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

Kenny Tenza, Julian S. Northen, David O'Hagan, Alexandra Martha Zoya Slawin

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6 Citations (Scopus)


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.

Original languageEnglish
Article number13
Number of pages5
JournalBeilstein Journal of Organic Chemistry
Issue number13
Publication statusPublished - 17 Oct 2005




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