新型手性三氮唑盐的设计合成及其在不对称氮杂环卡宾催化中的应用

As a unique Lewis base, the chiral N-Heterocyclic Carbene (NHC) has been extensively studied in asymmetric organocatalysis and also recognized as one of the most exciting research field in recent years. A variety of different kinds of NHC precursors have been designed and synthesized, leading to the development of elegant and diverse NHC catalytic models. However, problems such as challenges in stereocontrol, limitations in substrate types, regioselective remote activation, etc. are still remain unsolved in this area. In the aim of providing potential solutions to these long-standing problems, we will synthesize a series of new NHC catalysts based on triazolium moiety in this project, with a special focus on the development of chiral bifunctional NHCs. Then, the application of these catalysts in challenging reactions such as asymmetric intermolecular hydride-transfer reduction of ketone and ketimine, asymmetric Michael Umpolung reactions, regioselective remote activation of dienals and so on will be systematically investigated. Additionally, based on these NHCs, cooperative catalysis merging NHC organocatalysis and other catalytic protocols (for example, photoredox catalysis) will also be studied in parallel. In a word, these studies will further enrich the NHC catalytic systems, provide new solutions for discovering unconventional reactivity and enable the applicants to perform asymmetric synthesis in a novel way.

近年来，将手性氮杂环卡宾作为一类独特的路易斯碱，应用于不对称有机催化反应成为研究热点之一。人们设计合成了多种类型的手性卡宾前体，并以此建立了丰富多样的催化模型。尽管如此，该领域仍然存在反应立体选择性控制难度大、底物类型局限、区域选择性难以实现远端活化和控制等亟待解决的问题。本项目拟通过合理设计，快速合成一系列具有新颖手性骨架的三氮唑类卡宾前体，并在此基础上重点发展手性双功能卡宾小分子催化剂。随后，将其应用于催化酮或酮亚胺的不对称分子间负氢转移还原、不对称Michael受体极性反转反应以及对不饱和二烯醛的远端区域活化控制等已有催化体系难以解决问题的研究之中。同时基于此类催化剂，开展卡宾与其他类型催化体系（如可见光催化）协同催化模式的初步探索。本项目的成功实施，对于丰富卡宾催化体系、发现新反应途径等基础研究领域具有重要意义，并进一步指导申请人在不对称合成应用方向开展有特色的研究工作。

本项目以氮杂环卡宾这样一类独特的路易斯碱等有机小分子催化作为主要手段和工具，实现了多种类型底物的不对称催化反应。基于该领域中存在的立体选择性控制难度大、底物范围局限等问题，我们通过催化剂筛选、反应条件优化等多种方式，在保持目标反应高区域选择性、高立体选择性的同时，成功实现了低催化剂用量的卡宾小分子催化。除此之外，我们还发现了醛类底物的一类新颖的烯醇活化模式，并成功应用于高立体选择性的环加成反应。本项目所研究的不对称反应多数尚未见文献报道，通过这些新的不对称方法学研究，我们成功构建了结构多样的手性杂环骨架，主要包括：官能团富集的氧杂六元环、氮杂六元环、氮杂七元环以及多取代的三元环等小环结构等；除了单环、并环结构之外，还成功高效地合成了具有螺环或稠环结构的类天然产物（类药物）骨架。制备这些多手性中心的杂环衍生物，对于研究已知药物的构效关系，或者开发具有自主知识产权的手性候选药物都具有非常重要的理论和实践意义。