Stereoselective alpha-fluoroamide and alpha-fluoro-gamma-lactone synthesis by an asymmetric zwitterionic aza-Claisen rearrangement.

Background: Asymmetric introduction of fluorine alpha-to a carbonyl has become popular recently, largely because the direct fluorination of enolates by asymmetric electrophilic fluorinating reagents has improved, and as a result such compounds are becoming attractive synthons. We have sought an alternative but straightforward asymmetric method to this class of compounds, utilising the zwitterionic aza-Claisen rearrangement by reacting alpha-fluoroacid chlorides and homochiral N-allylpyrrolidines as starting materials.

Results: Treatment of N-allylmorpholine with 2-fluoropropionyl chloride under Yb(OTf)3 catalysis generated the zwitterionic aza-Claisen rearrangement product in good yield and demonstrated the chemical feasibility of the approach. For the asymmetric reaction, N-allyl-(S)-2-(methoxymethyl)pyrrolidine was treated with either 2-fluoropropionyl chloride or 2-fluorophenylacetic acid chloride under similar conditions and resulted in N-(alpha-fluoro-gamma-vinylamide)pyrrolidine products as homochiral materials in 99% de. These products were readily converted to their corresponding alpha-fluoro-gamma-lactones by iodolactonisation and in good diastereoselectivity.

Conclusion: Molecules which have fluorine at a stereogeneic centre are finding increasing utility in pharmaceutical, fine chemicals and materials research. The zwitterionic aza-Claisen rearrangement proved to be an effective and competitive complement to asymmetric electrophilic fluorination strategies and provides access to versatile synthetic intermediates with fluorine at the stereogenic centre.