Vinyl Sulfones Research Articles

Construction of Fused Azacyclic Systems via Cascade Cyclizations of Vinyl Sulfonium Salts

AbstractIn this work cascade cyclizations of vinyl sulfonium salts with either indolyl chalcones or ortho‐amino trifluoroacetophenones are described. This protocol enables the assembly of fused 2,3‐dihyro‐1H‐pyrrolo[1,2‐a]indoles and fused tetrahydroquinolines containing a CF3‐substituted tetrasubstituted carbon stereocenters.

Cobalt(II) catalyzed Michael-type hydroamination of activated olefins

The aza-Michael addition reaction of primary and secondary amines to α,β-unsaturated olefins viz; acrylonitrile, phenyl vinyl sulfone and dimethyl maleate has been carried out using 5–10 mol% Co(NO3)2.6H2O as a catalyst in t-BuOMe at 80–100 °C, giving rise to the desired β-aminocarbonyl compounds or sulfones in moderate to good yields. A wide range of aromatic amines, even those bearing electron withdrawing groups could be added to activated olefins via this strategy. Addition of (hetero)aromatic amines were also feasible, while in case of 2-aminopyridine the reaction was found to be effective only when AgOTf was added along with the catalyst. The aliphatic amines; benzylamine, dibenzylamine, di-n-butylamine were also smoothly added to acrylonitrile and phenyl vinyl sulfone. The methodology describes cobalt(II) nitrate as an eco-friendly, cheap and shelf available catalyst suitable for performing the Michael-type hydroamination reactions.

“Grafting-from” and “Grafting-to” Poly(N-isopropyl acrylamide) Functionalization of Glass for DNA Biosensors with Improved Properties

Surface-based biosensors have proven to be of particular interest in the monitoring of human pathogens by means of their distinct nucleic acid sequences. Genosensors rely on targeted gene/DNA probe hybridization at the surface of a physical transducer and have been exploited for their high specificity and physicochemical stability. Unfortunately, these sensing materials still face limitations impeding their use in current diagnostic techniques. Most of their shortcomings arise from their suboptimal surface properties, including low hybridization density, inadequate probe orientation, and biofouling. Herein, we describe and compare two functionalization methodologies to immobilize DNA probes on a glass substrate via a thermoresponsive polymer in order to produce genosensors with improved properties. The first methodology relies on the use of a silanization step, followed by PET-RAFT of NIPAM monomers on the coated surface, while the second relies on vinyl sulfone modifications of the substrate, to which the pre-synthetized PNIPAM was grafted to. The functionalized substrates were fully characterized by means of X-ray photoelectron spectroscopy for their surface atomic content, fluorescence assay for their DNA hybridization density, and water contact angle measurements for their thermoresponsive behavior. The antifouling properties were evaluated by fluorescence microscopy. Both immobilization methodologies hold the potential to be applied to the engineering of DNA biosensors with a variety of polymers and other metal oxide surfaces.

Identification of a cell-active chikungunya virus nsP2 protease inhibitor using a covalent fragment-based screening approach

Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that has been responsible for numerous large-scale outbreaks in the last twenty years. Currently, there are no FDA-approved therapeutics for any alphavirus infection. CHIKV nonstructural protein 2 (nsP2), which contains a cysteine protease domain, is essential for viral replication, making it an attractive target for a drug discovery campaign. Here, we optimized a CHIKV nsP2 protease (nsP2pro) biochemical assay for the screening of a 6,120-compound cysteine-directed covalent fragment library. Using a 50% inhibition threshold, we identified 153 hits (2.5% hit rate). In dose-response follow-up, RA-0002034, a covalent fragment that contains a vinyl sulfone warhead, inhibited CHIKV nsP2pro with an IC50 of 58 ± 17 nM, and further analysis with time-dependent inhibition studies yielded a kinact /KI of 6.4 × 103 M-1s-1. LC-MS/MS analysis determined that RA-0002034 covalently modified the catalytic cysteine in a site-specific manner. Additionally, RA-0002034 showed no significant off-target reactivity in proteomic experiments or against a panel of cysteine proteases. In addition to the potent biochemical inhibition of CHIKV nsP2pro activity and exceptional selectivity, RA-0002034 was tested in cellular models of alphavirus infection and effectively inhibited viral replication of both CHIKV and related alphaviruses. This study highlights the identification and characterization of the chemical probe RA-0002034 as a promising hit compound from covalent fragment-based screening for development toward a CHIKV or pan-alphavirus therapeutic.

Synthesis of Vinyl Sulfones and Benzoxathiins via Base‐Catalyzed Reactions of o‐Hydroxyaryl Thiosulfonates and Ynones

Synthesis of Vinyl Sulfones and Benzoxathiins via Base‐Catalyzed Reactions of o‐Hydroxyaryl Thiosulfonates and Ynones

Discovery and Optimization of a Series of Vinyl Sulfoximine-Based Analogues as Potent Nrf2 Activators for the Treatment of Multiple Sclerosis.

Multiple sclerosis (MS) is an immune-mediated neurodegenerative disease of the central nervous system (CNS), which leads to demyelination, axonal loss, and neurodegeneration. Increased oxidative stress and neurodegeneration have been implicated in all stages of MS, making neuroprotective therapeutics a promising strategy for its treatment. We previously have reported vinyl sulfones with antioxidative and anti-inflammatory properties that activate nuclear factor erythroid 2-related factor 2 (Nrf2), a transcription factor that induces the expression of cytoprotective genes against oxidative stress. In this study, we synthesized vinyl sulfoximine derivatives by modifying the core structure and determined therapeutic potential as Nrf2 activators. Among them, 10v effectively activated Nrf2 (EC50 = 83.5 nM) and exhibited favorable drug-like properties. 10v successfully induced expression of Nrf2-dependent antioxidant enzymes and suppressed lipopolysaccharide (LPS)-induced inflammatory responses in BV-2 microglial cells. We also confirmed that 10v effectively reversed disease progression and attenuated demyelination in an experimental autoimmune encephalitis (EAE) mouse model of MS.

Photoredox-Catalyzed Phosphine-Mediated Successive Deoxygenation of Sulfonyl Oxime Salts Enables Anti-Markovnikov Hydrothiolation of Alkenes.

Stable and easy-to-handle sodium salts of sulfonyl oximes were first identified to proceed via visible-light-driven phophine-mediated successive deoxygenation to realize the anti-Markovnikov hydrothiolation of alkenes, which could serve as an odorless sulfur source. Mechanistic studies revealed that the key thiyl radical intermediate could be generated in situ from the sulfonyl oxime anion via a phosphine-mediated fragmentation and a sequential deoxygenation process. Notably, a wide range of alkenes, including acrylamides, acrylates, vinyl ketones, vinyl sulfones, and acrylonitriles, are competent substrates for this protocol, which is highly beneficial for the construction of structurally diversified organosulfur compounds.

Covalent Probes To Capture Legionella pneumophila Dup Effector Enzymes.

Upon infection of host cells, Legionella pneumophila releases a multitude of effector enzymes into the cell's cytoplasm that hijack a plethora of cellular activities, including the host ubiquitination pathways. Effectors belonging to the SidE-family are involved in noncanonical serine phosphoribosyl ubiquitination of host substrate proteins contributing to the formation of a Legionella-containing vacuole that is crucial in the onset of Legionnaires' disease. This dynamic process is reversed by effectors called Dups that hydrolyze the phosphodiester in the phosphoribosyl ubiquitinated protein. We installed reactive warheads on chemically prepared ribosylated ubiquitin to generate a set of probes targeting these Legionella enzymes. In vitro tests on recombinant DupA revealed that a vinyl sulfonate warhead was most efficient in covalent complex formation. Mutagenesis and X-ray crystallography approaches were used to identify the site of covalent cross-linking to be an allosteric cysteine residue. The subsequent application of this probe highlights the potential to selectively enrich the Dup enzymes from Legionella-infected cell lysates.

Divergent Reaction of Alkynes and TsCN: Synthesis of β-Sulfinyl Alkenylsulfones and (E)-Vinyl Sulfones.

An efficient and high-selectivity approach for the divergent synthesis of β-sulfinyl alkenylsulfones and (E)-vinyl sulfones from alkynes and TsCN is described. A series of disulfurized products were constructed under mild conditions in the absence of transition metals. This transformation featured excellent regio- and stereoselectivity, good functional group compatibility, and broad substrate scope. The copper(I)-catalyzed sulfonation of alkynes with TsCN that affords (E)-vinyl sulfones in good to excellent yields was also developed.

Electrochemical Synthesis of Vinyl, Alkyl, and Allyl Sulfones from Sodium Sulfinates and Olefins.

An electrochemical synthesis of vinyl, alkyl, and allyl sulfones using sodium sulfinates and olefins was reported. This method uses direct current to pass through an undivided cell equipped with graphite carbon electrodes, and a series of diverse sulfone compounds can be synthesized at room temperature in high yields.

Catalytic Generation of Benzyl Anions from Aryl Ketones Utilizing [1,2]-Phospha-Brook Rearrangement and Their Application to Synthesis of Tertiary Benzylic Alcohols.

A synthetic method of tertiary alcohols was developed based on the formal umpolung addition of aryl ketones with electrophiles utilizing the [1,2]-phospha-Brook rearrangement under Brønsted base catalysis. The addition reaction of α-hydroxyphosphonates, derived from alkyl aryl- and diaryl ketones, with electrophiles such as phenyl vinyl sulfone, afforded phosphates having a tertiary alkyl group, which were readily convertible to the corresponding tertiary benzylic alcohols. This operationally simple protocol provides efficient complementary access to tertiary alcohols that are difficult to synthesize by conventional methods.

Easily water soluble cellulose-based fluorescent probes for the detection of 4-nitrophenol

Cellulose, an abundantly available natural polymer, is generally insoluble in water or common organic solvents. In this study, fluorescent probes based on cellulose were fabricated, rendering them soluble in H2O and capable of selectively recognizing 4-nitrophenol (4-NP). Firstly, the modified cellulose with -Cl was prepared by the substitution reaction of –OH and SOCl2 on cellulose. Secondly, the reversible addition-fragmentation chain transfer (RAFT) reagent FNT with –NO2 and –CHO was obtained by reacting p-nitrophenylthiophenol with p-chloromethyl benzaldehyde. It was then reacted with 2,4-dimethylpyrrole to obtain a fluoroboronodipyrrole fluorescent RAFT reagent BNT with –NO2, followed by the reduction of –NO2 to –NH2 to obtain ABT. RAFT polymerization was conducted using reagent ABT with sodium vinyl sulfonate (SVS), sodium p-styrene sulfonate (SSS), sodium allyl sulfonate (SAS) in DMF. In the polymerization process, azobisisobutyronitrile (AIBN) was used as the initiator, yielded polymers with superior water solubility. Finally, three cellulose based fluorescent probes were prepared by substitutional reaction between -Cl on cellulose and –NH2 on the as-prepared polymers. The solubility of the probes was much higher than that of the original cellulose, and it can be served as macromolecular probes for the detection of 4-NP, and applied in environmental systems.

Clickable Probes for Pathogen Proteasomes: Synthesis and Applications.

The 20S proteasome is a multimeric protease complex that is essential for proteostasis in the cell. Small molecule proteasome inhibitors are approved drugs for various cancers and are advancing clinically as antiparasitics. Although tools and technologies to study the 20S proteasome have advanced, only one probe is commercially available to image proteasome activity. This probe consists of a fluorescently labeled, peptidyl vinyl sulfone that binds to one or more of the catalytic proteasome subunits. Here, we synthesized two, active site-directed epoxyketone probes, LJL-1 and LJL-2, that were based on the peptidyl backbones of the anticancer drugs, carfilzomib and bortezomib, respectively. Each probe was conjugated, via click chemistry, to a bifunctional group comprising 5-carboxytetramethylrhodamine (TAMRA) and biotin to, respectively, visualize and enrich the 20S proteasome from protein extracts of two eukaryotic pathogens, Leishmania donovani and Trichomonas vaginalis. Depending on species, each probe generated a different subunit-binding profile by sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE), and the biotin tag enabled the enrichment of the bound subunits which were then formally identified by proteomics. Species differences in the order of electrophoretic migration by the β subunits were also noted. Finally, both probes reacted specifically with the 20S subunits in contrast to the commercial vinyl sulfone probe that cross reacted with cysteine proteases. LJL-1 and LJL-2 should find general utility in the identification and characterization of pathogen proteasomes, and serve as reagents to evaluate the specificity and mechanism of binding of new antiparasitic proteasome inhibitors.

Construction of Sulfone‐Based Polymer Electrolyte Interface Enables the High Cyclic Stability of 4.6 V LiCoO2 Cathode by In Situ Polymerization

AbstractLithium cobalt oxide (LiCoO2) is considered an indispensable cathode material in the realm of consumer electronic batteries due to its high volumetric energy density. However, at a charging cut‐off voltage as high as 4.6 V, significant interfacial side reactions between LiCoO2 and the electrolyte occur, which adversely impact the battery's cycle performance. The surface‐related issues of LiCoO2 at high charge voltages not only constrain its utilization in conventional lithium‐ion batteries with liquid electrolytes but also limit its application in solid‐state batteries. Although traditional coating methods using inert inorganic compounds can partially alleviate this issue, their point‐like coatings fail to completely prevent the surface of LiCoO2 from direct contact with the electrolyte. The exploration of novel surface protection strategies for LiCoO2 remains imperative to address the associated challenges. Herein, introducing a sulfone‐based polymer electrolyte interface is proposed on the surface of LiCoO2 using methyl vinyl sulfone (MVS) through in situ polymerization. Remarkably, LiCoO2 with sulfone‐based polymer electrolyte interface exhibits a capacity retention rate of 83% after 500 cycles when employing a carbonate electrolyte without additives at a charge cut‐off voltage of 4.6 V. Furthermore, the LiCoO2 and polymer electrolyte interface exhibits exceptional cycle stability when paired with polyether solid electrolytes that do not possess high voltage tolerance. Moreover, the incorporation of a polymer electrolyte interface not only enhances the cycle stability of LiCoO2 but also improves its thermal stability. This work presents novel research perspectives for exploring high‐voltage stable LiCoO2.

Thioester-rich degradable copolymers from a thionolactone and S-vinyl and P-vinyl monomers

The recent advent of the radical thiocarbonyl addition–ring-opening (TARO) copolymerization of thionolactones with vinyl monomers enables the production of degradable thioester backbone-functional vinyl copolymers promising for recycling and biomedical applications. To better understand the copolymerization behaviour of the prototypical thionolactone, dibenzo [c,e]oxepin-5(7H)-thione (DOT), copolymers with three S- and P-vinyl comonomers, phenyl vinyl sulfide (PVS), phenyl vinyl sulfone (PVSO), and diethyl vinylphosphonate (DEVP) were prepared through free and RAFT radical polymerizations. In all cases, DOT was incorporated faster than the vinyl comonomers which led to copolymers with up to 89 mol-% DOT content—surprising in light of past reports of significant retardation for high DOT feeds. All copolymers proved readily degradable. A postpolymerization oxidation enabled the conversion of a DOT–PVS copolymer into a corresponding DOT–PVSO species that remained degradable and offered a synthetic strategy to prepare copolymers with compositions not accessible through a direct copolymerization.

Electrophotocatalytic Tellurosulfonylation of Alkynes for the Synthesis of β-(Telluro)vinyl Sulfones.

Difunctionalization of alkynes has gained a lot of interest in current organic chemistry. Herein, we developed an electrophotocatalytic multicomponent cascade reaction of alkynes and indoles with sulfinic acid sodium salts using elemental tellurium as the tellurium source. Using synergistic anodic oxidation and visible-light irradiation, various β-(telluro)vinyl sulfones have been prepared. This strategy features mild reaction conditions, excellent substrate scope, readily available starting materials, and great functional group tolerance.

Cobalt-catalyzed Synthesis of Alkenes and Vinyl Sulfones via Dehydrogenative Coupling of Alcohols and Sulfones.

A novel protocol to access vinyl sulfones and internal/terminal olefins via cobalt-catalyzed acceptorless dehydrogenation coupling (ADC) has been established. This system enables the divergent synthesis of three kinds of olefin compounds through the coupling of alcohols and sulfones under oxidant-free conditions. The broad applicability of this procedure is demonstrated by over forty olefin products, including pharmaceutical-related compounds and complex substrates, in a one-pot process. Preliminary mechanistic studies were conducted, and a proposed reaction pathway was presented.

Visible-Light-Induced Synthesis of Vinyl Sulfones via Decarboxylative Sulfonylation of Cinnamic Acids Using Sulfonylazides/p-Toluenesulfonylmethyl Isocyanide/β-Keto Sulfones.

An efficient visible-light-induced synthesis of vinyl sulfones has been accomplished via decarboxylative sulfonylation of cinnamic acids using sulfonylazides, p-toluenesulfonylmethyl isocyanide, and β-keto sulfones as sulfonyl source, in the presence of inexpensive organic photocatalysts like rhodamine B and eosin Y. The reaction is facile, straightforward, and endowed with wide substrate scope and functional group tolerability.

Recent Advancements in Metal-Catalyst-Free Multicomponent Radical Sulfonylation of Alkynes.

Vinyl sulfones are crucial building blocks in synthetic chemistry and core structural units of pharmaceutically active molecules, thus extensive investigations have been conducted on the construction of these skeletons. In contrast to the classical synthetic approaches, the radical sulfonylation of alkynes for producing vinyl sulfones has garnered considerable interest because of its mild conditions and high efficiency. Radical sulfonation of alkynes typically begins with the sulfonyl radical attacking the alkynes, followed by further functionalization. Moreover, the association of metal-catalyst-free systems with multicomponent reactions (MCRs) offers an environmentally friendly pathway for efficiently constructing complex scaffolds from readily available partners. However, there is no comprehensive review summarizing the advancements in metal-catalyst-free multicomponent radical sulfonylation of alkynes. Hence, we provide a categorical overview based on the objects of sulfonylation of alkynes (hydrosulfonylation, carbosulfonylation, aminosulfonylation, oxysulfonylation, sulfosulfonylation, selenosulfonylation, and iodosulfonylation), along with interpretations of the reaction mechanisms.

Development of an Injectable, ECM-Derivative Embolic for the Treatment of Cerebral Saccular Aneurysms.

Cerebral aneurysms are a source of neurological morbidity and mortality, most often as a result of rupture. The most common approach for treating aneurysms involves endovascular embolization using nonbiodegradable medical devices, such as platinum coils. However, the need for retreatment due to the recanalization of coil-treated aneurysms highlights the importance of exploring alternative solutions. In this study, we propose an injectable extracellular matrix-derived embolic formed in situ by Michael addition of gelatin-thiol (Gel-SH) and hyaluronic acid vinyl sulfone (HA-VS) that may be delivered with a therapeutic agent (here, RADA-SP) to fill and remodel aneurysmal tissue without leaving behind permanent foreign bodies. The injectable embolic material demonstrated rapid gelation under physiological conditions, forming a highly porous structure and allowing for cellular infiltration. The injectable embolic exhibited thrombogenic behavior in vitro that was comparable to that of alginate injectables. Furthermore, in vivo studies in a murine carotid aneurysm model demonstrated the successful embolization of a saccular aneurysm and extensive cellular infiltration both with and without RADA-SP at 3 weeks, with some evidence of increased vascular or fibrosis markers with RADA-SP incorporation. The results indicate that the developed embolic has inherent potential for acutely filling cerebrovascular aneurysms and encouraging the cellular infiltration that would be necessary for stable, chronic remodeling.