Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 57, Issue 35, Pages 11374-11377Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201806956
Keywords
asymmetric catalysis; Bronsted acids; heterocycles; organocatalysis; stereochemistry
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Funding
- Leverhulme Trust [RPG-2015-2308]
- GSK
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The direct enantioselective synthesis of chiral azaheteroaryl ethylamines from vinyl-substituted N-heterocycles and anilines is reported. A chiral phosphoric acid (CPA) catalyst promotes dearomatizing aza-Michael addition to give a prochiral exocyclic aryl enamine, which undergoes asymmetric protonation upon rearomatization. The reaction accommodates a broad range of N-heterocycles, nucleophiles, and substituents 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.
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