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

During our research on novel non-traditional bicyclic beta-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-omega-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 (C) 2010 Elsevier Ltd All rights reserve