75454-03-4

Upstream product

• 54429-56-0 2-bromoethanesulfonyl chloride 
• 100-46-9 benzylamine 
• 1622-32-8 2-Chloroethanesulfonyl chloride 

Downstream Products

• 1092495-02-7 N-benzyl-[2-(N-acetamido)ethylthio]ethanesulfonamide 
• 1101838-53-2 C₁₂H₁₄BrNO₂S 
• 639008-13-2 N-benzyl-2-(1H-indole-5-yl)-N-methylethane-1-sulfonamide 

Relevant academic research and scientific papers

Vinyl sulfonamide synthesis for irreversible tethering via a novel α-selenoether protection strategy

Vinyl sulfonamides are valuable electrophiles for targeted protein modification and inhibition. We describe a novel approach to the synthesis of terminal vinyl sulfonamides which uses mild oxidative conditions to induce elimination of an α-selenoether masking group. The method complements traditional synthetic approaches and typically yields vinyl sulfonamides in high purity after aqueous work-up without requiring column chromatography of the final electrophilic product. The methodology is applied to the synthesis of covalent fragments for use in irreversible protein tethering and crucially enables the attachment of diverse fragments to the vinyl sulfonamide warhead via a chemical linker. Using thymidylate synthase as a model system, ethylene glycol is identified as an effective linker for irreversible protein tethering.

N-Phenyl-N-aceto-vinylsulfonamides as Efficient and Chemoselective Handles for N-Terminal Modification of Peptides and Proteins

A number of vinylsulfonamides were synthesized and screened to identify reagents that can be used to modify octreotide under biological pH and room temperature with improved efficiency. N-Phenyl-N-aceto-vinylsulfonamide exhibits higher reactivity and has emerged as an efficient reagent that has the ability to realize the selective modification of peptides and proteins at the N-terminus via aza-Michael addition. We showed that, after conjugation of peptides and proteins with the reagent containing a bioorthogonal functional group, the derivatives could be further labelled by functionalities, including fluorescent tags, modified drugs and polyethylene glycol (PEG) polymers without the need for prior treatment. Somatostatin, lysozyme, and RNaseA were selectively modified at the N-terminus, which illustrated the application of the method.

Exploring Partners for the Domino α-Arylation/Michael Addition Reaction Leading to Tetrahydroisoquinolines

Sulfonates, sulfonamides, and phosphonates have proven useful nucleophiles for palladium-catalyzed intramolecular α-arylation reactions leading to tetrahydroisoquinolines. Although the sulfonate α-arylation reaction can be successfully combined in a domino process with a broad range of Michael acceptors, only vinyl sulfones can be used in Michael additions when starting from sulfonamides. No domino process was developed with the phosphonate derivative. DFT calculations were carried out to gain more insights into the experimental differences observed in the reactions involving these substrates.

Selective lysine modification of native peptides: Via aza-Michael addition

A series of vinylsulfonamides were synthesized and screened for site-selective modification of the ?-amino group of lysine-bearing free α-amine residues. N-Methyl-N-phenylethenesulfonamide has emerged as an applicable reagent and has been developed for efficient and highly selective modification of the lysine residue of native peptides in the presence of a free N-terminus via aza-Michael addition. We demonstrated that functional N-phenylvinylsulfonamide derivatives with a fluorescent moiety or drug could also be conjugated to the lysine residue of octreotide and insulin with high specificity, without modifying the N-terminus. Our method provides a promising strategy for site-selective lysine functionalization in native peptides with a free N-terminus.

Styrylsulfonates and -Sulfonamides through Pd-Catalysed Matsuda–Heck Reactions of Vinylsulfonic Acid Derivatives and Arenediazonium Salts

Arene diazonium salts undergo Matsuda–Heck reactions with vinylsulfonates and -sulfonamides to give styrylsulfonic acid derivatives in high to excellent yields and with high to excellent selectivities. By quantifying the evolution of nitrogen over time in a gas-meter apparatus, the reactivities of ethylvinylsulfonate and the benchmark olefin methyl acrylate were compared for an electron-rich and an -deficient arene diazonium salt. Tertiary sulfonamides react in Matsuda–Heck couplings with high conversions, but require long reaction times, which prevents the determination of kinetic data through the measurement of nitrogen evolution. Secondary sulfonamides were found to be unreactive. From these results, the following order of reactivity could be deduced: H2C=CHCO2Me > H2C=CHSO2OEt > H2C=CHSO2N(Me)Bn >> H2C=CHSO2NHBn. Through the Matsuda–Heck coupling of 5-indolyldiazonium salt and a tertiary vinylsulfonamide, the synthesis of the C-5-substituted indole part of the antimigraine drug naratriptan was accomplished in high yield.

NOVEL AZA-OXO-INDOLES FOR THE TREATMENT AND PROPHYLAXIS OF RESPIRATORY SYNCYTIAL VIRUS INFECTION

The invention provides novel compounds having the general formula:(I) wherein R1, R2, R3, R4, W and X are as described herein, compositions including the compounds and methods of using the compounds.

Rapid, scalable assembly of stereochemically rich, mono- and bicyclic acyl sultams

A one-pot, sequential protocol is reported that involves complementary ambiphile pairing (CAP) of a vinyl sulfonamide with a variety of unprotected amino acids via aza-Michael addition and subsequent intramolecular amidation. The method generates diverse, sp3-rich mono- and bicyclic acyl sultams in a highly scalable manner. Modular pairing of stereochemically rich building blocks allows quick access to all possible isomers. Extension to include one-pot, sequential 3-, 4-, and 5-multicomponent protocols is also discussed.

Designing anti-inflammatory drugs from parasitic worms: A synthetic small molecule analogue of the acanthocheilonema viteae product ES-62 prevents development of collagen-induced arthritis

In spite of increasing evidence that parasitic worms may protect humans from developing allergic and autoimmune diseases and the continuing identification of defined helminth-derived immunomodulatory molecules, to date no new anti-inflammatory drugs have been developed from these organisms. We have approached this matter in a novel manner by synthesizing a library of drug-like small molecules based upon phosphorylcholine, the active moiety of the anti-inflammatory Acanthocheilonema viteae product, ES-62, which as an immunogenic protein is unsuitable for use as a drug. Following preliminary in vitro screening for inhibitory effects on relevant macrophage cytokine responses, a sulfone-containing phosphorylcholine analogue (11a) was selected for testing in an in vivo model of inflammation, collagen-induced arthritis (CIA). Testing revealed that 11a was as effective as ES-62 in protecting DBA/1 mice from developing CIA and mirrored its mechanism of action in downregulating the TLR/IL-1R transducer, MyD88. 11a is thus a novel prototype for anti-inflammatory drug development.

Parallel syntheses of eight-membered ring sultams via two cascade reactions in water

From vinyl sulfonamides as precursors to vinyl sulfonamide epoxides, two cascade reaction protocols were developed to synthesize eight-membered ring sultams in water. These protocols employ intermolecular Michael addition by NaOH or NaHS in water, followed by rapid proton transfer and intramolecular 8-endo-tet epoxide ring-opening to give medium-size sultams selectively in one-pot. Novel core structures and high synthetic efficiency make these cascade reactions highly suitable for sultam library production. Both reactions proceeded well and afforded the respective sultams in good yields under environmentally friendly conditions.

Synthesis of a unique isoindoline/tetrahydroisoquinoline-based tricyclic sultam library utilizing a Heck-aza-Michael strategy

The synthesis of a unique isoindoline- and tetrahydroisoquinoline (THIQ)-containing tricyclic sultam library, utilizing a Heck-aza-Michael (HaM) strategy is reported. Both isoindoline and THIQ rings are installed through a Heck reaction on a vinylsulfonamide, followed by one-pot deprotection and intramolecular aza-Michael reaction. Subsequent cyclization with either paraformaldehyde condensation or 1,1′-carbonyldiimidazole coupling generates a variety of tricyclic sultams. Overall, a 160-member library of these sultams, together with their isoindolines/THIQ and secondary sulfonamides precursors, were constructed using this strategy.