Asymmetric Deoxygenative Diversification of Alcohols and Carboxylic Acids

Project Summary This proposal centers on developing new deoxygenative functionalization of alcohols and carboxylic acids for accessing medicinally valuable chiral amines and fluorinated compounds through new sequential, stereo- controlled reactions. Alcohols and carboxylic acids are ubiquitous, structurally diverse, and stable feedstock chemicals, making the asymmetric deoxygenative diversification of their C–O bonds a highly attractive strategy for exploring new chemical space and discovering new therapeutics. While seminal approaches have demonstrated converting alcohols and carboxylic acids to pharmaceutically relevant chiral products, these methods often require multiple steps, undergo slow C–O bond activation, are limited in nucleophile scope, and lack stereo-control. To overcome these challenges, the Kim Group will employ a sulfonyl fluoride as a SuFEx (Sulfur Fluoride Exchange) clickable reagent for alcoholic C–O bond activation and a catalytically versatile base metal that will facilitate multiple C–O bond functionalizations of carboxylic acids. Our methods will allow one- step, rapid asymmetric C–O bond derivatization to construct C(sp3)–N/C bond formations between unfunctionalized starting materials and diverse nucleophiles with predictable stereochemical outcomes. Herein, we will develop the following Research Programs: (1) One-step, stereospecific and site-selective deoxygenative amination and perfluoroalkylation of alcohols via SuFEx, allowing direct installations of pharmaceutically relevant free amines, N-heterocycles, and perfluoroalkyl groups into alcohols, and (2) enantioselective deoxygenative diversification of carboxylic acids, providing a new platform for chiral amine synthesis via sequential geminal C– O bond functionalizations of a carboxyl group. Together, the successful realization of the goals described in these research programs will provide a new set of robust tools for rapid asymmetric derivatization of C–O bonds within widely available feedstock chemicals and complex molecules, which will expedite synthetic access to medicinally valuable products.