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 "Inverse Drug Discovery" strategy in which organic compounds of intermediate complexity harboring weak, but activatable, electrophiles are matched with the protein(s) they react with in cells or cell lysate, to identify and validate covalent ligands for 11 different human proteins.
Abstract: Drug candidates are generally discovered using biochemical screens employing an isolated target protein or by utilizing cell-based phenotypic assays. Both noncovalent and covalent hits emerge from such endeavors. Herein, we exemplify an “Inverse Drug Discovery” strategy in which organic compounds of intermediate complexity harboring weak, but activatable, electrophiles are matched with the protein(s) they react with in cells or cell lysate. An alkyne substructure in each candidate small molecule enables affinity chromatography–mass spectrometry, which produces a list of proteins that each distinct compound reacts with. A notable feature of this approach is that it is agnostic with respect to the cellular proteins targeted. To illustrate this strategy, we employed aryl fluorosulfates, an underexplored class of sulfur(VI) halides, that are generally unreactive unless activated by protein binding. Reversible aryl fluorosulfate binding, correct juxtaposition of protein side chain functional groups, and transi...
168 citations
TL;DR: In this article, an organic solvent called dimethylsulfamoyl fluoride (FSO2NC2H6), a fluorosulfonamide (FSA) with two methyl substituents, was developed to enable a highly reversible LMA with an excellent initial coulombic efficiency, and rapidly approaching 99% within only 10 cycles.
Abstract: High-voltage rechargeable lithium-metal batteries (LMBs) require electrolytes that are compatible with both the Li metal anode (LMA) and the metal-oxide cathode. Herein, by imitating the fluorosulfonyl imide group from a well-known LMA-compatible salt, lithium bis(fluorosulfonyl) imide (LiFSI), we come up with an organic solvent dimethylsulfamoyl fluoride (FSO2NC2H6), a fluorosulfonamide (FSA) with two methyl substituents, to develop a new “full fluorosulfonyl” (FFS) electrolyte. Remarkably, it enables a highly reversible LMA with an excellent initial coulombic efficiency (CE) ∼91%, and rapidly approaching 99% within only 10 cycles, with average CE outperforming the well-known LMA-compatible fluoroethylene carbonate (FEC)-based electrolyte. Furthermore, benefitting from its high anodic stability against the oxidative LiNi0.6Mn0.2Co0.2O2 (NMC622) and LiMn2O4 (LMO) surfaces, the Li‖NMC622 cell retains 89% of its original capacity after 200 cycles using a limited Li excess anode. This electrolyte design strategy opens a new avenue for exploring new medium-concentration organic electrolytes for 4 V class lithium-metal batteries (LMBs).
160 citations
TL;DR: The first method of SuFEx chemistry for the conversion of phenolic compounds to their respective arylfluorosulfate derivatives in situ in 96-well plates is reported, compatible with automated synthesis and screening to quickly assess the biological activities of the in situ generated, crude products.
Abstract: Sulfur(VI) Fluoride Exchange (SuFEx) is a new family of click chemistry transformations which relies on readily available materials to produce compounds bearing the SVI–F motif The potential of SuFEx in drug discovery has just started to be explored We report the first method of SuFEx chemistry for the conversion of phenolic compounds to their respective arylfluorosulfate derivatives in situ in 96-well plates This method is compatible with automated synthesis and screening to quickly assess the biological activities of the in situ generated, crude products Using this method, we perform late-stage functionalization of a panel of known anticancer drugs to generate the corresponding arylfluorosulfates These in situ generated arylfluorosulfates are directly tested in a cancer-cell growth inhibition assay in parallel with their phenolic precursors We discover three arylfluorosulfates that exhibit improved anticancer cell proliferation activities compared to their phenol precursors Among these three comp
160 citations
TL;DR: It is shown that machine learning can map the intricate reaction landscape and enable accurate prediction of high-yielding conditions for untested substrates in sulfonyl fluorides.
Abstract: Through fine-tuning of reagent and base structure, sulfonyl fluorides can efficiently fluorinate diverse classes of alcohols. We show that machine learning can map the intricate reaction landscape and enable accurate prediction of high-yielding conditions for untested substrates.
156 citations
TL;DR: This report describes a method for the deoxyfluorination of phenols with sulfuryl fluoride (SO2F2) and tetramethylammonium fluoride (NMe4F) via aryl fluorosulfonate (ArOFs) intermediates to afford a broad range of electronically diverse and functional group-rich aryL fluoride products.
Abstract: This report describes a method for the deoxyfluorination of phenols with sulfuryl fluoride (SO2F2) and tetramethylammonium fluoride (NMe4F) via aryl fluorosulfonate (ArOFs) intermediates. We first demonstrate that the reaction of ArOFs with NMe4F proceeds under mild conditions (often at room temperature) to afford a broad range of electronically diverse and functional group-rich aryl fluoride products. This transformation was then translated to a one-pot conversion of phenols to aryl fluorides using the combination of SO2F2 and NMe4F. Ab initio calculations suggest that carbon–fluorine bond formation proceeds via a concerted transition state rather than a discrete Meisenheimer intermediate.
141 citations
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10,370 citations
TL;DR: In this paper, 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 called click chemistry is defined, enabled, and constrained by a handful of nearly perfect "springloaded" reactions.
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.
9,069 citations
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.
7,397 citations
TL;DR: In contrast to the very large number of special methods applicable to syntheses in the heterocyclic series, relatively few general methods are available as discussed by the authors, and the 1,3-dipolar addition offers a remarkably wide range of utility in the synthesis of five-membered heterocycles.
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.
2,285 citations
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.
2,202 citations