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Journal ArticleDOI

Sulfur(VI) Fluoride Exchange (SuFEx): Another Good Reaction for Click Chemistry

01 Sep 2014-Angewandte Chemie (Angew Chem Int Ed Engl)-Vol. 53, Iss: 36, pp 9430-9448

TL;DR: It is shown that proton or silicon centers can activate the exchange of S�F bonds for SO 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 SF bonds for SO 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.
Topics: Sulfuryl chloride (51%), Sulfonyl (51%)
Citations
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Journal ArticleDOI
Arjun Narayanan1, Lyn H. Jones1Institutions (1)
20 Apr 2015-Chemical Science
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.

213 citations


Journal ArticleDOI
Eva Blasco1, Michael B. Sims2, Anja S. Goldmann1, Anja S. Goldmann3  +3 moreInstitutions (3)
26 Jun 2017-Macromolecules
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”.

210 citations


Journal ArticleDOI
Constanze N. Neumann1, Tobias Ritter1Institutions (1)
09 Mar 2015-Angewandte Chemie
TL;DR: It is outlined how an improved understanding of the bonding interactions of fluoride could lead to a new class of mild fluorinating reagents and a range of functional-group-tolerant reactions.
Abstract: Charming fluorine: This Essay examines the recent surge in late-stage fluorination reactions and outlines challenges that need to be overcome to increase the impact of modern fluorination methods on the synthesis of complex organofluorine compounds. It is outlined how an improved understanding of the bonding interactions of fluoride could lead to a new class of mild fluorinating reagents and a range of functional-group-tolerant reactions.

182 citations


Journal ArticleDOI
Matthias Gehringer1, Stefan Laufer1Institutions (1)
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.

181 citations


Journal ArticleDOI
Q Zhao1, Xiaohu Ouyang1, Xiaobo Wan1, Ketan S. Gajiwala2  +4 moreInstitutions (2)
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...

152 citations


References
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Journal ArticleDOI
01 Jun 2001-Angewandte Chemie
Abstract: Examination of nature's favorite molecules reveals a striking preference for making carbon-heteroatom bonds over carbon-carbon bonds-surely no surprise given that carbon dioxide is nature's starting material and that most reactions are performed in water. Nucleic acids, proteins, and polysaccharides are condensation polymers of small subunits stitched together by carbon-heteroatom bonds. Even the 35 or so building blocks from which these crucial molecules are made each contain, at most, six contiguous C-C bonds, except for the three aromatic amino acids. Taking our cue from nature's approach, we address here the development of a set of powerful, highly reliable, and selective reactions for the rapid synthesis of useful new compounds and combinatorial libraries through heteroatom links (C-X-C), an approach we call "click chemistry". Click chemistry is at once defined, enabled, and constrained by a handful of nearly perfect "spring-loaded" reactions. The stringent criteria for a process to earn click chemistry status are described along with examples of the molecular frameworks that are easily made using this spartan, but powerful, synthetic strategy.

8,828 citations


Journal ArticleDOI
TL;DR: A novel regiospecific copper(I)-catalyzed 1,3-dipolar cycloaddition of terminal alkynes to azides on solid-phase is reported, and the X-ray structure of 2-azido-2-methylpropanoic acid has been solved, to yield structural information on the 1, 3-dipoles entering the reaction.
Abstract: The cycloaddition of azides to alkynes is one of the most important synthetic routes to 1H-[1,2,3]-triazoles. Here a novel regiospecific copper(I)-catalyzed 1,3-dipolar cycloaddition of terminal alkynes to azides on solid-phase is reported. Primary, secondary, and tertiary alkyl azides, aryl azides, and an azido sugar were used successfully in the copper(I)-catalyzed cycloaddition producing diversely 1,4-substituted [1,2,3]-triazoles in peptide backbones or side chains. The reaction conditions were fully compatible with solid-phase peptide synthesis on polar supports. The copper(I) catalysis is mild and efficient (>95% conversion and purity in most cases) and furthermore, the X-ray structure of 2-azido-2-methylpropanoic acid has been solved, to yield structural information on the 1,3-dipoles entering the reaction. Novel Fmoc-protected amino azides derived from Fmoc-amino alcohols were prepared by the Mitsunobu reaction.

6,918 citations


Journal ArticleDOI
Rolf Huisgen1Institutions (1)
01 Oct 1963-Angewandte Chemie
Abstract: In contrast to the very large number of special methods applicable to syntheses in the heterocyclic series, relatively few general methods are available. The 1,3-dipolar addition offers a remarkably wide range of utility in the synthesis of five-membered heterocycles. Here the “1,3-dipole”, which can only be represented by zwitterionic octet resonance structures, combines in a cycloaddition with a multiple bond system – the “dipolarophile” – to form an uncharged five-membered ring. Although numerous individual examples of this reaction were known, some even back in the nineteenth century, fruitful development of this synthetic principle has been achieved only in recent years.

2,111 citations


Journal ArticleDOI
TL;DR: A strain-promoted [3 + 2] cycloaddition between cyclooctynes and azides that proceeds under physiological conditions without the need for a catalyst was demonstrated by selective modification of biomolecules in vitro and on living cells, with no apparent toxicity.
Abstract: Selective chemical reactions that are orthogonal to the diverse functionality of biological systems have become important tools in the field of chemical biology. Two notable examples are the Staudinger ligation of azides and phosphines and the Cu(I)-catalyzed [3 + 2] cycloaddition of azides and alkynes (“click chemistry”). The Staudinger ligation has sufficient biocompatibility for performance in living animals but suffers from phosphine oxidation and synthetic challenges. Click chemistry obviates the requirement of phosphines, but the Cu(I) catalyst is toxic to cells, thereby precluding in vivo applications. Here we present a strain-promoted [3 + 2] cycloaddition between cyclooctynes and azides that proceeds under physiological conditions without the need for a catalyst. The utility of the reaction was demonstrated by selective modification of biomolecules in vitro and on living cells, with no apparent toxicity.

1,903 citations


Performance
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No. of citations received by the Paper in previous years
YearCitations
20221
2021103
202097
201988
201866
201741