Total Synthesis and Reassignment of the Structures of the Antimicrobial Lipodepsipeptides Circulocin γ and δ.

Abstract

The structures of the naturally occurring antimicrobial lipodepsipeptides circulocin γ and circulocin δ have been reported to comprise a common cyclic depsipeptide core attached to 3-hydroxy,ω-guanidino fatty acid chains differing in length by two methylene units, but analysis of the reported data suggested that the originally reported structures had incorrect side chain lengths. The total synthesis of both side chain epimers of the originally reported structure of circulocin γ bearing a 19-guanidino-3-hydroxynonadecanoyl (GHND) side chain has been accomplished using a modular approach involving synthesis of the cyclic depsipeptide and side chain fragments followed by a late stage coupling reaction. This revealed that the originally reported structure for circulocin γ bearing the GHND side chain is incorrect and that this structure is actually that of circulocin δ. It has also enabled the absolute configuration of the side chain hydroxy group of the natural product to be assigned as (R). Subsequent synthesis of the analogue bearing a 17-guanidino-3-(R)-hydroxyheptadecanoyl (GHHD) side chain provided confirmation that this revised structure is that of circulocin γ.