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

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 beta-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 (mar. 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). (C) 1998 Elsevier Science Ltd. All rights reserved.