Synthetic Efficiency via Metal-Catalyzed Reductive and Oxidative Coupling Reactions

前言合成化学在维持和改善人类生活的技术发展中发挥着核心作用。私营和公共部门的有机化学从业者面临着越来越大的压力，要求他们以及时和资源高效的方式准备各种复杂的拓扑结构目标。加速构建分子和材料的新方法对包括药物发现和可持续能源技术在内的一些科学领域产生了积极影响。我们的研究项目开发了催化键形成过程，以满足化学合成中未得到满足的需求。这些方法以高产率和选择性提供产品，使用稳定的起始材料，避免过多的预活化步骤，并以模块化和可预测的方式进行。我们建立了金属催化的偶联反应，促进了多官能化底物的直接使用，而不需要官能团操作。这项建议概述了我们继续努力开发化学选择性金属催化成键过程的战略。将调查具有相似概念目标的两个主要专题领域。主题1：氧化交叉偶联我们将开发一组通用的反应，这些反应使用铜催化剂来氧化交叉偶联两种不同的亲核试剂。一个主要的焦点将是研究芳基乙酸衍生物作为脱羧基的苄基化试剂。为了补充我们现有的铜物种有氧再氧化的方法，我们将探索基于金属的氧化剂和电化学技术。这些方法将抑制不受欢迎的底物氧化，从而扩大在这些转化中有效的底物类别。主题2：甲酸盐介导的还原偶联我们将利用甲酸盐介导的铑催化的水合金属烯烃反应的非凡的化学和立体选择性来制备和衍生化小分子。新的二烯加氢功能化反应将被发明，以产生嵌入Z-烯烃单元的α-、β和伽马-氨基酸。我们的目标是开发一种新的方法，通过氢化铑催化多肽连接/大环化。在主题1和主题2中，建议通过双重催化方法来改善转化的范围和选择性，在双重催化方法中，第二种金属物种激活底物进行氧化或还原耦合。新工艺的应用将通过制备生物活性分子的关键支架和/或多功能商业药物或天然产品的后期衍生化来展示。HQP将在尖端环境中接受合成/物理有机化学和均相催化方面的培训，获得化学和制药部门领导职位所需的技能。

Introduction Synthetic chemistry plays a central role in the development of technology that sustains and improves human life. Practitioners of organic chemistry in the private and public sectors are under increasing pressure to prepare diverse, topologically complex targets in a time and resource-efficient manner. Novel methodologies that accelerate the construction of molecules and materials have a positive impact on a number of scientific areas including drug discovery and sustainable energy technologies. Our research program develops catalytic bond-forming processes that address unmet needs in chemical synthesis. These methods provide products in high yield and selectivity, use stable starting materials, avoid excessive preactivation steps, and proceed in a modular and predictable fashion. We establish metal-catalyzed coupling reactions facilitating the direct use of polyfunctionalized substrates without functional group manipulations. This proposal outlines strategies for our continued efforts to develop chemoselective metal-catalyzed bond-forming processes. Two major thematic areas will be investigated that share similar conceptual goals. Theme 1: Oxidative Cross-Coupling We will develop a general set of reactions that use copper catalysts to oxidatively cross-couple two different nucleophiles. A major focus will be investigation of aryl acetic acid derivatives as decarboxylative benzylating reagents. To complement our existing methods involving aerobic reoxidation of copper species, we will explore metal-based oxidants and electrochemical techniques. These methods will inhibit undesirable substrate oxidation, thereby expanding the classes of substrates effective in these transformations. Theme 2: Formate-Mediated Reductive Coupling We will exploit the remarkable chemo- and stereoselectivity of formate-mediated rhodium-catalyzed olefin hydrometallation to prepare and derivativatize small molecules. New diene hydrofunctionalization reactions will be invented to generate alpha-, beta, and gamma-amino acids with embedded Z-olefin units. We aim to develop new methods for peptide ligation/macrocyclization via rhodium-hydride catalysis. In both Theme 1 and Theme 2, the scope and selectivity of the transformations are proposed to be improved by dual catalytic approaches, in which a second metal species activates a substrate for oxidative or reductive coupling. Application of new processes will be showcased by the preparation of key scaffolds of bioactive molecules and/or the late-stage derivatization of polyfunctionalized commercial pharmaceuticals or natural products. HQP will receive training in synthetic/physical organic chemistry and homogeneous catalysis in a cutting-edge environment, gaining skills needed for leadership positions in the chemical and pharmaceutical sectors.