Ruthenium‐Catalyzed Cycloaddition for Introducing Chemical Diversity in Second‐Generation β‐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 β‐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 β‐lactamase KPC‐2 and promising activity against a hyperpermeable strain of Escherichia coli producing KPC‐2. Ruthenium(II)‐catalyzed cycloaddition (RuAAC) is a powerful way to access 1,5‐disubsituted and 1,4,5‐trisubstituted triazole DBOs with complete control of regioselectivity. The biological activity of di‐ and tri‐substituted DBOs gave promising activity against a hyperpermeable strain of Escherichia coli producing KPC‐2, and molecular docking showed favorable KPC‐2‐DBO interactions.