Diastereoselectivity in Lewis-Acid-Catalyzed Mukaiyama Aldol Reactions: A DFT Study

Abstract

The basis for diastereoselectivity in Lewis-acid-catalyzed Mukaiyama aldol reactions was studied using density functional theory. By exploring the conformations of the transition structures for the diastereodifferentiating step of seven different reactions, simple models were generated. The effects of varying the substituents on the enol carbon and the α-carbon of the silyl enol ether from methyl to <i>tert</i>-butyl groups and the substituent on the aldehyde from methyl to phenyl groups were investigated by comparison of the transition structures for different reactions. Expanding on the previous qualitative models by Heathcock and Denmark, we found that while the pro-<i>anti</i> pathways take place via antiperiplanar transition structures, the pro-<i>syn</i> pathways prefer synclinal transition structures. The relative steric effects of the Lewis acid and trimethyl silyl groups and the influence of <i>E</i>/<i>Z</i> isomerism on the aldol transition state were investigated. By calculating 36 transition structures at the M06/6-311G*//B3LYP/6-31G* level of theory and employing the IEFPCM polarizable continuum model for solvation effects, this study expands the mechanistic knowledge and provides a model for understanding the diastereoselectivity in Lewis-acid-catalyzed Mukaiyama aldol reactions