Nickel-Catalyzed Enantioselective Hydrophosphinylation of 2-Azadienes to Access Enantioenriched α-Aminophosphine Oxides

Abstract

The practical synthesis of C-stereogenic α-aminophosphine oxides, which exhibit a wide range of applications in medicinal chemistry, biochemistry, material science, and asymmetric catalysis, represents an unmet need. Herein, a Ni/(S,S)-BenzP* catalyst system is developed for asymmetric synthesis of branched α-aminophosphine oxides through an enantioselective Markovnikov addition of H-phosphine oxides to 2-azadienes. A variety of readily available 2-azadienes and H-phosphine oxides undergo hydrophosphinylation with high enantioselectivities (up to 99%) and good yields (up to 96%). These products can be readily hydrolyzed to afford synthetically valuable chiral α-aminophosphine oxides, which are key building blocks for the synthesis of bioactive compounds (such as phospholeucine synthesized herein), organocatalysts, and ligands. Mechanistic studies suggest a hydrofunctionalization process.