Dehydrophenylalanine (ΔPhe) was incorporated into an antibiotic peptide gramicidin S (GS) in place of D‐Phe4,4′ to prepare an unsaturated analog. Conformational analysis with 1H‐NMR indicated that the unsaturated analog has much the same backbone conformation as that of natural gramicidin S as shown by NOE experiments. Studies on temperature dependences and on the chemical shift differences showed that the hydrogen bonds between Val‐NH and Leu‐CO in the unsaturated analog are strengthened by the incorporation of ΔPhe4,4′. This resulted in the reinforcement of the β‐sheet structure which is the most important structural element for GS bioactivity. [ΔPhe4,4′]gramicidin S exhibited indeed very strong antimicrobial activities against Gram‐positive bacteria as well as the natural peptide.

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Analogs of gramicidin S, [1,1′-bis(α-aminoisobutyric acid)]gramicidin S (18) and [1-α-aminoisobutyric acid] semigramicidin S (11), have been synthesized by a conventional solution method. The cyclization reactions of a linear pentapeptide active ester and a linear decapeptide active ester yielded exclusively a protected cyclic pentapeptide and a protected cyclic decapeptide, respectively. After deprotection of these peptides, we obtained the final products (11 and 18). The mobility of 18 in paper electrophoresis was the same as that of gramicidin S, however, the CD spectrum of 18 in a methanol solution showed a markedly different pattern from that of gramicidin S. Both analogs (11 and 18) are inactive against the Gram-positive microorganisms tested. The results suggest that the positions of the valine residues in gramicidin S require a hydrophobic amino acid having l-configuration to show activity.

In order to investigate the relationship between the structure of a peptide backbone and the formation of an intramolecular disulfide bond (S–S) in the peptide, a linear analog (1) of gramicidin S and a heterodetic cyclic peptide containing an S–S bond (2) were synthesized by the conventional solution method. Since a disulfide bonded compound (2) was easily formed by a treatment of the acetamidomethyl(Acm)-protected linear peptide (1) with iodine in good yield (70%), it is suggested that the mutual position between Cys1 and Cys8 residues becomes approximate, owing to the contribution of –d-Phe–Pro– part of the sequence. A heterodetic cyclic peptide (2) showed about 1/16–1/8 fold activity compared to that of GS; 1 as inactive. By the construction of an S–S bridge on the peptide backbone (1), an inactive peptide derivative was effectively converted to an active analog (2). The CD spectrum pattern also suggests that the heterodetic cyclic peptide (2) has a GS-like structure.

A convenient procedure to prepare l-homoglutamic acid (l-2-aminoadipic acid; l-Aad) is described. Chlorination of ε-amino group in acetyl-l-lysine ethyl ester with t-butyl hypochlorite (t-BuOCl) followed by dehydrochlorination with pyridine gave ethyl 5-cyanovalerate which on acid hydrolysis afforded l-Aad in good yield.