Efficient Synthesis of Frutinone A and Its Derivatives through Palladium-Catalyzed C-H Activation/Carbonylation

Abstract

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