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Calcium Bistriflimide-Mediated Sulfur(VI)-Fluoride Exchange (SuFEx): Mechanistic Insights toward Instigating Catalysis.

ABSTRACT: We report a mechanistic investigation of calcium bistriflimide-mediated sulfur(VI)-fluoride exchange (SuFEx) between sulfonyl fluorides and amines. We determine the likely pre-activation resting state─a calcium bistriflimide complex with ligated amines─thus allowing for corroborated calculation of the SuFEx activation barrier at ∼21 kcal/mol, compared to 21.5 ± 0.14 kcal/mol derived via kinetics experiments. Transition state analysis revealed: (1) a two-point calcium-substrate contact that activates the sulfur(VI) center and stabilizes the leaving fluoride and (2) a 1,4-diazabicyclo[2.2.2]octane additive that provides Brønsted-base activation of the nucleophilic amine. Stable Ca-F complexes upon sulfonamide formation are likely contributors to inhibited catalytic turnover, and a proof-of-principle redesign provided evidence that sulfonamide formation is feasible with 10 mol % calcium bistriflimide.

SUBMITTER: Han B

PROVIDER: S-EPMC9241145 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Sulfur(VI) Fluoride Exchange (SuFEx)-Enabled High-Throughput Medicinal Chemistry.

Project description:Optimization of small-molecule probes or drugs is a synthetically 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 sulfur(VI) fluoride exchange (SuFEx) click chemistry. A high-throughput screening hit benzyl (cyanomethyl)carbamate (Ki = 8 ?M) 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 were directly screened to yield drug-like inhibitors with 480-fold higher potency (Ki = 18 nM). We showed that the improved molecule is active in a bacteria-host coculture. Since this SuFEx linkage reaction succeeds on picomole scale for direct screening, we anticipate our methodology can accelerate the development of robust biological probes and drug candidates.

| S-EPMC7751259 | biostudies-literature

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

Project description: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.

| S-EPMC5434761 | biostudies-literature

Sulfur(VI) Fluoride Exchange (SuFEx)-Mediated Synthesis of the Chitosan-PEG Conjugate and Its Supramolecular Hydrogels for Protein Delivery.

Project description:Supramolecular hydrogels are considered promising drug carriers in the tissue engineering field due to their versatile nature. Chitosan hydrogels without chemical cross-linkers have low cytotoxicity and good delivery capacity; however, they have lower mechanical properties for injectable hydrogel usage. In this study, we developed novel chitosan derivatives via click chemistry for fabricating supramolecular hydrogels with higher mechanical strength under mild conditions. The chitosan derivative was successfully synthesized by a sulfur fluoride exchange reaction, and the synthesized chitosan-mPEG/Pluronic-F127 (CS-mPEG/F127) interacted with α-cyclodextrin (α-CD) to form a supramolecular hydrogel via a host-guest reaction. The gelation dynamics, hydrogel properties, and bovine serum albumin (BSA) release could be modulated by the concentration ratio of chitosan-mPEG and F127. This supramolecular hydrogel is a promising protein releasing carrier candidate for long term regeneration therapy.

| S-EPMC7912644 | biostudies-literature

Modular Synthesis of Alkenyl Sulfamates and β-Ketosulfonamides via Sulfur(VI) Fluoride Exchange (SuFEx) Click Chemistry and Photomediated 1,3-Rearrangement.

Project description:Herein, we report a synthesis of medicinally relevant β-ketosulfonamides via a photomediated 1,3-rearrangement of alkenyl sulfamates. This protocol tolerates a wide array of sensitive functional groups including alkenes, alkynes, and nitrogen-based heterocycles. Additionally, this work provides a general approach toward alkenyl sulfamates via a two-step Sulfur(VI) Fluoride Exchange (SuFEx) sequence capitalizing on SO2F2 as a linchpin to efficiently couple readily available ketones and amines without a large excess of either partner.

| S-EPMC8384055 | biostudies-literature

A General Approach to O-Sulfation by a Sulfur(VI) Fluoride Exchange Reaction.

Project description:O-sulfation is an important chemical code widely existing in bioactive molecules, but the scalable and facile synthesis of complex bioactive molecules carrying O-sulfates remains challenging. Reported here is a general approach to O-sulfation by the sulfur(VI) fluoride exchange (SuFEx) reaction between aryl fluorosulfates and silylated hydroxy groups. Efficient sulfate diester formation was achieved through systematic optimization of the electronic properties of aryl fluorosulfates. The versatility of this O-sulfation strategy was demonstrated in the scalable syntheses of a variety of complex molecules carrying sulfate diesters at various positions, including monosaccharides, disaccharides, an amino acid, and a steroid. Selective hydrolytic and hydrogenolytic removal of the aryl masking groups from sulfate diesters yielded the corresponding O-sulfate products in excellent yields. This strategy provides a powerful tool for the synthesis of O-sulfate bioactive compounds.

| S-EPMC7794093 | biostudies-literature

Using sulfuramidimidoyl fluorides that undergo sulfur(VI) fluoride exchange for inverse drug discovery.

Project description:Drug candidates that form covalent linkages with their target proteins have been underexplored compared with the conventional counterparts that modulate biological function by reversibly binding to proteins, in part due to concerns about off-target reactivity. However, toxicity linked to off-target reactivity can be minimized by using latent electrophiles that only become activated towards covalent bond formation on binding a specific protein. Here we study sulfuramidimidoyl fluorides, a class of weak electrophiles that undergo sulfur(VI) fluoride exchange chemistry. We show that equilibrium binding of a sulfuramidimidoyl fluoride to a protein can allow nucleophilic attack by a specific amino acid side chain, which leads to conjugate formation. We incubated small molecules, each bearing a sulfuramidimidoyl fluoride electrophile, with human cell lysate, and the protein conjugates formed were identified by affinity chromatography-mass spectrometry. This inverse drug discovery approach identified a compound that covalently binds to and irreversibly inhibits the activity of poly(ADP-ribose) polymerase 1, an important anticancer target in living cells.

| S-EPMC7541551 | biostudies-literature

Sulfur-Phenolate Exchange: SuFEx-Derived Dynamic Covalent Reactions and Degradation of SuFEx Polymers.

Project description:The products of the SuFEx reaction between sulfonimidoyl fluorides and phenols, sulfonimidates, are shown to display dynamic covalent chemistry with other phenols. This reaction was shown to be enantiospecific, finished in minutes at room temperature in high yields, and useful for both asymmetric synthesis and sustainable polymer production. Its wide scope further extends the usefulness of SuFEx and related click chemistries.

| S-EPMC9540147 | biostudies-literature

Bifluoride-catalysed sulfur(VI) fluoride exchange reaction for the synthesis of polysulfates and polysulfonates.

Project description: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.

| S-EPMC5972039 | biostudies-literature

Chain-Growth Sulfur(VI) Fluoride Exchange Polycondensation: Molecular Weight Control and Synthesis of Degradable Polysulfates.

Project description:Sulfur(VI) fluoride exchange (SuFEx) click chemistry has offered a facile and reliable approach to produce polysulfates and polysulfonates. However, the current SuFEx polymerization methods lack precise control of target molecular weight and dispersity. Herein, we report the first chain-growth SuFEx polycondensation process by exploiting the unique reactivity and selectivity of S-F bonds under SuFEx catalysis. Given the higher reactivity of iminosulfur oxydifluoride versus fluorosulfate, the chain-growth SuFEx polycondensation is realized by using an iminosulfur oxydifluoride-containing compound as the reactive chain initiator and deactivated AB-type aryl silyl ether-fluorosulfates bearing an electron-withdrawing group as monomers. When 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) was utilized as the polymerization catalyst, precise control over the polymer molecular weight and polydispersity was achieved. The resulting polymers possess great thermal stability but are easily degradable under mild acidic and basic conditions.

| S-EPMC8614101 | biostudies-literature

Synthesis of Highly Enantioenriched Sulfonimidoyl Fluorides and Sulfonimidamides by Stereospecific Sulfur-Fluorine Exchange (SuFEx) Reaction.

Project description:Sulfonimidamides present exciting opportunities as chiral isosteres of sulfonamides, with potential for additional directional interactions. Here, we present the first modular enantioselective synthesis of sulfonimidamides, including the first stereoselective synthesis of enantioenriched sulfonimidoyl fluorides, and studies on their reactivity. A new route to sulfonimidoyl fluorides is presented from solid bench-stable, N-Boc-sulfinamide (Boc=tert-butyloxycarbonyl) salt building blocks. Enantioenriched arylsulfonimidoyl fluorides are shown to be readily racemised by fluoride ions. Conditions are developed, which trap fluoride and enable the stereospecific reaction of sulfonimidoyl fluorides with primary and secondary amines (100?%?es, es=enantiospecificity) generating sulfonimidamides with up to 99?%?ee. Aryl and alkyl sulfonimidoyl fluoride reagents are suitable for mild late stage functionalisation reactions, exemplified by coupling with a selection of complex amines in marketed drugs.

| S-EPMC7590120 | biostudies-literature

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