Stereospecific Synthesis of Phosphonate Analogues of Diaminopimelic Acid (DAP), Their Interaction with DAP Enzymes, and Antibacterial Activity of Peptide Derivatives

Article abstract of DOI:10.1021/jo00098a045

Analogues of diaminopimelic acid (DAP) in which the carboxyl groups are replaced with phosphonic acid moieties were synthesized as pure stereoisomers, examined as inhibitors of three DAP enzymes, and tested as antibacterial agents.Condensation of the enolate of (S)-1-benzoyl-2-tert-butyl-3-methyl-4-imidazolidinone (1) with 1,3-dibromopropane stereoselectively gave the expected monobromide 3 which was used to alkylate the (-)-camphor imine 7 of diethyl (aminomethyl)phosphonate to yield a 4:1 mixture of 1R and 1S diastereomers 8 and 9, respectively.Separation and hydrolytic deprotection gave stereochemically pure (1R,5S)-(1,5-diamino-5-carboxypentyl)phosphonic acid (P-DAP) (10) and its (1S,5S)-isomer 11.An analogous approach employing (+)-camphor imine 17 and monobromide 3 also allowed synthesis of 10 and 11, but in reversed 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-benzoyl-2-tert-butyl-3-methyl-4-imidazolidinone (2), 1,3-dibromopropane, and 7.A DAP bisphosphonate analogue 22, in which both carboxyl groups are replaced, was 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 followed by hydrolysis.A series of di- and tripeptides of individual P-DAP isomers with L-alanine were synthesized to enhance transport into bacterial cells for antimicrobial tests.Condensation of L-alanine N-carboxyanhydride (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 deprotection, 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 DAP epimerase from Escherichia coli.P-DAP 11 (a meso-DAP analogue) has the strongest effect on the decarboxylase and epimerase, and its enantiomer 14 is the strongest inhibitor of the dehydrogenase.Antibacterial tests show that the P-DAP isomers display negligible activity except against Salmonella typhimurium LT-2.Compound 11 is the most active isomer and its inhibition is reversed by DAP.Among the peptide derivatives, the antibacterial spectrum of 30 (the tripeptide containing 10) includes several strains of E. coli and Citrobacter freundii.