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

AimTo study asymmetric total synthesis of 14-nor-huperzine A 2 and its inhibitory activity on acetylcholinesterase. MethodsHighly 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. ResultsThe 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.