Catalytic Enantioselective Synthesis of Heterocyclic Vicinal Fluoroamines by Using Asymmetric Protonation: Method Development and Mechanistic Study |
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Authors: | Matthew W. Ashford Dr. Chao Xu Dr. John J. Molloy Cameron Carpenter-Warren Prof. Dr. Alexandra M. Z. Slawin Dr. Andrew G. Leach Dr. Allan J. B. Watson |
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Affiliation: | 1. EaStCHEM, School of Chemistry, University of St Andrews, North Haugh, St Andrews, Fife, KY16 9ST UK;2. School of Health Sciences, University of Manchester, Oxford Road, Manchester, M13 9PL UK |
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Abstract: | A catalytic enantioselective synthesis of heterocyclic vicinal fluoroamines is reported. A chiral Brønsted acid promotes aza-Michael addition to fluoroalkenyl heterocycles to give a prochiral enamine intermediate that undergoes asymmetric protonation upon rearomatization. The reaction accommodates a range of azaheterocycles and nucleophiles, generating the C−F stereocentre in high enantioselectivity, and is also amenable to stereogenic C−CF3 bonds. Extensive DFT calculations provided evidence for stereocontrolled proton transfer from catalyst to substrate as the rate-determining step, and showed the importance of steric interactions from the catalyst's alkyl groups in enforcing the high enantioselectivity. Crystal structure data show the dominance of noncovalent interactions in the core structure conformation, enabling modulation of the conformational landscape. Ramachandran-type analysis of conformer distribution and Protein Data Bank mining indicated that benzylic fluorination by this approach has the potential to improve the potency of several marketed drugs. |
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Keywords: | asymmetric synthesis Brønsted acids catalysis fluorine heterocycles |
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