The field of enantioselective organometallic chemistry has greatly benefited from the development of chiral ligands that covalently bind transition metal ions to generate an asymmetric environment under which a reaction occurs. Such a strategy, however, is not necessarily compatible with catalysts that require particular coordination geometries, highly electrophilic metal centers, or strong oxidants. As such, the overall goal of the proposed research is to devise an alternative strategy for enantioinduction in organometallic transformations using asymmetric ion-pairing catalysis. Chiral thioureas will be applied as co-catalysts in transformations mediated by transition metal catalysts. Anion abstraction from the transition metal catalyst by the thiourea could generate an asymmetric ion pair intermediate capable of influencing the stereochemical course of the reaction. In order to maximize the level of asymmetry relayed from the chiral hydrogen bond donors to the cationic metal center, catalysts will be evaluated for anion abstraction abilities and non-covalent interactions between the ion pairs. Specifically, the proposed research will apply this strategy to palladium-catalyzed olefin functionalization, a rich area of chemistry that has suffered from a shortage of enantioselective transformations. Established, non-stereoselective variants can generate significant levels of molecular complexity in a single operation. The ability to quickly access a wide range of saturated heterocycles like furans, pyrans, pyrrolidines, and piperidines in a stereocontrolled fashion is particularly appealing. Such structural elements are important components of bioactive natural products and pharmaceuticals and are difficult to synthesize efficiently and asymmetrically via other methods. This proposal seeks to address and achieve the following goals during the fellowship period: (1) Evaluate the ability of achiral and chiral hydrogen bond donors to abstract anions from transition metal salts; and (2) Design and synthesize asymmetric hydrogen bond donor co-catalysts for enantioselective, palladium catalyzed Wacker-type transformations. This represents a new approach to asymmetric palladium(0/II) catalytic transformations and an empowering extension of asymmetric anion binding catalysis. Pairing hydrogen-bond donor catalysis with transition metal catalysis creates a unique opportunity to create an asymmetric metal environment without diminishing, but rather enhancing, the electrophilicity of the metal center.
The proposed research is dedicated to the development of a new dual catalyst system for the selective and efficient generation of structural motifs commonly found in bioactive natural products and pharmaceuticals. The approach employs attractive interactions between substrate and catalysts, much like those used in enzymatic chemistry, to organize a tertiary complex of molecules to react with maximum selectivity.
