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Scientific Publications of Jos Aerts

An Improved Molecular Modeling Method for the Prediction of Enantioselectivity


J.Comp.Chem., 16, 914-922 (1995)


An improved method for the calculation of enantioselectivity by molecular mechanics is presented. This method does not use any a priory assumption on the conformation of the molecules in the complex and is equally applicable to weak as well as very strong complexes. High-temperature molecular dynamics is used for the creation of a large number (5000-20000) 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 lowest-energy complexes occur at least five times in the minimized data set. The enantioselectivity is then calculated from the free energies of the diastereomeric 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 succesfully applied to a range of chiral compounds. These include a weakly bonded Pirkle chiral stationary phase (CSP) system, a strong complex of diprotonated 1,2-diphenyl-1,2-diamino-ethane with two molecules of R,R-tartrate, and the intermediate-strength complexes of protonated and of neutral norephedrine with R,R-tartrate.