Synthesis of novel fused β-lactams by intramolecular 1,3-dipolar cyclo-additions. Part 7. (9RS,9aRS)-9,9a-dihydro-5-methyl-8-oxo-9-phenoxyacetamido-8H-azeto[1,2-a]-v-triazolo[5,1-c]pyrazine-6-carboxylic acids and (3bRS,4RS,7SR)-4,5-dihydro-5-oxo-4-phenoxyacetamido-3bH-azeto[1′,2′:3,4]-imidazo[1,5-c]-v-triazole-7-carboxylic acid

Abstract

Addition of the mixed anhydride derived from azidoacetic acid and trifluoroacetic anhydride to benzyl 2-(N-phenylpropynylideneamino)-3,3-ethylenedioxybutanoate (9) in the presence of triethylamine afforded (3RS,4SR)-3-azido-1-(1-benzyloxycarbonyl-2,2-ethylenedioxypropyl)-4-phenylethynyl-azetidin-2-one (14), which was converted into (3RS,4SR)-1-(1-benzyloxycarbonylmethyl-sulphonyloxyprop-1-enyl)-3-phenoxyacetamido-4-phenylethynylazetidin-2-one (21). Treatment of (21) with sodium azide, followed by thermolysis in benzene, and de-esterification, provided the desired (9RS,9aRS)-9,9a-dihydro-5-methyl-9-phenoxyacetamido-1-phenyl-8H-azeto[1,2-a]-v-triazolo-[5,1-c]pyrazine-6-carboxylic acid (26). A similar reaction sequence yielded the corresponding 1-unsubstituted carboxylic acid (27).

Another totally synthetic approach gave (3RS,4SR)-4-ethynyl-1-(4-methoxymethoxyphenyl)-3-phenoxyacetamidoazetidin-2-one (43), which was converted into (3RS,4SR)-1-[azido(benzyloxy-carbonyl) methyl]-4-ethynyl-3-phenoxyacetamidoazetidin-2-one (37). Thermolysis of compound (37) in refluxing toluene, followed by removal of the ester protecting group, gave (3bRS,4RS,7SR)-4,5-dihydro-5-oxo-4-phenoxyacetamido-3bH-azeto[1′,2′:3,4]imidazo[1,5-c]-v-triazole-7-carboxylic acid (48).

The acid (27) showed moderate antibacterial activity against Gram-positive organisms, but the compounds (26) and (48) were totally inactive.