Synthesis of novel fused β-lactams by intramolecular 1,3-dipolar cycloadditions. Part 2. (8S,8aR)-7,8-dihydro-7-oxo-8-phenoxyacetamido-8aH-azeto[1,2-a]-v-triazolo[3,4-c]pyrimidine-5-carboxylic acids

Abstract

The penicillin-derived (3R,4R)-4-methylthio-3-triphenylmethylaminoazetidin-2-one (10) has been converted into (3S,4R)-4-azido-1-(1-t-butoxycarbonylbut-3-ynyl)-3-triphenylmethylaminoazetidin-2-one (15a), which provided t-butyl(8S,8aR)-4,5,7,8-tetrahydro-7-oxo-8-triphenylmethylamino-8aH-azeto[1,2-a]-v-triazolo-[3,4-c]pyrimidine-5-carboxylate (16a) when heated in refluxing toluene. Conversion of (16a) into t-butyl (8S,8aR)-7,8-dihydro-7-oxo-8-triphenylmethylamino-8aH-azeto[1,2-a]-v-triazolo[3,4-c]pyrimidine-5-carboxylate (14a) was then accomplished via an α-selenenylation, oxidation sequence. Removal of the amino-protecting group from (14a), followed by acylation with phenoxyacetyl chloride and de-esterification provided the desired (8S,8aR)-7,8-dihydro-7-oxo-8-phenoxyacetamido-8aH-azeto[1,2-a]-v-triazolo[3,4-c]pyrimidine-5-carboxylic acid (20).

Another intramolecular cycloaddition between an acetylene and an azido-group afforded t-butyl (8S,8aR)-7,8-dihydro-7-oxo-4-hydroxy-4-methyl-8-triphenylmethylamino-8aH-azeto[1,2-a]-v-triazolo[3,4-c]-pyrimidine-5-carboxylate (27). Sequential treatment of (27) with thionyl chloride and 1,8-diazabicyclo[5.4.0]undec-7-ene gave t-butyl (8S,8aR)-7,8-dihydro-7-oxo-4-methyl-8-triphenylmethylamino-8aH-azeto[1,2-a]-v-triazolo-[3,4-c]pyrimidine-5-carboxylate (34), which was converted into (8S,8aR)-7,8-dihydro-7-oxo-4-methyl-8-phenoxyacetamido-8aH-azeto[1,2-a]-v-triazolo[3,4-c]pyrimidine-5-carboxylic acid (36).

Compounds (20), its 3-phenyl analogue (22), and (36), all showed varying degrees of antibacterial activity.