Enantioselective Thioetherification of Olefins Guided by CuH Catalysis

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PROJECT SUMMARY/ABSTRACT Olefins are abundant chemical feedstocks that many industries, including pharmaceutical development, rely on to prepare essential synthons in a stereo- and regioselective manner. Similar to the ubiquity of olefins, sulfur- containing molecules have been used in a medicinal context since antiquity, and continue to represent a large portion of new FDA approvals. The ability of sulfur to adopt five stable oxidation states further contributes to the structural diversity predicated on forming crucial C–S bonds. As such, the development of a chemo- and enantioselective method to construct C–S bonds (i.e., thioethers) from olefins would serve as a useful synthetic tool in the preparation of many pharmaceutically relevant targets. While many methods exist to prepare thioethers, they classically rely on the nucleophilic addition of thiolates to highly reactive species such as alkyl halides. This approach has poor chemo-selectivity, in that uncontrolled nucleophilic addition can occur at many sites within complex architectures, and has stereoselectivity that is predicated on first forming enantiopure alkyl halides. These two factors greatly limit the general utility of this approach and often dictate the order in which bonds must be constructed in targeted synthesis. Over the last decade, thiol-ene chemistry has emerged as a useful tool in constructing C–S bonds from olefins. However, thiol-ene chemistry proceeds with restricted regioselectivity, in that it only allows anti-Markovnikov functionalizations, and does not yield enantioenriched products. The object of this proposal is to provide a new synthetic approach to synthesize enantioenriched thioethers from widely available functionalized olefin precursors. Using copper(I) hydride catalysis in conjunction with a sulfenamide-based sulfur transfer reagent will yield a versatile method to construct both enantioenriched and linear thioethers. Furthermore, the prepared thioethers will serve as an entry point to other stereodefined sulfur- containing functional groups such as sulfoxides and sulfones. This versatile method will be beneficially adopted to the synthesis of many sulfur-containing pharmaceuticals, thereby demonstrating the overall utility of this approach. The proposed research is expected to provide novel approaches to tackle long-standing challenges in forging C–S bonds using CuH catalysis. The Buchwald laboratory at MIT is the ideal environment to accomplish the proposed research and training goals in preparation for a career in academia. In the Buchwald group, I will gain crucial training in many areas of organic chemistry including method development and physical organic chemistry. Furthermore, MIT will provide numerous opportunities to improve my skills as an educator and scientific mentor through the MIT Teaching and Learning Laboratory. Collectively, all of these factors led me to choose MIT as the optimal institution to pursue my ultimate goal of having a successful independent academic career.