Nuclear analogs of β-lactam antibiotics. VI. Synthesis of N-2-isocephems

Abstract

The syntheses of N-methyl and N-carboethoxy-7-β-phenoxyacetamido-Δ3-N-2-isocephem-4-carboxylic acids 17a and 17b are reported. Treatment of aldehyde 3c with methylamine followed by reduction of the Schiff base gave 4d which was converted to its trifluoroacetamide 5c. Acid catalyzed elimination of a mole of ethanol from 5c, gave 8b which was converted to the enol 10b via the vinylogous pyrrolidino amide 9b. Reductive removal of the trifluoroacetamide function led to spontaneous ring closure to give 11b. Alternatively treatment of bis-mesylate 12b with ammonia or methylamine gave 13a and 13b, respectively. Treatment of 13b with sodium hydride in DMSO gave 11b. Attempted acylation of 13a gave 14. Reduction of the azido functions in 11b and 14 followed by coupling of the amines to phenoxyacetic acid and reductive removal of the benzyl esters gave 17a and 17b, respectively. The structural assignments are discussed.