Development and Application of Enantioselective Lewis Acid-Lewis Base Bifunctional Catalyst

The design, synthesis, and application of a new bifunctional enantioselective catalyst containing both Lewis acidity and Lewis basicity are described. Recent developments of chiral quaternary stereocenter synthesis through catalytic enantioselective Reissert-type reaction and cyanosilylation of ketones forming the S-enantiomer are chiefly reviewed. The catalysts are composed of a Lewis acid metal (aluminum, titanium, or lanthanide) and a Lewis base (the oxygen atom of a phosphine oxide), of which positions are defined by 2,2'-binaphthol (BINOL) or a carbohydrate scaffold. Utilizing these catalysts, we have developed a variety of enantioselective cyanation reactions, such as cyanosilylation of aldehydes and ketones, Strecker-type reaction, and Reissert-type reaction. These reactions showed a broad substrate generality. Investigations toward the elucidation of the reaction mechanism, involving kinetic studies, comparison of the results by control catalysts, and absolute configurations of the products, revealed that these reactions are catalyzed by a dual activation of a substrate and trimethylsilyl cyanide (TMSCN) by the Lewis acid and the Lewis base of these catalysts. Catalytic enantioselective synthesis of several drug lead compounds, such as anti-cancer epothilones, potent N-methyl-D-aspartate (NMDA) receptor antagonists, phenytoin analogs, salsolinol carboxylic acid, and anti-cancer camptothecin was achieved, using these reactions as key steps.