具有多环稠合复杂结构和高度生物活性的C19-二萜生物碱-甲基牛扁碱（Methyllycaconitine）的全合成研究

Methyllycaconitine(MLA) is a representative Lycoctonine-type C19-diterpenoid alkaloids with distinguished biological activities, characterized by a fused hexacyclic system, heavily substituted by various oxygen function groups. As to be the most potent non-protein competitive antagonist of the neuronal nicotinic actylcholine receptor found, MLA has attracted much attention of a number of phamarcisits and chemists. However, chemical preparation of MLA by total synthesis has never been described yet，although it's detail structure has been completedly recognized since 1981. In this application，we propose a new strategy for synthesis of lycoctonine and MLA based on the novel mothod for construction of AEF ring system of lycoctonine-type alkaloid through an intramolecular transannular aziridination reaction followed by regio-selective ring cleavage. In addition,this synthetic strategy involve several other key transformations, including the Frieldel-Crafts alkylation to construct seven-membered B ring, stereoselective redution aryl ring to form D ring bearing 1,3-dicarbonyl group, intramolecular alpha-alkylation of ketone to construct [3.2.1] CD ring, and the key functional group interconversions at C-8, C-14, and C-16. Finally, the asymmetric synthetic access to (+) methylmycaconitine by application of copper-catalyzed asymmetric conjugated addition reaction to form chiral ring A precousor at early stage has been designed.

甲基牛扁碱是牛扁碱型C19-二萜生物碱中具有代表性的生物活性分子，具有高度氧取代和多环稠合的复杂结构，作为目前发现的最强的非蛋白烟碱乙酰胆碱受体竞争性拮抗剂，甲基牛扁碱受到众多药物学家和化学家们的高度重视，但迄今未见成功化学全合成报道。本项目在通过分子内跨环氮杂环丙烷化反应及区域选择性开环构建关键的具有C-7位氧取代的AEF环的基础上，合理设计了经分子内富电子芳香环与羰基的Friedel-Crafts加成反应构建七元B环、立体选择性Birch还原芳香环构建D环、分子内羰基alpha烷基化反应构建[3.2.1]CD桥环等关键反应以及C-8,C-14,C-16功能基转化，从而完成牛扁碱和甲基牛扁碱全合成的设计路线。并最终通过应用铜催化格式试剂不对称共轭加成反应制备手性六元A环前体，进而完成光学活性(+)甲基牛扁碱的不对称全合成。

甲基牛扁碱是牛扁碱型C19-二萜生物碱中具有代表性的生物活性分子，具有高度氧取代和多环稠合的复杂结构，作为目前发现的最强的小分子烟碱乙酰胆碱受体竞争性拮抗剂，甲基牛扁碱受到众多药物学家和化学家们的高度重视。尽管迄今已有数个C19-二萜生物碱的全合成被报道，但甲基牛扁碱的全合成却仍未成功。项目研究在通过分子内跨环氮杂环丙烷化反应及区域选择性开环构建关键的具有C-7位氧取代的AEF三环的基础上，尝试了经分子内富电子芳香环与羰基的Friedel-Crafts加成或自由基加成反应构建ABEDF五环的研究，未获成功。在此基础上提出先了先合成BCD三环再构建AEF环的新合成策略。在尝试经阳离子型分子内[5+2]环加成反应构建C19-二萜生物碱[6.2.1.0] BCD环系失败的基础上，完成了高立体选择性串联分子内D-A反应和Wagner-Meerwein重排构建高度功能化的C19-二萜生物碱[6.2.1.0] BCD环系和[7.2.1.0] BCD环系。继而 以Trost环异构化反应和SmI2促进的自由基偶联反应为基础完成了C19-二萜生物碱氮杂ABEF模型四环的构建；以及通过立体选择性自由基加成反应构建7,17-裂解型C19-二萜生物碱ABF模型三环；在上述模型反应基础上，最终实现了分子内腈氧化物[3+2]环加成 (INOC)构建C19-二萜生物碱ABCD四环和立体选择性自由基加成反应构建牛扁碱ABCDE五环的合成。

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