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;
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6 October 2004 Publikationsdatum: 29. November 2004 (online)
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.
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.
