A Photocleavage Approach for the Fmoc-based Solid-phase Peptide Synthesis of Vancomycin Aglycone Peptide Scaffold

Abstract

Vancomycin, the first and founding member of the glycopeptide antibiotics (GPAs), has been designated as the “last resort” medication in the fight against Gram-positive bacterial infections for decades. Based upon vancomycin’s mode of action that forms hydrogen bonds enabling the inhibition of cell wall synthesis, resistant Gram-positive bacteria develop evading strategies by switching the C-terminal peptide motif of its peptidoglycan precursor. To overcome these resistances, structural modifications of vancomycin are suggested and considered more expeditious approaches compared to exploring new antibiotic scaffolds. However, such efforts have been greatly challenged by its structural sensitivity with b-R-hydroxy-3-Cl-tyrosine and epimerization-prone L-3,5-dihydroxyphenylglycine in backbone. Here, with the aim of repurposing this critically important GPA, we demonstrate a photolabile approach for the solid-phase synthesis of vancomycin aglycone peptide. For this purpose, we develop expeditious synthetic routes generating the monomeric amino acids and derivatives, together with Merrifield resin-anchored o-nitrobenzyl type linkers that allowed reagent-free releasing of the target heptapeptide upon irradiation. This strategy enables the integration of multiple sensitive functionalities and maintenance of multiple racemization vulnerable stereocenters in the synthesis of vancomycin aglycone peptide, and the creation of its novel analogues in an efficient fashion.