3-METHYLIDENE-BETA-LACTAMS AS POTENTIAL INHIBITORS OF BETA-LACTAMASES.1. SYNTHESIS OF ALPHA-SUBSTITUTED DERIVATIVES FROM IMINES BY REFORMATZKY REACTION WITH CHLOROTRIMETHYLSILANE, SILYLATION AND PETERSON OLEFINATION

A new variation of the Reformatzy reaction with use of I-2/zinc and ch lorotrimethylsilane in THF and a shortened work-up is described allowi ng the synthesis of a wide variety of substituted beta-lactams 3 in fa irly good yield. These lactams are silylated according to the Peterson reaction yielding by reactions with appropriate carbonyl compounds E/ Z-mixturs of the substituted 3-methylidene beta-lactams 7, 8 and 10. T he isomers are separated by CC and completely characterized by spectro scopic methods, mainly H-1 NMR spectroscopy. Condensation of the 3-for myl methylidene derivative 10 with amines or malonate yields the conju gated products 11, and from the isopropylidene derivative 6 the pyridi nium sulfonate 14 is prepared via 12 and 13. All methylidene beta-lact ams are prepared as model compounds for studying their activity agains t beta-lactamases and for elucidating the mechanism of action.