The Chemoenzymatic Synthesis of the Glycopeptide Antibiotic Vancomycin

Abstract

The goal of this project is the chemoenzymatic synthesis of the glycopeptide antibiotic vancomycin. Vancomycin has been used for decades as the last resort drug against MRSA and other serious infections caused by gram-positive bacteria. Emergence of vancomycin resistant Enterococci and vancomycin resistant Staphylococcus aureus have generated widespread interest in the synthetic modification of this molecule. The proposed chemoenzymatic approach uses chemical synthesis to generate the linear heptapeptide precursor and then employs enzymes to conduct the macrocyclization, chlorination, and glycosylation steps to yield the biologically active molecule. The first step in this process is to generate Fmoc protected amino acid monomers in preparation for solid phase peptide synthesis. This paper describes in detail the synthesis of non-proteinogenic AA2 ((S,R)-β-hydroxy-tyrosine) and AA6 ((R,R)-β-hydroxy-tyrosine), the structures of which are shown below. Unforeseen complications with the solid phase peptide synthesis impeded progress, so the enzymatic steps have not yet been attempted. The future goalis the complete chemoenzymatic synthesis of vancomycin and semisynthetic analogs that show increased potency against vancomycin-resistant bacterial strains.