Phosphinothricins peptides

L-phenylalanine was prepared from L-tyrosine by chemical methods, in an overall yield of 75%. A series of peptides containing a-aza-amino acid residues has been prepared 7 one member of the series, N[(1-carboxyethyl)carbamoyl]-valylglyclyl-a-aza-alanine benzyl ester, is substantially more potent than several azapeptide inhibitors of elastase hitherto reported. D,L-Phosphinothricin (49), D,L-2-amino-4-phosphonobutyric acid (50), and aminocyclopropanecarboxylic acid have all been prepared from methyl-4-bromo-2-phthalimidobutyrate using simple procedures (Scheme 83).177... 

Functionalized phosphonic and phosphinic acids and their derivatives are obviously of interest to the organophosphorus chemist, but the importance, both actual and potential, in other areas, particularly in the biological sphere, cannot be overemphasized. Prominent amongst the many important compounds are, for example,the insecticide dipterex (1) and the herbicide glyphosate (2), both synthetic compounds. Several phosphonic acid antibiotics have been isolated from Streptomyces species. (2 S)-2-Amino-4-(hydroxymethyl-phosphinoyl)butanoic acid (3), otherwise known as phosphinothricin, and a substance which also possesses herbicidal activity, is a component of the peptide y-(hydrox-ymethylphosphinoyl)-L-a-aminobutanoyl-L-alanyl-L-alanine, also present in the same organism. (1,2-Epoxypropyl)phosphonic acid, [(3-methyloxiranyl)phosphonic acid] as the (2R,3S)-diastereoisomer (4), also known as phosphonomycin, is important from the pharmaceutical standpoint as a broad spectrum bactericide, and it is produced commercially. 

In 1972 the team of Professor Zaehner at Tubingen described a Streptomyces strain producing a novel compound with antibiotic properties. The antibiotic tripeptide produced by Streptomyces viridochromogenes consists of two alanine residues and a novel amino acid that was named phosphinothricin [14] (Fig. 6.3.2). Owing to its structural analogy to glutamate Bayer et al. [14] tested and proved the hypothesis that phosphinothricin acts as an inhibitor of bacterial GS enzyme, whereas the tripeptide phosphinothricyl-alanyl.alanine did not inhibit the isolated GS enzyme. Nevertheless the tripeptide was 1.000-10.000-fold more active in its growth inhibitory effect on different bacteria. The discrepancy is explained by the observation that free phosphinothricin cannot be taken up efficiently by bacteria, whereas the tripeptide is taken up into the bacteria by peptide carriers and, subsequently, the tripeptide is cleaved. 

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