First Total Synthesis of Hormaomycin, a Naturally Occurring Depsipeptide with Interesting Biological Activities

Some unique features were disclosed during the structure elucidation of the cyclic depsipeptide hormaomycin (1), first isolated in 1989 from a Streptomyces griseoflavus strain and found to have quite an interesting spectrum of biological activities. Besides one residue of the proteinogenic amino acid isoleucine [(S)‐Ile], it contains two units of 3‐methylphenylalanine [(βMe)Phe], one of (2R)‐allo‐threonine [a‐Thr] as well as two moieties of 3‐(trans‐2‐nitrocyclopropyl)alanine [(3‐Ncp)Ala] and one of 4‐(Z)‐propenylproline [(4‐PE)Pro]. The latter two have never been found in any natural product before. The side chain of 1 is terminated with the residue of 5‐chloro‐1‐hydroxypyrrole‐2‐carboxylic acid [Chpca]. This first synthetic access to hormaomycin 1 will make it possible to prepare structural analogues of this interesting natural depsipeptide in order to elucidate structure–activity relationships and the biologically active minimal unit. The first total synthesis of hormaomycin 1, a secondary metabolite from a Streptomyces griseoflavus strain with a wide spectrum of biological activities, is described. The 4‐methylbenzyloxycarbonyl (MeZ) group was successfully applied for the first time as an acid‐labile amino protective group in peptide synthesis.