Enabling Modular Click Chemistry Library through Sequential Ligations of Carboxylic Acids and Amines.

High-throughput synthesis and screening of chemical libraries play pivotal roles in drug discovery. Click chemistry has emerged as a powerful strategy for constructing highly modular chemical libraries. However, the development of new click reactions and unlocking new clickable building blocks remain exceedingly challenging. Herein, we describe a double-click strategy that enables the sequential ligations of widely available carboxylic acids and amines with fluorosulfuryl isocyanate (FSO2NCO) via a modular amidation/SuFEx (sulfur-fluoride exchange) process. This method provides facile access to chemical libraries of N-fluorosulfonyl amides (RCONHSO2F) and N-acylsulfamides (RCONHSO2NR'R'') in near-quantitative yields under simple and practical conditions. The robustness and efficiency of this double click strategy is showcased by the facile construction of chemical libraries in 96-well microtiter plates from a large number of carboxylic acids and amines. Preliminary biological activity screening reveals that some compounds exhibit high antimicrobial activities against Gram-positive bacterium S. aureus and drug-resistant MRSA (MIC up to 6.25 µg ⋅ mL-1). These results provide compelling evidence for the potential application of modular click chemistry library as an enabling technology in high-throughput medicinal chemistry.

Oxygen-Demanding Photocontrolled RAFT Polymerization Under Ambient Conditions.

A photocontrolled reversible addition-fragmentation chain transfer (RAFT) process is developed by initiating polymerization through a 1,3-diaminopropane-triethylborane (DAPTB)-diphenyl iodonium salt (Ph2 I+ ) complex (DAPTB/Ph2 I+ ) under ambient temperature and atmospheric conditions. Upon demand, this air-stable DAPTB/Ph2 I+ complex is photolyzed to liberate a reactive triethylborane that consumes atmospheric oxygen and generates ethyl radicals, which initiate and mediate RAFT polymerization. Controlled RAFT polymerization is thus achieved without any prior deoxygenation using a novel RAFT chain transfer agent, BP-FSBC, which contains both benzophenone and sulfonyl fluoride moieties. Furthermore, the kinetics of polymerization reveal that the reaction process is rapid, and well-defined polymers are produced by a 61% conversion of 2-hydroxyethyl acrylate (HEA) within 7 min and 77% conversion of N,N-dimethylacrylamide (DMA) within 10.5 min. The temporal and spatial control of this photopolymerization is also demonstrated by an "on/off" switch of UV irradiation and a painting-on-a-surface approach, respectively. In addition, active chain ends are demonstrated by preparing block copolymers by chain extension and click sulfur(VI)-fluoride exchange postreaction using RAFT-derived macrochain transfer agents.

Configurationally Chiral SuFEx-Based Polymers.

Novel methods to make synthetic chiral polymers are highly desirable given their potential in a rapidly increasing number of bio-inspired applications. The enantiospecific sulfur-fluorine exchange (SuFEx) reaction of chiral di-sulfonimidoyl fluorides (di-SFs) with diphenols, was used to produce high-molecular-weight chiral polymers with configurational backbone chirality. The resulting new class of polymers, polysulfonimidates, can be efficiently produced via this step-growth mechanism for a wide range of di-SFs and diphenols, yielding MnPS up to 283 kDa with a typical dispersity D around 1.6. The optical activity of the resulting chiral polymers is largely due to the intrinsic asymmetry of the S atoms (configurational chirality). Finally, the enantiospecificity (ee>98 %) of the polymerization reaction was demonstrated by the degradation of a disulfide-containing polysulfonimidate. This novel route towards configurational main-chain chirality opens up new approaches towards tailor-made chiral polymers with precisely defined properties.

Accelerated and Concerted Aza-Michael Addition and SuFEx Reaction in Microdroplets in Unitary and High-Throughput Formats.

The sulfur fluoride exchange (SuFEx) reaction is significant in drug discovery, materials science, and chemical biology. Conventionally, it involves installation of SO2 F followed by fluoride exchange by a catalyst. We report catalyst-free Aza-Michael addition to install SO2 F and then SuFEx reaction with amines, both occurring in concert, in microdroplets under ambient conditions. The microdroplet reaction is accelerated by a factor of ∼104 relative to the corresponding bulk reaction. We suggest that the superacidic microdroplet surface assists SuFEx reaction by protonating fluorine to create a good leaving group. The reaction scope was established by performing individual reactions in microdroplets of 18 amines in four solvents and confirmed using high-throughput desorption electrospray ionization experiments. The study demonstrates the value of microdroplet-assisted accelerated reactions in combination with high-throughput experimentation for characterization of reaction scope.

A Broad-Spectrum Catalytic Amidation of Sulfonyl Fluorides and Fluorosulfates*.

A broad-spectrum, catalytic method has been developed for the synthesis of sulfonamides and sulfamates. With the activation by the combination of a catalytic amount of 1-hydroxybenzotriazole (HOBt) and silicon additives, amidations of sulfonyl fluorides and fluorosulfates proceeded smoothly and excellent yields were generally obtained (87-99 %). Noticeably, this protocol is particularly efficient for sterically hindered substrates. Catalyst loading is generally low and only 0.02 mol % of catalyst is required for the multidecagram-scale synthesis of an amantadine derivative. In addition, the potential of this method in medicinal chemistry has been demonstrated by the synthesis of the marketed drug Fedratinib via a key intermediate sulfonyl fluoride 13. Since a large number of amines are commercially available, this route provides a facile entry to access Fedratinib analogues for biological screening.

Fluorosulfuryl Isocyanate Enabled SuFEx Ligation of Alcohols and Amines.

Fluorosulfuryl isocyanate (FSI, FSO2 NCO) is established as a reliable bis-electrophilic linker for stepwise attachment of an alcohol bearing module to an amine bearing module and thence a new module RO-C(=O)-NH-SO2 -NR'R'' is created. FSI's isocyanate motif fuses directly and quickly with alcohols and phenols, affording fluorosulfuryl carbamates in nearly quantitative yield. A new reagent and process to deliver the FSI-derived fluorosulfuryl carbamate fragment to amines are also developed. The resulting SVI -F motifs from step-1 are remarkably stable, given the great structural complexities in diverse products. In the step-2 reaction with amines, the best yield of the S-N linked products arise with water alone. This "on water" interfacial reactivity phenomenon is crucial, revealing the latent reactivity of SVI -F probe for potential covalent capture of proteins in vivo which is important in today's drug discovery. The scope of the SuFEx chemistry is largely expanded thereby and the facile entry to these phosphate-like connections should prove useful to click chemistry across diverse fields.

Protein Glycosylation through Sulfur Fluoride Exchange (SuFEx) Chemistry: The Key Role of a Fluorosulfate Thiolactoside.

Protein glycosylation is the most complex post-translational modification process. More than 50 % of human cells proteins are glycosylated, whereas bacteria such as E. coli do not have this modification machinery. Indeed, the carbohydrate residues in natural proteins affect their folding, immunogenicity, and stability toward proteases, besides controlling biological properties and activities. It is therefore important to introduce such structural modification in bioengineered proteins lacking the presence of carbohydrate residues. This is not trivial as it requires reagents and conditions compatible with the protein's stability and reactivity. This work reports on the introduction of lactose moieties in two natural proteins, namely ubiquitin (Ub) and l-asparaginase II (ANSII). The synthetic route employed is based on the sulfur(VI) fluoride exchange (SuFEx) coupling of a lactose tethered arylfluorosulfate (Lact-Ar-OSO2 F) with the ϵ-NH2 group of lysine residues of the proteins. This metal-free click SuFEx reaction relies on the properties of the fluorosulfate employed, which is easily prepared in multigram scale from available precursors and reacts chemoselectively with the ϵ-NH2 group of lysine residues under mild conditions. Thus, iterative couplings of Lact-Ar-OSO2 F to Ub and ANSII, afforded multiple glycosylations of these proteins so that up to three and four Lact-Ar-OSO2 groups were introduced in Ub and ANSII, respectively, via the formation of a sulfamoyl (OSO2 -NH) linkage.

Multidimensional SuFEx Click Chemistry: Sequential Sulfur(VI) Fluoride Exchange Connections of Diverse Modules Launched From An SOF4 Hub.

Sulfur(VI) fluoride exchange (SuFEx) is a new family of click chemistry based transformations that enable the synthesis of covalently linked modules via SVI hubs. Here we report thionyl tetrafluoride (SOF4 ) as the first multidimensional SuFEx connector. SOF4 sits between the commercially mass-produced gases SF6 and SO2 F2 , and like them, is readily synthesized on scale. Under SuFEx catalysis conditions, SOF4 reliably seeks out primary amino groups [R-NH2 ] and becomes permanently anchored via a tetrahedral iminosulfur(VI) link: R-N=(O=)S(F)2 . The pendant, prochiral difluoride groups R-N=(O=)SF2 , in turn, offer two further SuFExable handles, which can be sequentially exchanged to create 3-dimensional covalent departure vectors from the tetrahedral sulfur(VI) hub.

SuFEx-Based Polysulfonate Formation from Ethenesulfonyl Fluoride-Amine Adducts.

The SuFEx-based polycondensation between bisalkylsulfonyl fluorides (AA monomers) and bisphenol bis(t-butyldimethylsilyl) ethers (BB monomers) using [Ph3 P=N-PPh3 ]+ [HF2 ]- as the catalyst is described. The AA monomers were prepared via the highly reliable Michael addition of ethenesulfonyl fluoride and amines/anilines while the BB monomers were obtained from silylation of bisphenols by t-butyldimethylsilyl chloride. With these reactions, a remarkable diversity of monomeric building blocks was achieved by exploiting readily available amines, anilines, and bisphenols as starting materials. The SuFEx-based polysulfonate formation reaction exhibited excellent efficiency and functional group tolerance, producing polysulfonates with a variety of side chain functionalities in >99 % conversion within 10 min to 1 h. When bearing an orthogonal group on the side chain, the polysulfonates can be further functionalized via click-chemistry-based post-polymerization modification.

SuFEx-based synthesis of polysulfates.

High-molecular-weight polysulfates are readily formed from aromatic bis(silyl ethers) and bis(fluorosulfates) in the presence of a base catalyst. The reaction is fast and proceeds well under neat conditions or in solvents, such as dimethyl formamide or N-methylpyrrolidone, to provide the desired polymers in nearly quantitative yield. These polymers are more resistant to chemical degradation than their polycarbonate analogues and exhibit excellent mechanical, optical, and oxygen-barrier properties.

Discovery of Arylfluorosulfates as Novel Fungicidal Agents against Plant Pathogens.

A series of arylfluorosulfates were synthesized as fungicide candidates through a highly efficient sulfur fluoride exchange (SuFEx) reaction. A total of 32 arylfluorosulfate derivatives with simple structures have been synthesized, and most of them exhibited fungal activities in vitro against five agricultural pathogens (Rhizoctonia solani, Botrytis cinerea, Fusarium oxysporum, Pyricularia oryzae, and Phytophthora infestans). Among the target compounds, compound 31 exhibited great antifungal activity against Rhizoctonia solani (EC50 = 1.51 µg/mL), which was comparable to commercial fungicides carbendazim and thiabendazole (EC50 = 0.53 and 0.70 µg/mL, respectively); compounds 17 and 30 exhibited antifungal activities against Pyricularia oryzae (EC50 = 1.64 and 1.73 µg/mL, respectively) comparable to carbendazim (EC50 = 1.02 µg/mL). The in vitro antifungal effect of compound 31 was also evaluated on rice plants against Rhizoctonia solani. Significant preventive and curative efficacies were observed (89.2% and 91.8%, respectively, at 200 µg/mL), exceeding that of thiabendazole. Primary study on the mechanism of action indicated that compound 31 could suppress the sclerotia formation of Rhizoctonia solani even at a very low concentration (1.00 µg/mL), destroy the cell membrane and mitochondria, trigger the release of cellular contents, produce excessive reactive oxygen species (ROS), and suppress the activity of several related enzymes. This work could bring new insights into the development of arylfluorosulfates as novel fungicides.

A Mild Method for the Activation of Cation Exchange Membranes Used in Tubular PEM Electrolyzers.

Co-extrusion of both half-cells in tubular PEM water electrolyzers can lower the costs for hydrogen production, since the number of components is reduced and the production process is simplified. However, after co-extrusion of the inner half-cell and the ion exchange membrane, the membrane is in its fluoride sulfonyl form and must be hydrolyzed to achieve the proton conductive sulfonic acid to be ready for use. Common practice is the hydrolysis using concentrated alkaline solutions, which causes a corrosion of the laminated anode electrode. We developed a less corrosive method using triethylsilanol as reactant. Tubular membranes hydrolyzed with this new procedure were characterized and tested in an electrolyzer laboratory test setup.

PEG-functionalized aliphatic polycarbonate brushes with self-polishing dynamic antifouling properties.

Hydrophilic antifouling polymers provide excellent antifouling effects under usual short-term use conditions, but the long-term accumulation of contaminants causes them to lose their antifouling properties. To overcome this drawback, surface-initiated ring-opening graft polymerization (SI-ROP) was performed on the surface of the material by applying the cyclic carbide monomer 4'-(fluorosulfonyl)benzyl-5-methyl-2-oxo-1,3-dioxane-5-carboxylate (FMC), which contains a sulfonylfluoride group on the side chain, followed by a "sulfur(IV)-fluorine exchange" (SuFEx) post click modification reaction to link the hydrophilic polyethylene glycol (PEG) to the polyFMC (PFMC) brush, and a novel antifouling strategy for self-polishing dynamic antifouling surfaces was developed. The experimental results showed that the antifouling surface could effectively prevent the adsorption of proteins such as bovine serum albumin (BSA, ∼96.4%), fibrinogen (Fg, ∼87.8%) and lysozyme (Lyz ∼69.4%) as well as the adhesion of microorganisms such as the bacteria Staphylococcus aureus (S. aureus) (∼87.5%) and HeLa cells (∼67.2%). Moreover, the enzymatically self-polished surface still has excellent antifouling properties. Therefore, this modification method has potential applications in the field of biosensors and novel antifouling materials.

SuFEx modification of silk fibroin silicon aerogel and its adsorption behavior and antibacterial performance.

A silk fibroin silicon-based composite aerogel (SSA) has been modified via a SuFEx reaction for application in the adsorption of anionic pollutants and antimicrobials in water. The tyrosine fragment in the silk fibroin was modified by a high yielding SuFEx click reaction. A quaternary ammonium salt functionality was introduced into the silk fibroin protein and the modified silk fibroin protein was crosslinked with tetraethyl orthosilicate. The aerogel was then prepared by freeze-drying. The aerogel obtained has biocompatibility and biodegradability properties. Four types of dyes (Methyl orange, Rhodamine B, Methylene blue and Acid red) were applied as targets and the saturated adsorption amounts were calculated. The adsorption behavior of the dyes towards SSA was studied by fitting Langmuir and Freundlich adsorption models. A pseudo-first order kinetic model and a pseudo-second order kinetic model were used to study the kinetics of the adsorption process. After 6 cycles, the removal rate of methyl orange by SSA remained at 81.25%. The adsorption capacity and anti-interference ability of SSA on some other polluting anions such as PO43- and CrO42- were also measured and the efficiency adsorption reached up to 70.94% and 77.91%, respectively. The antibacterial effect of SSA was evaluated with Escherichia coli and Staphylococcus aureus as representative examples.

Synthesis of Novel Pesticidal N,N'-Disubstituted Sulfamide Derivatives Using Sulfur(VI) Fluorine Exchange Click Reaction.

Sulfur(VI) fluorine exchange click reaction was applied to the highly efficient synthesis of new N,N'-disubstituted sulfamide (R1NH-SO2-NHR2) derivatives as pesticide candidates. Bioassays were conducted to evaluate both insecticidal and fungicidal activities of the target compounds. Preliminary results showed that the target molecules exhibited good bioactivities. In particular, insecticidal activities of compounds D25 and D21 against Plutella xylostella (LC50 = 2.42 and 3.87 µg·mL-1) were superior or adequate to that of commercial insecticide indoxacarb (LC50 = 3.99 µg·mL-1). Moreover, some compounds could also exhibit satisfactory fungicidal activity toward plant pathogens Pyricularia grisea, Botrytis cinerea, and Thanatephorus cucumeris. This work could bring new insights into the application of heterocyclic N,N'-disubstituted sulfamides as novel pesticides.