While metal insertion into, and subsequent functionalization of, sp3 C?H bonds has the potential to afford transformative tools in synthesis, the impact of this approach on asymmetric catalysis has been moderate due to a number of unanswered challenges encountered in the development of asymmetric version of these reactions. This proposal centers on the development of two approaches for enantioselective C?H activation reactions of broadly useful substrates: (A) the design of bisdentate chiral ligands and (B) catalytic chiral directing groups. We will develop enantioselective C?H activation reactions of ?-methyl C?H bonds and methylene C?H bonds of carboxylic acids and carboxylate derived substrates, as well as ?-C?H bonds of amines and amine derived substrates. These reactions will provide novel and versatile methodologies for constructing ?-, ?-, and ?-chiral centers in asymmetric synthesis. The use of abundant and common substrates, as well as the diversity of the transformations will render palladium-catalyzed enantioselective C?H functionalization broadly useful for the synthesis of bioactive chiral molecules. Specifically, desymmetrization of isobutyric and pivalic acids via enantioselective C?H activation will be applied to the generation of a library of novel serine hydrolase inhibitors that can be evaluated by activity-based protein profiling to identify new drug leads for diabetes, cognitive dementia and bacterial infection.

Public Health Relevance

This proposal centers on development of enantioselective sp3 C?H activation reactions of readily available carboxylic acids, ketones and amines. These reactions provide new disconnections for constructing ?-, ?- and ?-chiral centers that are broadly useful in asymmetric syntheses of chiral bioactive compounds and drug molecules. In a collaborative effort, these new chiral technologies are applied to the discovery of promising new drug candidates for the treatment of human diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM084019-10
Application #
9309985
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Lees, Robert G
Project Start
2008-08-01
Project End
2021-06-30
Budget Start
2017-07-01
Budget End
2018-06-30
Support Year
10
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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