Heterocyclic Chemistry 2.

The Synthesis of Bicyclic b-Lactams

The Azomethine Ylid Strategy for the Synthesis of Bicyclic b-Lactams  

This has been a major area of activity since the mid-90s and involved a close collaboration with Dr. Neil Hales (Zeneca Pharmaceuticals, now AstraZeneca Pharmaceuticals). More recently, we have worked with Drs Peter O’Hanlon and John Bateson at GlaxoSmithKline.

Our initial objective was to define a general “one step” method for the synthesis of bicyclic b-lactams. To do this we aimed to generate a reactive 1,3-dipole (an azomethine ylid) where the dipolar character straddles the b-lactam nucleus and explore the reaction of this species with a host of different dipolarophiles - alkenes and alkynes, but also C=O, C=NR, C=S and other dipolarophiles.


The major challenge was how to generate the necessary azomethine ylid reactivity.

This crucial reactivity profile is released by thermolysis of a bicyclic oxazolidinone, and the resulting azomethine ylid reacts with a wide range of heteroatom-containing dipolarophiles and this includes C=O, C=S, C=NR, and C=Se. This provides a wide range of novel b-lactam derivatives very directly and the chemistry has also been extended to provide penems (see below).

The mechanism by which the key azomethine ylid is released is both unusual and novel, and departs from the generally accepted mechanism associated with the fragmentation of N-alkyl oxazolidinones; our b-lactam derivatives are N-acyl oxazolidinones. Current evidence suggests that the strained bicyclic oxazolidinone fragments and tautomerises to provide the carboxylated azomethine ylid highlighted in the Scheme. It is this key intermediate which then undergoes cycloaddition followed by decarboxylation.

So, we suggest that decarboxylation takes place AFTER dipolar cycloaddition; this is not the usual pathway observed for simpler oxazolidinones which undergo decarboxylation in order to generate the azomethine ylid. Details of the mechanistic work, including extensive computational studies that were carried out Dr Colin Fishwick (University of Leeds), have been published, as has a general account of the programme to date.

Most recent work in this area has focussed on 6-alkylidene penems e.g. BRL-427145 a synthetically very challenging but also potentially very important group of b-lactamase inhibitors. These molecules present two challenges: the 6-alkylidene component and the 2-unsubstituted penem unit. We have pursued both aspects, and a general route into 2-unsubstituted penems has been developed. This has involved an extension of our earlier work but necessitated developing more general entries to dithioformates, an unusaul and poorly studies class of C=C dipolarophiles, and presenting these reactive dipolarophiles in such a way as to enable us to trap with our b-lactam based azomethine ylid. This was done by initial trapping of methyl dithioformate as its cyclopentadiene adduct and then releasing the reactive C=S moiety in the presence of the b-lactam based oxazolidinone. This process, and related reactions, are dramatically improved when carried out in a microwave reactor.

This b-lactam chemistry was cited in 1999 as part of the International Society of Heterocyclic Chemistry Katritzky Award in Heterocyclic Chemistry (to Tim Gallagher).