Graduate Thesis Or Dissertation
 

Total Synthesis of Isotopologues of Xanthohumol and its Congeners for Biological Studies

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  • Xanthohumol [XN, (E)-6´-methoxy-3´-(3-methylbuten-2-yl)-2´,4´,4´´-trihydroxychalcone], the principal prenylated chalcone from hops, and its 2,3-dihydro- (DXN) and O6-desmethyl-2,3-dihydro- (DDXN) congeners, are of potential utility for the amelioration of metabolic syndrome; however, their complex bioactivity profiles cannot be properly studied and understood without access to appropriately produced synthetic materials. In the first part of the thesis (Chapter 2), total syntheses of five variously 2H- and 13C-labeled isotopologues of xanthohumol are described. 1,3-[13C]2-Xanthohumol was prepared by an adaptation of the known elaboration by Khupse and Erhardt in seven steps and 6% 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 (14) 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. Substitution of natural abundance iodomethane (12CH3I) for 13CH3I, 12CD3I, and 13CD3I during the Williamson ether synthesis that installs the 6´-methoxy group from the corresponding phenol enabled straightforward access to three additional XN isotopologues of +3, +5, and +6 mass units above the monoisotopic value, in addition to the +2 compound already prepared. A penta-13C-labeled XN isotopologue [(E)-2,3-[13C]2-6´-[13C]-methoxy-3´-(1,2-[13C]2-3-methylbut-2-enyl)-2´,4´,4´´-trihydroxychalcone], was similarly prepared by using 1,3-[13C]2-prenyl alcohol at the appropriate juncture in addition to the aforementioned 13C-atom containing precursors. In the second part of the thesis (Chapter 3), the exploration of two different novel approaches to DXN and DDXN that do not employ XN as a precursor is described. In the first approach, an acetophenone enolate alkylation strategy was pursued to forge the central C2-C3 bond; however, this tactic suffers from over-alkylation of the acetophenone by the 4-alkoxybenzyl bromide electrophile. For example, 1-[13C]-DDXN was synthesized in three steps and 2% yield from the previously prepared acetophenone derivative [13C]-12 by alkylation of its Li-enolate with 4-(methoxymethyloxy)benzyl bromide (33% yield mono alkylation, 9% double alkylation), Eu(fod)3 catalyzed Claisen-Cope rearrangement (44% and 28% of a cyclic ether derived from the Claisen rearrangement adduct), and acid-mediated deprotection (13% and 77% 2´O-BOM DXN). In the second approach, the conversion of the commercially available natural product phloretin [1-(2,4,6-trihydroxyphenyl)-3-(4-hydroxyphenyl)propiophenone] to DXN/DDXN was evaluated via (step-wise) 6´O-prenylation followed by Claisen-Cope rearrangement. In each case, difficulties were encountered in attempting to achieve the required level of regiocontrol within the context of selectively chemically manipulating the multifunctional phloretin molecule. It was concluded that DXN and DDXN are better accessed via the known selective hydrogenation of XN to DXN.
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  • NIH (5R01AT009168)
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