A combined experimental and computational chiroptical approach to establish the biosynthesis and absolute configuration of licochalcone L

Abstract

Often, chiral natural products exist as single stereoisomers; however, simultaneous occurrences of both enantiomers can exist in nature, resulting in scalemic or racemic mixtures. Ascertaining theabsolute configuration (AC) of natural products is pivotal for attributing their specific biological signature. Specific rotation data commonly characterize chiral non-racemic natural products; however, measurement conditions, viz., solvent and concentration, can influence the sign of specific rotation values, especially when characterizing natural products possessing small values. For example, licochalcone L, a minor constituent of Glycyrrhiza inflata, was reported with a specific rotation of [α]D22= +13 (c 0.1, CHCl3); however, not establishing the AC and the reported zero specific rotation for an identical compound, licochalcone AF1, resulted in debatable chirality and its biogenesis. In this study, a combined experimental and computational chiroptical approach involving specific rotation and electronic circular dichroism (ECD) data, supported by time-dependent density functional theory (TDDFT), were effectively utilized to establish the AC of licochalcone L as the (E, 2″S)-isomer. Establishing the 2″S absolute configuration permitted the conception of a reasonable biosynthetic pathway involving intramolecular ‘5-exo-tet’ ring opening of a chiral oxirane to form chiral licochalcone L in G. inflata.