Chemoenymatic Synthesis of the Eight Stereoisomeric Muscarines

Article abstract of DOI:10.1021/jo00001a015

Efficient synthesis of the eight stereoisomers of muscarine have been accomplished by dehydrogenase-catalyzed reduction of iodo ketones (+/-)-3a and (+/-)-3b. 3α,20β-Hydroxysteroid dehydrogenase from Streptomyces hydrogenans exhibited high enantiomeric and diastereotopic selectivity for (+/-)-3a, yielding an equimolar mixture of iodo alcohol (-)-4 (2S,4S,5S) (96percent ee) and iodo ketone (+)-3a (2R,5R) (96percent ee) which was reduced by sodium borohydride to a mixture of (+)-4 and (+)-5. 3β,17β-Hydroxysteroid dehydrogenase from Pseudomonas testosteroni reduced (+/-)-3b wih high diasterotopic selectivity to give an equimolar mixture of iodo alcohols (+)-6 (2R,4S,6S) (>99percent ee) and (-)-7 (2S,4S,5R) (81percent ee).Synthesis of the remaining iodo alcohols <(-)-5, (-)-6, and (+)-7> was achieved by applying the Mitsunobo 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.