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

Andrea N L Batista,Quezia Cass,Fernando M Dos Santos,João Batista

doi:10.3390/molecules23020492

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.

Highlights

Secondary metabolites play a significant role in drug discovery and development processes [1], as they are intrinsically endowed with both architectural and stereochemical complexity
Chiroptical methods, which arise from the differential interaction of a chiral non-racemic sample with left- and right-circularly polarized radiation, can be used for the determination of e.e., since the signal intensity of OR, electronic circular dichroism (ECD), vibrational circular dichroism (VCD), and ROA spectroscopies is proportional to the enantiomeric excess [85,86,87,88,89,90]
Chiroptical spectroscopy can be used for the determination of e.e., this should not be performed based on single measurements, even if this is a common practice in natural product chemistry

Summary

Introduction

Secondary metabolites play a significant role in drug discovery and development processes [1], as they are intrinsically endowed with both architectural and stereochemical complexity. On examining the chiral drug market, Calcaterra and D’Acquarica [3] noticed that all new small-molecule drugs approved by the US Food and Drug Administration (FDA) in 2015 were single enantiomers with defined absolute configuration (AC), with the exception of lesinurad (a racemate of two enantiomeric atropoisomers). They noted that the chiral-switching practice had not been reported in the 2015 version of the examined dossiers. In the absence of such evidence, the relationship between biological activity and structure may be seriously compromised

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Conclusion