Cyclodimerization by ring-closing metathesis: synthesis, computational, and biological evaluation of novel bis-azetidinyl-macrocycles

During our research on novel, non-traditional, bicyclic β-lactams as potential inhibitors of Penicillin Binding Proteins (PBPs), we focused on the synthesis of 1,3-bridged 2-azetidinones by RCM reaction from 1,3-bis-ω-alkenoyl-3(S)-amino-2-azetidinone precursors. Submitting the precursors to RCM, we faced an unexpected problem: cyclodimerization was the preferred outcome. This peculiar reactivity, explained by a computational study, led to unprecedented bis-azetidinyl-macrocycles acting as potent inhibitors of R39 D,D-carboxypeptidase, a bacterial model enzyme for PBPs.