Leaps-MPS: expanding asymmetric catalysis with thiamine-dependent enzymes

Federal Grant Award Summary

The National Science Foundation's Directorate for Mathematical and Physical Sciences awarded $151,966.00 to Randolph-Macon College under the Mathematical and Physical Sciences (CFDA 47.049) program on September 15, 2025, with a completion date of September 30, 2026. Professor Reynolds and his research team will conduct fundamental research on thiamine diphosphate-dependent enzymes to expand the scope of asymmetric catalysis applications in chemical synthesis. The project deliverables include development of enzymatic catalysts for carbon-carbon bond-forming reactions, particularly for stereoselective formation of α-substituted ketones that serve as precursors to bioactive compounds. Research activities will involve screening enzyme panels against substrates with multiple chiral centers and exploring alternative single electron reaction pathways to produce stereochemically complex products.

This LEAPS-MPS (Launching Early-Career Academic Pathways) initiative, managed through the Division of Chemistry's Broadening Participation program, emphasizes the integration of research and educational outcomes. Key deliverables include the development of enzymatic dynamic kinetic cross-benzoin condensation reactions and course-based undergraduate research experiences. The project prioritizes retention of underrepresented students in STEM through dedicated mentoring and research opportunities, advancing both scientific knowledge in green catalysis and workforce development in chemical sciences.

Abstract

In this project funded by the mathematical and physical sciences directorate launching early-career academic pathways (MPS-leaps) program and managed by the broadening participation (CHE-BP) program in the division of chemistry, professor reynolds and his students at campbell university will study the application of thiamine diphosphate-dependent enzymes towards current challenges in chemical synthesis. Enzymes represent attractive green catalysts for sustainable synthesis due to their ability to perform under mild, aqueous conditions and carry out highly selective transformations. However, their adoption in industry has been hampered by the limited scope of enzymatic reactions available. This research seeks to overcome this limitation by taking advantage of enzymes? Promiscuity towards substrates not found in nature. In particular, professor reynolds and his students will explore the use of thiamine-dependent enzymes for the stereoselective formation of ?-substituted ketones, which are important precursors to more complex, bioactive compounds. This will be accomplished by screening a panel of enzymes against substrates possessing multiple chiral centers to form stereochemically complex products. The ability of the enzymes to catalyze reactions through alternative single electron pathways will also be explored. Additionally, this work promotes the retention of diverse talent in stem through a program that incorporates research and mentoring opportunities for underrepresented students in stem, along with integration of the project into a course-based undergraduate research experience. Professor reynolds and his students will seek to address current challenges in asymmetric synthesis through the development of thiamine-dependent enzyme catalysts for carbon-carbon bond forming reactions. This will be accomplished by developing enzymatic dynamic kinetic cross-benzoin condensation reactions and asymmetric radical transformations to produce chiral alpha-substituted ketones. The approach to these aims involves screening a library of thiamine-dependent enzymes against unique substrates to identify active catalysts for the desired transformations. Reaction optimization and directed evolution experiments will be performed to further enhance the enzyme?s activity and stereoselectivity in these reactions. This research could expand the scope of reactions available to thiamine-dependent enzymes, making them more broadly useful for chemical synthesis. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the foundation's intellectual merit and broader impacts review criteria.- subawards are not planned for this award.