Asymmetric synthesis of functionalized piperidine derivatives: Synthesis of (S)-anatabine

Article abstract of DOI:10.1016/S0957-4166(98)00225-0

A short and efficient chiral synthesis of 6-aryl-5-phenylsulfonyl- l,2,5,6-tetrahydropyridines was achieved in moderate yield and with good selectivity. The absolute configurations were assigned by extending the methodology to (S)-anatabine and as well with NMR experiments.

Full text of DOI:10.1016/S0957-4166(98)00225-0

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 2201–2205
Asymmetric synthesis of functionalized piperidine derivatives:
synthesis of (S)-anatabine1
Thiagarajan Balasubramanian and Alfred Hassner ∗
Department of Chemistry, Bar-Ilan University, Ramat-gan 52900, Israel
Received 28 April 1998; accepted 29 May 1998
Abstract
A short and efficient chiral synthesis of 6-aryl-5-phenylsulfonyl-1,2,5,6-tetrahydropyridines was achieved in
moderate yield and with good selectivity. The absolute configurations were assigned by extending the methodology
to (S)-anatabine and as well with NMR experiments. © 1998 Elsevier Science Ltd. All rights reserved.
Pyrrolidine and piperidine ring systems form the basic skeleton in many naturally occurring alkaloids
and pharmaceutically important compounds.2 Several simple piperidine derivatives exhibit important bio-
logical activities, to mention a few: 1-deoxynojirimycin is a glycosidase inhibitor,3a (−)-paroxetine·HCl
is a serotonine uptake inhibitor,3b pipecolic acid derivatives are NMDA antagonists,3c and minor tobacco
alkaloids are used for cognitive disorders.3d Hence, considerable attention has been focused in recent
years on the synthesis of enantiopure piperidine building blocks for the construction of biologically
active compounds.4
In connection with our studies towards chiral pyrrolidine and piperidine derivatives, we recently
reported the synthesis of chiral non-racemic 2-arylpyrrolidines via a 3+2 cyclization.5a Furthermore, we
have shown that lithiated sulfone carbanions can undergo stereoselective Michael additions to unsaturated
esters.5b In this communication we wish to report a general synthesis of 6-aryl-5-phenylsulfonyl-1,2,5,6-
tetrahydropyridines 6a–f as single stereoisomers in three steps and moderate yields starting from readily
accessible 4-phenylsulfonyl cis-but-2-en-1-ol 1 and chiral non-racemic aryl sulfinimines 2.
The required chiral sulfinimines 2a–f were prepared employing the method of Davis et al.6 and
allylsulfone 1 was obtained in two steps from commercially available cis-but-2-en-1,4-diol.7
Our initial attempts to prepare the piperidine derivatives in one step from 1-chloro-4-phenylsulfonyl
cis-but-2-ene and chiral aryl sulfinimines 2 under the usual LDA conditions at low temperatures failed to
give the expected products. However, when the dianion of 1 (2.4 equiv. LiHMDS, −78°C to −70°C, 0.5 h)
was treated with chiral sulfinimine 2a at −100°C, and allowed to warm to −60°C (1.5 h), quenching with
saturated aqueous NH4Cl solution at −60°C followed by work up afforded the crude addition products
in 80–85% yield.8
∗
Corresponding author. E-mail: hassna@mail.biu.ac.il
0957-4166/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00225-0

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T. Balasubramanian, A. Hassner / Tetrahedron: Asymmetry 9 (1998) 2201–2205
Table 1
Synthesis of 3a–f and elaboration to piperidine derivatives 6a–fa
The 1H NMR spectrum of the crude product indicated the presence of four diastereomers, one being
major (60–65%). Due to the overlapping of proton signals in the NMR, the ratio of diastereomers
could not be assigned. Remarkably, purification by flash column chromatography (silica) followed by
recrystallization (CH2Cl2/pet.ether) afforded the major diastereomer 3a in 48% isolated yield9 and in
1
>95% diastereomeric purity based on H and 13C NMR. This reaction was found to be general with
other aryl sulfinimines 2b–e giving rise to the respective addition products 3b–e in moderate yield and
good diastereoselectivity10 (Table 1, Scheme 1). The observed diastereoselectivity can be attributed to
Li+ chelation between the sulfonyl oxygen and the sulfinimine nitrogen forming a six-membered chair-
like transition state which directs the aryl group to the equatorial position due to 1,3-diaxial Ar/Ph(SO2)
repulsion.11
Scheme 1.
The attempted Mitsunobu cyclization of 3a or 3b to N-sulfinyl pyridines 6a or 6b respectively under
a variety of conditions was unsuccessful. This might be due to poor nucleophilicity of the nitrogen
which is attached to an aryl sulfoxide group. Hence the N-sulfoxide group in 3a was removed by
treatment with TFA to furnish 4a. The Mitsunobu cyclization afforded the required piperidine 6a in 60%
yield.12 However the yields were not satisfactory with other substrates under similar conditions. Hence an
alternative general pathway to the target compounds was sought. Treatment of 3a with Ph3P and a mixture
of CCl4:Et3N:CH3CN at 0–25°C for 2–3 h under argon resulted in the corresponding chloro-derivative
5a in 80% yield.13 Interestingly, attempts to remove the N-sulfoxide group in 5a by treatment with
TFA furnished 6-(p-toluyl)-5-phenylsulfonyl-1,2,5,6-tetrahydropyridine 6a directly in quantitative yield
after passing through a prepacked silica gel column with ether:pet. ether (4:1) containing 1.5% Et3N.14
Similarly, other addition products 3b–e were also successively transformed into the corresponding

T. Balasubramanian, A. Hassner / Tetrahedron: Asymmetry 9 (1998) 2201–2205
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hitherto unknown tetrahydropyridine derivatives 6b–e in good yields15 (Table 1, Scheme 2). The relative
stereochemistry of aryl and phenylsulfonyl groups in 6a–e was established as trans and as occupying
pseudoaxial positions since the H5 and H6 protons are in a gauche relationship based on high resolution
1H NMR and NOSEY experiments.16 We tentatively assigned the absolute configuration of 6a–e as 5(S)-
phenylsulfonyl-6(R)-aryl-1,2,5,6-tetrahydropyridine based on our subsequent synthesis of (S)-anatabine
7 from 3f and our earlier studies with pyrrolines.5a
Scheme 2.
The synthesis of anatabine is outlined in Scheme 3. Compound 3f was obtained as a 82:18 mixture
of diastereomers (see Table 1) which could not be separated either by repeated column chromatography
or by recrystallization. Though the chloro derivative 5f was obtained in 68% yield, it failed to give
6f under the conditions described in Scheme 2. Hence the N-sulfoxide group was removed from the
addition product 3f to get 4f and after modification of the mode of addition in the Mitsunobu reaction17,
1
6f was obtained in a 70% yield (Scheme 3). The H and 13C NMR of 6f showed only one set of
signals, however the presence of an enantiomer cannot be ruled out. Treatment of 6f with Na(Hg) in
MeOH under buffered conditions18 afforded anatabine 719 in 60% isolated yield which showed [α]25
D
1
−128 [c 0.5, CHCl3], lit.19c [α]D −176. H and 13C NMR spectroscopic data of 7 were identical to
those reported for (+)-anatabine.19b,e Based on the specific rotation, natural (S)-anatabine had been
formed and the ee of 7 is 70%. By comparison with (S)-anatabine the absolute configuration of the
precursor 6f can be assigned as 5(S)-phenylsulfonyl-6(R)-3-pyridinyl-1,2,5,6-tetrahydropyridine and
similarly the absolute configurations of 5a–e can also be assigned as (5S)-phenylsulfonyl-6(R)-aryl-
1,2,5,6-tetrahydropyridines.
Scheme 3.
In summary, we have accomplished a simple generalized route to functionalized chiral piperidine
derivatives and also their absolute configurations were assigned based on a short synthesis to (S)-
anatabine, a minor tobacco alkaloid. Further work is in progress to enhance selectivity and to find other
routes to chiral pyrrolidine and piperidine derivatives.

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T. Balasubramanian, A. Hassner / Tetrahedron: Asymmetry 9 (1998) 2201–2205
Acknowledgements
Support of this research by a grant from the US-Israel Binational Science Foundation is gratefully
acknowledged. We thank Professor A. I. Meyers for useful suggestions and Dr. H. E. Gottlieb for valuable
help with NMR spectra.
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1
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1
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3.60 (m, 2H), 4.68 (ddd, J=11, 3.5, 1 Hz, 1H), 4.92 (dd J=8, 3.2 Hz, 1H), 5.64 (dt, J=11, 1 Hz, 1H), 5.69 (d, J=8 Hz,
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2205
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