CHEMOENZYMATIC SYNTHESIS OF THE 8 STEREOISOMERIC MUSCARINES

Efficient syntheses of the eight stereoisomers of muscarine have been accomplished by dehydrogenase-catalyzed reduction of iodo ketones (+/-)-3a and (+/-)-3b. 3-alpha,20-beta-Hydroxysteroid dehydrogenase from Streptomyces hydrogenans exhibited high enantiomeric and diastereotopic selectivity for (+/-)-3a, yielding an equimolar mixture of iodo alcohol (-)-4 (2S,4S,5S) (96% ee) and iodo ketone (+)-3a (2R,5R) (96% ee) which was reduced by sodium borohydride to a mixture of (+)-4 and (+)-5. 3-beta,17-beta-Hydroxysteroid dehydrogenase from Pseudomonas testosteroni reduced (+/-)-3b with high diastereotopic selectivity to give an equimolar mixture of iodo alcohols (+)-6 (2R,4S,5S) (> 99% ee) and (-)-7 (2S,4S,5R) (81% ee). Synthesis of the remaining iodo alcohols [(-)-5, (-)-6, and (+)-7] was achieved by applying the Mitsunobu procedure to (-)-4, (-)-7, and (+)-6. The enantiomeric excess of intermediates 4-7 was determined by HPLC analysis of the (R)-(+)-MTPA esters. The chiral iodo alcohols 4-7 were then transformed into the final derivatives by conventional chemical manipulations.