Total Synthesis of Coelichelin, Cochinmicin I, and Cochinmicin V

Abstract

Natural product total synthesis provides efficient access to privileged scaffolds with unique biological activities. Herein, we describe our efforts in the synthesis of three peptidic natural products: coelichelin, cochinmicin I, and cochinmicin V. To date, we have developed synthetic strategies to access the bacterial sideorophore coelichelin as well as its unnatural congener acetyl coelichelin. This represents the first total synthesis of these bacterial siderophores, which enables on-going evaluation of the preparation of siderophore-conjugates to further study bacterial metal acquisition. To date, we also report the development of novel methodology to access unique structural motifs within the aryl glycine-rich cochinmicins as well as the first reported synthesis of these cyclic depsipeptides. We employed a novel amide bond forming reaction referred to as Umpolung Amide Synthesis (UmAS) to access these epimerization-prone peptides. This synthesis of cochinmicins I and V employing a late-stage UmAS approach represents the most complex application of UmAS in a natural product synthesis to date. While our approach furnished the desired depsipeptides, further efforts to improve this synthesis are enabled by the findings described herein. We hope to report our further advancements in the preparation of complex depsipeptides in due course. The ultimate goal of these synthetic endeavors to prepare sufficient quantities of these peptidic natural products and analods to enable biological evaluation.