This proposal outlines the vision of a systematic, ongoing effort directed towards the fundamental understanding of catalytic asymmetric reactions and its application to the development of more selective catalysts and discovery of novel concepts in asymmetric organocatalysis. Our research program, since its inception in September 2013, has accumulated a vast body of mechanistic information including experimental kinetic isotope effect (KIE) studies and transition state analysis of several important organocatalytic reactions with a special emphasis on proline-enamine catalysis. This proposal describes our current efforts in utilizing this information to design more selective catalysts and to develop novel concepts in enamine catalysis. These efforts have met with some initial success and we have successfully developed a general strategy to obtain synthetically useful enantiodivergence ? access to both antipodes of a target molecule using the same enantiomer of chiral catalyst ? in proline-enamine catalysis. In this proposal, we are extending the application of this concept to develop two novel concepts in proline-enamine catalysis ? chemodivergent and diastereodivergent enamine catalysis. The latter concept, diastereodivergent catalysis, provides access to complementary diastereomers of a chiral molecule in high enantiopurity using the same chiral catalyst ? a phenomenon that has no precedent in asymmetric catalysis. Finally, we are seeking to expand the physical organic toolkit available to the synthetic organic community by developing probes for the rapid elucidation of reaction mechanisms. We have developed a novel methodology ? intramolecular designed reactant (IDR) ? for the rapid determination of 13C KIEs at natural abundance. We propose to apply the IDR method to conduct a high-throughput mechanistic study of several palladium catalyzed cross-coupling reactions. Cross-coupling reactions are the most-utilized carbon-carbon bond-forming strategy in medicinal chemistry and the mechanistic information gleaned from this study is expected to have a significant impact on process development in the pharmaceutical industry.

Public Health Relevance

The development of highly selective catalytic methods for the synthesis of complex molecules used in medicinal applications can be greatly accelerated by developing a predictable framework for catalyst design. This proposal aims to address this challenge by (a) inventing novel concepts and methods that enable organic chemists to expedite the design of robust catalysts and streamline the synthesis of complex medicinal targets, and (b) developing new tools to probe the mechanisms of some of the most widely used reactions in medicinal chemistry.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM126283-01
Application #
9427316
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Lees, Robert G
Project Start
2017-12-10
Project End
2022-11-30
Budget Start
2017-12-10
Budget End
2018-11-30
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
State University of NY, Binghamton
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
090189965
City
Binghamton
State
NY
Country
United States
Zip Code
13902