Biomimetic synthesis of a peptide antibiotic, gratisin

Abstract

Recently, we reported the direct formation of a peptide antibiotic, gramicidin S (GS), cyclo(-D-Phe-Pro-Val-Orn-Leu-)₂, by the dimerization–cyclization of pentapeptide active esters, D-Phe-Pro-Val-Orn-Leu-ONSu (-ONSu: succinimide ester), having the sequence identical with that of the linear precursor pentapeptide in the biosynthesis of GS and no protecting group on the side-chain of the Orn residue. This biomimetic approach has been extended to the synthesis of a peptide antibiotic, gratisin (GR), cyclo(-D-Phe-Pro-D-Tyr-Val-Orn-Leu-)₂, isolated from Bacillus brevis Y-33. In the cyclization of six hexapeptide succinimide esters having a Val, Orn, Leu, D-Phe, Pro or D-Tyr residue at each C-terminus, only H-D-Phe-Pro-D-Tyr-Val-Orn-Leu-ONSu gave semi-GR and GR in yields of 31 and 8%, respectively. Other hexapeptide esters did not give semi-GR and GR. In both biomimetic syntheses of GS and GR, the amino acid sequences having a Leu residue at the C-terminus are essential. In addition, a change in the concentration of peptide and the polarity of reaction solvents influenced greatly the yields of cyclic monomer (semi-GR) and cyclic dimer (GR). However, the yield of GR by dimerization–cyclization of hexapeptide active ester was lower when compared with the direct formation of GS (38%). The difference may result from differences in the chain length and the configurations of amino acid residues around the Pro residue.