Biomimetic Synthesis and Analytics of the Human aryl Hydrocarbon Receptor Agonist 1-(furan-2-yl)-2-(1H-indol-3-yl)ethanone, and its 1-(thiophen-2-yl) and 1- (pyrrol-2-yl) Analogues

Abstract

1-(2-Furanyl)-2-(3-indolyl)ethanone (FIE, 4) is a potent ligand of the human aryl hydrocarbon receptor (AhR), the so-called dioxin receptor, and the estrogen receptors (ERs), with high activities in transactivation assays. Direct synthesis approaches towards 4 have been hampered by the high oxidative instability of both the indole moiety and the furan part. A biomemetic synthetic pathway was devised that provides the compound for the first time in gram amounts sufficient for comprehensive testing. In the first step, ascorbigen (11) - a breakdown product of glucobrassicins in cruciferous vegetables - is formed according to a rare example of direct C-alkylation of non-protected ascorbic acid (vitamin C) by (3-indolyl)-methyl intermediates under physiological conditions. Ascorbigen is then decarboxylated and rearranged to the target compound 4 under similarly mild conditions in the presence of zinc oxide on silica gel, providing 88% overall yield. The same reaction can be carried out without catalyst but at slightly elevated temperatures under carefully profiled microwave heating, though at somewhat decreased yields along this path (60%), i.e. 28% yield penalty. The thiophene analogue and pyrrol analogue of the target were synthesized according to the same protocol. The reaction conditions were thoroughly optimized, and all compounds were comprehensively analytically characterized, including complete NMR resonance assignment in the 1H- and 13C-domains, MS and pyrolysis-GCMS characterization, and X-ray crystal structure analysis of the thiophene derivative. Keywords: AhR, Ascorbate, Ascorbic acid, Ascorbigen, C-alkylation, Decarboxylation, Human aryl hydrocarbon receptor, 3-indolylcarbinol, (3-indolyl)methyl ketones, Rearrangement.