Synthetic studies of huperzine A and its fluorinated analogues. 1. Novel asymmetric syntheses of an enantiomeric pair of huperzine A

Abstract

Syntheses of an enantiomeric pair of huperzine A were accomplished by employing two types of methods which feature the tandem Cinchona alkaloids-promoted asymmetric Michael addition / aldol reaction of the β-keto ester 3 with methacrolein ( 4) (max. 64% ee, 3+4→5 , Scheme 2) and the asymmetric bicycloannulation of 3 with 2-methylene-1,3-propanediol diacetate ( 7) catalyzed by palladium catalysts carrying chiral ferrocenylphosphine ligands (max. 64% ee, 3+7→8 , Scheme 3) as the key steps. Recrystallization of the partially optically active tricycles (+)- and (−)- 6 derived from the products of the asymmetric reactions, readily provided the corresponding optically pure samples (both >99% ee). According to the reported method, the total synthesis of an enantiomeric pair of 1 [(−)- and (+)- 1] was completed starting with optically pure (+)- and (−)- 6 ( Scheme 4).