Penam-3-carboxylic acid derivatives

Penam p-Lactamase Inhibitors. Penam is the trivial name of 4-thia-l-azabicyclo[3.2.0]heptane. The report that 6-/3-bromopenicillanic acid, [2(5)-(2or. 5 . 6/8)]-6-bromo-3,3-dimethyl-7-oxo-4-thia-l-azabicyclo [3.2.0]lieptane-2-carboxylic acid, (R = Br, R1 = H. R = R1 = CHi) is a potent inhibitor led to intense study both of this compound and analogues. The microbiology profile of 6-/3-bromopenicillanic acid has been reported and the compound has progressed to clinical trials. Mechanistic studies have demonstrated that the dihydrothiazine derivative is responsible for inactivation of /3-lactamases. 

Direct transformation [21] of p-lactams into the corresponding imino-p-lac-tams 19 has been effected with N-chlorosulphonylisocyanate (CSI) (Scheme 6). The reaction probably involves a [2 + 2] cycloaddition-cycloreversion sequence. The same experimental conditions applied to penam or cephem derivatives gave ring-enlarged products only [22]. Silylation of trichloroethyl 6p-phenoxyacetamido-penicillinate followed by reaction with CSI and reduction with metabisulphite yielded the bicyclic pyrimidine-2,4-dione 20a (1 1 mixture of epimers). The carboxylic acid 20b is devoid of antibiotic activity (Scheme 7). 

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