Irreversible Cysteine‐Selective Protein Labeling Employing Modular Electrophilic Tetrafluoroethylation Reagents

Abstract

Fluoroalkylation reagents based on hypervalent iodine are widely used to transfer fluoroalkyl moieties to various nucleophiles. However, the transferred groups have so far been limited to simple structural motifs. We herein report a reagent featuring a secondary amine that can be converted to amide, sulfonamide, and tertiary amine derivatives in one step. The resulting reagents bear manifold functional groups, many of which would not be compatible with the original synthetic pathway. Exploiting this structural versatility and the known high reactivity toward thiols, the new-generation reagents were used in bioconjugation with an artificial retro-aldolase, containing an exposed cysteine and a reactive catalytic lysine. Whereas commercial reagents based on maleimide and iodoacetamide labeled both sites, the iodanes exclusively modified the cysteine residue. The study thus demonstrates that modular fluoroalkylation reagents can be used as tools for cysteine-selective bioconjugation.

Supramolecular Aggregation of Perfluoroorganyl Iodane Reagents in the Solid State and in Solution

“…A similar behavior was reported for an acid reagent related to 1 , which forms a crystalline 2:1 complex with Zn(OTf) 2 (OTf = trifluoromethanesulfonate) through the coordination of the exposed carbonyl oxygen atom , , . Moreover, several examples of the clean protonation of the acid and alcohol reagents with strong acids resulted in fairly stable iodonium salts , . For instance, 1 forms an adduct with 1 equiv.…”

Advances in the Synthesis and Application of Tetrafluoroethylene‐ and 1,1,2,2‐Tetrafluoroethyl‐Containing Compounds

“…Several other structurally diverse silanes have been reported. However, they have not been studied as sources of the [RCF 2 CF 2 – ] species for nucleophilic additions, but used as precursors for the synthesis of electrophilic fluoroalkylation reagents 108 and 109 based on hypervalent iodine (for information on their reactivity, see Chapter 3.4) . These compounds were prepared by a fluoride‐initiated Umpolung reaction with shelf‐stable 1‐fluoro‐3,3‐dimethylbenziodoxole or in situ prepared 1‐fluoro‐benziodoxol‐3‐one, respectively (Scheme ).…”

“…In this context, new λ 3 ‐iodane 115 , containing a secondary amine group, was recently introduced. Late‐stage derivatization of the reagent via mild formation of amides, sulfonamides, and tertiary amines was made possible (Scheme ) . Reagents prepared in this way contained manifold useful functional groups (halogen, azide, boronate ester, aldehyde, nitrile, sulfonyl fluoride, and alkyne) and units, such as tetraethylene glycol, biotin, and several fluorophores (pyrene, coumarin, fluorescein, and rhodamine).…”

“…Cysteine, one of the most popular targets for bioconjugation, is also an excellent nucleophilic substrate for the hypervalent iodine‐based fluoroalkylation reagents described in Chapter 3.4. The recently reported reagent 115 allows for late‐stage derivatization with many useful functional groups and other biologically relevant moieties, such as fluorescent dyes or biotin (see Chapter 3.4). The excellent reactivity and selectivity toward thiols together with a high degree of modularity makes the electrophilic tetrafluoroethylation reagents attractive candidates for thiol bioconjugation.…”

Reductant‐Induced Free Radical Fluoroalkylation of Nitrogen Heterocycles and Innate Aromatic Amino Acid Residues in Peptides and Proteins

“…Trifluoromethylated cyclic l 3 -iodanes (Togni reagents) and their tetrafluoroethylene-containing analogues 1 have been previously used as electrophilic fluoroalkylating speciesi nr eactions with various sulfur-,o xygen-, phosphorus-,a nd carboncentered nucleophilesa nd also thiol containing biomolecules includingb ioconjugations of Cys residues ( Figure 1A). [10][11][12] The concept of reductive trifluoromethylation of small molecules, such as alkenes or aromatics by usingT ogni reagentsa nd transition-metal (Cu, Fe and the photochemical use of Ru or Ir) or non-metallic [NaI, TEMPONa (TEMPO = 2,2,6,6-tetramethylpiperidin-1-yl)oxyl)] reductants has been realizeds uccessfully on several examples ( Figure 1B). [13,14] However,t he reported conditionsd id not allow to perform thisf unctionalization with biomolecules in aqueous environment under ambient conditions.…”