He Xu-chang, Yu Geng-li, Bai Dong-lu
Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
Yao Xue Xue Bao. 2003 May;38(5):346-9.
To study asymmetric total synthesis of 14-nor-huperzine A 2 and its inhibitory activity on acetylcholinesterase.
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.
The inhibitory activity of synthetic (-)-14-nor-huperzine A was 8 fold less potent than that of (-)-huperzine A.
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.
研究14-去甲石杉碱甲2的不对称全合成及其对乙酰胆碱酯酶的抑制活性。
使用新型手性二茂铁基膦配体（如10、11），通过钯催化的双环化反应，由β-酮酯3和二乙酸2-亚甲基-1,3-丙二醇酯4高对映选择性合成化合物5，随后进行区域选择性双键迁移生成化合物6。对映体富集重结晶后得到光学纯的6。然后，按照石杉碱甲合成的类似步骤，制备目标化合物14-去甲石杉碱甲2。用大鼠红细胞膜乙酰胆碱酯酶测试其抑制活性。
合成的（-）-14-去甲石杉碱甲的抑制活性比（-）-石杉碱甲低8倍。
（-）-石杉碱甲的14-甲基与His 440的主链氧之间的氢键对于石杉碱甲的高乙酰胆碱酯酶抑制活性是必需的。
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