The overarching goal of this proposal is to develop new nickel-catalyzed enantioselective reductive cross- coupling reactions for applications in the synthesis and study of bioactive molecules. It is well established that the two enantiomers of a drug can exhibit remarkably different biological properties. As a result, the enantioselective synthesis of chiral small molecules has become an important area of research in both academic and industrial laboratories. Recently, Nickel-catalyzed reductive cross-coupling reactions have emerged as direct methods for carbon-carbon bond formation. These reactions typically tolerate an array of functional groups, occur under mild conditions, and employ inexpensive, earth abundant metals as stoichiometric reductants. Most importantly, they do not require the use of pre-generated organometallic reagents. In order to realize the full synthetic potential of Ni-catalyzed reductive cross-coupling reactions, it is critical to develop enantioselective variants o these transformations. This proposal describes the first significant progress toward this objective: the development of four new Ni-catalyzed enantioselective cross- coupling reactions. Preliminary results obtained for each transformation provide compelling evidence for the feasibility of this research. This research will be carried out by a team composed of the PI, three chemistry graduate students and one postdoctoral researcher. As part of this project, the graduate students and postdoctoral researchers will receive rigorous training in the theory, methods, and strategies of organic chemistry. The successful execution of this research will provide new tools to enable the synthesis of small molecules for the study and treatment of human disease.

Public Health Relevance

It is well established that the two enantiomers of a drug can exhibit remarkably different biological properties. As a result, the enantioselective synthesis of chiral small molecules has emerged as an important area of research by both academic and industrial laboratories. This proposal seeks to develop new catalytic reductive cross-coupling reactions to prepare enantioenriched small molecules. These efforts will provide new tools for the preparation of biologically active molecules, and in so doing, will enable the study and treatment of human disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM111805-02
Application #
8887353
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Lees, Robert G
Project Start
2014-07-15
Project End
2016-06-30
Budget Start
2015-07-01
Budget End
2016-06-30
Support Year
2
Fiscal Year
2015
Total Cost
Indirect Cost
Name
California Institute of Technology
Department
Type
Schools of Arts and Sciences
DUNS #
009584210
City
Pasadena
State
CA
Country
United States
Zip Code
91125
Hofstra, Julie L; Cherney, Alan H; Ordner, Ciara M et al. (2018) Synthesis of Enantioenriched Allylic Silanes via Nickel-Catalyzed Reductive Cross-Coupling. J Am Chem Soc 140:139-142
Poremba, Kelsey E; Kadunce, Nathaniel T; Suzuki, Naoyuki et al. (2017) Nickel-Catalyzed Asymmetric Reductive Cross-Coupling To Access 1,1-Diarylalkanes. J Am Chem Soc 139:5684-5687
Kadunce, Nathaniel T; Reisman, Sarah E (2015) Nickel-Catalyzed Asymmetric Reductive Cross-Coupling between Heteroaryl Iodides and ?-Chloronitriles. J Am Chem Soc 137:10480-3
Cherney, Alan H; Kadunce, Nathaniel T; Reisman, Sarah E (2015) Enantioselective and Enantiospecific Transition-Metal-Catalyzed Cross-Coupling Reactions of Organometallic Reagents To Construct C-C Bonds. Chem Rev 115:9587-652
Cherney, Alan H; Reisman, Sarah E (2014) Nickel-catalyzed asymmetric reductive cross-coupling between vinyl and benzyl electrophiles. J Am Chem Soc 136:14365-8