Efficient synthesis of frutinone A and its derivatives through palladium-catalyzed C-H activation/carbonylation

Abstract

Frutinone A, a biologically active ingredient of an antimicrobial herbal extract, demonstrates potent inhibitory activity towards the CYP1A2 enzyme. A three-step total synthesis of frutinone A with an overall yield of 44 is presented. The construction of the chromone-annelated coumarin core was achieved through palladium-catalyzed C-H carbonylation of 2-phenolchromones. The straightforward synthetic route allowed facile substitutions around the frutinone A core and thus rapid exploration of the structure-activity relationship (SAR) profile of the derivatives. The inhibitory activity of the synthesized frutinone A derivatives were determined for CYP1A2, and ten compounds exhibited one-to-two digit nanomolar inhibitory activity towards the CYP1A2 enzyme. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim