(-)-14-去甲基石杉碱甲的不对称全合成及其乙酰胆碱酯酶抑制活性老年痴呆症药物石杉碱甲类似物研究VI.(-)-14-去甲基石杉碱甲的不对称全合成及其乙酰胆碱酯酶抑制活性

目的(-)-14-去甲基石杉碱甲的合成及其抑制乙酰胆碱酯酶活性研究。方法从β-酮酯3与2-亚甲基-1,3-丙二醇双醋酸酯4在手性膦配体钯催化下,对映选择性的形成双环化合物5,双键移位后得到关键中间体6,进而复结晶富集后,得到光学纯6。经Wittig反应,得双键化合物7,酯基水解后,得到相应酸8。经改良的Curtius重排,产生氨基甲酸酯9。除去保护后,得目标化合物2。结果(-)-14-去甲基石杉碱甲仅是天然(-)-石杉碱甲抑制乙酰胆碱酯酶活性1/8。结论由电鳐乙酰胆碱酯酶与(-)-石杉碱甲复合物X-射线衍射结构分析揭示,14-甲基与酶形成氢键是(-)-石杉碱甲高抑制活性的一个必要基团。

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 beta-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.