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

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.

CH functionalization; carbonylation; frutinone A; palladium; structure-activity relationships.