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 ¹³C‐labeled isotopomers of this compound are of potential use as molecular probes and as analytical standards to study metabolism and mode of action. 1,3‐¹³C]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 1‐¹³C]‐2′,4′‐bis(benzyloxymethyloxy)‐6′‐methoxy‐3′‐(3‐methylbuten‐2‐yl)acetophenone and 1′‐¹³C]‐4‐(methoxymethyloxy)benzaldehyde. The ¹³C‐atom in the methyl ketone was derived from 1‐¹³C]‐acetyl chloride while that in the aryl aldehyde was derived from ¹³C]‐iodomethane. Tri‐ and penta‐¹³C‐labeled xanthohumols were similarly prepared by applying minor modifications to the route.