New Frontiers in Chemical Reactivity Via Catalytic Hydrogen Atom Transfer

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PROJECT SUMMARY Hydrogen atom transfer (HAT), or the movement of one proton and one electron simultaneously, is an increasingly important element in synthetic methodology. While nature has made extensive use of HAT steps in processes such as those performed by desaturase and mutase enzymes, synthetic chemists are just beginning to realize the potential of this powerful, radical transformation. This MIRA proposal describes two important new areas enabled by HAT that the PI will explore over the next 5 years: modular radical hydrogenation and transpositional functionalization. The PI is prepared to make an impact in this important field from his mentored career, where he designed catalytic dehydrogenation and dehydroformylation systems functioning via HAT. The first area of research concerns development of a modular, stereoselective hydrogenation system able to completely control the configuration and isotopic composition at each reduced center (Project 1). Preliminary work by the PI has demonstrated radical hydrogenation can be achieved using cooperative hydrogen atom transfer (cHAT), a mechanism where each hydrogen atom arrives from a separate catalyst, allowing for each catalyst to be modified independently. One goal of this project is independent stereocontrol of each new stereocenter though use of two asymmetric catalysts (Project 1a). This design will allow for enantioselective anti- reduction, a currently impossible transformation. A simultaneous, independent goal builds on preliminary data showing each catalyst receives its hydrogen atom from an orthogonal source, permitting different isotopes to be predictably delivered in the same reaction (Project 1b). Together, this project area will provide a method to install H, D, or T in any configuration starting from an unsaturated bond, selecting between all possible isotopologues and stereoisotopomers via catalyst and reagent control. The second research area focuses on the development of new mustase-like reactions, where functionality is regioselectively transposed in a 1,2-fashion to remodel molecular architectures (Project 2). However, unlike mutase enzymes, these methods will exchange the functional group during the transposition, allowing rapid diversification of complex molecules. Preliminary data from the PI demonstrates this principle using vitamin B12 and Co(Salen) cocatalysts to achieve “remote elimination”, where primary alkyl electrophiles are translated into a 2-alkenes with terminal methyl group. We anticipate this approach will be general, allowing for transpositional C–X, C–N, C–O, and C–C bond-forming reactions (Project 2a). In parallel, the ability of vitamin B12 to enantioselectively convert meso-epoxides and aziridines to allylic alcohols and amines will be used to achieve enantioselective C–H functionalization of the epoxides and aziridines (Project 2b). Together, the proposed research will leverage the unique reactivity of HAT to deliver a suite of new catalytic reactions both making -and using- olefins to streamline the synthesis of molecules important to human health.