C-H Functionalization for the Synthesis of Amines and Nitrogen Heterocycles

点击翻译按钮获取中文摘要

 DESCRIPTION (provided by applicant): The direct formation of carbon-carbon bonds by transition metal-catalyzed C-H bond functionalization has emerged as a powerful new approach for the synthesis of compounds for drug discovery and production. This approach has two characteristics in common with the more established and enormously important olefin metathesis and cross-coupling methods; (1) it enables the preparation of the essential carbon frameworks present in bioactive natural products and drugs, and (2) when the appropriate transition metals are used it can be highly functional group compatible. The ubiquitous presence of C-H bonds in organic compounds also provides a potentially vast array of diverse inputs to enable the more rapid preparation of analogs for drug discovery as well as to minimize steps, cost and waste in drug production. Past funding periods of this grant have resulted in a number of powerful methods that constitute marked progress toward the long-term goal to develop efficient and general C-H bond functionalization methods that enable rapid access to structures with a level of molecular complexity commonly found in drugs and natural products. The overall objective of this application is to develop catalytic C-H bond activation and carbon-carbon bond formation for the convergent assembly of amine containing compounds, which represent 84% of small-molecule drugs. The synthesis of nitrogen heterocycles, which are present in 59% of drugs, is emphasized. Our central hypothesis is that these structures can be prepared efficiently by the two complementary transition metal-catalyzed approaches defined in the two specific aims: 1) Develop efficient and general methods to prepare amine containing compounds and heterocycles by transition metal-catalyzed C-H bond addition to C=O/C=N bonds; and 2) Develop efficient and general C-H bond functionalization/electrocyclization cascades to 1,2-dihydropyridines followed by rapid elaboration to drug relevant nitrogen heterocycles. Under the first aim, Rh(III)-catalyzed methods for catalytic C-H bond addition to C=O and C=N bonds first developed in the lab will be advanced to asymmetric C-H bond additions to imines as well as to sequential C-H bond cascade additions across alkenes and C=O or C=N bonds to form two new carbon-carbon single-bonds. New earth abundant Co(III) catalysts will also be developed to complement Rh(III) catalysts. Under the second aim simple and readily available precursors are converted to 1,2-dihydropyridines that are then elaborated with high regio- and stereocontrol to give piperidines, pyridines, tropanes, and even more complex nitrogen heterocycles, including pharmaceutical agents. The approaches are innovative because new types of reactivity in C-H bond functionalization will be explored and fundamentally new methods will be developed for elaborating the initially formed C-H bond addition products. The research is significant because successful development of these methods will enable the more efficient discovery and cost effective production of drugs, bioactive natural products and chemical biology tools.