Stereoselective Transition Metal Catalysis Enabled by Hydrogen-Bond Donor Mediated Electrophile Activation

项目摘要 富含对映体的胺是多种生物活性化合物中普遍存在的官能团， 制药公司。目前获取它们的方法都有局限性，如原子经济性差、 选择性、反应性差或对高压气体的要求。过渡金属催化的交叉偶联 反应是获得对映体富集胺化合物的一种有效方法，这可能 用当前最先进的技术克服一些固有的问题。然而，新的不对称的发现 过渡金属催化过程通常需要详尽的配体筛选和寻找一组最优的 具有满意的活性、化学选择性和立体选择性的条件。在某些过程中，最好的 所使用的金属催化剂是那些没有添加任何配体或含有没有手性等价物的配体的催化剂 存在，为对映体诱导提出了具有挑战性的场景。这项提议概述了一种替代方法。 利用氢键施主(HBD)开发新的过渡金属催化方法 催化C(SP3)-O键向镍催化的交叉偶联反应。这种双重催化平台 是一种在概念上尚未探索的交叉偶联化学方法，其中HBD的作用是 加速氧化加成，同时通过离子配对赋予步骤的立体选择性。 然而，这些角色传统上被分配给配体性质，作为反应发展的驱动力 这项拟议的研究将证明利用这两种催化模式协同参与的可行性 温和的亲电体在对映体聚合体C(Sp3)-C(Sp2)的交叉偶联中生成胺类化合物。铃木- Miyaura和Mizoroki-Heck类型的易于接近的半椎板底物联轴器将由 利用HBD介导的衬底电离来产生亚胺离子。HBD已经被证明 是生成亚胺离子和它们随后参与对映体选择性的有效催化剂 被标准的亲核试剂捕获。与这些传统的反应曲线不同的是，通过一种 金属在这里被提出。有趣的是，各种Ni催化的C(SP3)-O键的立体选择性偶联都有 据报道，在“无配体”的条件下或在含有不容易的烯烃配体的情况下表现最好 转化为手性等价物，从而突出了这一方法的战略。成功地执行此操作 提案将揭示一种获取对映体富集胺的新方法，并为 HBD-催化与过渡金属催化的协同作用。

Project Summary Enantioenriched amines are prevalent functional groups found in various bioactive compounds and pharmaceuticals. Current methods for accessing them come with limitations, such as poor atom-economy, poor selectivity, poor reactivity, or requirement for high-pressure gases. Transition metal catalyzed cross-coupling reactions represent a powerful approach towards accessing enantioenriched amine compounds, which could overcome some of the inherent issues with current state-of-the-art. However, the discovery of new asymmetric transition metal catalyzed processes often requires exhaustive ligand screening and search for an optimal set of conditions that enable satisfactory activity, chemoselectivity, and stereoselectivity. In some processes, the best metal catalysts employed are those without any added ligands or with ligands to which no chiral equivalents exist, presenting challenging scenarios for enantioinduction. This proposal outlines an alternative approach towards the development of new transition metal catalyzed methodology, utilizing hydrogen-bond donor (HBD) catalysis to activate C(sp3)–O bonds towards a Ni-catalyzed cross-coupling reaction. This dual catalytic platform is a conceptually unexplored approach towards cross-coupling chemistry, wherein the role of the HBD is to accelerate the oxidative addition while simultaneously imparting stereoselectivity to the step through ion pairing. These roles have traditionally been assigned to ligand properties as the driver of reaction development, however this proposed research will demonstrate the feasibility of leveraging both catalytic modes to cooperatively engage mild electrophiles in an enantioconvergent C(sp3)–C(sp2) cross-coupling to generate amine compounds. Suzuki- Miyaura and Mizoroki-Heck type couplings of readily-accessible hemiaminal substrates will be explored by leveraging HBD-mediated substrate ionization for the generation of iminium ions. HBDs have been demonstrated to be effective catalysts for the generation of iminium ions, and their subsequent engagement in enantioselective trapping by standard nucleophiles. Unlike these traditional reaction profiles, the trapping of iminium ions by a metal is proposed here. Interestingly, various stereoselective Ni-catalyzed couplings of C(sp3)–O bonds have been reported to perform the best under “ligandless” conditions or with olefinic ligands that are not easily converted to chiral equivalents, thus highlighting the strategy of this approach. Successful execution of this proposal will reveal a new method for accessing enantioenriched amines and establish a proof-of-concept for the synergistic cooperation of HBD-catalysis with transition metal catalysis.