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

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.