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

Abstract

Xanthohumol [ (E)-6′-methoxy-3′-(3-methylbuten-2-yl) -2′,4′,4″-trihydroxychalcone], the principal prenylated flavonoid from hops, has a complex bioactivity profile and 13C-labelled 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-labelled xanthohumols were similarly prepared by applying minor modifications to the route.

Anticancer Activity and Mechanism of Xanthohumol: A Prenylated Flavonoid From Hops (Humulus lupulus L.)

“…However, it was still unable to meet the clinical needs ( Chen et al, 2012 ). Therefore, a total synthesis method for Xn was further investigated ( Khupse and Erhardt, 2007 ; Ellinwood et al, 2017 ). Unfortunately, the process was complicated and the overall yield is relatively low (10% overall yield from phloracetophenone after six steps) ( Khupse and Erhardt, 2007 ).…”

Xanthohumol Pyrazole Derivative Improves Diet-Induced Obesity and Induces Energy Expenditure in High-Fat Diet-Fed Mice

“…XN is also characterized by a strong hydrogen bond between one hydroxyl group and its carbonyl moiety, favoring the fully conjugated tautomer. 22 Compound 2 was treated with DDQ in dichloromethane to afford derivative 3 with 56% yield. For the final deprotection, two strategic approaches were undertaken.…”

“…Indeed, the presence of a far downfield signal in the 1 H NMR (12.0–12.5 ppm) of XP and XP intermediates (Figures S1–S8) could suggest the formation of a highly conjugated enamine/orthoquinomethide tautomer (Figure S9). XN is also characterized by a strong hydrogen bond between one hydroxyl group and its carbonyl moiety, favoring the fully conjugated tautomer . Compound 2 was treated with DDQ in dichloromethane to afford derivative 3 with 56% yield.…”

“…The samples were extracted with 200 μL of acetonitrile containing 100 ng/mL of [ 13 C3]-XN. 22 The supernatant was transferred to a new tube and vacuum-dried, and the pellet was reconstituted in 100 μL of 50% methanol in water. UPLC-MS was performed using a hybrid triple quadrupole linear ion trap mass spectrometer (4000 QTRAP, AB SCIEX, Toronto, Canada) as previously reported 72 with some modifications.…”

Synthesis of xanthohumol and xanthohumol-d3 from naringenin

“…15,16 Deuterated compounds are also considered as attractive drug candidates due to the inuence of the kinetic isotope effect on pharmacokinetics. [17][18][19] Although approaches to 13 C-enriched xanthohumol 20,21 and hydrogen/ deuterium exchange in 1a 22 were reported, no scalable and cost-effective synthesis of the deuterium-labeled derivative of 1a (i.e. 1b) has been disclosed to date.…”