Total Synthesis of the CP-molecules (Phomoirides A & B)€¦ · Total Synthesis of the CP-molecules...
26
Total Synthesis of the CP-molecules (Phomoirides A & B) Nicolaou = March 20, 2000 (As.) Fukuyama = May 15, 2000 (As.) Shair = June 2, 2000 (As.) Danishefsky = August 22, 2000 August 23, 2005 Nathan Duncan-Gould
Transcript of Total Synthesis of the CP-molecules (Phomoirides A & B)€¦ · Total Synthesis of the CP-molecules...
Total Synthesis
of the CP-molecules
(Phomoirides A & B)
Nicolaou = March 20, 2000 (As.)
Fukuyama = May 15, 2000 (As.)
Shair = June 2, 2000 (As.)
Danishefsky = August 22, 2000
August 23, 2005
Nathan Duncan-Gould
Isolation & Structure Determination
• Isolated from an unidentified fungus from a Juniper twig in Texas
• 15L of broth allowed isolation of 31mg of CP-225,917 ; 18mg of CP-263,114 and 8mg of zaragozic acid
• Characterized by FAB-MS, FT-IR, Optical Rotation, UV, NMR (1H, 13C,DEPT, COSY, HMBC, ROESY & nOe) and conversion of CP-225,917into CP-263,114
• Inhibits Ras-farnesyl transferase (cancer) and Squalene synthase(cholesterol)
OH
O
O
O
OOH
O
O
HO2C
CH3
CH3
CH2Cl2, 24h
0.1eq CH3CO2H
O
O
O
OO
O
O
H
HO2C
CH3
CH3
J. Am. Chem. Soc. 1997, 119, 1594Antibiotics 1997, 50, 1
Absolute Configuration Unknown
CP-263,114CP-225,917
(Phomoidride A) (Phomoidride B)
Originally Proposed Biosynthesis
9
CO2HHO2C
CH3
CH3HO2C
HO2C
HO2C
HO2C
OH
OH
O
O
O
OOH
O
O
HO2C
CH3
CH3
9
O
CH3
CH3
OO
HO2C
HO2C
HO2C
HO2C
CO2HHO
HO2C
CO2H
HO2C OH
CO2H
HO2C
O
CO2H
CO2H
J. Am. Chem. Soc. 1997, 119, 1594
Chemical Challenges
1. Stereochemistry
• Four contiguous st. centers flanked by double bond
• One quaternary st. center adjacent to bridgehead olefin
• Epimerizable C7 Hydroxy?
O
C5H9
O
O
O O
C8H15
O
O
H
HO2C
OH
O
C5H9
O
O
OOH
C8H15
O
O
H
HO2C
CP-263,114CP-225,917Phomoidride A Phomoidride B
2. Steric
• Four rings total
• Adorned with functionality
3. Functionality
• Maleic anhydride
• Gamma-hydroxy lactol
Nicolaou: Retrosynthesis
[O] [O]
Arndt-Eistert
[-PG]Anhydride
C8H15
O
O
C5H9
TBSO
O
O
O
O
PMBO
C8H15
O
PMBO
O
O
C5H9
HO
O
Dithiane
C8H15
O
PMBO
O
O
OTBSTBSO
SS
CH3
Li
DA
PMBO
O O
C8H15
O
TBSO
OTBS
Vinyl Addition
OPMBO
O O
C8H15H
TBSO
OTBS
Li
C8H15
O
HO
HO2C
C5H9
TBSO
O
O
O
O
O
C5H9O
OO
C8H15
O
O
HO
H
OH
OC8H15
O
HO
HO
C5H9
TBSO
O
O
O
O
Nicolaou’s Synth. IHO
O
CO2MeMeO2C
TBSO
O O
H3C CH3
N1
N6
N7
N8
N5N4N3
N2
76%
1. NaH, THF, 65oC2. allylBr, NaH, DME, rt TBSO I
1. O3, CH2Cl2, -78oC, PPh3
2. Cyclohexylamine, PhH, 80oC97%
1. LDA, Et2O, -78oC, 1h
H
O
6
80% two step
TBSO
N
O O
H3C CH3
HO6
2. oxalic acid, 0oC, 1h
1. KH, PMBCl, 15min 0oC
2. TBAF, THF, rt
3. SO3•py, TEA, DMSO
51%
+
1. n-BuLi, THF,
-78oC, 30min
steps
3. LIBH4, THF4. CSA, CH2Cl2
2. DMP, CH2Cl2,
NaHCO3, 1h
TBSO
OTBS
I
OPMBO
O O
H3C CH3
C8H15
PMBO
O O
H3C CH3
C8H15
O
TBSO
OTBS
O
C5H9O
OO
C8H15
O
O
HO
H
OH
O
1. TMSCCLi, THF
2. TBSOTf, 2,6-lutidine, CH2Cl23. K2CO3, MeOH, rt, 12h
4. [Cp2Zr(H)Cl], PhH
5. I2, CCl4, 25oC
N1’(CH3)2C(OME)2
TBSO
O
O O
6
62%
44%
Nicolaou’s Synth. IIPMBO
O O
H3C CH3
C8H15
O
TBSO
OTBS
C8H15
O
PMBO
O
O
H3C
H3C
OTBSTBSO
BHTAlCl2 (20mol%), PhCH3, -80oC
88% 1. TBAF, THF, 25oC, 2h
2. NaIO4, NaOH, EtOH, OoC to rt
3. THF, 8min
SS
CH3
Li
65%
20% RSM
2. KHMDS, PhNTf2, THF,
OoC, 10min
1. NaH, TesOTf, THF,
O oC to rt, 2h
Pd(OAc)2, (PPh3
MeOH, TEA, CO(1atm),
50oC, 40min
64%overall
2. DIBAL-H, PhMe, -78oC
3. V(O)(acac)2, t-BuOOH, PhH, rt, 30min
1. PhI(O2CCF3)2, CaCO3, MeOH, rt, 6min
79%
10.7:1
Et2AlCN, PhMe,
OoC, 15min, rt, 1h
73%
10 Rxns to add and alkyl group and the carbons for the Maleic anhydride
5.7:1 dr
11:1 dr
C8H15
O
PMBO
O
O
C5H9
HO
S S
C8H15
TfO
PMBO
O
O
C5H9
TBSOS S
C8H15
MeO2C
PMBO
O
O
C5H9
TBSOS S
C8H15
PMBO
O
O
C5H9
TBSO
H3CO OCH3
O
OH
C8H15
PMBO
O
O
C5H9
TBSO
H3CO OCH3
HOOH
NC
N-7
N-8
N-9N-10N-11
N-12N-13
Nicolaou’s Synth. III
C8H15
PMBO
O
O
C5H9
TESO
H3CO OCH3
HOOH
NC
75%
1. CSA, CH2Cl2, 25oC
2. TBSOTf, CH2Cl2
56%
2. Et2O, Air, oxalic acid, 30min
1. DDQ
2. PDC
b. K2CO3, MeOH, 1h
1. a. MsCl, TEA,
THF,. OoC, 5min
43%40%
2. TESOTf
3. DMP, PhH, 80oC, 25min
1. AcOH, 25oC, 6h
1. a. TFA, CH2Cl2 b. MeSO3H, CHCl3,
rt, 2h
2. DMP, PhH, rt, 2h
3. TBSOTf, 2,6-lut.,
4. NaClO2, NaH2PO4
t-BuOH / H2O, 25oC
1. MsCl, TEA, THF, OoC, 5min
2. CH2N2, Et2O/THF, OoC to rt
3. Ag2O, DMF/H2O, 120oC, 1min
35%
49%
C8H15
PMBO
O
O
C5H9
TBSO
H3CO OCH3
O
O
O
C8H15
PMBO
O
O
C5H9
TBSO
O
O
O
O
C8H15
O
O
O
C5H9
TBSO
O
O
O
O
OTBS
O
C5H9O
OOH
C8H15
O
O
H
OTES
HO
O
C5H9O
OO
C8H15
O
O
H
HO2C
TBSO
H
O
C5H9O
OO
C8H15
O
O
HTBSO
H
CO2H
N-12N-13
N-14N-15N-16
N-17N-18
Nicolaou’s Synth. IV
O
C5H9O
OO
C8H15
O
O
HTBSO
H
CO2H
O
C5H9O
OO
C8H15
O
O
HO
H
N
O
LiOH, THF
O
C5H9
O
OOH
C8H15
O
O
HO
HO
OH
O
quench w/NaH2PO4
O
C5H9O
OO
C8H15
O
O
HO
H
OH
O
MeSO3H
CP-225,917CP-263,114
1. indoline, EDC, DMAP
2. TFA/CH2Cl2/H2O
3. DMP, NaHCO3, CH2Cl2, rt, 35h
4. p-chloranil, PhMe, 110oC, 2.5h
52%72%
90%
N-18N-19
N-20N-21
Nicolaou Quick Summary
Building Blocks
HOO
TBSO
OTBS
Li CO2MeMeO2C
TBSO I
Br
SS
CH3
Li
H
O
6
PMBO
O O
C8H15
O
TBSO
OTBS
O
C5H9O
OO
C8H15
O
O
HO
H
OH
O CO
CN
40 Total Steps
12 Total Ox changes
10 Total P / DP
.00013% overall
Fukuyama Retrosynthesis
O
C5H9O
OO
C8H15
O
O
HO
H
CO2H
OHC
OR
RX*
O
EtS
C8H15
RO2C
RO2C
C8H15
EtS
RO2C
RO2C
RRO
X
O OR
RO2C
C8H15
O
H
RO2C
RO
X
O
EtS
•
CO2R
EtS
C8H15M
IMDAFGM
Pummerer
RAR
1,4 addition Aldol
Cuprate Addition
Fukuyama IEtS
CO2CH3
C8H15Cu
DBU, TMSCl, HMPA,
Me2S, -78oC
80%
1. LHMDS, ClCO2Me
2. Cs2CO3, 50oC
82%
NO
O
Bn
O1. Bu2OTf, TEA, OoC
2. SO3•pyr, DMSO, DIPEA
allyl t hioglycolate,
LHMDS, ether, OoC, 3h
DBU, THF, rt, 1.5h
ZnCl2Et2O, Py, CH2Cl2
1. cat Pd(OAc)2, PPh3, pyrrolidine, CH3CN, rt, 15min
2. Py, Ac2O, 100oC, 1h
X = CO2Allyl
1. TBSCl, DBU, CH2Cl2
2. NIS, CH2Cl2, rt
3. AgNO3, DMSO, 50oC, 1h
C8H15EtS
CO2CH3
C8H15EtS
CO2CH3H3CO2C
O
N
O
O
Bn
OC5H9
C8H15
EtS
O
H3CO2C
H3CO2C
Xp
OO
OC5H9
C8H15
EtS
O
H3CO2C
H3CO2C
S
OO
CO2Allyl
C5H9
C8H15
EtS
O
H3CO2C
H3CO2C
S
OO
HO
X
C5H9
C8H15
EtS
O
H3CO2C
H3CO2C
O
OO
O
87% overall
93%
53% overall
60%
68%
58% overall
F-1F-2
F-3
F-4
F-5F-6
F-7
F-8 F-9 F-10
OC5H9
C8H15
EtSO
H3CO2C
H3CO2C
Xp
OO
C5H9
C8H15
EtS
O
H3CO2C
HO2C
S
OO
C5H9
OHC
OO
Fukuyama II
LiOH•H2O, MeOH, rt, 1h;
then Ba(OH)2•8H2O, rt, 1h
1. (COCl)2, CHCl2, rt, CH2N2,
ether, -15oC, 10min
3. 80%aq AcOH,
70oC, 13h,
2. TFAA, DIPEA,
PhMe, OoC, 1h
1. mCPBA, CH2Cl2,
-20oC, 5min
1. Jones ox. OoC, 20min
54% 3 steps
49%51%
CP-263,114
2. PhCO2Ag, t-BuOH,
50oC, 1h,
2. HCO2H, rt, 1h
C5H9
C8H15
EtS
O
H3CO2C
O
OO
CO2t-Bu
O
O
C5H9O
OO
C8H15
O
O
HO
H
CO2H
F-11F-12
F-13 F-14
F-15
OH
C5H9O
O O
C8H15
O
O
HO
H
CO2t-Bu
C5H9
C8H15
EtS
O
H3CO2C
H3CO2C
O
OO
OC5H9
C8H15
EtS
O
H3CO2C
HO2C
O
OO
O
Fukuyama: Quick Summary
29 Total Steps
7 Total Redox
10 Total P / DP
.00013% overall
•Bought 1 st. center
•Oxizolidinone: 1. Set C12 then used to control
IMDA
2. Served as oxidation state
place holder for C30
Maleic Anhydride
•Sulfonyl Ether 1. DA
2. Pummerer RAR to
install C26 ketone
C8H15EtS
CO2CH3H3CO2C
O
N
O
O
Bn
C8H15EtS
CO2CH3H3CO2C
O
N
O
O
Bn
C5H9
OOO
•Anhydride survived 8 steps!
OC5H9
C8H15
EtS
O
H3CO2C
H3CO2C
Xp
OO
O
C5H9O
OO
C8H15
O
O
HO
H
CO2H
Still 2 1-C homologations
C5H9
OHC
OO
Danishefsky Retrosynthesis
MC5H9
FGM
RM addition
1C Homologations
O
R
X
O
H
O
Aldol
Heck
O
O
O
R[O]
Install
Alkyl groups
O
R
H
OC
SPh
O
O
Install
Alkyl groups
O
R
H
OC
SPh
O
TMS
O
O RO
R
H
RO2C
RO2C
TMS
O
O
O
OO
O
O
H
HO2C
CH3
CH3
Danishefsky IO
HO
O
HO
TBS
Bu3Sn
O
NC
TBS
I
O
TBS
I
O
H
79% plus 10% diasteromer
O
2. n-BuLi, HMPA,
THF, -78oC to rt, 16h
1. TBSCl, DIPEA, CH2Cl2, rt, 1h
3. a. n-BuLi, DME,
-78oC to 0oC, 15min
b. Bu3SnCl, 0oC, 1h
70%
1. I2, CH2Cl22. KF, Et2O, rt, 16h
3. MsCl, TEA, CH2Cl2,
-78oC, 2h
4. KCN, DMF, rt, 16h
94%
DIBAl-H, PhMe, rt, 1h
1. LDA, THF,
-78oC, 1 hD-1
D-7
D-2 D-3 D-4
D-5
D-6D-6
O
TBS
I
O
OH
O
TBS
OTBS
O
2. [Pd(OAc)2(PPh3)2], TEA, THF, reflux, 4d
1. TBSOTf, 2,6-lutidine,
CH2Cl2., 0oC to rt, 1h
78%1. DIBAl-H, CH2Cl2,
-78oC to -30oC
2. TBSOTf, 2,6-lutidine,
CH2Cl2, 0oC to rt, 16h,
O
TBS
OTBS
TBSO
O
TBS
OH
TBSO
I
O
1. SeO2, 1,4-dioxane,
100oC, 2h
2. TPAP, NMO, CH2Cl2,
3. I2, Pyridine, CH2Cl2
1. [PdCl2(dppf)], Cs2CO3, AsPh3, H2O, R3B
2. HF•pyridine
3. allyltrimethylsilane,
TiCl4, CH2Cl2, -78oC
O
TBS
OH
TBSO
O
OBn
6
D-8 D-9 D-10
61%
73% 47%
O
OTBS
I
HOH
Danishefsky II
O
TBS
OH
TBSO
O
OBn
6
1. LAH, Et2O
2. (COCl)2, DMSO,
CH2Cl2, TEA, -78oC
3. a. DMAP, CH2Cl2, MsCl
b. TEA, MsCl
O
TBS
O
TBSO
OBn
6
4. DBU, PHMe, 80oC
O
TBS
OBn
6O
HO
1. Tebbe reagent, THF,
-78 to -10oC2. trichloroacetyl chloride, Zn, Et2O, DME, ultrasound
3. a. Zn, NH4Cl, MeOH, ultrasound
b. TBAF, THF, 0oC
2. DMP, CH2Cl2
1. PhSSPh, NaH/KH, THFO
TBS
OBn
O
O
PhS
1. H2O2, MeOH
2. OsO4, NMO, Acetone/water
NaOMe, MeOH
O
TBS
OBn
6
O
PhOS
O
OHO OH
(COCl)2, DMSO, CH2Cl2,
TEA, -78oC
O
TBS
OBn
6
O
O
CO2CH3
O
HO
H
O
TBS
OBn
6
O
O
OH
CO2CH3
HO
H
D-10
D-11
D-12D-13
D-14
D-15
D-16
30%
43%
72%49%
42%70%
Danishefsky III
MgBr
1. Et2O, -78oC
2. DMP
O
TBS
OBn
6
O
O
CO2CH3
O
HO
H
1. 1,1-diiodoethane, CrCl2, THF
2. hv O2, rose Bengal,
DIPEA, CH2Cl2, 0oC
1. DDQ, H2O, CH2Cl2
2. DMP, CH2Cl2
TPAP, NMO, CH2Cl2,
O
TBS
OBn
6
O
O
CO2CH3
O
HO
O
TBS
O
O
CO2CH3
O
HO
O
H
O
O
O
O
CO2CH3
O
HO
O
LiOH, THFOH
O
O
O
OOH
O
O
HO2C
(7S)-CP0225,917
F-16F-17
F-18F-19
F-20
F-21
60% 48%
70%
50%
90%
O
O
O
O
CO2CH3
O
HO
OH
Danishefsky: Quick Summary
41 (47) Total Steps
14 (2) Total Redox
5 (7) Total P / DP
.000103% overall
Aldol Heck
O
O
O
OO
O
O
H
HO2C
CH3
CH3Sulfur Mediated
Cleavage
Pyran
Shair: Restrosynthesis
O
C5H9
O
O
O O
C8H15
O
O
H
HO2C
Carbonylation
FGM
Fries-like
RAR
5
X
O
GPO2C
CO2PG
O
OCH3
CH32
H OO
OO
CH3
OMOM
CH35
O
O
OPG
2
CH3M
OPG
O O
OO
CH3
OPG
CH3
O
O
OPGOPG
RO2C
RM Addition
[3,3] RAR
O
I
CH3M
Cross
Coupling
O
CO2PG
CH3
GPO5
1,4 Add’n
and
Trap
Shair ICH3Me3Sn
O
I
S-1
S-2
O
CH3
5
S-3
1. Li2(PMBOCH2)Cu(thiophene)CN,
TMSCl, THF, -78oC
2. nBuLi, Et2O, -78->OoC, NCCO2Me,
62%80%
Pd2(dba)3, PPh3,
DMF, 65oC
resolved with
CBS
S-4
CH3
BrMg
OMOM
O OO
CO2ch3
CH3
PMBO5
OO
CH3
OMOM
CH35
O
O
OPMB
2
S-6S-5
1. BCl3, -78 -30oC
2. Dess-Martin, pyridine, H2O/CH2Cl2, rt
3. NaClO2, NaH2PO4,
2-methyl-2-butene, MeOH/H2O, rt
4. MOMCl, TEA, CH2Cl2, rt
OO
CH3
OMOM
CH35
O
O
2
OOH3CO
O
O
H3CO2C
5. KHMDS, THF then NCCO2Me, -78 -30oC
6. TMSOTf, HC(OMe)3, CH2Cl2,-78 -30oC
S-7S-8
5
O
O
H3CO2C
CO2H
O
OCH3
CH32
H OO
90% ee31%
27%
83-92% over 6 steps
2. KHMDS, THF then NCCO2Me,
O
CO2CH3
CH3
PMBO5
Shair II1. a. MsCl, TEA, THF, 0oC
b. CH2N2, -50oC
2. hv, tBuOH/Et2O, 23oC
3. KNi-Pr, Et2O, then Tf2O,
Pd(OAc)2 P(OMe)3
CO(500 psi), TEATHF/MeCN, rt
70%
5
O
CO2t-Bu
O
OCH3
CH32
H OO
O
O
AcO
H3CO
1. HCO2H, 23oC
5
O
CO2H
O
OCH3
CH32
H
O
O
O
O
S-10
S-8 S-9
S-10
5
O
O
H3CO2C
CO2H
O
OCH3
CH32
H OO
5
TfO
O
H3CO2C
CO2t-Bu
O
OCH3
CH32
H OO
7%
79%
Shair: Quick Summary
23 Total Steps
3 Total Redox
5 Total P / DP
.0006% overall
Step 17 and 18 combined: 12%
Four 1C homologations
5
O
CO2H
O
OCH3
CH32
H
O
O
O
O
OCH3
5
XCO2CH3
CO
CH3BrMg
OMOM
O O
Arndt-Eistert
Side-by-Side
CO2MeMeO2C
SS
CH3
Li
H
O
6
CO
CN
Nicolaou [DA]
TBSO
OTBS
Li
Fukuyama [DA]C5H9
OHC
OO
O
C5H9O
OO
C8H15
O
O
HO
H
CO2H
O
C5H9O
OO
C8H15
O
O
HO
H
CO2H
C8H15EtS
CO2CH3H3CO2C
O
N
OO
Bncuprate + allene
1,4 addition
Danishefsky [Ald.-Heck] Shair [Cope-Fries]
O
R
I
O
H
O
O
O
O OO
O
H
HO2C
CH3
CH3
I OBn
6
O
Sulfur-mediatedcyclobutanonecleavage
TMS
BrMg
O
CH3
5CH3BrMg
OMOM
O O
NCCO2CH3
Arndt-Eistert
5
O
CO2H
O
OCH3
CH32
H
O
O
O
O
CO
Br
Final Statements
• Three Drastically Different Approaches werecompleted
• All ran into oxidation problems
• Four unique solutions to installing maleicanhydride moiety
• Three of the four used Arndt-Eistert
• Four different methods used to set quat.Center…all relied on chirality alreadyestablished
• Many one and two carbon homologations
References
Isolation (Pfizer)
JACS, 1997, 119, 1594
Antibiotics 1997, 50, 1
Nicolaou
ACIE, 2002, 41, 2678
JACS, 2002, 124, 2183
JACS, 2002, 124, 2190
JACS, 2002, 124, 2202
ACIE, 2000, 39, 1829
OL, 1999, 1, 63
ACIE, 1999, 38, 549
ACIE, 1999, 38, 1676
Classics in Tot. Syn. II, 2003, Whiley
FukuyamaTL, 1998, 39, 6015JACS, 2000, 122, 7825ShairJACS, 1998, 120, 10784JACS, 2000, 122, 7424DanishefskyACIE, 1999, 38, 1485ACIE, 1999, 38, 1877ACIE, 1999, 38, 3197ACIE, 1999, 38, 4509ACIE, 1998, 37, 1880
