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.
Gürtler
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Institute of Pharmaceutical/Medicinal Chemistry, University of Greifswald, Germany.
Ruf
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Johner
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Otto
H H
HH
D000475:Alkenes / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D013055:Spectrophotometry, Infrared; D014297:Trimethylsilyl Compounds; D065093:beta-Lactamase Inhibitors; D047090:beta-Lactams / Q000138:chemical synthesis* / Q000494:pharmacology
D000475:Alkenes; D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D014297:Trimethylsilyl Compounds; D065093:beta-Lactamase Inhibitors; D047090:beta-Lactams; C039293:trimethylchlorosilane