Synthesis of benzocarbacephem and benzocarbapenem derivatives by copper-promoted intramolecular aromatic substitution

Abstract
Copper-mediated cyclisation of 4-[2-(o-bromophenyl)ethyl] azetidinones and 4-[o-bromophenyl)methyl]azetidinones proved to be a route to benzocarbacephem and benzocarbapenem derivatives respectively. The effect of functionalities present in the alkyl part of the ring to be formed was considered with regard to cyclisation efficiency and further chemical modifications. Conversion, into halide, of the diastereoisomeric mixture (4R,6S; 4S,6R; 4R,6R; and 4S,6S) of t-butyl 2-hydroxybenzocarbacephem-4′-carboxylate (14f) afforded either the chloride (17a) as racemic diastereoisomers or the fluoride (17c) as a single racemic diastereoisomer. The corresponding free carboxylic acids (18a, c) were designed as inactivators of beta-lactamases.