Sulfur(VI) Fluoride Exchange (SuFEx): Another Good Reaction for Click Chemistry
TL;DR: It is shown that proton or silicon centers can activate the exchange of S�F bonds for SO bonds to make functional products, and that the sulfate connector is surprisingly stable toward hydrolysis.
Abstract: Aryl sulfonyl chlorides (e.g. Ts-Cl) are beloved of organic chemists as the most commonly used S(VI) electrophiles, and the parent sulfuryl chloride, O2 S(VI) Cl2 , has also been relied on to create sulfates and sulfamides. However, the desired halide substitution event is often defeated by destruction of the sulfur electrophile because the S(VI) Cl bond is exceedingly sensitive to reductive collapse yielding S(IV) species and Cl(-) . Fortunately, the use of sulfur(VI) fluorides (e.g., R-SO2 -F and SO2 F2 ) leaves only the substitution pathway open. As with most of click chemistry, many essential features of sulfur(VI) fluoride reactivity were discovered long ago in Germany.6a Surprisingly, this extraordinary work faded from view rather abruptly in the mid-20th century. Here we seek to revive it, along with John Hyatt's unnoticed 1979 full paper exposition on CH2 CH-SO2 -F, the most perfect Michael acceptor ever found.98 To this history we add several new observations, including that the otherwise very stable gas SO2 F2 has excellent reactivity under the right circumstances. We also show that proton or silicon centers can activate the exchange of SF bonds for SO bonds to make functional products, and that the sulfate connector is surprisingly stable toward hydrolysis. Applications of this controllable ligation chemistry to small molecules, polymers, and biomolecules are discussed.
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TL;DR: An overview of warheads-beyond α,β-unsaturated amides-recently used in the design of targeted covalent ligands is provided, with special emphasis on the discussion of reactivity and of case studies illustrating applications in medicinal chemistry and chemical biology.
Abstract: Targeted covalent inhibitors (TCIs) are designed to bind poorly conserved amino acids by means of reactive groups, the so-called warheads. Currently, targeting noncatalytic cysteine residues with acrylamides and other α,β-unsaturated carbonyl compounds is the predominant strategy in TCI development. The recent ascent of covalent drugs has stimulated considerable efforts to characterize alternative warheads for the covalent-reversible and irreversible engagement of noncatalytic cysteine residues as well as other amino acids. This Perspective article provides an overview of warheads—beyond α,β-unsaturated amides—recently used in the design of targeted covalent ligands. Promising reactive groups that have not yet demonstrated their utility in TCI development are also highlighted. Special emphasis is placed on the discussion of reactivity and of case studies illustrating applications in medicinal chemistry and chemical biology.
349 citations
TL;DR: The use of sulfonyl fluoride probes in chemical biology is reviewed and three new probes are introduced that provide new insights into the mechanism behind the formation of fluoride in seawater.
Abstract: Sulfonyl fluoride electrophiles have found significant utility as reactive probes in chemical biology and molecular pharmacology. As warheads they possess the right balance of biocompatibility (including aqueous stability) and protein reactivity. Their functionality is privileged in this regard as they are known to modify not only reactive serines (resulting in their common use as protease inhibitors), but also context-specific threonine, lysine, tyrosine, cysteine and histidine residues. This review describes the application of sulfonyl fluoride probes across various areas of research and explores new approaches that could further enhance the chemical biology toolkit. We believe that sulfonyl fluoride probes will find greater utility in areas such as covalent enzyme inhibition, target identification and validation, and the mapping of enzyme binding sites, substrates and protein–protein interactions.
309 citations
TL;DR: The translation of small molecule chemistries into efficient methodologies for polymer functionalization spans several decades, enabling critical advances in soft matter materials synthesis with tailored and adaptive property profiles.
Abstract: The translation of small molecule chemistries into efficient methodologies for polymer functionalization spans several decades, enabling critical advances in soft matter materials synthesis with tailored and adaptive property profiles. The present Perspective explores—based on selected examples—50 years of innovation in polymer functionalization chemistries. These span a diverse set of chemistries based on activated esters, thiol–ene/yne processes, nucleophilic systems based on isocyanates, reactions driven by the formation of imines and oximes, ring-opening processes, cycloadditions, and—in a recent renaissance—multicomponent reactions. In addition, a wide variety of chain types and architectures have been modified based on the above chemistries, often with exquisite chemical control, highlighted by key examples. We conclude our journey through polymer functionalization with the—in our view—most critically required advances that have the potential to move from “science fiction” to “science fact”.
295 citations
TL;DR: This review discusses the growing number of applications of SuFEx, which can be found in nearly all areas of modern chemistry; from drug discovery to materials science.
Abstract: SuFEx (Sulfur Fluoride Exchange) is a modular, next generation family of click reactions, geared towards the rapid and reliable assembly of functional molecules. This review discusses the growing number of applications of SuFEx, which can be found in nearly all areas of modern chemistry; from drug discovery to materials science.
227 citations
TL;DR: The design of sulfonyl fluoride probes that covalently label a broad swath of the intracellular kinome with high efficiency are reported, highlighting the utility of lysine-targeted sulfonyL fluoride probes in demanding chemoproteomic applications.
Abstract: Protein kinases comprise a large family of structurally related enzymes. A major goal in kinase-inhibitor development is to selectively engage the desired kinase while avoiding myriad off-target kinases. However, quantifying inhibitor interactions with multiple endogenous kinases in live cells remains an unmet challenge. Here, we report the design of sulfonyl fluoride probes that covalently label a broad swath of the intracellular kinome with high efficiency. Protein crystallography and mass spectrometry confirmed a chemoselective reaction between the sulfonyl fluoride and a conserved lysine in the ATP binding site. Optimized probe 2 (XO44) covalently modified up to 133 endogenous kinases, efficiently competing with high intracellular concentrations of ATP. We employed probe 2 and label-free mass spectrometry to quantify intracellular kinase engagement by the approved drug, dasatinib. The data revealed saturable dasatinib binding to a small subset of kinase targets at clinically relevant concentrations, h...
214 citations
References
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TL;DR: This workFloat their problematic reactions on water and to send observations of success or failure to us at onwater@scripps.edu for public dissemination with attribution.
Abstract: [*] Dr. S. Narayan, Dr. J. Muldoon, Prof. M. G. Finn, Prof. V. V. Fokin, Prof. H. C. Kolb, Prof. K. B. Sharpless Department of Chemistry and the Skaggs Institute of Chemical Biology The Scripps Research Institute 10550 North Torrey Pines Road La Jolla, CA 92037 (USA) Fax: (+ 1)619-554-6738 E-mail: sharples@scripps.edu [**] We thank Dr. Vladislav Litosh for carrying out preliminary work. Support from the National Institutes of Health, National Institute of General Medical Sciences (GM 28384), the National Science Foundation (CHE9985553), the Skaggs Institute for Chemical Biology, and the W. M. Keck Foundation is gratefully acknowledged. S.N. thanks the Skaggs Institute for a postdoctoral fellowship. We also thank Dr. Suresh Suri, Edwards Air Force Base, California, for a generous gift of quadricyclane. We urge our fellow chemists to float their problematic reactions on water and to send observations of success or failure to us at onwater@scripps.edu for public dissemination with attribution. Supporting information for this article is available on the WWW under http://www.angewandte.org or from the author. Angewandte Chemie
1,393 citations
TL;DR: In this paper, the authors show how in der Natur am haufigsten vorkommenden Verbindungen, so fallt auf, dass the Bildung von Kohlenstoff-Heteroatom-Bindungen gegenuber der von KHO-Kohlenstoffs-KHO-Bindingsen deutlich bevorzugt is, and das Medium naturlicher Reaktionen zumeist Wasser ist.
Abstract: Betrachtet man die in der Natur am haufigsten vorkommenden Verbindungen, so fallt auf, dass die Bildung von Kohlenstoff-Heteroatom-Bindungen gegenuber der von Kohlenstoff-Kohlenstoff-Bindungen deutlich bevorzugt ist Da zum einen Kohlendioxid die Basisverbindung der Natur ist und andererseits das Medium naturlicher Reaktionen zumeist Wasser ist, uberrascht dies sicherlich nicht Nucleinsauren, Proteine und Polysaccharide sind polymere Kondensationsprodukte kleiner Untereinheiten, die durch Kohlenstoff-Heteroatom-Bindungen verknupft sind Sogar die etwa 35 Baueinheiten, aus denen diese essentiellen Verbindungen bestehen, enthalten nicht mehr als sechs aufeinander folgende C-C-Bindungen, sieht man einmal von den drei aromatischen Aminosauren ab Mit der Natur als Vorbild richteten wir unser Interesse auf die Entwicklung leistungsfahiger, gut funktionierender und selektiver Reaktionen fur die effiziente Synthese neuartiger nutzlicher Verbindungen sowie kombinatorischer Bibliotheken mittels Heteroatomverknupfungen (C-X-C) Diese Synthesestrategie nennen wir „Click-Chemie“ Click-Chemie ist durch eine Auswahl einiger weniger nahezu idealer Reaktionen charakterisiert, mit all ihren Grenzen und Moglichkeiten In diesem Beitrag werden zum einen die strengen Kriterien, die Reaktionen erfullen mussen, um die Bezeichnung „Click-Chemie“ zu verdienen, definiert, zum anderen werden Beispiele fur molekulare Strukturen gegeben, die mit dieser spartanischen, aber dennoch leistungsfahigen Synthesestrategie leicht hergestellt werden konnen
1,380 citations
TL;DR: In der 1.3-Dipol-Addition as mentioned in this paper, ein nur bescheidener Satz an Aufbaumethoden von allgemeiner Verwendungsbreite is gegenuber.
Abstract: Einer sehr grosen Zahl spezieller Synthesewege in die heterocyclische in die Reihe steht ein nur bescheidener Satz an Aufbaumethoden von allgemeiner Verwendbarkeit gegenuber. Eine erstaunliche Anwendungsbreite bei der Synthese funfgliedriger Heterocyclen kommt der 1.3-Dipolaren Addition zu. Dabei vereinigt sich der nur mit zwitterionischen Oktett-Grenzformeln wiederzugebende „1.3-Dipol” mit einem Mehrfachbindungssystem, dem „Dipolarophil”, in einer Cycloaddition zum ladungsfreien funfgliedrigen Ring. Wenngleich die Kenntnis zahlreicher Einzelbeispiele bis ins vorige Jahrhundert zuruckreicht, gelangte das Syntheseprinzip erst in den letzten Jahren zu fruchtbarer Entfaltung.
1,135 citations
TL;DR: Activity-based protein profiling (ABPP) has emerged as a powerful chemical proteomic strategy to characterize enzyme function directly in native biological systems on a global scale as mentioned in this paper, and the basic technology of ABPP, the enzyme classes addressable by this method, and the biological discoveries attributable to its application.
Abstract: Genome sequencing projects have provided researchers with a complete inventory of the predicted proteins produced by eukaryotic and prokaryotic organisms. Assignment of functions to these proteins represents one of the principal challenges for the field of proteomics. Activity-based protein profiling (ABPP) has emerged as a powerful chemical proteomic strategy to characterize enzyme function directly in native biological systems on a global scale. Here, we review the basic technology of ABPP, the enzyme classes addressable by this method, and the biological discoveries attributable to its application.
1,051 citations
TL;DR: This work introduced an electrochemical method to generate and protect catalytically active CuI–ligand species for CuAAC bioconjugation and synthetic coupling reactions with miminal effort to exclude air.
Abstract: Since its discovery in 2002, the copper-catalyzed azide-alkyne cycloaddition (CuAAC)[1] reaction—the most widely recognized example of click chemistry[2]—has been rapidly embraced for applications in myriad fields.[3] The attractiveness of this procedure (and its copper-free strained-alkyne variant[4]) stems from the selective reactivity of azides and alkynes only with each other. Because of the fragile nature and low concentrations at which biomolecules are often manipulated, bioconjugation presents significant challenges for any ligation methodology. Several different CuAAC procedures have been reported to address specific cases involving peptides, proteins, polynucleotides, and fixed cells, often with excellent results,[5] but also occasionally with somewhat less satisfying outcomes.[6] We describe here a generally applicable procedure that solves the most vexing click bioconjugation problems in our laboratory, and therefore should be of use in many other situations.
The CuAAC reaction requires the copper catalyst, usually prepared with an appropriate chelating ligand,[7] to be maintained in the CuI oxidation state. Several years ago we developed a system featuring a sulfonated bathophenanthroline ligand,[8] which was optimized into a useful bioconjugation protocol.[9] A significant drawback was the catalyst’s acute oxygen sensitivity, requiring air-free techniques which can be difficult to execute when an inert-atmosphere glove box is unavailable or when sensitive biomolecules are used in small volumes of aqueous solution. We also introduced an electrochemical method to generate and protect catalytically active CuI–ligand species for CuAAC bioconjugation and synthetic coupling reactions with miminal effort to exclude air.[10] Under these conditions, no hydrogen peroxide was produced in the oxygen-scrubbing process, resulting in protein conjugates that were uncontaminated with oxidative byproducts. However, this solution is also practical only for the specialist with access to the proper equipment. Other protocols have employed copper(I) sources such as CuBr for labeling fixed cells[11] and synthesizing glycoproteins.[12] In these cases, the instability of CuI in air imposes a requirement for large excesses of Cu (greater than 4 mm) and ligand for efficient reactions, which raises concerns about protein damage or precipitation, plus the presence of residual metal after purification.
The most convenient CuAAC procedure involves the use of an in situ reducing agent. Sodium ascorbate is the reductant of choice for CuAAC reactions in organic and materials synthesis, but is avoided in bioconjugation with a few exceptions.[13] Copper and sodium ascorbate have been shown to be detrimental to biological[14] and synthetic[15] polymers due to copper-mediated generation of reactive oxygen species.[16] Moreover, dehydroascorbate and other ascorbate byproducts can react with lysine amine and arginine guanidine groups, leading to covalent modification and potential aggregation of proteins.[6a,17] We hoped that solutions to these problems would allow ascorbate to be used in fast and efficient CuAAC reactions using micromolar concentration of copper in the presence of atmospheric oxygen. This has now been achieved, allowing demanding reactions to be performed with biomolecules of all types by the nonspecialist.
For purposes of catalyst optimization and reaction screening, the fluorogenic coumarin azide 1 developed by Wang et al. has proven to be invaluable (Scheme 1).[18] The progress of cycloaddition reactions between mid-micromolar concentrations of azide and alkyne in aqueous buffers was followed by the increase in fluorescence at 470 nm upon formation of the triazole 2.
Scheme 1
Top: Reaction used for screening CuAAC catalysts and conditions. Below: Accelerating ligand 3 and additive 4 used in these studies. DMSO=dimethylsulfoxide.
897 citations