Enantiomeric Mixtures in Natural Product Chemistry: Separation and Absolute Configuration Assignment

Abstract

Chiral natural product molecules are generally assumed to be biosynthesized in an enantiomerically pure or enriched fashion. Nevertheless, a significant amount of racemates or enantiomerically enriched mixtures has been reported from natural sources. This number is estimated to be even larger since the enantiomeric purity of secondary metabolites is rarely checked in the natural product isolation pipeline. This latter fact may have drastic effects on the evaluation of the biological activity of chiral natural products. A second bottleneck is the determination of their absolute configurations. Despite the widespread use of optical rotation and electronic circular dichroism, most of the stereochemical assignments are based on empirical correlations with similar compounds reported in the literature. As an alternative, the combination of vibrational circular dichroism and quantum chemical calculations has emerged as a powerful and reliable tool for both conformational and configurational analysis of natural products, even for those lacking UV-Vis chromophores. In this review, we aim to provide the reader with a critical overview of the occurrence of enantiomeric mixtures of secondary metabolites in nature as well the best practices for their detection, enantioselective separation using liquid chromatography, and determination of absolute configuration by means of vibrational circular dichroism and density functional theory calculations.

Furoic acid derivatives from the endophytic fungus Coniothyrium sp.

“…The experimental ECD spectrum had to be multiplied by 20 to be comparable with the calculated ECD spectra, which implies about more than one order of magnitude difference. This indicated that the sample is probably a scalemic mixture with slight excess of the ( S ) stereoisome . Partial racemization of the chirality center is certainly aided by the benzylic position, since the C‐6 chirality center is α position to both a benzene and a furan ring.…”

Structural Elucidation and Cytotoxicity of a New 17-Membered Ring Lactone from Algerian Eryngium campestre

“…In the last decade, VCD spectroscopy has become a popular technique for the elucidation of absolute configurations of chiral molecules [31,32,33]. Therefore, in order to determine the stereochemistry of the asymmetrical carbon-17 of Campestrolide, the VCD spectrum of a sample containing 80% of compound 33 was measured in CD 2 Cl 2 .…”

Sesquiterpene Lactones from Calea pinnatifida: Absolute Configuration and Structural Requirements for Antitumor Activity

“…Once the relative configuration of Compound 1 was unambiguously assigned by NOESY analysis, vibrational circular dichroism (VCD) experiments and calculations were used to determine its absolute stereochemistry for the first time in the literature. VCD associated with density functional theory (DFT) calculations has been demonstrated as a powerful probe for chirality in natural products [14,15].…”

“…Many of the experiments carried out on these molecules were based on X-ray crystallography and degradation reactions, as in the case of neurolenin B, a sesquiterpene lactone that had its relative configuration assigned based on X-ray crystallographic data [9]. Nowadays, bidimensional NMR experiments, combined with vibrational circular dichroism (VCD) measurements and calculations, represent powerful complementary tools to unambiguously define both the relative and absolute configurations of a given molecule directly in solution [14,15].…”