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.

Public Health Relevance

The majority of therapeutic agents used to treat human disease are composed of amine-containing compounds. This proposal describes powerful and general new C-H bond functionalization methods to efficiently prepare drug-like amine-containing compounds from simple and readily available precursors. The proposed methods will broadly enable more rapid drug discovery and more cost effective drug production.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM069559-14
Application #
8962538
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Lees, Robert G
Project Start
2004-01-05
Project End
2019-11-30
Budget Start
2015-12-01
Budget End
2016-11-30
Support Year
14
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Yale University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
Potter, Tyler J; Kamber, David N; Mercado, Brandon Q et al. (2017) Rh(III)-Catalyzed Aryl and Alkenyl C-H Bond Addition to Diverse Nitroalkenes. ACS Catal 7:150-153
Hummel, Joshua R; Boerth, Jeffrey A; Ellman, Jonathan A (2017) Transition-Metal-Catalyzed C-H Bond Addition to Carbonyls, Imines, and Related Polarized ? Bonds. Chem Rev 117:9163-9227
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Boerth, Jeffrey A; Hummel, Joshua R; Ellman, Jonathan A (2016) Highly Stereoselective Cobalt(III)-Catalyzed Three-Component C-H Bond Addition Cascade. Angew Chem Int Ed Engl 55:12650-4
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Boerth, Jeffrey A; Ellman, Jonathan A (2016) Rh(III)-Catalyzed Diastereoselective C-H Bond Addition/Cyclization Cascade of Enone Tethered Aldehydes. Chem Sci 7:1474-1479
Weinstein, Adam B; Ellman, Jonathan A (2016) Convergent Synthesis of Diverse Nitrogen Heterocycles via Rh(III)-Catalyzed C-H Conjugate Addition/Cyclization Reactions. Org Lett 18:3294-7
Matsushima, Yuji; Phillips, Eric M; Bergman, Robert G et al. (2015) Rh(I)-Catalyzed Cycloisomerization of 1,6-Enynes. Synlett 26:1533-1536

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