Total Synthesis of Melicoptelines C–E: Antiviral Cyclopeptides Containing a Hexahydropyrrolo[2,3-b]indole Moiety

Abstract

Melicoptelines, natural cyclopeptides containing a 3a-hydroxy hexahydropyrrolo[2,3-b]indole (HPI) moiety, exhibit anti-influenza activity. Herein, we report the first total synthesis of melicoptelines C−E (1−3, respectively). The core 3a-hydroxy HPIs were synthesized in a diastereoselective manner from Ltryptophan using dimethyldioxirane-mediated oxidation. Subsequently, sequential peptide couplings and cyclization completed the synthesis of melicoptelines C−E and unnatural melicopteline 4. The synthesized melicoptelines were evaluated for their antiinfluenza activity, and melicopteline E showed the most potent inhibition of cytopathic effects.