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Chapter 4

}lza variant of intramofecufar :NC}l£

reaction

Aza variant of intramolecular NCAL reaction Chapter4

4.1. Introduction

Polyhydroxylated pyrrolidines, piperidines (often called "aminosugars" or "aza sugars")

and their synthetic analogues have attracted considerable interest due to their ability to

mimic sugars in which the ring oxygen has been substituted for a nitrogen atom.1 Their

often potent inhibitory activity towards glycosidases and glycosyltransferases of

carbohydrate processing. enzymes make them useful in a wide range of potential

therapeutic strategies including the treatment of viral infections/ cancer,3 diabetes,4

tuberculosis,5 lysosomal storage diseases,6 and parasitic protozoa.7

0

?>" t:( "OH

OH

BCX-4208

OH 0

c!f'~

~ H OH

3-Hydroxy-2-hydroxymethyl pyrrolidines

OH

fa: C .. JOH

N H

4-( hydroxymethyl) piperidin-3-ol

OH

HO

OH

HO,,.~OH

lN~OH H

1-deoxygalactonojirimycin

HN~COOH s~o NH2

HN 0 0~

~~ OH

HO

tetrazomine cv: 0 Cycloth;and;ne

~ l~ N

isofebrifugine

Figure 1. Aza sugars

Hydroxylated piperidine structural framework is found in a wide variety of

natural and synthetic compounds of biomedical significance; for example cis-3-

hydroxypipecolic acid is an important constituent of a naturally occurring antibiotic

tertazomine8 whereas its acid reduced analogue is found in 1-deoxygalactonojirimycin

173


which has shown to be the strong inhibitors of a-galactosidase A and is currently in

undergoing preclinical trials as a potential therapy for Farby's disease, a severe

lysosomal storage disorder.9 Also (2R,3R}-3-hydroxy-2-hydroxymethylpiperidine is a

structural unit found in the antimalarial isofebrifugine.10 Amongst the pyrrolidine class,

cyclothialidine11 (a potent DNA-gyrase inhibitor}, slaframine/2 castanospermine13 and

detoxinine14 contains a cis-3-hydroxyproline structural motif whereas a literature search

revealed only one reported synthesis of its acid reduced congener, cis-3-hydroxy-2-

hydroxymethylpyrrolidine (the "azaDNA" analog} starting from serine.15 Included among

the polyhydroxylated pyrrolidine, 4-hydroxymethyl-pyrrolidin-3-ol is used as the

precursor for the BCX-4208, a clinical candidate evolved from the second generation of

PNB inhibitors (Fig. 1}.16-18

4.2. Basis of work and Retro-synthesis

,LHactones (2-oxetanones} have recently emerged as important synthetic targets owing

to their occurrence in a variety of natural products and their utility as versatile synthetic

intermediates in the synthesis of chiral products due to their masked aldol functionality

and their inherent reactivity. 19'20 In 1982, Wyn berg and co-workers successfully reported

the first catalytic, asymmetric [2+2] addition of ketene with highly electrophilic

aldehydes (eg. a~chlorinated} in the presence of cinchona alkaloids to yield ,8-lactones 3

in high yield (89%} and enantioselectivity (98% ee} (Scheme 1}.21

2

4moi%QD

PhMe, -25 °C

3

89%yield 98%ee

Scheme 1. Wynberg's ,8-lactone synthesis

174

QD


The proposed mechanism involves the formation of a zwitterionic ammonium

enolate intermediate, arising from the nucleophilic attack of the quinuclidine ring of the

catalyst on the ketene, followed by a stepwise addition to the aldehyde (Scheme 2). One

drawback associated with Wynberg and co-workers' original process was the

requirement of highly reactive aldehydes, presumably to compete with ketene

dimerization. As a result of this, only aldehydes containing electronwithdrawing groups

adjacent to the carbonyl were suitable coupling partners, and although the reaction

often returned good results, it was restricted in scope.22

Scheme 2. Mechanism of j3-lactone formation

Recently, Romo eta/. have reported a high enantioselective synthesis of a series

of bicyclic beta-lactones via intramolecular nucleophile-catalyzed aldol lactonization

(NCAL) of aldehyde acids, which provided the first strategy to beta-lactone synthesis

with unactivated aldehydes.23 The mechanism involves formation of the activated

carboxyl function (Scheme 3) from the carboxylic acid 4 (using the Mukaiyama salt, 5),

that can be subsequently intercepted with the nucleophilic catalyst, 0-acetylquinidine.

The acyl ammonium intermediate forms the Cl ammonium enolate, and an

175


intramolecular aldol reaction proceeds through a similar pathway to that outlined in

Scheme 2 to form bicyclic ,8-lactone (6) in high ee and moderate-to-good yields using 10

mol % of the catalyst. Both enantiomers are accessible using either the Ac-QD (0-acetyl

quinidine) or Ac-Q (0-acetyl quinine) catalysts. In a modification to their original

process, Rome and co-workers showed that an analogue of the Mukaiyama salt (TfO- or

BF4- counter ion instead of r) can be used to improve the output from the reaction. The

new salts are more soluble as well as prevent side reactions associated with the r

attacking the electrophilic pyridinium leading to a deactivated system.24

;--/COOH

~CHO

4

j +NR*3 (= AcQUIN)

+

10 mol% AcQUI N i-Pr 2NEt (4.0 equiv) Cl

®N 8 Cl I X

5 {3.0 equiv) 82% yield, 92% ee if X= OTf 54% yield, 92% ee if X= I

® -H

OMe Z" ~.,

0-Acetyl Quinidine

8 c))®.

NR 3

J

H

CWO 6

t

Scheme 3. Intramolecular nucleophile catalyzed aldollactonization

Literature reports thus clearly make obvious the utility of azasugars and this area

has seen resurgence in synthetic efforts directed towards convenient and efficient

synthetic routes to cis-aza sugars and their synthetic analogues. However many of these

strategies utilizing either chemical and enzymatic resolution 25, or by the use of amino

acids,26 or carbohydrates27 as chiral pool, have multi steps and/or selectivity deficient.

176


We, therefore, thought it prudent to develop new short catalytic synthetic strategy for

chiral synthesis of this class of compounds.

Derivatives of cinchona alkaloids have shown great promise as catalyst for a

broad range of asymmetric transformations thereby providing access to chiral products

of high enantiopurity.28 1nspired from Ramo's eta/. enantioselective synthesis of a series

bicyclic beta-lactones via intramolecular nucleophile-catalyzed aldol lactonization

(NCAL) of aldehyde acids, we envisaged a general synthetic strategy towards the chiral

synthesis of several cis-aza sugars and related molecules by utilizing formal

intramolecular NCAL reaction of particularly inexpensive achiral amino acid derivatives

via intermediary beta-lactone fused pyrrolidines and piperidines (intermediate A), as

depicted in the retrosynthetic scheme. (Fig. 2)

aza-sugars c::::::> Cbz -GJ:t c::::::> 0

intermediate A

Figure 2. Retro-synthesis

4.3. Synthesis of aldehyde-acid precursors

c::::::> a ch ira I amino acids

Achiral amino acids 9a-d required as the starting point for intramolecular NCAL

reactions were prepared either by N-allylation of Cbz-GABA (7a) or Cbz-AiaOH (7b)

ROUTEB

8 <±> Br--(CH2Vm If HN co Me /'.... ~"'m "-..../" 2 Cl H3N C02Me ------- 'l' \'7.,.

ROUTE A

K2C03, CH3CN (m=2,3)

m=2; 7c (73.3%) m=3; 7d (68.1%)

J Cbz-CI, TEA, CH2CI2

then LiOH.H 20, THF:Hp;

Cbz H allylbromide, NaH, DMF I N Co H ~ vmNxvn C02H

0 3,-78 ° C, Me2S

80-82% / XV 2 -:;...- \'1rr \In Cbz nn

n=2;7a n=3; 7b

n=2, m=l; Sa (80.8%) n=3, m=l; Sb (68.6%) n=l, m=2; 8c (90.6%) n=l, m=3; 8d (78.5%)

Scheme 4. Synthesis of aldehyde-acid 177

n=2, m=l; 9a n=3, m=l; 9b n=l, m=2; 9c n=l, m=3; 9d


followed by ozonolysis to give aldehyde-acid 9a-b (Route A) or via employed a three

step procedure comprising of (i) N-w-alkenylation of glycine methyl ester (7c-d) (ii) one

pot Cbz protection, hydrolysis of ester group (Se-d) and (iii) subsequent ozonolysis

(Route B), to give aldehyde-acids 9c-d {Scheme 4).

4.3.1. ROUTE A:

N-Cbz amino acids 7a-b were prepared from ,8-alanine and GABA respectively by

treating them with Cbz-CI and NaOH, almost in quantitative yields according to the

method reported in literature.29 Allylation of 7a-b with allyl bromide, employing NaHas

a base in DMF, afforded the intermediates Sa-bin good yields {69-81%) which were fully

characterized by spectroscopic methods using NMR, IR and MS. Both products gave

their molecular ion peak at m/z corresponds to their molecular weights (Sa, m/z 264;

Sb, m/z 278) in their MS spectra. Compound 7a gave broad carbonyl absorption at 1689

cm-1 in IR spectrum corresponding to carboxylic acid whereas carbonyl absorption

appears at 1692 cm-1 in the IR spectrum of Sb. The terminal olefinic bond of Sa-b was

oxidised by bubbling ozone to their solution in CH2CI2 at -78 octo give the desired key

intermediate 9a-b possessing both the aldehyde and acid functionalities.

4.3.2. ROUTE 8:

Glycine methyl ester hydrochloride was prepared by treating glycine with thionyl

chloride in methanol and was confirmed by comparison of their melting point with that

of reported data.30 Treatment of methyl glycinate.HCI (1.2 equiv.) with K2C03 (2.3

equiv.) and 1-bromobutene {1.0 equiv.) in CH3CN gave monomer 7c in 73.2% yield.

Similarly 7d was obtained in 68% yield. 7c-d thus obtained showed the molecular ion

peaks at m/z corresponding to their molecular weights (7c, m/z 144; 7d, m/z 158) in

their MS spectra. The IR spectra of 7c and 7d showed the characteristic absorption at

1740 and 1739 cm-1 respectively due to ester carbonyl whereas the 1H-NMR spectra of

7c showed characteristic peaks at o 5.8 (m, 1H), o 5.09 (m, 2H), o 3.74 (s, 3H) and o 3.44

(s, 2H) due to CH2=CH, CH2=CH, COOCH3 and NHCH2C02CH3 respectively (Fig. 3).

178

"' U>

"' _../""" 0

1.06 ---.. U> u.

_../"""

lilQ.._ ~

:!I !"-IQ' U•

c:: ~ ~

!"-0

.... =t: m:::: < w

1-' s:: I][: v.

-..J :::0 lO ~ w

0 r, 0

~ 1.90

0 '" u. t: :::, Q.. 1.97

~ !" 0

liil_ u.

0

I';

]

~ :i z ;;:: ?J w 0

~ IZ 0

) ;;::

() if 0 () 0 0 () ()

;I- ..

im 5.8758 5.8642 5.8539 5.8417

~5.8191 5.8070 5.7967 5.7849 5.7628

~5.0n9 5.0670

,5.0157 5.0098 4.9979 4.9639

--3.7482

--3.4286

"6558 _.........- 2:6321 ~2.6077

_/2.1589 ~2.1352 ~2.1107

2.0870

./ 1.6617 ::::::;;=======~---------- :::::-- 1.6253

~1.5882 "-1.5640

"' :r: + ;f. 0

~t.l:~Ji~'H'!~l ~~;.!~

~ g -~

" ., ~~] i:<>;<>ie:~~

:::!! IQ c:: ~ ~

.... :r::

I

~ :::0

~ r, 0 3

1:::! 0 t: :::, Q..

~

"' 0 __r 1.00 ~

U> u.

__/ 2.03 Vl

~0

... u.

.. 0

Til(

bill._~

__, 1Q:!.__

__, 2.08 ---..

w 0

'" u.

"' 0

u.

0

c u.

]

:£ z ;;:: ? ~ 0

;;::

!f () 0

£l

~ (:t J:Z

) ()

8 ()

;I-

r::;~~;~~::~ ~~~B i I

"" ~ ~) !; .?; g

'i " '

;,.,~ .. -~! m.r

15.8584 5.8472 5.8358 5.8243

,5.8014 5.7901 5.7786 5.7673 5.7447

.L5.1565 5.1507

~5.0934 5.0593 5.0563

--3.7466

--3.4422

_.........- 2.7210 ........____ 2.6981

2.6755

L2.3166 ~2.2940

~2.2713 2.2486

)::. ,... Q

t§ ~ -· Q :::, '""' ~ -· :::, ~ Q

3 0 -(1) r, t: -Q ~

< II

Q r-

~ II Q

r,

II '""' o· :::,

9 .g ~ .l::lo,


Similar pattern was also observed in the 1H spectrum of compound 7d (Fig. 4). The

amino group of amino ester 7e-d was then protected by Cbz group using Cbz-CI and TEA

to give N-Cbz protected derivative which were taken up directly for the hydrolysis step.

Basic hydrolysis of methyl ester with LiOH.H20 afforded acids 7e-d in 90% and 79%

isolated yields respectively.

Acids Se-d thus obtained were fully characterized by spectroscopic methods

using NMR, IR and MS. Compound Se and Sd showed M+1 peak at m/z 264 and 278

respectively corresponding to their molecular weight. The IR spectrum of Se showed

characteristic absorptions at 1696 cm-1 due to acid functionality whereas it appeared at

1699 cm-1 for acid Sd. The terminal olefinic bond of Se-d was then oxidised to aldehydes

9e-d by ozonylsis. All the aldehyde acid 9a-d thus obtained were characterized by their

IR and MS spectra and were utilized immediately for NCAL reaction without any further

purification.

4.4. Racemic NCAL reactions

The scope of intramolecular aza NCAL reaction was studied using substrates 9a-d and

mukaiyama's reagent lOa under conditions as described by Romo et a/. The reactions

were performed by slow syringe pump addition of aldehyde-acids 9a-d over a period of

10 h to the mixture of Mukaiyama reagent lOa and TEA in acetonitrile at room

temperature (Scheme 5, condition A). The results are summarized in Table 1.

G:l N X re R y

n=m=l,2,3

9a-d

10a-c (3.0 equiv) TEA (4.0 equiv)

CH3CN, rt, 12 h

condition A-C

lOa: R=Me; X=CI; Y=l lOb: R=Me; X=Br; Y=OTf 10c: R=Et;X=Br;Y=BF4

i:"r? Cbz-N~

0

(±)-lla-d

condition A: lOa, addn. time (10 h) condition 8: lOb, addn. time (3 h) condition C: lOc, addn. time (3 h)

Scheme 5. Racemic NCAL reaction

180


Table 1. Optimization of racemic aza-NCAL reactions

entry aldehyde-acid (±) bicyclic-,8-lactone condition %yielda

A 53

1-CHO Cbz-N~ Cbz-N B 76 1 ~

9a COzH 0 lla

c 69

A 51 Cbz, /"-.... Cb''()::.t N CHO N 0

2 ~C02H B 71 6 0

9b llb c 63

b

rCHO rn A

3 N~ B 55 1 C02H I 0 Cbz Cbz

9c llc c 51

eCHO CA 4 N~CO H B 52 I 2 I Q Cbz Cbz

9d lld

•Isolated yield

bN-benzyloxycarbonyl-4,5-dihydro-lH-Pyrrole-2-carboxylic acid (12) was isolated albeit in low yields.

It was found that the reactions with 9a and 9b afforded racemic beta lactones, lla and

llb in 53% and 51% yield, respectively (Table 1, entries 1 and 2). However reaction with

c~ 8 , o ___ cbz,,~-{co12 (Et ~

llc ( 8 I

~-elim.

12

Scheme 6. Undesired decomposition pathway

181


aldehyde-acid 9c gave only the decomposed 12 product presumably produced by the

attack of iodide ion at the ,8-carbon of the resulting ,8-lactone followed by ,8-elimination

(Scheme 6).

Since Mukaiyama reagents with non-nucleophilic counter ions such as triflate

and tetrafluoroborate reduces this undesired ring opening, the NCAL reactions with

pyridinium salts lOb and lOc were studied next. The pyridinium salt lOb was

synthesized in a sealed tube by N-methylation of 2-bromopyridine with the

corresponding methyl triflate in nearly quantitative yield as colorless crystals by

literature procedures (Scheme 7). A singlet of three protons corresponding to N-CH3

apper at o 4.48 in the 1H-NMR spectrum of lOb (Fig. 4).

u N Br sealed tube, CH2CI2

-78 to 25 °C, 12 h

u 0 N Br

1 e 1ob OTf

Scheme 7. Synthesis of Mukaiyamas reagent {lOb}

1H-NMR, 300 MHz, CDCI3+C0300

C1 ®7 eBr

OTt 10b

~V'"'~ ~ "''"

1~)..'1! Hl:!3

,,;xi~ t'\J:!l~

'" ' g:~~;!g ~~ ~--·,.~:l~~; ~"'"'·

;~.nen

G.CC zn.~

:. ur~·Jccc~

5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 ppm

I~(

Figure 4. 1H-NMR of compound lOb 182


Use of N-Methyl-2-bromopyridinium triflate (lOb) and N-Ethyl-2-

bromopyridinium tetrafluoroborate (lOc) greatly improved efficiency of the reaction

and better yields of the cyclised products were obtained (Scheme 5, Table 1). These

results were in conformity with the observations of Romo et al.ret All the bicyclic fJ

lactone fused pyrrolidine and piperizines lla-b were characterized by their IR, HRMS,

NMR and HSQC spectra.

4.5. Catalytic, asymmetric intramolecular NCAL reaction

Having optimized reaction conditions, we next studied the asymmetric NCAL reactions

of substrate 9a-c by employing chiral amine catalysts (Scheme 8). It was observed that

slow addition of aldehyde acid 9a-c to a mixture of 0-Acetyl quinidine,31 10b and hunig's

base in CH3CN gave the enantiomeric bicyclic lactones, (+)-lla, (+}-llb and (-)-11c with

an ee of 92, 97 and 91% respectively as determined by chiral HPLC (Table 2, entries 1, 3

and 5). Likewise the enantiomeric bicyclic lactones, (-)-lla, (-)-11b and (+)-llc were

synthesized using 0-acetyl quinine32 with an ee of 83, 88 and 95% respectively (Table 2,

entries 2, 4 and 6).

8 "'0 Cbz-N I

Ill~

0

(-)-lla, (-)-llb, (+)-llc

DIPEA (4.0 equiv), lOb (3.0 equiv)

10 mol% 0-Ac Quinine

CH3CN, rt, 30 h condition B (Table 1)

OAc D-Ac quinine

DIPEA (4.0 equiv), Cbz lOb (3.0 equiv) I 10 mol% 0-Ac Quinidine

~Nrr,;C02H -------0 m n CH3CN, rt, 30 h

3a-c condition B (Table 1)

n = m =1, 2,3

OAc

0-Ac quinidine

Cbz-N&_

0

(+)-lla, (+)-llb, (-)-llc

Scheme 8. Catalytic, asymmetric intramolecular NCAL reaction

183

l


Table 2. Ccatalytic, asymmetric intramolecular NCAL reactions

entry bicyclic-,8-lactone %eea %yieldb

55

1 Cbz-N~

92 65 15 0

(+)-lla

SR

2 Cbz-N:J'''t

83 ····~ 66 1R O

(-)-lla

Cb,,~ N 0

3 65 0 97 63

(+)-llb

Cbz, ~1R N '''0

4 v. .... ~ 88 67 6R O

(-)-llb

5 ffi 1N 1s O

Cbz 91 51

(-)-llc

6

df .. o ""~

1N 1R O 95 53

Cbz (+)-llc

a enantiomeric excess was determined by chiral HPLC

bisolated yields

The (15,55) configuration of bicyclic lactone (+)-lla was confirmed by its

reduction with DIBAL-H to the known Cbz protected (35,4R) 4-

(hydroxymethyl)pyrrolidin-3-ol (13a) in 43% yield which was compared with the

authentic sample ([a]290 +2.01 (c 0.71, MeOH) [lit.33 [af5

0 +2.6 (c 0.835, MeOH)].

184

l


Likewise, (-)-13a could also be obtained from lactone (-)-lla with an overall yield of 45

%which has not been reported in literature so far ([a] 290 -5.00° (c 0.69, MeOH) (Scheme

9}.

4.6. Conclusion

Cbz-NA

15 0 (+)-lla

~OH Cbz-N~

4R OH

{+)-13a

Cbz-N/j~~'? 0·~~·~

lR 0 {-)-lla

~

8~~'0H Cbz-N

""" 45 OH

(-)-13a

Scheme 9. Synthesis of diols

Aza variant of intramolecular catalytic, asymmetric nucleophile-catalyzed, aldol

lactonization (NCAL} reaction has been explored to synthesize ,8-lactone fused nitrogen

hetrocyclics as aza-sugars precursors by employing achiral amino acids. The utility of

these bicyclic fJ -lactones is presented by the formal synthesis of aza-sugars, (35,4R} and

(3R,45} 4-(hydroxymethyl)pyrrolidin-3-ol.

185


4. 7. Experimental

4.7.1. General Methods

All NCAL reactions were done using flame-dried glassware under nitrogen atmosphere.

Acetonitrile (CH3CN), Triethylamine (TEA), N,N-diisopropylethylamine (DIPEA) and

dichloromethane (CH2Cb) were distilled over calcium hydride. Reactions were

monitored by thin layer chromatography (TLC) using 0.25 mm E. Merck pre-coated

(Merch 60 F254) silica gel plates and using ninhydrine or KMn04 as visualizing agent.

Purification was performed by flash chromatography using silica gel (230-400 mesh).

NMR spectra were recorded on a Bruker Advance-300 spectrometer. Chemical shifts are

reported as ppm (delta) relative to TMS as internal standard. Mass spectra were

recorded on LCQ Advantage MAX (ESI) and JOEL JMS-600H (EI/HRMS) mass

spectrometers. IR spectra were recorded on a Perkin-Elmer FT-IR RXI spectrometer.

Microanalytical data were obtained using Vario-EL-111 elemental analyzer. Optical

rotations were determined on an Autopol Ill polarimeter. Chiral HPLC analysis were

performed using Daicel Chiralpak lA column. 7a/9 7b/9 Methyl glycinate.HCI/0 O

Acetylquinidine31 and O-Acetylquinine32 were prepared according to the literature

procedures.

4.7.2. Experimental details

General procedure for N-allylation (Sa-b)

N-allyi-N-benzyloxycarbonyl-f3-alanine (Sa)

To a cooled (0 oq suspended stirred solution of NaH (4.48 g, 112.1 mmol, 60% NaH in

mineral oil) in anhydrous DMF (25 ml) was added a solution of 7a (5.0 g, 22.4 mmol) in

DMF (25 ml) dropwise under nitrogen. Once the hydrogen evolution ceased, allyl

bromide (2.9 ml, 33.6 mmol) was added dropwise into the above heterogenous solution

and stirring was continued for additional 2 h at 0 oc. The reaction mixture was quenched

at same temperature by addition of 1N HCI to become acidic (pH 2); diluted with water

(250 ml) and extracted with ethyl acetate (3 x 80 ml). The combined organic extracts

186


were washed with brine (2 x 40 ml), dried (Na2S04) and concentrated in vacuo. The

resulting crude oil was purified by flash chromatography over silica gel using ethyl

acetate-hexane (3:7) to afford Sa as clear oil (4. 76 g, 80.81%).

Cbz I

~N~C02H Sa

R1 (1:1, EtOAc/Hexane) 0.25; Anal. Calcd: [Found: C, 63.58; H,

6.39; N, 5.12. C13H15N04 requires C, 63.87; H, 6.51; N, 5.32%];

IR (neat, cm-1) 3069, 2928, 1688, 1474, 1419, 1249, 1135,

1104, 1032, 990, 926; 1H NMR (300 MHz, CDCI3) 7.33 (br s, 5H),

5.75-5.77 (br, 1H), 5.13 (br s, 4H), 3.93 (br, 2H), 3.51-3.56 (t, 2H, J 6.9 Hz), 2.59 (br, 2H);

13C NMR (75 MHz, CDCI3) 176.7, 156.1, 136.6, 133.5, 128.6, 128.1, 127.9, 117.0, 67.4,

50.5, 43.4, 36.8; MS (ESI) m/z 263, found 264 [M+Ht.

N-allyi-N-benzyloxycarbonyi-GABA {Sb)

The acid was prepared from 7b (6.0 g, 25.2 mmol), NaH (5.05 g, 126.4 mmol, 60% NaH in

mineral oil) and allyl bromide (3.28 ml, 37.9 mmol) at room temperature in 10 h.

Purification by flash chromatography over silica gel using ethyl acetate-hexane (1:4)

afforded Sb as clear oil (4.8 g, 68.57%).

R1 (3:2, EtOAc/Hexane) 0.3; Anal. Calcd: [Found: C, 64.73; H, Cbz I

~ N~co2H 6.96; N, 5.00. C1sH1gN04 requires C, 64.97; H, 6.91; N,

sb 5.05%]; IR (neat, cm-1) 3020, 2360, 1692, 1597, 1472, 1422,

1216, 1045; 1H NMR (300 MHz, CDCI3) 7.32-7.34 (br m, 5H), 5.76 (br, 1H), 5.13 (br s, 4H),

3.87 (br, 2H), 3.31 (br, 2H), 2.34 (br, 2H), 1.86 (br, 2H); 13C NMR (75 MHz, CDCI3) 178.2,

156.4, 136.7, 133.6, 128.5, 128.1, 127.9, 117.0, 67.4, 49.7, 46.3, 31.2, 23.3; MS (ESI) m/z

277, found 278 [M+Ht

General procedure for mono N-alkenylation {7c-d)

Methyl N-{but-3-enyl)glycinate {7c)

K2C03 (9.39 g, 67.9 mmol) was added to a solution of methyl glycinate.HCI (3.15 g, 35.4

mmol) in CH3CN (150 ml) and the mixture was stirred for 1 h. 4-Bromo-1-butene (3.0 ml,

29.5 mmol) was added to the mixture and the reaction mixture was stirred for 48 h. The 187


insoluble materials were filtered off and the filtrate was concentrated under reduced

pressure. To the residue was added water (150 ml) and extracted with ethyl acetate {3 x

60 ml). The combined organic extracts were washed with brine (2 x 25 miL dried

(Na2S04) and concentrated in vacuo to afford a clear liquid. Purification by flash

chromatography on silica gel using ethyl acetate-hexane (4:6 -710:0) furnished 7c as

clear oil {3.1 g, 73.28%).

R1 (EtOAc) 0.3; Anal. Calcd: [Found: C, 58.82; H, 9.10; N, 9.81. H

~N'-../C02Me C7H13N02 requires C, 58.72; H, 9.15; N, 9.78%]; IR (neat, cm-1)

3020, 1743, 1634, 1437, 1215; 1H NMR (300 MHz, CDCI3)

5.74-5.88 (m, 1H), 5.05-5.15 (m, 2H), 3.74 (s, 3H), 3.44 (s, 3H), 2.67-2.72 (t, J = 6.9 Hz,

7c

2H), 2.24-2.31 (q , J = 6.9, 13.8 Hz, 2H); 13C NMR (75 MHz, CDCb) 172.9, 136.1, 166.6,

51.8, 50. 7, 48.5, 34.3; MS (ESI) m/z 143, found 144 [M+Ht

Methyl N-(pent-3-enyl)glycinate (7d)

7d was prepared from methyl glycinate.HCI (3.15 g, 35.4 mmol), K2C03 {9.39 g, 67.9

mmol) and 5-Bromo-1-pentene {3.5 ml, 29.5 mmol). Purification by flash column

chromatography on silica gel using chloroform as eluant isolated 7d as clear oil {3.16 g,

68%);

Rt (CHCI3) 0.3; Anal. Calcd: [Found: C, 61.01; H, 9.28; N,

8.93. C8H15N02 requires C, 61.12; H, 9.62; N, 8.91%]; IR

(neat, cm-1) 3020, 2933, 1740, 1639, 1439, 1217; 1H NMR

{300 MHz, CDCI3) 5.76-5.89 (m, 1H), 4.96-5.07 (m, 2H), 3.74 (s, 3H), 3.42 (s, 3H), 2.60-

H ~N'-../C02Me

7d

2.65 (t, J = 7.1 Hz, 2H), 2.08-2.15 (q, J = 7.1, 14.4 Hz, 2H), 1.56-1.66 (m, 2H); 13C NMR (75

MHz, CDCI3) 173.1, 138.4, 114.8, 51.8, 50.8, 49.1, 31.4, 29.2; MS (ESI) m/z 157, found

158 [M+Ht

General procedure for one pot Cbz protection and hydrolysis of ester (Se-d)

N-(benzyloxycarbonyi)-N-(but-3-enyl)glycine (8c)

To a cooled (0 oq stirred solution of 7c (2.63 g, 18.3 mmol) and TEA (5.63 ml, 40.4

mmol) in anhydrous CH2Ch (45 ml) was added Cbz-CI (2.97 ml, 21.2 mmol) dropwise 188


under nitrogen. The clear yellow solution was warmed to room temperature and stirred

for 2 h, at which point the volatiles were removed under reduced pressure to afford

yellow oil. The crude oil was then dissolved in THF/H 20 (4:1, 50 ml) with stirring

followed by the addition of liOH.H20 (2.31 g, 55.1 mmol) at room temperature. After

stirring for 2 h, the reaction mixture was diluted with water (30 ml) and extracted with

ether (2 x 35 ml). The pH of aqueous layer was adjusted to 2-3 by the addition of dilute

hydrochloric acid (1:1) at 0 oc and extracted the liberated oil with ethyl acetate (4 x 50

ml). The combine organic extracts were washed with brine (2 x 45 ml) and dried

(Na2S04). Removal of the solvent in vacuo gave the analytically pure product Sc as clear

oil (4.38 g, 90.6%).

R1 (7:3, EtOAc/Hexane) 0.35; Anal. Calcd: [Found: C, 63.76; H, Cbz I

~ N~co2H 6.40; N, 5.12. C14H11N04 requires C, 63.87; H, 6.51; N, 5.32%];

8c IR (neat, cm-1) 3020, 2361, 1696, 1475, 1431, 1367, 1217, 1149;

1H NMR (300 MHz, CDCI3) 7.27-7.37 (br m, 5H), 5.72-5.78 (m, 1H), 5.03-5.19 (m, 4H),

4.06 (br, 2H), 3.43 (br, 2H), 2.32 (br, 2H); 13C NMR (75 MHz, CDCI3) 174.5/174.3

(rotamers), 156.8/156.0 (rotamers), 136.4/136.3 (rotamers), 135.0/134.8 (rotamers),

128.57/128.51 (rotamers), 128.1/128.0 (rotamers), 127.8/127.7 (rotamers), 117.2/117.0

(rotamers), 67.7/67.5 (rotamers), 49.4/48.9 (rotamers), 48.4/48.0 (rotamers), 32.9/32.4

(rotamers); MS (ESI) m/z 263, found 264 [M+Ht

Cbz N-(benzyloxycarbonyi)-N-(pent-3-enyl)glycine (Sd) I

~N~C02H Clear oil (78.8%); Anal. Calcd: [Found: C, 64.73; H, 6.77; N,

8d 4.99. C15Hi9N04 requires C, 64.97; H, 6.91; N, 5.05%]; R1

(1:9, MeOH/CHCI3) 0.3; IR (neat, cm-1) 2935, 2363, 1699, 1470, 1433, 1221; 1H NMR

(300 MHz, CDCI3) 7.28-7.37 {m, 5H), 5.71-5.83 (m, 1H), 4.96-5.19 (m, 4H), 4.02-4.07 (d, J

= 12.6 Hz, 2H), 3.33-3.40 {m, 2H), 2.01-2.12 (m, 2H), 1.30-1.68 (m, 2H); 13C NMR (75

MHz, CDCI3) 175.2/174.8 (rotamers), 156.9/156.0 (rotamers), 137.8/137.6 (rotamers),

136.4, 128.6, 128.2/128.1 (rotamers), 127.9/127.8 (rotamers), 115.3/115.2 (rotamers),

189


67.8/67.6 (rotamers), 49.1/48.7 (rotamers), 48.5/48.0 (rotamers), 30.9/30.8 (rotamers),

27.5/27.1 (rotamers); MS (ESI) m/z 277, found 278 [M+Ht

General procedure for ozonolysis as described for 9a

Ozone was bubbled through a cooled (-78 oq solution of 8a (3.2 g, 11.0 mmol) in 75 ml

of anhydrous CH2Cb for 1 h. After that, a stream of argon was passed through the

cooled solution for 30 min to eliminate the excess of ozone. The cooled reaction mixture

was then quenched with excess of Me2S (3.57 ml, 48.6 mmol), allowed to warm up to

room temperature and treated with cold water (40 ml), extracted with CH2CI2 (3 x 45

ml), dried (Na2504) and concentrated in vacuo to obtain the aldehyde 9a (2.59 g, 80.4%}.

· Similarly 9b-d were obtained from 8b-d in 81-82% and were used immediately for NCAL

reaction without any further purification

G1 N G Br I -

OTf

N-methyl-2-bromopyridinium triflate (lOb)

Pyridinium salt lOb was prepared from 2-bromopyridine (2.0 ml, 20.9

mmol) and methyl trifluoromethanesulfonate (2.3 ml, 20.9 mmol) in

lOb CH2Cb (10 ml) according to the literature method5 as white crystalline

solid (6.46 g, 96%}; mp 158-160 oc; IR (KBr, cm-1) 3087, 1616, 1491, 1443, 1267, 1156,

1032; 1H NMR (300 MHz, CDCI3+CD30D) 9.10-9.12 (d, J = 5.2 Hz, 1H), 8.27-8.40 (m, 2H),

8.0-8.05 (m, 1H), 4.48 (s, 3H); 13C NMR (75 MHz, CDCI3) 149.0, 146.3, 133.9, 127.1,

122.5, 118.2, 50.8.

General procedure for the Racemic Aza-NCAL reaction as described for ,8-lactone -(±)

lla

benzyl 7-oxo-6-oxa-3-azabicyclo[3.2.0]heptane-3-carboxylate[(±)-lla]

Condition B: To a stirred solution of Mukaiyama's reagent lOb {1.65 g, 5.13 mmol, 3.0

equiv) and TEA {0.95 ml, 6.85 mmol, 4.0 equiv) in CH3CN (30 ml) at 25 oc was added via

syringe pump a solution of aldehyde-acid 9a {0.45 g, 1.71 mmol) in CH3CN (20 ml) over a

190


period of 3 h. Stirring of the resulting dark red solution was continued for another 12 h.

The volatiles were removed under reduced pressure and to the crude reaction mixture

was added ethyl acetate (150 ml) and saturated aqueous NH4CI (150 ml). The phases

were separated, and the aqueous layer was extracted with ethyl acetate {2 x 50 ml). The

combined organic phases were washed with brine {100 ml), dried (NazS04), filtered, and

concentrated to afford a brown residue. Purification of the crude residue by flash

chromatography on Si02 using ethyl acetate-hexane (13:7) afforded the ,B-Iactone lla

as light yellow oil {0. 7 g, 76.07%).

Cbz-N:q 1 0

{±)-lla

R1 (7:3, EtOAc/Hexane) 0.35; Anal. Calcd: [Found: C, 63.23; H,

5.41; N, 5.65. C13H13N04 requires C, 63.15; H, 5.30; N, 5.67%]; IR

(neat, cm-1) 1836, 1705, 1423, 1356, 1261, 1227, 1187, 1114; 1H

NMR (300 MHz, CDCI3) 7.32-7.40 (SH, m, ArH), 5.15 (2H, br s,

PhCH2), 5.09-5.12 (1H, dd, J 4.0, 5.9 Hz, H-5), 4.23-4.28 {2H, br m, H-2+H-4), 4.08-4.12

{1H, m, H-1), 3.29-3.35 {2H, m, H-2'+H-4'); 13C NMR (75 MHz, CDCI3) 168.6 (C=O,

lactone), 155.0 (C=O, carbamate), 136.1 (qC), 128.5, 128.2, 128.0 (ArC), 74.9/74.3 (C-5,

rotamers), 67.5 (PhCHz), 56.1/55.4 (C-1, rotamers), 49.6 {C-4), 45.6 (C-2); HRMS (ESI}:

calcd for C13H14N04 [M+Ht 248.0922, found 248.0919.

benzyl 7 -oxo-8-oxa-3-azabicyclo[ 4.2.0]octane-3-carboxylate[(±}-11b]

This lactone was prepared from oxo-acid 9b (0.286 g, 1.02 mmol), pyridinium salt lOb

{0.989 g, 3.07 mmol), TEA {0.49 ml, 3.55 mmol). Purified by flash column

chromatography using ethyl acetate-CH2CI 2 (7:93) as eluant isolated llb as clear viscous

oil (0.19 g, 71.16%).

cbz,~r9 ~ 6 0

{±)-llb

Rt {1:9, Et0Ac/CH2CI2) 0.5; Anal. Calcd: [Found: C, 64.24; H, 5.81;

N, 5.34. C14H1sN04 requires C, 64.36; H, 5.79; N, 5.36%]; IR (neat,

cm-1) 1826, 1698, 1421, 1353, 1290, 1224, 1117, 1052; 1H NMR

{300 MHz, CDCI3) 7.34 (SH, br s, ArH), 5.08-5.21 (2H, m, PhCH2),

4.74-4.80 (1H, br d, J 15.6 Hz, H-1), 4.42-4.47 {0.5 H, d, J 15.6 Hz, H-2, rotamers), 4.32-

191


4.37 {0.5 H, d, J 15.6 Hz, H-2, rotamers), 3.82-3.87 (1H, m, H-6), 3.67-3.69 {1H, br, H-4),

3.46-3.56 (1H, td, J 4.5, 12.6 Hz, H-4'), 3.36-3.41 {1H, d, J 15.6 Hz, H-2'), 2.09-2.18 {1H,

app t, J 15.5 Hz, H-5), 1.89-2.02 (1H, m, H-5'); 13C NMR (75 MHz, CDCI3) 169.6 (C=O,

lactone), 155.8 (C=O, carbamate), 136.4 (qC}, 128.6, 128.2, 127.9 (ArC}, 69.1/68.7 {C-1,

rotamers), 67.5 (PhCH2), 47.6 (C-6), 42.0/41.5 (C-2, rotamers), 39.9 (C-4), 19.7 (C-5);

HRMS (ESI): calcd for C14H16N04 [M+Ht 262.1079, found 262.1080.

benzyl 7-oxo-8-oxa-2-azabicyclo[4.2.0]octane-2-carboxylate[(±}-11c]

This lactone was prepared from oxo-acid 9c (0.225 g, 0.84 mmol), pyridinium salt lOb

(0.819 g, 2.54 mmol), TEA (0.47 ml, 3.39 mmol). Purified by flash column

chromatography using ethyl acetate-CH2CI2 {1:49) as eluant isolated llc as viscous oil

(0.114 g, 55%).

Rt (1:9, EtOAc/CH2Cb) 0.6; Anal. Calcd: [Found: C, 63.05; H, 5.39; N,

5.61. C13H 13N04 requires C, 63.15; H, 5.30; N, 5.67%]; IR (neat, cm-1)

1837, 1708, 1422, 1347, 1306, 1266, 1216, 1108, 1059; 1H NMR {300

MHz, CDCI3) 7.32-7.36 (5H, m, ArH), 5.53-5.65 (1H, br, H-1), 5.15-5.17

(3H, m, PhCH2+H-5), 4.12-4.19 (1H, app t, J 9.7 Hz, H-3), 3.37-3.46 (1H, td, J 6.2, 11.5 Hz,

H-3'), 2.29-2.36 {1H, dd, J 6.2, 14.8 Hz, H-4), 1.87-2.00 (1H, m, H-4'); 13C NMR (75 MHz,

CDCI3) 166.7 (C=O, lactone), 153.3 (C=O, carbamate), 135.9 (qC}, 128.7, 128.4, 128.2

(ArC}, 77.8 (C-5), 70.2/69.8 (C-1, rotamers), 67.9 (PhCH2), 44.0 (C-3), 29.1 (C-4); HRMS

(ESI): calcd for C13H13NNa04 [M+Nat 270.0737, found 270.0741.

benzyl 8-oxo-7-oxa-2-azabicyclo[4.2.0]octane-2-carboxylate[(±}-11d]

This lactone was prepared from oxo-acid 9d {0.41 g, 1.46 mmol), pyridinium salt lOb

{1.418 g, 4.4 mmol), TEA {0.81 ml, 5.87 mmol). Purified by flash column chromatography

using ethyl acetate-hexane (3:7) as eluant isolated lld as viscous oil {0.202 g, 53%). Rt

(1:1, EtOAc/Hexane) 0.45; Anal. Calcd: [Found: C, 64.29; H, 5.65; N, 5.39. C14H15N04

requires C, 64.36; H, 5.79; N, 5.36]; IR(neat, cm-1) 1832, 1703, 1418, 1310, 1216, 1114,

1037; 1H NMR {300 MHz, CDCI3) 7.35 {5H, br s, ArH), 5.80-5.82 {0.5H, d, J 6.6 Hz, H-1,

192


()to I Cbz

(±)-lld

rotamersL 5.58-5.60 (O.SH, d, J 6.6 Hz, H-1, rotamersL 5.12-5.22 (2H,

m, PhCH2), 4.97 {1H, br s, H-6), 3.68-3.72 (1H, dd, J 3.6, 11.8 Hz, H-3),

3.36-3.41 (1H, m, H-3'}, 2.26-2.30 {1H, d, J 12.6 Hz, H-4), 1.80-1.99

(3H, m, H-5+H-5'+H-4'); 13C NMR (75 MHz, CDCI3) 170.5/169.9 (C=O,

lactone, rotamers), 155.7/154.6 (C=O, carbamate, rotamers), 136.0 (qC), 128.6, 128.4,

128.1 (ArC), 72.1/71.9 (C-6, rotamers), 68.1/68.0 (PhCH2, rotamers), 59.7/59.5 (C-1,

rotamers), 43.0/42.9 (C-3, rotamers), 25.9 (C-4), 16.1/15.8 (C-5, rotamers); HRMS (ESI):

calcd for C14H1GN04 [M+Ht 262.1079, found 262.1094.

General procedure for asymmetric Aza-NCAL reaction as described for 13-lactones-(+)

lla

Cbz-N~ 15 0

(+}-lla

(lS,SS)-benzyl 7-oxo-6-oxa-3-azabicyclo[3.2.0]heptane-3-

carboxylate[(+)-11a]

To a stirred solution of 0-Acetylquinidine {71 mg, 0.196 mmoiL

Mukaiyama's reagent lOb {1.895 g, 5.88 mmol) and DIPEA (1.36

ml, 7.84 mmol) in CH3CN {35 ml) was added a solution of aldehyde-acid 9a {0.52 g, 1.96

mmol) in CH3CN {30 ml} via syringe pump over 3 h. After the addition was complete, the

reaction was stirred for additional 30 h at 25 oc. The solvent was removed in vacuo, and

the residue was partitioned between ethyl acetate {150 ml) and saturated NH4CI (100

ml). The phases were separated, and the aqueous layer was extracted with ethyl acetate

(2 x SO ml). The combined organic phases were washed with brine (100 ml), dried

(Na2S04), and concentrated in vacuo. Purification of the crude residue by flash

chromatography on Si02 using ethyl acetate-hexane {13:7) afforded the beta lactone

(+)-lla as light yellow oil {0.315 g, 65%). [af9o +111.4° (c 0.20, CHCI3}. Enantiomeric

excess (ee) was determined to be 92% by chiral stationary phase HPLC analysis using

Daicel Chiralpak lA column (MtBE/EtOH = 99:1, flow rate 0.6 ml/min, Amax 213.9 nm),

t1s,ss = 20.74 min (major), t1R,sR = 22.66 min (minor). All other spectroscopic data

matched that displayed by (±)-lla.

193


cbz,~r9 ( 15,65)-benzyl 7-oxo-8-oxa-3-azabicyclo[ 4.2.0]octane-

3-carboxylate[( +)-Sb]

This lactone was prepared from oxo-acid 9b (0.25 g, 0.89 mmol),

pyridinium salt lOb {0.864 g, 2.68 mmol), DIPEA (0.62 ml, 3.58

mmol) and 0-Acetylquinidine (32 mg, 0.089 mmol). Purification by flash column

~ 65 0

(+)-llb

chromatography on silica gel using ethyl acetate-CH2Cb (7:93) as eluant gave (+}-llb as

viscous oil (0.147 g, 63%). [a]290 +118.r (c 1.09, MeOH). Enantiomeric excess (ee) was

determined to be 97% by chiral stationary phase HPLC analysis using Daicel Chiralpak lA

column (MtBE/EtOH = 99:1, flow rate 0.6 ml/min, Amax 209 nm), t15,65 = 20.98 min

(major), t 1R,GR = 32.31 min (minor). All other spectroscopic data matched that displayed

by (±)-llb.

!T-9 }~o

Cbz {-}-llc

(15,SR)-benzyl 7-oxo-8-oxa-2-azabicyclo[4.2.0]octane-2-

carboxylate[(-)-llc]

This lactone was prepared from oxo-acid 9c {0.29 g, 1.09 mmol),

pyridinium salt lOb {1.05 g, 3.27 mmol), DIPEA (0.76 ml, 4.37 mmol)

and 0-Acetylquinidine (40 mg, 0.109 mmol). Purification by flash column

chromatography on silica using ethyl acetate-CH2CI2 (1:49) as eluant gave (-)-llc as

viscous oil (0.137 g, 51%). [a]27 0 -132.4° (c 0.16, MeOH). ). Enantiomeric excess (ee) was


column (MtBE/EtOH = 98:2, flow rate 0.8 ml/min, Amax 213 nm), t1R,ss = 8.82 min (minor),

t 1s,sR = 11.64 min (major). All other spectroscopic data matched that of the racemic

compound (±)-llc

Cbz- N /---?· , ? 0 .... ~

lR Q

(-}-lla

(lR,SR)-benzyl 7-oxo-6-oxa-3-azabicyclo[3.2.0]heptane-3-

carboxylate[(-)-lla]

The lactone was prepared from aldehyde-acid 9a (0.348 g, 1.31

mmol), pyridinium salt lOb {1.268 g, 3.93 mmol), DIPEA (0.91 ml,

5.25 mmol) and 0-Acetylquinine (48 mg, 0.13 mmol) following the procedure as

described for (+)-lla. Purification by flash chromatography on Si02 using ethyl acetate-

194


hexane (13:7) gave the (-)-lla as colorless oil {0.214 g, 66% yield). [a] 29 0 -39.1 o (c 0.44,

CHCI3). Enantiomeric excess (ee) was determined to be 83% by chiral stationary phase

HPLC analysis using Daicel Chiralpak lA column (MtBE/EtOH = 99:1, flow rate 0.6 ml/min,

"-max 213.9 nm), t 15,55 = 20.56 min (minor), t1R,SR = 22.42 min (major). All other

spectroscopic data matched with (±)-lla.

Cbz,OlR N '"0

""~ 6R 0

(-)-llb

( 1R,6R)-benzyl 7 -oxo-8-oxa-3-azabicyclo[ 4.2.0]octane-3-

carboxylate[(-)-llb]

This lactone was prepared from oxo-acid 9b {0.195 g, 0.698

mmol), pyridinium salt lOb {0.674 g, 2.09 mmol), DIPEA {0.48 ml,

2.79 mmol) and 0-Acetylquinine {25 mg, 0.069 mmol). Purification by flash column

chromatography on silica gel using ethyl acetate-CH2Cb {7:93) as eluant gave (-)-llb as

viscous oil (0.12 g, 67%). [a] 290 -63.3° (c 1.11, MeOH). Enantiomeric excess (ee) was


column (MtBE/EtOH = 99:1, flow rate 0.6 ml/min, "-max 209 nm), t15,65 = 20.05 min

(minor), t1R,GR = 33.36 min (major). All other spectroscopic data matched with the

racemic compound (±)-llb

(j~"O

""~ N lR 0 cb.f

(+)-llc

( lR,SS)-benzyl 7-oxo-8-oxa-2-azabicyclo[ 4.2.0]octane-2-

carboxylate[(+)-11c]

This lactone was prepared from oxo-acid 9c (0.2 g, 0.753 mmol),

pyridinium salt lOb {0.728 g, 2.26 mmol), DIPEA {0.52 ml, 3.01 mmol)

and 0-Acetylquinine (27 mg, 0.075 mmol). Purification by flash column chromatography

on silica using ethyl acetate-CH2Cb (1:49) as eluant gave (+)-llc as viscous oil {0.098 g,

53%). [a]280 +67.r (c 0.37, MeOH). Enantiomeric excess (ee) was determined to be 95%

by chiral stationary phase HPLC analysis using Daicel Chiralpak lA column (MtBE/EtOH =

98:2, flow rate 0.8 ml/min, A-max 213 nm), t1R,ss = 8. 76 min (major), t1s,sR = 11.63 min

(minor). All other spectroscopic data matched with the,racemic compound (±)-llc

195


(35,4R) N-benzyloxycarbonyl-4-( hydroxymethyl)pyrrolidi n-3-ol [ ( + )-13a]

To a magnetically stirred solution of (+)-lla {0.17 g, 0.687 mmol) in CH2CI2 (5.3 ml) was

added dropwise a solution of DIBAI-H {1.0 M in toluene, 0.738 ml, 0.742 mmol) at 0 °C.

After 5 min, the solution was warmed to room temperature and stirred overnight. The

reaction mixture was then cooled to 0 oc, diluted with ethyl acetate (2.4 ml) and

quenched with acetone {1.5 ml) and Rochelle's salt (4.0 ml). The mixture was vigorously

stirred at 25 oc for 10 h. The layers were separated and the aqueous layer was extracted

with ethyl acetate (2 x 4 ml). The combined organic layers were washed with brine (8

ml), dried over Na2S04, filtered, and concentrated in vacuo. Purification by flash

chromatography on Si02 using MeOH-ethyl acetate (1:9) gave the dial (+)-13a as

colorless oil (74 mg, 43.19% yield).

Cbz-N~ 4R OH

(+)-13a

Rt {1:9, MeOH/EtOAc) 0.3; Anal. Calcd: [Found: C, 62.23; H, 6.75;

N, 5.52. C13H11N04 requires C, 62.14; H, 6.82; N, 5.57%]; IR (neat,

cm-1) 3389, 2920, 1682, 1433, 1358, 1216, 1136, 1097; [a] 29

0

+2.01 (c 0.71, MeOH) [lit.6 [a] 250 +2.6 (c 0.835, MeOH)]; 1H NMR

(300 MHz, CDCI3) 7.28-7.32 (SH, m, ArH), 5.04-5.14 (2H, m, PhCH2), 4.41 {1H, br s, H-3),

3.78-3.83 {2H, t, J 7.8 Hz, CH20H), 3.44-3.56 (3H, m, H-2+H-2'+H-5), 3.32-3.39 (1H, t, J

10.5, H-5'), 2.28-2.29 (1H, br, H-4); 13C NMR {75 MHz, CDCI3) 155.5 (C=O), 136.8 (qC),

128.6, 128.1, 127.9 (ArC), 72.3/71.5 (C-3, rotamers), 67.1 (PhCH2), 60.3 (CH20H),

55.2/54.9 (C-2, rotamers), 45.9/45.6 (C-5, rotamers), 45.1/44.3 (C-4, rotamers); MS (ESI)

m/z 251, found 252 [M+Ht; HRMS (ESI): calcd for C13H18N04 [M+Ht 252.1235, found

252.1216.

{3R,4S) N-benzyloxycarbonyl-4-(hydroxymethyl)pyrrolidin-3-ol [(-)-13a]

Cbz-N~ 4s OH

(-)-13a

The dial was prepared from lactone (-)-lla (0.142 g, 0.574 mmol)

and DIBAI-H {1.0 M in toluene, 0.618 ml, 0.62 mmol). Purification

by flash chromatography on Si02 using MeOH-ethyl acetate (1:9)

gave the dial (-)-13a as colorless oil {58 mg, 44.16% yield). [a]290 -

5.0° (c 0.69, MeOH). All other spectroscopic data matched with dial (+)-13a.

196

Aza variant of intramolecular NCAL reaction

4.8. Spectral data

7.5 7.0 6.5 6.0 5 . .1 5.0 4.5 4.0

1~1 1~( ~slisl 3.5 3.0

!5(

1H NMR, 300 MHz, CDC!,

;--.,:... Cbz-N~

' "o (.:!)-11a

2.5 2.0 1..1

Figure 5. 1H-NMR of lactone (t}-lla

J). x. Dibb.it .bl'MPY-91

"""'' i-4-01

C.ta Collect...S oct eckUOD·i.Don.~OO

kehiw 4inct.ozyl

j:~i --~ ,1

---:<:::::::=J- '

5

J 6

8

9

10

- 0

180 160 140 120 100 80 60

Fl (ppml

Figure 6. 1H-13C-HSQC of lactone (t)-lla 197

Chapter4

1.0 0.5 ppm

- 0 0

1H-13C-HSQC, 600 MHz, CDCI3

Cbz-N:f:J 1 "-·o

(±)-11a

40 20 0


1 H NMR, 300 Mz. CDCI3

Cbz, ~

tJ.J:o (±)-11b

7.5 7.0 6.5 M ~ ~ ~ U ~ ~ 2.5 2.0 1.5 1.0 0.5 ppm

I~( I~( i§( ~s( \§~§~~~~ 1sns(

Figure 7. 1H-NMR of lactone (:!)-11b

0

20

40

60

80

100

1H-13C, HSOC, 300 Mz, CDCI3 120

Cbz, /"....' N ro ~~'

0 140 (±)·11b

8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm

Figure B. 1 H-13 C-HSQC of lactone (:!)-11b

198


f""'-C\ '.0~QCV'lC'.t"-N V'lM t-\Otr. \CV'l---..n.r. or) or;..,.;

\1 \V 1H NMR, 300 Mz, CDCia

CON'"' I

1 Q

Cbz (±)-11c

8.0 7.5 7.0 6.5 6.0 5.5 5.0

)~( I~( I~( ~.5 ~.0

~3( 2.5 1.0 .1.5 1.0 0.5 0.0

ls(~s(

Figure 9. 1H-NMR of lactone (t)-llc

0

1 H-13C HSQC. 300 Mz. CDC!3

rt N:q, I Q

Cbz (±)-11c

r r··-~~ , .....,~·······T··--···...,---~~ ·"·····-T·~~....,.,..,---.,-.~r···~·~r~-~..,...~

Chapter4

ppm

8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm

Figure 10. 1H-13C-HSQC of lactone (t)-11c

199


--

-

--

-

~ '"' I

I 1H NMR, 300 Mz, CDC~

cu N , ~ ' 0

Cbz

(±)-11d

g~~~~~~~~~ ~<:"I ""'~ 0\ 0\ ~ :-.e te ::A; r-i ri...:.....;,..;:-'-' _;-'...:

75 7J) tl.5 (1.0 5.5 5.0 4.5 4.0 3.5 3.1! 2.5 2.0 1.5

I~(

J

.. I

1~1 l~nsl lsi Is( !~( ~~(

Figure 11. 1 H-NMR of lactone (t)-11d

A A ~ A.A JL.I\ J

-- -.. -

•

Figure 12. 1H-13C-HSQC of lactone (t)-11d 200

Chapter4

1.0 0.5 ppm

1H-13C HSQC, 300 Mz,

c;q'o 0P" Cbz

(+)-11d

'.:;.v

' ::n

'


7.5 7.0

I~(

"l .,., ~

160 150

1 H-NMR, 300 MHz, CDCI,

6.5 6.0

N .,-,oo

"' \0 -a-. ._; oOoOt' ::) ~s.!~

\V

140 130

5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0

Is( i§( l~rl~('l~( Is( Figure 13. 1H-NMR of diol (+}-13a

120

1H-NMR, 75 MHz, CDC~

3S

Cbz-N:t.:',H

4R OH

(+)-13a

1l0 HXl 90 80 70 60

Figure 14. 13C-NMR of diol (+}-13a

201

Chapter4

cuu'>r•t r:"~c ru"-"""'t.<"'" Nl\.l'e .:h..o:py H~·-!H

f:Xlf:r) 34:': i'lloct<O !

i:'1 · A::q•>iution P<>r<>r.>->t.e:·:. !Jl!l!~- ~t\lCCt~l

h""' ~c.tn l~IS':i't!N "P"C~ i'HO!l"O S ""' Ot-'l" 1!1!1, Pu~.;.·xtx; t.<:3:1 T'' <;.S.>H-so;.,;,·:rNr ~c.lJ

~ ;~ ~lf~. f.~~~-"" llr. l"fi,J<J:'$ C. 09~~/.:1 II<

~ ~-~~5~;~~ ,e;r: :;>;It ij(l,~~:l I'U"::

~~ 2:~ ~~ ~"~" ~G l.Cco:woo•,i-.c

~--····· c;u\.'l:<lr.:, n -···-·· ~EJCl ~H

rJ lL~O "~'"' ?t.l ··L!lO ,..,; srv! !0·~-nH~J-: ¥.H~

~-~ - P~"<.<.:<:,.<lir.<; p~n"""';;e!( !;.l 3~'/11.~

Sf ~00. ~>CCC!! :<iff;:

~~~ ll~ Lll C.C!J)lz cs !: i'C 1.1)!)

1.5 1.0 0.5 ppm

50 40 30 20 ppm


(I

......

1H-13C-HSQC, 300 MHz, CDCI3

Cbz-N~,H "" OH

(+)-13a

Figure 15. 1H-13C-HSQC of diol (+}-13a

202

Chapter4

30

40

50

60

70

80

90

100

110

120

130

140

150


4.9. Chiral HPLC data

CDRI SAIF GLC & HPLC LAB Lucknow

SAMPLE INFORMATION

Safll)leNarrc: SanpleType: Yiat kljectX)t;lt hleet!onVOk.!rre: ~nTi:Te:

OMJY·4C2 lklld'.,OW'r. 14 1 3.00ul 30.0Mnu!es

·············

Acq>.nred 8"/. RK_AII'Shottam SarrpteNarre £lM""f -4C 2

Acq. tl.etl'lod Set a<D_fwElHOD P."oeessina l~ttlod: Lifter A Ol'.tnnel ~ 213.9nm

Date Acqu;rea: 612412010 3:57:12 FM 1ST Date A'ocessed: 512-4i2010 4'34:13 PfA 1ST

0.050·!

o.o.~oj I

' oooo)

<. 0.0'20

o.o;o

Peak Results ........... , •••••••••••• y ............. ,

... :~~ .. ~=-~-~.~-~+ ~ .. ~.,' 1913409:569:.\.4: S0.2'J'

DAICEL CHIRAL PAK lA COLUMN, MtBE'EtOH = 99: I, FLOW RATE 0.6 mL/min, A...x 213.9 nm

Figure 16. HPLC of lactone-(!:}-11a


SAMPLE INFORMATION

.. ,.."""'. Sarmlelype: Vial: njectiOnii: tJie<:tionVoturre Runfr.oo:

DIM'Y-58 lk'lkr,owo

" 1 .'iOOu! 30.0Mnutes

O:lte Acqurred; 5124rlQ10 5:04:34 PM 1ST Date Rocessed: 512412010 5:~:47 Ftf. 1ST

,.,,.,,,

AcqulredBy: RK_F\Jishoftam

Safl1)ieNarre DM'Y-58

Acq. Method Set: 0<0_ ~ Processi'lp tkttloc1 LMer A

21:3.9nm

Auto-5cated Chromatogram

-~-~~~Etts R '!" I Ar.l ~ l<•:gM ~ "4 Ar•a"1

DAICEL CHIRAL PAK lA COLUMN, MtBE'EtOH = 99: I, FLOW RATE 0.6 rnUmin, 1.,., 213.9 nm

Figure 17. HPLC of lactone-(+}-11a

203

Chapter4


SarrpeNarre: 1 Sarllie Type:

Vial

CDRI SAIF GLC & HPLC LAB Luck now

SAMPLE INFORMATION

IJIW(.68 ~own 12

Ac:p!redBy: Sarrpie:i'e!Tl!'C».f'Y-68

RK_A.Jrshottum

tlje(:tion# nieclionVo!urre:

1 A.cq, Method Set: O<.D_~.£n-oo

3.00ul Aocessirv Method Uter A Rmrrne. 30.0 tMli!es 0\anr.e! Narre: 213 Snm

Ootle Acquired: 612412010 4:29.51 PM 1ST O!teA'"ocessed. 6l24o'20105:1t30PMIST

Auto-Scaled Chromatogram

~- ··~· """¥

2.0!1 400 soo a.OO 1o·oo 12.00

Arn : H~illht!%Arta! t···s;;.;;;-r·25ii(i;4~ "-5<'' ~-a_~:;:oo;·t:znii!/ 9145!

DAICEL CHIRAL PAK lA COLUMN, MtBE/EtOH = 99: I, FLOW RATE 0.6 mL/min, Am, 213.9 nm

Figure 18. HPLC of lactone (-)-11a


SAMPLE INFORMATION

Sa!TJiei'G:Te: Df..p( ... 78 A:quired By: RK_F\:fsbottam Sarrp!e Type: lklknoWn Viat 15

SiltTpleN<ure Ot..PY -78

tljeeboo# 1 ~!eCticn Vobre: 3.00 lJI

Acq. ~.-lethod Set O<D_NETI-00 A"~esshQ Metnod: Uter A

Run rrne: 45.0 Mnl.lte$ Olannei Nan-e: 209 0nm

OateAcquired: S125120102.i4:59PMIST Date Processe-d: &'25'2010 3:C-5:53 RA 1ST

Aut<>-Sca1ed Chromatogram

Cbz ... /"-.....'

~ 0

(±~11b

DAICEL CHJRAL PAK lA COLUMN, MtBE!EtOH = 99: I, FLOW RATE 0.6 mUmin, '-m, 209 nm

Figure 19. HPLC of lactone (t}-11b

204

Chapter4


&urp!flf'.brre SarrpleType: v:a1 ~;j.ection::::. lnieclionVoltJ:ne· RunT1rre


SAMPLE INFORMATION

flt-.PY-9 Unknov1n 1T

' 3.00ul

Acquired By: RK_Purshcttam Sa~1N3rre Ot-.Pf -9

Acq. f/ett:od Set: CKO_fE:'t-ro Ftocessir!Q !>.-\11hod: Utef A

45.0 Mm.rtes O'lannel Narre: 2G9 Onm

euteAcquired 6!25/20101:11:19tlvl1ST DateA'~sed: 6J25..'20102:·1841 FMIST

Auto-Scaled Chromatogfam

DAICEL CHIRAL PAK lA COLUMN, MtBEIEtOH = 99: I, FLOW RATE 0.6 mL/min, J..""" 209 nm

Figure 20. HPLC of lactone (+)-11b

-t·t ..

& ..

Sarrplef'.arre $arrpleType: V13l: hjection#: hieCIIOnVofurre: RunTrne.


SAMPLE INFORMATION

01.\!py'-8 !Jfl.kncWn

16

' 3.00<11 4~.0Mnutea

Acquiri:1d By: RK_P.Jr5;hottam Sarrple~.Brre!l.\'P!'-8

~cq. Method Set EKD _ :\t:1!-00 FtocesSir:~ f.1ethod: Litter J.. Ct'.armel Narre: 209.01'\m

Da+.e Acq:Jil'ed. 6l25120~0 12.2£55 Ft.l! 1ST Dlrte Rocessed· 6/25.'2010 2:40.47 PM 1ST

Auto-Seated Chromatogram

Cbz~Ovt

···~ 6R. Q

(-)-11b

2:ioo· 2~.co so.oo '<>.oo

DAICEL CHIRAL PAK lA COLUMN, MtBEIEtOH = 99: I, FLOW RATE 0.6 mUm in,~ 209 nm

Figure 21. HPLC of lactone (-}-11b

205

Chapter4


Sa!TpleNarre: Sa:rple Type Via!: ~je:::t!o!"#. tliect:onVO~Jme RunTI('I"e:


SAMPLE INFORMATION

Dif.JPY-01~A Unlc'la.vn 8 1 4.00u! 300/..tnutes

k:r:;uired By R!<_F\.tmhOiiam San-pleNa!reOM"'¥·C1.A

Aeq ~hod Set O<..O_~,aroo

A"OCe$SinQ ~/elhod Lilt~ A

Olar:nel Narre. 213.5nm

!l:iieAcq!.:ted: 5123/2010112.9:33AM1Si !)ate M"ocessed: 5.'2312010 12:02:41 A.-liST

Auto-Seated Chrom.rtogram

u.ns-·

/1-o \N~ ' 0 Cbz (±~11c

i i

,.,._, ,! ,,

aoo·!·-··· ···-· ...... fh'-.. .. A -,,'···'tc····{···-~'o:,-················-···············································- __ ··---· __ 1

1<1.00 1'!..00 ' '.,. ~-~ ~ : ~ .. i

22.00 24.00 16.00 2S.OO 30.00

DAICEL CHIRAL PAK lA COLUMN, MtBE!EtOH ~ 98:2, FLOW RATE 0.8 mUmin, \,x 213 nm

Figure 22. HPLC of lactone (t)-11c

Satfl'loe Name: SafrPeType: Vial: r~ieclbn# hjeclionVoJurre: RunTime·

COR! SAIF GLC & HPLC LAB Lucknow

SAMPLE INFORMATION

""""·02 t.r.ia'lown 9 1 •tOOut 30.0Mnutes

Acqu;redB"f RK_A.rrshottam

SarrpleNiirreOWr'-02

Acq. fkt'tod Set O<D_fvETt-00 Rocessin!l f.-P-fhOCI: Uter A

2~3.5nm

DaleAcquired: 6J23120'1012:10:43RAIST t::ate ftocessed €/2"",j/)010 12:56.27 FM 1ST

"' o.oof"··~--

;:,.00 2.0;)

Auto-Scaled Chromatogram

8.GO 1000 12.00

DAICEL CHIRAL PAK lA COLUMN, MtBE!EtOH ~ 98:2, FLOW RATE 0.8 mUmin, \,."' 213 nm

Figure 23. HPLC of lactone (-}-11c

206

Chapter4


CDRI SAIF GLC & HPLC lAB Lucknow

SAMPLE INFORMATION

Salrole Nlrre: DM'Y' -03 Sarri:lleType: ll":IO'lO'Ivn Vial: 10 Fl}<.">C""Jon#. 1 fliectlonVct"Jm;o: -1.00UI ~r. TCTe: 30.0 Mnvtes

Date Acqul"ed: GIT.d2010 12:43:53 PM 1ST ()ate Ro=essect 6/2312010 1·19:22 PM 1ST

.·· ................. ' y··· ·················-------·----

Acquired By: RK_A.:rsnottam Sar.'pleNa:'re [)1,PY -03

Acq. Wett1od Set D<O_r.ErtOO Ftocessma ~ Utter A

Qlanr.el Nan-e: 213.5nm

Auto-Seated Chromatogram , ..................•.................................................

n II

e.oo 10.00 ~$.00 1!J:.OO 20~00 22:00 N:o0

~•m.•tes

DAICEL CHIRAL PAKIA COLUMN. MtBE/EtOH = 98:2, FLOW RAlE 0.8 mUmin, \m 213 nm

Figure 24. HPLC of lactone (+}-11c

207

Chapter4


4.10. References

1. (a) Winchester, B.; Fleet, G. W. J. Glycobiology 1992, 2, 199. {b) O'Hagan, D. Nat.

Prod. Rep. 1997, 14, 637. (c) Stu .. tz, A. E. lminosugars as Glycosidase Inhibitors;

Wiley: Weinheim, 1999. (d) Asano, N.; Nash, R. J.; Molyneux, R. J.; Fleet, G. W. J.

Tetrahedron: Asymmetry 2000, 11, 1645.

2. (a) Karpas, A.; Fleet, G. W. J.; Dwek, R. A.; Petursson, S.; Namgoong, S. K.;

Ramsden, N. G.; Jacob, G. S.; Rademacher, T. W. Proc. Nat/. Acad. Sci., U.S.A.

1988, 85, 9229. (b) Block, T. M.; Xu, X. L.; Platt, F. M.; Foster, G. R.; Gerlich, W. H.;

Blumberg, B. S.;. Dwek, R. A. Proc. Nat/. Acad. Sci., U.S.A. 1994, 91, 2235.

3. Goss, P. E.; Baker, M.A.; Carver J. P.; Dennis, J. W. Clin. Cancer Res. 1995, 1, 935.

4. Watson, K. A.; Mitchell, E. P.; Johnson, L. N.; Son, J. C.; Bichard, C. J. F.; Orchard,

M. G.; Fleet, G. W. J.; Oikonomakos, N. G.; Leonidas, D. D.; Kontou, M.;

Papageorgiou, A. C. Biochemistry 1994, 33, 5745.

5. (a) Davis, B. G.; Brandstetter, T. W.; Hackett, L.; Winchester, B. G.; Nash, R. J.;

Watson, A. A.; Griffiths, R. C.; Smith, C.; Fleet, G. W. J.; Tetrahedron 1999, 55,

4489. (b) Shilvock, J. P.; Wheatley, J. R.; Nash, R. J.; Watson, A. A.; Griffiths, R. C.;

Butters, T. D.; Muller, M.; Watkin, D. J.; Winkler, D. A.; Fleet, G. W. J. J. Chern.

Soc., Perkin Trans. 11999, 2735.

6. Fan, J. Q.; Ishii, S.; Asano N.; Suzuki, Y. Nat. Med. 1999, 5, 112.

7. (a) Li, C. M.; Tyler, P. C.; Furneaux, R. H.;. Kicska, G.; Xu, Y. M.; Grubmeyer, C.;

Girvin, M. E.; Schramm, V. L. Nat. Struct. Bioi. 1999, 6, 582. {b) Miles, R. W.; Tyler,

P. C.; Evans, G. B.; Furneaux, R. H.; Parkin, D. W.; Schramm, V. L. Biochemistry

1999, 38, 13147.

8. (a) Scott, J. D.; Tipple, T. N.;Williams, R. M. Tetrahedron Lett. 1998, 39, 3659; (b)

Scott, J. D.; Williams, R. M. Tetrahedron Lett. 2000, 41, 8413.

9. Asano, N.; Ishii, S.; Kizu, H.; Ikeda, K.; Yasuda, K.; Kato, A.; Martin, 0. R.; Fan, J. Q.

Eur. J. Biochem. 2000, 267,4179-4186.

10. (a) Kuehl, F. A., Jr.; Spencer, C. F.; Folkers, K. J. Am. Chern. Soc. 1948, 70, 2091. (b)

Kobayashi, Sh.; Ueno, M.; Suzuki, R. Tetrahedron Lett. 1999,40, 2175. 208


11. (a) Watanabe, J.; Nakada, N.; Sawairi, S.; Shimada, H.; Ohshima, S.; Kamiyama, T.;

Arisawa, M. J. Antibiot. 1994, 47, 32. (b) Lewis, R. J.; Singh, 0. M. P.; Smith, C. V.;

Maxwell, A.; Skarzynski, T.; Wonacott, A. J.; Wigley, D. B. J. Mol. Bioi. 1994, 241,

128.

12. Gardiner, R. A.; Rinehart, K. L.; Snyder, J. J.; Broquist, H. P. J. Am. Chern. Soc. 1968,

90, 5639-5640.

13. Hohenschutz, L. D.; Bell, E. A.; Jewess, P. J.; leworthy, D. P.; Pryce, R. J.; Arnold, E.;

Clardy, J. Phytochemistry 1981, 20, 811-814.

14. Kakinuma, K.; Otake, N.; Yonehara, H. Tetrahedron Lett. 1972, 2509-2512.

15. Linda M. Mascavage, Qing Lu, Jessica Vey, David R. Dalton, Patrick J. Carroll J. Org.

Chern. 2001, 66, 3621-3626.

16. Evans, G. B.; Furneaux, R. H.; Tyler, P. C.; Schramm, V. L. Org. Lett. 2003, 5, 3639-

3640.

17. Evans, G. B.; Furneaux, R. H.; Lewandowicz, A.; Schramm, V. L.; Tyler, P. C. J. Med.

Chern. 2003,46,5271-5276.

18. Kotian, P. L.; Chand, P. Tetrahedron Lett. 2005, 46, 3327-3330.

19. (a) For a review describing routes to optically active ~-lactones, see: Yang, H. W.;

Romo, D. Tetrahedron 1999, 51, 6403-6434. (b) For a recent excellent advance in

this area, see: Nelson, S. G.; Peelen, T. J.; Wan, Z. J. Am. Chern. Soc. 1999, 121,

9742-9743.

20. (a) Pommier, A.; Pons, J. M. Synthesis 1993, 441-459. (b) For more recent

transformations, see: Yang, H. W.; Romo, D. J. Org. Chern. 1999, 64, 7657-7660

and references cited therein.

21. Wynberg, H.; Staring, E. G. J. Am. Chern. Soc. 1982, 104, 166.

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atoms were required, see: Wynberg, H.; Staring, E. G. J. J. Org. Chern. 1985, 50,

1977-1979. (b) For other activated carbonyl compounds that participate in this

reaction, see: Ramiandrasoa, P.; Guerin, P.; Girault, J. P.; Bascou, P.; Hammouda,

A.; Cammas, S.; Vert, M. Polym. Bull. 1993, 30, 501-508.

209


23. (a) Cortez, G. S.; Tennyson, R. L.; Romo, D. J. Am. Chern. Soc. 2001, 123, 7945. (b)

Purohit, V. C.; Richardson, R. D.; Smith, J. W.; Romo, D. J. Org. Chern. 2006, 71,

4549. (c) Cortez, G. 5.; Oh, S. H.; Romo, D. Synthesis 2001, 1731.

24. Oh, S. H.; Cortez, G. S.; Romo, D. J. Org. Chern. 2005, 70, 2835.

25. (a) Scott, J. D.; Tippie, N. R.; Williams, R. M. Tetrahedron Lett. 1998, 39, 3659-

3662. (b) Knight, D.W.; Lewis, N.; Share, A. C.; Haigh, D. Tetrahedron Asymmetry

1993, 4, 625-628. (c) Ohara, C.; Takahashi, R.; Miyagawa, T,; Yoshimura, Y.; Kato,

A.; Adachib, 1.; Takahataa, H. Bioorg. Med. Chern. Lett. 2008, 18, 181Q-1813.(d)

Quibell, M.; Benn, A.; Flinn, N.; Monk, T.; Ramjee, M.; Wang, Y.; Watts, J. Bioorg.

Med. Chern. 2004, 12, 5689; (e) Sugisaki, C: H.; Carroll, P. J.; Correia, C. R. D.

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Uosaki, Y.; Mori, H.; Yoshida, M.; Ozaki, A. Tetrahedron Lett. 1999, 40, 5227-5230.

(g) Gotschi, E.; Jenny, C. J.; Reindl, P.; Ricklin, F. Helvitica Chimica Acta. 1996, 79,

2219.

26. (a) Jourdant A.; Zhu, J. Tetrahedron Lett. 2000, 41, 7033-7036 (b) Takahata, H.;

Banba, Y.; Ouchi, H.; Nemoto, H.; Kato, A.; Adachi, I. J. Org. Chern. 2003, 68,

3603-3607 (c) Liang, N.; Datta, A. J. Org. Chern. 2005, 70, 10182-10185 (d)

Karjalainen, 0. K.; Passiniemi, M.; Koskinen, A. M. P. Org. Lett. 2010, 12, 1145 (e)

Gryko, D.; Prokopowicza, P.; Jurczaka, J. Tetrahedron: Asymmetry 2002, 13,1103-

1113

27. (a) Kalamkar, N. B:; Kasture, V. M.; Dhavale, D. D. J. Org. Chern. 2008, 73, 3619-

3622 (b) Patil, N. T.; John, 5.; Sabharwalb, S. G.; Dhavalea, D. D. Bioorg. Med.

Chem. 2002, 10, 2155-2160 (c) Steiner, A. J.; $chitter, G.; StOtz, A. E.; Wrodnigg, T.

M.; Tarling, C. A.; Withers, S. G.; Fantur, K.; Mahuran, D.; Paschke, E.; Tropak, M.

Bioorg. Med. Chern. 2008, 16, 10216-10220 (d) Boucheron, C.; Compain, P.;

Martin, 0. R. Tetrahedron Lett. 2006, 47, 3081-3084

28. For a review see: Kacprzak, K.; Gawronski, J. Synthesis 2001, 961-998.

29. Schmuck, C.; Rehm, T.; Geiger, L.; Schfer, M. J. Org. Chern. 2007, 72, 6162-6170.

210

Aza variant of intramolecular NCAL reaction Chapter 4

30. Almeida, J. F.; Anaya, J.; Martin, N.; Grande, M.; Moran, J. R.; Caballero, Ma. C.

Tetrahedron: Asymmetry, 1992, 3, 1431-1440.

31. Waddell, T. G.; Woods, L. A.; Harrison, W.; Meyer, G. M. J. Tennessee Acad. Sci.

1984,59,48-50.

32. Pracejus, H.; Matje, H. J. Prak. Chern. 1964, 195-205.

33. Asahina, Y.; Takei, M.; Kimura, T.; Fukuda, Y. J. Med. Chern. 2008, 51, 3238-3249.

211

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