New Methods for Nitrogen and Oxygen Heterocycle Synthesis

Project Summary/Abstract The efficient production of small organic molecules and chemical processes impacts pharmaceutical research, both drug discovery and process chemistry. Chiral compounds make up a substantial portion of bioactive small organic molecules. Their enantioselective synthesis minimizes use of chiral separation technology, which can be time and resource intensive, and the production of undesired enantiomers, which are often considered chemical waste. New copper-catalyzed alkene difunctionalization reactions that enable efficient and stereoselective synthesis of chiral amine derivatives and ethers, predominantly saturated heterocycles, are being developed. The products of these reactions readily map on to structures contained in bioactive organic small molecules such as natural products and pharmaceuticals. In Objective 1, reactions involving the propagation of chirality, initiated by enantioselective copper-catalyzed reactions, are being explored. This new synthesis approach can provide an unconventional, yet streamlined route to complex and potentially bioactive molecules. In Objective 2, a new synthesis of enantioenriched oxygen heterocycles functionalized with a pendant carbon-carbon double bond is being explored. Application of this strategy in the efficient synthesis of bioactive natural products is proposed. One natural product synthesis will complete its structural assignment, while another will provide an authentic sample for bioactivity profiling. In Objective 3, our new aerobic enantioselective alkene aminooxygenation reaction will be applied to the synthesis of drug analogs aimed at increased stability and selectivity in biological settings. In Objective 4, we outline plans to develop a catalytic enantioselective reaction for the synthesis of amine derivatives with bioactivities related to a range of disease states including cancer and diabetes. Mechanistic aspects of the reactions developed in Objectives 1-4 will be explored, which will enable their rational optimization and predictable application. Development of these chemical transformations will enable their use in in drug discovery and chemical biology applications. Lessons learned in reaction engineering for efficiency and selectivity should be applicable to the invention and development of related useful chemical processes. The inclusion of select biochemical analysis of a subset of small molecules made in this project will give insight into their potential as therapeutic agents.