Project Summary/Abstract Stereoselective chemical reactions have transformed the practice of human medicine by providing access to chemical tools to study biological systems and pharmaceutical drugs to treat disease. Although several methods exist for the synthesis of biologically valuable chiral compounds, there is great potential for discovering conceptually novel strategies in catalysis for the stereoselective synthesis of molecules not easily accessed by known methods. In particular, there are many synthetically useful reactions that are underdeveloped in the realm of asymmetric metal catalysis. We propose to develop the first stereoselective and regioselective allylic oxidation of internal olefins via a hetero-ene reaction and a new approach to synthesizing halogenated compounds via stereoselective halonium ylide rearrangements. Our long-term goals for this research program include the discovery of general strategies for the catalytic conversion of simple starting materials into structurally complex and biologically active small molecules. We also anticipate that these methods will challenge established opinions of chemical reactivity that have been held about certain classes of non-selective reactions for years. We are taking advantage of unique opportunities for biomedical collaborations at UT Southwestern Medical Center by utilizing our innovative chemical strategies to make new discoveries in biology. The research strategy is divided into two project areas: A. Selective Allylic Oxidation of Unactivated Internal Olefins: Project A is guided by the innovative hypothesis that the ene reaction between internal olefins and chalcogen-based oxidants is amenable to asymmetric catalysis, despite the propensity for facile thermal ene reactions and the lack of models for stereoinduction with this class of hetero-enophiles. Specific Aim A.1: Catalytic, Enantioselective, Regioselective, and E/Z Selective Allylic Oxidation of Unactivated Internal Olefins Specific Aim A.2: A.2: Therapeutic Agents for the Prevention and Treatment of Preterm Premature Rupture of the Fetal Membranes and Preterm Labor – Collaboration with Ann Word B. Enantioselective Synthesis of Halogenated Compounds: Project B is guided by the innovative hypothesis that rearrangements of halonium ylides can be rendered stereoselective and regioselective by chiral catalysts, despite the precedence for unselective reactions of these intermediates. Specific Aim B.1: Catalytic Enantioselective Rearrangements of Halonium Ylides