Chiral Proton Catalysis:  A Catalytic Enantioselective Direct Aza-Henry Reaction

Abstract

Despite Nature's longstanding ability to use a proton, the most prevalent Lewis acid, to both activate and orient a substrate during an enantioselective reaction, this work represents the first example of this phenomenon outside of a protein. A chiral, nonracemic BisAMidine (BAM) ligand was designed, synthesized, and complexed to the proton of a Brønsted acid. The resulting coordination compound catalyzed the production of enantioenriched product from the combination of a Schiff base and nitroalkane (the aza-Henry reaction). This particular reaction is also considered a model for many analogous carbon-carbon bond-forming reactions catalyzed by enzymes (e.g., the Mannich reaction). This discovery suggests the use of ionic hydrogen bonds in asymmetric catalysis may not only be more general than previously thought, but also a viable "green" approach to single-enantiomer organic compounds.