Rapid and reliable access to synthetically-derived chemical structures plays an essential role in many aspects of biomedical research. The underlying objective of this proposal is to provide fundamentally new strategies for highly selective bond formations that will enable more rapid and efficient access to biologically active compounds of potential therapeutic value. A common theme throughout the proposal is the development of methods that accomplish highly selective bond formations when two or more similarly reactive parts of a structure are present. Using small molecule transition metal catalysts, the regioselective derivatization of simple structural subunits such as alkenes and alkynes will be addressed. Through careful mechanistic analysis, new insights will be provided to guide general strategies toward this objective in a broad range of contexts. Using engineered biological catalysts, strategies will be developed to enable regioselective oxidations of C-H bonds in complex substrates, using a novel substrate engineering approach that directs cytochrome P450-mediated oxidations towards a desired C-H bond embedded within a complex molecular framework. The development of new methods for the installation of carbohydrates will also be addressed. A new class of carbohydrate-derived silane reagents will enable considerable generality and control of stereochemistry during the installation of glycosidic bonds. The goals of this research program, including the precise generation of molecular frameworks, the selective oxidation of C-H bonds, and the installation of stereodefined carbohydrates, are all highly effective strategies for impacting and enhancing the biological properties of complex structures. Put together, the strategies present a toolbox of methods for enabling novel approaches for the synthesis of bioactive compounds. In collaborative work, these studies will be combined with the unique capabilities of biosynthetic enzymes to provide a synergistic combination of synthesis and biocatalysis to address key hurdles in the preparation of biologically active structures. The approach represents a merger of rarely combined fields of chemistry and biology: transition metal catalysis, C-H oxidation methodology, carbohydrate chemistry, and biocatalysis. This unique multidisciplinary perspective allows examination of strategies that cannot be addressed by conventional approaches. The improved entries to biomedically important structures made possible by this research will enable their biological function and therapeutic potential to be more efficiently studied.

Public Health Relevance

The goal of this research effort is to develop versatile new methods for the preparation of compounds of biomedical significance. Through a multidisciplinary approach, improvements in the speed, efficiency, selectivity, and cost of introducing structural subunits that impact the biological properties and function of complex structures will be developed.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Unknown (R35)
Project #
5R35GM118133-02
Application #
9250166
Study Section
Special Emphasis Panel (ZGM1-TRN-Y (MR))
Program Officer
Lees, Robert G
Project Start
2016-04-01
Project End
2021-03-31
Budget Start
2017-04-01
Budget End
2018-03-31
Support Year
2
Fiscal Year
2017
Total Cost
$366,183
Indirect Cost
$123,039
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
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