Practical Asymmetric Synthesis of Fluorinated Amino Acids and Their Application to Peptide Engineering

Abstract

Fluorine-containing amino acids have attracted considerable recent attention, owing to their potential application in widespread scientific fields. To date, several types of fluorinated α- and β-amino acids have been studied, whose characteristics change dramatically depending on the position of fluorine atoms. Among them, γ-fluorinated α-amino acids and γ-fluorinated β-amino acids are of particular importance, because they serve as suitable components for peptide-bond formation, because of their stability, tolerance toward racemization, and proper reactivity. By incorporating these fluorinated amino acids into peptides and proteins, their structures and functions can be analyzed and controlled in a rational way. At present, however, stereoselective synthesis of these fluorinated amino acids still remains a challenge. We have developed highly practical asymmetric synthesis of ᴅ-4,4,4-trifluoro-allo-threonine and (S)-3-trifluoromethyl-β-alanine. Each of them can be synthesized in a stereopure form and in a large scale without using any expensive reagent and special apparatus. In particular, the synthesis of (S)-3-trifluoromethyl-β-alanine does not require column chromatography for the purification process of all steps. By using (R)-3-trifluoromethyl-β-alanine as a component of peptides, we also investigated the effects of the attachment of CF₃ groups to the backbone of an oligo-β-peptides that tend to adopt a 14-helix structure. Our systematic studies revealed that the attachment of CF₃ groups to the peptide backbones enhances the hydrogen-bonding ability of the NH groups adjacent to the CF₃ groups, so that the 14-helix structure of the oligo-β-peptides was significantly stabilized.