A significant obstacle to the creation of the next generation of small molecule therapeutics is the lack of general and efficient methods for accessing certain stereochemically dense structures that contain functionality important for bioactivity. This project seeks to provide simple access to a range of new functionalized small molecule building blocks based on the implementation of new reactions. The proposal focuses on new chemistry of ?-keto esters and their derivatives. ?-Keto acids occupy a central role in biology, for example in the biosynthesis of amino acids, but are underutilized in organic synthesis. The enantioselective reduction of racemic ?-keto esters is the archetypal dynamic kinetic resolution and is performed on ton scale annually. In stark contrast, the complementary dynamic reduction of racemic ?-keto esters is unknown, despite the enormous potential of this method for the creation of bioactive natural products and medicinal agents. We will develop a broad range of new transformations of racemic substrates that undergo catalyst-mediated deracemization to provide enantiomerically enriched, value-added products. Targeted product structures include ?-hydroxy-?-amino acids, ?,?-diamino acids, unnatural ?-amino acids, and fully substituted glycolates. Access to these compounds will be enabled via new dynamic kinetic resolutions of appropriately configured racemic ?-keto esters and ?-hydroxy phosphonoacetates. The specific goals of this research proposal are to (i) develop dynamic kinetic resolutions (DKRs) of ?-keto esters and their derivatives through the development of novel hydrogenation catalysts;(ii) implement new carbon-carbon bond constructions by using DKRs of hydroxyphosphonates;(iii) develop useful new biomimetic dynamic kinetic transaminations for the green preparation of unnatural ?- amino acids.

Public Health Relevance

The reactions that are targeted in this study have the capacity to deliver functional group-rich compounds that will be immediately useful for preparation of a range of chiral small molecule building blocks. The proposal seeks to provide those in the biomedical community straightforward access to new families of molecules that will be useful for a range of applications.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM103855-01
Application #
8417276
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Lees, Robert G
Project Start
2013-09-05
Project End
2017-05-31
Budget Start
2013-09-05
Budget End
2014-05-31
Support Year
1
Fiscal Year
2013
Total Cost
$184,552
Indirect Cost
$54,552
Name
University of North Carolina Chapel Hill
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Goodman, C Guy; Johnson, Jeffrey S (2014) Dynamic kinetic asymmetric cross-benzoin additions of ?-stereogenic ?-keto esters. J Am Chem Soc 136:14698-701
Corbett, Michael T; Xu, Qihai; Johnson, Jeffrey S (2014) Trisubstituted 2-trifluoromethyl pyrrolidines via catalytic asymmetric Michael addition/reductive cyclization. Org Lett 16:2362-5