RESUMO
Multicomponent reactions hold the potential to maximize the synthetic efficiency in the preparation of diverse and complex molecular scaffolds. An unprecedented formal [3+1+1+1] annulation approach for the one-step synthesis of fluoroalkylated 2-H-pyrimidines commencing from perfluoroalkyl alkenes, paraformaldehyde, and ammonium carbonate is described. By harnessing readily accessible (CH2O)n and cheap (NH4)2CO3 as a formamidine surrogate, this method effectively replaces traditionally preformed amidines with a pyrimidine assembly. The multicomponent reaction proceeds in a step-economical, operationally simple, metal-free, and additive-free manner, featuring a broad substrate scope, excellent functional group compatibility, and scalability. The potential for the synthetic elaboration of the obtained 2-H-pyrimidine is further demonstrated in the alkylation and vinylation of its C2 position.
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A silver-promoted three-component heterocyclization of alkynes, perfluoroalkyl halides, and 1,3-dinucleophiles was developed for the efficient synthesis of privileged (E)-perfluoroalkenyl pyrroles. The reaction proceeded through a rationally designed sequence of radical perfluoroalkylation and intramolecular defluorinative [3 + 2]-heterocyclization. The utility of perfluoroalkyl halide as a perfluoroalkenyl reagent, by selective and controllable functionalization of two inert C(sp3)-F bonds at vicinal carbon centers on the perfluoroalkyl chain, provides a new reaction mode for the synthesis of value-added organofluorides starting from the easily available and low-cost fluorinated feedstock.
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A three-component strategy was developed to enable hydrodefluoroamination of ß-trifluoromethyl enones by selectively activating two C(sp3)-F bonds in the trifluoromethyl group. The method involved a sequence of carbonyl reduction, hydrodefluorination, and defluoroamination under transition-metal-free conditions. Synthetically useful (E)-stereospecific α-fluoroenamides were obtained in good yields with diverse functional group tolerance, which could be easily transformed into valuable organofluorides and heterocycles. The carbonyl auxiliary exerts both electronic and steric impacts on the CF3-alkenes, allowing for controllable and selective defluorination.
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The hydroboration and hydrosilylation of alkenes catalyzed by the unsymmetrical ß-diketiminate magnesium methyl complex [(DippXylNacnac)MgMe (THF)] (1) have been reported. When complex 1 was employed as a highly efficient catalyst in the hydroboration of various alkenes with HBpin, only the anti-Markovnikov hydroboration products were obtained in high yields and with high regioselectivities under mild reaction conditions (60 °C). To our surprise, it showed different regioselectivities in the hydrosilylation of a range of alkenes with PhSiH3. Aromatic alkene substrates afforded the corresponding branched Markovnikov hydrosilylation products in high yields and with high regioselectivities; conversely, aliphatic alkenes produced the linear anti-Markovnikov products in moderate yields. This is completely consistent with the corresponding density functional theory (DFT) calculations. In addition, the practical utility was demonstrated via scale-up reactions of boronate esters and a preliminary plausible mechanism of hydroboration and hydrosilylation have been investigated as well.
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Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by amyloid-ß (Aß) deposition and neurofibrillary tangles. Although the NAD+ -dependent deacetylases SIRT1 and SIRT2 play pivotal roles in age-related diseases, their cooperative effects in AD have not yet been elucidated. Here, we report that the SIRT2:SIRT1 ratio is elevated in the brains of aging mice and in the AD mouse models. In HT22 mouse hippocampal neuronal cells, Aß challenge correlates with decreased SIRT1 expression, while SIRT2 expression is increased. Overexpression of SIRT1 prevents Aß-induced neurotoxicity. We find that SIRT1 impedes SIRT2-mediated APP deacetylation by inhibiting the binding of SIRT2 to APP. Deletion of SIRT1 reduces APP recycling back to the cell surface and promotes APP transiting toward the endosome, thus contributing to the amyloidogenic processing of APP. Our findings define a mechanism for neuroprotection by SIRT1 through suppression of SIRT2 deacetylation, and provide a promising avenue for therapeutic intervention of AD.
Assuntos
Doença de Alzheimer , Sirtuína 1 , Camundongos , Animais , Sirtuína 1/genética , Sirtuína 1/metabolismo , Sirtuína 2/genética , Sirtuína 2/metabolismo , Acetilação , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismoRESUMO
A chemo-, regio-, and stereoselective reaction of trifluoromethyl enones, phenylsilane, and phosphine oxides through a sequential hydrodefluorination and defluorophosphorylation relay is developed for the synthesis of distinctive gem-fluorophosphine alkenes. This multicomponent reaction occurred under transition-metal-free conditions with good functional group tolerance. Moreover, the preinstalled carbonyl auxiliary is important for tuning the reactivity of ß-trifluoromethyl enones, thereby enabling controllable and selective functionalization of two fluorine atoms in trifluoromethylated enones.
RESUMO
Herein, we have successfully developed a convergent paired electrolysis strategy for the defluorinative thiolation process utilizing thiols and gem-difluoroalkenes as precursors. This protocol exhibits remarkable tolerance toward a wide range of functional groups, as exemplified by the successful late-stage defluorothiolation of complex molecules. Additionally, this strategy is amenable to gram-scale synthesis, making use of both anodic oxidation and cathodic reduction processes in an efficient manner. Several control studies were conducted and suggested a convergent paired electrolysis mechanism.
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A nickel-catalyzed direct cross-coupling of unactivated aryl fluorides with aryl bromides is realized. The one-pot reaction, which avoids the use of preformed and sensitive organometallic reagents, proceeds effectively via C-F bond cleavage at room temperature in THF in the presence of the phosphine ligand and magnesium powder (with or without TMSCl) to produce the desired biaryls in modest to good yields.
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A heterogeneous redox-neutral palladium-catalytic platform was reported for the preparation of deuterated (hetero) arenes from (hetero) arenes mediated by regioselective C(sp2)-H thianthrenation utilizing commercially available and recyclable Pd/C catalyst. A wide range of deuterated compounds could be obtained in high yields with excellent levels of deuterium incorporation under these simple heterogeneous catalytic conditions with the requirement of stable and easily handled DCOONa as a deuterium source. The late-stage deuteration of pharmaceuticals and bioactive molecules was also achieved by this approach.
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Herein, we report the rhodium-catalyzed domino arylation/cyclization reaction of unactivated internal alkynes to afford the optically active indenols in excellent yields (up to 92%) and extremely high enantioselectivities (up to 99% ee) in the presence of new amide substituted chiral diene ligands. Notably, a total of 21 new chiral diene ligands are synthesized, which are potential choices for other asymmetric reactions.
RESUMO
An unprecedented defluorocyclization of perfluorobutyl tetralones with Na2S·9H2O was developed for the synthesis of trifluoromethyl 1,2-dithioles, which provided chemists novel access to biologically and pharmaceutically relevant organofluorides. Successive C(sp3)-F bond functionalization at the perfluoroalkyl chain is vital for the formation of four C-H/C-S/S-S bonds and a five-membered S-heterocycle assembly. Cheap, weakly toxic, and odorless inorganic sulfide Na2S·9H2O acts as both a disulfurating precursor and a hydrodefluorinating reagent in this tandem multi-bond-interconverting reaction.
Assuntos
TetralonasRESUMO
The auxiliary function of a carbonyl group in the tunable defluorophosphination and defluorophosphorylation of trifluoromethylated enones with P(O)-containing compounds was demonstrated. Controlled replacement of one or two fluorine atoms in trifluoromethylated enones while maintaining high chemo- and stereoselectivity was achieved under mild conditions, thus enabling diversity-oriented synthesis of skeletally diverse organophosphorus librariesâ(Z)-difluoro-1,3-dien-1-yl phosphinates, (1Z,3E)-4-phosphoryl-4-fluoro-buta-1,3-dien-1-yl phosphinates, and (E)-4-phosphoryl-4-fluoro-1,3-but-3-en-1-onesâin good yields with excellent functional group tolerance.
RESUMO
Alkaline-earth metals have attracted increasing attention because they are cheap, Earth abundant and environmentally friendly, and have gradually become inexpensive and sustainable alternatives to traditional precious transition metal catalysts in many organic reactions. Recently, the hydroboration of unsaturated organic substrates has been extensively investigated. However, reports on alkaline-earth metal catalyzed hydroboration of isocyanates and ketones are rare. Herein, we report that simple, commercially available, and air-stable magnesium halides have been successfully employed as highly efficient catalysts in the hydroboration of isocyanates and ketones. Various boronate products were obtained in high yields with low catalyst loading under mild conditions.
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Lithium-sulfur batteries (LSBs) have been considered as one of the most promising energy storage systems owing to their high theoretical energy density and abundant sulfuric resources. However, their commercial application is limited by rapid capacity decline and low Coulombic efficiency. Metal-organic frameworks (MOFs) made of metallic nodes and organic ligands can suppress polysulfide shuttling and promote redox kinetics. In this paper, the effects of crystallographic dimensions and metallic categories on chemical performance of LSBs have been meticulously explored electrochemical performance. As a result, exposed Ni active sites in a lamellar Ni-MOF was found to deliver a superior electrochemical performance. The as-assembled LSBs with 2D-Ni-MOF/CNTs cathode deliver a much superior initial discharge capacity, (820â mAh g-1 at 0.5â C), and exhibit excellent cycling stability over 550â cycles than those analogues of 3D stereoscopic Ni-MOF and 2D lamellar Co-MOF. This work proposed a perspective in elevating LSBs performance through synergistic optimization of the MOFs dimensions and the metallic nuclei in the cathodes.
RESUMO
Oncogenic stress induces DNA damage repair (DDR) that permits escape from mitotic catastrophe and allows early precursor lesions during the evolution of cancer. SAMHD1, a dNTPase protecting cells from viral infections, has been recently found to participate in DNA damage repair process. However, its role in tumorigenesis remains largely unknown. Here, we show that SAMHD1 is up-regulated in early-stage human carcinoma tissues and cell lines under oxidative stress or genotoxic insults. We further demonstrate that de-ubiquitinating enzyme USP7 interacts with SAMHD1 and de-ubiquitinates it at lysine 421, thus stabilizing SAMHD1 protein expression for further interaction with CtIP for DDR, which promotes tumor cell survival under genotoxic stress. Furthermore, SAMHD1 levels positively correlates with USP7 in various human carcinomas, and is associated with an unfavorable survival outcome in patients who underwent chemotherapy. Moreover, USP7 inhibitor sensitizes tumor cells to chemotherapeutic agents by decreasing SAMHD1 in vitro and in vivo. These findings suggest that de-ubiquitination of SAMHD1 by USP7 promotes DDR to overcome oncogenic stress and affect chemotherapy sensitivity.
Assuntos
Dano ao DNA , Reparo do DNA , Humanos , Peptidase 7 Específica de Ubiquitina/genética , Proteína 1 com Domínio SAM e Domínio HD/genética , UbiquitinaçãoRESUMO
A rhodium-catalyzed tandem arylation/cyclization reaction of 3-(ortho-boronated aryl) conjugated enones with unactivated alkynes is reported. By using a rhodium(I)/chiral-diene complex as the catalyst, the protocol was processed smoothly to provide various 2,3-disubstituted indene compounds in high yields with excellent regioselectivities and enantioselectivities. The approach outlined herein is appealing, as simple diarylalkynes, diakylalkynes, and alkyl(aryl)alkynes are the starting materials.
RESUMO
A straightforward cross-coupling of aryl thioether with aryl bromide with the aid of nickel salt, magnesium, and lithium chloride in tetrahydrofuran at ambient temperature was accomplished. The one-pot reactions proceeded efficiently via C-S bond cleavage to produce the desired biaryls in modest to good yields, avoiding the use of pregenerated or commercial organometallic reagents.
RESUMO
A one-pot, direct cross-coupling of aryl fluorosulfate with aryl bromide, which is step-economical and avoids the use of a preprepared/commercial organometallic reagent, could be accomplished by performing the reaction in THF at room temperature in the presence of nickel catalyst, magnesium turnings, and lithium chloride, giving rise to the corresponding biaryls in moderate to good yields with reasonable functional group compatibility.
RESUMO
A simple and efficient electrochemical sulfonylation of organoboronic acids with sodium arylsulfinate salts has been reported for the first time. A variety of aryl, heteroaryl, and alkenylsulfones were obtained in good to excellent yields via a simple electrochemical sulfonylation of various arylboronic acids, heterocyclic boronic acids, or alkenylboronic acids with sodium arylsulfinate at room temperature in 5 h under the catalyst-free and additive-free conditions. A plausible mechanism has been proposed based on various radical-trapping and CV control experiments.