Discovery and Development of Organic Reactions Catalyzed by Transition-Metal Complexes Valuable for Medicinal Chemistry The proposed research focuses on the discovery, development, and mechanistic evaluation of a series of chemical reactions catalyzed by transition-metal complexes that provide new approaches to the synthesis of organic molecules that are important for human health. Research on these reactions addresses several of the major unmet needs in chemical synthesis: 1) the need for reactions that occur at C-H bonds with high selectivities and high tolerance for auxiliary functional groups; 2) the need for reactions that occur with catalyst-controlled site selectivity for one of many similar functional groups; 3) the need to functionalize complex molecules directly to modulate the structures and properties of biologically active compounds; 4) the need to assemble aliphatic sub-structures with control of the absolute and relative configurations of stereogenic centers to create more complex three-dimensional architectures; and 5) the need for greater mechanistic understanding of catalytic methods to help select or invent catalysts and reagents that achieve these synthetic goals. The types of reactions proposed for study include some of the most widely used catalytic reactions during the drug-discovery process. For example, these reactions include selective functionalizations of C-H bonds to form main group compounds that have become common synthetic intermediates. The proposed research further includes C-H bond functionalizations that form organic azides and halides that can serve as intermediates or biogically important final products. The proposed research also encompasses reactions occuring in aliphatic structures by addition and substitution reactions, including the addition of N-H bonds across unactivated alkenes with unprecedented efficiency, coupling processes forming carbon-heteroatom bonds with organic electrophiles that have rarely coupled with heteroatom nucleophiles, and coupling processes forming carbon-heteroatom and carbon-carbon bonds with unique control over the combination of regioselectivity, enantioselectivity, and diastereoselectivity. New small-molecule catalysts also will be studied that reverse the typical site selectivity observed for oxidation of alcohols, allowing modification of complex natural products, such as polyols. Finally, the proposed research includes reactions catalyzed by a new class of hybrid system generated by formally exchanging the metal of natural metalloenzymes with a platinum-group metal. These artificial metalloenzymes can form products with site-selectivity and stereoselectivity that are difficult or impossible to achieve with natural enzymes or small-molecule catalysts. In all cases, the proposed research includes detailed mechanistic analysis by kinetic stuides and independent synthesis of catalytic intermediates, as well as the use of these mechanistic data to select or design next-generation systems.

Public Health Relevance

The catalysts and reactions that are the subject of the proposed research will improve methods to prepare pharmaceutical candidates. New reactions, new applications of the catalytic reactions, and a mechanistic understanding of these systems will result from the proposed research. Thus, successful development of the proposed research will significantly increase the accessibility of compounds that improve human health.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Unknown (R35)
Project #
1R35GM130387-01
Application #
9626684
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Lees, Robert G
Project Start
2019-01-01
Project End
2023-12-31
Budget Start
2019-01-01
Budget End
2019-12-31
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of California Berkeley
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
124726725
City
Berkeley
State
CA
Country
United States
Zip Code
94704