几个akuammiline类生物碱的合成研究

Akuammiline-type alkaloids have long been a class of attractive targets for chemical synthesis. Taking advantage of the common structural features of them, we plan to develop divergent total syntheses of strictamine and scholarisines A and I from an advanced common intermediate. The bridged ring systems of these molecules would be constructed through metal-catalyzed alkyne cyclization, and the indole C3 quaternary center could be introduced by intramolecular alkylation. We will explore the ether C−O bond activation and the umpolung reactivity of α,β-unsaturated hydrazone as well. On the basis of highly efficient and scalable syntheses of them, the biological activities of the above mentioned natural products are expected to be evaluated by a variety of cell-based assays.

在数量巨大的吲哚生物碱中，akuammiline类生物碱是一类合成化学家密切关注的化合物。针对这类吲哚单萜生物碱的结构特征，我们拟利用一个通用的四环中间体，发散性地合成scholarisines A和I以及strictamine两类分子。桥环体系的构建拟利用金属催化的炔烃环化反应，吲哚3位季碳中心的构建则利用分子内烷基化反应；在合成过程中还将探索醚键的活化和共轭腙的极性反转等反应转化。我们希望实现上述分子的高效不对称合成，获得较大量的合成样品，并对其生物活性进行评价。

通过本项目的资助，我们实现了echitamine/akuammiline家族吲哚单萜生物碱strictamine、scholarisines A和I、akuammiline、deacetylakuammiline、echitamine、N-demethylechitamine、pseudoakuammigine、rhazimal和rhazicine的全合成。利用银催化内炔环化反应构建了akuammiline类天然产物的氮杂桥环结构，再通过C−O键切断和C−N键形成反应构建了该类分子的五环骨架，进而实现了strictamine、akuammiline和deacetylakuammiline的全合成。通过Polonovski−Potier反应和[1,2]-Meisenheimer重排反应两种途径，均切断了akuammiline类分子骨架中的C3−N4键，进而实现了N-demethylechitamine和echitamine的全合成。利用自由基环化反应形成了scholarisine A类天然产物骨架中的C5−C20键，建立了正确的立体化学，进而完成了scholarisines A和I的全合成。项目负责人作为通讯作者/共同通讯作者发表标注本项目资助的学术论文5篇，其中包括发表在Angew. Chem. Int. Ed.上的研究论文1篇和发表在J. Am. Chem. Soc.上的研究论文2篇。