Full Research Paper

Stereoselective α-fluoroamide and α-fluoro-γ-lactone synthesis by an asymmetric zwitterionic aza-Claisen rearrangement

Kenny Tenza¹, Julian S Northen², David O'Hagan¹ and Alexandra MZ Slawin¹

¹School of Chemistry, University of St Andrews, North Haugh, St Andrews, Fife, UK KY16 9ST

²Onyx Scientific Ltd., Units 97/98 Silverbriar, Sunderland Enterprise Park East, Sunderland UK, SR5 2TQ

Beilstein Journal of Organic Chemistry 2005, 1:13doi:10.1186/1860-5397-1-13

Published:	17 October 2005

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Abstract

Background

Asymmetric introduction of fluorine α-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 α-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-(α-fluoro-γ-vinylamide)pyrrolidine products as homochiral materials in 99% de. These products were readily converted to their corresponding α-fluoro-γ-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.

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