3-Methylidene-beta-lactams as potential inhibitors of beta-lactamases. Part 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 I2/zinc and chlorotrimethylsilane in THF and a shortened work-up is described allowing the synthesis of a wide variety of substituted beta-lactams 3 in fairly 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. The isomers are separated by CC and completely characterized by spectroscopic methods, mainly 1H NMR spectroscopy. Condensation of the 3-formyl methylidene derivative 10 with amines or malonate yields the conjugated products 11, and from the isopropylidene derivative 6 the pyridinium sulfonate 14 is prepared via 12 and 13. All methylidene beta-lactams are prepared as model compounds for studying their activity against beta-lactamases and for elucidating the mechanism of action.