Aromatic interactions in asymmetric catalysis: control of enantioselectivity in Diels–Alder reactions catalysed by camphor-derived hydrazides

Abstract

Density functional theory calculations (M06-2X//B3LYP) have been performed to determine the factors responsible for enantioselectivity in Diels–Alder reactions catalysed by two series of camphor-derived amines. Hydrazides 2 and sulfonylhydrazides 3 catalyze the reaction of cyclopentadiene with cinnamaldehyde to give the same enantiomer of cycloadduct. The calculations reveal that the two classes of catalysts control enantioselectivity by opposite mechanisms. Hydrazides 2 favour addition to the bottom face of a trans iminium cation, while sulfonylhydrazides 3 favour addition to the top face of a cis iminium ion. In the transition state for cycloadditions catalysed by 2, a stabilising CH–π interaction between the diene and a benzyl substituent α to the iminium nitrogen accelerates the reaction and enhances the enantioselectivity. The facial selectivity can be reinforced by appending onto the benzyl side-arm an α-methyl group that sterically hinders addition to the top face.