[Studies on analogues of huperzine A for treatment of senile dementia. VI. Asymmetric total synthesis of 14-nor-huperzine A and its inhibitory activity of acetylcholinesterase].

Aim To study asymmetric total synthesis of 14 nor huperzine A 2 and its inhibitory activity on acetylcholinesterase. Methods Highly enantioselective synthesis of compound 5 from β keto ester 3 and 2 methylene 1,3 propanediol diacetate 4 by palladium catalyzed bicycloannulation was carried out using new chiral ferrocenylphosphine ligands, such as 10, 11, followed by regioselective double bond migration to produce compound 6. Optically pure 6 was obtained after enantio enrichment recrystallization. Then, according to similar procedures of huperzine A synthesis, the target compound 14 nor huperzine A 2 was prepared. The inhibitory activity was tested with rat erythrocyte membrame acetylcholinesterase. Results The inhibitory activity of synthetic (-) 14 nor huperzine A was 8 fold less potent than that of (-) huperzine A. Conclusion A hydrogen bond between 14 methyl group of (-) huperzine A and the main chain oxygen of His 440 is necessary for the highly acetylcholinesterase inhibitory activity of huperzine A.