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Site-selective radical reactions of benzylic C-H bonds are now highly effective methods for C(sp3-H) functionalization and cross-coupling. The existing methods, however, are often ineffective with heterobenzylic C-H bonds in alkyl-substituted pyridines and related aromatic heterocycles that are prominently featured in pharmaceuticals and agrochemicals. Here, we report new synthetic methods that leverage polar, rather than radical, reaction pathways to enable the selective heterobenzylic C-H chlorination of 2- and 4-alkyl-substituted pyridines and other heterocycles. Catalytic activation of the substrate with trifluoromethanesulfonyl chloride promotes the formation of enamine tautomers that react readily with electrophilic chlorination reagents. The resulting heterobenzyl chlorides can be used without isolation or purification in nucleophilic coupling reactions. This chlorination-diversification sequence provides an efficient strategy to achieve heterobenzylic C-H cross-coupling with aliphatic amines and a diverse collection of azoles, among other coupling partners.
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Cysteine-based Michael addition is a widely employed strategy for covalent conjugation of proteins, peptides, and drugs. The covalent reaction is irreversible in most cases, leading to a lack of control over the process. Utilizing spectroscopic analyses along with X-ray crystallographic studies, we demonstrate Michael addition of an engineered cysteine residue in human Cellular Retinol Binding Protein II (hCRBPII) with a coumarin analog that creates a non-fluorescent complex. UV-illumination reverses the conjugation, yielding a fluorescent species, presumably through a retro-Michael process. This series of events can be repeated between a bound and non-bound form of the cysteine reversibly, resulting in the ON-OFF control of fluorescence. The details of the mechanism of photoswitching was illuminated by recapitulation of the process in light irradiated single crystals, confirming the mechanism at atomic resolution.
Asunto(s)
Cisteína , Proteínas , Humanos , Cisteína/química , FluorescenciaRESUMEN
In contrast to Aß plaques, the spatiotemporal distribution of neurofibrillary tangles of hyperphosphorylated tau (p-tau) predicts cognitive impairment in Alzheimer's disease (AD), underscoring the key pathological role of p-tau and the utmost need to develop AD therapeutics centering upon the control of p-tau aggregation and cytotoxicity. Our drug discovery program is focused on compounds that prevent the aggregation and cytotoxicity of p-tau moieties of the tau isoform 1N4R due to its prevalence (1 N) and long-distance trans-synaptic propagation (4R). We prepared and tested twenty-four newly synthesized small molecules representing the urea (1, 2, 3), sulfonylurea (4), and sulfonamide (5-24) series and evaluated their anti-aggregation effects with biophysical methods (thioflavin T and S fluorescence assays, transmission electron microscopy) and intracellular inclusion cell-based assays. Pre-evaluation was performed on alpha-synuclein (α-syn) to identify molecules to be challenged with p-tau. The sulfonamide derivatives 18 and 20 exhibited an anti-fribrillization activity on α-syn and p-tau. Sulfonamide compounds 18 and 20 reduced inclusion formation in M17D neuroblastoma cells that express inclusion-prone αSynuclein3K::YFP. This project advances new concepts in targeting prone-to-aggregate proteins such as α-syn and p-tau, and provides a molecular scaffold for further optimization and pre-clinical studies focused on AD drug development.
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Substituted fluorene structures have demonstrated unusual photochemical properties. Previous reports on the substituted fluorene Schiff base FR0-SB demonstrated super photobase behavior with a ΔpKb of â¼14 upon photoexcitation. In an effort to understand the basis for this unusual behavior, we have examined the electronic structure and relaxation dynamics of the structural precursor of FR0-SB, the aldehyde FR0, in protic and aprotic solvents using time-resolved fluorescence spectroscopy and quantum chemical calculations. The calculations show three excited singlet states in relatively close energetic proximity. The spectroscopic data are consistent with relaxation dynamics from these electronic states that depend on the presence and concentration of solvent hydroxyl functionality. These results underscore the central role of solvent hydrogen bonding to the FR0 aldehyde oxygen in mediating the relaxation dynamics within this molecule.
Asunto(s)
Fluorenos , Bases de Schiff , Enlace de Hidrógeno , Solventes , Espectrometría de FluorescenciaRESUMEN
Several fluorene derivatives exhibit excited-state reactivity and relaxation dynamics that remain to be understood fully. We report here the spectral relaxation dynamics of two fluorene derivatives to evaluate the role of structural modification in the intramolecular relaxation dynamics and intermolecular interactions that characterize this family of chromophores. We have examined the time-resolved spectral relaxation dynamics of two compounds, NCy-FR0 and MK-FR0, in protic and aprotic solvents using steady-state and time-resolved emission spectroscopy and quantum chemical computations. Both compounds exhibit spectral relaxation characteristics similar to those seen in FR0, indicating that hydrogen bonding interactions between the chromophore and solvent protons play a significant role in determining the relaxation pathways available to three excited electronic states.
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Fluorenos , Enlace de Hidrógeno , Soluciones , Solventes , Espectrometría de FluorescenciaRESUMEN
Nitroolefins are important synthetic intermediates in the field of organic synthesis as well as in medicinal chemistry. The high reactivity of nitroalkenes due to the polarized double bond which enables them to act as Michael acceptor in conjugate addition reactions, or as a dienophile in cycloaddition makes it an essential synthetic handle for accessing complex molecules. The classical method to prepare nitroolefins is indeed the Henry nitroaldol reaction, where a carbonyl compound and nitroalkane are condensed in presence of base. Direct nitration of olefin, on the other hand, serves as a useful alternative as olefins are abundant, have broad commercial availability and easy to manipulate. In this context, numerous methods have been developed over the last few decades, focusing on direct nitration of styrene and aliphatic olefins. Furthermore, thorough literature search revealed that implementation of this class of reactions are gaining momentum as a preferred pathway to access nitroolefins, despite the presence of a powerful technique such as Henry reaction. In this review, we aim to cover recent advances in direct olefin nitration and their importance in accessing biorelevant molecules, total synthesis targets and future outlook in this specific research area.
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Unactivated olefins usually react poorly in conventional alkenylation reactions. Their introduction via C-H activation is limited to aromatic acids. Herein, we disclose a C-H functionalization protocol of aromatic amines with unactivated olefins, which shows exclusive allylic selectivity for the distal ring of the biphenyl system by exploiting a readily available cobalt(II) catalyst. The allylation proceeds smoothly involving a broad set of unbiased olefins and biaryls, giving access to the functionalization of the biphenyl scaffold.
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Enfermedad de Alzheimer/tratamiento farmacológico , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Bencimidazoles/farmacología , Inhibidores Enzimáticos/farmacología , Simulación de Dinámica Molecular , Fármacos Neuroprotectores/farmacología , Enfermedad de Alzheimer/enzimología , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Animales , Conducta Animal/efectos de los fármacos , Bencimidazoles/síntesis química , Bencimidazoles/química , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Transferencia Resonante de Energía de Fluorescencia , Masculino , Ratones , Ratones Endogámicos BALB C , Estructura Molecular , Fármacos Neuroprotectores/síntesis química , Fármacos Neuroprotectores/química , Relación Estructura-ActividadRESUMEN
α-Branched amines are present in hundreds of pharmaceutical agents and clinical candidates and are important targets for synthesis. Here we show the convergent synthesis of α-branched amines from three readily accessible starting materials: aromatic C-H bond substrates, terminal alkenes, and aminating agents. This reaction proceeds by an intermolecular formation of C-C and C-N bonds at the sp 3 carbon branch site through an uncommon 1,1-alkene addition pathway. The reaction is carried out under mild conditions and has high functional group compatibility. Ethylene and propylene feedstock chemicals are effective alkene inputs with ethylene in particular providing for the one step synthesis of α-methyl branched amines, a motif prevalent in drug structures. The reaction is scalable, and 1% loading of an air stable dimeric rhodium precatalyst is effective for several different types of products. The use of chiral catalysts also enables the asymmetric synthesis of α-branched amines.
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Two-component C-H bond additions to a large variety of coupling partners have been developed with applications towards materials, natural product and drug synthesis. Sequential three-component C-H bond addition across two different coupling partners potentially enables the convergent synthesis of complex molecular scaffolds from simple precursors. Here, we report three-component Co(III)-catalyzed C-H bond additions to dienes and aldehydes that proceeds with high regio- and stereoselectivity resulting in two new carbon-carbon σ-bonds and from four to six new stereocenters. The reaction relies on the synergistic reactivity of the diene and aldehyde with neither undergoing C-H bond addition alone. A detailed mechanism is supported by X-ray structural characterization of a Co(III)-allyl intermediate, observed transfer of stereochemical information, and kinetic isotope studies. The applicability of the method to biologically relevant molecules is exemplified by the rapid synthesis of the western fragment of the complex ionophore antibiotic lasalocid A.
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The catalytic alkenylation of the unactivated distal γC(sp3)-H bonds of aliphatic acids with simple acrylates and vinyl iodides is described. This method allows for the introduction of an alkene group into aliphatic acid derivatives in the form of activated olefins and vinyl iodides. Notably, olefination with vinyl iodides provides access to a wide range of challenging γ-vinyl acid derivatives with aliphatic olefin functionality introduced in a diastereoselective manner.
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Unactivated acyclic internal aliphatic olefins are often found to be unreactive in conventional alkenylation reactions. To address this problem, a cobalt catalyzed allylic selective dehydrogenative Heck reaction with internal aliphatic olefins has been developed. The method is highly regio- and stereoselective, the conditions are mild and a wide variety of functional groups can be tolerated. Remarkably, both internal and terminal aliphatic olefins can be employed, thereby significantly expanding the scope of alkenylation chemistry with aliphatic olefins.
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A series of 2,3-disubstituted-4(3H)-quinazolinones were synthesised via a copper-catalysed Csp3-H functionalisation/cyclisation of 2-amino-N,N-dialkylbenzamides. In comparison to the reported methods this strategy allows an easy access to diversely substituted quinazolinones under mild conditions in air. The reaction also exhibits good functional group tolerance and would be of value to heterocyclic researchers as well as pharmaceutical process chemists. The reaction is proposed to proceed through a double SET type radical mechanism.
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Palladium catalyzed selective distal C-H activation with nitrile based templates has been of significant research interest in recent times. In this report, we disclose the distal C-H olefination of biphenyl systems with high regio- and stereo-selectivity and useful synthetic yields. The utility of this method has been demonstrated through its wide olefin scope, its operation at the gram scale and the easy removal/recovery of the directing group.
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Regioselective functionalization of aromatic arenes has created a rapid insurgence in the modern era of organic chemistry. While the last few years have witnessed significant developments on site-selective ortho- and meta-C-H transformations, there existed very few reports on para-C-H functionalization. Recent advancements on template assisted protocols in para-C-H activation has emerged as a popular and convenient feat in this area. This review highlights the various protocols developed over the years for selective installation of suitable functional groups at the para-position of arenes thereby transforming them into value-added organic cores.
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Palladium-catalyzed oxidative annulations between phenols and alkenylcarboxylic acids produced a library of benzofuran compounds. Depending on the nature of the substitution of the phenol precursor, either 2,3-dialkylbenzofurans or 2-alkyl-3-methylene-2,3-dihydrobenzofurans can be synthesized with excellent regioselectivity. Reactions between conjugated 5-phenylpenta-2,4-dienoic acids and phenol gave 3-alkylidenedihydrobenzofuran alkaloid motifs while biologically active 7-arylbenzofuran derivatives were prepared by starting from 2-phenylphenols. More interestingly, selective incorporation of deuterium from D2O has been discovered, which offers an attractive one-step method to access deuterated compounds.
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Site-selective C-H functionalization has emerged as an efficient tool in simplifying the synthesis of complex molecules. Most often, directing group (DG)-assisted metallacycle formation serves as an efficient strategy to ensure promising regioselectivity. A wide variety of ortho- and meta-C-H functionalizations stand as examples in this regard. Yet despite this significant progress, DG-assisted selective para-C-H functionalization in arenes has remained unexplored, mainly because it involves the formation of a geometrically constrained metallacyclic transition state. Here we report an easily recyclable, novel Si-containing biphenyl-based template that directs efficient functionalization of the distal p-C-H bond of toluene by forming a D-shaped assembly. This DG allows the required flexibility to support the formation of an oversized pre-transition state. By overcoming electronic and steric bias, para-olefination and acetoxylation were successfully performed while undermining o- and m-C-H activation. The applicability of this D-shaped biphenyl template-based strategy is demonstrated by synthesizing various complex molecules.
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Insertion of unsaturated systems such as alkynes and olefins into unactivated sp(3) C-H bonds remains an unexplored problem. We herein address this issue by successfully incorporating a wide variety of functionalized alkynes and electron-deficient olefins into the unactivated sp(3) C-H bond of pivalic acid derivatives with excellent syn- and linear- selectivity. A strongly chelating 8-aminoquinoline directing group proved beneficial for these insertion reactions, while an air-stable and inexpensive Ni(II) salt has been employed as the active catalyst.
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An efficient method for stereoselective nitroaminoxylation of alkyne has been reported. The reaction enjoys a broad substrate scope, good functional group tolerance, and high yields. Synthetically useful α-nitroketones can be accessed through these products in a single step.
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An intramolecular dehydrogenative (sp(3))C-O bond formation in salicylamides can be initiated by an active Cu/O2 species to generate pharamaceutically relevant dihydro-oxazinones. Experimental findings suggest that stereoelectronic parameters in both coupling partners are controlling factors for site selectivity in bond formation. Mechanistic investigations including isotope labeling, kinetic studies helped to propose a catalytic cycle. The method provides a convenient synthesis of an investigational new medicine CX-614, which has potential in finding treatment for Parkinson's and Alzheimer's diseases.