Abstract
An improved method for the calculation of enantioselectivity by molecular mechanics is presented. This method does not use any a priori assumption on the conformation of the molecules in the complex and is equally applicable to weak as well as very strong complexes. Highโtemperature molecular dynamics is used for the creation of a large number (5000โ20,000) of random conformations and configurations of a 1:1 (or 1:2) complex of chiral molecules with a chiral selector. All configurations are energy minimized. The data set is only accepted if all lowestโenergy complexes occur at least five times in the minimized data set. The enantioselectivity is then calculated from the free energies of the diasteromeric complexes (chiral chromatography) or from the ratio of the sum of the Boltzmann weights (distribution of enantiomers over a chiral organic phase and a nonchiral water phase). This approach has been successfully applied to a range of chiral compounds. These include a weakly bonded Pirkle chiral stationary phase (CSP) system, a strong complex of diprotonated 1,2โdiphenylโ1,2โdiaminoโethane with two molecules of R,Rโtartrate, and the intermediateโstrength complexes of protonated and of neutral norephedrine with R,Rโtartrate. ยฉ 1995 by John Wiley & Sons, Inc.