New Radical and Fluorination Methods for the Syntheses of Pharmaceuticals

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Summary of Proposal:       This research proposal focuses on the discovery of innovative synthetic organic methods with a focus on developing new bond formation technologies for which there are currently no alternative. We plan to explore two main themes: (A) new applications of commodity chemicals in synthetic processes and (B) new single electron processes for the synthesis of pharmaceutically- and agrochemically-relevant motifs. For the first theme, we will continue to explore the use of sulfuryl fluoride (SO2F2), an industrial fumigant. We have found that SO2F2 can be used to enable multi-step reactions in a single reaction pot. This grant describes our future exploration of the development of new sulfuryl fluoride-mediated reactions for which there are currently no competitive one-pot alternatives. We will also examine the synthesis of new SO2F2-based reagents for pharmaceutically-relevant reactions. These methods are anticipated to enable greater efficiency and, thus lower the cost, of pharmaceutical and agrochemical production.       The second theme (B), based on single electron processes, is subdivided into three main areas. First, we will explore applications of a recent breakthrough from my laboratory on the synthesis of chiral 1,4-diamines, which are laborious to synthesize using existing technology. We plan to prepare a small library of these relatively underexplored chiral 1,4-diamines and explore their use both as motifs in chiral ligands for pharmaceutical production as well as components of protease inhibitors for use in the treatment of HIV. Second, we will explore new strategies for enantioselective radical cyclizations, an area that has very few solutions. The strategy that we will explore utilizes a key Lewis acid-accelerated single electron reduction to promote selective radical formation and cyclization. Success in this area will provide new, efficient synthetic routes to pharmaceuticals. Finally, we will explore new radical fluorine trapping agents for use in synthesis. Fluorine is ubiquitous in modern pharmaceuticals, and any new developments help cut the cost of existing medications and allow the study of new ones. We recently discovered that existing electrophilic fluorination reagents can be applied to single electron processes. This discovery has created a new field of synthetic fluorination. Despite the success of these reagents, the rate of fluorine transfer for these reagents is not sufficiently fast to trap many highly reactive species. This proposal outlines the exploration of a new class of C-F radical transfer agents and explores their use in transformations that are not currently possible using existing synthetic technology.