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dc.contributor.author
Tanriver, Matthias
dc.contributor.author
Dzeng, Yi-Chung
dc.contributor.author
Da Ros, Sara
dc.contributor.author
Lam, Erwin
dc.contributor.author
Bode, Jeffrey W.
dc.date.accessioned
2021-11-18T08:57:43Z
dc.date.available
2021-11-13T07:54:45Z
dc.date.available
2021-11-18T08:57:43Z
dc.date.issued
2021-10-27
dc.identifier.issn
0002-7863
dc.identifier.issn
1520-5126
dc.identifier.other
10.1021/jacs.1c07354
en_US
dc.identifier.uri
http://hdl.handle.net/20.500.11850/514995
dc.description.abstract
Potassium acyltrifluoroborates (KATs) undergo chemoselective amide-forming ligations with hydroxylamines. Under aqueous, acidic conditions these ligations can proceed rapidly, with rate constants of ∼20 M–1 s–1. The requirement for lower pH to obtain the fastest rates, however, limits their use with certain biomolecules and precludes in vivo applications. By mechanistic investigations into the KAT ligation, including kinetic studies, X-ray crystallography, and DFT calculations, we have identified a key role for a proton in accelerating the ligation. We applied this knowledge to the design and synthesis of 8-quinolyl acyltrifluoroborates, a new class of KATs that ligates with hydroxylamines at pH 7.4 with rate constants >4 M–1 s–1. We trace the enhanced rate at physiological pH to unexpectedly high basicity of the 8-quinoline-KATs, which leads to their protonation even under neutral conditions. This proton assists the formation of the key tetrahedral intermediate and activates the leaving groups on the hydroxylamine toward a concerted 1,2-BF3 shift that leads to the amide product. We demonstrate that the fast ligations at pH 7.4 can be carried out with a protein substrate at micromolar concentrations.
en_US
dc.language.iso
en
en_US
dc.publisher
American Chemical Society
en_US
dc.title
Mechanism-Based Design of Quinoline Potassium Acyltrifluoroborates for Rapid Amide-Forming Ligations at Physiological pH
en_US
dc.type
Journal Article
dc.date.published
2021-10-14
ethz.journal.title
Journal of the American Chemical Society
ethz.journal.volume
143
en_US
ethz.journal.issue
42
en_US
ethz.journal.abbreviated
J. Am. Chem. Soc.
ethz.pages.start
17557
en_US
ethz.pages.end
17565
en_US
ethz.identifier.wos
ethz.identifier.scopus
ethz.publication.place
Washington, DC
en_US
ethz.publication.status
published
en_US
ethz.leitzahl
ETH Zürich::00002 - ETH Zürich::00012 - Lehre und Forschung::00007 - Departemente::02020 - Dep. Chemie und Angewandte Biowiss. / Dep. of Chemistry and Applied Biosc.::02514 - Laboratorium für Organische Chemie / Laboratory of Organic Chemistry::03861 - Bode, Jeffrey W. / Bode, Jeffrey W.
ethz.leitzahl.certified
ETH Zürich::00002 - ETH Zürich::00012 - Lehre und Forschung::00007 - Departemente::02020 - Dep. Chemie und Angewandte Biowiss. / Dep. of Chemistry and Applied Biosc.::02514 - Laboratorium für Organische Chemie / Laboratory of Organic Chemistry::03861 - Bode, Jeffrey W. / Bode, Jeffrey W.
ethz.date.deposited
2021-11-13T07:56:53Z
ethz.source
WOS
ethz.eth
yes
en_US
ethz.availability
Metadata only
en_US
ethz.rosetta.installDate
2021-11-18T08:57:49Z
ethz.rosetta.lastUpdated
2022-03-29T16:03:07Z
ethz.rosetta.versionExported
true
ethz.COinS
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