Synthesis of an N-Galactosyl Norbornane Aziridine and its Potent Mixed Inhibition of Aspergillus oryzae β-Galactosidase.

Aziridine-bearing cyclic polyols are established as irreversible covalent inhibitors of glycosyl hydrolases and have been employed as activity-based probes. In the present study, the stereoselective synthesis of a novel N-galactosyl aziridine derivative on a norbornane scaffold and its subsequent evaluation as an inhibitor of glycosyl hydrolase activity are described. The diastereoselective Huisgen cycloaddition between 2,3,4,6-tetra-O-acetyl-β-d-galactopyranosyl azide and norbornene yields exo-triazoline intermediates of norbornane. Following the removal of the acetyl protecting groups and a silica gel-mediated decomposition of the triazoline intermediates, exo N-galactopyranosyl norbornane aziridine (N-(β-d-galactopyranosyl)-exo-3-azatricyclo[3.2.1.02,4]octane, NGNA) is obtained. Enzymatic assays demonstrate that NGNA exerts potent mixed-mode inhibition of Aspergillus oryzae β-galactosidase, while exhibiting significant selectivity over green coffee bean α-galactosidase.