Asymmetric synthesis of 1,3- and 1,3,4-substituted pyrrolidines

Article abstract of DOI:10.1016/S0040-4039(00)00278-1

Diastereoselective alkylation of N-acylnorbornene sultams 2 afforded a variety of enantiomerically pure products 3a-3e. Reduction with LiAlH₄ (LAH) followed by ditosylation furnished chiral 1,4-ditosylates 5a-5e which underwent a cyclization reaction with primary amines to afford chiral 1,3- and 1,3,4-substituted pyrrolidines. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00278-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 2949–2951
Asymmetric synthesis of 1,3- and 1,3,4-substituted pyrrolidines
Jing Lin,a Wing Hong Chan,a,∗ Albert W. M. Lee,a Wai Yeung Wong a and Pei Qiang Huang b
aDepartment of Chemistry, Hong Kong Baptist University, Kowloon Tong, Kowloon, Hong Kong
bDepartment of Chemistry, Xiamen University, Xiamen, China
Received 8 November 1999; revised 31 January 2000; accepted 14 February 2000
Abstract
Diastereoselective alkylation of N-acylnorbornene sultams 2 afforded a variety of enantiomerically pure products
3a–3e. Reduction with LiAlH4 (LAH) followed by ditosylation furnished chiral 1,4-ditosylates 5a–5e which
underwent a cyclization reaction with primary amines to afford chiral 1,3- and 1,3,4-substituted pyrrolidines.
© 2000 Elsevier Science Ltd. All rights reserved.
Keywords: asymmetric synthesis; sultams; cyclization; pyrrolidines.
Chiral pyrrolidines are common structural subunits found in a variety of natural and unnatural products
which possess interesting and diverse biological activities.1 In addition, several enantiopure pyrrolidines
have been used as auxiliaries for a number of important transformations.2 As a result, the development
of asymmetric methods for the synthesis of nonracemic substituted pyrrolidines has drawn the attention
of many investigators.
We recently described the design and synthesis of the enantiopure norbornene sultams 1. Subse-
quently, their use as effective chiral auxiliaries in asymmetric Diels–Alder and alkylation reaction has
been demonstrated.3,4 In particular, outstanding diastereoselectivity was consistently obtained from the
alkylation of N-acylnorbornene sultams 2a–2c with α-bromoacetate.4 Enantiopure alkylated products
3a, 3d, ent-3d and 3e were obtained (Scheme 1). These results are reminiscent of the findings of
Oppolzer’s sultams.5 However, we have demonstrated the outstanding chiral induction of our auxiliar-
ies during asymmetric alkylations. When N-acylnorbornene sultams were alkylated with α-alkyl α-
bromoalkanoates, two new stereogenic centers were generated in a highly stereoselective manner. Thus,
under the experimental conditions, enantiopure 3b, ent-3b and 3c were obtained as single alkylated
products from the corresponding reactions.4
LAH reduction of 3a–3e gave the corresponding chiral diols 4a–4e in 72–92% yield, together with the
regeneration of the chiral auxiliaries 1 or ent-1 in over 65% yield. The optical integrity of the recovered
norbornene sultams was proved to be intact, as indicated by optical measurements. Furthermore, because
some of the diols are known compounds, their optical purity and the absolute configuration of the
∗
Corresponding author. Fax: (852) 2339 7348; e-mail: whchan@hkbu.edu.hk (W. H. Chan)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00278-1
tetl 16558

2950
Scheme 1.
stereogenic center were established by comparison with the literature. The new diols 4c and 4e prepared
by this work were adequately characterized by NMR spectroscopic methods and elemental analysis. To
set the stage for pyrrolidine ring formation, diols 4a–4e were further transformed into the corresponding
ditosylates by treating with tosyl chloride in pyridine. When the diols were allowed to react with excess
tosyl chloride at −5°–0°C for 5 h, good to excellent yields of the ditosylates were obtained (Table 1).
Table 1
Synthesis of enantiomerically pure pyrrolidines
To demonstrate the feasibility of preparing chiral substituted pyrrolidines, treatment of ditosylates
5a–5e with 4 equivalents of either phenylethylamine or 3-methylbutylamine in refluxing triethylamine
for 16 h afforded the desired cyclization products in good yield (Table 1).
In summary, our synthetic approach provides a facile access to chiral 1,3-disubstituted and 1,3,4-
trisubstituted pyrrolidines. Two naturally occurring pyrrolidines 6a and 6b were synthesized for the first
time and our results supported the absolute configuration assignment proposed by Veith et al.6

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Acknowledgements
Financial support from the Faculty Research Committee of the Hong Kong Baptist University
(FRG/98-99/II-11) and the Croucher Foundation for providing a Visitorship for P. Q. Huang are gratefully
acknowledged.
References
1. Numata, A.; Ibrika, T. In The Alkaloids; Brossi, A., Ed.; Academic Press: New York, 1987; Vol. 31, Chapter 6.
2. Huryn, D. M. Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 1, pp. 64–71.
3. Chan, W. H.; Lee, A. W. M.; Jiang, L. S.; Mak, T. C. W. Tetrahedron: Asymmetry 1997, 8, 2501.
4. Lin, J.; Chan, W. H.; Lee, A. W. M.; Wong, W. Y. Tetrahedron 1999, 55, 13 983.
5. Oppolzer, W.; Moretti, R.; Thorni, S. Tetrahedron Lett. 1989, 30, 5603.
6. Koob, R.; Rudolph, C.; Veith, H. J. Helv. Chim. Acta 1997, 80, 267.