Catalytic Asymmetric Oxidation of Alkenes and Alkanes

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Project Summary The discovery of new methodologies to advance the fields of synthetic organic, medicinal, and material chemistry is critical in the synthesis of pharmaceuticals. Particularly, catalytic asymmetric oxidation reactions are economic, since only a small amount of the catalyst is needed. The oxidation reactions provide chiral molecules and additional functionalities onto the molecules for functional group manipulation. Recently, we discovered a new class of polymers, namely chiral-substituted poly-N-vinylpyrrolidinones (CSPVPs), for stabilization of bimetallic nanoclusters such as palladium/gold or copper/gold nanoparticles in the induction of chirality. These chiral polymers wrap around (or incarcerate) the nanometer-sized (~3 nm) bimetallic nanoparticles and catalyze a number of enantioselective oxidation reactions using oxygen or hydrogen peroxide as the oxidant. For example, alkenes were oxidized by 0.5 mol% of Pd/Au (3:1)-chiral polymer 2R under 2 atmospheric of oxygen in water to give the syn-dihydroxylated products in 73 – 86% chemical and 97 - 99% ee optical yields. Various cycloalkanes underwent regio- and enantio-selective C-H oxidation with 5 mol% Cu/Au (3:1)-2R and 30% hydrogen peroxide to produce the corresponding chiral oxo-molecules in very good chemical and excellent optical yields. We further discovered enantioselective desymmetrization of -dialkenyl-alkanols and -dialkenyl–amino acid ethyl esters with 4 mol% Cu/Au-2R and hydrogen peroxide to give chiral disubstituted lactones and lactams, respectively, in 91 – 96% ee. A number of medium-sized natural products and drugs including N- acetylamantadine, oxymetrine, ambroxide, and 3-pivaloyl estrone were also oxidized regioselectively to give the corresponding mono-oxygenated products in good yields. These exciting results prompted us to propose studies of the scope and mechanisms of the catalytic asymmetric oxidation reactions and late-stage aliphatic C-H oxidation of bioactive complex molecules. Our goal is to discover useful synthetic methodologies in catalytic asymmetric synthesis. Three specific aims are designed to achieve our goal: (1) optimization of the CSPVPs and studies of the scope, mechanisms, and regio- and enantio-selectivity in the oxidation of alkenes and alkanes; (2) investigation of the catalytic asymmetric ring closing reactions by forming C-O and C-N bond from dienols and diene amines, respectively, and the asymmetric imine-Heck C-C bond forming reaction; and (3) investigation of the predictive regioselectivity of C-H oxidation of bioactive complex molecules, which may alter or improve the pharmacological and biological properties of the molecules.