Design and Synthesis of a Monofluoro‐Substituted Aromatic Amino Acid as a Conformationally Restricted 19 F NMR ­Label for Membrane‐Bound Peptides

A monofluoro‐substituted amino acid was designed to serve as a conformationally restricted label for solid‐state 19 F NMR distance measurements in membrane‐bound peptides. The aromatic cis and trans isomers of 1‐amino‐3‐(4‐fluorophenyl)cyclobutanecarboxylic acid were synthesized in five steps from diethyl 2‐(4‐fluorophenyl)propanedioate. They were incorporated into the antimicrobial peptide gramicidin S to replace a native D Phenylalanine residue. Because the Cα‐tetrasubstituted amino acid cannot racemize, it showed full compatibility with solid‐phase peptide synthesis protocols. According to circular dichroism analysis and molecular modeling, the 19 F‐labeled analogues of the known helix‐inducing amino acid (1‐aminocyclobutane‐1‐carboxylic acid) do not disrupt the peptide conformation when substituted for Phe, neither in a β‐turn nor in an α‐helix.