Selective Chemical Synthesis and Catalysis Enabled by Single-Electron Oxidation of Aromatic N-oxides

点击翻译按钮获取中文摘要

Project Summary/Abstract The straightforward laboratory preparation of structural motifs commonly found in therapeutic agents in a selective fashion and utilizing readily available chemicals is a major driving force in the development of new synthetic strategies and catalysis. In our laboratory, we have adopted synthesis and catalysis development via unconventional single-electron transfer chemistry of aromatic N-oxides, readily accessible, tunable, and versatile compounds. Our long-term research goal is to develop and understand the single-electron transfer process of aromatic N-oxides that could offer new chemical space and access to synthesis and catalysis enabling discovery and innovation across synthetic and biological systems. The five-year research program will lead to a greater understanding of the currently underdeveloped single-electron transfer chemistry of aromatic N-oxides, and it is expected to broadly expand its use as a new and practical means of accessing new chemical space for synthetic methodology and catalysis development. The outcomes of the proposed research will have the potential to be transformational in that they will 1) aid in ushering in the future development of single-electron chemistry of aromatic N-oxides; 2) expedite the design, development and manufacture of medicines to manage and treat diseases; 3) conceptualize catalytic and selective transformations of societal importance, thereby moving synthesis and therapeutic development vertically. Based on our research accomplishments and exciting preliminary data we have obtained in the arenas of 1) vinyl radical chemistry for concise and efficient synthesis of complex molecules, and 2) hydrogen-atom transfer (HAT) catalysis for selective C-H functionalization. The proposed research in Area 1 will establish an original and innovative strategy utilizing readily available alkynes and pyridine N-oxides for the facile generation of - oxypyridinium vinyl radical to unleash its synthetic potential. Such a strategy will enable the development of a variety of radical cascade reactions leading to the discovery of new transformations and synthetic methods that could not be accomplished by conventional methods. This contribution is expected to broadly expand the synthetic applications of vinyl radical mediated reactions and it will provide new synthetic opportunities for the design and development of new clinical agents using alkynes for the construction of a wide range of carbo- and hetero-cycles, and carbonyl functionalities. Our proposed research in Area 2 is expected to establish an innovative and modular catalyst system for regio- and stereoselective C-H functionalization by developing aromatic N-oxide based photoinduced HAT catalysts with effective reactivity towards unactivated C(sp3)−H bonds. The proposed multiple strategies incorporated with experimental and computational studies, including catalyst structure development, cooperative approach, and bifunctional catalysts, will enable a series of site- and regio-selective aliphatic C-H functionalization reactions of simple and complex molecular architectures.