The Size-Accelerated Kinetic Resolution of Secondary Alcohols.

Abstract

The factors responsible for the kinetic resolution of alcohols by chiral pyridine derivatives have been elucidated by measurements of relative rates for a set of substrates with systematically growing aromatic side chains using accurate competitive linear regression analysis. Increasing the side chain size from phenyl to pyrenyl results in a rate acceleration of more than 40 for the major enantiomer. Based on this observation a new catalyst with increased steric bulk has been designed that gives enantioselectivity values of up to s=250. Extensive conformational analysis of the relevant transition states indicates that alcohol attack to the more crowded side of the acyl‐catalyst intermediate is favoured due to stabilizing CH‐π‐stacking interactions. Experimental and theoretical results imply that enantioselectivity enhancements result from accelerating the transformation of the major enantiomer through attractive non‐covalent interactions (NCIs) rather than retarding the transformation of the minor isomer through repulsive steric forces.