Three-component synthesis of C2F5-substituted pyrazoles from C2F5CH2NH2·HCl, NaNO2 and electron-deficient alkynes

A one-pot reaction between C2F5CH2NH2·HCl, NaNO2 and electron-deficient alkynes gives C2F5-substituted pyrazoles in excellent yields. The transformation smoothly proceeds in dichloromethane/water, tolerates the presence of air, and requires no purification of products by column chromatography. Mechanistically, C2F5CH2NH2·HCl and NaNO2 react first in water to generate C2F5CHN2, that participates in a [3 + 2] cycloaddition with electron-deficient alkynes in dichloromethane

gamma-(S)-Trifluoromethyl proline: evaluation as a structural substitute of proline for solid state F-19-NMR peptide studies

gamma-(4S)-Trifluoromethyl proline was synthesised according to a modified literature protocol with improved yield on a multigram scale. Conformational properties of the amide bond formed by the amino acid were characterised using N-acetyl methyl ester model. The amide populations (s-trans vs. s-cis) and thermodynamic parameters of the isomerization were found to be similar to the corresponding values for intact proline. Therefore, the.-trifluoromethyl proline was suggested as a structurally low-disturbing proline substitution in peptides for their structural studies by F-19-NMR. Indeed, the exchange of native proline for gamma-trifluoromethyl proline in the peptide antibiotic gramicidin S was shown to preserve the overall amphipathic peptide structure. The utility of the amino acid as a selective F-19-NMR label was demonstrated by observing the re-alignment of the labelled gramicidin S in oriented lipid bilayers

Peptidyl-Prolyl Model Study: How Does the Electronic Effect Influence the Amide Bond Conformation?

The triple-helical structure of collagen, the most abundant protein in animal bodies, owes its stability to post-translationally installed hydroxyl groups at position 4 of prolyl residues. To shed light on the nature of this phenomenon, we have examined the influence of the 4-substituent on the amide isomerism in peptidyl-prolyl analogues. The rigid bicyclic skeleton of 2,4-methanoprolines allowed us to follow the through-bond impact of the substituent group (electronic effect) without the side-chain conformation being affected by a stereoelectronic effect. These proline analogues were prepared by [2 + 2] photocycloaddition of (2-allylamino)­acrylic acid derivatives. Subsequent p<i>K</i>_a studies demonstrated a remarkable electronic effect of the 4-fluorine substitution, while the effect of the 4-methyl group was negligible. The <i>trans</i>/<i>cis</i> amide ratio was measured in model compounds under low temperature conditions. The observed prevalence for a <i>trans</i>-amide is extraordinary, and in this regard, 2,4-methanoproline is closer to primary α-amino acids than to proline. At the same time the amide rotation velocities were 3−4 orders of magnitude ​higher when compared to <i>N</i>-acetylprolyl. Finally, our results indicate that the electronic effect of the 4-substituent only affects the kinetics of the amide isomerization but not the thermodynamic prevalence for the <i>trans</i>-rotamer

Design and Synthesis of Novel ¹⁹F‑Amino Acid: A Promising ¹⁹F NMR Label for Peptide Studies

Novel aliphatic ¹⁹F-substituted amino acid was designed as a ¹⁹F NMR label for peptide studies. The synthesis was performed in 11 steps and 9% overall yield from a commercially available starting material. The key transformation was a decarboxylative fluorination of an aliphatic carboxylic acid with XeF₂ in C₆F₆

Incorporation of <i>cis</i>- and <i>trans</i>-4,5-Difluoromethanoprolines into Polypeptides

Substituted prolines exert diverse effects on the backbone conformation of proteins. Novel difluoro-analogues were obtained by adding difluorocarbene to N-Boc-4,5-dehydroproline methyl ester, which gave the <i>trans</i>-adduct as the sole product with 71% yield. Upon cleavage of the N-protection group the free amino acid decomposed rapidly. Its incorporation into the proline-rich cell-penetrating “sweet arrow peptide” was thus accomplished using a dipeptide strategy. Two building blocks, containing either <i>cis</i>- or <i>trans</i>-4,5-difluoromethanoproline, were obtained by difluorocyclopropanation of the aminoacyl derivatives of 4,5-dehydroproline. The resulting dipeptides were stable under standard conditions of Fmoc solid phase peptide synthesis and, thus, suitable to study conformational effects