Pentafluorophosphato‐Phenylalanines: Amphiphilic Phosphotyrosine Mimetics Displaying Fluorine‐Specific Protein Interactions

Phosphotyrosine residues are essential functional switches in health and disease. Thus, phosphotyrosine biomimetics are crucial for the development of chemical tools and drug molecules. We report here the discovery and investigation of pentafluorophosphato amino acids as novel phosphotyrosine biomimetics. A mild acidic pentafluorination protocol was developed and two PF5‐amino acids were prepared and employed in peptide synthesis. Their structures, reactivities, and fluorine‐specific interactions were studied by NMR and IR spectroscopy, X‐ray diffraction, and in bioactivity assays. The mono‐anionic PF5 motif displayed an amphiphilic character binding to hydrophobic surfaces, to water molecules, and to protein‐binding sites, exploiting charge and H−F‐bonding interactions. The novel motifs bind 25‐ to 30‐fold stronger to the phosphotyrosine binding site of the protein tyrosine phosphatase PTP1B than the best current biomimetics, as rationalized by computational methods, including molecular dynamics simulations. The more fluorine the better? Pentafluorophosphato amino acids A and B are stable new molecular entities showing surprisingly high binding affinities to the phosphotyrosine binding site of a protein tyrosine phosphatase—better than the current gold standard for phosphotyrosine mimetics. PF5 motifs display remarkable fluorine‐specific interactions and thus might enable a new class of potent tools for medicinal chemistry and chemical biology.