- Understanding the Conformational Behavior of Fluorinated Piperidines: The Origin of the Axial-F Preference
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Gaining an understanding of the conformational behavior of fluorinated compounds would allow for expansion of the current molecular design toolbox. In order to facilitate drug discovery efforts, a systematic survey of a series of diversely substituted and protected fluorinated piperidine derivatives has been carried out using NMR spectroscopy. Computational investigations reveal that, in addition to established delocalization forces such as charge–dipole interactions and hyperconjugation, solvation and solvent polarity play a major role. This work codifies a new design principle for conformationally rigid molecular scaffolds.
- Nairoukh, Zackaria,Strieth-Kalthoff, Felix,Bergander, Klaus,Glorius, Frank
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- SYNTHESE DE FLUORO-3 AZACYCLANES : ACTION DE L'ACIDE FLUORHYDRIQUE SUR LES AZA-1 BICYCLO ALCANES
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The addition of liquid hydrogen fluoride or Olah's reagent (pyrimidine-10 HF) to 1-aza bicyclo(n.1.0> alkanes leads to the formation of 3-fluoro 1-aza heterocyclic compounds.Isomeric 3-fluoro azetidines, 3-fluoro-piperidines and a 3-fluoro azepine have been prepared by this procedure.
- Alvernhe, G.,Laurent, A.,Touhami, K.,Bartnik, R.,Mloston, G.
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- Accessing (Multi)Fluorinated Piperidines Using Heterogeneous Hydrogenation
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Fluorinated piperidines are desirable motifs for pharmaceutical and agrochemical research. Nevertheless, general synthetic access remains out of reach. Herein, we describe a simple and robust cis-selective hydrogenation of abundant and cheap fluoropyridines to yield a broad scope of (multi)fluorinated piperidines. This protocol enables the chemoselective reduction of fluoropyridines while tolerating other (hetero)aromatic systems using a commercially available heterogenous catalyst. Fluorinated derivatives of important drug compounds are prepared, and a straightforward strategy for the synthesis of enantioenriched fluorinated piperidines is disclosed.
- Bergander, Klaus,Daniliuc, Constantin G.,Glorius, Frank,Heusler, Arne,Nairoukh, Zackaria,Wagener, Tobias
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p. 12052 - 12057
(2020/11/27)
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- γ-amino-substituted analogues of 1-[(S)-2,4-diaminobutanoyl]piperidine as highly potent and selective dipeptidyl peptidase II inhibitors
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Using 1-[(S)-2,4-diaminobutanoyl]piperidine as lead compound, we developed a large series of highly potent and selective dipeptidyl peptidase II (DPP II) inhibitors. γ-Amino substitution with arylalkyl groups, for example, a 2-chlorobenzyl moiety, resulted in a DPP II inhibitor with an IC50 = 0.23 nM and a high selectivity toward DPP IV (IC50 = 345 μM). Furthermore, it was shown that the basicity of the γ-amino is important and that α-amino substitution is not favorable. Piperidine-2-nitriles did not show an increase in potency but rather reduced the selectivity. Introduction of a 4-methyl or a 3-fluorine on piperidine improved selectivity and preserved the high potency.
- Senten, Kristel,Van Der Veken, Pieter,De Meester, Ingrid,Lambeir, Anne-Marie,Scharpé, Simon,Haemers, Achiel,Augustyns, Koen
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p. 2906 - 2916
(2007/10/03)
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