Study on the absolute configuration of levetiracetam via density functional theory calculations of electronic circular dichroism and optical rotatory dispersion

Abstract

Theoretical calculation of chiroptical properties has been a powerful tool for the absolute configuration assignment of chiral compounds including synthetic drugs and natural products. In the present work, time-dependent density functional theory (TDDFT) calculations of electronic circular dichroism (ECD) and optical rotatory dispersion (ORD) were employed to investigate the absolute configuration of levetiracetam, which is a widely used anticonvulsant drug. Nine conformers were generated by conformation search using the MMFF94 molecular mechanics force field, and the geometries were then optimized using the Becke 3–Lee–Yang–Parr (B3LYP) exchange-correlation functional. The population-averaged ECD spectrum was obtained by adding ECD spectrum of each conformer using Boltzmann statistics. The predicted ECD spectrum is in excellent agreement with the measured ECD spectrum of levetiracetam. Theoretical ORD spectra show the same tendency as the experimental data of levetiracetam, further confirming the absolute configuration derived from the ECD spectra. Our results demonstrated that the only chiral carbon atom of levetiracetam is unambiguously to be S configuration.