Tertiary stereogenic centers are a common motif in a variety of molecules with biological activities against targets associated with human disease. Cross coupling reactions of secondary alkyl electrophiles hold exciting promise for the synthesis of these scaffolds, but the couplings of these electrophiles to deliver enantioenriched products are underdeveloped. Those that have been reported often rely on reactive coupling partners and/or halide electrophiles. To solve these limitations, this research program will develop cross coupling reactions of amine- and alcohol-derived electrophiles with air-stable, functional group tolerant coupling partners. Amine and alcohol derivatives are ideal electrophiles due to their wide availability in both racemic and enantioenriched form. In the first aim, enantiospecific, nickel-catalyzed cross couplings of alkyl ammonium salts are proposed. Despite the fact that amines can be conveniently prepared in near perfect enantipurity, amine-derived electrophiles remain virtually unexplored in cross coupling chemistry. Based on preliminary results in the cross couplings of benzylic ammonium triflates, enantiospecific cross couplings of a range of alkyl ammonium salts with various coupling partners are proposed.
The second aim outlines the development of cross coupling reactions of alcohol-derived substrates to deliver enantioenriched products. Based on preliminary results with benzylic pivalate substrates, enantiospecific, nickel-catalyzed cross couplings of other enantioenriched alkyl pivalates will be developed. Enantioselective, nickel-catalyzed cross couplings of racemic alcohol-derived substrates will also be established. To date, couplings of alcohol derivatives have been largely limited to enantiospecific transformations. This research will circumvent the requirement for enantioenriched alcohol starting materials and demonstrate the potential of enantioselective cross couplings of readily available, racemic alcohol derivatives to deliver highly enantioenriched products. By exploiting the broad availability of amines and alcohols as starting materials and prioritizing the use of mild, air-stable coupling partners, this research will vastly improve the installation of tertiary stereocenters within an array of potentially bioactive target molecules. By expediting the synthesis of these targets in highly enantioenriched form, these methods will positively impact the discovery and development of new molecules with the potential to increase our understanding of and ability to treat human disease.

Public Health Relevance

The proposed research is relevant to public health, because it will enable efficient synthesis of a range of highly enantioenriched molecules with known or promising biologically activity from widely available and inexpensive amine and alcohol derivatives. The ultimate goal of this research is to positively and significantly impact the discovery and development of new molecules with the potential to increase our understanding of and ability to treat human disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM111820-01
Application #
8766156
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Lees, Robert G
Project Start
2014-08-15
Project End
2019-07-31
Budget Start
2014-08-15
Budget End
2015-07-31
Support Year
1
Fiscal Year
2014
Total Cost
$287,888
Indirect Cost
$97,888
Name
University of Delaware
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
059007500
City
Newark
State
DE
Country
United States
Zip Code
19716