2 research outputs found
Incorporation of CF<sub>3</sub>–Pseudoprolines into Peptides: A Methodological Study
The peptide coupling reactions allowing
the incorporation of trifluoromethyl
substituted oxazolidine-type pseudoprolines (CF<sub>3</sub>-ΨPro)
into peptide chains have been studied. While standard protocols can
be used for the peptide coupling reaction at the <i>C</i>-terminal position of the CF<sub>3</sub>-ΨPro, acid chloride
activation has to be used for the peptide coupling reaction at the <i>N</i>-terminal position to overcome the decrease of nucleophilicity
of the CF<sub>3</sub>-ΨPro. We demonstrate that the <i>N</i>-amidification of a diastereomeric mixture of CF<sub>3</sub>-ΨPro using Fmoc-protected amino acid chloride without base
gave the corresponding dipeptides as a single diastereomer (6 examples).
The ratio of the <i>cis</i> and <i>trans</i> amide
bond conformers was determined by NMR study, highlighting the role
of the Xaa side chains in the control of the peptide backbone conformation.
Finally a tripeptide bearing a central CF<sub>3</sub>-ΨPro has
been successfully synthesized
Local Control of the <i>Cis</i>–<i>Trans</i> Isomerization and Backbone Dihedral Angles in Peptides Using Trifluoromethylated Pseudoprolines
NMR studies and theoretical calculations have been performed on model peptides Ac-Ser(ΨPro)-NHMe, (<i>S</i>,<i>S</i>)Ac-Ser(Ψ<sup>H,CF3</sup>Pro)-NHMe, and (<i>R,S</i>)Ac-Ser(Ψ<sup>CF3,H</sup>Pro)-NHMe. Their thermodynamic and kinetic features have been analyzed in chloroform, DMSO, and water, allowing a precise description of their conformational properties. We found that trifluoromethyl C<sup>δ</sup>-substitutions of oxazolidine-based pseudoprolines can strongly influence the <i>cis</i>–<i>trans</i> rotational barriers with only moderate effects on the <i>cis</i>/<i>trans</i> population ratio. In CHCl<sub>3</sub>, the configuration of the CF<sub>3</sub>–C<sup>δ</sup> entirely controls the ψ-dihedral angle, allowing the stabilization of γ-turn-like or PPI/PPII-like backbone conformations. Moreover, in water and DMSO, this C<sup>δ</sup>-configuration can be used to efficiently constrain the ring puckering without affecting the <i>cis</i>/<i>trans</i> population ratio. Theoretical calculations have ascertained the electronic and geometric properties induced by the trifluoromethyl substituent and provided a rational understanding of the NMR observations