- Chemoselective reaction of bifunctional carboxysulfonic acid systems: Preparation of useful intermediates for chemiluminescent, fluorescent and UV absorbing bifunctional linkers
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Heterobifunctional compounds are of considerable interest in convergent synthesis strategies as well as in the labeling/tagging of biological molecules. Herein is described a synthetic strategy to functionalize sulfonic acids in the presence of carboxylic acids without the need for protection/deprotection steps. Bifunctional carboxysulfonic acids are transformed under mild conditions to the corresponding carboxysulfonyl fluorides which are reacted with the amine of choice to provide sulfonamides. The carboxylic acid remains free and is available for subsequent activation and further chemical elaboration. The generality of this approach is demonstrated herein, and an example of utility is outlined in which carboxysulfonyl-containing chemiluminescent reagents are transformed into unique red-shifted chemiluminescent reagents.
- Haack, Richard A.,Hershberger, Stefan J.,Best, Quinn A.,Swift, Kerry M.,Tetin, Sergey Y.
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- Desulfonative Suzuki–Miyaura Coupling of Sulfonyl Fluorides
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Sulfonyl fluorides have emerged as powerful “click” electrophiles to access sulfonylated derivatives. Yet, they are relatively inert towards C?C bond forming transformations, notably under transition-metal catalysis. Here, we describe conditions under which aryl sulfonyl fluorides act as electrophiles for the Pd-catalyzed Suzuki–Miyaura cross-coupling. This desulfonative cross-coupling occurs selectively in the absence of base and, unusually, even in the presence of strong acids. Divergent one-step syntheses of two analogues of bioactive compounds showcase the expanded reactivity of sulfonyl fluorides to encompass both S?Nu and C?C bond formation. Mechanistic experiments and DFT calculations suggest oxidative addition occurs at the C?S bond followed by desulfonation to form a Pd-F intermediate that facilitates transmetalation.
- Bahadori, Maryam,Brykczyńska, Daria,Chatelain, Paul,Moran, Joseph,Muller, Cyprien,Rowley, Christopher N.,Sau, Abhijit
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supporting information
p. 25307 - 25312
(2021/10/25)
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- Copper-free Sandmeyer-type Reaction for the Synthesis of Sulfonyl Fluorides
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A copper-free Sandmeyer-type fluorosulfonylation reaction is reported. Utilizing Na2S2O5 and Selectfluor as the sulfur dioxide and fluorine sources, respectively, aryldiazonium salts were transformed into sulfonyl fluorides. The one-pot direct synthesis of sulfonyl fluorides from aromatic amines was also realized via in situ diazotization. The practicality of this method was demonstrated by the broad functional group tolerance, gram-scale synthesis, and late-stage fluorosulfonylation of natural products and pharmaceuticals.
- Zhong, Tao,Pang, Meng-Ke,Chen, Zhi-Da,Zhang, Bin,Weng, Jiang,Lu, Gui
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supporting information
p. 3072 - 3078
(2020/04/10)
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- Development of Covalent Ligands for G Protein-Coupled Receptors: A Case for the Human Adenosine A3 Receptor
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The development of covalent ligands for G protein-coupled receptors (GPCRs) is not a trivial process. Here, we report a streamlined workflow thereto from synthesis to validation, exemplified by the discovery of a covalent antagonist for the human adenosine A3 receptor (hA3AR). Based on the 1H,3H-pyrido[2,1-f]purine-2,4-dione scaffold, a series of ligands bearing a fluorosulfonyl warhead and a varying linker was synthesized. This series was subjected to an affinity screen, revealing compound 17b as the most potent antagonist. In addition, a nonreactive methylsulfonyl derivative 19 was developed as a reversible control compound. A series of assays, comprising time-dependent affinity determination, washout experiments, and [35S]GTPγS binding assays, then validated 17b as the covalent antagonist. A combined in silico hA3AR-homology model and site-directed mutagenesis study was performed to demonstrate that amino acid residue Y2657.36 was the unique anchor point of the covalent interaction. This workflow might be applied to other GPCRs to guide the discovery of covalent ligands.
- Yang, Xue,Van Veldhoven, Jacobus P. D.,Offringa, Jelle,Kuiper, Boaz J.,Lenselink, Eelke B.,Heitman, Laura H.,Van Der Es, Daan,Ijzerman, Adriaan P.
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p. 3539 - 3552
(2019/04/16)
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- Sulfur(VI) fluoride compounds and methods for the preparation thereof
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This application describes a compound represented by Formula (I): (I) wherein: Y is a biologically active organic core group comprising one or more of an aryl group, a heteroaryl aryl group, a nonaromatic hydrocarbyl group, and a nonaromatic heterocyclic group, to which Z is covalently bonded; n is 1, 2, 3, 4 or 5; m is 1 or 2; Z is O, NR, or N; X1 is a covalent bond or —CH2CH2—, X2 is O or NR; and R comprises H or a substituted or unsubstituted group selected from an aryl group, a heteroaryl aryl group, a nonaromatic hydrocarbyl group, and a nonaromatic heterocyclic group. Methods of preparing the compounds, methods of using the compounds, and pharmaceutical compositions comprising the compounds are described as well.
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Page/Page column 19; 20; 36; 45; 46
(2018/11/23)
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- Phosphoramidite containing sulfonyl fluoride group
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The invention provides phosphoramidite containing a sulfonyl fluoride group. The structure of phosphoramidite containing the sulfonyl fluoride group is shown as a formula I, and R1, R2 and R3 in the formula are defined in the claims and description. Phosphoramidite can be used as a solid phase synthesis reagent for synthesis to obtain oligomeric nucleic acid containing the sulfonyl fluoride group.The formula I is shown in the description.
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Paragraph 0023; 0024; 0025
(2018/07/30)
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- A study of the reactivity of S(VI)-F containing warheads with nucleophilic amino-acid side chains under physiological conditions
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Sulfonyl fluorides (SFs) have recently emerged as a promising warhead for the targeted covalent modification of proteins. Despite numerous examples of the successful deployment of SFs as covalent probe compounds, a detailed exploration of the factors influencing the stability and reactivity of SFs has not yet appeared. In this work we present an extensive study on the influence of steric and electronic factors on the reactivity and stability of the SF and related SVI-F groups. While SFs react rapidly with N-acetylcysteine, the resulting adducts were found to be unstable, rendering SFs inappropriate for the durable covalent inhibition of cysteine residues. In contrast, SFs afforded stable adducts with both N-acetyltyrosine and N-acetyllysine; furthermore, we show that the reactivity of arylsulfonyl fluorides towards these nucleophilic amino acids can be predictably modulated by adjusting the electronic properties of the warhead. These trends were largely conserved when the covalent reaction occurred within a protein binding pocket. We have also obtained a crystal structure depicting covalent modification of the catalytic lysine of a tyrosine kinase (FGFR1) by the ATP analog 5′-O-3-((fluorosulfonyl)benzoyl)adenosine (m-FSBA). Highly reactive warheads were demonstrated to be unstable with respect to hydrolysis in buffered aqueous solutions, indicating that warhead reactivity must be carefully tuned to provide optimal rates of protein modification. Our results demonstrate that the reactivity of SFs complements that of more commonly studied acrylamides, and we hope that this work spurs the rational design of novel SF-containing covalent probe compounds and inhibitors, particularly in cases where a suitably positioned cysteine residue is not present.
- Mukherjee,Debreczeni,Breed,Tentarelli,Aquila,Dowling,Whitty,Grimster
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supporting information
p. 9685 - 9695
(2017/11/30)
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- Aromatic sulfonyl fluorides covalently kinetically stabilize transthyretin to prevent amyloidogenesis while affording a fluorescent conjugate
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Molecules that bind selectively to a given protein and then undergo a rapid chemoselective reaction to form a covalent conjugate have utility in drug development. Herein a library of 1,3,4-oxadiazoles substituted at the 2 position with an aryl sulfonyl fluoride and at the 5 position with a substituted aryl known to have high affinity for the inner thyroxine binding subsite of transthyretin (TTR) was conceived of by structure-based design principles and was chemically synthesized. When bound in the thyroxine binding site, most of the aryl sulfonyl fluorides react rapidly and chemoselectively with the pK a-perturbed K15 residue, kinetically stabilizing TTR and thus preventing amyloid fibril formation, known to cause polyneuropathy. Conjugation t50s range from 1 to 4 min, ～1400 times faster than the hydrolysis reaction outside the thyroxine binding site. X-ray crystallography confirms the anticipated binding orientation and sheds light on the sulfonyl fluoride activation leading to the sulfonamide linkage to TTR. A few of the aryl sulfonyl fluorides efficiently form conjugates with TTR in plasma. Eleven of the TTR covalent kinetic stabilizers synthesized exhibit fluorescence upon conjugation and therefore could have imaging applications as a consequence of the environment sensitive fluorescence of the chromophore.
- Grimster, Neil P.,Connelly, Stephen,Baranczak, Aleksandra,Dong, Jiajia,Krasnova, Larissa B.,Sharpless, K. Barry,Powers, Evan T.,Wilson, Ian A.,Kelly, Jeffery W.
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p. 5656 - 5668
(2013/06/04)
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