Catalytic enantioselective synthesis of α-chiral azaheteroaryl ethylamines by asymmetric protonation

Chao Xu, Calum W. Muir, Andrew G. Leach, Alan R. Kennedy, Allan J. B. Watson

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Abstract

The direct enantioselective synthesis of chiral azaheteroarylethylamines from vinyl aza-heterocycles and anilines is reported. A chiral phosphoric acid (CPA) catalyst promotes dearomatizing aza-Michael addition giving a prochiral exocyclic aryl enamine, which undergoes asymmetric protonation upon rearomatization. The reaction accommodates a broad range of azaheterocycle, nucleophile, and substituent on the prochiral centre, generating the products in high enantioselectivity. DFT studies support a facile nucleophilic addition based on catalyst-induced LUMO lowering, with site-selective, rate-limiting, intramolecular asymmetric proton transfer from the ion-paired prochiral intermediate.
Original languageEnglish
JournalAngewandte Chemie International Edition
Early online date1 Aug 2018
DOIs
Publication statusE-pub ahead of print - 1 Aug 2018

Keywords

  • asymmetric catalysis
  • Brønsted acids
  • heterocycles
  • organocatalysis
  • stereochemistry

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