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

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.