Synlett 2005(1): 164-166  
DOI: 10.1055/s-2004-836037
LETTER
© Georg Thieme Verlag Stuttgart · New York

Enantioselective Approach to Tropane Skeleton: Synthesis of (1S,5S,6R)-6-Hydroxy-8-methyl-8-azabicyclo[3.2.1]octan-3-one

Gian Piero Pollini*, Carmela De Risi, Flavio Lumento, Paolo Marchetti, Vinicio Zanirato
Dipartimento di Scienze Farmaceutiche, Via Fossato di Mortara 19, 44100 Ferrara, Italy
Fax: +39(0532)291296; e-Mail: pol@unife.it;
Further Information

Publication History

Received 6 October 2004
Publication Date:
29 November 2004 (online)

Abstract

The original and classical Mannich-type construct for the tropane skeleton, developed over half a century ago by Willstätter, Robinson and Schöpf as the first biomimetic synthesis, has been employed for the enantioselective construction of 6β-hydroxytropinone. The component compounds of this novel one-step Mannich-type condensation sequence are acetonedicarboxylic acid, methyl­amine hydrochloride and (2R)-hydroxy-1,4-butanedial, in turn prepared from tert-butyl (R)-3-hydroxy-4-pentenoate as the starting chiral synthon.

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Typical Procedure for the Synthesis of (+)-1.
A pentane solution of racemic alcohol (10.0 mmol) and vinyl acetate (20.0 mmol) was stirred at r.t. for 19 h in the presence of PS-C (Pseudomonas cepacia lipase immobilized on ceramic particles). The suspension was filtered to recover the supported enzyme (we found that it might be reused several times without loss of activity) and the solvent was evaporated. Column chromatography of the residue on silica gel (Et2O-petroleum ether 2:8) yielded (+)-1 (4.6 mmol) with >95% ee.

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All new compounds gave satisfactory analytical and spectroscopic data. Compound (+)-5: [α]D 25 +18.4 (c 2.0, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 1.71 (m, 1 H), 1.91 (m, 1 H), 2.67 (d, J = 2.0 Hz, 1 H), 3.34 (s, 3 H), 3.35 (s, 3 H), 3.42 (s, 3 H), 3.43 (s, 3 H), 3.80 (m, 1 H), 4.16 (d, J = 6.0 Hz, 1 H), 4.62 (dd, J = 5.2 and 6.5 Hz, 1 H). Compound (-)-6: 1H NMR (400 MHz, CDCl3): δ = 1.90-2.00 (m, 1 H), 2.00-2.05 (m, 1 H), 2.05-2.08 (m, 1 H), 2.14-2.19 (m, 1 H), 2.61 (s, 3 H), 2.60-2.68 (m, 2 H), 3.00 (br s, 1 H), 3.34 (d, J = 4.8 Hz, H-5), 3.56 (m, H-1), 4.03 (dd, J = 2.4 and 6.8 Hz, H-6). 13C NMR (100 MHz, CDCl3): δ = 34.6, 41.0, 41.4, 43.4, 58.9, 68.2, 75.1, 207.8.