老年痴呆症药物石杉碱甲的类似物研究Ⅱ(±)-失二碳石杉碱甲类似物的合成

石衫碱甲(1)是从中草药干层塔中提取分离到的一种高效可逆的乙酰胆碱酯酶抑制剂,经临床试验证实对老年痴呆症有显著疗效。本文报道保持石杉碱甲分子基本骨架,失二个甲基类似物7和8的合成。β-酮酯2和丙烯醛发生Michael-Aldol反应得直立键和平伏键的羟基化合物9和10,其相应的甲磺酸酯11和12分别在丙二酸钠和醋酸中130℃回流,直立键甲磺酸酯11发生消去反应得需要的环内双键中间体13,而平伏键甲磺酸酯12则发生SN₂取代反应得直立键醋酸酯14。基于全合成路线,合成了失二碳石杉碱甲类似物7和8,其乙酰胆碱酯酶抑制活性均低于天然石杉碱甲。

STUDIES ON ANALOGUES OF HUPERZINE A FOR TREATMENT OF SENILE DEMENTIAⅡSYNTHESIS OF ANALOGUES OF (±)-DINOR HUPERZINE A

Huperzhe A(1),isolated from the Chinese folk medicine Huperzia Serrata, is a potent and reversible inhibitor of acetylcholinesterase. Clinical trials have confirmed that huperzine Ais effective in the treatment of senile dementia,In this paper we report the synthesis of analogues 7and 8 retaining structurally the basic carbon skeleton of huperzine A. he β-keto ester 2 reacted with acrolein to perform in situ Michael-Aldol condensations and toafford the axial and equatorial hydroxy compounds 9 and 10,separated by silica gel columnchromatography.The hydroxy compounds were converted into mesylates 11and 12,respectively.Byrefluxing the mesylate in acetic acid with sodium malonate at 130℃,elimination product 13 wasformed only from axial mesylate 11 and SN₂ reaction occurred with equatorial mesylates 12 to giveaxial acetate 14.Intermediate 13 was finally transformed into analogue 7 according to the totalsynthesis route,involving Wittig olefination of ketone, hydrolysis of ester,modified Curtiusrearrangement and TMSI- promoted deprotection,Similarly,analogue 8 was synthesized fromintermediate 23, which was prepared from compound 13 by catalytic hydrogenation. Antiacetylcholinesterase activities of analogues 7 and 8 were found to be much lower than that ofhuperzine A.