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. 2026 Jun 12;91(25):8473–8486. doi: 10.1021/acs.joc.6c00904

Incorporation of the Trifluoromethylthio Group (CF3S−) into Biomolecules: A Versatile Tool for Advancing Life Sciences

Jure Gregorc †,‡,§, Nathalie Lensen ‡,§, Grégory Chaume ‡,§,*, Jernej Iskra †,*, Thierry Brigaud ‡,§,*
PMCID: PMC13316985  PMID: 42284465

Abstract

The trifluoromethylthio functional group (CF3S−) has gained considerable attention in synthetic and medicinal chemistry due to its ability to enhance the pharmacokinetic profiles of functionalized compounds. This Synopsis highlights recent progress in the incorporation of the CF3S group into biomolecules and bioactive compounds, with a focus on its influence on physicochemical properties and its applications in medicinal chemistry and chemical biology.

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The association of fluoroalkyl groups with chalcogen atoms leads to functional groups with increased lipophilicity and tunable electronic properties, often significantly affecting the acidity or basicity of proximal moieties. While such characteristics are highly desirable in drug optimization programs, chalcogen-associated substituents (R–XRF) remain underrepresented in FDA-approved pharmaceuticals compared to monofluorine (R–F) and trifluoromethyl (R–CF3) chemotypes. Among these emerging motifs, the trifluoromethylthio group (CF3S−) is of particular interest due to its high lipophilicity and strong electron-withdrawing character. , Compared to CF3, the CF3S group is significantly more lipophilic (π = 1.44) and exhibits comparable electronic effects. Moreover, the CF3S group features three magnetically equivalent fluorine atoms in an isolated spin system, rendering it a sensitive 19F NMR probe for structural and dynamics studies of biomolecules such as peptides, , proteins, − and nucleic acids. −

Over the past 15 years, numerous shelf-stable reagents for direct trifluoromethylthiolation of structurally complex substrates have been developed. ,, These advances have been complemented by indirect strategies involving trifluoromethyl­ation of sulfur-containing precursors, such as thiols or disulfides. Collectively, the methodology for CF3S introduction has undergone substantial development and has been comprehensively reviewed elsewhere. ,,, In addition to these reviews dedicated to synthetic aspects, this Synopsis provides a focused overview of recent advances in the incorporation of the trifluoromethylthio group into bioactive small molecules and biomolecules, including amino acids, peptides, and oligonucleotides, emphasizing the pronounced effect of trifluoromethylthiolation on their physicochemical and pharmacokinetic properties. We summarize the use of CF3S– substitution in medicinal chemistry, particularly in structure–activity relationship (SAR) studies, and highlight its potential use in chemical biology as a probe for 19F NMR spectroscopy and 18F-PET imaging.

1. CF3S-Containing Bioactive Small Molecules

Rational incorporation of lipophilic groups can enhance membrane permeability and metabolic stability, therefore, trifluoromethylthiolation is regarded as a promising strategy for optimizing the pharmacokinetic properties of biomolecules and bioactive compounds. Representative examples of trifluoro­methylthiolated drug candidates in clinical use or advanced trials, together with CF3S-containing biologically active compounds are shown in Figure .

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Selected CF3S-containing registered pharmaceutics,a those in clinical trials,b and biologically active compounds.c  −

The development of the potent antitumor agent TAK-243 (3, formerly MLN7243) exemplifies a recent exploitation of CF3S group properties. TAK-243 has been proposed to adopt a planar conformation that enables strong anchoring within the hydrophobic binding pocket, while the meta-CF3S substituent likely acts as a hydrophobic hook, enhancing binding through favorable contacts between the trifluoro­methyl­thiobenzene moiety and the protein’s hydrophobic patch.

An inspiration for the design of new biologically active compounds was the synthesis of SCF3 analogues of known drugs containing the OCF3 group. A study on ADME properties of the SCF3 analogue of the riluzole drug 6 (Figure ) further highlighted the non-metabolizable lipophilicity effect of the trifluoromethylthio group and its potential to prolong in vivo half-life. Replacement of oxygen by sulfur led to an increase in lipophilicity of 0.5 logP and a reduced solubility, which was attributed to higher lattice energy. The CF3S-analogs retained stability in human liver microsome and showed no inhibition of CYP3A4. In vitro safety profiling revealed no significant off-target activity, indicating that the CF3S group does not present intrinsic safety concerns.

The trifluoromethylthio group’s ability to enhance in vitro biological activity has been explored in multiple SAR studies. Selected successful examples of potent biological active compounds that emerged from these studies are highlighted in Figure . This literature survey suggests that the trifluoromethylthio group is typically introduced via convergent strategy, using robust couplings of commercially available CF3S-substituted benzene derivatives. In general, trifluoromethylthiolated bioactive analogs demonstrated increased metabolic stability, improved bioavailability and low toxicity in human cell lines at pharmacologically relevant concentrations. An exception is a class of antibacterial N-trifluoromethylthiosulfonimidamides and sulfoximines 14, which exhibited high cytotoxicity in human cell lines, a property not observed for the C-SCF3 compounds 1–13 (Figure ). SAR analysis attributed the cytotoxicity to the N-SCF3 group, as the corresponding N-CF3 analogs displayed neither antibacterial nor cytotoxic activity. The N–SCF3 bond is presumed to be more labile than the C–SCF3 bond and could release the trifluoromethanethiol toxicophore. This potential liability should be considered in future applications of the trifluoromethylthio group in drug design.

2. Trifluoromethylthiolated Amino Acids and Peptides

Trifluoromethionine and Trifluoromethylcysteine Derivatives

Until recently, the synthesis and incorporation of trifluoro­methylcysteine (TfmCys) and trifluoromethionine (TFM) into peptides have dominated reports on CF3S-containing amino acids (AAs). , The main strategies for accessing TfmCys and TFM building blocks include radical trifluoro­methylation of (homo)­cystines using CF3SO2Na/t-BuOOH or electrophilic trifluoromethylation of protected (homo)­cysteines using the Togni hypervalent iodine­(III)–CF3 reagent (Scheme ). , More recently, TfmCys synthesis was reported within a broad scope of substrates undergoing efficient electrophilic S-trifluoromethylation using the CF3-thianthrenium triflate reagent. Moreover, nucleophilic trifluoromethylthiolation of 1,2- and 1,3-sulfamidates with [Me4N]­SCF3 enabled the preparation of optically pure fluorinated derivatives of cysteine, homocysteine and β-methylated cysteine in 58–98% yield.

1. Reported Synthetic Routes toward TFM and TfmCys Derivatives.

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The incorporation of TFM and TfmCys into peptides has mainly been achieved in solution via standard peptide coupling or by late-stage S-trifluoromethylation of Cys-containing peptides. The latter was demonstrated by Togni, Seebach and co-workers using their hypervalent iodine­(III) trifluoromethylation reagent (Scheme ). The reaction yielded TfmCys-containing dipeptides in 55–92% yields with fairly good functional group tolerance. However, C2-trifluoro­methyl­ation of the tryptophan residue of Octreotide was observed as a side reaction. The authors also noted the CF3S group β-elimination from TfmCys in basic media, implying its inherent limitations relative to TFM in peptide chemistry applications.

2. Direct S-Trifluoromethylation of Cys Residues in Selected Peptides Using the Togni Reagent .

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The Noël group later developed a visible-light photocatalytic method for S-trifluoromethylation of Cys and Cys-containing dipeptides using CF3I in both batch and in continuous flow. Following a single electron transfer event, the transient electrophilic trifluoromethyl radical reacts rapidly to form the S–CF3 bond, affording TfmCys derivatives in moderate to excellent yield while avoiding disulfide byproduct formation.

The incorporation of TFM and particularly TfmCys into peptides via solid-phase peptide synthesis (SPPS) has been scarcely reported until recently. ,− Our group has reported both solution-phase and solid-phase strategies for incorporating TfmCys and TFM to probe the hydrophobic effects of CF3S in peptides. , Boc/Bn-protected building blocks were prepared by radical trifluoromethylation in moderate yield (30–42%) and incorporated into tripeptides by iterative solution phase peptide coupling (Scheme ). N-Boc-protected TfmCys was also incorporated by standard Fmoc-SPPS in comparable yield (30%). Furthermore, late-stage S-trifluoromethylation of disulfide-linked tripeptides using the iodine­(III)–CF3 reagent was also demonstrated (Scheme ).

3. Solution-Phase or Solid-Phase Integration of TfmCys and TFM in Tripeptides and Late-Stage Trifluoromethylation of (Homo)­cystine-Containing Peptides Reported by Our Group .

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Furthermore, in our studies on fluorinated peptide-based hydrogels, we evaluated the importance of aromaticity versus hydrophobicity by introducing TFM, among other fluorinated amino acids (FAAs), in a hexapeptide hydrogel sequence. Fmoc-TFM was prepared on gram-scale in 34% overall yield and excellent purity and subsequently used in standard SPPS (Scheme A). Replacement of a phenylalanine residue in the reference peptide hydrogel (P1) with TFM at the C-terminus (P19) afforded a hydrogel peptide with similar CD profile to P1 but with increased storage (G′) relative to the elastic properties of the material and loss moduli (G″) describing the viscous portion of the material. Although P19 formed more polymorphic fibers, it exhibited good in vitro release properties and a comparable in vivo stability profile to the reference peptide P1.

4. (A) Gram-Scale Synthesis of TFM Building Block and Representative Hexapeptide Hydrogels; (B) Pepstatin A and Pepstatin A-Based CF3S-Peptides with Nanomolar Cathepsin D Inhibitory Activity .

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In 2024, Pytkowicz and co-workers reported the solid-phase synthesis and biological evaluation of trifluoromethylthiolated pepstatin A analogs as potent inhibitors of Cathepsin D (CD) (Scheme B). To improve the pharmacokinetic properties of pepstatin A, CF3S-Statin and (S)- or (R)-TFM residues were incorporated into the sequence. The ligand where the first valine was replaced by (R)-TFM displayed sub-nanomolar IC50 against CD. This increased potency is likely due to enhanced hydrophobic interactions with the lipophilic residues in the catalytic pocket, as supported by molecular docking study.

Trifluoromethylthiolated Aromatic Amino Acid Derivatives

In 2012, Billard and co-workers first demonstrated the reactivity of tryptophan, among other C3-substituted indoles, toward direct electrophilic trifluoromethylthiolation using their first-generation trifluoromethanesulfenamide reagent (Scheme A). While this method was effective for tryptamine and other C3-substituted indoles, tryptophan analogs showed low conversion (13–16%) and were not successfully isolated. Nevertheless, this work demonstrated the feasibility of direct CF3S-incorporation into activated aromatic AA residues and prompted further investigation. In 2023, our group made progress in the synthesis of CF3S-Trp derivatives, achieving quantitative conversion of tryptophan derivatives to C2-SCF3 analogs using a more effective para-chloro trifluoromethanesulfenamide reagent in combination with either trifluoro­methane­sulfonic acid or BF3·OEt2 as activators (Scheme B). Under optimized conditions, a series of C2-trifluoromethylthiolated tryptophan analogs with varied terminal protecting groups (PGs) were synthesized (>90%) together with CF3S-analogs of biologically important tryptamines (66–92%). The reaction scope was extended to tyrosine and DOPA derivatives, featuring less-activated phenolic or catechol moieties (Scheme C). In these cases, a slightly larger reagent excess was required to achieve quantitative conversion, affording products in moderate to high yield (68–97%). For DOPA or dopamine derivatives, the additional hydroxyl group’s directing effect changed the regioselectivity of CF3S-incorporation.

5. (A) Direct Electrophilic Trifluoromethylthiolation of Tryptophan Derivatives Using the First-Generation Trifluoromethanesulfenamide Reagent; Scope of Our Electrophilic Trifluoromethylthiolation Method for (B) Tryptophan and (C) Tyrosine/DOPA Analogs .

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Recently, Sutherland and co-workers developed a Lewis acid/base dual catalytic system using N-trifluoromethylthiosaccharin, enabling trifluoromethylthiolation of less-activated arenes (Scheme A). This reaction is effective for a wide range of complex and biologically significant substrates including N-Cbz-protected tyrosine derivative, which was isolated in 70% yield as a single CF3S-regioisomer. Based on our literature review, no trifluoromethylthiolated histidine analogs have been reported so far while only one phenylalanine derivative has been synthesized from the corresponding aryl iodide. The reaction proceeds via photoredox-mediated trifluoromethylthiolation using a bench-stable Ni­(II) salt and an iridium photocatalyst in combination with AgSCF3 affording the CF3S-Phe analog in 62% yield (Scheme B).

6. Other Strategies for the Synthesis of CF3S-Functionalized Aromatic Amino Acids: (A) Lewis Acid/Base Dual Catalysis; (B) Ni-Catalyzed Photoredox-Mediated Trifluoromethylthiolation .

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Using our protocol, enantiopure SCF3-containing N-Fmoc-protected tryptophan, tyrosine and dimethyltyrosine (Dmt) building blocks were synthesized on gram-scale in good to excellent yield (66–93%; see Scheme ). These aromatic SCF3-containing amino acids and trifluoromethionine (TFM) were used in standard Fmoc-SPPS to prepare a series of trifluoromethylthiolated opioid peptides analog to endomorphin-1 (EM1) (Scheme ). , In vitro μ-opioid receptor (μOR) binding assays demonstrated that these fluorinated analogs retained binding affinity and potency accompanied by an increased hydrophobicity. The (CF3S)­Dmt-containing analog showed the most favorable profile (K i = 1.4 nM, EC50 = 0.9 nM) and revealed a significant increase in half-life plasma stability studies (72-fold relative to EM1).

7. Synthesized Endomorphin-1 (EM1) Analogs Incorporating (CF3S)­Tyr, (CF3S)­Dmt, (CF3S)­Trp and TFM ,

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Complementary to SPPS, we developed late-stage C2-trifluoromethylthiolation of tryptophan residues in short peptides in moderate to high yield (66–80%, Scheme ), demonstrating excellent Trp vs Tyr selectivity. The late-stage reaction was also successfully applied to EM1 consisting of three aromatic AAs.

8. Late-Stage C2-Trifluoromethylthiolation of Trp Residues in Short Peptides and Endomorphin-1 .

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Recently, Li and co-workers reported tryptophan diversification in native peptides via late-stage catalyst-free electrophilic C2-sulfenylation (Scheme ). The reaction employs quinoline-based thiosulfonates (QSO2SRF) as electrophilic SRF sources (sulfur-associated fluoroalkyl groups) under trifluoroacetic acid (TFA) conditions and proceeds with high chemoselectivity, showing compatibility with other canonical AAs, disulfide linkages, and O-glycosylated peptides. The use of TFA as the solvent was crucial as it enhances the electrophilicity of the SR F moiety via H-bonding interaction with the quinoline ring and has high peptide dissolving capability. An impressive library of model peptides and marketed peptide drugs was subjected to C2-trifluoromethyl­thiolation and isolated in exceptionally high yields relative to peptide post-modification protocols (35–93% after HPLC purification). In the case of the bioactive peptide melittin, the CF3S analog demonstrated increased stability in human serum (from 8 h to >24 h) while retaining anticancer activity comparable to that of native melittin.

9. Late-Stage Electrophilic C2-Sulfenylation of Trp Residues Using Quinoline-Based Thiosulfonates and Selected Examples from Protein Sequences and Peptides Drugs .

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Miscellaneous Trifluoromethylthio-Containing Amino Acids

Thiols have been reported to undergo electrophilic S-trifluoromethylthiolation with trifluoromethanesulfenamides, yielding S-SCF3 disulfide analogs. As an example, S-trifluoromethylthiolated cysteine derivative was isolated in 58% yield (Scheme A). Furthermore, Zhang and co-workers developed a hypervalent trifluoromethylthio-iodine­(III) reagent (TFTI) that enabled efficient S-trifluoromethyl­thiolation of thiols, including cysteine and cysteine-containing dipeptides, under mild HFIP activation (70–88%, Scheme A). Very recently Li and co-workers also reported the late-stage penicillamine-selective S-sulfenylation in native peptides via thiosulfonate chemistry.

10. Examples of Miscellaneous CF3S-AA Syntheses: (A) S-SCF3 Analogs of Cys; , (B) CF3S-Pro via Stereospecific Dehydroxytrifluoromethylthiolation; (C) α-SCF3-β2,2-AAs via Asymmetric Catalysis; , (D) CF3S-Leucine ,

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TFTI in combination with N-heterocyclic carbenes has also been used to form an intermediate CF3S-benzimidazolium salt, providing stereospecific dehydroxytrifluoromethylthiolation of alcohols. This method, compatible with various structurally complex alcohols, provided access to the optically pure (2S,4S)-4-SCF3 proline analog from commercially available 4-hydroxyproline in 76% yield (Scheme B). Two groups independently reported the synthesis of α-trifluoromethylthio-β2,2-amino acids by asymmetric trifluoromethylthiolation of α-substituted isoxazolidin-5-ones via chiral quarternary ammonium salt phase-transfer organocatalysis, followed by reductive N–O bond cleavage of the enantioenriched masked α-SCF3-β2,2-AAs (Scheme C). , Waser, Cahard and co-workers further incorporated synthesized CF3S-β-AA into a model dipeptide and performed the CF3S post-oxidation to the corresponding sulfone derivative. Additional examples of CF3S-AAs have been reported as isolated examples without further application in peptide chemistry. Tertiary CF3S-leucine analogs were obtained either by AgSCF3/Na2S2O8-mediated oxidative trifluoromethylthiolation of inactivated aliphatic C–H bonds or by photoredox-mediated HAT using the phthalimide N-SCF3 reagent (Scheme D). In addition, a CF3S-substituted biaryl phenylalanine derivative was synthesized via Suzuki–Miyaura cross-coupling using the CF3S-arylboronic ester as part of a broader mechanistic investigation.

Hydrophobic Contribution Scale of Trifluoromethylthio-Containing Amino Acids in Peptides

In our research on the rational design of peptides featuring fluorinated amino acids, we investigated their hydrophobic contribution compared to canonical amino acids. For this purpose, we established a comparative and accurate scale of intrinsic hydrophobicity of amino acids. Chromatographic hydrophobicity indexes (HI) were determined for model tripeptides containing varied residues at the internal position, enabling assessment of the local hydrophobicity contribution of each amino acid within a peptide (Figure ). ,

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Hydrophobicity index (HI) scale of model tripeptides TFA·H2N-Ala-AA-Leu-OH comparing values for canonical and trifluoromethylthiolated amino acids at pH 7. ,

Trifluoromethylthio-containing AAs showed significantly increased local hydrophobicity relative to their proteinogenic counterparts, with the magnitude depending on the nature of the respective side-chain. Trifluoromethylcysteine and trifluoro­methionine are significantly more hydrophobic than methionine or other aliphatic AAs. Aromatic CF3S analogs of tyrosine and tryptophan were the most hydrophobic AAs reported to date. Beyond hydrophobicity, side-chain functional group acidity and hydrogen bonding propensity are important for peptide–protein recognition and peptide folding. We observed that trifluoromethylthiolation of the Tyr residue increased the acidity of the phenolic hydroxyl ∼50-fold (pK a(H2O) = 8.1). This pK a value is comparable to that reported for ortho-trifluoromethylated phenols.

3. CF3S Motif: A Sensitive Probe for Chemical Biology

CF3S as a Label in 19F NMR Spectroscopy

The CF3S group, containing three magnetically equivalent fluorine atoms in an isolated spin system, can serve as a 19F NMR spectroscopy sensor for probing macromolecular structures and dynamics, as well as for monitoring RNA or protein binding events and ligand interactions at micromolar concentrations. However, its distinct stereoelectronic properties may perturb native structure and function, which should be considered when using it as a 19F NMR probe.

In 2012, Micura and co-workers reported the first trifluoromethylthio-labeled RNA, achieved by solid-phase incorporation of the 2′-SCF3 uridine unit (Scheme A). The ribose 2′-deoxy-2′-trifluoromethylthio building block was prepared in high yield on a multi-gram scale via S-trifluoromethylation using the Togni reagent. 2-SCF3 uridine exhibited high stability when subjected to coupling, deprotection, and oxidative conditions of standard solid-phase RNA synthesis. While the label did not alter the secondary structure of single-stranded regions, it disrupted planar base-pairing and thermodynamically destabilized RNA duplexes. This effect was attributed to the modified nucleoside’s preference for the C2′-endo ribose conformation, rather than the native C3′-endo conformation characteristic of A-form RNA duplexes, leading to steric interference and weakened stacking and H-bonding interactions. Compared to 2′-SCH3 uridine modifications, which only slightly destabilize duplexes, the diminished electronegativity of sulfur in SCF3 plays a significant role. In a subsequent study, the authors expanded the repertoire of 2′-SCF3 nucleosides with adenosine and guanosine phosphoramidite analogs suitable for solid-phase RNA synthesis.

11. (A) Synthesis of 2′-SCF3-Uridine-Labeled RNA; (B) Synthesis of 4′-SCF3-Thymidine Phosphoramidite via Electrophilic Trifluoromethylthiolation .

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Plavec, Zhou and co-workers reported the synthesis of 4′-SCF3-thymidine phosphoramidite and its incorporation into DNA using standard solid-phase protocols (Scheme B). Protected 5′-aldehyde-thymidine underwent stereoselective electrophilic trifluoromethylthiolation with an N-SCF3 phthalimide reagent, followed by NaBH4 reduction to yield 4′-SCF3-deoxythymidine, which was converted to the corresponding phosphoramidite for automated DNA synthesis. In contrast to the structural perturbation caused by the 2′-SCF3 modification in RNA, structural analysis showed that the 4′-SCF3 substitution only slightly constrained the deoxyribose conformation and was well accommodated in DNA duplexes. 19F NMR studies demonstrated that the 4′-SCF3 label enables detection of single-nucleotide polymorphisms, DNA topology, and DNA–protein interactions at sub-millimolar concentrations. The authors recently extended the synthetic strategy to prepare 4′-SCF3-uridine phosphoramidite and incorporated it into RNA strands via solid-phase synthesis. The 4′-SCF3 modification was well accommodated within the minor groove and did not induce significant distortion of the RNA duplex. A specific interaction between the 4′-SCF3 and 2′-OH of the 5′-adjacent ribonucleotide was identified to be a key feature for RNA secondary structure elucidation with excellent sensitivity, both in vitro and in living cells.

In proteins, trifluoromethionine (TFM) has primarily been used for 19F NMR studies. In 1997, Honek and co-workers reported the first TFM bioincorporation into bacteriophage λ lysozyme, which contains three Met residues in its wild-type sequence. The native aminoacyl-tRNA synthetase recognized l-TFM, enabling overexpression of LaL with high (70%) or partial (31%) methionine substitution. The labeled lysozyme retained wild-type folding and catalytic activity, and exhibited increased hydrophobicity. In a later study, Holzberger et al. reported 82% l-TFM substitution of 14 Met residues in DNA polymerase I (KlenTaq, 63 kDa). Despite most Met sites being located in the hydrophobic core of the polymerase, the TFM-modified enzyme retained high activity and substrate selectivity, albeit with moderately reduced stability. The CF3S label was used to investigate the dynamics of substrate recognition and DNA synthesis. Internalized TFM residues exhibited broader 19F resonances than flexible surface-exposed sites, but conformational changes of the enzyme during nucleotide incorporation could be clearly detected. TFM labeling has also been applied to investigate larger assemblies and synthetic peptides. In 2017, Davis and co-workers used TFM to monitor the disassembly of virus-like particles (VLPs) by 19F NMR. Analysis of CF3S resonances allowed assessment of VLPs assembly state and degradation level when exposed to denaturants or reductants, which guided particle design for controlled VLP-carried cargo release in cells. In peptides, site-selective incorporation of TFM into the amyloidogenic Aβ1–40 peptide via Fmoc-SPPS enabled real-time monitoring of oligomer formation and irreversible aggregation by 19F NMR. Other TFM derivatives, particularly difluoromethionine (DFM) and 2,2,2-trifluoroethanethiol cysteine (TFET-Cys), have also been used as 19F NMR probes. , As the repertoire of SPPS-compatible CF3S-AAs continues to expand, new opportunities are emerging for 19F-labeled peptides to investigate structural transitions and dynamics.

[18F]­SCF3 Construction for Applications in 18F-Based PET Imaging

In positron emission tomography (PET) imaging, incorporation of the 18F isotope into small molecules or peptides is one of the key strategies for the preparation of radiotracers. Several methods for synthesizing 18F-labeled trifluoromethyl sulfides have emerged in the past decade and have been partially reviewed elsewhere. , In 2015, Gouverneur and co-workers reported the first construction of [18F]­SCF3 moiety via Ag­(I)-promoted halogen exchange between C­(sp2)–SCF2Br precursors and [18F]­KF/K222, affording unprecedented [18F]­CF3S-functionalized compounds in 12–92% radiochemical yield (RCY) (Scheme A).

12. Seminal Synthetic Methods for the Preparation of [18F]­CF3S-Containing Compounds.

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Concurrently, Zheng and co-workers developed a transition-metal-free exogenous fluoride-mediated method for [18F]­CF3S-radiolabeling of (hetero)­benzyl and alkyl halides based on difluorocarbene chemistry (Scheme B). In situ decarboxylation of difluoromethylene phosphobetaine (PDFA) generates difluorocarbene, which is readily trapped by radiolabeled fluoride and further converted to the [18F]­CF3S– anion in the presence of elemental sulfur. This anion undergoes nucleophilic substitution at benzyl or alkyl position in moderate to high radiochemical conversion (RCC). The method tolerates diverse functional groups, and is compatible with 18F-labeling due to its sub-1 min reaction time. An extension of this approach employed Cu­(I)-catalyzed [18F]­trifluoro­methyl­thiol­ation of α-bromo carbonyl derivatives using in situ-generated 18F-labeled tetraethylammonium fluoride (TEAF), affording α-[18F]­CF3S carbonyl derivatives in moderate RCC (Scheme C). Subsequent advances of these seminal methods include the use of radiolabeled [18F]­fluoroform for rapid conversion of diaryl disulfides to [18F]­CF3S-substituted arenes in moderate radiochemical yield (45–74% RCY, >95% purity). Gouverneur, Shen and co-workers further expanded the precursor scope to BrCF2S-substituted arenes by utilizing corresponding (hetero)­aryl boronic pinacol esters, which underwent Ag-mediated halogen exchange 18F-labeling to yield novel [18F]­CF3S (hetero)­arenes. This strategy also enabled preparation of [18F]-Umemoto reagent, an electrophilic [18F]­CF3 donor for site-selective radiolabeling of cysteine residues in peptides (Scheme A). Optimized reaction conditions provided high chemoselectivity for Cys residues in the presence of most proteinogenic AAs (except Trp and His), affording biologically relevant [18F]­CF3S-labeled peptide analogs such as glutathione, a prostate-specific membrane antigen (PSMA) radioligand, a β-amyloid fragment, and cyclic RGD in high RCY (10–33%). In vivo study of the RGD conjugate confirmed the expected biodistribution and stability with no 18F-fluoride elimination detected. l- and d-[18F]­TfmCys were also evaluated as PET tracers for glioma imaging.

13. (A) 18F-Labeled TfmCys-Containing Biologically Relevant Peptides; (B) Synthesis of [18F]­SCF3-Labeled Arenes from Corresponding Thiophenols Using the [18F]-Labeled Ruppert–Prakash Reagent; (C) Synthesis of 18F-Labeled Trifluoromethyl Sulfides Using [18F]­Trifluoroiodomethane .

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More recently, 18F-labeled CF3S­(O) n (n = 0, 1, 2) substituted arenes were prepared from thiophenols or aryl sulfonyl fluorides using the [18F]-labeled Ruppert–Prakash reagent (Scheme B). A one-pot process proceeding via sulfenyl chloride intermediate gave [18F]­CF3S products in 31–91% RCC with high functional group and heterocyclic substrate tolerance. Related 18F-labeled sulfoxides and sulfones, including PET tracers such as clofibrate and celecoxib were also prepared on a larger scale. Moreover, a recent study reported a photoredox-mediated synthesis of 18F-labeled trifluoromethyl sulfides using [18F]­trifluoroiodomethane, achieving moderate to high RCC (Scheme C). The development of [18F]­CF3I represents an important milestone in radical, photoredox-mediated [18F]­trifluoromethylation chemistry and offers new opportunities in 18F-labeling.

4. Conclusion and Future Perspectives

This Synopsis highlights the unique effects of CF3S-substitution, recent methodological advances enabling its incorporation into biomolecules, and its potential as a 19F NMR and 18F PET label. Among the steadily expanding repertoire of synthetic methods for the CF3S-group introduction, recent studies on trifluoromethylthiolation of aromatic AAs and its resulting impact on peptide properties are particularly noteworthy. Site-selective incorporation of the trifluoromethylthio group into biomolecules has been shown to address inherent pharmacokinetic limitations of peptides by increasing their metabolic stability and bioavailability through enhanced hydrophobicity. Interestingly, the stereo-electronic features of the CF3S group do not present major drawbacks regarding the selectivity of the interactions of the CF3S-analogs with their biological targets. Robust preparation of diverse enantiopure CF3S-AA building blocks on a multi-gram scale and their efficient implementation in SPPS now enable specific application in yet unexplored systems such as membrane-active or macrocyclic peptides, among others. For the future perspectives, development of biocompatible and late-stage site-specific modification method for incorporation of the CF3S group into complex biomolecules such as native peptides and proteins should also be considered to avoid de novo synthesis. The physicochemical and biological activity studies conducted by our group and others contribute to a more detailed understanding of the impact of sulfur-associated fluorinated motifs on biomolecule properties. These developments provide a basis for further evaluation of emergent chalcogen-associated fluorinated groups such as (a) CF3S­(O) n (n = 1, 2); (b) CHF2S, CH2FS, CF3CF2S; (c) CF3S–N; (d) CF3Se­(O) n (n = 0, 1, 2) and sulfur–selenium-associated motifs in the rational design of small molecules, peptides, proteins, and nucleic acids with tunable stability, bioactivity, and imaging capabilities.

Acknowledgments

The authors gratefully acknowledge the financial support from the Slovenian Research Agency (ARIS) (P1-0134 Research Core Funding Grant and Young Researcher Grant to J.G.). We thank the Eutopia and CY Initiative of Excellence (grant Investissements d’Avenir, ANR-16-IDEX-0008).

Biographies

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Jure Gregorc is a Research Fellow at the Faculty of Chemistry and Chemical Technology, University of Ljubljana, Slovenia. He earned his Ph.D. in organic chemistry in 2025 through a cotutelle program between the University of Ljubljana and CY Cergy Paris Université (BioCIS, CNRS, France). His research interests include organofluorine and peptide chemistry, as well as method development in accordance with the principles of green chemistry.

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Nathalie Lensen received her Ph.D. from the University P. and M. Curie under the supervision of D. R. A. Alexakis. She then held a post-doctoral position at UCLA (Prof. M. E. Jung). After two years as an associate professor at University Paris VII, she is currently an associate professor at CYU Cergy-Paris University. Her research focuses on the synthesis of fluorinated peptides and their biological applications.

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Grégory Chaume is a Full Professor of Organic Chemistry at the BioCIS laboratory (UMR 8076), CY Cergy Paris Université (France). His research interests focus on the synthesis of fluorinated biomolecules, including amino acids, peptides, and peptidomimetics, as well as their biophysical and biological evaluation, with applications in areas such as nociception, antimicrobial peptides, collagen model peptides, PPIase inhibition, and peptide-based hydrogelators.

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Jernej Iskra is a Professor of Organic Chemistry at the Faculty of Chemistry and Chemical Technology, University of Ljubljana (Slovenia). He received his B.Sc. degree in Chemistry in 1993 and his Ph.D. in Organic Chemistry in 1998 from the same institution. He was a Marie Curie Individual Fellow at BioCIS (CNRS/Université Paris XI) from 2000 to 2002 and was subsequently affiliated with the Jožef Stefan Institute. He returned to the University of Ljubljana, where he was promoted to Full Professor in 2022. His research interests focus on fluorine chemistry and green chemistry, including the design of functional molecules and biomass valorization.

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Thierry Brigaud is a Professor at Cergy Paris Université (France) since 2002 after a Ph.D. obtained in Lyon, a postdoc in SBU (Prof Iwao Ojima) and 10 years as an associate professor in Reims (France). His current research interests focus on the synthesis of fluorinated biomolecules (amino acids, peptides, pseudopeptides, etc.) for medicinal chemistry and chemical biology.

The data underlying this study are available in the published article.

The authors declare no competing financial interest.

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Data Availability Statement

The data underlying this study are available in the published article.

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