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. 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 highly convergent manner. In the key step, a one‐pot cascade initiated by fragment coupling (cyclocondensation) was followed by a spontaneous retro‐Claisen rearrangement to afford a 2,5‐dihydrooxepin‐fused heterotricyclic product.