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dc.contributor.authorAshford, Matthew
dc.contributor.authorXu, Chao
dc.contributor.authorMolloy, John J.
dc.contributor.authorCarpenter-Warren, Cameron Lewis
dc.contributor.authorSlawin, Alexandra Martha Zoya
dc.contributor.authorLeach, Andrew G.
dc.contributor.authorWatson, Allan J. B.
dc.date.accessioned2020-08-19T09:30:03Z
dc.date.available2020-08-19T09:30:03Z
dc.date.issued2020-09-21
dc.identifier.citationAshford , M , Xu , C , Molloy , J J , Carpenter-Warren , C L , Slawin , A M Z , Leach , A G & Watson , A J B 2020 , ' Catalytic enantioselective synthesis of heterocyclic vicinal fluoroamines using asymmetric protonation : a method development and mechanistic study ' , Chemistry - A European Journal , vol. 26 , no. 53 , pp. 12249-12255 . https://doi.org/10.1002/chem.202002543en
dc.identifier.issn0947-6539
dc.identifier.otherPURE: 268490951
dc.identifier.otherPURE UUID: dc0a9bc4-9743-42c2-a200-40d999a23816
dc.identifier.otherORCID: /0000-0002-9527-6418/work/79226755
dc.identifier.otherORCID: /0000-0002-1582-4286/work/79226951
dc.identifier.otherWOS: 000560365600001
dc.identifier.otherScopus: 85089537153
dc.identifier.urihttps://hdl.handle.net/10023/20485
dc.descriptionFunding: Leverhulme Trust (Grant Number(s): RPG-2015-308), University of St Andrews, University of Manchester.en
dc.description.abstractA 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.
dc.format.extent8
dc.language.isoeng
dc.relation.ispartofChemistry - A European Journalen
dc.rightsCopyright © 2020 The Authors. Published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.en
dc.subjectAsymmetricen
dc.subjectBrønsted aciden
dc.subjectCatalysisen
dc.subjectFluorineen
dc.subjectHeterocyclesen
dc.subjectQD Chemistryen
dc.subjectDASen
dc.subject.lccQDen
dc.titleCatalytic enantioselective synthesis of heterocyclic vicinal fluoroamines using asymmetric protonation : a method development and mechanistic studyen
dc.typeJournal articleen
dc.contributor.sponsorThe Leverhulme Trusten
dc.description.versionPublisher PDFen
dc.contributor.institutionUniversity of St Andrews. Sir James Mackenzie Institute for Early Diagnosisen
dc.contributor.institutionUniversity of St Andrews. School of Chemistryen
dc.contributor.institutionUniversity of St Andrews. EaSTCHEMen
dc.identifier.doihttps://doi.org/10.1002/chem.202002543
dc.description.statusPeer revieweden
dc.identifier.urlhttps://doi.org/10.26434/chemrxiv.11920947.v1en
dc.identifier.grantnumberRPG-2015-308en


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