STUDIES ON ANALOGUES OF HUPERZINE A Ⅲ. SYNTHESIS OF N-METHYL PYRIDONE ANALOGUES OF HUPERZINE A

Huperzinc A(1),an alkaloid isolated from the Chinese folk medicine Huperzia serrata, is a potent and reversible inhibitor of acetylcholinesterase.Clinical trials have confirmed thathuoerzine A is effective in the treatment of senile dementia including Alzheimer's disease.In thispaper the synthesis of N-methyl pyridone analogues 2 and 3 of huperzine A is reported.The selective deprotection of intermediate 9 with chlorotrimethylsilane and sodium iodide inacetonitrile gave a quantitative yield of pyridone 10, which was regioselectively converted to N-methyl pyridone 11 in 94% yield with sodium methoxide and iodomethane.Hydrolysis of ester 11,followed by medified Curtius rearrangement and TMSI- promoted decarbomethoxylation affordedanalogue 2.Similarly,analogue 3 was prepared by using methacrolein instead of acrolein in Michael-Aldol condensations. The acetylcholinesterase inhibitory activities of analogues 2 and 3 were found to be much weakerthan that of huperzine A.