Conjugate addition coupled to cationic cyclization: new methods for small molecule synthesis

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With this Award, the Chemical Synthesis Program of the NSF Division of Chemistry is supporting the research of Professor Alison Frontier of the University of Rochester, whose research program is focused on building small molecules with different three-dimensional architectures. The spatial array of carbon, nitrogen and oxygen atoms of molecules is critical to the behavior of the molecules, specifically, their reactivity in different environments, and their ability to bind to other molecules. However, many natural and man-made molecules with potential uses as materials, catalysts, or pharmaceutical agents, are difficult to prepare using existing chemical protocols. The research conducted by Professor Frontier and her students expands the range of three-dimensional molecules that can be assembled using chemical methods, and at the same time, develops chemical reactions that have not been previously described. Through methods that form several new bonds in a single, controlled process, the group develops chemical strategies useful in a broad set of applications. Professor Frontier also continues to develop and maintain the "Not Voodoo" website, an educational resource. The site is designed to help students demystify laboratory protocols and procedures. It serves hundreds of organic experimental chemists each day, from students just beginning independent research, to advanced students looking for more efficient synthetic methods. Synthetic chemists are constantly searching for versatile new methods for building densely functionalized molecules containing bridged, spirocyclic and fused ring systems, ideally with heteroatoms embedded in the scaffold of the three-dimensional molecules. The new methods Professor Frontier and her students are studying simplify the synthesis of targets with unusual, densely functionalized ring systems, including cycloheptane systems and nitrogen-rich heterocycles. Novel pericyclic reactions are being developed in the context of reaction cascades that build complex ring systems from simple precursors, with the formation of up to three carbon-carbon or carbon-nitrogen bonds in one synthetic operation. Given the stereochemical control imparted by these pericyclic processes, the work represents efforts to develop efficient, stereoselective reaction sequences while garnering a new understanding of the factors critical to successful multi-step processes with pericyclic components. Students engaged in this work learn to devise synthetic strategies, analyze complex reaction outcomes ,and characterize small three-dimensional molecules. Professor Frontier's long-standing website project (Not Voodoo: Demystifying Synthetic Organic Chemistry) provides a resource for students learning laboratory techniques for the first time, and supporting more advanced students seeking to explore unfamiliar territory in their experimental work.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.