Total Synthesis of (+)-Cinereain and (−)-Janoxepin through a Fragment Coupling/Retro-Claisen Rearrangement Cascade

Total syntheses of (+)-cinereain and (−)-janoxepin, two fungal cyclotripeptides featuring a complex heterocyclic core and interesting phytotoxic and antimalarial activities, have been achieved in a convergent manner. A key step in this synthesis is a one-pot cascade initiated by the cyclocondensation of two fragments—a hindered 2-vinylcyclopropane-1-acyl fluoride and an electron-deficient cyclic amidine—to release a reactive spiro[2-vinylcyclopropane-1,5′-pyrimidine-4′,6′-dione]. This intermediate underwent a spontaneous retro-Claisen rearrangement that was rationalized by DFT calculations. The cascade directly afforded a 2,5-dihydrooxepin-fused heterotricyclic product, and the challenging oxepin ring was finally forged by the palladium-catalyzed β-hydride elimination of an allylic fluoride intermediate.