Stereoselective chemical reactions have transformed the practice of human medicine by providing access to chemical tools to study biological systems and pharmaceutical drugs to treat disease. Although several methods exist for the synthesis of biologically valuable chiral compounds, there is great potential for discovering conceptually novel strategies in catalysis for the stereoselective synthesis of classes of medicinally relevant molecules that are not easily synthesized by known methods. In particular, there are many synthetically useful rearrangements that are underdeveloped in the realm of asymmetric metal catalysis. The long- term goals for this research program include the discovery of general strategies for the catalytic conversion of simple starting materials into structurally complex and biologically active small molecules. These new methods will challenge established opinions on the chemistry of reactive zwitterions and tertiary amines as substrates for metal-catalyzed rearrangement processes. In addition to developing innovative chemical strategies, the proposed research program will explore unique opportunities for biomedical collaborations with cancer biologists at UT Southwestern Medical Center. The research strategy is divided into two project areas: A. Enantioselective [2,3]-Rearrangements of Reactive Zwitterions: Project A is guided by the innovative hypothesis that reactive zwitterionic intermediates can be subjected to metal- catalyzed enantioselective [2,3]-rearrangements, despite their propensity to undergo facile thermal sigmatropic rearrangements.
Specific Aim A.1: Metal-Catalyzed Enantioselective Allylic Amination Specific Aim A.1: Stereoselective Synthesis of Amino alcohols and Selectively Protected Monosaccharides B. Tandem Allylic Amination / Rearrangement Reactions with Tertiary Amines: Project B is guided by the innovative hypothesis that tertiary amines can serve as general nucleophiles for metal-catalyzed allylic aminations in the context of stereoselective tandem processes, despite the long-held belief that these substrates are not general nucleophiles in metal catalysis.
Specific Aim B.1: Development of an Enantioselective [2,3]-Stevens Rearrangement Specific Aim B.2: Stereoselective Synthesis of Small Molecule Inhibitors of PDK 2 (cancer drug target) - Collaboration with David Chuang

Public Health Relevance

Chiral compounds have impacted human health in the form of chemical tools to study biological systems and pharmaceutical drugs to treat disease (for example, 8 out of the top 10 selling drugs in the US in 2010 are chiral and are marketed as enantiopure chemical entities). Although several methods exist for the efficient synthesis of chiral compounds, many chiral structures still present unique challenges in synthesis. We believe there is great potential for discovering conceptually novel catalytic rearrangements for the stereoselective synthesis biologically active chiral small molecules.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM102604-02
Application #
8516538
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Lees, Robert G
Project Start
2012-09-01
Project End
2017-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
2
Fiscal Year
2013
Total Cost
$299,198
Indirect Cost
$111,023
Name
University of Texas Sw Medical Center Dallas
Department
Biochemistry
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
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Tso, Shih-Chia; Qi, Xiangbing; Gui, Wen-Jun et al. (2014) Structure-guided development of specific pyruvate dehydrogenase kinase inhibitors targeting the ATP-binding pocket. J Biol Chem 289:4432-43
Bao, Hongli; Bayeh, Liela; Tambar, Uttam K (2014) Allylic functionalization of unactivated olefins with Grignard reagents. Angew Chem Int Ed Engl 53:1664-8