Basic principles of substrate activation through non-covalent bond interactions

In the last twenty years, chiral Brønsted acid and chiral counteranion catalysis have emerged as a fundamental area of organocatalysis. The development of chiral acidic catalysts has allowed extending many known Brønsted catalyzed reactions to the stereoselective domain. Moreover, the controlled conditions under which these catalysts can be used, allowed accessing reactivity of increasing complexity with extraordinary selectivity levels. However, compared to the explosion of this branch of organocatalysis in an applicative direction, only little has been done to understand and rationalize the observed reaction outcomes. This is due, in part, to the complex nature of the weak interactions (H-bonds, electrostatic, and dispersion interactions) governing this class of reactions. Here we review relevant mechanistic analyses from both chiral Brønsted acid and chiral counteranion directed catalysis. Both experimental and computational work is included that aimed at unveiling the nature of the interactions governing the a number of reactions. These include the: enantioselective reduction of ketoimines with Hantzsch esters; ring opening reactions of epoxides, oxetanes, aziridinium, and sulfonium ions; stereoselective fluorination of allylic alcohols; oxidative aminations of benzylic thioethers (enantioselective Pummerer reaction). These case studies are analyzed and discussed in order to highlight key features and similarities across the different catalytic systems.