Origins of Stereoselectivity in Mannich Reactions Catalyzed by Chiral Vicinal Diamines

The origins of the enantio- and diastereoselectivities in the Mannich reactions between aldehydes and ketimines catalyzed by chiral vicinal diamines have been determined by density functional theory calculations and distortion–interaction analysis. Computational results indicate a strong energetic preference for hydrogen-bonded nine-membered cyclic transition states. The favored transition states involve eight heavy atoms in the crown (chair–chair) conformation using the nomenclature of the analogous cyclic hydrocarbons. Energetic discrimination in the chirality-imparting step arises from pseudogauche-butane-type interactions in the disfavored transition states, as well as steric clashes between the <i>N</i>-Boc protecting group and the ammonium <i>N</i>-substituents