Heterobiaryls are an important class of substructures found in a large number of biologically active molecules and FDA approved drugs. These scaffolds are typically constructed through traditional cross-coupling strategies. Unfortunately, these protocols are inefficient for the incorporation of heteroaryl fragments. The objective of the work proposed here is to develop a fundamental understanding of the cross-coupling reactions of heteroarenes. We also aim to apply our findings to the development of new efficient and predictable cross-coupling reactions of heteroaromatic coupling partners. This work will ultimately allow synthetic and medicinal chemists to design predictable and reliable synthetic strategies to access these biologically relevant intermediates and target compounds. We recently identified the field effect of ortho- substituents as being a dominant predictor in the rate of decarboxylation and oxidative decarboxylative coupling (ODC) reactions of benzoic acids. The first phase of research will extend this predictive power to the ODC reactions of heteroaromatic carboxylates and benzoates without the typically required ortho-substituents. We hypothesize that new ligand scaffolds can be designed to mitigate the need for ortho-substituents in these reactions because the field effect parameter describes a through-space influence. In the final phase of our study, we will apply these new ligand structures to other classes of cross-coupling reactions that have historically suffered from related ortho-substituent limitations. The development of a large collection of predictable and reliable cross-coupling reactions that operate efficiently for a broad scope of (hetero)aromatic coupling partners is significant because it provides access to a large library of biologically relevant core structures. Thus, the development of a fundamental understanding of the trends and limitations in these and other coupling reactions of heteroarenes would allow existing and developing synthetic methods to be adapted for the construction of complex and pharmaceutically relevant structures.

Public Health Relevance

Heterobiaryls are an important class of biologically active scaffolds and are substructures in a large number of current pharmaceuticals. The objective of the work proposed here is to develop a fundamental understanding of the cross-coupling reactions of heteroarenes, which will ultimately provide synthetic and medicinal chemists with the ability to design predictable and reliable synthetic strategies to access these important precursors and pharmaceutically active compounds for the treatment of human diseases. !

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Unknown (R35)
Project #
5R35GM133566-02
Application #
10001029
Study Section
Special Emphasis Panel (ZGM1)
Program Officer
Yang, Jiong
Project Start
2019-09-01
Project End
2024-08-31
Budget Start
2020-09-01
Budget End
2021-08-31
Support Year
2
Fiscal Year
2020
Total Cost
Indirect Cost
Name
West Virginia University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
191510239
City
Morgantown
State
WV
Country
United States
Zip Code
26506