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Hydrogen Bonding Phase-Transfer Catalysis with Ionic Reactants: Enantioselective Synthesis of γ-Fluoroamines

Giulia Roagna, David M. H. Ascough, Francesco Ibba, Anna Chiara Vicini, Alberto Fontana, Kirsten E. Christensen, Aldo Peschiulli, Daniel Oehlrich, Antonio Misale, Andrés A. Trabanco, Robert S. Paton, Gabriele Pupo* and Véronique Gouverneur*

*University of Oxford, Chemistry Research Laboratory, 12 Mansfield Road, Oxford OX1 3TA, U.K., Email: gabriele.pupochem.ox.ac.uk, veronique.gouverneurchem.ox.ac.uk

G. Roagna, D. M. H. Ascough, F. Ibba, A. C. Vicini, A. Fontana, K. E. Christensen, A. Peschiulli, D. Oehrich, A. Misale, A. A. Tranco, R. S. Paton, G. Pupo, V. Gouverneur, J. Am. Chem. Soc., 2020, 142, 14045-14051.

DOI: 10.1021/jacs.0c05131



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Abstract

Azetidinium triflates are suitable substrates for enantioselective ring opening with CsF and a chiral bis-urea catalyst. The ability of hydrogen bonding phase-transfer catalysts to couple two ionic reactants, affords enantioenriched γ-fluoroamines in high yields.

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Details

This study explores the use of hydrogen bonding phase-transfer catalysis (HB-PTC) with ionic reactants for the enantioselective synthesis of γ-fluoroamines. The researchers demonstrate that azetidinium triflates can be effectively desymmetrized using cesium fluoride (CsF) and a chiral bis-urea catalyst, resulting in high yields of enantioenriched γ-fluoroamines. The process leverages the ability of hydrogen bonding catalysts to couple two ionic reactants, a novel approach in asymmetric C-F bond construction. Mechanistic studies reveal that the catalyst facilitates phase-transfer and that the configuration at nitrogen in the electrophile does not affect enantioselectivity. Optimization of reaction conditions showed that N-benzhydryl groups significantly enhance reactivity and enantioselectivity. The scope of the reaction includes various 3-arylazetidinium triflates, yielding products with high enantioselectivity and pharmaceutical relevance. Computational studies support the experimental findings, indicating that the enantioconvergence of diastereomers is due to the projection of azetidinium N-substituents away from the catalyst. This research provides new insights into HB-PTC and its potential for transforming ionic starting materials into valuable enantioenriched products, encouraging further studies in this area.


Key Words

fluorination, azetidines, organocatalysis


ID: J48-Y2020