Studies on Nonconventionally Fused Bicyclic β-Lactams

Described in this article are studies of structurally novel 3.2.0bicyclic β-lactam ring systems that are isomeric to those of the penicillin, penem, and clavulanic acid families of antibiotics, but which have the lactam functionality arranged in alternative orientations within the four-membered ring. Semiempirical calculations indicate that the thermodynamic stabilities of the three alternative isomeric ring systems are similar to that of the classical penam or penem structure, and ab initio methods reveal that the LUMO energies of the two C-fused ring structures 11 and 12 are more than 1 eV lower than that of 2-azetidinone, but 0.22 to 0.73 eV higher than that of the penem ring 13. The LUMO energy of the N−S fused penem structure 14 is about 0.2 eV lower than that of 13. These studies also suggest that the N-fused bicyclic β-lactams are considerably more electrophilic than the corresponding C-fused compounds. Several of the new heterocyclic rings were synthesized using a two-step cyclization strategy to assemble the bicyclic core. First, the β-lactam ring was created by a Staudinger reaction of an acid chloride and α,β-unsaturated imine, and the sulfur heterocycle was closed through a halogen-promoted cyclization reaction of a sulfur substituent onto a neighboring alkenyl or alkynyl side chain. Using palladium catalysis, iodopenem adducts 18, 31a, and 56a were converted to vinyl- and heteroaryl-substituted derivatives, carboxylic esters, and carboxylic acids. Four of the bicyclic β-lactams prepared in this study (58b, 80, 87, and 89) showed weak levels of activity against Staphylococcus aureus or Vibrio cholerae.