Akuammiline型吲哚生物碱corymine和echitamine的合成研究

Corymine, a structurally unique Akuammiline-type indoline alkaloid from Hunteria zeylanica, is characterized by a highly congested 6/5/5/6/7/7 hexa-ring system, and six continuous chiral centers including three quaternary carbon centers. Biological results revealed that corymine inhibited the glycine receptors expressed in Xenopus oocytes. Because of its interesting biological activity and inspiring architecture, we would like to initiate a synthetic program. Starting with trypamine, a readily developed synthetic method mediated by PIDA will be used to construct the core C ring and D ring. Subsequently, the seven-member E ring will be installed by a Michael addition or reductive Heck reaction, elaborating the key intermediate.Thereafter several functionality manipulations, an enantioselective toal synthesis of corymine will be realized. Echitamine, a congener of corymine, can be furnished through reduction of F ring and selective N-alkylation. On the other hand, another Picraline-type indoline alkaloid, scholarisine F, will be attacked from key intermediate. Inspired by Polonovski-Potier reaction, the key intermediate will be first selectively oxidated at N-13 and then rearrange to scholarisine F by treatment of TFAA/TFA.

Corymine是从泰国产仔榄树叶中分离得到的一个结构独特的Akuammiline型单萜吲哚生物碱，它由六个环紧凑骈合而成，含有六个连续的手性中心，其中包括三个手性季碳。活性研究表明，该化合物具有良好的抗惊厥作用。本项目拟基于高效简洁的策略，以色胺为原料，基于本课题组发展的Lewis酸催化、三价碘介导的反应，一步构建C环和D环；再利用Michael加成反应或还原Heck反应构建七元E环，合成关键中间体，然后进一步通过一系列官能团转化实现Corymine的不对称全合成。在此基础上，从corymine出发，经过还原及选择性N烷基化合成其同系物echitamine。此外，我们还将尝试从上述关键中间体出发，基于Polonovski-Potier反应，先选择性形成13位氮氧化物，再在TFAA/TFA条件下重排加水形成胺缩酮，进而合成Picraline型单萜吲哚生物碱scholarisine F。

本项目主要开展了akuammiline 型单萜吲哚生物碱corymine 和echitamine全合成研究，发展了具有特色的合成路线，采用非过渡金属催化的吡啶盐偶联反应为关键步骤，经15步反应得到天然产物corymine，17步反应得到echitamine。