Total synthesis of [13 C]2 -, [13 C]3 -, and [13 C]5 -isotopomers of xanthohumol, the principal prenylflavonoid from hops

Abstract

Xanthohumol [(E)-6'-methoxy-3'-(3-methylbuten-2-yl)-2',4',4″-trihydroxychalcone], he principal prenylated flavonoid from hops, has a complex bioactivity profile, and ¹³ C-labeled isotopomers of this compound are of potential use as molecular probes and as analytical standards to study metabolism and mode of action. 1,3-[¹³ C]₂ -Xanthohumol was prepared by an adaptation of the total synthesis of Khupse and Erhardt in 7 steps and 5.7% overall yield from phloroglucinol by a route incorporating a cascade Claisen-Cope rearrangement to install the 3'-prenyl moiety from a 5'-prenyl aryl ether and an aldol condensation between 1-[¹³ C]-2',4'-bis(benzyloxymethyloxy)-6'-methoxy-3'-(3-methylbuten-2-yl)acetophenone and 1'-[¹³ C]-4-(methoxymethyloxy)benzaldehyde. The ¹³ C-atom in the methyl ketone was derived from 1-[¹³ C]-acetyl chloride while that in the aryl aldehyde was derived from [¹³ C]-iodomethane. Tri- and penta-¹³ C-labeled xanthohumols were similarly prepared by applying minor modifications to the route.

Keywords: Claisen rearrangement; aldol condensation; chalcones; cope rearrangement; phytochemicals.