Rapid mild macrocyclization of depsipeptides under continuous flow: total syntheses of five cyclodepsipeptides

Abstract

The total synthesis of five natural products destruxin B, pseudodestruxin B, isaridin A, cladoamide A, and cladoamide B was accomplished. These depsipeptides were synthesized though a flow macrocyclization method from linear precursors, which were obtained by the solid-phase peptide synthesis (SPPS) method, and three different cyclization points (–CONHR, –CONR₂, –COOR) were designed to improve the total yield. In this study, the first examples of macrolactonization under flow were reported, and all 5 macrocyclizations were found to be significantly accelerated from hours to minutes. In addition, selective control of trans/cis conformers at the –CONR₂ cyclization point was revealed to be possible by employing suitable coupling reagents for macrolactamization.