A Holistic Approach to Determining Stereochemistry of Potential Pharmaceuticals by Circular Dichroism with β-Lactams as Test Cases †

This paper’s main objective is to show that many different factors must be considered when solving stereochemical problems to avoid misleading conclusions and obtain conclusive results from the analysis of spectroscopic properties. Particularly in determining the absolute configuration, the use of chiroptical methods is crucial, especially when other techniques, including X-ray crystallography, fail, are not applicable, or give inconclusive results. Based on various β-lactam derivatives as models, we show how to reliably determine their absolute configuration (AC) and preferred conformation from circular dichroism (CD) spectra. Comprehensive CD analysis, employing both approaches, i.e., traditional with their sector and helicity rules, and state-of-the-art supported by quantum chemistry (QC) calculations along with solvation models for both electronic (ECD) and vibrational (VCD) circular dichroism ranges, allows confident defining stereochemistry of the β-lactams studied. Based on an in-depth analysis of the results, we have shown that choosing a proper chiroptical method/s strictly depends on the specific case and certain structural features.