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

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-S-carboxypentyl)phosphonic acid (P-DAP) (10) and its (1S,5S)-isomer 11.(...)