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

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 C-13-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-[C-13](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-[C-13]-2,4-bis(benzyloxymethyloxy)-6-methoxy-3-(3-methylbuten-2-yl)acetophenone and 1-[C-13]-4-(methoxymethyloxy)benzaldehyde. The C-13-atom in the methyl ketone was derived from 1-[C-13]-acetyl chloride while that in the aryl aldehyde was derived from [C-13]-iodomethane. Tri- and penta-C-13-labeled xanthohumols were similarly prepared by applying minor modifications to the route.