基于金属卡宾对芳环C-H键官能团化的不对称多组分反应

Metal carbene-involved C-H functionalization is among the most important and powerful strategies in modern organic synthesis. Compared with the well-developed sp3 C-H functionalization, aromatic sp2 C-H functionalization via metal carbenes are far less developed, probably owing to the undesired Buncher ring expansion and poor regioselectivity. Recently, by introducing hetero-atom substitutent on the aromatic ring (such as aniline or phenol), several metal-catalyzed highly regioselectivie aromatic C-H functionalization via metal carbenes have been realized. Such transformation took advantage of the existence of the hetero-atom substitutent, which could stabilize the active zwitterionic intermediate formed in the metal carbene insertion step. However, research in this area still suffers the limited reaction pathways (all reported examples ended up with rapid “proton transfer”) and difficult asymmetric controls (so far only one asymmetric example was reported by Zhou and coworkers). .In this proposal, we will develop a trapping strategy by introducing different kinds of electrophiles or in situ generated electrophilic species (such as pi-allyl metal intermediates) to trap the active zwitterionic intermediate formed from metal carbene insertion into the aromatic C-H bonds, and thus establish a new strategy for metal carbene-involved aromatic C-H bond functionalizations; meanwhile, to develop cooperative catalytic systems to realize asymmetric control of such transformations. The established asymmetric multicomponent reaction via the metal carbene-involved aromatic C-H functionalization pathway will provide a straightforward one-step construction of chiral all carbon benzylic quaternary centers starting from simple arenes, as well as to enrich the application of metal carbenes in organic synthesis.

金属卡宾参与的C–H 键官能团化是有机合成中的重要研究领域。相比sp3 C–H键官能团化的广泛发展，金属卡宾对芳环C–H键的官能团化由于受到扩环副反应及区域选择性等问题而较少研究。近几年来，通过在芳环上引入杂原子取代基而稳定金属卡宾对芳环C-H键插入所生成的活泼两性离子中间体，该领域取得了一些突破，几例高区域选择性的例子被报道。然而，金属卡宾对芳环C-H键的官能团化仍存在很大挑战，如反应历程比较单一，不对称催化反应发展较少。为此，本项目将探索不同类型的亲电试剂或现场生成的亲电中间体对活泼两性离子中间体的捕捉策略，实现金属卡宾对芳环C-H键官能团化的新反应类型；开发高效的协同催化体系，通过对捕捉试剂或中间体的手性控制实现高立体选择性的金属卡宾对芳环C-H键的不对称官能团化，克服传统反应历程中“质子转移”步骤难以实现手性控制的缺点，实现从简单芳环化合物到苄位季碳全碳手性中心的一步高效转化。

金属卡宾所参与的不对称多组分反应近年来逐渐成为了一种兼具效率和多样性的高效合成策略。围绕此类不对称反应的类型拓展，包括与金属卡宾作用生成活泼中间体物种的亲核试剂前体的种类拓展、用于实现亲电捕捉的亲电试剂的种类拓展、以及用于调控反应的高效性及高选择性的催化体系的设计与发展，是制约该研究领域发展的主要问题，也正是本项目所聚焦的主要研究目标。本项目以开发金属卡宾所参与的新类型不对称催化多组分反应为主要研究内容，从金属卡宾对芳环碳氢键的官能团化研究入手，围绕亲核试剂的拓展、亲电试剂的拓展、催化体系的开发等几个关键问题，开展了系统的研究工作，发展了一系列基于金属卡宾而实现的不对称多组分反应。深入研究了围绕金属卡宾而形成的不同类型的活性中间体，包括基于芳环碳氢键活化而生成的活泼两性离子中间体、基于不同类型亲核试剂如硫、硒、末端炔烃等生成的活泼叶立德中间体，在适当的不对称催化策略，包括利用过渡金属催化剂与手性配体的组合，或利用过渡金属与手性有机小分子催化剂如手性磷酸等的协同催化作用，通过选取不同类型的亲电捕捉试剂，实现了系列新型的不对称催化多组分反应。进一步拓宽了亲电试剂的种类，借助低价过渡金属催化剂，实现了以不饱和烃如共轭二烯、甲基炔烃等作为现场生成的金属-烯丙基化前体，对不同类型的亲核物种如噁唑酮、简单酮等的捕捉，并实现了高效的不对称催化控制，为后续开发新类型的原子经济性不对称催化多组分反应奠定了基础。