A new cyclic depsipeptide aureobasidin A (1), isolated as a major component from the culture medium of the black yeast Aureobasidium pullulans R106, exhibits a strong antifungal activity against pathogenic fungi such as Candida albicans, Cryptococcus neoformans, and some species of Aspergillus with a low toxicity. For purpose of investigation of a structure-activity relationship of the aureobasidin family antibiotic, we attempted a total synthesis of aureobasidin A, aiming an establishment of a synthetic technique of the cyclic depsipeptide containing N-methyl amino acids, known as a difficult component in condensation reaction because of its steric bulkiness. The linkage between alle^1 and Pro^9 was chosen as a site of the final cyclization to avoid the coupling at an N-methyl amino acid as an amino component, which otherwise may diminish a yield of the cyclization reaction due to its steric characters. A linear nonapeptide(1-9) was synthesized according to the Boc strategy. Thus, a coupling between Leu^3-HOMeVal^4-Hmp^5 (Segment B) and MeVal^6-Phe^7-MePhe^8-Pro^9 (Segment C) was first attempted, followed by condensation of the coupling product (3-9) with alle^1-MeVal^2 (Segment A) by the fragment condensation. The linear nonapeptide 24 was cyclized with PyBroP in CH_2Cl_2 under high-dilution condition (10^<-3>M) to afford the cyclic monomer predominantly. The synthetic cyclic peptide thus obtained is completely identical with the natural antibiotic in all respects (TLC, HPLC, ^1H-NMR, and antifungal activities). Thus, we could achieve the first total synthesis of the unique depsipeptide, aureobasidin A.
