基于环钯中间体合成中环化合物的分子间串联反应研究

Medium-sized rings are quite significant in organic chemistry as they form the structural core of a large number of natural products and biologically active compounds. However, efficient access to medium-sized rings remains to be a challenge in synthetic organic chemistry due to the high level of transannular interactions and unfavorable entropic factors. Intramolecular reactions are still the most important method in medium-ring synthesis, although these methods often suffer from complicated substrates prefabrication problems. To address these thorny problems, this project aims to provide an efficient synthetic method for the synthesis of medium-sized cyclic compounds through palladium-catalyzed intermolecular tandem reactions. The ability of five-membered palladacycles in forming multiple chemical bonds and the sequential ring closure/ring expansion strategy are key factors for the novel method. Additionally, the medium-ring building method can be applied to the construction of natural products and biologically active compounds.

许多天然产物和具有重要生理活性的化合物分子都含有中环骨架结构。然而，由于存在跨环作用力和熵效应等不利因素，中环化合物的合成一直是有机化学中一个很大的挑战。此外，目前中环化合物大多通过分子内反应合成，反应底物往往需要复杂的预制备。针对这些问题，本课题以五元环钯中间体在串联反应中连续构筑多根化学键的能力为关键，以先闭环构筑环钯中间体后扩环实现环的增长为策略，力求发展一种通过钯催化分子间串联反应高效合成中环化合物的新方法，并运用到天然产物和具有生理活性的中环化合物的合成中。

杂环结构广泛存在于天然产物和具有重要生理活性的化合物中，可作为药物先导化合物应用于新药研发中。因此，环状化合物的合成与修饰具有重要的理论和实际意义。本项目主要研究了杂环的构筑和烷基化修饰两个方面的内容，具体包括：（a）发展了零价钯催化的苯炔与氯甲酰烯丙基胺的串联环化反应，完成了一系列内酰胺类杂环化合物的合成；（b）研究了铜催化的8-酰胺基喹啉与卤代烷烃的偶联反应，实现了喹啉环5-位碳氢键卤化和氟烷基化反应；（c）开发了苯并呋喃和卤代烷烃的无金属参与氧化自由基烷基化反应，向苯并呋喃杂环中引入烷基并构筑了季碳中心；（d）探索了2-溴异丁酰苯胺的无金属氧化自由基环化反应，实现了吲哚酮类杂环化合物的绿色合成。