Synthetic Efficiency via Metal-Catalyzed Reductive and Oxidative Coupling Reactions

点击翻译按钮获取中文摘要

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.