Abstract
We have recently described efforts for the exploitation of a novel lipase-catalyzed asymmetric demethoxycarbonylation of tetramethyl 3,7-dioxo-cis-bicyclo[3.3.0]octane-2,4,6,8-tetracarboxylate (1) and for its application to the syntheses of Corey lactone and some natural products. We have now turned our interest in the substrate i.e., 8-alkyl-3-oxo-8-azabicyclo[3.2.1]octane-2,4-dicarboxylates (3, 4) which was readly prepared by Robinson's tropinone synthesis from succindialdehyde and primary amine, and 1,3-acetonedicarboxylate in one step, because this skeleton is closely related to the cocaine related alkaloids, including radiopharmaceuticals, for diagnosis of Parkinson's disease. We examined the lipase-catalyzed demethoxycarbonylation of 3 with various lipases such as PPL (Porcine Pancreatic Lipase) in a toluene-phosphate buffer (pH=7.2), but the obtained 5 were racemic. After searching for a suitable substrate and enzyme, we found that the tropinone diester 4 bearing a benzyl group as an aminoprotective group gave optically active monoester [(-)-6a-e] by the use of PLE (Porcine Liver Esterase). Especially the n-butyl ester (4d) was the best for giving the highest yield and enantiomeric excess (51% yield, 95%ee) among the ester moieties examined. The absolute configuration of the obtained monoester was estimated from the following experiments: (1) the methyl ester (6a) derived from 6b-e showed the same (-)-direction in optical rotation, (2) the specific rotation of anhydroecgonine methyl ester [(-)-7] derived from 6a-e was identical with that of (-)-7 derived from the known (-)-cocaine. As an synthetic application of optically active tropinone monoester [(-)-6d], we synthesized β-CIT and β-CIT-FP which is radiopharmaceuticals, (-)-ferruginine which is opposite configuration of natural (-)-cocaine, and alkaloid KD-B which is tropane alkaloid.
