Y-Lactam analogues of carbapenems have been synthesized using a [3+2] cyclisation approach. Slight antibiotic activity was observed in one case. S-Lactam antibiotics' mechanism of action involves active site acylation of key enzymes (penicillin binding proteins_PBP's) required for bacterial cell wall synthesis.' We hypothesized that a suitably activated lactam of a different structural type could be operative in this mechanism and chose the following Y-lactam analogues of carbapenems as synthetic targets.* RCONH Central to this hypothesis was the reasoning that electron withdrawing groups (W = COzMe,CN) at C-2 would heighten the reactivity of the lactam linkage by delocalization of the lone pair of electrons on the bridgehead nitrogen away from the C-8 carbonyl group.3'4 Additionally, incorporation of classical cephalosporin side-chains at C-7 (provided such structures proved to be chemically stable') would offer the best opportunity for biological activity by exertion of their well-known influence on PBP binding and outer membrane penetration.
The strategy developed for the synthesis of these compounds is outlined below. Deprotonation of a substituted 5-iodomethylpyrrolidinone and treatment with a B-phenylsulfinyl-~ g-carboalkoxy (or 8-cyano) acrylate should generate stabilized anion i capable of intra-molecular alkylation and elimination. 6 The phenylsulfinyl group was chosen upon the prediction that the stabilized anion i would not only facilitate initial Michael reaction but also aid in the alkylation step. Additionally, this disconnection allows for ready preparation of substituted pyrrolidinones from derivatives of S-pyrroglutamic acid, the asymmetry of which has the same absolute configuration as that found in B-lactam antibiotics.