Synthesis of novel fused β-lactams by intramolecular 1,3-dipolar cycloadditions. Part 8. 6,7,7a,7b-Tetrahydro-3-methyl-6-oxo-1H-azeto-[1,2-a]azirino[2,1-c]pyrazine-4-carboxylic acids

Abstract

4-Vinylazetidin-2-one (4) was converted into t-butyl (7aRS, 7bRS)-6,7,7a,7b-tetrahydro-3-methyl-6-oxo-1H-azeto[1,2-a]azirino[2,1-c]pyrazine-4-carboxylate (12; R = Bu^t)via thermolysis of the vinyl azide (9) in refluxing benzene. The configuration of the aziridine ring was assigned on the basis of nuclear Overhauser enhancement difference spectroscopy. t-Butyl was not an appropriate acid protecting group, but the corresponding diphenyl-t-butylsilyl ester (12; R = SiPh₂Bu^t) was cleanly deprotected to give potassium (7aRS,7bRS)-6,7,7a,7b-tetrahydro-3-methyl-6-oxo-1 H-azeto[1,2,a]-azirino[2,1-c]pyrazine-4-carboxylate (12; R = K).

The known (3RS, 4SR)-3-azido-1-(1-benzyloxycarbonyl-2,2-ethylenedioxypropyl)-4-styryl-azetidin-2-one (21) was used to prepare benzyl (1RS, 7SR, 7aSR, 7bSR)-6,7,7a,7b-tetrahydro-3-methyl-6-oxo-7-phenoxyacetamido-1 -phenyl-1H-azeto[1,2-a]azirino[2,1-c]pyrazine-4-carboxylate (15)via the vinyl azide (19). In the 7-acylamino series neither benzyl nor diphenyl-t-butylsilyl proved amenable acid protecting groups, but 2,2,2-trichloroethyl was found to be a convenient alternative. Thus heating (3RS, 4SR)-1-[2-azido-1-(2,2,2-trichloroethoxycarbonyl)prop-1-enyl]-3-phenoxyacetamido-4-vinylazetidin-2-one (20) in refluxing benzene provided 2,2,2-trichloroethyl (7RS, 7aRS, 7bRS)-6,7,7a,7b-tetrahydro-3-methyl-6-oxo-7-phenoxyacetamido-1H-azeto[1,2-a]azirino[2,1-c]-pyrazine-4-carboxylate (17), which was deprotected to give the corresponding acid (18). The 4-vinyl functionality of the azide (20), was introduced at an earlier stage by semi-hydrogenation of an ethynyl group present in a suitably substituted precursor.

The potassium salt (12; R = K) and the acid (18) were both antibacterially inactive.