Total synthesis of a depsidomycin analogue by convergent solid-phase peptide synthesis and macrolactonization strategy for antitubercular activity

Depsidomycin is a cyclic heptadepsi-peptide isolated from the cultured broth of Streptomyces lavendofoliae MI951-62F2. It exhibits significant antimicrobial and immunosuppressive activity. The total synthesis of a depsidomycin analogue in which 1,2-piperazine-3-carboxylic acid was substituted with proline is described. After several trials using different strategies, the desired depsidomycin analogue was obtained via stepwise synthesis starting by the amino acid 'head' and macrolactonization under Yamaguchi conditions. The cyclic depsipeptide was evaluated to have an minimum inhibitory concentration (MIC) of 4 mu g/ml against H37RV and 16 mu g/ml against MDR clinical strains of MTB (MDR-MTB), while the linear precursor 8 also had MICs of 4 and 16 mu g/ml for the susceptible and resistant strains, respectively. Copyright (C) 2011 European Peptide Society and John Wiley & Sons, Ltd.