Incorporation of Trifluoromethylated Proline and Surrogates into Peptides: Application to the Synthesis of Fluorinated Analogues of the Neuroprotective Glycine-Proline-Glutamate (GPE) Tripeptide

The incorporation into a peptide chain of highly hindered and weakly nucleophilic trifluoromethylated prolines, pseudoprolines and oxazolidines has been achieved. As an application, the synthesis of a new class of fluorinated analogues of the neuroprotective tripeptide glycine-proline-glutamate (GPE) is reported. These analogues have been elaborated from a panel of five-membered ring trifluoromethylated amino acids (Tfm-AAs) through the coupling reaction with a glutamate residue at the <i>C</i>-terminus and a glycine at the <i>N</i>-terminus. Although the peptide coupling reaction at the <i>C</i>-terminal position of the fluorinated amino acid was conveniently performed under standard conditions, the very challenging coupling reaction at the highly deactivated <i>N</i>-terminal position proved to be much more problematic. A methodological study was needed to identify suitable reaction conditions for this difficult peptide coupling

Synthesis of Enantiopure <i>trans</i>-2,5-Disubstituted Trifluoromethylpyrrolidines and (2<i>S</i>,5<i>R</i>)‑5-Trifluoromethylproline

Enantiopure <i>trans</i>-2,5-disubstituted trifluoromethylpyrrolidines were prepared on a several gram scale starting from a readily available chiral fluorinated oxazolidine (Fox). A pure oxazolopyrrolidine intermediate could be obtained after an efficient separation by selective diastereomer destruction. The addition of various Grignard reagents on this oxazolopyrrolidine provided disubstituted pyrrolidines with moderate to complete <i>trans</i> diastereoselectivity. The highly valuable compound (2<i>S</i>,5<i>R</i>)-5-trifluoromethylproline could be synthesized from the same oxazolopyrrolidine intermediate via a Strecker-type reaction

Synthesis of Enantiopure <i>trans</i>-2,5-Disubstituted Trifluoromethylpyrrolidines and (2<i>S</i>,5<i>R</i>)‑5-Trifluoromethylproline

Enantiopure <i>trans</i>-2,5-disubstituted trifluoromethylpyrrolidines were prepared on a several gram scale starting from a readily available chiral fluorinated oxazolidine (Fox). A pure oxazolopyrrolidine intermediate could be obtained after an efficient separation by selective diastereomer destruction. The addition of various Grignard reagents on this oxazolopyrrolidine provided disubstituted pyrrolidines with moderate to complete <i>trans</i> diastereoselectivity. The highly valuable compound (2<i>S</i>,5<i>R</i>)-5-trifluoromethylproline could be synthesized from the same oxazolopyrrolidine intermediate via a Strecker-type reaction

Incorporation of CF₃–Pseudoprolines into Peptides: A Methodological Study

The peptide coupling reactions allowing the incorporation of trifluoromethyl substituted oxazolidine-type pseudoprolines (CF₃-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 CF₃-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 CF₃-ΨPro. We demonstrate that the <i>N</i>-amidification of a diastereomeric mixture of CF₃-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 CF₃-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^H,CF3Pro)-NHMe, and (<i>R,S</i>)­Ac-Ser­(Ψ^CF3,HPro)-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^δ-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 CHCl₃, the configuration of the CF₃–C^δ 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^δ-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