Analysis of deuterium chiral switch characteristics of thalidomide analogues using Beyond Born–Oppenheimer quantum chemical calculations
Kohei MOTOKI *, Hirotoshi MORI
Department of Applied Chemistry, Faculty of Science and Engineering, Chuo University
【Purpose】
Strategic deuteration of drug molecules for enhanced efficacy and safety requires a quantum-chemical framework that explicitly captures nuclear quantum effects (NQEs) beyond the Born–Oppenheimer approximation. We have previously shown, using nucleic-acid base pairs, that Beyond Born–Oppenheimer (Beyond BO) calculations—which constrain nuclear coordinates to the expectation values of nuclear wavefunctions—enable rigorous quantification of NQEs contributions to intermolecular interactions and bonding [K. Motoki & H. Mori, Phys. Chem. Chem. Phys. 27, 8898–8902 (2025)]. In this work, we extend that methodology to chiral thalidomide analogues to elucidate how deuterium substitution modulates racemization pathways and electronic structure.
【Methods and Theory】
Thalidomide analogues registered in ChEMBL and their selectively deuterated isotopologues—where the stereocenter hydrogens are replaced by deuterium—were subjected to Beyond BO quantum-chemical treatment at the B3LYP/aug-cc-pVDZ;PB4-F1 level, incorporating extensive electronic and nuclear polarization functions. Unbiased reaction-path searches located the racemization pathways, and kinetic isotope effects (KIE = kK /kD) were determined with high precision.
【Results and Discussion】
Racemization proceeds via keto–enol tautomerism as the rate-determining step. The parent thalidomide exhibits a KIE of 3.1, however, this decreases to 2.5 in analogues with altered partial structures. This attenuation arises from modifications to the phthalimide ring—specifically, substituting one carbonyl group with a methylene unit perturbs the charge balance around proton-transfer centers, narrowing the energy gap between H- and D-mediated pathways and thereby reducing isotopic suppression.
【Conclusions】
Beyond BO quantum-chemical insights identify local charge-distribution control at proton-transfer centers as a decisive design parameter for racemization suppression. These findings provide a mechanistic blueprint for engineering stereochemically robust, deuterium-stabilized drug candidates.