Assignment of the Absolute Configuration of Molecules that are Chiral by Virtue of Deuterium Substitution Using Chiral Tag Molecular Rotational Resonance Spectroscopy

Publication Summary

Originally published in Chirality, this study demonstrates the use of chiral tag molecular rotational resonance (MRR) spectroscopy to assign the absolute configuration of molecules whose chirality arises solely from deuterium substitution. As interest in deuterated pharmaceutical compounds continues to grow, the ability to accurately characterize enantioisotopomers has become increasingly important. The researchers developed an approach that uses noncovalent complexation with a small chiral tag to generate spectrally distinct diastereomeric complexes that can be analyzed by MRR spectroscopy.

To enable absolute configuration assignment, the team combined conformational searching using CREST, a computational chemistry tool, and geometry optimization based on dispersion-corrected density functional theory. The resulting workflow allowed reliable identification of chiral tag complexes and differentiation of homochiral and heterochiral species. The method was successfully applied to three oxygenated substrates produced through enantioselective copper-catalyzed hydrodeuteration chemistry, highlighting the utility of chiral tag MRR spectroscopy for challenging chiral analyses involving deuterium-labeled compounds.