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ABSTRACT: Aliphatic N,N'-linked oligoureas are peptidomimetic foldamers that adopt a well-defined helical secondary structure stabilized by a collection of remote three centred H-bonds closing 12- and 14-membered pseudo rings. Delineating the rules that govern helix formation depending on the nature of constituent units is of practical utility if one aims to utilize this helical fold to place side chains in a given arrangement and elaborate functional helices. Herein, we have tested whether the helix geometry is compatible with alternative substitution patterns. The central -NH-CH(R)-CH2-NH-CO-residue in a model oligourea pentamer sequence was replaced by guest units bearing various substitution patterns (e.g. -NH-CH2-CH2-NH-CO-, -NH-CH2-CH(R)-NH-CO-, -NH-CH(R1)-CH(R2)-NH-CO-), different levels of preorganization (cyclic versus acyclic residues) and stereochemistries, and helix formation systematically assessed. The extent of helix perturbation or stabilization was primarily monitored in solution by FT-IR spectroscopy, NMR spectroscopy and electronic circular dichroism (ECD). Although three new substitution patterns were accommodated in the 2.5-helix, our results indicate that the helical urea backbone in short oligomers is particularly sensitive to residue substitution pattern variations (position and stereochemistry). For example, the trans-1,2-diaminocyclohexane unit but not the corresponding cis-unit, was experimentally found to break helix nucleation. Theoretical calculations helped to rationalize these results. The conformational preferences in this series of oligoureas were also studied at high resolution by X-ray structure analyses of a representative set of modified oligomers.
Journal of the American Chemical Society 02/2013; · 9.91 Impact Factor
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ABSTRACT: A practical and efficient microwave-assisted solid-phase method for the synthesis of N,N'-linked oligoureas and related amide/urea hybrid oligomers, featuring the use of succinimidyl (2-azido-2-substituted ethyl) carbamate monomers, is reported. The rate enhancement of urea formation under microwave irradiation combined with the mild conditions of the phosphine-based azide reduction makes this approach very effective for routine synthesis of oligoureas and possibly for library production.
Organic Letters 05/2012; 14(12):3130-3. · 5.86 Impact Factor
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ABSTRACT: Ab initio calculations of two oligoureas stabilized in helix and sheet organization have been performed. The hydrogen bond distances were found to be almost the same for both structures. The vibrational assignment of the two oligourea structures and the direction of the transition moment of each vibration have been determined. From these results, and using the experimental isotropic optical index determined for one oligourea, we have established the anisotropic infrared optical files for the two structures. Interestingly, most urea absorptions vibrate in only one principal direction. Also, the shift of the carbonyl band is weaker and inverse to what was reported for corresponding protein secondary structures. Finally, simulations of the Polarization Modulation Infrared Reflection Absorption Spectroscopy (PMIRRAS) and Attenuated Reflection Spectroscopy (ATR) infrared spectra demonstrate the possibility to determine the orientation of the oligoureas in thin or ultrathin films, even if in some cases it may be difficult to unambiguously assign their secondary structure.
The Journal of Physical Chemistry B 03/2011; 115(15):4446-52. · 3.70 Impact Factor
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ABSTRACT: A new N-Boc-protected monomer for the synthesis of oligourea foldamers containing the (1H-imidazolyl-4yl)methyl side chain of histidine, has been prepared in seven steps from Trt-His(τ-Trt)-OMe. This protecting group combination on histidine was found to be critical to ensure efficient access to the requisite activated building block. This new derivative, suitable for solid phase synthesis, expands the current arsenal of building blocks with proteinogenic side chains useful for the design of peptidomimetic oligourea foldamers.
Tetrahedron 01/2011; · 3.03 Impact Factor
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Angewandte Chemie International Edition 02/2010; 49(6):1067-70. · 13.45 Impact Factor
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Paul Claudon,
Aude Violette,
Karen Lamour,
Marion Decossas,
Sylvie Fournel,
Béatrice Heurtault,
Julien Godet,
Yves Mély,
Brigitte Jamart-Grégoire,
Marie-Christine Averlant-Petit,
Jean-Paul Briand,
Guy Duportail,
Henri Monteil,
Gilles Guichard
Angewandte Chemie International Edition 12/2009; 49(2):333-6. · 13.45 Impact Factor
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ABSTRACT: Sixteen and 24 membered aza-beta(3)-peptidic macrocycles containing a alpha-hydrazinoacid or a beta(3)-aminoacid were synthesized. The conformation of these pseudopeptides was determined by using NH chemical shift analysis, NH extinction, VT-NMR experiments, and X-ray diffraction. The study shows that a stable conformation is retained between 223 and 413 K. The latter is characterized by an uninterrupted internal H-bond network and a syndiotactic arrangement of the asymmetric centers. It means that the presence of the optically pure residue acts as a conformational lock to select a single enantiomer through the cyclization by controlling the absolute configuration of all the nitrogen atoms. To our knowledge, this represents the first example of a dynamic enantioselection process involving several centers prone to pyramidal inversion. These results give a new impulsion to the control of nitrogen chirality, which remained limited to small cycles for 60 years.
Journal of the American Chemical Society 10/2009; 131(40):14521-5. · 9.91 Impact Factor
