Catalytic enantioselective synthesis of α-chiral azaheteroaryl ethylamines by asymmetric protonation
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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.
Xu , C , Muir , C , Leach , A , Kennedy , A & Watson , A J B 2018 , ' Catalytic enantioselective synthesis of α-chiral azaheteroaryl ethylamines by asymmetric protonation ' Angewandte Chemie International Edition , vol. In press . https://doi.org/10.1002/anie.201806956
Angewandte Chemie International Edition
© 2018 Wiley‐VCH Verlag GmbH & Co. KGaA, Weinheim. This work has been made available online in accordance with the publisher’s policies. This is the author created accepted version manuscript following peer review and as such may differ slightly from the final published version. The final published version of this work is available at https://doi.org/10.1002/anie.201806956
DescriptionThe authors thank the Leverhulme Trust for funding (C.X.; RPG-2015- 308) and GSK for a PhD studentship (C.W.M.). The authors thank the EPSRC UK National Mass Spectrometry Facility at Swansea University for analyses.
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