Physical Organic Studies on the Stereoionic Interactions in Asymmetric Primary Aminocatalysis

ConspectusNoncovalent interactions are ubiquitously utilized in enzymes and chemical catalysis in order to achieve exquisite control of reaction selectivity. Due to the often weak and nondirectional nature of these noncovalent interactions, delineating the origin and basis for catalysis and enantioselective control remains extremely challenging and has been regarded as the holy grail in the rational design and evolution of asymmetric catalysis. Vicinal diamine represents a privileged skeleton for chiral organocatalysis, and vicinal primary or secondary diamines, in the form of acid-base conjugates, have been developed as versatile aminocatalysts for a plethora of transformations. Previous studies indicated that the protonated amino moieties mainly serve as a H-bonding donor in dictating the enamine-facial selections. Due to their charged features, other weak NCIs are usually overshadowed by these strong interactions, and their roles in reaction control are generally overlooked. Inspired by Nature's aminocatalytic enzymes such as type I aldolase, we have developed chiral primary vicinal diamine catalysts as both functional and mechanistic enzyme mimics, showing unprecedented scopes in fundamental transformations of carbonyls. Over the course of 20 years' physical organic studies, we have uncovered distinctive noncovalent interactions associated with the protonated amines of this type of chiral diamines. Beyond the typical protonated N-H bonding, the protonated vicinal diamine also functions through proton-shuttle-network (I) in enabling stereospecific enamine protonation, 2e-oxidation of enamine as well as in the assembly of multicatalytic systems. A generally observed steric effect (II) of the protonated tertiary amines was also uncovered in the exploitation of 1+x synergistic catalysis with our primary amine catalyst. Additionally, the protonated tertiary amine moiety not only functions through ion pairing (III) in a manner closely resembling tetra-alkylated ammonium in phase transfer catalysis, but also exhibits a distinctive like-charge repulsion effect. By changing the alkylated amine to aromatic amine, we have identified arene-π interaction (IV) in dictating the stereocontrol in the synergistic chiral primary amine/Pd catalysis. In this account, we present our recent efforts in delineating the noncovalent interactions (I-IV) with the protonated amines in our chiral primary amine catalysts. The account is categorized according to the interaction modes and in each mode the physical organic studies involving both experimental and theoretical approaches are presented and discussed.