Synthetic Efficiency via Metal-Catalyzed Reductive and Oxidative Coupling Reactions

合成化学在维持和改善人类生活的技术发展中起着核心作用。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，他们需要以时间和资源效率高的方式制备多样化、拓扑复杂的目标。加速分子和材料构建的新方法对包括药物发现和可持续能源技术在内的许多科学领域产生了积极影响。我们的研究项目开发催化成键工艺，以解决化学合成中未满足的需求。这些方法提供高收率和选择性的产品，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，促进了多功能化底物的直接使用，而不需要官能团的操纵。本提案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策略。将调查两个具有相似概念目标的主要专题领域。我们将开发一套通用的反应，使用铜催化剂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苄基化试剂。为了补充我们现有的涉及铜种有氧再氧化的方法，我们将探索金属基氧化剂和电化学技术。这些方法将抑制不希望的底物氧化，从而扩大在这些转化中有效的底物类别。我们将利用甲酸介导的铑催化烯烃金属加氢反应的化学选择性和立体选择性来制备和衍生小分子。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-、-和-氨基酸。我们的目标是通过氢化铑催化发展肽连接/大环化的新方法。在主题1和主题2中，提出了通过双催化方法来改善转化的范围和选择性，其中第二种金属物质激活底物进行氧化或还原偶联。新工艺的应用将通过制备生物活性分子的关键支架和/或多功能化商业药物或天然产物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，获得在化学和制药领域担任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.