Natural product disaccharide engineering through tandem glycosyltransferase catalysis reversibility and neoglycosylation

Abstract

A two-step strategy for disaccharide modulation using vancomycin as a model is reported. The strategy relies upon a glycosyltransferase-catalyzed 'reverse' reaction to enable the facile attachment of an alkoxyamine-bearing sugar to the vancomycin core. Neoglycosylation of the corresponding aglycon led to a novel set of vancomycin 1,6-disaccharide variants. While the in vitro antibacterial properties of corresponding vancomycin 1,6-disaccharide analogs were equipotent to the parent antibiotic, the chemoenzymatic method presented is expected to be broadly applicable.

Figure 1

(A) Classical GT reaction in which glycoside formation is thermodynamically favored. (B) GT reaction where an appropriately ‘activated’ glycoside donor (Donor*) shifts the reaction thermodynamics to favor sugar nucleotide formation. (C) One-pot coupled dual-GT-catalyzed reaction which combines GT-driven (OleD) sugar nucleotide synthesis with a subsequent GT-catalyzed (GtfE) glycosylation reaction to ultimately accomplish transglycosylation from a synthetic aromatic glycoside to a targeted aglycon (in this case, the vancomycin aglycon 3).

Figure 2

Structures of the natural glycopeptide antibiotics vancomycin (5) and teicoplanin (6) and known natural products containing D-forosamine.

Figure 3

The neoglycosylation of the 6′-alkoxyaminosugar-substituted vancomycin neoaglycon (4) (upper). The products of the neoglycosylation reaction with corresponding conversions based upon HPLC are illustrated (lower). Full characterization of 9–16 is presented in supporting information.