¹⁸F-Trifluoromethanesulfinate Enables Direct C–H ¹⁸F-Trifluoromethylation of Native Aromatic Residues in Peptides

Abstract

18 F labeling strategies for unmodified peptides with [ 18 F]fluoride require 18 F-labeled prosthetics for bioconjugation more often with cysteine thiols or lysine amines. Here we explore selective radical chemistry to target aromatic residues applying C− H 18 F-trifluoromethylation. We report a one-step route to [ 18 F]CF 3 SO 2 NH 4 from [ 18 F]fluoride and its application to direct [ 18 F]CF 3 incorporation at tryptophan or tyrosine residues using unmodified peptides as complex as recombinant human insulin. The fully automated radiosynthesis of octreotide[Trp(2-CF 2 18 F)] enables in vivo positron emission tomography imaging.Communication pubs.acs.org/JACS

Site‐Selective Trifluoromethylation Reactions of Oligopeptides

“…As highlighted before, Davis and Gouverneur have recently reported the synthesis of a novel, yet efficient, radiolabeled trifluoromethylating reagent for the late‐stage 18 F‐trifluoromethylation of electron‐rich Trp and Tyr residues embedded into native peptides of great complexity ( vide supra ) . As disclosed in Scheme , Tyr‐containing peptides including His or highly sensitive thioether‐containing Met unit could be radiolabeled in a late‐stage fashion.…”

“…In yet another impressive and elegant display of efficient radiolabeling of peptides, Davis and Gouverneur designed a one‐step synthesis of the radiolabeling trifluoromethyl source [ 18 F]CF 3 SO 2 NH 4 and its application to the late‐stage 18 F‐trifluoromethylation of a sheer number of Trp‐containing native peptides of high structural complexity and certain Tyr‐containing biomolecules ( vida infra ) (Scheme ). In‐depth experimental studies led to the optimal synthesis of the corresponding 18 F reagent, which was eventually performed via reaction of 2,2,‐difluoro‐2‐(triphenylphosphonio)acetate (PDFA) with N ‐methylmorpholine ⋅ SO 2 (NMM ⋅ SO 2 ) in the presence of [ 18 F]KF/K 222 in a mixture of propylene carbonate and DMF as solvent at 110 °C.…”

Highlight selection of radiochemistry and radiopharmacy developments by editorial board (January–June 2020)

“…Ideally, fluorine-18 is introduced directly without premodification, with high high yields at ambient temperature. A method was developed to introduce a [ 18 F]trifluoromethyl group using Langlois’ reagent onto the native aromatic peptide residues tyrosine and tryptophan (Kee et al 2020 ). The method was nicely applied to multiple amino acids, peptides (including somatostatin-14) and recombinant insulin.…”

Visible‐Light‐Driven Fluoroalkylation of Tryptophan Residues in Peptides

“…Selective functionalization of tryptophan residues was achieved using stabilized vinyl diazo compound and a rhodium catalyst, [9] with stabilized aminoxyl radical in a metal‐free process [10] or with N ‐carbamoylpyridinium salts in a photochemical process using UV−B light (302 nm) [11] . Sodium trifluoromethanesulfinate in a combination with organic oxidant allowed radical trifluoromethylation of tryptophan residues to form protein constructs for 19 F NMR studies [12] and related 18 F labelled trifluoromethylsulfinate trifluoromethylated aromatic residues of peptides for positron emission tomography (PET) study [13] . Sodium trifluoromethanesulfinate was also used in copper‐catalyzed [14] or photoredox (iridium‐catalyzed) [15] trifluoromethylation of tryptophan residues in peptides.…”