450-451
[60] Witczak Z J Chhabra R Chojnacki J C-Disaccharides IStereoselective Approach to β-(1rarr4)-3-Deoxy-C-Disaccharidesfrom Levoglucosenone Carb Res 1997 301 167-175
[61] Vogel P Synthesis of Rare Carbohydrates and Analogues Startingfrom Enantiomerically Pure 7-Oxabicyclo[221]heptyl Derivatives(ldquoNaked Sugarsrdquo) Current Org Chem 2000 4 455-480
[62] Viodeacute C Vogel P Synthesis of The C-Disaccharide α-C(1rarr3)-L-Fucopyranoside of N-Acetylgalactosamine J Carb Chem2001 20 733-746
[63] Xin Y C Mallet J M Sinayuml P An Expeditious Synthesis of AC-Disaccharide Using A Temporary Silaketal Connection J ChemSoc Chem Commun 1993 864-865
[64] (a) Petitou M Herault P Lormeau J-C Helmboldt A MalletJ-M Sinayuml P Herbert J-M Introducing A C-InterglycosidicBond in A Biologically Active Pentasaccharide Hardly Affects ItsBiological Properties Bioorg Med Chem 1998 6 1509-1516 (b)Sinayuml P Advances in The Synthesis of the Carbohydrate MimicsPure Appl Chem 1998 70 1495-1499
[65] Sinayuml P Chemical Synthesis of Oligosaccharide Mimetics PureAppl Chem 1998 70 407-410
[66] Sinayuml P Chemical Synthesis of Oligosaccharide Mimetics PureAppl Chem 1998 69 459-463
[67] Vauzeilles B Sinayuml P Selective Radical Synthesis of β-C-Disaccharides Tetrahedron Lett 2001 42 7269-7272