Synthesis of Chiral α‐Trifluoromethyl α,α‐Disubstituted α‐Amino Acids and Conformational Analysis of L‐Leu‐Based Peptides with ( R )‐ or ( S )‐α‐Trifluoromethylalanine

Various racemic α‐trifluoromethyl α,α‐disubstituted α‐amino acids were synthesized by the reaction of methyl 3,3,3‐trifluoropyruvate imines with Grignard reagents. The optical resolution of racemates using ( R )‐1,1’‐bi‐2‐naphthol {( R )‐BINOL} esters gave optically active α‐trifluoromethylated α,α‐disubstituted α‐amino acids, such as α‐trifluoromethylalanine (αCF 3 Ala), α‐trifluoromethylleucine (αCF 3 Leu), and α‐trifluoromethylphenylalanine (αCF 3 Phe). The optically active ( R )‐ or ( S )‐αCF 3 Ala was incorporated into the L–Leu‐based pentapeptides, and their preferred conformation in solution and in the crystal state was studied by Fourier transform infrared (FT‐IR) absorption, nuclear Overhauser effect spectroscopy (NOESY) NMR, and circular dichroism (CD) spectra, as well as X‐ray crystallographic analysis. Both L–Leu‐based peptides with ( R )‐ or ( S )‐αCF 3 Ala formed right‐handed 3 10 ‐helical structures. Both peptide‐backbones at the N‐terminal residues 1–3 were very similar, but the φ and ψ torsion angles of residues 4 and 5 between peptides with ( R )‐ or ( S )‐ αCF 3 Ala were different.