邻亚甲基苯醌的不对称光反应研究

Precise synthesis of chiral molecules is one of the most important areas in the modern organic chemistry. The “synergistic multicatalytic activation mode” comprising of two or more than two catalytic enties provides a powerful platform for simultaneously in situ-generation of multiple highly reactive species and design of new catalytic enantioselective reactions with such species. Over recent years, visible light-driven photocatalysis, using visible light as a renewable energy source, has been established as a powerful and mild technique to facilitate activation of organic molecules and engineer new chemical processes selectively. However, it is still a challenging task for organic chemists to develop the visible light-driven photocatalytic enantioselective transformations... In this project, we will mainly focus on the development of a series of new “synergistic multicatalytic activation modes” by rational combination of visible light photocatalysis with metal- or organocatalyst-based asymmetric catalysis; with these catalytic systems in hand, we will then try to develop several types of catalytic enantioselective cyclization reactions of in situ-formed (aza)-ortho-quinone methides for precise construction of various biologically active chiral heterocycles, mainly including: 1) catalytic asymmetric (aza)-ortho-quinone methides and trifluoromethyl radical-based multi-component cyclization reaction; 2) catalytic asymmetric (aza)-ortho-quinone methides and C-centered radical-based addition/cyclization cascade reaction; 3) catalytic asymmetric [4+2] cycloaddition reactions of aza-ortho-quinone methides with 1,3-dicarbonyl compounds; 4) catalytic enantioselective formal [4+2] cycloaddition between (aza)-ortho-quinone methides and α,β-unsaturated ketones; 5) mechanistic studies and design of new cycloaddition reactions with (aza)-ortho-quinone methides. By executing this project, we will try to achieve several efficient “synergistic multicatalytic activation systems” comprising of photocatalysts and Lewis acids or organocatalysts for catalytic asymmetric cycloaddition reaction of (aza)-ortho quinone methides, providing some new strategies and concepts for the green synthesis of diversely functionalized enantioenriched heterocycles in a highly stereoselectivce manner. And we hope that these studies will also stimulate the further advances of enantioselective synthetic chemistry in our country.

手性分子的精准构筑一直是有机合成化学中的重要研究领域。基于两种或两种以上催化方法的“协同多重催化活化模式”为多种活泼物种的原位产生和立体选择性反应设计提供了新的催化策略。最近，可见光驱动的光氧化还原催化为有机分子活化和新反应设计提供了一个新的平台。本项目将探索可见光驱动活化与不对称催化共同作用的“协同多重催化活化模式”，发展（氮杂）亚甲基苯醌试剂参与的立体选择性环化反应，为官能团丰富、具有潜在生物活性的手性杂环精准合成提供新的方法。重点研究：1）（氮杂）邻亚甲基苯醌与三氟甲基自由基参与的多组分环化反应；2）（氮杂）邻亚甲基苯醌与碳自由基参与的加成/环化串联反应；3）氮杂邻亚甲基苯醌与1,3-二羰基化合物的[4+2]环化反应；4）（氮杂）邻亚甲基苯醌与不饱和酮的[4+2]环化反应；5）机理研究，指导后续多重催化活化模式和新反应设计。希望通过本项目的实施进一步推动我国在手性科学领域的创新能力。

(氮杂)邻亚甲基苯醌是一类重要的活泼中间体，被广泛应用于含氮和含氧杂环的构建。由于其高度活泼，往往只能用合适的前体原位产生。可见光促进的光氧化还原催化策略具有光源易得、反应条件温和、操作简单以及官能团兼容性好等优点。随着对光氧化还原催化反应模式和机理研究的不断深入，这一方法已经成为化学键选择性活化、切断和重建、以及功能有机分子和复杂分子构建的重要策略。.为此，我们提出了“可见光驱动自由基介导邻亚甲基苯醌产生”策略，利用易得的前体和自由基物种原位产生氮杂-邻亚甲基苯醌和邻亚甲基苯醌，并发展新型的自由基多组分反应，以期合成结构多样的官能化杂环化合物。.在项目执行期内，申请人围绕“(氮杂)邻亚甲基苯醌的可控产生和反应设计”等关键科学问题，基于几类易制备的自由基前体，并通过“协同催化体系”的合理设计，开发了一系列可见光驱动的邻亚甲基苯醌和氮杂邻亚甲基苯醌的产生策略，并发展了一系列多组分环化反应。也开发了一些可见光驱动的不对称催化体系，为自由基反应的手性控制提供了新的思路。另外，还发展了一系列光/铜催化体系，为自由基反应的手性控制提供了一些新的催化体系。.基于这些研究，取得了一些有创新性的进展，圆满完成研究计划。共发表SCI论文32篇。包括J. Am. Chem. Soc. (1篇)， Angew. Chem. Int. Ed. (1篇)，Nat. Commun. (1篇)，ACS. Catal. (1篇)，Org. Lett. (9篇)，Chem. Commun. (2篇)等，并应邀撰写了2篇关于有机自由基化学合成方面的综述 (Chem. Rev. 2021, 121, 506; Green Synth. Catal. 2020, 1, 42)，撰写了1个人评述 (Acc. Chem. Res. 2020, 53, 1066)。设计开发了一套用于开展低温光反应研究的内嵌式光反应器，并获1项中国实用新型专利授权。荣获2019年中国光化学-泊菲莱优秀青年科学家奖。.共培养了5硕士研究生和3名博士研究生。其中2人获得研究生国家奖学金，1人获得德国洪堡博士后奖学金。1名博士毕业后进入高校工作。2名硕士研究生先后继续攻读博士学位。

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