Protecting group free radical C-H trifluoromethylation of peptides  

The resurgence of peptide and protein-based therapeutics and the demand for chemical probes to elucidate complex biological pathways has driven the development of synthetic chemistry compatible with post translational modification and/or bioconjugation. The use of fluorine-modified biomolecules has enabled the 19F nucleus to be used in NMR experiments to study protein structure, dynamics and protein-ligand interactions. Traditional approaches to incorporation of fluorine have involved synthesis using 19F-labelled amino acids, however these approaches frequently compromise the structure of the molecule. A team lead by Shane Krska at Merck Sharp & Dohme in New Jersey recently described late stage C-H functionalization of unprotected peptides and proteins utilizing radical trifluoromethylation chemistry (Chem. Sci. 2018, 9, 4168).[1] The team adopted two complementary approaches to trifluoromethylate aromatic amino acid residues in a wide range of peptide substrates using trifluoromethylsulfinate salts.[2] The first was based on use of stochiometric oxidant (Zn(SO2CF3)2 / tBuOOH, aq AcOH, 37°C, 16hrs) and the  second a catalytic photoredox approach (cat Ir[dFCF3ppy], NaSO2CF3, CH3CN/AcOH, 26°C, 20hrs, blue LED). Both gave good yields, with the photoredox approach generally being cleaner and higher yielding. Insulin, a peptide with 51 amino acid residues was successfully at all of its 4 tyrosine residues in 30% overall conversion. Isolation of an A19 mono-trifluoromethylated product and testing in binding and functional assays confirmed that this modification did not disrupt the structural integrity compared with native, unmodified insulin. The approach also has the potential to extended beyond CF3 incorporation using a similar approach.[3]

[1] Late stage functionalization of drug-like molecules, see Chem. Soc. Rev. 2016, 45, 546

[2] See Tett. Lett. 1991, 32, 7525; J. Fluorine. Chem. 1992, 59, 197

[3] Sodium azidofluoroalkylsulfinate has been used to install an azidofluoroalkyl chain on cyclic peptides