Attaching Metal-Containing Moieties to β-Lactam Antibiotics: The Case of Penicillin and Cephalosporin

Abstract

Procedures for the preparation of transition metal complexes having intact bicyclic cepham or penam systems as ligands have been developed. Starting from readily available 4-azido-2-azetidinones, a synthetic approach has been tuned using a copper-catalyzed azide–alkyne cycloaddition between 3-azido-2-azetinones and alkynes, followed by methylation and transmetalation to Au(I) and Ir(III) complexes from the mesoionic carbene Ag(I) complexes. This methodology was applied to 6-azido penam and 7-azido cepham derivatives to build 6-(1,2,3-triazolyl)penam and 7-(1,2,3-triazolyl)cepham proligands, which upon methylation and metalation with Au(I) and Ir(III) complexes yielded products derived from the coordination of the metal to the penam C⁶ and cepham C⁷ positions, preserving intact the bicyclic structure of the penicillin and cephalosporin scaffolds. The crystal structure of complex 28b, which has an Ir atom directly bonded to the intact penicillin bicycle, was determined by X-ray diffraction. This is the first structural report of a penicillin-transition-metal complex having the bicyclic system of these antibiotics intact. The selectivity of the coordination processes was interpreted using DFT calculations.

Penicillin and cephalosporin derivatives containing C6–M and C7–M (M = Ir, Au) bonds have been synthesized, and the X-ray structure of the C6–Ir penam complex has been resolved. This research may be significant for the development of new active compounds targeting β-lactamase-producing bacteria.