The azomethine ylide strategy for beta-lactam synthesis. An evaluation of alternative pathways for azomethine ylide generation

Following the generation of azomethine ylide 3 from the beta -lactam-based oxazolidinone 1, a series of alternative entries to this and related 1,3-di poles have been explored. The first approach is based on the use of monocyc lic azetidinones 6-12 and 14 carrying a leaving group at C(4) and an activa ted (acidic) proton adjacent to the ring nitrogen, structural moieties whic h are both associated with 1. These monocyclic substrates show no tendency towards azomethine ylide formation, which points towards the ring strain pr esent in 1 as an important prerequisite for azomethine ylide formation. The reactivity associated with the racemic Glaxo betaine 17, the structure of which has now been confirmed by X-ray crystallography, appears to involve a n azomethine ylide 19, which is very similar to 3. However, attempts to tra p 19 using an intermolecular cycloaddition failed; the intramolecular proce ss involving an enolate as a trapping agent to give oxapenem 18 is more eff ective. Two novel thia-substituted bicyclic oxazolidinones 22 and 23, as we ll as the unsubstituted variant 33, have been prepared. In the case of 22 a nd 23, products derived from an alternative mode of iminium ion formation a re observed. This pathway is a consequence of C-S bond cleavage, and this r eactivity profile has been evaluated computationally. The data suggest that relief of strain within the four-membered ring-as opposed to 1 in which fi ve-membered ring cleavage leads to an iminium ion-provides a driving force for C-S bond cleavage. As a result, the ability of 22 and 23 to give a synt hetically useful azomethine ylide is compromised by the siting of an altern ative leaving group adjacent to the azetidinone nitrogen. The unsubstituted bicyclic oxazolidinone 33 is thermally unstable, and no cycloadducts have been characterized from this system. Again, computational studies suggest t hat both direct and stepwise decarboxylation of 33 are energetically demand ing processes.