Mechanism-Based Design of Quinoline Potassium Acyltrifluoroborates for Rapid Amide-Forming Ligations at Physiological pH
datasetposted on 14.10.2021, 15:41 authored by Matthias Tanriver, Yi-Chung Dzeng, Sara Da Ros, Erwin Lam, Jeffrey W. Bode
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.
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unexpectedly high basicityincluding kinetic studieskey tetrahedral intermediateundergo chemoselective amide3 </ subquinoline potassium acyltrifluoroboratesquinolyl acyltrifluoroborateskey rolerapid amideamide product∼ 20vivo applicationsray crystallographyrate constantsprotonation evenprotein substrateproceed rapidlyphysiological phph 7new classneutral conditionsmicromolar concentrationsmechanistic investigationslower phleaving groupshydroxylamine towardfastest ratesenhanced ratedft calculationsconcerted 1certain biomoleculesacidic conditions