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Journal of the American Chemical Society Jan 2020Heteroaromatic sulfones react with cysteine via nucleophilic aromatic substitution, providing a mechanistically selective and irreversible scaffold for cysteine...
Heteroaromatic sulfones react with cysteine via nucleophilic aromatic substitution, providing a mechanistically selective and irreversible scaffold for cysteine conjugation. Here we evaluate a library of heteroaromatic sulfides with different oxidation states, heteroatom substitutions, and a series of electron-donating and electron-withdrawing substituents. Select substitutions profoundly influence reactivity and stability compared to conventional cysteine conjugation reagents, increasing the reaction rate by >3 orders of magnitude. The findings establish a series of synthetically accessible electrophilic scaffolds tunable across multiple centers. New electrophiles and their corresponding alkyne conjugates were profiled directly in cultured cells, achieving thiol saturation in a few minutes at submillimolar concentrations. Direct addition of desthiobiotin-functionalized probes to cultured cells simplified enrichment and elution to enable the mass spectrometry discovery of >3000 reactive and/or accessible thiols labeled in their native cellular environments in a fraction of the standard analysis time. Surprisingly, only half of the annotated cysteines were identified by both iodoacetamide-desthiobiotin and methylsulfonylbenzothiazole-desthiobiotin in replicate experiments, demonstrating complementary detection by mass spectrometry analysis. These probes offer advantages over existing cysteine alkylation reagents, including accelerated reaction rates, improved stability, and robust ionization for mass spectrometry applications. Overall, heteroaromatic sulfones provide modular tunability, shifted chromatographic elution times, and superior in-cell cysteine profiling for in-depth proteome-wide analysis and covalent ligand discovery.
Topics: Alkynes; Cysteine; Indicators and Reagents; Molecular Probes; Oxidation-Reduction; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Sulfones
PubMed: 31881155
DOI: 10.1021/jacs.9b08831 -
The Journal of Organic Chemistry Feb 2020Multimeric antigen display and high overall valency are increasingly regarded as strategic goals for potent and broadly efficacious synthetic vaccines with potential...
Multimeric antigen display and high overall valency are increasingly regarded as strategic goals for potent and broadly efficacious synthetic vaccines with potential market prospects. Herein, a modular and versatile approach to multifunctional peptide-based vaccine platforms at multimilligram scale in reasonable yields is reported. Preparation of chemoselectively modified peptide building blocks of medium-to-large size, conjugation of these subunits, and final assembly were achieved by a combination of Michael-type thiol-ene addition and copper(I)-mediated alkyne-azide cycloaddition. The size and structural complexity of the building blocks required exploration of a further level of orthogonality, namely furan/maleimide Diels-Alder chemistry. After process optimization, a finely tuned, stepwise click approach has emerged as a workable, on-demand strategy to create macromolecular therapeutic vaccine assemblies.
Topics: Alkynes; Azides; Click Chemistry; Cycloaddition Reaction; Peptides
PubMed: 31782300
DOI: 10.1021/acs.joc.9b02798 -
Accounts of Chemical Research Jan 2020Cycloaddition reactions are a hallmark in organic synthesis because they provide an efficient way to construct highly substituted carbo- and heterocycles found in... (Review)
Review
Cycloaddition reactions are a hallmark in organic synthesis because they provide an efficient way to construct highly substituted carbo- and heterocycles found in natural products and pharmaceutical agents. Most cycloadditions occur under thermal or photochemical conditions, but transition-metal complexes can promote reactions that occur beyond these circumstances. Transition-metal complexation with alkynes, alkenes, allenes, or dienes often alters the reactivity of those π-systems and facilitates access to diverse cycloaddition products. This Account describes our efforts toward the design of novel five-carbon synthons for use in rhodium-catalyzed (5 + ) cycloadditions, which include 3-acyloxy-1,4-enynes (ACEs) for (5 + 1) and (5 + 2) cycloadditions and 3-hydroxy-1,4-enynes (HYEs) for (5 + 1) cycloadditions. Furthermore, this Account includes relevant computational information, mechanistic insights, and applications of these cycloadditions in the synthesis of various highly substituted carbo- and heterocycles. The (5 + ) cycloaddition reactions presented herein share the following common mechanistic features: the 1,2-migration of an acyloxy group in propargyl esters or the ionization of a hydroxyl group in propargylic alcohols, oxidative cyclization to form a metallacycle, insertion of the one- or two-carbon component, and reductive elimination to yield the final product. In conjunction with a cationic rhodium catalyst, we used ACEs for the intramolecular (5 + 2) cycloaddition with tethered alkynes, alkenes, and allenes. In some cases, an electron-deficient phosphine ligand improved the reaction yields, especially when the ACE featured an internal alkyne. We also demonstrated that chirality could be efficiently transferred from a relatively simple starting material to a more complex bicyclic product. Products derived from ACEs with tethered alkenes and allenes contained one or more stereocenters, and high diastereoselectivity was achieved in most of these cases. For ACEs tethered to an allene, the reaction preferentially occurred at the internal alkene. We also switched the positions of the alkene and the alkyne in the 1,4-enyne of our original ACE to provide an inverted ACE variant, which produced products with complementary functionalities. After we successfully developed the Rh-catalyzed intramolecular (5 + 2) cycloaddition, we optimized conditions for the intermolecular version, which required a neutral rhodium catalyst and phosphine ligand. When a terminal alkyne was used as the two-carbon component, high regioselectivity was observed. While investigating the effect of esters on the rate of the intermolecular (5 + 2) cycloadditions, we determined that an electron-rich ester significantly accelerated the reaction. Subsequently, we demonstrated that (5 + 1) cycloadditions undergo this rate enhancement as well in the presence of an ester. Aside from ACEs, we synthesized HYEs in four steps from commercially available 2-aminobenzoic acid for use in the (5 + 1) cycloaddition. Mechanistically, HYEs were designed so that the aniline nitrogen could serve as the nucleophile and the -OH could serve as the leaving group. Using HYEs, we developed a novel method to make substituted carbazoles, dibenzofurans, and tricyclic compounds with a cyclohexadienone moiety. Although the occurrence of transition-metal-catalyzed acyloxy migrations has been known for decades, only recently has their synthetic value been realized. We hope our studies that employ readily available 1,4-enynes as the five-carbon components in (5 + ) cycloadditions can inspire the design of new two-component and multicomponent cycloadditions.
Topics: Alkynes; Carbon; Catalysis; Cycloaddition Reaction; Cycloparaffins; Molecular Structure; Rhodium
PubMed: 31820914
DOI: 10.1021/acs.accounts.9b00477 -
Bioconjugate Chemistry Sep 2022Through a modified Kinugasa reaction, a novel method of amidation on terminal oligo alkyne conjugates by copper-promoted oxidation with nitrones has been developed....
Through a modified Kinugasa reaction, a novel method of amidation on terminal oligo alkyne conjugates by copper-promoted oxidation with nitrones has been developed. Unprotected bifunctional carboxylic acid-amine reagents can be transformed directly to the respective amide products under these edited Kinugasa reaction conditions. 3-Cycle DNA-encoded libraries (DELs) can be built in three steps of chemical conversion.
Topics: Alkynes; Amides; Amines; Carboxylic Acids; Catalysis; Copper; DNA
PubMed: 36001094
DOI: 10.1021/acs.bioconjchem.2c00340 -
The Journal of Organic Chemistry Jun 2021Vinyl sulfones and sulfonamides are valued for their use as electrophilic warheads in covalent protein inhibitors. Conversely, the S(VI) aza-isosteres thereof, vinyl...
Vinyl sulfones and sulfonamides are valued for their use as electrophilic warheads in covalent protein inhibitors. Conversely, the S(VI) aza-isosteres thereof, vinyl sulfoximines and sulfonimidamides, are far less studied and have yet to be applied to the field of protein bioconjugation. Herein, we report a range of different synthetic methodologies for constructing vinyl sulfoximine and vinyl sulfonimidamide architectures that allows access to new areas of electrophilic chemical space. We demonstrate how late-stage functionalization can be applied to these motifs to incorporate alkyne tags, generating fully functionalized probes for future chemical biology applications. Finally, we establish a workflow for determining the absolute configuration of enantioenriched vinyl sulfoximines and sulfonimidamides by comparing experimentally and computationally determined electronic circular dichroism spectra, enabling access to configurationally assigned enantiomeric pairs by separation.
Topics: Alkynes; Circular Dichroism; Stereoisomerism; Sulfonamides
PubMed: 34003635
DOI: 10.1021/acs.joc.1c00373 -
Organic & Biomolecular Chemistry May 2022Herein, we report a catalyst-free 'click' reaction: metal-free [2 + 2] cycloaddition-retro-electrocyclisation (CA-RE) of arylynamines with the sluggish acceptor...
Herein, we report a catalyst-free 'click' reaction: metal-free [2 + 2] cycloaddition-retro-electrocyclisation (CA-RE) of arylynamines with the sluggish acceptor tetracyanoquinodimethane (TCNQ) to provide orthogonal electron-push-pull light-harvesting small molecules: N-heterocyclic dicyanoquinodimethane-substituted methylene malononitriles. Ynamines are reactive alkynes and tend to induce over-reactions with the CA-RE adducts. The reactivity of arylynamines was balanced properly by ensuring the electron-density of the nitrogen atom was delocalised more over the aromatic rings than the triple bond.
Topics: Alkynes; Catalysis; Cycloaddition Reaction; Electrons
PubMed: 35521652
DOI: 10.1039/d2ob00677d -
Yakugaku Zasshi : Journal of the... 2021The interaction between transition metals and ligands is important for catalytic reactions. The ligands are largely dominated by the covalent X-type (hydride, alkyl and... (Review)
Review
The interaction between transition metals and ligands is important for catalytic reactions. The ligands are largely dominated by the covalent X-type (hydride, alkyl and halogen) and/or dative L-type ligands (e.g., P, N, CO, olefin, etc.). Therefore, the interaction of the Z-type ligands (B, Al and Si, etc.) with transition metals is emerging as a new concept for the reactivity of the metal center. Recently, we developed the synthesis of the gold complex Au(DPB)X (DPB=diphosphine-borane) featuring the Z-type ligand, and their catalytic reaction. The gold catalysts showed a high activity compared to the general catalysts (without Z-ligand) for the various cyclization reactions due to the electron-withdrawing effect of the Z-ligand on the coordinating gold center. In this review, first the structure analysis of the synthesized Au→Z complex is introduced in detail, and second, the catalytic reactions based on the alkyne activation are described.
Topics: Alkynes; Catalysis; Cyclization; Electrons; Gold; Gold Compounds; Ligands; Molecular Structure
PubMed: 33642496
DOI: 10.1248/yakushi.20-00179-1 -
The Journal of Organic Chemistry Mar 2022An efficient multigram synthesis of alkynyl amino acid Fmoc-l-homopropargylglycine-OH is described. A double Boc protection is optimized for high material throughput,...
An efficient multigram synthesis of alkynyl amino acid Fmoc-l-homopropargylglycine-OH is described. A double Boc protection is optimized for high material throughput, and the key Seyferth-Gilbert homologation is optimized to avoid racemization. Eighteen grams of the enantiopure (>98% ee) noncanonical amino acid was readily generated for use in solid phase synthesis to make peptides that can be functionalized by copper-assisted alkyne-azide cycloaddition.
Topics: Alkynes; Amino Acids; Azides; Fluorenes; Glycine; Solid-Phase Synthesis Techniques
PubMed: 35133817
DOI: 10.1021/acs.joc.1c03027 -
The Journal of Organic Chemistry Aug 2022Tanshinlactone has been found in several natural products and biologically active compounds. Herein, a new FeCl-catalyzed strategy using 1-indene-1,2,3-triones and...
Tanshinlactone has been found in several natural products and biologically active compounds. Herein, a new FeCl-catalyzed strategy using 1-indene-1,2,3-triones and alkynes as starting materials is reported to obtain various tanshinlactone derivatives. This protocol has the advantages of involving low cost, environmentally benign catalysts, simple reaction conditions, and a broad range of substrates.
Topics: Alkynes; Catalysis; Indenes
PubMed: 35914246
DOI: 10.1021/acs.joc.2c01254 -
Organic Letters Jun 2023In this report we describe an atom-economic, practical strategy for the synthesis of tri/tetra-substituted furans through electrochemical [3 + 2] annulation between...
In this report we describe an atom-economic, practical strategy for the synthesis of tri/tetra-substituted furans through electrochemical [3 + 2] annulation between alkynes and β-keto compounds with ferrocene (Fc) as the catalyst. This protocol features the use of a graphite felt (GF) anode and a stainless steel (SST) cathode, mild conditions, and excellent tolerance with various alkynes and β-keto compounds. Additionally, the application of this method is highlighted by the late-stage functionalization of complex structures and a gram-scale experiment.
Topics: Molecular Structure; Furans; Alkynes; Catalysis
PubMed: 37306286
DOI: 10.1021/acs.orglett.3c01582