The overarching goal of the research proposed herein is to develop new catalytic, asymmetric hydrogen atom transfer (HAT) reactions of unactivated C?H bonds, enabling a host of stereoselective free radical C?H functionalization chemistries difficult to achieve by other means. We intend to advance this objective by designing a novel, bifunctional catalyst platform?the amidophosphate?in which an amide is tethered to a monobasic phosphate within a chiral 1,2-aminoalcohol framework. Intramolecular hydrogen bonding with the Brnsted basic phosphate activates the amide N?H bond toward homolysis via oxidative proton-coupled electron transfer upon one-electron oxidation by an excited-state photocatalyst. The resulting nitrogen-centered amidyl radical is highly electrophilic and competent to abstract hydrogen atoms (H-atoms) from inert C?H bonds due to the strong thermodynamic driving force for N?H bond formation. Additionally, the amide and phosphate moieties of the proposed amidophosphate catalysts offer multiple points of contact for non-covalent association with substrates, providing a rare opportunity to achieve enantioselective HAT catalysis. These features, in combination with the highly modular and tunable chiral scaffold, make this class of catalysts well suited for application in synthetically important, asymmetric H-atom abstraction reactions, including, but not limited to, the specific aims of this proposal. This research also provides an opportunity to study the fundamental non-covalent interactions between the catalysts and open- shell intermediates in the context of these potentially impactful transformations. We initially intend to demonstrate the power of this approach by employing the chiral amidophosphate catalysts in two unique and synthetically useful asymmetric transformations: (1) the dehydrogenative desymmetrization of tertiary alcohols and (2) the cyclic deracemization of arylglycines. The first reaction provides access to chiral allylic and/or homoallylic alcohols from symmetrical 3 alcohols through amidophosphate-catalyzed, enantioselective aliphatic H-atom abstraction, followed by biomimetic, cobaloxime-mediated dehydrogenation. This transformation enables the direct conversion of an achiral alkane into a chiral alkene, which can be further elaborated into more complex, drug-like molecules using reliable reactions of (homo)allylic alcohols. In the second reaction, the chiral amidophosphates are proposed to catalyze the enantioenrichment of racemic arylglycines via amidyl-mediated, asymmetric H-atom abstraction from the a-C?H bond and subsequent, asymmetric enolate protonation. This process would deliver enantioenriched arylglycines, a pharmaceutically important class of amino acids that cannot be asymmetrically synthesized by conventional methods, from the corresponding racemates driven only by the consumption of visible light. Such a process is highly coveted in organic synthesis, and the structural and electronic features of the chiral amidophosphate catalysts make them well poised to achieve this goal. Both of these methods have the potential to advance the mission of the NIH by enabling the efficient production of medicinally relevant compounds using cutting-edge synthetic technologies.
The objective of this proposed research project is to develop novel asymmetric or site-selective hydrogen atom transfer reactions of unactivated, aliphatic C?H bonds through the design and implementation of chiral amidophosphate precatalysts, which are converted to the active amidyl radical catalysts in situ using a proton-coupled electron transfer activation mechanism. The designed catalyst platform embeds the highly reactive, nitrogen-centered radical within a modular, chiral scaffold bearing multiple functional group handles for non-covalent interactions with substrates. We intend to demonstrate the power of this approach in a dehydrogenative desymmetrization of tertiary alcohols and a cyclic deracemization of arylglycines, both of which involve enantioselective, amidyl radical-catalyzed hydrogen atom abstractions and provide access to enantioenriched pharmaceutical building blocks.
