Natural product synthesis via attached ring formation

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With this award, the Chemical Synthesis Program of the NSF Division of Chemistry is supporting the research of Professor Ryan Shenvi of the Scripps Research Institute. Professor Shenvi and his team are developing new chemical reactions to force two molecules to bond between crowded atoms. Over the last four decades, organic chemists have learned how to connect relatively simple, flat (two-dimensional) rings of atoms. Connecting three-dimensional rings, however, remains challenging, especially when the atoms that constitute the connection points are crowded or possess different geometries. Some of the most complex molecules found in nature exhibit these congested, attached-ring structures, yet there are few good ways to make them in the laboratory. In this project, the Shenvi group is developing ways to synthesize molecules with attached-rings and apply the new methods to making molecules with potential biological applications. For example, the target molecules, Illicium terpenes, are approved by the FDA to treat peripheral arterial disease. Professor Shenvi teaches advanced topics in chemical synthesis, mentors summer undergraduate researchers, and conducts public outreach in science education. Professor Shenvi and his students are exploring two reactions capable of forging challenging attached-ring motifs from simple building blocks. In the first area of study, the group is developing an understanding of the very low energy barrier to butenolide heterocoupling, which establishes polyfunctional attached rings bearing vicinal, fully-substituted carbons. The origin of specificity and selectivity is being investigated and applied to the synthesis of Illicium terpenes. In the second area of study, the group is developing a catalytic cross-coupling method that alters the normal steric demand for arylation reactions. Application to the synthesis of attached rings embedded within polycyclic alkaloids is being explored. This work is helping to expand the repertoire of chemical reactions that can forge attached rings beyond biaryls, which heavily populate synthetic libraries, and where sp3-sp3 attached ring motifs are underrepresented. Students in the laboratory are gaining experience in mechanistic inquiry, chemical methods development, and complex molecule 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.