Bifunctional Asymmetric Catalysis: Amplification of Bronsted Basicity Can Orthogonally Increase the Reactivity of a Chiral Bronsted Acid

The reactivity of a series of symmetrical chiral Bronsted acids (polar ionic hydrogen-bond donors) follows the counterintuitive trend wherein the more Bronsted basic member is a more effective catalyst for the aza-Henry (nitro-Mannich) reaction. This new design element leads to a substantially more reactive catalyst for the aza-Henry reaction, one that can promote the addition of a secondary nitroalkane. Additionally, when an achiral Bronsted acid (TfOH) is used in slight excess of the neutral, chiral bisamidine lipid, diastereoselection can be optimized to levels generally greater than 15:1 while the enantioselection remains unchanged at generally >90% ee.