Automated Quantum Chemistry-Based Calculation of Optical Rotation for Large Flexible Molecules.

Abstract

The calculation of optical rotation (OR, [α]D) for nonrigid molecules was limited to small systems due to the challenging problem of generating reliable conformer ensembles, calculating accurate Boltzmann populations and the extreme sensitivity of the OR to the molecules' three-dimensional structure. Herein, we describe and release the crenso workflow for the automated computation of conformer ensembles in solution and corresponding [α]D values for flexible molecules. A comprehensive set of 28 organic drug molecules (28-144 atoms) with experimentally determined values is used in our assessment. In all cases, the correct OR sign is obtained with an overall mean relative deviation of 72% (mean absolute deviation of 82 °[dm(g/cm3)]-1 for experimental values in the range -160 to 287 °[dm(g/cm3)]-1). We show that routine [α]D computations for very flexible, biologically active molecules are both feasible and reproducible in about a day of computation time on a standard workstation computer. Furthermore, we observed that the effect of energetically higher-lying structures in the ensemble on the OR is often averaged out and that in 23 out of 28 cases, the correct OR sign is obtained by just considering only the lowest free energy conformer. In four example cases, we show that the approach can also describe the OR of pairs of flexible diastereomers properly. In summary, even very sensitive, multifactorial physicochemical properties appear reliably predictable with minimal user input from efficiently automated quantum chemical methods.