Lowell D. Hatfield

Molecular modeling of γ-lactam analogues of β-lactam antibacterial agents: synthesis and biological evaluation of selected penem and carbapenem analoques

Abstract Computational chemistry made possible the prediction of the three-dimensional structures of γ-lactam analogues of penems and carbapenems before the analogues were made. Molecular superpositioning showed that these novel structures with a 7β-acylamino side-chain present the pharmacophoric groups in close spatial similarity to the groups in biologically active cephalosporin and penicillin antibiotics. This suggests that 8-oxo-7-acylamino-1-azabicyclo[3.3.0]-oct-2-ene-2-carboxylates and the 4-thia-analogues can be accommodated in the same active sites of essential bacterial penicillin-binding proteins where cephalosporins and penicillins are recognized. The syntheses of these compounds are reported. The γ-lactams exhibit low, but detectable levels of antibacterial activity and suggest promise that substantial activity can be achieved with other γ-lactams.

γ-Lactam analogues of carbapenems

Abstract γ-Lactam analogues of carbapenems have been synthesized using a [3+2] cyclization approach. Slight antibiotic activity was observed in one case.

γ-Lactam analogues of the penems

Abstract Racemic γ-lactam analogues of the penems have been prepared and tested for biological activity. The 7-acylamino derivatives exhibited low levels of antibiotic activity.

Cleavage of chiral 4-phenyl-2-oxalidinones with TMSI: Application to the synthesis of carbacephems

Abstract A new technique for cleaving N-substituted 4-phenyl-2-oxazolidinones is described. Thus reaction of a 7-[4-phenyl-2-oxazolidinone]-carbacephem with TMSI and HMDS in acetonitrile, followed by DABCO, then aqueous hydrochloric acid gives the carbacephem nucleus, carbon dioxide, and acetophenone. This method allows a more versatile use of 4-phenyl-2-oxazolidinone as a chiral auxiliary and N-protective group in the synthesis of carbacephems.