STUDIES ON ANALOGUES OF HUPERZINE A FOR TREATMENT OF SENILE DEMENTIA V. SYNTHESIS OF OPTICALLY ACTIVE (-)-1-METHYL HUPERZINE A

AIM: to study the synthesis and the acetylcholinesterase inhibitory activity of optically active (-)-1-methyl hyperzine A(11). METHODS: The optically pure intermediate (+)-(5S,9R)-5 was used as the starting material. Wittig olefination of 5, followed by isomerization of double bond afforded (E)-(+)-6. Selective deprotection of 6 by Me₃SiCl/NaI in acetonitrile produced pyridione compound (-)-7, which was selectively N-methylated by NaOMe/CH₃I to give (+)-8. Subsequently, the title compound (-)-11 was obtained by hydrolysis of ester (+)-8, modified Curtius rearrangement of acid 9 and deprotection of urethane (+)-10.RESULTS: The acetylcholinesterase inhibitory activities of analogues 11 was found to be much lower than that of natural huperzine A.CONCLUSION: 1-Methyl group in analogue 11 may influence the formation of hydrogen bond between the ring nitrogen and the protein residue in the active site of the acetylcholinesterase.