Development of Enantioselective Sm-Catalyzed Transformations

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Project Summary Reductive SmIII2-mediated transformations are ubiquitous in the synthesis of biologically active natural products, however, they require a stoichiometric quantity of SmIII2, which prohibits their utility on large-scale and impedes the design of enantioselective variants. In principle, strategies to perform reductive SmIII2-mediated processes with catalytic quantities of Sm could lay the foundation to overcome these limitations, but efforts have been inhibited by a paucity of mechanistic understanding. In this project, these challenges will be addressed through the mechanistically-guided development of asymmetric reductive Sm-catalyzed reactions. Initially, we will translate the conditions we developed for the Sm-catalyzed reduction of ketones, which uses Mg0 as an exogenous reductant, to electrochemical conditions. Electroanalytical techniques will provide insight into the mechanism of the reaction and will provide a platform reaction scouting. This information will be used to develop an electrocatalytic system for Sm-catalyzed reduction of ketones on preparative-scale. The strategies discovered through this work will be leveraged to develop other electrochemically-driven reductive Sm-catalyzed transformations, such as the coupling of ketones with ethyl acrylate to produce g-lactones. This scalability of this reaction will be demonstrated using a continuous flow reactor. Next, we will introduce a diverse series of chiral ligands into the coupling reaction between ketones with ethyl acrylate to promote the enantioselective formation of g-lactones. Once a lead hit is identified in ligand screening, a family of analogues of this ligand will be judiciously prepared featuring systematically altered steric, electronic, and hydrogen bonding properties. This family of ligands will be screened in catalysis, and the resulting product enantiomeric enrichment will be correlated to various physical organic molecular descriptors of the ligands using multivariate linear regression analysis. This will provide unprecedented insight into what factors are important for the design of asymmetric reductive Sm-catalyzed reactions, which will be used to guide reaction optimization and result in one of the first reported enantioselective reductive Sm-catalyzed reactions. The practical utility of this transformation will be demonstrated through a concise synthesis of (-)-bipinnatin J, which is a biosynthetic intermediate towards several natural products with potent cytotoxicity properties. Overall, this work will contribute to the fundamental understanding of reductive Sm catalysis, which will provide a robust foundation for the development of future systems and, more broadly, facilitate the discovery and manufacturing of new drugs.