SuFEx (Sulfur Fluoride Exchange) is a modular, next generation family of click reactions, geared towards the rapid and reliable assembly of functional molecules.

Polysulfates and polysulfonates possess exceptional mechanical properties making them potentially valuable engineering polymers. However, they have been little explored due to a lack of reliable synthetic access. Here we report bifluoride salts (Q+[FHF]−, where Q+ represents a wide range of cations) as powerful catalysts for the sulfur(VI) fluoride exchange (SuFEx) reaction between aryl silyl ethers and aryl fluorosulfates (or alkyl sulfonyl fluorides). The bifluoride salts are significantly more active in catalysing the SuFEx reaction compared to organosuperbases, therefore enabling much lower catalyst-loading (down to 0.05 mol%). Using this chemistry, we are able to prepare polysulfates and polysulfonates with high molecular weight, narrow polydispersity and excellent functional group tolerance. The process is practical with regard to the reduced cost of catalyst, polymer purification and by-product recycling. We have also observed that the process is not sensitive to scale-up, which is essential for its future translation from laboratory research to industrial applications.

Sulfur fluoride exchange (SuFEx) has emerged as the new generation of click chemistry. We report here a SuFEx-enabled, agnostic approach for the discovery and optimization of covalent inhibitors of human neutrophil elastase (hNE). Evaluation of our ever-growing collection of SuFExable compounds toward various biological assays unexpectedly revealed a selective and covalent hNE inhibitor: benzene-1,2-disulfonyl fluoride. Synthetic derivatization of the initial hit led to a more potent agent, 2-(fluorosulfonyl)phenyl fluorosulfate with IC50 0.24 μM and greater than 833-fold selectivity over the homologous neutrophil serine protease, cathepsin G. The optimized, yet simple benzenoid probe only modified active hNE and not its denatured form.

A Heck-Matsuda process for the synthesis of the otherwise difficult to access compounds, β-arylethenesulfonyl fluorides, is described. Ethenesulfonyl fluoride (i.e., vinylsulfonyl fluoride, or ESF) undergoes β-arylation with stable and readily prepared arenediazonium tetrafluoroborates in the presence of the catalyst palladium(II) acetate to afford the E-isomer sulfonyl analogues of cinnamoyl fluoride in 43–97% yield. The β-arylethenesulfonyl fluorides are found to be selectively addressable bis-electrophiles for sulfur(VI) fluoride exchange (SuFEx) click chemistry, in which either the alkenyl moiety or the sulfonyl fluoride group can be the exclusive site of nucleophilic attack under defined conditions, making these rather simple cores attractive for covalent drug discovery.

Optimization of small-molecule probes or drugs is a lengthy, challenging and resource-intensive process. Lack of automation and reliance on skilled medicinal chemists is cumbersome in both academic and industrial settings. Here, we demonstrate a high-throughput hit-to-lead process based on the biocompatible SuFEx click chemistry. A modest high-throughput screening hit against a bacterial cysteine protease SpeB was modified with a SuFExable iminosulfur oxydifluoride [RN=S(O)F2] motif, rapidly diversified into 460 analogs in overnight reactions, and the products directly screened to yield drug-like inhibitors with 300-fold higher potency. We showed that the improved molecule is drug-like and biologically active in a bacteria-host coculture. Since these reactions can be performed on a picomole scale to conserve reagents, we anticipate our methodology can accelerate the development of robust biological probes and drug candidates. The introduction of high-throughput screening (HTS) robotics, liquid handler systems, and assay miniaturization have revolutionized screening of bioactive molecules. Relatively inexpensive HTS processes are now routinely used in cell-based and in vitro assays against biomedically relevant targets. Nevertheless, compound optimization is typically necessary to improve target specificity, potency, and stability. Lead optimization relies heavily on medicinal chemists, and extensive time and labor costs remain significant hurdles for probe and drug development. Click chemistry has found broad applications in materials chemistry, chemical biology, and drug development since the concept was first introduced in 1999 1-2. The sulfur(VI) fluoride exchange (SuFEx) represents the most recent set of ideal click chemistry transformations 3. Specifically, aryl fluorosulfates (ArOSO2F) and iminosulfur oxydifluorides (RN=S(O)F2) are readily synthesized using two connective oxyfluoride gases, sulfuryl fluoride (SO2F2) and thionyl tetrafluoride (O=SF4), respectively 4. These two S VI −F motifs have been successfully used as connective linkers in polymer synthesis and for construction of various functional molecules 5-7. Sulfonyl fluoride (RSO2F) and aryl fluorosulfate moieties have been successfully introduced into bioactive molecules in chemical biology and drug discovery 8-11 , especially as covalently binding warheads 12. However, the potential of SuFEx to unite diverse modules using an O=SF4 hub has not been explored in medicinal chemistry. While the copper(I)catalyzed azide-alkyne cycloaddition (CuAAC) reaction has been used in proof-of-concept studies on lead Statistical analysis was performed using one-way ANOVA with Dunnett's multiple comparisons test, *≤ 0.05. Supporting Information Additional texts, figures, and tables are provided. AUTHOR INFORMATION # Authors contributed equally.