Tailored Approaches towards the Synthesis of l-S-(Trifluoromethyl)cysteine- and l-Trifluoromethionine-Containing Peptides
Among the fluorinated noncanonical amino acids, l-trifluoromethionine (TFM) and l-S-(trifluoromethyl)cysteine (TfmCys), fluorinated analogues of methionine and cysteine, are of particular interest because of their ability to locally increase the hydrophobicity of peptides. We report herein the synthesis of tert-butoxycarbonyl/benzyl-protected TFM and TfmCys by using a cheap and user-friendly radical trifluoromethylation approach. The benzyl protecting group of these fluorinated amino acids could be conveniently removed by hydrogenolysis, which circumvented troublesome saponification reactions. For the first time, TfmCys was inserted into a peptide sequence by liquid- or solid-phase peptide synthesis. Finally, a late trifluoromethylation strategy with the use of Togni's reagent on disulfide-bridged peptides was also efficient to incorporate TFM or TfmCys at both N-terminal and internal positions.