Studies of peptide antibiotics. XLIII. Syntheses of gramicidin S analogs containing D-serine or dehydroalanine in place of D-phenylalanine and asymmetric hydrogenation of the dehydroalanine residue

Gramicidin S (GS) analogs, D-Ser4,4']-GS and its precursor O-benzyl-D-Ser4,4']-GS, were synthesized by the conventional method in order to evaluate the role of the hydroxymethyl side chains in D-Ser at 4,4' positions on the biological activity. Another analog L-Orn(delta-Boc)2,2',delta Ala4,D-Ser4']-GS was prepared from D-Ser4,4']-GS by t-butyloxycarbonylation and successive dehydration using dicyclohexylcarbodiimide-CuCl as dehydrating reagent. The delta Ala residue was asymmetrically hydrogenated to D-Ala in the presence of Pd-black. On the microbial assays, O-benzyl-D-Ser4,4']-GS showed high antimicrobial activity as natural GS, but D-Ser4,4']-GS showed low activity; the structure-activity relationships of the analogs were discussed.