Absolute Configuration of Isosilybin A by X‑ray Crystallography of the Heavy Atom Analogue 7‑(4-Bromobenzoyl)isosilybin A

Abstract

Isosilybin A (<b>1</b>) is one of the major flavonolignans that constitute silymarin, an extract of the fruits (achenes) of milk thistle (<i>Silybum marianum</i>). The chemistry of the <i>Silybum</i> flavonolignans has been studied for over four decades, and the absolute configuration of <b>1</b> has been determined previously by electronic circular dichroism and X-ray crystallography via correlating the relative configuration of the phenylpropanoid moiety to the established absolute configuration of the 3-hydroxyflavanone portion of the molecule. Herein we report the X-ray crystallographic structure of the product of the reaction of <b>1</b> with 4-bromobenzoyl chloride, and, thus, the absolute configuration of <b>1</b> was established as (2<i>R</i>, 3<i>R</i>, 7″<i>R</i>, 8″<i>R</i>) directly via X-ray crystallography of an analogue that incorporated a heavy atom. The results were consistent with previously reported assignments and verified the absolute configuration of the diastereoisomer of <b>1</b>, isosilybin B, and the related diastereoisomeric regioisomers, silybin A and silybin B