Excellence in Research: Stereoselective Synthesis of Spiro-Oxepin Core: Toward the Total Synthesis of Psammaplysin Natural Product and Analogues for Biological Study

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This project is jointly funded by the Chemical Synthesis Program and the Established Program to Stimulate Competitive Research (EPSCoR). It supports the research of Professor Ashton Hamme who is developing a synthetic route to a class of naturally occurring molecules called the "psammaplysins" and their analogues. Collectively, their biological activity will be studied by the co-Principal Investigator in this project, Professor Clement Yedjou. The total synthesis of natural products is an indispensable and dynamic tool in chemical biology research and is often challenging and exciting. Dr. Hamme is focusing on developing methods for the synthesis of a "functional group" found in the psammaplysins whose synthesis and biological evaluation are scarcely studied. In this project, Dr. Hamme is using a stepwise bond-breaking and bond-making approach to synthesize the core of the natural product using organic molecules that can act as catalysts. These catalysts are selectively constructing the challenging architecture found in these target molecules. Further transformation of this unit leads to the total synthesis of psammaplysin and its analogues. Jackson State University (JSU), the seventh largest among Historically Black Colleges and Universities (HBCU) and the only urban University in Mississippi, has a unique opportunity to attract and retain minority students in the educational pipeline. Underrepresented minority students are encouraged to engage in STEM careers through a research-based educational program at JSU. The outcome of the project is associated with world-class scientific publications, professional presentations, and participation in regional/national meetings, where students extend their career training and opportunities via networking and globalization.In this proposal, Professor Hamme is developing an enantioselective route to the highly substituted and unusual spiro-oxepin core found in the psammaplysins. The route being developed involves a stereoselective, tandem ketalization/Michael addition reaction sequence catalyzed by various quinine and chiral urea, thiourea, and squaramide organocatalysts. These catalysts are designed to activate the ketone thereby initiating the reaction sequence. This work is solving a synthetic challenge, and the biological component of the study probes the relationship between the structure and biological activity of these molecules. The undergraduate, graduate, and STEM students involved in this project are being trained and confronted with challenges at the interface of chemistry and biology, broadening their exposure to diverse fields and to opportunities in academia, government laboratories, pharmaceutical industries, and defense research laboratories.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.