Total Synthesis of (+)-Cinereain and (-)-Janoxepin through a Fragment Coupling/Retro-Claisen Rearrangement Cascade
Résumé
The 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. In addition, the challenging oxepin ring was finally forged by the palladium-catalyzed β-hydride elimination of an allylic fluoride intermediate. Beyond the development of these original transformations, this work contributes to the first achievement of the asymmetric total syntheses of (+)-cinereain and (–)-janoxepin.
Domaines
Chimie organiqueOrigine | Fichiers produits par l'(les) auteur(s) |
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