Stereochemistry of protected ornithine side chains in gramicidin S derivatives and their resistance to N-methylation

Abstract

Derivatives of gramicidin S (GS) and its mono- and di-d-cyclohexylalanined-Cha) analogs possessing various protecting groups on Orn side chains were prepared.1H NMR spectra of the unsymmetrically protected analogs [Orn(X)2, Orn(X′)2′,d-Cha4]GS were similar to the composites of the spectra of the symmetrical derivatives [Orn(X)2,2′,d-Cha4,4′]GS and [Orn(X′)2,2′]Gs, revealing the proximity of the protecting groups of NδH of Orn residues at the 2 and 2′ positions to the side chains ofd-Phe (ord-Cha) residues at the 4 and 4′ positions, respectively. The results indicated the presence of H-bonds between the N°H of Orn and the carbonyl ofd-Phe residues in the i→i+2 sense and not in i→i-3, which was also supported by the ROESY analysis. The substantially strong H-bonds can explain the observed resistance of the urethane NH of the Orn side chains in the GS derivatives to the N-methylation with CH3I−Ag2O in DMF.