Ruthenium-Catalyzed Cycloaddition for Introducing Chemical Diversity in Second-Generation beta-Lactamase Inhibitors

Ruthenium(II) alkyne azide cycloaddition (RuAAC) is an attractive reaction to access 1,5-triazole derivatives and is applicable to internal alkynes. Here, we explore RuAAC to introduce molecular diversity on the diazabicyclooctane (DBO) scaffold of beta-lactamase inhibitors. The methodology presented is fully regioselective and enabled synthesis of a series of 1,5-triazole DBOs and trisubstituted analogues. Molecular modelling and biological evaluation revealed that the DBO substituents provided putative stabilizing interactions in the active site of broad-spectrum beta-lactamase KPC-2 and promising activity against a hyperpermeable strain of Escherichia coli producing KPC-2.