ENANTIOSELECTIVE TOTAL SYNTHESES OF [6R,7R] AND [6S,7S] TRICYCLIC BETA-LACTAMS

The reaction of Ox-glycyl chloride with a chiral imine derived from th e combination of D-(R)-glyceraldehyde acetonide and protected D-threon ine afforded optically active, highly functionalized cis-substituted b eta-lactams 11 and 12. These beta-lactams provide versatile intermedia tes for the syntheses of biologically important carbacephalosporins, i sooxacephems, and other multicyclic beta-lactams. Desilylation and oxi dation of 12 with Dess-Martin periodinane followed by intramolecular c yclization produced a novel tricyclic beta-lactam 17 and a 1-(hydroxym ethyl)-O-2-isocephem 18 with [6R,7R] absolute configuration. Removal o f the Ox protecting group and acylation of 17 in a one-pot reaction fo llowed by saponification furnished the target salt 24. Alternatively, reaction of phthaloylglycyl chloride with the chiral imine derived fro m the combination of L-(S)-glyceraldehyde acetonide and protected D-th reonine gave only one enantiomeric azetidinone 27 in high yield. Furth er manipulation of 27 provided a new tricyclic beta-lactam 39 with [6S ,7S] absolute configuration which satisfies the stereochemistry typica lly required for antibacterial activity, This synthetic procedure prov ides a short, versatile and enantioselective method of preparing polyc yclic beta-lactams. Biological testing of these tricyclic beta-lactams indicated that salt 39 has potential inhibitory activity against four typical strains of bacteria.