sulfur(VI) Fluoride Exchange Research Articles

N-Fluorosulfurylamidines Enable Modular Synthesis of 1,5-Disubstituted Tetrazoles.

Here we report the modular synthesis of 1,5-disubstituted tetrazoles using two highly chemoselective reactions, ligations of N-fluorosulfurylamidines with amines and diazotransfer reactions between FSO2N3 and N-monosubstituted amidines, respectively. Enabled by sulfur(VI) fluoride exchange (SuFEx) click chemistry, we have successfully synthesized a series of N-fluorosulfurylamidines and identified them as stable and scalable organic synthons. We then discover that N-fluorosulfurylamidines react selectively toward a series of aliphatic amines, resulting in the formation of N-monosubstituted amidines that can react further with FSO2N3 to deliver 1,5-disubstituted tetrazoles. Our work provides a new platform for generating a library of 1,5-disubstituted tetrazoles with diverse structures, which is unprecedented.

Application of Sulfonyl Fluorides in Organic Transformation

ulfonyl fluorides, due to their balanced potential reactivity and stability as well as their compatibility with biological systems, have become important synthetic intermediates and building blocks in the fields of organic synthesis, drug discovery, and materials science. Especially after the report of sulfur(VI) fluoride exchange (SuFEx) chemistry by Sharpless and others, research on sulfonyl fluoride compounds and related compounds has increased significantly.This review summarizes the applications of sulfonyl fluorides in organic synthesis over the past decade, different types of organic reactions including C–X bond formation (including C–C, C–N, C–F bond formation etc.), S–C bond formation, S–N bond formation, S–O bond formation, multicomponent “one-pot” synthesis, and cyclization were discussed.

Leveraging Covalency to Stabilize Ternary Complex Formation For Cell-Cell "Induced Proximity".

Recent advances in the field of translational chemical biology use diverse "proximity-inducing" synthetic modalities to elicit new modes of "event driven" pharmacology. These include mechanisms of targeted protein degradation and immune clearance of pathogenic cells. Heterobifunctional "chimeric" compounds like Proteolysis TArgeting Chimeras (PROTACs) and Antibody Recruiting Molecules (ARMs) leverage these mechanisms, respectively. Both systems function through the formation of reversible "ternary" or higher-order biomolecular complexes. Critical to function are key parameters, such as bifunctional molecule affinity for endogenous proteins, target residence time, and turnover. To probe the mechanism and enhance function, covalent chemical approaches have been developed to kinetically stabilize ternary complexes. These include electrophilic PROTACs and Covalent Immune Recruiters (CIRs), the latter designed to uniquely enforce cell-cell induced proximity. Inducing cell-cell proximity is associated with key challenges arising from a combination of steric and/or mechanical based destabilizing forces on the ternary complex. These factors can attenuate the formation of ternary complexes driven by high affinity bifunctional/proximity inducing molecules. This Account describes initial efforts in our lab to address these challenges using the CIR strategy in antibody recruitment or receptor engineered T cell model systems of cell-cell induced proximity. ARMs form ternary complexes with serum antibodies and surface protein antigens on tumor cells that subsequently engage immune cells via Fc receptors. Binding and clustering of Fc receptors trigger immune cell killing of the tumor cell. We applied the CIR strategy to convert ARMs to covalent chimeras, which "irreversibly" recruit serum antibodies to tumor cells. These covalent chimeras leverage electrophile preorganization and kinetic effective molarity to achieve fast and selective covalent engagement of the target ternary complex protein, e.g., serum antibody. Importantly, covalent engagement can proceed via diverse binding site amino acids beyond cysteine. Covalent chimeras demonstrated striking functional enhancements compared to noncovalent ARM analogs in functional immune assays. We revealed this enhancement was in fact due to the increased kinetic stability and not concentration, of ternary complexes. This finding was recapitulated using analogous CIR modalities that integrate peptidic or carbohydrate binding ligands with Sulfur(VI) Fluoride Exchange (SuFEx) electrophiles to induce cell-cell proximity. Mechanistic studies in a distinct model system that uses T cells engineered with receptors that recognize covalent chimeras or ARMs, revealed covalent receptor engagement uniquely enforces downstream activation signaling. Finally, this Account discusses potential challenges and future directions for adapting and optimizing covalent chimeric/bifunctional molecules for diverse applications in cell-cell induced proximity.

Innovative Peptide Bioconjugation Chemistry with Radionuclides: Beyond Classical Click Chemistry.

Background: The incorporation of radionuclides into peptides and larger biomolecules requires efficient and sometimes biorthogonal reaction conditions, to which click chemistry provides a convenient approach. Methods: Traditionally, click-based radiolabeling techniques have focused on classical click chemistry, such as copper(I)-catalyzed alkyne-azide [3+2] cycloaddition (CuAAC), strain-promoted azide-alkyne [3+2] cycloaddition (SPAAC), traceless Staudinger ligation, and inverse electron demand Diels-Alder (IEDDA). Results: However, newly emerging click-based radiolabeling techniques, including tyrosine-click, sulfo-click, sulfur(VI) fluoride exchange (SuFEx), thiol-ene click, azo coupling, hydrazone formations, oxime formations, and RIKEN click offer valuable alternatives to classical click chemistry. Conclusions: This review will discuss the applications of these techniques in peptide radiochemistry.

Targeted sulfur(VI) fluoride exchange-mediated covalent modification of a tyrosine residue in the catalytic pocket of tyrosyl-DNA phosphodiesterase 1

Developing effective inhibitors of the DNA repair enzyme tyrosyl-DNA phosphodiesterase 1 (TDP1) has been challenging because of the enzyme shallow catalytic pocket and non-specific substrate binding interactions. Recently, we discovered a quinolone-binding hot spot in TDP1’s active site proximal to the evolutionary conserved Y204 and F259 residues that position DNA. Sulfur (VI) fluoride exchange (SuFEx) is a biocompatible click chemistry reaction that enables acylation of protein residues, including tyrosine. Selective protein modifications can provide insights into the biological roles of proteins and inform ligand design. As we report herein, we used SuFEx chemistries to prepare covalent TDP1-bound binders showing site-specific covalent bonds with Y204. Our work presents the first application of SuFEx chemistries to TDP1 ligands. It validates the ability to covalently modify specific TDP1 residues by designed targeting and adds to the chemical biology resource toolbox for studying TDP1.

Engineering SuFEx-derived macrocyclic polysulfates for superior dynamic iodine capture at high temperatures

Efficient dynamic capture of radioiodine vapor from reprocessing of spent nuclear fuel under industrial conditions (∼423.15 K) is critically required due to its detrimental environmental and health impacts. However, conventional adsorbents often suffer from reduced binding affinity and structural degradation at elevated temperatures. To address these challenges, we have engineered a series of advanced polysulfate networks using sulfur (VI) fluoride exchange (SuFEx) click chemistry. These innovative networks integrate supramolecular macrocycle calix[4]pyrrole (C[4]P) and nitrogen-rich co-monomers as building blocks, and utilize polar sulfate bonds as important linkers, which provide availability of adsorptive sites and enhance the structural stability, thereby affording unexpected iodine capture performance at high temperatures. Among these SuFEx-derived materials, C[4]P-Azo exhibits exceptional iodine affinity through cooperative interactions involving multiple binding motifs, achieving an impressive iodine uptake capacity of 0.45 g g−1 at 423.15 K under dynamic adsorption conditions, setting a new benchmark in this field. Comprehensive characterizations and DFT calculations elucidate that advanced linker sulfate bonds enabling the marriage of C[4]P and N-rich monomers, play pivotal roles in facilitating iodine adsorption and maintaining structural integrity. These findings may pave the way for designing robust macrocyclic polysulfate-based adsorbents for dynamic radioiodine capture under industrial conditions.

Highly Functionalized SuFEx-able Hub Bearing All-Carbon Quaternary Center via Rapid Brønsted Superbase Catalysis.

A rapid Brønsted superbase catalysis for highly functionalized sulfur(VI)-fluoride exchange (SuFEx) hubs bearing all-carbon quaternary centers was developed. Remarkable functional group tolerance toward esters and nitriles was achieved by Michael addition of cyanoacetate derivatives to ethenesulfonyl fluoride with low catalyst loadings (∼0.5 mol %) within a short reaction time (0.5-30 min). Gram-scalability, water tolerance, and compatibility in polymeric catalysis showcase its unique practicability. SuFEx click conjugations were demonstrated using various amines, including DNA-tethered biomolecules.

A Unified Synthesis of Diazenes from Primary Amines Using a SuFEx/Electrochemistry Strategy.

The electrochemical synthesis of 1,2-disubsituted diazenes via anodic oxidation of bench stable symmetrical and unsymmetrical sulfamides is reported. This work capitalizes on the streamlined preparation of diverse N,N'-disubstituted sulfamides using Sulfur(VI) Fluoride Exchange (SuFEx) click chemistry that were subsequently subjected to electrochemical oxidation to afford the desired diazenes. The electrochemical nature of the reaction conditions obviated the need for chlorinating reagents, which considerably improved the sustainability of the overall process. Noteworthy, in addition to the synthesis of alkyl diazenes, these milder conditions were shown to be competent for the formation of azobenzenes, albeit in lower yields. Mechanistic experiments were conducted to delineate the reaction pathway and to rationalize the formation of side products observed during the electro-oxidation of N,N'-diarylsulfamides.

Fe-Catalyzed Fluorosulfonylation of Alkenes via Sulfur Dioxide Insertion: Synthesis of Lactam-Functionalized Alkyl Sulfonyl Fluorides.

A novel Fe-catalyzed fluorosulfonylation of alkenes with Na2S2O4 and N-fluorobenzenesulfonimide (NFSI) for assembling various lactam-functionalized alkyl sulfonyl fluorides is disclosed. In this reaction, Na2S2O4 acts as both an SO2 source and a reductant. Furthermore, the resulting products can be efficiently transformed into valuable chemicals, including sulfonyl esters and sulfonamides, via the sulfur(VI) fluoride exchange (SuFEx) click reaction. Preliminary mechanistic studies suggest that the transformation proceeds through intramolecular radical cyclization, SO2 insertion, sulfite anion formation, and fluorination.

De novo design of covalent bonding peptides for target protein

To rapidly develop hyper-stable inhibitors that bind specifically and covalently to functional proteins is critical for diagnostics and therapeutics. Taking targeting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants as an example, we report a fast and low-cost de novo design strategy on covalent bonding peptides toward the SARS-CoV-2 spike protein receptor-binding domain (RBD), hence blocking its interaction with the human angiotensin-converting enzyme 2 (hACE2). As a proof-of-concept, peptide scaffolds built by ligating the hotspot residues at the hACE2-Omicron RBD interface were docked against RBD, and then the chemically modified peptides were designed by predicting their reactivity against RBD using a modified Amber ff14SB force field. Two peptides (15- and 16-mer peptides) were equipped with sulfonyl fluoride warheads bound with the conserved Y449 residue of RBD via the sulfur (VI) fluoride exchange (SuFEx) click chemistry. With permanent bonding and without dissociation, the two peptides blocked Omicron BA.2 pseudovirus infection with IC50 values of 1.07 μM and 1.56 μM, respectively. Our design approach greatly promotes the discovery of hyper-stable inhibitors against SARS-CoV-2 variants and other rapidly evolving viruses, potentially applicable to combat future viral outbreaks efficiently.

Sulfur (VI) fluoride exchange (SuFEx): a versatile tool to profile protein-biomolecule interactions for therapeutic development

Sulfur (VI) fluoride exchange (SuFEx): a versatile tool to profile protein-biomolecule interactions for therapeutic development

Sulfur(VI) Fluoride Exchange Chemistry in Solid-Phase Synthesis of Compound Arrays: Discovery of Histone Deacetylase Inhibitors.

Multistep synthesis performed on solid support is a powerful means to generate small-molecule libraries for the discovery of chemical probes to dissect biological mechanisms as well as for drug discovery. Therefore, expansion of the collection of robust chemical transformations amenable to solid-phase synthesis is desirable for achieving chemically diverse libraries for biological testing. Here, we show that sulfur(VI) fluoride exchange (SuFEx) chemistry, exemplified by pairing phenols with aryl fluorosulfates, can be used for the solid-phase synthesis of biologically active compounds. As a case study, we designed and synthesized a library of 84 hydroxamic acid-containing small molecules, providing a rich source of inhibitors with diverse selectivity profiles across the human histone deacetylase enzyme family. Among other discoveries, we identified a scaffold that furnished inhibitors of HDAC11 with exquisite selectivity in vitro and a selective inhibitor of HDAC6 that was shown to affect the acetylation of α-tubulin over histone sites H3K18, H3K27, as well as SMC3 in cultured cells. Our results encourage the further use of SuFEx chemistry for the synthesis of diverse small-molecule libraries and provide insight for future design of selective HDAC inhibitors.

Covalent targeted radioligands potentiate radionuclide therapy.

Targeted radionuclide therapy, in which radiopharmaceuticals deliver potent radionuclides to tumours for localized irradiation, has addressed unmet clinical needs and improved outcomes for patients with cancer1-4. A therapeutic radiopharmaceutical must achieve both sustainable tumour targeting and fast clearance from healthy tissue, which remains a major challenge5,6. A targeted ligation strategy that selectively fixes the radiopharmaceutical to the target protein in the tumour would be an ideal solution. Here we installed a sulfur (VI) fluoride exchange (SuFEx) chemistry-based linker on radiopharmaceuticals to prevent excessively fast tumour clearance. When the engineered radiopharmaceutical binds to the tumour-specific protein, the system undergoes a binding-to-ligation transition and readily conjugates to the tyrosine residues through the 'click' SuFEx reaction. The application of this strategy to a fibroblast activation protein (FAP) inhibitor (FAPI) triggered more than 80% covalent binding to the protein and almost no dissociation for six days. In mice, SuFEx-engineered FAPI showed 257% greater tumour uptake than did the original FAPI, and increased tumour retention by 13-fold. The uptake in healthy tissues was rapidly cleared. In a pilot imaging study, this strategy identified more tumour lesions in patients with cancer than did other methods. SuFEx-engineered FAPI also successfully achieved targeted β- and α-radionuclide therapy, causing nearly complete tumour regression in mice. Another SuFEx-engineered radioligand that targets prostate-specific membrane antigen (PSMA) also showed enhanced therapeutic efficacy. Considering the broad scope of proteins that can potentially be ligated to SuFEx warheads, it might be possible to adapt this strategy to other cancer targets.

Perfluorooxosulfate Salts as SOF4-Gas-Free Precursors to Multidimensional SuFEx Electrophiles.

Sulfur(VI) Fluoride Exchange (SuFEx) chemistry stands as a well-established method for swiftly constructing complex molecules in a modular fashion. An especially promising segment of this toolbox is reserved for multidimensional SuFEx hubs: three or more substituents pluggable into a singular SVI centre to make 'beyond-linear' clicked constructions. Sulfurimidoyl difluorides (RNSOF2) stand out as the prime example of this, however their preparation from the scarcely available thionyl tetrafluoride (SOF4) limits this chemistry to only a few laboratories with access to this gas. In this work, we identify silver pentafluorooxosulfate (AgOSF5) as a viable SuFEx hub with reactivity equal to SOF4. The AgF2-mediated oxidation of SOCl2 gives rise to the hexacoordinate AgOSF5 adduct, which in contact with primary amines produces the sulfurimidoyl fluorides in high yields. In addition, we have found this workflow to be fully extendable to the trifluoromethyl homologue, AgOSF4CF3, and we propose the use of AgOSF4X salts as a general route to azasulfur SuFEx electrophiles from commercial starting materials.

“On-Water” accelerated dearomative cycloaddition via aquaphotocatalysis

Sulfur(VI) fluoride exchange (SuFEx) has emerged as an innovative click chemistry to harness the pivotal connectivity of sulfonyl fluorides. Synthesizing such alkylated S(VI) molecules through a straightforward process is of paramount importance, and their water-compatibility opens the door to a plethora of applications in biorelevant and materials chemistry. Prior aquatic endeavors have primarily focused on delivering catalysts involving ionic mechanisms, studies regarding visible-light photocatalytic transformation are unprecedented. Herein we report an on-water accelerated dearomative aquaphotocatalysis for heterocyclic alkyl SuFEx hubs. Notably, water exerts a pronounced accelerating effect on the [2 + 2] cycloaddition between (hetero)arylated ethenesulfonyl fluorides and inert heteroaromatics. This phenomenon is likely due to the high-pressure-like reactivity amplification at the water-oil interface. Conventional solvents proved totally ineffective, leading to the isomerization of the starting material.

Multidimensional detection of roxarsone via AIE-based sulfates

Improper abuse of roxarsone (ROX) in industrial production leads to harmful effects on water, soil, food, and living creatures. It is significant to detect its concentration in the environment and biosystem. Herein, two aggregation-induced emission (AIE)-active fluorescence probes, TPE-TPE and TPE-TPE-CN, are successfully synthesized via a sulfur (VI) fluoride exchange (SuFEx) click reaction and first employed to detect ROX in the environment and living 3T3 cells. These two probes can selectively detect ROX in water due to the synergistic effect of photoinduced electron transfer (PET) and fluorescence resonance energy transfer (FRET) between the probes and ROX. The detection limit of TPE-TPE and TPE-TPE-CN is 0.154 and 0.385 μmol/L, respectively, much lower than the safety concentration stipulated by the World Health Organization (WHO). In addition, with the aid of a color discrimination application in a smartphone, these two probes can also detect ROX in real samples (such as water, soil, and cabbage), demonstrating their excellent potential for monitoring ROX in a practical environment.

SuFEx-Enabled Direct Deoxy-Diversification of Alcohols.

We introduce a new use of sulfonyl fluoride as a bifunctional reagent that facilitates the one-step deoxy-diversification of complex alcohol libraries. Our reaction design features a Sulfur(VI) Fluoride Exchange (SuFEx) mediated activation of alcohols and fluoride-induced activation of silicon-bound nucleophiles. This method enables the direct conversion of alcoholic C-O bonds in complex molecules into diverse analogues via C-C, C-N, C-Cl, and C-Br bond formation while suppressing any elimination side-products.

SuFEx-based chemical diversification for the systematic discovery of CRBN molecular glues

Molecular glues are small molecules that stabilize protein–protein interactions, enabling new molecular pharmacologies, such as targeted protein degradation. They offer advantages over proteolysis targeting chimeras (PROTACs), which present challenges associated with the size and properties of heterobifunctional constructions, but glues lack the rational design principles analogous to PROTACs. One notable exception is the ability to alter the structure of Cereblon (CRBN)-based molecular glues and redirect their activity toward new neo-substrate proteins. We took a focused approach toward modifying the CRBN ligand, 5′-amino lenalidomide, to alter its neo-substrate specificity using high-throughput chemical diversification by parallelized sulfur(VI)-fluoride exchange (SuFEx) transformations. We synthesized over 3,000 analogs of 5′-amino lenalidomide using this approach and screened the crude products using a phenotypic screen for cell viability, identifying dozens of analogs with differentiated activity. We characterized four compounds that degrade G-to-S phase transition 1 (GSPT1) protein, providing a proof-of-concept model for SuFEx-based discovery of CRBN molecular glues.

Identification of clickable HIV-1 capsid-targeting probes for viral replication inhibition

Of the targets for HIV-1 therapeutics, the capsid core is a relatively unexploited but alluring drug target due to its indispensable roles throughout virus replication. Because of this, we aimed to identify "clickable" covalent modifiers of the HIV-1 capsid protein (CA) for future functionalization. We screened a library of fluorosulfate compounds that can undergo sulfur(VI) fluoride exchange (SuFEx) reactions, and five compounds were identified as hits. These molecules were further characterized for antiviral effects. Several compounds impacted invitro capsid assembly. One compound, BBS-103, covalently bound CA via a SuFEx reaction to Tyr145 and had antiviral activity in cell-based assays by perturbing virus production, but not uncoating. The covalent binding of compounds that target the HIV-1 capsid could aid in the future design of antiretroviral drugs or chemical probes that will help study aspects of HIV-1 replication.

Chemoselective Reactions of Functionalized Sulfonyl Halides.

Chemoselective transformations of functionalized sulfonyl fluorides and chlorides are surveyed comprehensively. It is shown that sulfonyl fluorides provide an excellent selectivity control in their reactions. Thus, numerous conditions are tolerated by the SO2 F group - from amide and ester formation to directed ortho-lithiation and transition-metal-catalyzed cross-couplings. Meanwhile, sulfur (VI) fluoride exchange (SuFEx) is also compatible with numerous functional groups, thus confirming its title of "another click reaction". On the contrary, with a few exceptions, most transformations of functionalized sulfonyl chlorides typically occur at the SO2 Cl moiety.