基于氮杂环卡宾(NHC)催化的新型串联反应的环状骨架高效构建

Developing new synthetic methods and reaction systems for the efficient erections of cyclic skeletons is of great theoretical and practical significance, due to the extensive distribution of these scaffolds in natural products, medicine, agrochemical and functional materials. By use of the unique umpolung reactivity of aldehyde under the catalysis of N-Heterocyclic Carbene (NHC), this project will focus on the development of new NHC-catalyzed cascade reactions and their applications in the efficient assembly of cyclic scaffolds. Firstly, some diarylated heterocycles will be synthesized efficiently via NHC-catalyzed multi-component cascade reactions incorporating Benzoin and Stetter reaction. Secondly, some designed substrates with multiple reactive sites will be synthesized and react with other reagents to fabricate the cyclic scaffolds under NHC-catalysis. Thirdly, the reaction mechanism and the relationship among the structure of NHC, catalytic activity and reaction selectivity will be studied to provide effective guidance to the design and synthesis of catalysts with the assistance of computational organic chemistry. This study will not only pave efficient avenues to the diversified and stereoselective construction of important cyclic frameworks, but also highlight the uniqueness and superiority of NHC as organocatalysts. At the same time, this research will broaden the application scope of NHC in organocatalytic synthesis and lay a foundation for the discovery of new cyclic compounds with potential application prospect..

环状骨架广泛存在于天然产物及人工合成的医药、农药、功能材料分子中，因此高效构建这些骨架的方法学研究具有重要的理论和应用价值。本项目利用氮杂环卡宾(NHC)能使醛基发生极性反转这一独特性质，将重点开展基于NHC催化的新型串联反应的高效构建环状骨架的方法学研究：一是在NHC 催化的Stetter 反应和安息香反应参与下，通过多组分串联反应，实现二芳基化杂环化合物的高效合成；二是设计合成多反应位点底物，寻找有效的NHC催化剂，经过串联反应构建重要环状骨架；三是通过计算有机化学手段解释反应机理，探究NHC的结构与催化活性、反应选择性三者关系，为催化剂的设计提供有效指导。本项目的实施将不仅为重要环状化合物的合成提供高效、立体选择性高、产物多样性高的方法，而且将凸显NHC在催化有机合成方面的独特性和优越性并拓展NHC在有机催化领域的应用范围，同时也为新的具有潜在应用前景的环状化合物的发现奠定基础。

本项目首先以醛和邻亚甲基醌为原料，在氮杂环卡宾(N-Heterocyclic Carbene, NHC)催化下，经过Stetter反应和酸催化关环，合成了苯并呋喃。醛与邻溴苄溴经过NHC催化的偶联和Pd催化环化，也可以构建苯并呋喃骨架。带有γ-H的烯醛经过NHC催化，在氧化剂存在下，转变为烯基烯醇负离子。它与靛红发生形式上的[4+2]反应，得到了螺氧化吲哚-吡喃酮类化合物。在碱性条件下，带有γ-H的α-溴代烯醛经过NHC催化，同样可以转化为烯基烯醇负离子。它与C=O、C=N、C=C双键发生[4+2]反应，构建六元环状骨架。为了拓展NHC催化有机反应的底物范围，我们尝试了NHC催化下带有γ-H的α,β-不饱和羧酸酯与靛红的反应。发现它可以顺利地给出螺氧化吲哚-吡喃酮类化合物。受多肽合成中使用肽偶联促进试剂(Peptide Coupling Reagents, PCRs)活化羧酸的启发，我们采用原位活化策略，将α,β-不饱和羧酸与靛红及1,3-二羰基化合物在NHC催化下直接反应，合成了螺氧化吲哚-吡喃酮及吡喃酮类化合物。进一步的研究发现，饱和的羧酸也可以经过原位活化后，通过NHC催化转变为烯醇负离子、高烯醇负离子及烯基烯醇负离子。这些中间体与其它底物发生环化后，不仅构建了香豆素、螺氧化吲哚-γ-丁内酯及δ-内酰胺等骨架，而且实现了饱和羧酸α，β及γ位的高效活化。这些合成方法具有产率高，条件温和，对映选择性高等优点，体现了NHC催化的独特性和高效性。