A rational approach to predict and modulate stereolability of chiral α substituted ketones

An effective strategy to assess and modulate the stereolability of chiral a substituted ketones (CaSKs) is presented. The tendency of CaSKs to retain or change their configuration in water is analyzed as a function of thermodynamic proton-release attitude of a asymmetric atoms inside the structures by linear Bronsted correlations. A molecular modeling procedure was developed to analyze and suggest chemical modifi- cations of CaSKs in view to obtain the desired grade of stereochemical stability. The approach was employed to predict the tendency to enantiomerize in water of two ketones (1 and 2) endowed with inhibitory activity against monoamine oxidases (MAOs) and the results were confirmed by experimental kinetics measurements per- formed in organic medium. As a demonstration of practical potentialities of the approach, four new structures, conceived as simple chemical modifications of 1 and 2, were designed to improve/reduce the stereostability grade of the starting anti-MAO ketones. The possibility to extend easily the procedure to other classes of C� � H acids appears of interest. Chirality 21:24-34, 2009. V V C 2008 Wiley-Liss, Inc.