Synthesis and Evaluation of Vancomycin Aglycon Analogues That Bear Modifications in the N-Terminal d -Leucyl Amino Acid

The synthesis and biological evaluation of a series of vancomycin aglycon analogues bearing alternative residue 1 N-methyl-D-amino acids are described. The analogues were prepared to define whether H-bonding d-amino acids could improve the affinity for the model ligands N,N'-Ac(2)-L-Lys-D-Ala-D-Ala (2) and N,N'-Ac(2)-L-Lys-D-Ala-D-Lac (3) and improve antimicrobial activity against vancomycin-sensitive or vancomycin-resistant bacteria. Additionally, a series of analogues with appended nucleophiles (hydrazines and amines) on the residue 1 D-amino acids are described that were examined for their ability to react with the C-terminal ester of 3, forming a covalent attachment of L-Lys-D-Ala to the natural product analogues.