Fluorinated amino acids can have dramatic effects on protein stability and protein-protein interactions due to the unique stereoelectronic properties of fluorine. Previous approaches to assessing their properties have mainly focused on helical systems, even though fluoro-amino acids are known to exhibit lower intrinsic helix propensities than their hydrocarbon analogues. Fluorination of specific b-sheet positions within globular proteins has been shown to have a stabilizing effect, suggesting that fluorinated amino acids may generally be well suitable for modulating non-helical structures. Still, fluorinated amino acids have rarely been studied in amyloid forming peptides, which take on a characteristically high cross-b-sheet content. Here, we examine the substitution of natural amino acids within an amyloid forming model peptide by amino acids that contain different stoichiometries of fluorine in their side chains. This approach enables a systematic evaluation of the impact of fluorine on amyloid formation. We have investigated the impact of size, hydrophobicity and secondary structure propensities of the fluorinated amino acids on the amyloid formation process. The structure of the model peptide is based on an engineered coiled coil folding motif that was designed to provide an a-helical starting structure that can fold into b-sheet rich amyloids under controlled conditions. Substitution with fluorinated amino acids was accomplished for two neighboring valine residues that play a key role in the structural transition. The resulting peptides show an unexpected folding behavior as a consequence of the interplay of stereoelectronic effects, helix propensity, hydrophobicity and position of the particular substitution within the amyloid forming system.

A novel conjugate hydrofluoroalkylation of α,β-unsaturated acyl-oxazolidinones is described. Using this method, enantiomerically pure β-trifluoromethylated amino acids were prepared. Trifluorovaline and trifluoroisoleucine were incorporated into peptides and found to show extremely low α-helix propensities.

SummaryA practical route for the stereoselective synthesis of (2S,3S)-5,5,5-trifluoroisoleucine (L-5-F3Ile) and (2R,3S)-5,5,5-trifluoro-allo-isoleucine (D-5-F3-allo-Ile) was developed. The hydrophobicity of L-5-F3Ile was examined and it was incorporated into a model peptide via solid phase peptide synthesis to determine its α-helix propensity. The α-helix propensity of 5-F3Ile is significantly lower than Ile, but surprisingly high when compared with 4’-F3Ile.

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All syntheses involving air-and moisture-sensitive compounds were carried out using standard Schlenk-type glassware (or in a glove box) under an atmosphere of argon. Solvents were dried with the solvent purification system MB-SPS 800 from M. Braun or predistilled according to standard laboratory methods. Unless stated otherwise all chemicals were purchased from Acros or Aldrich and used without further purification. The following instruments were used for characterization of the compounds: 1 H, 13 C, and 19 F NMR spectra were recorded at room temperature using a Bruker AC 250, JEOL ECX 400,