Overall, this program will develop a variety of new metal-catalyzed synthetic methods for the construction and late-stage diversification of biologically relevant molecules. The proposed work encompasses many different types of chemical reactions but is unified by two central themes. First, it focuses on developing transformations that provide access to new chemical space and/or that streamline the synthesis of existing structures. Second, the proposed efforts are guided by detailed mechanistic analysis and organometallic chemistry. A first project continues the Sanford group's long-standing efforts in developing new approaches to carbon? hydrogen bond functionalization. The traditional approach in this area focuses on the discovery of highly selective reactions, in which the catalyst, substrate, and reaction conditions are tailored to convert a single, specific C?H bond into a new functional group. While successful, this approach is limited by a disproportionate focus on relatively simple substrates that contain only one ?reactive? C?H site. The proposed efforts will contribute to shifting this paradigm by targeting reactions in which a single starting material is converted into multiple C?H functionalization products. This will provide access to new structures that are of high interest in medicinal chemistry. Additionally, it will provide a wealth of mechanistic data about the factors responsible for reactivity and selectivity that will be used to drive next-generation catalyst design and new reaction discovery. A second project will target the development of new metal-catalyzed cross coupling reactions. Notably, cross- coupling is among the most widely used transformations in organic synthesis. The proposed efforts present a unified approach to target three central challenges associated with modern cross-coupling methods: (1) the use of abundant carboxylic acid-derived electrophiles as coupling partners; (2) elimination of the requirement for added base; and (3) the invention of reactions that form new types of bonds, with a focus on introducing fluorine- containing functional groups that are of high value in medicinal chemistry. All three goals will be accomplished in an integrated fashion via a common mechanistic foundation. A third project leverages the Sanford group's expertise in organometallic chemistry, mechanistic analysis, and catalytic reaction development to identify and tackle an emerging challenge in organic synthesis. SF5- substituted (hetero)aromatic rings are gaining increasing prominence as entities for integration into drug candidates. However, despite the growing significance of this functional group, synthetic methods for accessing aryl?SF5 derivatives remain extremely limited. This proposal outlines fundamental studies of the synthesis and reactivity of metal?SF5 complexes (species that are currently unprecedented). These studies will then be used to drive the development of catalytic aryl?SF5 coupling reactions.

Public Health Relevance

This program focuses on developing new synthetic methods for the construction and late-stage diversification of biologically relevant molecules. Specifically, it leverages the PI's expertise in synthetic methods development, physical organic chemistry/mechanistic analysis, and organometallic chemistry to address important challenges in the areas of transition metal-catalyzed C?H functionalization and cross-coupling reactions.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Unknown (R35)
Project #
1R35GM136332-01
Application #
9931737
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Yang, Jiong
Project Start
2020-04-01
Project End
2025-01-31
Budget Start
2020-04-01
Budget End
2021-01-31
Support Year
1
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109