Probing the role of the vancomycin e-ring aryl chloride: selective divergent synthesis and evaluation of alternatively substituted E-ring analogues.

The selective functionalization of vancomycin aglycon derivatives through conversion of the E-ring aryl chloride to a reactive boronic acid and its use in the synthesis of a systematic series of vancomycin E-ring analogues are described. The series was used to examine the E-ring chloride impact in binding d-Ala-d-Ala and on antimicrobial activity. In contrast to the reduced activity of the unsubstituted E-ring derivatives, hydrophobic and relatively nonpolar substituents approach or match the chloro-substituted vancomycin and were insensitive to the electronic character of the substituent (e.g., Cl vs CN/OMe), whereas highly polar substituents fail to provide the enhancements. Moreover, the active permethylated vancomycin aglycon derivatives exhibit VanB VRE antimicrobial activity at levels that approach (typically within 2-fold) their activity against sensitive bacteria. The robust borylation reaction also enabled the functionalization of a minimally protected vancomycin aglycon (N-Boc-vancomycin aglycon) and provides a direct method for the preparation of previously inaccessible analogues.