Carbon-carbon bonds are present in virtually all drugs, bioactive natural products, and chemical tools for the study of biological systems. Consequently, methods for the formation of carbon-carbon bonds are of central importance to the synthesis of bioactive small molecules, with transition metal catalyzed processes such as olefin metathesis (2005 Nobel Prize) and cross coupling (2010 Nobel Prize) having a profound impact due to their high functional group compatibility. Transition metal catalyzed carbon-carbon bond formation via the direct functionalization of C-H bonds has enormous potential to accelerate drug discovery and production by eliminating the need to preactivate starting materials with halide/pseudohalide or organometallic functionality. This dramatically increases the number and variety of available inputs to enable the more efficient preparation of drug analogues necessary for drug discovery and optimization and also reduces the number of steps, cost and waste in drug production. The research funded by the NIH in the current grant cycle resulted in a number of highly significant advances with considerable impact on drug discovery and production, including (1) highly functional group compatible Rh-catalyzed methods for the direct arylation of pharmaceutically important heterocycles, including azoles and azines, for which direct ortho-arylation had not previously been reported, (2) pioneering enantioselective catalytic C-H bond functionalization, and (3) application to the efficient synthesis of complex bioactive natural products. The overall objective of this application is the development of general methods to prepare amine containing compounds through catalytic C-H bond activation and C-C bond formation. Despite the fact that a large majority of drugs contain amine functionality, only very limited examples of amine synthesis through C-H bond functionalization have been reported to date. The central hypothesis is that a broad range of amines can efficiently be prepared by the two complementary transition metal catalyzed approaches defined by the specific aims: (1) Develop efficient and general methods to prepare amine containing compounds by transition metal catalyzed activation of unreactive C-H bonds followed by addition across C-N ? bonds, and (2) Develop efficient and general methods to prepare pharmaceutically important 6-membered nitrogen heterocycles by transition metal catalyzed addition of C-H bonds across alkynes to provide azatrienes that undergo in situ C-N bond formation via electrocyclization. The expected outcomes will be the more rapid and efficient syntheses of drug like amine containing compounds by reducing the need for prefunctionalized starting materials. Because amines are present in a large majority of drugs and drug candidates, considerable positive impacts upon the pace and cost of drug discovery and production are anticipated. The research proposed in this application is innovative because it provides two new approaches for the convergent preparation of amines by C-H bond functionalization that are marked departures from previously reported strategies.
The majority of therapeutic agents used to treat human disease are composed of small amine-containing compounds. This proposal describes powerful and general new C-H bond functionalization methods to rapidly prepare drug-like amine-containing compounds from simple and readily available precursors. The proposed methods will broadly enable accelerated drug discovery and more cost effective drug production.
|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|
|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|
|Tran, Gaël; Hesp, Kevin D; Mascitti, Vincent et al. (2017) Base-Controlled Completely Selective Linear or Branched Rhodium(I)-Catalyzed C-H ortho-Alkylation of Azines without Preactivation. Angew Chem Int Ed Engl 56:5899-5903|
|Wangweerawong, Apiwat; Hummel, Joshua R; Bergman, Robert G et al. (2016) Preparation of Enantiomerically Pure Perfluorobutanesulfinamide and Its Application to the Asymmetric Synthesis of ?-Amino Acids. J Org Chem 81:1547-57|
|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|
|Potter, Tyler J; Ellman, Jonathan A (2016) Rh(III)-Catalyzed C-H Bond Addition/Amine-Mediated Cyclization of Bis-Michael Acceptors. Org Lett 18:3838-41|
|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|
|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|
|Chen, Shuming; Bacauanu, Vlad; Knecht, Tobias et al. (2016) New Regio- and Stereoselective Cascades via Unstabilized Azomethine Ylide Cycloadditions for the Synthesis of Highly Substituted Tropane and Indolizidine Frameworks. J Am Chem Soc 138:12664-70|
|Chen, Shuming; Mercado, Brandon Q; Bergman, Robert G et al. (2015) Regio- and Diastereoselective Synthesis of Highly Substituted, Oxygenated Piperidines from Tetrahydropyridines. J Org Chem 80:6660-8|
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