老年痴呆症药物石杉碱甲类似物研究V.光学活性(-)-1-甲基石杉碱甲的合成

目的：光学活性（－）１甲基石杉碱甲的合成及其乙酰胆碱酯酶抑制活性的研究。方法：从光学纯的（５Ｓ，９Ｒ）５出发，经Ｗｉｔｉｇ反应和双键异构化得化合物６。用三甲基氯硅烷和碘化钠选择性脱保护得吡啶酮７后，用甲醇钠和碘甲烷选择性Ｎ甲基化得８，经酯水解、Ｃｕｒｔｉｕｓ重排和脱保护合成了光学活性１位氮上甲基取代的石杉碱甲类似物１１。结果：类似物１１的乙酰胆碱酯酶抑制活性低于石杉碱甲。结论：１甲基能影响类似物１１和蛋白活性之间形成氢键的作用，因此降低其抑制活性。

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

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