SuFEx Click Chemistry in Drug Discovery and Chemical Biology

Sulfur(VI) fluoride exchange (SuFEx) click chemistry has emerged as a transformative platform for the modular assembly of complex molecules in both drug discovery and chemical biology. At its core, SuFEx exploits the unique reactivity of the S–F bond in sulfonyl fluorides and related connectors, which combine exceptional stability under physiological conditions with the capacity for rapid, chemoselective reaction with a range of nucleophiles. Since its introduction, SuFEx has enabled the rapid construction of diverse linker libraries, the late‐stage functionalisation of bioactive scaffolds and the design of covalent warheads for targeted protein modulation. Synthetic advances—from gas‐phase SO2F2 and SOF4 hubs to radical and photoredox‐mediated protocols—have broadened the repertoire of available connectors, while metal‐mediated and organomediated routes have improved access to aryl, aliphatic and heterocyclic sulfonyl fluorides. In chemical biology, these reagents have underpinned the development of activity‐based probes, bioconjugation strategies and covalent inhibitors that selectively label serine, threonine, lysine and cysteine residues. Together, these innovations have profound implications for fragment‐based screening, in situ target validation and the generation of precision therapeutics.

Research from Nature Portfolio

Recent studies have advanced the synthesis and application of sulfonyl fluoride reagents under exceptionally mild and operationally simple conditions. An organomediated electrochemical protocol enables the transformation of aryl triflates into aryl sulfonyl fluorides via selective C–O bond cleavage, offering a transition‐metal‐free approach with broad functional‐group tolerance and direct applicability to bioactive molecules. Complementing this, photoredox‐catalysed radical fluorosulfonylation using bench‐stable benzoimidazolium salts (FABI reagents) has unlocked the direct difunctionalisation of olefins, forging β-alkoxyl sulfonyl fluorides in high yield and expanding late‐stage diversification pathways. In addition, an air-stable, crystalline imidazolium fluorosulfonate reagent has been introduced for stereoselective radical fluorosulfonylation of unsaturated hydrocarbons, delivering alkenyl and alkyl sulfonyl fluorides with precise control over geometry and opening new avenues for functional SO₂F motifs in chemical biology.

SuFEx Click Chemistry in Drug Discovery and Chemical Biology publication trend

The graph below shows the total number of articles in sufex click chemistry in drug discovery and chemical biology across all publications each year (not limited to Nature Index journals).

Technical terms

SuFEx click chemistry: A class of click reactions that engage a sulfur(VI)–fluoride bond with nucleophiles under mild conditions to form robust S–O, S–N or S–C linkages.

Sulfonyl fluoride: An organosulfur functional group (R–SO₂F) combining aqueous stability with electrophilicity, widely used as a covalent warhead and bioconjugation handle.

Photoredox catalysis: A light‐driven approach that employs photoactive catalysts to mediate single‐electron transfer events, generating reactive radical intermediates.

Radical fluorosulfonylation: A method in which a sulfonyl fluoride radical adds across unsaturated bonds, enabling rapid installation of SO₂F motifs onto diverse substrates.

References

1. Organomediated electrochemical fluorosulfonylation of aryl triflates via selective C–O bond cleavage. Nature Communications (2023).
2. Photoredox catalytic radical fluorosulfonylation of olefins enabled by a bench-stable redox-active fluorosulfonyl radical precursor. Nature Communications (2022).
3. A practical fluorosulfonylating platform via photocatalytic imidazolium-based SO2F radical reagent. Nature Communications (2022).
4. Advances in the construction of diverse SuFEx linkers. National Science Review (2023).
5. Photoredox-catalyzed aminofluorosulfonylation of unactivated olefins. Chemical Science (2021).
6. Redox-Neutral Organometallic Elementary Steps at Bismuth: Catalytic Synthesis of Aryl Sulfonyl Fluorides. Journal of the American Chemical Society (2021).
7. Sulfonyl fluorides as privileged warheads in chemical biology. Chemical Science (2015).