Manifestation of Felkin-Anh Control in Enantioselective Acyl Transfer Catalysis: Kinetic Resolution of Carboxylic Acids

摘要

Polar α-substituents have long been known to control the diastereofacial selectivity of nucleophilic addition to a car-bonyl group. The transition-state model proposed by Felkin et al. and subsequently refined by Anh and Eisenstein successfully explained the observed selectivity in terms of stereoelectronic control exerted by an electron-withdrawing group X at the α-position of the carbonyl (e.g., see Equation (1) in Scheme 1). For years, it has been used to predict which diastereomer will form predominantly in the addition of a Grignard reagent to a chiral aldehyde or in the hydride reduction of a chiral ketone, to name just the two most common examples. Does stereoelectronic control manifest itself in nucleophilic acyl substitution reactions, and if so, how? At first glance, which face of an acyl carbonyl is attacked by a nucleophile may appear to be a moot question, because the subsequent (or concerted) elimination of the leaving group destroys the transient new stereogenic center Eq. (2). However, if chirality is present in the nucleophile Y Eqs. (3a) and (3b) or the leaving group Z Eqs. (4a) and (4b), then the energy differences between the diastereomeric transition states may lead to alternative modes of diastereo-selectivity, as illustrated in Scheme 2. Computational studies reported herein, combined with our recent experimental results, demonstrate that stereoelectronic effects indeed play a key role in controlling the enantioselectivity of catalytic, asymmetric alcoholysis of α-substituted acyclic anhydrides. Although the venerable Felkin-Anh model has been the subject of many theoretical investigations, to the best of our knowledge, this is the first one extending its scope to stereochemical analysis of nucleophilic acyl substitution.