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West Virginia University chemists have developed an experiment to improve the efficiency of creating new medicine.
The research, conducted by Associate Professor of Chemistry Jessica Hoover and doctoral student Robert Crovak, was published earlier this year in the Journal of the American Chemical Society, a top chemistry-focused journal.
Using a predictive model, Hoover and Crovak explored a complex, multi-variable analysis of a promising but vexing class of reactions called decarboxylative cross-couplings.
“This old-school, rigorous and meticulous work led to a breakthrough in understanding a specific aspect of organic chemistry,” said Gregory Dudley, chair of the C. Eugene Bennett Department of Chemistry. “Hoover’s insights will lead to more efficient catalytic reactions and better organic synthesis. They have now received generous support from NIH to build on these insights to lay a stronger foundation for future advances in human health.”
Hoover and Crovak found that a frequently overlooked variable, the field effect, was the key to understanding the reaction.
“The field effect is a through-space electronic interaction, which is unusual,” Hoover said. “We don’t fully understand why it matters yet, but we want to, and that’s where we’re headed.”
The field effect variable influences the rate of decarboxylation of benzoate complexes. Hoover and Crovak’s predictive model provides an opportunity to overcome limitations associated with the reaction and to enable widespread use of these reactions in organic synthesis.
“This coupling reaction only works on very select carboxylic acids right now. The acids need specific structures to undergo the reaction. Because we want to make this method into one that people will use, it needs to apply to a variety of carboxylic acids,” Hoover said. “The study looked at the underlying cause of the reaction’s limitation. Because we now understand where it comes from, the field effect, we can move beyond it. We identified new classes of acids that will also couple, allowing us to expand the scope of this chemistry based on a really fundamental understanding of the obstacles.”
To continue refining the method, Hoover received a three-year, $450,000 National Institutes of Health grant this fall. She will investigate heteroarenes, an important class of substructures found in many biologically active molecules used in FDA-approved drugs.
“The target we’re after now is to form new carbon-carbon bonds between heteroarenes using our decarboxylation strategy. Heteroarenes contain oxygen and nitrogen atoms, which make these molecules common in pharmaceutical targets,” Hoover said. “But the routes to access them efficiently are a bit more limited and not as well understood.
Through the next phase of her research, Hoover aspires to improve access to those bonds for other chemists.
“A fundamental understanding of the trends and limitations in these and other coupling reactions of heteroarenes would allow synthetic methods to be adapted for the construction of pharmaceutically relevant structures,” Hoover said. “We’d really like a medicinal chemist to have new choices for efficient and predictable reactions so that they can very logically design improved synthetic routes to some of these targets.”
