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SuFEx Activation with Ca(NTf2)2: A Unified Strategy to Access Sulfamides, Sulfamates, and Sulfonamides from S(VI) Fluorides.

ABSTRACT: A method to activate sulfamoyl fluorides, fluorosulfates, and sulfonyl fluorides with calcium triflimide and DABCO for SuFEx with amines is described. The reaction was applied to a diverse set of sulfamides, sulfamates, and sulfonamides at room temperature under mild conditions. Additionally, we highlight this transformation to parallel medicinal chemistry to generate a broad array of nitrogen-based S(VI) compounds.

SUBMITTER: Mahapatra S

PROVIDER: S-EPMC7294807 | biostudies-literature |

REPOSITORIES: biostudies-literature

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A Unified Strategy for Arylsulfur(VI) Fluorides from Aryl Halides: Access to Ar-SOF<sub>3</sub> Compounds.

Project description:A convenient protocol to selectively access various arylsulfur(VI) fluorides from commercially available aryl halides in a divergent fashion is presented. Firstly, a novel sulfenylation reaction with the electrophilic N-(chlorothio)phthalimide (Cl-S-Phth) and arylzinc reagents afforded the corresponding Ar-S-Phth compounds. Subsequently, the S(II) atom was selectively oxidized to distinct fluorinated sulfur(VI) compounds under mild conditions. Slight modifications on the oxidation protocol permit the chemoselective installation of 1, 3, or 4 fluorine atoms at the S(VI) center, affording the corresponding Ar-SO2 F, Ar-SOF3 , and Ar-SF4 Cl. Of notice, this strategy enables the effective introduction of the rare and underexplored -SOF3 moiety into various (hetero)aryl groups. Reactivity studies demonstrate that such elusive Ar-SOF3 can be utilized as a linchpin for the synthesis of highly coveted aryl sulfonimidoyl fluorides (Ar-SO(NR)F).

| S-EPMC7756513 | 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

Synthesis of unsymmetrical sulfamides and polysulfamides <i>via</i> SuFEx click chemistry.

Project description:As hydrogen-bond donors and acceptors, N,N'-disubstituted sulfamides have been used in a range of applications from medicinal chemistry to anion-binding catalysis. However, compared to ureas or thioureas, the utilization of this unique moiety remains marginal, in part because of a lack of general synthetic methods to access unsymmetrical sulfamides. Specifically, polysulfamides are a virtually unknown type of polymer despite their potential utility in non-covalent dynamic networks, an intense area of research in materials science. We report herein a practical and efficient process to prepare unsymmetrical sulfamides via Sulfur(vi)-Fluoride Exchange (SuFEx) click chemistry. This process was then applied to synthesize polysulfamides. Thermal analysis showed that this family of polymers possess high thermal stability and tunable glass transition temperatures. Finally, hydrolysis studies indicated that aromatic polysulfamides could be recycled back to their constituting monomers at the end of their life cycle.

| S-EPMC8163303 | biostudies-literature

Silicon-Free SuFEx Reactions of Sulfonimidoyl Fluorides: Scope, Enantioselectivity, and Mechanism.

Project description:SuFEx reactions, in which an S-F moiety reacts with a silyl-protected phenol, have been developed as powerful click reactions. In the current paper we open up the potential of SuFEx reactions as enantioselective reactions, analyze the role of Si and outline the mechanism of this reaction. As a result, fast, high-yielding, "Si-free" and enantiospecific SuFEx reactions of sulfonimidoyl fluorides have been developed, and their mechanism shown, by both experimental and theoretical methods, to yield chiral products.

| S-EPMC7216998 | biostudies-literature

Novel Oxindole Sulfonamides and Sulfamides: EPZ031686, the First Orally Bioavailable Small Molecule SMYD3 Inhibitor.

Project description:SMYD3 has been implicated in a range of cancers; however, until now no potent selective small molecule inhibitors have been available for target validation studies. A novel oxindole series of SMYD3 inhibitors was identified through screening of the Epizyme proprietary histone methyltransferase-biased library. Potency optimization afforded two tool compounds, sulfonamide EPZ031686 and sulfamide EPZ030456, with cellular potency at a level sufficient to probe the in vitro biology of SMYD3 inhibition. EPZ031686 shows good bioavailability following oral dosing in mice making it a suitable tool for potential in vivo target validation studies.

| S-EPMC4753551 | 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

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

A rapid access to aliphatic sulfonyl fluorides.

Project description:The past few years have witnessed a fast-growing research interest on the study of sulfonyl fluorides as reactive probes in chemical biology and molecular pharmacology, which raises an urgent need for the development of effective synthetic methods to expand the toolkit. Herein, we present the invention of a facile and general approach for the synthesis of aliphatic sulfonyl fluorides via visible-light-mediated decarboxylative fluorosulfonylethylation. The method is based on abundant carboxylic acid feed stock, applicable to various alkyl carboxylic acids including primary, secondary, and tertiary acids, and is also suitable for the modification of natural products like amino acids, peptides, as well as drugs, forging a rapid, metal-free approach to build sulfonyl fluoride compound libraries of considerable structural diversity. Further diversification of the SO2F-containing products is also demonstrated, which allows for access to a range of pharmaceutically important motifs such as sultam, sulfonate, and sulfonamide.

| S-EPMC6704106 | biostudies-literature

SuFEx Chemistry of Thionyl Tetrafluoride (SOF4 ) with Organolithium Nucleophiles: Synthesis of Sulfonimidoyl Fluorides, Sulfoximines, Sulfonimidamides, and Sulfonimidates.

Project description:Thionyl tetrafluoride (SOF4 ) is a valuable connective gas for sulfur fluoride exchange (SuFEx) click chemistry that enables multidimensional linkages to be created via sulfur-oxygen and sulfur-nitrogen bonds. Herein, we expand the available SuFEx chemistry of SOF4 to include organolithium nucleophiles, and demonstrate, for the first time, the controlled projection of sulfur-carbon links at the sulfur center of SOF4 -derived iminosulfur oxydifluorides (R1 -N=SOF2 ). This method provides rapid and modular access to sulfonimidoyl fluorides (R1 -N=SOFR2 ), another array of versatile SuFEx connectors with readily tunable reactivity of the S-F handle. Divergent connections derived from these valuable sulfonimidoyl fluoride units are also demonstrated, including the synthesis of sulfoximines, sulfonimidamides, and sulfonimidates.

| S-EPMC6005182 | biostudies-literature

A Heck-Matsuda Process for the Synthesis of ?-Arylethenesulfonyl Fluorides: Selectively Addressable Bis-electrophiles for SuFEx Click Chemistry.

Project description:A Heck-Matsuda process for the synthesis of the otherwise difficult to access compounds, ?-arylethenesulfonyl fluorides, is described. Ethenesulfonyl fluoride (i.e., vinylsulfonyl fluoride, or ESF) undergoes ?-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 ?-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.

| S-EPMC5102157 | biostudies-literature

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