Cinchona-Based Hydrogen-Bond Donor Organocatalyst Metal Complexes: Asymmetric Catalysis and Structure Determination

In this study, we describe the synthesis of cinchona (thio)squaramide and a novel cinchona thiourea organocatalyst. These catalysts were employed in pharmaceutically relevant catalytic asymmetric reactions, such as Michael, Friedel-Crafts, and A3 coupling reactions, in combination with Ag(I), Cu(II), and Ni(II) salts. We identified several organocatalyst-metal salt combinations that led to a significant increase in both yield and enantioselectivity. To gain insight into the active catalyst species, we prepared organocatalyst-metal complexes and characterized them using HRMS, NMR spectroscopy, and quantum chemical calculations (B3LYP-D4/def2-TZVP), which allowed us to establish a structure-activity relationship. Three different cinchona-based organocatalysts containing different hydrogen-bond donor moieties worked together with inorganic transition metal salts to catalyze pharmaceutically relevant asymmetric reactions. They were also studied experimentally and quantum chemically, providing insight into the complex structures of these catalytically active species. In many cases, the application of these catalysts led to significant increases in both yield and enantioselectivity.image