Synthesis and biological activity of substituted [[3(S)-(acylamino)-2-oxo-1-azetidinyl]oxy]acetic acids. A new class of heteroatom-activated beta-lactam antibiotics.

The synthesis of substituted [[3(S)-(acylamino)-2-oxo-1-azetidinyl]oxy]acetic acids (1) is described. 3-[(Carbobenzyloxy)amino]-N-hydroxy-2-azetidinones (13a,b), prepared from serine and threonine, were alkylated with 2-(trimethylsilyl)ethyl bromoacetate in the presence of potassium carbonate in THF/H2O. Alkylation with secondary alpha-bromo esters was accomplished with potassium hydroxide in dimethyl sulfoxide. The Cbz group was replaced with the 2-(2-amino-4-thiazolyl)-2(Z)-(methoxyimino)acetamido side chain by catalytic hydrogenation followed by treatment with 21. Removal of the 2-(trimethylsilyl)ethyl ester with fluoride ion provided derivatives suitable for antimicrobial evaluation. In vitro tests showed that the title compounds possess significant activity predominantly against Gram-negative bacteria.