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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM069559-12
Application #
8585858
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Lees, Robert G
Project Start
2004-01-05
Project End
2015-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
12
Fiscal Year
2014
Total Cost
$455,112
Indirect Cost
$172,038
Name
Yale University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Wangweerawong, Apiwat; Bergman, Robert G; Ellman, Jonathan A (2014) Asymmetric synthesis of ?-branched amines via Rh(III)-catalyzed C-H bond functionalization. J Am Chem Soc 136:8520-3
Otley, Kate D; Ellman, Jonathan A (2014) A Lewis Acid Catalyzed annulation to 2,1-benzisoxazoles. J Org Chem 79:8296-303
Duttwyler, Simon; Chen, Shuming; Lu, Colin et al. (2014) Regio- and stereoselective 1,2-dihydropyridine alkylation/addition sequence for the synthesis of piperidines with quaternary centers. Angew Chem Int Ed Engl 53:3877-80
Lian, Yajing; Hummel, Joshua R; Bergman, Robert G et al. (2013) Facile synthesis of unsymmetrical acridines and phenazines by a Rh(III)-catalyzed amination/cyclization/aromatization cascade. J Am Chem Soc 135:12548-51
Martin, Rhia M; Bergman, Robert G; Ellman, Jonathan A (2013) Synthesis of isoquinuclidines from highly substituted dihydropyridines via the Diels-Alder reaction. Org Lett 15:444-7
Lian, Yajing; Huber, Tatjana; Hesp, Kevin D et al. (2013) Rhodium(III)-catalyzed alkenyl C-H bond functionalization: convergent synthesis of furans and pyrroles. Angew Chem Int Ed Engl 52:629-33
Brasse, Mikael; Campora, Juan; Ellman, Jonathan A et al. (2013) Mechanistic study of the oxidative coupling of styrene with 2-phenylpyridine derivatives catalyzed by cationic rhodium(III) via C-H activation. J Am Chem Soc 135:6427-30
Ischay, Michael A; Takase, Michael K; Bergman, Robert G et al. (2013) Unstabilized azomethine ylides for the stereoselective synthesis of substituted piperidines, tropanes, and azabicyclo[3.1.0] systems. J Am Chem Soc 135:2478-81
Duttwyler, Simon; Chen, Shuming; Takase, Michael K et al. (2013) Proton donor acidity controls selectivity in nonaromatic nitrogen heterocycle synthesis. Science 339:678-82
Lian, Yajing; Bergman, Robert G; Lavis, Luke D et al. (2013) Rhodium(III)-catalyzed indazole synthesis by C-H bond functionalization and cyclative capture. J Am Chem Soc 135:7122-5

Showing the most recent 10 out of 46 publications