Studies of peptide antibiotics. XLVI. Syntheses of gramicidin S analogs containing D‐α, β‐diaminopropionic acid or α,β‐dehydroalanine*

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Abstract
A gramicidn S (GS) analog ([D-Dpr4,4'']GS) containing D-.alpha.,.beta.-diaminopropionic acid (D-Dpr) in place of D-Phe at 4,4'' positions was derived from [L-Orn(.delta.-formyl-ornithine)2,2'', D-Dpr(.beta.-Z)4,4[D-.beta.-benzyloxycarbonyl-.alpha.,.beta.-diaminopropionic acid]]GS, which was synthesized by conventional method in soultion. An analog [.DELTA.Ala4,4'']GS was synthesized from [L-Orn(.delta.-Boc[tert-butyloxycarbonyl])2,2'', D-Dpr4,4'']GS through Hofmann degradation of the D-Dpr residues. Antimicrobial activities of these analogs were tested; [D-Dpr(.beta.-Z)4,4'']GS and [.DELTA.Ala4,4'']GS showed high antimicrobial activities against Gram-positive bacteria. [D-Dpr4,4'']-GS showed an appreciable activity against Gram-negative bacteria such as Escherichia coli. Four semigramicidin S (semiGS) analogs such as [.DELTA.Ala4] semiGS were synthesized; these had no antimicrobial activity. Analogs containing .DELTA.Ala residues were hydrogenated and the formation of L-Ala or D-Ala residues was determined. The .DELTA.Ala residues in [.DELTA.Ala4,4'']GS were reduced to DL-Ala and .DELTA.Ala in [.DELTA.Ala4]semiGS mostly to L-Ala. The relationships of the antimicrobial activity, CD [circular dichroism] curves and asymmetric hydrogenation to the structure were discussed.