Catalytic enantioselective synthesis of heterocyclic vicinal fluoroamines using asymmetric protonation: a method development and mechanistic study

Matthew Ashford, Chao Xu, John J. Molloy, Cameron Lewis Carpenter-Warren, Alexandra Martha Zoya Slawin, Andrew G. Leach, Allan J. B. Watson

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4 Citations (Scopus)
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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.
Original languageEnglish
Pages (from-to)12249-12255
Number of pages8
JournalChemistry - A European Journal
Volume26
Issue number53
Early online date18 Aug 2020
DOIs
Publication statusPublished - 21 Sept 2020

Keywords

  • Asymmetric
  • Brønsted acid
  • Catalysis
  • Fluorine
  • Heterocycles

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