Biomimetic synthesis of gramicidin S. Direct formation of the antibiotic from pentapeptide active esters having no protecting group on the side chain of the Orn residue

The direct formation of gramicidin S (GS) by the dimerization-cyclization of pentapeptide active esters having no protecting group on the side chain of the Orn residue was examined. Among the five succinimide esters (-ONSu) carrying the Val, Orn, Leu, D-Phe, or Pro residue at each C-terminus, only H-D-PhoPro-Val-Orn-Leu-ONSu, having the sequence identical with that of the linear precursor pentapeptide in the biosynthenis of GS, gave semi-GS (cyclic monomer) and GS (cyclic dimer) in yields of 15 and 38%, respectively. Other pentapeptide esters did not give GS. The process of the cyclization of H-D-Phe-Pro-Val-Orn-Leu-ONSu is proposed as follows. In the intramolecular reaction, the active ester of the Leu residue couples slowly with the α-amino group of the D-Phe residue to give the semi-GS but not with the δ-amino group of the Orn residue. In the GS formation, the active ester dimerizes to a decapeptide active ester, which takes the GS-like β-pleated sheet conformation and cyclizes to afford GS