Experimental
determination of the absolute stereochemistry of chiral
molecules has been a fundamental challenge in natural sciences for
decades. Vibrational circular dichroism (VCD) spectroscopy represents
an attractive alternative to traditional methods like X-ray crystallography
due to the use of molecules in solution. The interpretation of measured
VCD spectra and thus the assignment of the absolute configuration
relies on quantum-mechanical calculations. While such calculations
are straightforward for rigid molecules with a single conformation,
the need to estimate the correct conformational ensemble and energy
landscape to obtain the appropriate theoretical spectra poses significant
challenges for flexible molecules. In this work, we present the development
of a VCD spectra alignment (VSA) algorithm to compare theoretical
and experimental VCD spectra. The algorithm determines which enantiomer
is more likely to reproduce the experimental spectrum and thus allows
the correct assignment of the absolute stereochemistry. The VSA algorithm
is successfully applied to determine the absolute chirality of highly
flexible molecules, including commercial drug substances. Furthermore,
we show that the computational cost can be reduced by performing the
full frequency calculation only for a reduced set of conformers. The
presented approach has the potential to allow the determination of
the absolute configuration of chiral molecules in a robust and efficient
manner.
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