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