Transition metal catalyzed carbon-carbon bond forming reactions such as metal-catalyzed cross-coupling and alkene metathesis have become some of the most extensively used reactions in the synthesis of important pharmaceutical agents and naturally occurring bioactive compounds. The importance of these transformations is in large part due to their broad functional group compatibility combined with the large and diverse array of compounds that can serve as starting materials. Metal-catalyzed C-H bond activation followed by carbon-carbon bond formation has the potential to become exceptionally powerful for the synthesis of bioactive compounds. C-H activation processes catalyzed by late transition metals are highly functional group compatible. In addition, because virtually every organic compound contains C-H bonds, the availability of starting materials for C-H activation pathways is enormous. This proposal describes the development and application of powerful catalytic methods for C-H activation and functionalization of two very important classes of nitrogen-containing compounds. 1. Imine directed C-H activation. The catalytic alkylation of aromatic and 1,2-unsaturated imines will be performed to obtain useful and complex bioactive compounds. Catalytic enantioselective alkylation will enable the efficient synthesis of single enantiomers of drugs and drug candidates. Catalytic alkenylation of 1,2-unsaturated imines followed by electrocyclization will provide 1,2-dihydropyridines, which are extremely versatile intermediates in the synthesis of pyridines and piperidines. Due to the immense importance of pyridines and piperidines in drug discovery and production, the alkenylation/electrocyclization sequence will be developed for the rapid and practical synthesis of these compounds. 2. Nitrogen heterocycle C-H activation. Catalytic alkylation and arylation of nitrogen heterocycles will be performed. A particular emphasis will be placed on heterocycles of huge pharmaceutical importance such as pyridines, quinolines, benzodiazepines and azoles. Catalytic enantioselective alkylation will be developed as an efficient method to prepare single enantiomers of important drugs and drug candidates. Mechanistic studies designed to enhance the utility and generality of the chemistry will also be pursued. The majority of therapeutic agents used to treat human disease are composed of synthetic organic compounds. This proposal describes powerful and general new methods to rapidly prepare complex, drug-like compounds from simple precursors. The proposed methods will enable accelerated drug discovery and more cost effective drug production at the same time that undesired chemical waste byproducts are minimized.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM069559-09
Application #
7993103
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Lees, Robert G
Project Start
2004-01-05
Project End
2011-11-30
Budget Start
2010-12-01
Budget End
2011-11-30
Support Year
9
Fiscal Year
2011
Total Cost
$389,085
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
06520
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, Gaƫl; 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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