Stereoselective construction of X-azabicyclo[m.2.1]alkanes by [3+2]-cycloaddition of non-stabilized cyclic azomethine ylides: Synthesis of enantiopure constrained amino acids and formal total synthesis of optically active epibatidine

Article abstract of DOI:10.1016/S0040-4020(02)00322-8

A new and general strategy for the stereoselective construction of X-azabicyclo[m.2.1]alkanes has been developed by the [3+2]-cycloaddition of cyclic azomethine ylides with suitable achiral dipolarophiles. The cyclic azomethine ylides, where the whole of the ylide conjugation is in the ring, have been generated by the sequential double desilylation of the N-alkyl-α,α′-bis(trimethylsilyl) cyclic amines utilizing Ag(I)F as one electron oxidant. The structural rigidity of cyclic azomethine ylides has allowed preferential facial discrimination by the dipolarophile resulting into very good exolendo selectivity. The exolendo selectivity associated with these cycloadditions has been further exploited to access optically pure X-azabicyclo[m.2.1]alkanes by carrying out the cycloadditions with the Oppolzer's acryloyl dipolarophile. Application of this methodology is demonstrated by the construction of few constrained amino acids related to azabicyclic structural framework and the formal total synthesis of optically active epibatidine.

Full text of DOI:10.1016/S0040-4020(02)00322-8

TETRAHEDRON
Pergamon
Tetrahedron 58 32002) 3525±3534
Stereoselective construction of X-azabicyclo[m.2.1]alkanes by
[312]-cycloaddition of non-stabilized cyclic azomethine ylides:
synthesis of enantiopure constrained amino acids and formal total
synthesis of optically active epibatidineq
Ganesh Pandey,p Joydev K. Laha and G. Lakshmaiah
Division of Organic Chemistry ꢀSynthesis), National Chemical Laboratory, Pune 411 008, India
Received 19 November 2001; revised 12 February 2002; accepted 14 March 2002
AbstractÐA new and general strategy for the stereoselective construction of X-azabicyclo[m.2.1]alkanes has been developed by the [312]-
cycloaddition of cyclic azomethine ylides with suitable achiral dipolarophiles. The cyclic azomethine ylides, where the whole of the ylide
conjugation is in the ring, have been generated by the sequential double desilylation of the N-alkyl-a,a0-bis3trimethylsilyl) cyclic amines
utilizing Ag3I)F as one electron oxidant. The structural rigidity of cyclic azomethine ylides has allowed preferential facial discrimination by
the dipolarophile resulting into very good exo/endo selectivity. The exo/endo selectivity associated with these cycloadditions has been further
exploited to access optically pure X-azabicyclo[m.2.1]alkanes by carrying out the cycloadditions with the Oppolzer's acryloyl dipolarophile.
Application of this methodology is demonstrated by the construction of few constrained amino acids related to azabicyclic structural
framework and the formal total synthesis of optically active epibatidine. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
by synthetic chemists.9 In recent years, a resurgence of
interest has also surfaced in the synthesis of structural
derivatives of 1b 3nˆ2) owing to the recognition of their
utility in probing the study of the neurochemistry of cocaine
abuse.10 Anatoxin-a 36),11 the only representative alkaloid
possessing the unusual 9-azabicyclo[4.2.1]nonane skeleton
31c, nˆ3), is shown to have exquisite potency towards the
nAChR.12 Few other ligands such as PHT 37)13 and UB-165
38)14 having the 9-azabicyclo[4.2.1]nonane ring systems
The compounds displaying the X-azabicyclo[m.2.1]alkane
framework 31) are endowed with a variety of biological
activities as they represent an important class of ligands
for the nicotinic acetylcholine receptors 3nAChRs).1 There-
fore, research activities in this area have led to the registra-
tion of several nAChRs ligands of this class.2 For
illustration, 7-azabicyclo[2.2.1]heptane derivatives such as
2 and 3 were shown to have local anesthetic3 and long acting
anticholinergic bronchodilator4 activities, respectively.
Epibatidine 34) an important analgesic, 200±500 times
more potent than morphine with the non-opioid mode of
action, isolated by Daly et al.5 in 1992 from the Ecuadorian
tree frog Epipedobates tricolor, is another important
member of this class of compounds 3Fig. 1). Recent studies
have also suggested that 4 is extremely potent naturally
occurring nicotinic acetylcholine receptor known to date.6
The 8-azabicyclo[3.2.1]octane skeleton 31b, nˆ2) is the
basic structural feature of all the tropane class of alkaloids.7
Cocaine 35) and its synthetic analogues show high binding
af®nity to serotonin 35HT) and nor-epinephrine trans-
porters.8 The profound behavioral and neuronal reinforcing
properties of these alkaloids have attracted serious attention
q This report is Part 11 in this series. For part 10, see ref. 44.
Keywords: non-stabilized; azomethine ylides; constrained; enantiopure.
Corresponding author. Fax: 191-0212-335153;
e-mail: pandey@ems.ncl.res.in
p
Figure 1.
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020302)00322-8

3526
G. Pandey et al. / Tetrahedron 58ꢀ2002) 3525±3534
Scheme 2.
Figure 2.
double desilylation of N,N0-bis-trimethylsilylmethyl
benzylamine 39) initiated by one electron oxidation either
by photoinduced electron transfer 3PET) processes20 or by
using Ag3I)F21 as a one-electron oxidant as shown in
Scheme 1.
were identi®ed as potent nicotinic ligands and have been
shown to possess intermediate potency between 6 and 4
3Fig. 2).
In view of the growing importance of compounds posses-
sing the X-azabicyclo[m.2.1]alkane framework as effective
nAChR ligands, considerable synthetic efforts have been
directed towards the development of new strategies to
synthesize these classes of molecules. As a consequence, a
diverse array of synthetic approaches have been devised to
set-upthe individual basic skeleton of the X-azabicyclo-
[m.2.1]alkane system.15±17 Although few general synthetic
strategies have appeared in the literature18 to build-upthe
basic skeleton 1, they seem to be inappropriate to initiate a
complex total synthesis. Therefore, it was imperative to
envisage the development of an ef®cient and general
approach for the construction of these structural frame-
works.
Based on our continuing interest in this area, we designed
the following general retrosynthetic route 3Scheme 2) for
the construction of structural frameworks of 1 and are
pleased to disclose herein the full details22,23 of the strategy
for the construction of 1 in racemic as well as in optically
pure form and demonstrate the application of this strategy
for the construction of enantiopure constrained amino acids
and for the formal total synthesis of optically pure
epibatidine.
2. Results and discussion
2.1. Synthesis of a,a0-bis-trimethylsilyl cyclic amines
,15)
A closer look at the X-azabicyclo[m.2.1]alkane framework
31) reveals the presence of a a,a0-pyrrolidine ring system
fused to a cyclic amine. As the [312]-cycloaddition of a
non-stabilized azomethine ylide provides a convenient route
for synthesizing a stereo-de®ned pyrrolidine moiety,19
cycloaddition of appropriate cyclic azomethine ylides with
ole®nic dipolarophiles was envisaged to provide an attrac-
tive and general strategy for the construction of 1. Our group
have reported20,21 earlier a very simple strategy of generat-
ing non-stabilized azomethine ylides 3AMY) by sequential
The designed precursors 15 for the generation of 13 were
prepared24 from the corresponding cyclic amines 16 by
following the general reaction sequences as shown in
Scheme 3.
Since generation of the non-stabilized azomethine ylides 13
involves electron transfer processes20,21 of the amine func-
tionality, it was necessary to transform 20a±c into their
corresponding N-alkyl derivatives 15 as no ylide generation
could be achieved directly from 20.
2.2. Construction of racemic X-azabicyclo[m.2.1]alkanes
by [312]-cycloaddition reaction
Phenyl vinyl sulfone 321) was chosen as a suitable dipolaro-
phile for the cycloaddition reaction due to the ease of iso-
lation and puri®cation of the cycloadducts. A typical
cycloaddition reaction involved slow addition of a solution
of 15 in dry DCM to a stirring mixture of Ag3I)F and 21
under an argon atmosphere. The progress of the reaction
was followed by the deposition of silver mirror on the
wall of the reaction ¯ask and the reaction mixture was
allowed to stir for an additional 2 h. The reaction mixture
was ®ltered through a plug of Celite and evaporation of the
Scheme 1.

G. Pandey et al. / Tetrahedron 58ꢀ2002) 3525±3534
3527
patterns of the norbornane system25 where no coupling is
observed between bridgehead and adjacent endo hydrogens
due to a dihedral angle close to 908.
2.3. Construction of optically pure X-azabicyclo-
[m.2.1]alkanes
In spite of the growing interest prevailing in the synthesis of
compounds possessing X-azabicyclo[m.2.1]alkane frame-
works, there remains an absence of a general asymmetric
protocol to construct the basic skeleton. Although, a few
asymmetric approaches to construct the individual basic
skeleton have been reported,26±28 no effort has been made
to provide a general strategy for the asymmetric construc-
tion of these structural frameworks.
Taking advantage of the high exo/endo selectivity in the
cycloaddition of 15 with phenyl vinyl sulfone, we envisaged
that such cycloadditions with a suitable chiral dipolarophile
having excellent facial selectivity may provide a new and
general synthetic methodology to access optically pure
X-azabicyclo[m.2.1]alkanes. As Oppolzer's chiral acryloyl
sultam29 has been used widely as an ef®cient dipolarophile
in asymmetric cycloaddition reactions, we decided to
evaluate the facial selectivity of this dipolarophile in our
[312]-cycloaddition reaction for the construction of 1 in
optically pure form. The dipolarophile 32)-24 was prepared
essentially by following the reported literature30 procedure.
The cyclic AMYs 13, generated from 15 by the reaction of
Ag3I)F in dry DCM as described above, underwent smooth
[312]-cycloaddition reaction with 32)-24 giving rise to
cycloadducts 25 and 26 in 58±68% overall yield. The dia-
stereomeric ratio 3exo/endo) of the cycloadducts was deter-
mined by comparing the integration values of the proton a
Scheme 3. Reagents and conditions: 3a) Boc-N3, Et3N, Dioxan, 90±95%;
3b) TMEDA, s-BuLi, TMSCl, 2788C, 80±90%; 3c) TMEDA, s-BuLi,
TMSCl, 250 to 2308C, 1 h 3nˆ1 and 2), 68±71%; 2408C, 5 h 3for
nˆ3), 62%; 3d) TFA, DCM, quantitative; 3e) PhCH2Cl, K2CO3, CH3CN
3for nˆ1 and 3), 80±85%; HCHO, NaBH3CN, CH3CN, gl. CH3COOH 3for
nˆ2), 80%.
®ltrate gave crude mixture of the cycloadducts. Puri®cation
of the crude residue by silica-gel column chromatography
gave cycloadducts 22 and 23 in 70±75% yield. The dia-
stereomeric ratio of 22/23 was determined by HPLC
analysis and was found to be excellent 3.98% de) in each
case. Pure cycloadducts 22 were obtained by careful column
chromatography 3Scheme 4).
1
to the amide functionality from each H NMR spectrum.
These ylides where all of the ylide conjugation is in the ring,
are rigid and restrict the facial attack of the dipolarophile
resulting in the excellent exo/endo selectivity. The major
cycloadduct 22 was fully characterized and the endo-
relative stereochemistry of H2 in 22 was determined by
detailed H NMR decoupling and H COSY experiments,
thereby indicating the exo-orientation of the phenyl sulfonyl
groupin all the cycloadducts. For illustration, in 22a the
proton H2 at d 3.18 3dd, Jˆ9.4, 4.8 Hz) was found to couple
only with the adjacent two H3exo and H3endo, but not with the
bridgehead H1. This observation is in line with the 1H NMR
The two diastereomers were separated carefully by ¯ash
column chromatography. These cycloadducts were charac-
terized by IR, 1H NMR, 13C NMR, mass and HRMS
1
analyses. It should be noted that the H NMR spectra of
cycloadducts in CDCl3 were not very helpful in establishing
the relative stereochemistry of diastereomeric cycloadducts
due to overlapping signals. Better resolution was
obtained by adding varying amounts of C6D6 in CDCl3.
The relative stereochemistry of the H2 proton in both the
cycloadducts 25 and 26 was con®rmed by a similar analogy
as described earlier. It has been found that in all the major
cycloadducts 25, the H2 proton is endo-oriented, a diagnos-
tic feature for the exo-orientation of the amide functionality
3Scheme 5).
1
1
The success of our asymmetric [312]-cycloaddition
methodology in the chiral synthesis of X-azabicyclo-
[m.2.1]alkanes was evaluated after the hydrolytic removal
of the chiral auxiliary from the major diastereomeric
cycloadducts 25 and measuring the optical rotation of the
corresponding methyl esters. The chiral auxiliary from
cycloadducts 25 was removed by warming with LiOH´H2O
in MeOH/H2O 33:1) for 45 min and the crude acids 27,
thus obtained, were isolated as their corresponding methyl
esters 28 by treating with SOCl2 in dry MeOH at 08C. The
optical purity of 28 was further con®rmed by chiral HPLC
analysis.
Scheme 4.

3528
G. Pandey et al. / Tetrahedron 58ꢀ2002) 3525±3534
Scheme 7.
selectivity for biological receptors/acceptors. Incorporation
of conformationally constrained amino acid analogues such
as X-azabicyclo[m.2.1]alkane amino acids, containing the
pendent side chain of the parent amino acid, to the backbone
of a peptide might produce an effective peptidomimetics. To
date, however, only two such types of peptidomimetics have
been reported.34,35
Scheme 5.
2.4. Synthesis of optically pure conformationally
constrained amino acids
Considering the structural homology of this particular class
of amino acids with the cycloadducts 25, we became inter-
ested in gaining access to a few of these constrained amino
acids to show the diverse synthetic applications of these
cycloadducts. Thus, we approached this problem with a
desire to utilize the major diastereomeric cycloadducts to
generate a few potential peptidomimetic groups that could
be appropriate in solid phase peptide synthesis by virtue of
their rigid and chemically inert structures. The rigidity
inherent in these constrained acids should signi®cantly
bind the conformation of the resultant peptide, thereby
stabilizing the speci®c conformational motifs. Towards
this goal, the major diastereomeric cycloadducts 25 were
®rst hydrolyzed to their corresponding acids that on subse-
quent N-dealkylation gave constrained amino acids 29 as
shown in Scheme 6.
Constrained amino acids are introduced in to the sequences
of bioactive peptides31 to provide local constraints32 for
restricting the rotation of the N±C, C±C3O), C3O)±NH
bonds and side chain conformations by covalent or non-
covalent steric interactions. Such modi®cations are
known33 to improve signi®cantly the physical and pharma-
cological properties of bioactive peptides and peptidomi-
metics including improvement in their af®nities and
Hydrolysis of the amide functionality in the cycloadducts 25
was successfully carried out with LiOH´H2O in MeOH/H2O
33:1), as described in the previous section. N-Debenzylation
of the corresponding acids 27a and 27c was carried out
smoothly, almost in quantitative yield, by hydrogenolysis
using Pd/C and H2 370 psi) in MeOH. N-Demethylation of
the corresponding acid 27b was carried out in 68% yield by
re¯uxing with the a-chloroethyl chloroformate36 in the
presence of N,N,N0,N0-tetramethyl-1,8-naphthalene diamine
followed by re¯uxing with MeOH.
Scheme 6. Reagents and conditions: 3a) LiOH´H2O, MeOH/H2O 33:1),
608C, 45 min 90±95%; 3b) H2 380 psi), Pd/C, MeOH, rt, 90±92% for
nˆ1, 3; a-chloro ethyl chloroformate, N,N,N0,N0-tetramethyl-1,8-naptha-
lene diamine, 1,2-dichloroethane 3for nˆ2), then MeOH, re¯ux, 68%.
2.5. Formal total synthesis of optically active epibatidine
Due to intriguing structural features and important biological

G. Pandey et al. / Tetrahedron 58ꢀ2002) 3525±3534
3529
activities of epibatidine 34), its synthesis has attracted
intense research activities.24,37 All the synthetic strategies
related to the synthesis of 4 involve a key stepof construct-
ing the 7-azabicyclo[2.2.1]heptane framework starting from
different precursors. Remarkably, in spite of the intense
research activities associated with the synthesis of 4,
approaches concerning with its synthesis in optically pure
form are limited.26 However, all these approaches involve
multi-stepreaction sequences and suffer from overall poor
yield.
Having demonstrated the validity of our [312]-cyclo-
addition methodology for the construction of the enantio-
pure X-azabicyclo[m.2.1]alkane framework,23 it was
realized that this novel methodology could be exploited
for the total synthesis of epibatidine 34) in optically pure
form. Towards this goal, we envisaged two complementary
3asymmetric approaches) retrosynthetic approaches as
shown in Scheme 7.
It was envisaged that enantiopure 25a could easily be trans-
formed into a non-racemic 7-azabicyclo[2.2.1]hept-2-ene
system 30 3EWGˆCO2Me/camphor sultamp) 3Route I) on
which the Michael addition of 5-32-chloro) lithiopyridine
would provide an easy access to enantiopure epibatidine.
Since nucleophilic addition in the norbornene system is
known38 to give an adduct with an exo-orientation, it was
reasonable to assume that Michael addition of 5-32-chloro-
lithiopyridine) on to 30 would lead to the correct isomer of
enantiopure epibatidine. Towards this end, the cycloadduct
25a was converted to its corresponding N-Boc derivative
31a following N-debenzylation by stirring with an equal
wt. of Pd/C in HCOOH/MeOH 35:95 by volume).39 It is
interesting to mention that N-debenzylation of 25a by cata-
lytic hydrogenation 3Pd/C, H2 or Pd3OH)2/C, H2) was
unsuccessful. Our attempt to create unsaturation in the
azabicyclic ring involving 33a via incorporating a SePh
group a to the sulfonamide moiety of 25a followed by
oxidative elimination40 failed as we could not convert 31a
to 33a in spite of using a variety of different bases 3e.g.
LDA, KHMDS, etc.) to generate the anion. Alternatively,
we also tried to obtain 30b 3EWGˆCO2Me) via the corre-
sponding 33b, but this approach also failed in spite of our
best effort. Therefore, we decided to abandon this route at
this stage 3Scheme 8).
Scheme 8.
determined by decoupling experiment and 1H COSY
experiment.
The synthetic potential of the major cycloadduct 37 towards
the enantioselective synthesis of epibatidine was visualized
by removing the chiral auxiliary followed by simple
chemical manipulation of the functional groups. Although,
the cycloaddition of the corresponding 35 without a chiral
auxiliary had given the major cycloadduct 36 in which the
2-chloropyridyl moiety was endo-oriented, the reversal of
exo/endo ratio in this case was a pleasant surprise. However,
at this stage we do not have any reasonable explanation for
the formation of compound 37 as the major cycloadduct.
The conversion of 38 3EWGˆCO2Et) to epibatidine has
already been earlier reported24 by us.
In order to pursue the synthesis of enantiopure epibatidine
via Route II, a chiral dipolarophile 32)-35 was ®rst synthe-
sized by a novel Heck-coupling reaction41 of the 2-chloro-5-
iodopyridine42 34 onto Oppolzer's acryloyl chiral dipolaro-
phile 24 3Scheme 9).
A typical cycloaddition reaction of cyclic AMY 13 with the
dipolarophile 32)-35 gave two cycloadducts 36 and 37 with
good exo/endo selectivity 39:1) as shown in Scheme 10.
The two diastereomers were separated by careful ¯ash
column chromatography. They were characterized by IR,
1H NMR, 13C NMR, mass and HRMS analyses. The ratio
of two diastereomeric cycloadducts was determined from
their crude 1H NMR spectrum by comparing the integration
values of H2 and/or H3. The stereochemical orientation of
the amide functionality and the chloropyridinyl moiety was
Scheme 9.

3530
G. Pandey et al. / Tetrahedron 58ꢀ2002) 3525±3534
AC-200, Bruker MSL-300, DRX-500 instruments using
CDCl3 and/or C6D6 as solvent. Chemical shifts are reported
in d. 13C NMR spectra were recorded on Bruker AC-200
and Bruker MSL-300 instruments operating at 50.32 and
75.3 MHz, respectively. Mass spectra were recorded on
Finnigan-Mat 1020C mass spectrometer and were obtained
at an ionization potential of 70 eV. HPLC analyses were
carried out on Perkin±Elmer Model 135C equipped with
Diode-array detector using either Merck Purospher RP-
18e or Daicel Chiralpak OD-R column.
N-Alkyl-a,a0-bis 3trimethylsilyl)-cyclic amines 315a±b)
were obtained from the corresponding N-tert-butoxy-
carbonyl cyclic amines 317) by the strategy reported by us
earlier.24 Compound 15c was also prepared by following the
identical approach. 15c: IR 3neat): 2921, 2850, 1450,
1
1245 cm21. H NMR 3CDCl3, 200 MHz): d 0.05 3s, 18H),
1.58±165 3m, 2H), 1.78±1.98, 3m, 6H), 2.38±2.48 3m, 2H),
3.78 3d, Jˆ13.6 Hz, 1H), 3.88 3d, Jˆ13.6 Hz, 1H), 7.30±
7.45 3m, 5H). 13C NMR 3CDCl3, 50.32 MHz): d 21.5, 27.8,
29.2, 29.6, 51.9, 58.1, 126.5, 127.7, 127.8, 129.8, 141.2. MS
3m/z, relative intensity): 333 3M1, 1), 318 36), 260 3100),
188 338), 91 332), 73 329). Anal. calcd for C19H35NSi2: C,
68.46; H, 10.51; N, 4.20. Found: C, 68.32; H, 10.33; N, 4.11.
4.1.1. [312]-Cycloaddition reaction. A two neck ¯ask,
equipped with a magnetic stir bar and argon gas balloon,
was charged with Ag3I)F 31.3 g, 10.25 mmol) 3dried
previously under vacuum at 408C) and with a solution of
dipolarophile 21 31.03 g, 6.15 mmol) in 30 mL of dry DCM.
Compound 15 34.10 mmol) dissolved in 15 mL of dry DCM
was introduced into the reaction ¯ask drop-wise over a
period of 15 min. The color of the reaction mixture
gradually turned dark brown with the concomitant
deposition of the silver on the surface of the reaction ¯ask
in the form of a mirror and the progress of the reaction was
periodically monitored by TLC. After stirring for 6 h, the
reaction mixture was ®ltered through a small plug of Celite
and the solvent was evaporated to give a brown residue.
Puri®cation of the crude residue by silica gel 360±120)
column chromatography gave 22 with 70±75% cyclo-
addition yield. 22a 3gummy paste): IR 3CHCl3): 3040,
Scheme 10. Reagents and conditions: 3a) Ag3I)F, DCM; 3b) LiOH´H2O,
THF/H2O 33:1), 458C, 1 h, 3c) MeOH, SOCl2.
3. Conclusion
In summary, we have developed a new and general method-
ology for the construction of X-azabicyclo[m.2.1]alkanes in
the racemic as well as in the optically pure form by the
[312]-cycloaddition of cyclic azomethine ylides with a
suitable dipolarophile. The application of this methodology
is demonstrated in the synthesis of conformationally
constrained amino acids and in the formal total synthesis
of enantiopure epibatidine.
1
1230, 1160 cm21. H NMR 3CDCl3, 200 MHz): 1.35±1.45
3m, 1H), 1.72±1.85 3dd, Jˆ9.4, 4.3 Hz, 1H), 1.85±2.15 3m,
3H), 2.18±2.28 3m, 1H), 3.18 3dd, Jˆ9.4, 4.8 Hz, 1H),
3.26±3.38 3m, 1H), 3.40 3d, Jˆ13.5 Hz, 1H), 3.48 3d,
Jˆ13.5 Hz, 1H), 3.76 3d, Jˆ4.8 Hz, 1H), 7.02±7.15 3m,
2H), 7.22±7.35 3m, 3H), 7.47±7.72 3m, 3H), 7.83±8.02
3m, 2H). 13C NMR 3CDCl3, 50.32 MHz): 25.8, 27.2, 33.8,
51.2, 58.8, 61.4, 68.9, 127.1, 128.4, 128.6, 129.2, 129.4,
133.5, 139.1, 139.4. MS 3m/z, relative intensity): 327 3M1,
22), 186 3100), 158 370), 91 368). Anal. calcd for
C19H21NO2S: C, 69.72; H, 6.42; N, 4.28; S, 9.78. Found:
C, 69.56; H, 6.22; N, 4.18; S, 9.54. 22b 3gummy paste): IR
4. Experimental
4.1. General
All reactions requiring anhydrous conditions were
performed under a positive pressure of argon using oven-
dried glassware 31108C) that was dried under argon. All
organic layers obtained from extractions were dried over
anhydrous Na2SO4. Solvents for anhydrous reactions were
dried according to the procedures reported in the literature.43
All the commercial reagents were obtained from Aldrich
Chemical Co. Silica gel for column chromatography was
60±120 or 230±400 mesh obtained from S.D. Fine
Chemical, India or SRL, India. All melting points were
uncorrected in degree Celsius and were recorded on a
Thermonik melting point apparatus. IR spectra were
recorded on a Perkin±Elmer infrared spectrometer model
599-B and model 1620 FT-IR. 1H NMR spectra were
recorded using TMS as internal reference on Bruker
3neat): 3400, 2930, 2880, 1670, 1450 cm21 1H NMR
.
3CDCl3, 200 MHz): 1.46±1.76 3m, 3H), 1.82±2.10 3m,
4H), 2.55 3s, 3H), 2.50±2.65 3dd, Jˆ12.2, 7.3 Hz, 1H),
3.32±3.40 3m, 1H), 3.62 3dd, Jˆ9.7, 7.3 Hz, 1H), 3.75
3bs, 1H), 7.55±7.75 3m, 3H), 7.79±8.20 3m, 2H). 13C
NMR 3CDCl3, 50.32 MHz): 16.9, 27.0, 28.2, 30.8, 38.4,
61.6, 62.3, 69.0, 128.5, 129.3, 133.6, 139.6. MS 3m/z,
relative intensity): 265 3M1, 65), 124 3100), 97 315), 84
318). Anal. calcd for C14H19NO2S: C, 63.39; H, 7.16; N,

G. Pandey et al. / Tetrahedron 58ꢀ2002) 3525±3534
3531
5.28; S, 12.07. Found: C, 63.19; H, 7.09; N, 5.11; S, 12.01.
22c 3gummy paste): H NMR 3CDCl3, 500 MHz): d 1.25±
3C6D6/CDCl3ˆ1:1, 500 MHz): d 0.72 3s, 3H), 1.05 3s,
3H), 1.20±1.30 3m, 3H), 1.40±1.75 3m, 9H), 1.80±2.10
3m, 2H), 2.12±2.20 3m, 1H), 2.21 3m, 3H), 2.95±3.10 3m,
3H), 3.65 3t, Jˆ5.6 Hz, 1H), 3.75 3m, 1H), 4.15 3dd, Jˆ7.9,
5.6 Hz, 1H). 13C NMR 3CDCl3, 75.3 MHz): d 15.1, 19.8,
20.6, 26.4, 26.9, 28.4, 31.4, 32.8, 38.5, 41.1, 44.6, 46.4,
47.67, 47.9, 53.0, 61.8, 65.5, 65.7, 171.3. MS 3m/z, relative
intensity): 366 3M1, 11), 152 325), 124 365), 97 3100), 82
330). 25c: mp205±207 8C. IR 3neat): 3028, 1669,
1
1.45 3m, 4H), 1.60±1.70 3m, 2H), 1.75±1.90 3m, 3H), 2.62±
2.70 3m, 1H), 3.50 3t, Jˆ5.5 Hz, 1H), 3.60 3dd, Jˆ9.7,
4.3 Hz, 1H), 3.85 3s, 1H), 3.87 3d, Jˆ13.5 Hz, 1H), 3.97
3d, Jˆ13.5 Hz, 1H), 7.30 3t, Jˆ7.2 Hz, 1H), 7.38 3t,
Jˆ7.5 Hz, 2H), 7.45 3d, Jˆ7.2 Hz, 2H), 7.62 3t, Jˆ7.0 Hz,
2H), 7.70 3t, Jˆ7.5 Hz, 1H), 7.98 3d, Jˆ9.5 Hz, 2H). 13C
NMR 3CDCl3, 75.3 MHz): d 24.2, 25.2, 29.7, 35.0, 36.2,
59.4, 63.9, 64.0, 73.6, 126.8, 128.2, 128.6, 129.2, 133.4,
140.7. MS 3m/z, relative intensity): 355 3M1, 6), 298 31),
214 3100), 186 33), 158 34), 91 353), 77 314). Anal. calcd for
C21H25NO2S: C, 70.98; H, 7.04; N, 3.94; S, 9.01. Found: C,
70.78; H, 6.98; N, 3.78; S, 8.95.
1
1425 cm21. H NMR 3C6D6, 500 MHz): d 0.52 3s, 3H),
0.68±0.75 3m, 1H), 0.82±0.90 3m, 1H), 1.08 3s, 3H),
1.17±1.25 3m, 1H), 1.37±1.45 3m, 3H), 1.62±1.70 3m,
1H), 1.78±2.18 3m, 8H), 2.33±2.43 3m, 1H), 2.48±2.57
3m, 1H), 2.87 3d, Jˆ13.7 Hz, 1H), 2.92 3d, Jˆ13.7 Hz,
1H), 3.22 3bs, 1H), 3.63 3d, Jˆ13.4 Hz, 1H), 3.80 3t,
Jˆ5.5 Hz, 1H), 3.94 3d, Jˆ13.4 Hz, 1H), 4.20 3t,
Jˆ4.1 Hz, 1H), 4.45 3dd, Jˆ8.9, 3.6 Hz, 1H), 7.10±7.30
3m, 3H), 7.50±7.60 3m, 2H). 13C NMR 3CDCl3,
75.3 MHz): d 19.7, 20.6, 24.6, 26.4, 29.5, 31.5, 32.6,
34.9, 36.1, 38.6, 44.3, 47.4, 47.7, 48.1, 53.0, 61.2, 62.6,
65.5, 66.7, 126.4, 127.8, 128.2, 140.9, 172.3. MS 3m/z,
relative intensity): 456 3M1, 7), 242 36), 214 3100), 186
311), 91 366), 81 349), 69 398). HRMS: calculated for
C26H36N2O3S: 456.2446, observed: 456.2442. 26c: mp
4.1.2. Asymmetric [312]-cycloaddition reaction.
Cycloaddition of 15 with 32)-24 was carried out in a similar
manner as described above. Puri®cation of the crude residue
by silica gel 360±120) column chromatography gave
mixture of stereoisomers 3exo and endo) in 58±68% overall
yield. The two isomers were separated by careful ¯ash
column chromatography. 25a: mp135±137 8C. IR
1
3CHCl3): 3018, 1683 cm21. H NMR 3C6D6, 500 MHz): d
0.52 3s, 3H), 0.70±0.78 3m, 1H), 0.88±0.95 3m, 1H), 1.05 3s,
3H), 1.20±1.30 3m, 1H), 1.40±1.45 3m, 2H), 1.55±1.65 3m,
2H), 1.75±1.85 3m, 2H), 1.94±1.98 3m, 1H), 2.01±2.08 3m,
2H) 2.30 and 2.35 3d, Jˆ4.0, 4.4 Hz, 1H), 2.85 3d,
Jˆ13.6 Hz, 1H), 2.92 3d, Jˆ13.6 Hz, 1H), 3.18 3t,
Jˆ4.4 Hz, 1H), 3.55 3d, Jˆ13.5 Hz, 1H), 3.68 3d,
Jˆ13.5 Hz, 1H), 3.80 3t, Jˆ5.6 Hz, 1H), 4.23 3bs, 1H),
4.30 3dd, Jˆ5.6, 3.8 Hz, 1H), 7.2 3t, Jˆ7.3 Hz, 1H), 7.35
3t, Jˆ7.5 Hz, 2H), 7.55 3d, Jˆ7.6 Hz, 2H). 13C NMR 3C6D6,
125 MHz): d 19.1, 20.1, 24.6, 25.9, 28.5, 29.5, 31.8, 38.3,
44.2, 46.9, 47.4, 47.8, 51.6, 52.1, 60.2, 63.6, 64.8, 126.5,
127.9, 128.6, 139.9, 172.5. MS 3m/z, relative intensity): 428
3M1, 17), 337 35), 214 39), 186 329), 159 386), 91 3100), 68
39). HRMS: calculated for C24H32N2O3S: 428.2133,
observed: 428.2134. 26a: mp133±135 8C. IR 3neat): 3019,
210±2128C. IR 3CHCl3): 3025, 1669, 1428 cm21 1H
.
NMR 3C6D6/CDCl3ˆ1:1, 500 MHz): d 0.46 3s, 3H), 0.58±
0.88 3m, 3H), 1.10 3s, 3H), 1.28±1.45 3m, 4H), 1.75±2.08
3m, 8H), 2.3±2.45, 3m, 2H), 2.78 3d, Jˆ13.5 Hz, 1H), 2.82
3d, Jˆ13.5 Hz, 1H), 3.15±3.27 3m, 1H), 3.65 3dd, Jˆ5.6,
4.2 Hz, 1H), 3.75 3d, Jˆ13.6 Hz, 1H), 3.95 3d, Jˆ13.6 Hz,
1H), 4.25±4.45 3m, 2H). 13C NMR 3CDCl3, 75.3 MHz): d
19.7, 20.5, 24.4, 24.8, 26.4, 31.3, 32.2, 32.7, 34.7, 38.5,
44.6, 47.6, 47.9, 48.6, 52.9, 61.1, 62.9, 65.3, 66.4, 126.4,
127.8, 128.2, 140.9, 171.7. MS 3m/z, relative intensity): 456
3M1, 7), 242 36), 214 3100), 186 312), 91 365), 81 349), 69
395).
4.1.3. Preparation of X-alkyl-2-exo-carbomethoxy-X-
azabicyclo[m.2.1] alkanes ,28). A solution of 25
1
1683 cm21. H NMR 3C6D6: CDCl3, 500 MHz): d 0.42 3s,
3H), 0.92±0.99 3m, 1H), 1.02±1.08 3m, 2H), 1.23 3s, 3H),
1.32±1.48 3m, 2H), 1.55±1.70 3m, 1H), 1.85±1.95 3m, 1H,
2.05±2.35 3m, 6H), 2.95 3d, Jˆ13.6 Hz, 1H), 3.08 3d,
Jˆ13.6 Hz, 1H), 3.32 3t, Jˆ4.3 Hz, 1H), 3.68 3d,
Jˆ13.3 Hz, 1H), 3.72 3d, Jˆ13.3 Hz, 1H), 3.75 3t,
Jˆ5.5 Hz, 1H), 4.08±4.15 3m, 1H), 4.35 3t, Jˆ4.1 Hz,
1H), 7.25±7.35 3m, 3H), 7.55 3d, Jˆ7.5 Hz, 2H). 13C
NMR 3CDCl3, 75.3 MHz): d 19.9, 20.8, 24.2, 26.5, 28.6,
29.6, 32.9, 38.8, 44.6, 45.8, 47.8, 48.3, 51.4, 53.2, 60.4,
63.6, 65.7, 126.8, 128.2, 128.7, 140.3, 173.7. MS 3m/z,
relative intensity): 428 3M1, 15), 337 37), 214 39), 186
330), 159 386), 91 3100), 68 39). 25b: mp165±167 8C. IR
3neat): 3018, 2927, 1689 cm21. 1H NMR 3C6D6/CDCl3ˆ1:1,
500 MHz): d 0.70 3s, 3H), 1.05 3s, 3H), 1.12±1.28 3m, 3H),
1.40±1.80 3m, 9H), 1.92±1.95 3m, 2H), 2.30 3s, 3H), 2.78±
2.85 3m, 1H), 2.95 3d, Jˆ13.6 Hz, 1H), 3.08 3d, Jˆ13.6 Hz,
1H) 3.17±3.20 3m, 1H), 3.37 3bs, 1H), 3.42 3dd, Jˆ7.6,
4.3 Hz, 1H), 3.75 3t, Jˆ5.6 Hz, 1H). 13C NMR 3CDCl3,
75.3 MHz): d 16.1, 19.4, 20.4, 26.1, 28.3, 28.4, 28.8,
29.1, 32.4, 38.1, 39.0, 44.2, 47.3, 47.8, 52.8, 61.7, 65.3,
67.3, 174.4. MS 3m/z, relative intensity): 366 3M1, 10),
152 324), 124 361), 97 3100), 82 329). HRMS: calculated
for C19H30N2O3S: 366.1977, observed: 366.1967. 26b: mp
31.10 mmol) in 12 mL MeOH/H2O 33:1) mixture containing
LiOH´H2O 34.6 mg, 1.10 mmol) was warmed to 458C while
stirring. After 45 min, mixture was cooled and the resulting
solution was extracted with EtOAc 33£5 mL) to remove the
sultam chiral auxiliary. The aqueous layer was acidi®ed to
pH 6±7 by careful addition of 3N HCl under an ice-cold
condition. The crude acid 27, thus obtained, by evaporating
the aqueous layer was used as such without further puri®ca-
tion for the next step. The crude acid 27 was dissolved in
15 mL of dry MeOH and was transferred to a 25 mL ¯ask
equipped with argon gas balloon. The freshly distilled
SOCl2 30.7 mL, excess) was added to that solution at 08C
over a period of 15 min. The solution was allowed to stir at
this temperature for 4 h and it was allowed to stir afterwards
for 6 h at rt. The solution was evaporated to dryness and dry
CHCl3 320 mL) was added to it. The ammonia gas was
passed through this suspension until basic 3pH 8). The
suspension was ®ltered and the evaporation of the solution
gave crude methyl ester 28. Puri®cation of the crude mixture
by the column chromatography afforded optically pure
methyl ester 28 in 82±85% yield. 28a: IR 3CHCl3): 2954,
1
1731, 1215 cm21. H NMR 3CDCl3, 200 MHz): d 1.35±
1.42 3m, 2H), 1.60 3dd, Jˆ12.2, 9.2 Hz, 1H), 1.82±1.95
1
169±1718C. IR 3neat): 3018, 2928, 1690 cm21. H NMR
3m, 2H), 2.22±2.36 3m, 1H), 2.45 3dd, Jˆ9.2, 4.9 Hz, 1H),

3532
G. Pandey et al. / Tetrahedron 58ꢀ2002) 3525±3534
3.42 3t, Jˆ5.9 Hz, 1H), 3.50 3d, Jˆ13.7 Hz, 1H), 3.60 3d,
Jˆ13.7 Hz, 1H), 3.65 3bs, 1H), 3.7 3s, 3H), 7.20±7.35 3m,
5H). MS 3m/z, relative intensity): 245 3M1, 54), 230 32), 216
310), 186 331), 158 384), 91 3100), 65 326). HRMS: calcu-
lated for C15H19NO2: 245.1415, observed: 245.1411. 28b:
Anal: calcd for C9H15NO2: C, 63.90; H, 8.87; N, 8.28.
Found: C, 63.66; H, 8.63; N, 8.18.
4.1.5. Preparation of 7-,tert-butoxycarbonyl)-2-exo-
bornane-2,10-sultam-7-azabicyclo-[2.2.1]heptane 31a.
To a solution of 25a 30.5 g, 1.16 mmol) in 50 mL of 5%
HCOOH±MeOH was added Pd/C 30.5 g) and the resultant
suspension was stirred at rt for 36 h. The reaction mixture
was ®ltered, the ®ltrate was evaporated and the crude amine
was dissolved in 30 mL of dry DCM and treated with a
solution of 3Boc)2O 30.305 g, 1.40 mmol) in 10 mL DCM
followed by Et3N 30.8 mL) under argon atmosphere. The
resulting mixture was stirred for 18 h and concentrated.
The residue was puri®ed by silica gel column chromato-
graphy, eluting with hexane/EtOAc 37:3) to afford 0.62 g
of 31a 382%) as a white solid, mp173±175 8C. IR
1
IR 3CHCl3): 2925, 2851, 1712 cm21. H NMR 3CDCl3,
200 MHz): d 1.35±1.6 3m, 4H), 1.75±1.95 3m, 3H), 2.25
3s, 3H), 2.45 3m, 1H), 2.85 3dd, Jˆ9.8, 5.9 Hz, 1H), 3.17±
3.27 3m, 1H), 3.55 3bs, 1H), 3.70 3s, 3H). 13C NMR 3CDCl3,
75.3 MHz): 16.5, 29.2, 29.8, 30.0, 39.8, 46.6, 51.5, 61.8,
65.3, 176.0. MS 3m/z, relative intensity): 183 3M1, 10),
168 3,1), 152 39), 140 328), 124 347), 96 395), 82 3100).
HRMS: calculated for C10H17NO2: 183.1259, observed:
1
183.1258. 28c: IR 3CHCl3): 2927, 1731, 1225 cm21. H
NMR 3CDCl3, 200 MHz): 1.25±1.45 3m, 4H), 1.60±1.85
3m, 5H), 2.52±2.65 3m, 1H), 2.83 3dd, Jˆ8.9, 3.6 Hz, 1H),
3.45±3.62, 3m, 2H), 3.70 3s, 3H), 3.85 3s, 2H), 7.25±7.35
3m, 5H). 13C NMR 3CDCl3, 75.3 MHz): d 24.4, 25.1, 33.1,
34.7, 36.1, 51.2, 51.7, 60.2, 64.1, 67.6, 126.6, 128.1, 128.2,
140.6, 177.2. MS 3m/z, relative intensity): 273 3M1, 56), 258
31), 242 310), 214 3100), 158 345), 186 321), 91 392), 65 319).
HRMS: calculated for C17H23NO2: 273.1728, observed:
273.1726.
1
3CHCl3): 2945, 1679 cm21. H NMR 3CDCl3, 200 MHz):
d 0.95 3s, 3H), 1.12 3s, 3H), 1.32±1.60 3m, 4H), 1.45 3s,
9H), 1.65±1.95 3m, 6H), 2.05±2.15 3m, 3H), 3.40 3d,
Jˆ13.6 Hz, 1H), 3.50 3d, Jˆ13.6 Hz, 1H), 3.55 3dd,
Jˆ7.9, 4.3 Hz, 1H), 3.90 3t, Jˆ5.6 Hz, 1H), 4.20 3t,
Jˆ4.8 Hz, 1H), 4.60±4.70 3m, 1H). 13C NMR 3CDCl3,
50.32 MHz): d 19.9, 20.1, 24.8, 26.4, 28.0, 29.0, 31.5,
32.9, 34.45, 38.8, 44.8, 47.0, 48.1, 53.5, 57.5, 58.9, 66.2,
79.0, 154.5, 171.2. MS 3m/z, relative): 438 3M1, 5), 365
315), 338 3100), 135 317), 83 325). Anal. calcd for
C22H34N2O4S: C, 60.27; H, 7.76; N, 6.39; S, 7.30. Found:
C, 60.13; H, 7.47; N, 6.36; S, 7.27.
4.1.4. Preparation of constrained amino acids 29a±c. The
hydrolysis of 25 with LiOH´H2O in MeOH/H2O 33:1) to
obtain corresponding acids 27 is already described.
N-Debenzylation of acids 27a and 27c was carried out by
the hydrogenation over Pd/C 310%, 20 mg) in MeOH at rt
for 24 h. The reaction mixture was ®ltered; the ®ltrate was
evaporated to give corresponding amino acids 29a and 29c
in almost quantitative yield 390±92%) as a white crystalline
solid.
4.1.6. Preparation of 31b. To a solution of 28a 30.5 g,
0.4 mmol) in 30 mL of ethanol was added palladium
hydroxide 350 mg) and the resultant suspension was hydro-
genated 350 psi, rt) for 2 days. The reaction mixture was
worked-upas mentioned above and was converted to its
N-Boc derivative to afford 0.48 g of 31b 392%) as a color-
The crude acid 27b 30.20 g, 3.82 mmol) was treated with
a-chloroethyl chloroformate 30.165 g, 7.69 mmol) in the
presence of proton sponge 3N,N,N0,N0-tetramethyl-1,8-
naphthalene diamine) 30.365 g, 3.82 mmol) in 1,2-dichloro-
ethane 315 mL) and the mixture was re¯uxed for 6 h. Dry
HCl was bubbled into the reaction mixture, resulting
precipitate was ®ltered off and the ®ltrate was evaporated
under reduced pressure. The resulting viscous liquid was
dissolved in dry MeOH 310 mL) and was re¯uxed for 1 h.
The mixture was washed with CHCl3 33£5 mL) and the
resultant mass was basi®ed to obtain 29b 30.068 g) in 68%
25
1
less oil. [a]D ˆ212.1 3c 1.06, CHCl3). H NMR 3CDCl3,
200 MHz): d 1.38±1.42 3m, 2H), 1.43 3s, 9H), 1.61 3dd,
Jˆ12.4, 8.9 Hz, 1H), 1.71±1.82 3m, 2H), 2.25±2.29 3m,
1H), 2.55 3dd, Jˆ8.9, 5.1 Hz, 1H), 3.70 3s, 3H), 4.29±4.35
3m, 1H), 4.45±4.52 3m, 1H). 13C NMR 3CDCl3,
50.32 MHz): 28.1, 28.7, 29.3, 33.1, 47.3, 51.9, 55.8, 59.1,
99.5, 154.7, 173.6. MS 3m/z, relative intensity): 255 3M1,
0.9), 196 325), 169 352), 96 342), 69 3100). Anal. calcd for
C13H21NO4: C, 61.17; H, 8.23; N, 5.49. Found: C, 61.01; H,
8.11; N, 5.23.
25
yield. 29a: [a]D ˆ25.278 3c 1.2, MeOH), mp238±241 8C.
1
IR 3nujol): 3417, 2968, 1635, 1209 cm21. H NMR 3D2O)
4.1.7. Preparation of ,2)-35 by Heck-coupling. K2CO3
35.37 g, 0.02 mmol), Pd3OAc)2 30.25 g, 0.001 mmol) and
PPh3 30.59 g, 0.002 mmol) were added to a stirring solution
of ole®n 32)-24 33.03 g, 0.01 mmol) and 34 32.70 g,
0.01 mmol) in 30 mL of dry CH3CN. The mixture was
purged with nitrogen and the mixture was re¯uxed for 4 h
under argon atmosphere. The solvent was removed under
reduced pressure and the whole dark-brown mass was taken
into CHCl3, the organic layer was washed with 0.1N HCl
33£10 mL) followed by water 32£10 mL) and brine. The
crude residue was puri®ed by column chromatography
eluting with EtOAc/CHCl3 32:8) to afford 3.65 g 385%) of
35 as a white solid, mp225±227 8C. IR 3Nujol): 3018, 1679,
3200 MHz): 1.75±1.90 3m, 2H), 1.95±2.10 3m, 3H), 2.15±
2.25 3m, 1H), 3.40 3dd, Jˆ8.8, 4.2 Hz, 1H), 4.25±4.35 3m,
1H), 4.45 3t, Jˆ5.6 Hz, 1H). MS 3m/z, relative intensity):
141 3M1, 75), 124 356), 112 332), 96 395), 67 3100). Anal.
calcd for C7H11NO2: C, 59.57; H, 7.80; N, 9.92. Found: C,
25
59.32; H, 7.71; N, 9.80. 29b: [a]D ˆ204.768 3c 0.78,
1
MeOH), mp210±215 8C. IR 3Nujol): 3419, 1648 cm21. H
NMR 3D2O): d 1.25±1.65 3m, 6H), 1.90±2.15 3m, 2H), 2.70
3dd, Jˆ7.9, 4.3 Hz), 3.75±3.82 3m, 1H), 3.87 3t, Jˆ5.2 Hz,
1H). MS 3m/z, relative intensity): 155 3M1, 65), 140 325),
126 312), 110 327), 82 3100), 68 317). Anal. calcd for
C8H13NO2: C, 61.93; H, 8.38; N, 9.03. Found: C, 61.78;
H, 8.21; N, 9.01. 29c: [a]D ˆ29.188 3c 1.1, MeOH), mp
1334, 1215 cm21. H NMR 3CDCl3, 200 MHz): d 0.98 3s,
25
1
1
225±2278C. H NMR 3D2O): d 1.25±1.55 3m, 4H), 1.65±
3H), 1.20 3s, 3H), 1.35±1.52 3m, H), 1.87±2.05 3m, 3H),
2.18 3d, Jˆ7.3 Hz, 1H), 3.45 3d, Jˆ13.6 Hz, 1H), 3.55 3d,
Jˆ13.6 Hz, 1H), 3.98 3t, Jˆ6.3, Hz, 1H), 7.20 3d,
1.85 3m, 6H), 2.25 3dd, Jˆ7.6, 3.9 Hz, 1H), 2.90±3.05 3m,
2H). MS 3m/z): 169 3M1, 65), 96 365), 87 3100), 65 382).

G. Pandey et al. / Tetrahedron 58ꢀ2002) 3525±3534
3533
Jˆ15.6 Hz, 1H), 7.38 3d, Jˆ8.3 Hz, 1H), 7.75 3d,
Jˆ15.6 Hz, 1H), 7.9 3dd, Jˆ8.3, 2.4 Hz, 1H), 8.5 3d,
Jˆ2.5 Hz, 1H). 13C NMR 3CDCl3, 50.32 MHz): d 19.6,
20.6, 26.3, 32.7, 38.2, 44.6, 47.7, 48.5, 52.9, 65.0, 120.2,
124.3, 129.1, 136.6, 139.6, 149.9, 163.1. MS 3m/z, relative
intensity): 381 3M1, 10), 317 315), 274 35), 167 3100), 138
329), 102 384), 76 355). Anal. calcd for C17H21N2O2SCl: C,
56.76; H, 5.51; N, 7.35; S, 8.4. Found: C, 56.72; H, 5.55; N,
7.78; S, 8.72.
3CDCl3, 200 MHz): d 1.52±1.70 3m, 2H), 1.90±2.30 3m,
2H), 2.85 3t, Jˆ5.1 Hz, 1H), 3.10 3d, Jˆ5.3 Hz, 1H), 3.30
3d, Jˆ4.2 Hz, 1H), 3.6 3s, 2H), 3.70 3s, 3H), 3.60±3.70 3t,
Jˆ4.4 Hz, 1H), 7.15±7.45 3m, 6H), 7.80 3dd, Jˆ8.4, 2.6 Hz,
1H), 8.5 3d, Jˆ2.4 Hz, 1H). 13C NMR 3CDCl3, 75.3 MHz):
21.6, 26.5, 47.3, 51.4, 57.1, 61.3, 66.1, 66.1, 123.3, 126.7,
128.0, 128.2, 137.6, 138.9, 139.7, 148.6, 149.0, 172.2. MS
3m/z, relative intensity): 356 3M1, 5), 297 31), 159 356), 131
314), 91 3100), 65 312). HRMS: calculated for
C20H21N2O2Cl: 356.1290, observed: 356.1292.
4.1.8. [312] Cycloaddition of 15 with ,2)-35. A typical
cycloaddition of 15 31.50 g, 4.91 mmol) with 35 32.24 g,
5.90 mmol) using Ag3I)F 31.54 g, 0.01 mol) followed by
column puri®cation of the crude cycloaddition mixture
using 360:120) silica gel gave mixture of diastereomeric
cycloadducts 336 and 37) in a ratio of 9:1 with 64% overall
yield. The two diastereomers were separated by careful ¯ash
column chromatography eluting with acetone/hexane
32.5:7.5) to afford 1.53 g 358%) of 36 as a white prism
shaped solid, mp 237±2398C and further elution with the
same polarity of the solvent gave 0.17 g 37%) of 37. 36: IR
Acknowledgements
We thank DST, New Delhi for generously funding this
project. We are grateful to Dr M. Vairamani 3Indian
Institute of Chemical Technology, Hydrabad, India) for
providing HRMS data. J. K. L. thanks CSIR, New Delhi
for the award of research fellowship.
1
3Nujol): 1683, 1215 cm21. H NMR 3CDCl3, 500 MHz):
0.98 3s, 3H), 1.23 3s, 3H), 1.34±1.43 3m, 2H), 1.45±1.51
3m, 1H), 1.62±1.67 3m, 1H), 1.86±1.95 3m, 4H), 2.01±2.08
3m, 2H), 2.09±2.15 3m, 1H), 3.22 3d, Jˆ4.4 Hz, 1H), 3.37
3d, Jˆ4.8 Hz, 1H), 3.41 3d, Jˆ13.7 Hz, 1H), 3.49 3d,
Jˆ13.1 Hz, 1H), 3.53 3d, Jˆ13.1 Hz, 1H), 3.61 3t,
Jˆ4.2 Hz, 1H), 3.72 3d, Jˆ13.7 Hz, 1H), 3.90 3t,
Jˆ5.1 Hz, 1H), 4.06 3t, Jˆ4.4 Hz, 1H), 7.20 3d, Jˆ8.3 Hz,
1H), 7.21±7.29 3m, 1H), 7.31±7.39 3m, 4H), 7.82 3dd,
Jˆ8.3, 2.4 Hz, 1H), 8.3 3d, Jˆ2.4 Hz, 1H). 13C NMR
3CDCl3, 75.3 MHz): 20.2, 21.2, 22.2, 26.8, 27.2, 33.1,
39.1, 45.1, 47.0, 48.1, 48.6, 52.0, 53.4, 58.6, 64.0, 65.8,
66.2, 124.2, 127.4, 128.7, 128.8, 138.4, 139.6, 139.7,
149.4, 149.7, 171.2. MS 3m/z, relative intensity): 539 3M1,
8), 506 35), 380 310), 297 318), 242 37), 160 397), 91 3100).
HRMS: calculated for C29H34N3O3SCl: 539.2009, observed:
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4.1.9. Preparation of 38. A solution of 36 30.5 g,
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25
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