Asymmetric α-Fluoroalkyl-α-Amino Acids: Recent Advances in Their Synthesis and Applications.

Due to the specific properties provided by fluorine atoms to biomolecules, amino acids with fluorinated side chains are of great interest for medicinal chemistry and chemical biology. Among them, α-fluoroalkyl-α-amino acids constitute a unique class of compounds. In this review, we outline the strategies adopted for their syntheses in enantiopure or enantioenriched forms and their incorporation into peptides. We then describe the consequences of the introduction of fluorine atoms in these compounds for the modulation of their hydrophobicity and the control of their conformation. Emerging applications are presented in the areas of enzyme inhibition, medicinal chemistry, hydrolytic stability of peptides, antimicrobial peptides, PET, and 19F NMR probes.

Difluoroalanine: Synthesis, Incorporation in Peptides, and Hydrophobic Contribution Assessment.

The straightforward synthesis of chiral (R)- and (S)-difluoroalanine is reported. The key step is a Strecker-type reaction followed by hydrogenolysis, Fmoc protection, and acidic hydrolysis. Peptide coupling reactions at its N- and C-terminal positions provide diastereomerically pure tripeptides. On the basis of hydrophobicity index measurements, the hydrophobic contribution of difluoroalanine in a peptide chain was found to be similar to that of isoleucine for a smaller van der Waals volume of the side chain.