Computational chemistry applied to the design of chiral stationary phases for enantiomeric separation

Abstract

A general computational scheme for the rational design of chiral stationary phases for the chromatographic separation of enantiomers has been established. The developed scheme was based on applying different interaction models (force field methods versus semi empirical quantum chemical methods), different docking algorithms (systematic grid search methods versus interactive methods guided by rules based on binding modes) and different levels of approximations (rigid versus flexible docking) to a representative test problem containing the 3,5-dinitrobenzoyl group. The computational methods in use covered the most sophisticated methods which could presently be applied to problems of such a size (about 80 atoms). It has been shown that the current computational approaches using rigid body approximations for the docked molecules and simple molecular mechanics (not taking pi-"effects" into account) are invalid in view of the required predictive precision of about 1-2 Kcal/mole for the differential binding energy. Another surprising result was the failure of the commonly used systematic search methods in determining the most favorable binding modes. Based on our calculations on the representative test problem we propose a new arrangement for the most stable complexes without parallel stacking of the aromatic pi-donor and the 3,5-dinitrobenzoyl pi-acceptor systems.

A ?quasi-flexible? automatic docking processing for studying stereoselective recognition mechanisms. Part I. Protocol validation

“…8b and c) both in the angular deviations for most of the torsionals (i = 2, 4, 5,6,8,9,10), and in the RMS value (0.20) (Fig. 9), confirming that the procedure of "quasi-flexible" docking can keep track of induced fit effects of specific nonbonded interactions at the intermolecular level.…”

“…8a) point out that the energetic minimization changes appreciably only eight torsion angles (ns. 1, 2, 4, 5,6,7,8,12) out of the 12 chosen, causing a distortion in the coordinates characterized by 0.41 RMS. This distortion is essentially present in (S)-1.…”

Structure, Selectivity, and Solvation of a Model Chiral Stationary Phase

“…Stationary phases that tend to form inclusion complexes are also amenable to this type of modeling, and recent work by Lipkowitz 15 on selection by cyclodextrin is particularly noteworthy. Recent emphasis [16][17][18][19] on comprehensive and automated search algorithms over the conformational space of the diastereomeric complexes has improved the accuracy of the predicted free energies for discrimination. An entirely different approach to the prediction of selectivity by CSPs invokes statistical modeling.…”

Enantiodiscrimination by a quinine-based chiral stationary phase: A computational study

“…In this regard, we point out that several docking strategies exist for this purpose, as described in a recent review on the topic of computing enantiodifferentiation. 16 Owing to the large number of rotatable bonds for both the selector and the selectand in this study, along with the complexity associated with locating the position and the orientation of the molecules with respect to each other, a full assessment of all possible starting geometries was deemed impractical for this problem and the "motif-based" docking strategy of Däppen et al 17 was adopted. In this method, one admits in advance that all of phase space cannot be searched, but that the most important regions on the diastereomeric complex's potential energy surface can be located by taking advantage of the known intermolecular interactions that can take place between two molecules.…”