Synthesis of the first stable phosphonamide transition state analogue.
Three methods were selected for the one-pot synthesis of the fully protected beta-fluoroaminophosphonic acids, using the readily accessible N-protected beta-fluoroaminals. These were activated by acylation leading, by beta-elimination, to a transient N-acylimine immediately trapped by reactive forms of dialkyl phosphites. Avoiding basic conditions, the complete or partial deprotection of these N-protected beta-fluoroaminophosphonic esters allowed the synthesis of the free amino acids, their esters, and a racemic beta-trifluorophosphonamidic acid. The latter, which represents a transition state analogue formed by the bacterial transpeptidase, is perfectly stable at pH 4.7, contrary to the nonfluorinated compounds.
Laboratoire de Synthèse et Physicochimie de Molécules d'Intérêt Biologique, Unité Mixte de Recherche no. 5068 associée au Centre National de la Recherche Scientifique, Université Paul Sabatier, 118 Route de Narbonne, 31062 Toulouse O4, France.
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de Medina
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Ingrassia
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ME
Mulliez
D000215:Acylation; D000577:Amides / Q000138:chemical synthesis*; D000588:Amines / Q000737:chemistry; D000596:Amino Acids / Q000737:chemistry; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis; D015195:Drug Design; D004952:Esters / Q000737:chemistry; D005461:Fluorine / Q000737:chemistry; D008968:Molecular Conformation; D063065:Organophosphonates / Q000138:chemical synthesis; D009943:Organophosphorus Compounds / Q000138:chemical synthesis*; D010447:Peptide Hydrolases / Q000737:chemistry; D013237:Stereoisomerism
D000577:Amides; D000588:Amines; D000596:Amino Acids; D000900:Anti-Bacterial Agents; D004952:Esters; D063065:Organophosphonates; D009943:Organophosphorus Compounds; D005461:Fluorine; D010447:Peptide Hydrolases