The need for analytical methods for the determination of the enantiomeric excess of chiral compounds increased significantly in the last decades, and enantioselective separation techniques resulted particularly efficient to this purpose. Moreover, when detection systems based on chiroptical properties (optical rotation or circular dichroism) are employed in high-performance liquid chromatography (HPLC), the stereochemistry of a chiral analyte can be fully determined. Indeed, the coupling of HPLC with chiroptical detection systems allows the simultaneous assessment of the absolute configuration of stereoisomers and the evaluation of the enantiomeric/diastereomeric excess of samples. These features are particularly important in the study of drugs and natural products provided with biological activity, because the assignment of their absolute stereochemistry is essential to establish reliable structure-activity relationships. The following review aims to discuss the analytical advantages arising from the employment of electronic circular dichroism (ECD) detection systems in stereochemical analysis by HPLC upon chiral and non-chiral stationary phases and their use for the stereochemical characterization of chiral drugs and natural compounds. The different methods for the correlation between absolute stereochemistry and chiroptical properties are critically discussed. Relevant HPLC applications of ECD detection systems are then reported, and their analytical advantages are highlighted. For instance, the importance of the concentration-independent anisotropy factor (g-factor; g=Δɛ/ɛ) for the determination of the stereoisomeric composition of samples upon non-chiral stationary phases is underlined, since its sensitivity makes ECD detection very well suited for the enantioselective analysis of large libraries of chiral compounds in relatively short times.
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