This proposal outlines a research program designed to develop new carbon-carbon bond-forming methodology for the synthesis of chiral diarylalkanes by stereoconvergent nickel- catalyzed arylation of benzylic electrophiles. Chiral diarylalkanes are an important class of organic structures commonly found in commercialized single-enantiomer pharmaceuticals including sertraline (ZoloftTM), tolterodine (DetrolTM), and many antihistamines. Existing methods for the preparation of single-enantiomer diarylalkanes rely on late-state resolution, discarding half of the material in the process. We plan to apply mechanistic insight gained from model studies on a stoichiometric system to the development of a catalytic, benzylic arylation reaction capable of converting racemic benzylic electrophiles to enantioenriched 1,1-diarylalkanes. In doing so, we will be advancing relatively new nickel-catalyzed C-C bond-forming chemistry which has already begun to prove its value to the field of synthetic organic chemistry for the synthesis of bio-active natural products and pharmaceutically-relevant core structures.

Public Health Relevance

Many organic drug molecules are prepared and administered as mixtures of two different molecules which are mirror images (enantiomers) of one another because of the difficulty and cost related to preparing or separating only one of the components. The U.S. Food and Drug Administration encourages the separate study of enantiomers because they often have very different biological properties in the human body. This proposal provides for the development of new synthetic methodology for the preparation of single enantiomer molecules with a very common core structure to many commercial pharmaceuticals.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32GM105295-02
Application #
8615918
Study Section
Special Emphasis Panel (ZRG1-F04-A (09))
Program Officer
Lees, Robert G
Project Start
2013-02-01
Project End
2016-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
2
Fiscal Year
2014
Total Cost
$49,214
Indirect Cost
Name
California Institute of Technology
Department
None
Type
Schools of Engineering
DUNS #
009584210
City
Pasadena
State
CA
Country
United States
Zip Code
91125
Schley, Nathan D; Fu, Gregory C (2014) Nickel-catalyzed Negishi arylations of propargylic bromides: a mechanistic investigation. J Am Chem Soc 136:16588-93