STEREOSPECIFIC SYNTHESIS OF PHOSPHONATE ANALOGS OF DIAMINOPIMELIC ACID (DAP), THEIR INTERACTION WITH DAP ENZYMES, ND ANTIBACTERIAL ACTIVITYOF PEPTIDE DERIVATIVES

Analogues of diaminopimelic acid (DAP) in which the carboxyl groups ar e replaced with phosphonic acid moieties were synthesized as pure ster eoisomers, examined as inhibitors of three DAP enzymes, and tested as antibacterial agents. Condensation of the enolate of (S)-1-benzoyl-2-t ert-butyl-3- methyl-4-imidazolidinone (1) with 1,3-dibromopropane ster eoselectively gave the expected mono-bro;nide 3 which was used to alky late the (-)-camphor imine 7 of diethyl (aminomethyl)phosphonate to yi eld a 4:1 mixture of 1R and 1S diastereomers 8 and 9, respectively. Se paration and hydrolytic deprotection gave stereochemically pure (1R,5S )-(1,5-diamino-5-carboxypentyl)phosphonic acid (P-DAP) (10) and its (1 S,5S)-isomer 11. An analogous approach employing (+)-camphor imine 17 and monobromide 3 also allowed synthesis of 10 and 11, but in a revers ed ratio (ca. 2:3). The pure (1R,5R)-P-DAP (14) and (1S,5R)-P-DAP (15) could be made by a similar procedure using (R)-1- benzyl-2-tert-butyl -3-methyl-4-imidazolidinone (2), 1,3-dibromopropane, and 7. A DAP bis- phosphonate analogue 22, in which both carboxyl groups are replaced, w as synthesized as a mixture of all possible isomers by condensation of 2 equiv of the enolate of imine 7 or 17 with 1,3-dibromopropane follo wed by hydrolysis. A series of di- and tripeptides of individual P-DAP isomers with L-alanine were synthesized to enhance transport into bac terial cells for antimicrobial tests. Condensation of L-alanine N-carb oxyanhydride (23) with individual P-DAP isomers 10, 11, 14, and 15 in aqueous Na2CO3/DMF gave acylation only on the amino group adjacent to the carboxyl to generate dipeptides 24-27. Acylation of P-DAP isomers 10 or 11 with Boc-L-Ala-L-Ala proceeded similarly to give, after depro tection, tripeptides 30 and 32. The P-DAP isomers were generally weak competitive inhibitors of purified DAP decarboxylase from wheat germ ( Triticum vulgaris), DAP dehydrogenase from Bacillus sphaericus, and DA P epimerase from Escherichia coli. P-DAP 11 (a meso-DAP analogue) has the strongest effect on the decarboxylase and epimerase, and its enant iomer 14 is the strongest inhibitor of the dehydrogenase. Antibacteria l tests show that the P-DAP isomers display negligible activity except against Salmonella typhimurium LT-2. Compound 11 is the most active i somer and its inhibition Is reversed by DAP. Among the peptide derivat ives, the antibacterial spectrum of 30 (the tripeptide containing 10) includes several strains of E. coli and Citrobacter freundii.