基于亲核-亲电双重反应活性底物设计和氧化型氮杂环卡宾催化的多取代手性环状化合物的合成研究

Chiral cyclic compounds are important intermediates for organic synthesis, and skeleton structures or key units in bioactive substances such as medicines and natural products. In recent years, N-heterocyclic carbene (NHC) catalyzed annulation reactions have witnessed dramatic progress, especially in the synthesis of chiral cyclic molecules. In this project, we plan to make a series of substrates with both nucleophilicity and electrophilicity, which will react with oxidative NHC activated α, β-unsaturated acyl azolium to afford cyclic products with multiple chiral centers. Scientific issues, such as accurate reactivity control of several reaction positions in cascade annulation reactions and synthesis of several different types of polysubstituted chiral cyclic compounds through one single approach, can be solved in this project. It is also supposed that this methodology can be developed to a general strategy in organic synthesis, which will direct the retro-synthetic analysis of chiral cyclic compounds and provide methodological support for medicine discorvery and natural product synthesis.

手性环状分子是重要的有机合成中间体，也是众多药物和生物活性分子的骨架结构或重要组成单元，所以多取代手性环状分子的合成是有机化学研究热点之一。最近几年，氮杂环卡宾作为有机小分子催化剂在手性环状分子的合成中显示出其独特的作用。本项目拟设计合成多类具有亲核-亲电双重反应活性的底物分子，与氧化型氮杂环卡宾催化产生的的α, β-不饱和酰基氮鎓盐发生多步串联环合反应，以制备出多种类型的多取代手性环状化合物，从而解决多步串联反应中多个位点的反应性能调控和同一途径合成多类型多取代手性环状分子等科学问题。这一方法也有望发展成具有普适性的氮杂环卡宾催化的环合策略，为更多的手性环状化合物反合成分析提供借鉴，也为新药研发和天然产物合成提供有力的方法学支持。

发展有机催化的串联合成反应构建多立体中心手性分子对于天然产物和药物活性分子的快速合成有重要意义。本项目使用氮杂环卡宾作为仿生催化剂，实现了一系列亲核-亲电双重反应活性底物与不饱和酰基氮鎓盐的串联环合，制备了多类重要的手性分子如二氢萘、环己烯等；同时使用醛基的极性反转策略，实现了多类醛酮底物的分子内环合，制备了一系列重要的手性分子如四氢萘酮、色满酮、黄烷酮等，为药物活性分子库的快速建立提供了有力的方法学支持。