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Accounts of Chemical Research Jan 2016Rh-carbenes derived from α-diazocarbonyl compounds have found broad utility across a remarkable range of reactivity, including cyclopropanation, cyclopropenation, C-H...
Rh-carbenes derived from α-diazocarbonyl compounds have found broad utility across a remarkable range of reactivity, including cyclopropanation, cyclopropenation, C-H insertions, heteroatom-hydrogen insertions, and ylide forming reactions. However, in contrast to α-aryl or α-vinyl-α-diazocarbonyl compounds, the utility of α-alkyl-α-diazocarbonyl compounds had been moderated by the propensity of such compounds to undergo intramolecular β-hydride migration to give alkene products. Especially challenging had been intermolecular reactions involving α-alkyl-α-diazocarbonyl compounds. This Account discusses the historical context and prior limitations of Rh-catalyzed reactions involving α-alkyl-α-diazocarbonyl compounds. Early studies demonstrated that ligand and temperature effects could influence chemoselectivity over β-hydride migration. However, effects were modest and conflicting conclusions had been drawn about the influence of sterically demanding ligands on β-hydride migration. More recent advances have led to a more detailed understanding of the reaction conditions that can promote intermolecular reactivity in preference to β-hydride migration. In particular, the use of bulky carboxylate ligands and low reaction temperatures have been key to enabling intermolecular cyclopropenation, cyclopropanation, carbonyl ylide formation/dipolar cycloaddition, indole C-H functionalization, and intramolecular bicyclobutanation with high chemoselectivity over β-hydride migration. Cyclic α-diazocarbonyl compounds have been shown to be particularly resilient toward β-hydride migration and are the first class of compounds that can engage in intermolecular reactivity in the presence of tertiary β-hydrogens. DFT calculations were used to propose that for cyclic α-diazocarbonyl compounds, ring constraints relieve steric interaction for intermolecular reactions and thereby accelerate the rate of intermolecular reactivity relative to intramolecular β-hydride migration. Enantioselective reactions of α-alkyl-α-diazocarbonyl compounds have been developed using bimetallic N-imido-tert-leucinate-derived complexes. The most effective complexes were found by computation and X-ray crystallography to adopt a "chiral crown" conformation in which all of the imido groups are presented on one face of the paddlewheel complex in a chiral arrangement. Insight from computational studies guided the design and synthesis of a mixed ligand paddlewheel complex, Rh2(S-PTTL)3TPA, the structure of which bears similarity to the chiral crown complex Rh2(S-PTTL)4. Rh2(S-PTTL)3TPA engages substrate classes (aliphatic alkynes, silylacetylenes, α-olefins) that are especially challenging in intermolecular reactions of α-alkyl-α-diazoesters and catalyzes enantioselective cyclopropanation, cyclopropenation, and indole C-H functionalization with yields and enantioselectivities that are comparable or superior to Rh2(S-PTTL)4. The work detailed in this Account describes progress toward enabling a more general utility for α-alkyl-α-diazo compounds in Rh-catalyzed carbene reactions. Further studies on ligand design and synthesis will continue to broaden the scope of their selective reactions.
Topics: Alkenes; Catalysis; Cyclization; Diazonium Compounds; Hydrogen; Methane; Molecular Structure; Organometallic Compounds; Rhodium; Stereoisomerism
PubMed: 26689221
DOI: 10.1021/acs.accounts.5b00425 -
Bioconjugate Chemistry May 2022Glycan binding often mediates extracellular macromolecular recognition events. Accurate characterization of these binding interactions can be difficult because of...
Glycan binding often mediates extracellular macromolecular recognition events. Accurate characterization of these binding interactions can be difficult because of dissociation and scrambling that occur during purification and analysis steps. Use of photocrosslinking methods has been pursued to covalently capture glycan-dependent interactions ; however, use of metabolic glycan engineering methods to incorporate photocrosslinking sugar analogs is limited to certain cell types. Here, we report an exo-enzymatic labeling method to add a diazirine-modified sialic acid (SiaDAz) to cell surface glycoconjugates. The method involves the chemoenzymatic synthesis of diazirine-modified CMP-sialic acid (CMP-SiaDAz), followed by sialyltransferase-catalyzed addition of SiaDAz to desialylated cell surfaces. Cell surface SiaDAzylation is compatible with multiple cell types and is facilitated by endogenous extracellular sialyltransferase activity present in Daudi B cells. This method for extracellular addition of α2-6-linked SiaDAz enables UV-induced crosslinking of CD22, demonstrating the utility for covalent capture of glycan-mediated binding interactions.
Topics: Diazomethane; Glycoproteins; N-Acetylneuraminic Acid; Polysaccharides; Sialic Acids; Sialyltransferases
PubMed: 35437982
DOI: 10.1021/acs.bioconjchem.2c00037 -
Journal of the American Chemical Society Feb 2022α-Alkynyldiazomethanes, generated in situ from the corresponding sulfonyl hydrazones in the presence of a base, can serve as effective metalloradicophiles in...
α-Alkynyldiazomethanes, generated in situ from the corresponding sulfonyl hydrazones in the presence of a base, can serve as effective metalloradicophiles in Co(II)-based metalloradical catalysis (MRC) for asymmetric cyclopropanation of alkenes. With -symmetric chiral amidoporphyrin 2,6-DiMeO-QingPhyrin as the optimal supporting ligand, the Co(II)-based metalloradical system can efficiently activate different α-alkynyldiazomethanes at room temperature for highly asymmetric cyclopropanation of a broad range of alkenes. This catalytic radical process provides a general synthetic tool for stereoselective construction of alkynyl cyclopropanes in high yields with high both diastereoselectivity and enantioselectivity. Combined computational and experimental studies offer several lines of evidence in support of the underlying stepwise radical mechanism for the Co(II)-catalyzed olefin cyclopropanation involving a unique α-metalloradical intermediate that is associated with two resonance forms of α-Co(III)-propargyl radical and γ-Co(III)-allenyl radical. The resulting enantioenriched alkynyl cyclopropanes, as showcased with several stereospecific transformations, may serve as valuable chiral building blocks for stereoselective organic synthesis.
Topics: Alkenes; Cobalt; Cyclization; Diazonium Compounds; Molecular Structure
PubMed: 35099966
DOI: 10.1021/jacs.1c13154 -
The Open Medicinal Chemistry Journal 2016The in situ formed 4-oxo-4H-thieno[3,4-c]chromene-3-diazonium sulfate (5) in the coupling reactions involving the parent 2-aminothiophene (4) and various phenolic and...
The in situ formed 4-oxo-4H-thieno[3,4-c]chromene-3-diazonium sulfate (5) in the coupling reactions involving the parent 2-aminothiophene (4) and various phenolic and arylamines' couplers, readily undergoes homocyclotrimerization at low temperature to afford in fairly good yield the first ever reported eighteen member ring heteroaromatic holigomer 6. Compound 6 was fully characterized by its elemental analysis, IR, UV-Vis, (1)H-NMR, (13)C-NMR and HRMS spectral data. The HMBC and HSQC techniques were used to ascertain the structural assignments. A comparative study on the antimicrobial and antioxidant activities of compounds 3, 4 and 6 was carried out to assess the SAR due to the transformations (from 3 to 6 via 4) on the tested compounds. It was found that compounds 6 and 4 were respectively the most active compounds against bacteria (MIC = 32-64 μg/ml) and yeasts (MIC = 16-64 μg/ml). Compound 6 also showed high radical-scavenging activities and ferric reducing power when compared with vitamin C and BHT used as reference antioxidants.
PubMed: 27583034
DOI: 10.2174/1874104501610010021 -
Chemical & Pharmaceutical Bulletin 2015Photoaffinity labeling has become increasingly important with the development of powerful specific probes that are synthesized by installing a photo-activatable... (Review)
Review
Photoaffinity labeling has become increasingly important with the development of powerful specific probes that are synthesized by installing a photo-activatable functional group (photophore) on the framework of biological ligands. The present review summarizes the development of diazirine-based photoaffinity labeling by focusing on its application to the structural elucidation of ligand-accepting sites within proteins.
Topics: Biotin; Diazomethane; Ligands; Light; Molecular Docking Simulation; Photoaffinity Labels; Proteins
PubMed: 25743188
DOI: 10.1248/cpb.c14-00645 -
Nature Chemistry Jul 2021DNA-protein interactions regulate critical biological processes. Identifying proteins that bind to specific, functional genomic loci is essential to understand the...
DNA-protein interactions regulate critical biological processes. Identifying proteins that bind to specific, functional genomic loci is essential to understand the underlying regulatory mechanisms on a molecular level. Here we describe a co-binding-mediated protein profiling (CMPP) strategy to investigate the interactome of DNA G-quadruplexes (G4s) in native chromatin. CMPP involves cell-permeable, functionalized G4-ligand probes that bind endogenous G4s and subsequently crosslink to co-binding G4-interacting proteins in situ. We first showed the robustness of CMPP by proximity labelling of a G4 binding protein in vitro. Employing this approach in live cells, we then identified hundreds of putative G4-interacting proteins from various functional classes. Next, we confirmed a high G4-binding affinity and selectivity for several newly discovered G4 interactors in vitro, and we validated direct G4 interactions for a functionally important candidate in cellular chromatin using an independent approach. Our studies provide a chemical strategy to map protein interactions of specific nucleic acid features in living cells.
Topics: Alkynes; Aminoquinolines; Cell Line, Tumor; Cross-Linking Reagents; DNA; DNA-Binding Proteins; Diazomethane; G-Quadruplexes; HEK293 Cells; Humans; Ligands; Proof of Concept Study; Protein Binding; Ultraviolet Rays
PubMed: 34183817
DOI: 10.1038/s41557-021-00736-9 -
ACS Chemical Neuroscience Aug 2016γ-Secretase is a multiprotein complex that catalyzes intramembrane proteolysis associated with Alzheimer's disease and cancer. Here, we have developed potent...
γ-Secretase is a multiprotein complex that catalyzes intramembrane proteolysis associated with Alzheimer's disease and cancer. Here, we have developed potent sulfonamide clickable photoaffinity probes that target γ-secretase in vitro and in cells by incorporating various photoreactive groups and walking the clickable alkyne handle to different positions around the molecule. We found that benzophenone is preferred over diazirine as a photoreactive group within the sulfonamide scaffold for labeling γ-secretase. Intriguingly, the placement of the alkyne at different positions has little effect on probe potency but has a significant impact on the efficiency of labeling of γ-secretase. Moreover, the optimized clickable photoprobe, 163-BP3, was utilized as a cellular probe to effectively assess the target engagement of inhibitors with γ-secretase in primary neuronal cells. In addition, biotinylated 163-BP3 probes were developed and used to capture the native γ-secretase complex in the 3-[(3-cholamidopropyl)dimethylammonio]-2-hydroxy-1-propanesulfonate (CHAPSO) solubilized state. Taken together, these next generation clickable and biotinylated sulfonamide probes offer new tools to study γ-secretase in biochemical and cellular systems. Finally, the data provide insights into structural features of the sulfonamide inhibitor binding site in relation to the active site and into the design of clickable photoaffinity probes.
Topics: Amyloid Precursor Protein Secretases; Amyloid beta-Peptides; Animals; Benzophenones; Binding Sites; Biotinylation; Catalytic Domain; Cells, Cultured; Cerebral Cortex; Cholic Acids; Diazomethane; HeLa Cells; Humans; Neurons; Peptide Fragments; Photoaffinity Labels; Presenilin-1; Substrate Specificity; Sulfonamides
PubMed: 27253220
DOI: 10.1021/acschemneuro.6b00127 -
Molecules (Basel, Switzerland) May 2020This study depicts the use of a fiber-optic coupled Fourier transform infrared spectroscopy-attenuated total reflection (FTIR-ATR) probe for the in-depth study of arene...
This study depicts the use of a fiber-optic coupled Fourier transform infrared spectroscopy-attenuated total reflection (FTIR-ATR) probe for the in-depth study of arene diazonium salt formation and their utilization in the Heck-Matsuda reaction. The combination of these chemical reactions and in situ IR spectroscopy enabled us to recognize the optimum parameters for arene diazonium salt formation and to track the concentrations of reactants, products and intermediates under actual reaction conditions without time consuming HPLC analysis and the necessity of collecting the sample amid the reaction. Overall advantages of the proposed methodology include precise reaction times as well as identification of keto enol tautomerization in allylic alcohols supporting the 'path a' elimination mechanism in the Heck-Matsuda reaction.
Topics: Diazonium Compounds; Spectroscopy, Fourier Transform Infrared
PubMed: 32397126
DOI: 10.3390/molecules25092199 -
Angewandte Chemie (International Ed. in... May 2017A mild, asymmetric Heck-Matsuda reaction of five-, six- and seven-membered ring alkenes and aryl diazonium salts is presented. High yields and enantioselectivities were...
A mild, asymmetric Heck-Matsuda reaction of five-, six- and seven-membered ring alkenes and aryl diazonium salts is presented. High yields and enantioselectivities were achieved using Pd and chiral anion co-catalysts, the latter functioning as a chiral anion phase-transfer (CAPT) reagent. For certain substrate classes, the chiral anion catalysts were modulated to minimize the formation of undesired by-products. More specifically, BINAM-derived phosphoric acid catalysts were shown to prevent alkene isomerization in cyclopentene and cycloheptene starting materials. DFT(B3LYP-D3) computations revealed that increased product selectivity resulted from a chiral anion dependent lowering of the activation barrier for the desired pathway.
Topics: Anions; Catalysis; Cyclohexenes; Diazonium Compounds; Molecular Structure; Phase Transition; Phenol; Stereoisomerism
PubMed: 28418118
DOI: 10.1002/anie.201702107 -
Journal of Lipid Research Mar 2019Cholesterol is an essential structural component of cellular membranes and precursor molecule for oxysterol, bile acid, and hormone synthesis. The study of intracellular...
Cholesterol is an essential structural component of cellular membranes and precursor molecule for oxysterol, bile acid, and hormone synthesis. The study of intracellular cholesterol trafficking pathways has been limited in part due to a lack of suitable cholesterol analogues. Herein, we developed three novel diazirine alkyne cholesterol probes: LKM38, KK174, and KK175. We evaluated these probes as well as a previously described diazirine alkyne cholesterol analogue, -sterol, for their fidelity as cholesterol mimics and for study of cholesterol trafficking. LKM38 emerged as a promising cholesterol mimic because it both sustained the growth of cholesterol-auxotrophic cells and appropriately regulated key cholesterol homeostatic pathways. When presented as an ester in lipoprotein particles, LKM38 initially localized to the lysosome and subsequently trafficked to the plasma membrane and endoplasmic reticulum. LKM38 bound to diverse, established cholesterol binding proteins. Through a detailed characterization of the cellular behavior of a panel of diazirine alkyne probes using cell biological, biochemical trafficking assays and immunofluorescence approaches, we conclude that LKM38 can serve as a powerful tool for the study of cholesterol protein interactions and trafficking.
Topics: Alkynes; Biological Transport; Cell Line, Tumor; Chemistry Techniques, Synthetic; Cholesterol; Diazomethane; Homeostasis; Humans; Intracellular Space; Lipoproteins; Lysosomes; Molecular Probes
PubMed: 30617147
DOI: 10.1194/jlr.D091470