Enantioselective total syntheses of [6R,7R] and [6S,7S] tricyclic beta-lactams

The reaction of Ox-glycyl chloride with a chiral imine derived from the combination of D-(R)-glyceraldehyde acetonide and protected D-threonine afforded optically active, highly functionalized cis-substituted beta-lactams 11 and 12. These beta-lactams provide versatile intermediates for the syntheses of biologically important carbacephalosporins, isooxacephems, and other multicyclic beta-lactams. Desilylation and oxidation of 12 with Dess-Martin periodinane followed by intramolecular cyclization produced a novel tricyclic beta-lactam 17 and a 1-(hydroxymethyl)-O-2-isocephem 18 with [6R,7R] absolute configuration. Removal of the Ox protecting group and acylation of 17 in a one-pot reaction followed by saponification furnished the target salt 24. Alternatively, reaction of phthaloylglycyl chloride with the chiral imine derived from the combination of L-(S)-glyceraldehyde acetonide and protected D-threonine gave only one enantiomeric azetidinone 27 in high yield. Further manipulation of 27 provided a new tricyclic beta-lactam 39 with [6S,7S] absolute configuration which satisfies the stereochemistry typically required for antibacterial activity, This synthetic procedure provides a short, versatile and enantioselective method of preparing polycyclic beta-lactams. Biological testing of these tricyclic beta-lactams indicated that salt 39 has potential inhibitory activity against four typical strains of bacteria.