催化不对称跨环动态动力学拆分及相关生物碱的集合式合成研究

Transannular reaction is one of the most important approaches to access polycyclic structures and for natural product synthesis. Notable advances have been overserved. However, there are only four reports on the catalytic asymmetric version, two of which were applied to natural product synthesis. Developing new catalytic asymmetric transannular reaction remains a challenging research topic. In this proposal, we are going to develop the first catalytic asymmetric transannular dynamic kinetic resolutions (CATDKR). Subsequently, the first catalytic asymmetric synthesis of (-)-rhazinicine will be completed, and a collective biomimetic syntheses of its related leuconolam-leuconoxine-mersicarpine mono-terpenoid indole alkaloids isolated from Apocynaceae such as (-)-rhazinilam, (-)-rhazinal, kopsiyunnanines, leuconodine E, etc., will be presented. Moreover, we will actively evaluate the scope of the new method and prepare a series of analogues of the natural alkaloid. Then various biological and mechanism studies will be taken to find suitable lead compound(s) for further modifications, improvement and studies to develop natural product-type drugs. The execution of this project should be able to shed some light on developing new catalytic asymmetric transannular reactions and for natural product synthesis.

合理设计跨环反应，可以快速、高选择性构建多环环系，在复杂多环类天然产物合成中已取得了瞩目的进展。然而，关于催化不对称跨环反应的研究报道却屈指可数。发展新型催化不对称跨环反应，具有一定的挑战性。本项目拟发展首例催化不对称跨环动态动力学拆分反应，以实现(-)-rhazinicine的首次催化不对称合成（7~8步）及其相关的leuconolam-leuconoxine-mersicarpine家族单萜吲哚类生物碱(-)-rhazinilam，(-)-rhazinal，kopsiyunnanines，leuconodine E等的集合式仿生合成。同时，通过拓展新方法、开展多样性导向合成，建立全新小分子化合物库，进而全面、系统的生物学活性及作用机制研究，进行该类天然产物类（抗癌）药物开发。本项目的实施，为发展新型催化不对称跨环反应及多环类天然产物的合成设计，能提供一定的借鉴和指导。

跨环反应，可以快速、高选择性构建多环环系，是一种构建复杂多环结构和合成天然产物的重要方法。然而，关于催化不对称跨环反应的研究报道却屈指可数。发展新型催化不对称跨环反应，具有一定的挑战性。本项目开展了基于吡咯和苯环的跨环前体的合成研究，并系统研究了苯环类大环化合物的催化不对称跨环动态动力学拆分研究。.同时，利用研究过程中开发的新型P,N及双膦配体，我们首次实现了富电子苯并呋喃类衍生物的催化不对称烯丙基化反应，取得了优异的结果（0.2-1.0% 钯催化剂，90-96% ee）；并实现了flavagline类天然产物的多样性导向合成，为该类天然产物类药物的开发奠定了良好的基础。