RESUMO
The intermolecular [4 + 2] cycloaddition of o-hydroxy benzyl alcohols with isochroman ketals was realized by CF3CO2H catalysis. A broad range of bisbenzannulated [6,6]-spiroketals were formed under the metal-free mild conditions in moderate to excellent yields (45-98%) with mostly excellent diastereoselectivities (up to >20 : 1 dr). Furthermore, the enantioselective version was also preliminarily investigated and the bisbenzannulated [6,6]-spiroketal was obtained with 61% ee in the presence of Sc(OTf)3/Feng's chiral N,N'-dioxide ligand. Some of the bisbenzannulated [6,6]-spiroketal products showed good in vitro antifungal activities against Sclerotinia sclerotiorum and Rhizoctonia solani.
RESUMO
The enantioselective cascade reaction between racemic 2-(1-hydroxyallyl)phenols and alkynols/alkynamides was realized by using a gold and iridium sequential catalytic system. In this procedure, the in situ generated exocyclic vinyl ethers or enamides undergo the asymmetric allylation/spiroketalization with π-ally-Ir amphiphilic species, which provides an efficient and straightforward access to spiroketals and spiroaminals with excellent enantioselectivities. Moreover, racemic 2-(1-hydroxyallyl)anilines were also suitable in this reaction along with a kinetic resolution process, affording enantioenriched spiroaminals and 2-(1-hydroxyallyl)anilines in good yields. The synthetic utility of this method has been demonstrated by efficient enantioselective synthesis of the analogue of Paecilospirone.
Assuntos
Ouro , Irídio , Compostos de Anilina , Catálise , Furanos , Compostos de Espiro , EstereoisomerismoRESUMO
An unprecedented asymmetric γ-allylic alkylation of free dienolates via Sc/Ir dual catalysis is reported, which affords a range of synthetically versatile γ-allylic crotonaldehydes in high efficiency with excellent chemo-, regio-, and enantioselectivities. The dienolates bearing no essential auxiliary groups were generated in situ by scandium triflate-mediated Meinwald rearrangement of vinyloxiranes atom-economically. With the assistance of computational density functional theory calculations, a Sc/Ir bimetallic catalytic cycle was proposed to illustrate the reaction mechanism.
Assuntos
Irídio , Escândio , Alquilação , Catálise , EstereoisomerismoRESUMO
We reported herein an iridium/silver/acid ternary catalytic system to access bisbenzannulated [6,6]-spiroketals in high efficiency with generally high diastereo- and enantioselectivities (up to >20 : 1 dr, >99 % ee). In this procedure, readily available o-alkynylacetophenones undergo cycloisomerization to generate isochromenes in situ that participate in stereoselective allylation/spiroketalization sequence with 2-(1-hydroxyallyl)phenols. Meanwhile, 2-(1-hydroxyallyl)anilines were also compatible in this cascade reaction, furnishing structurally novel bisbenzannulated [6,6]-spiroaminals with good diastereoselectivities (8 : 1-12 : 1 dr) and excellent enantioselectivities (98 %->99 % ee). Moreover, experimental studies and theoretical calculations were performed to illustrate the reaction mechanism and stereochemistry.
Assuntos
Irídio , Prata , Compostos de Anilina , Catálise , Furanos , Fenóis , Compostos de Espiro , EstereoisomerismoRESUMO
The palladium-catalyzed asymmetric [4+3] cyclization of trimethylenemethane donors with benzofuran-derived azadienes furnishes chiral benzofuro[3,2-b]azepine frameworks in high yields (up to 98 %) with exclusive regioselectivities and excellent stereoselectivities (up to >20:1â d.r., >99 %â ee). This catalytic asymmetric [4+3] cyclization of Pd-trimethylenemethane can enrich the arsenal of Pd-TMM reactions in organic synthesis. In addition, this strategy provides an alternative approach to chiral azepines by a transition-metal-catalyzed asymmetric [4+3] cyclization.
RESUMO
A highly efficient asymmetric 1,3-dipolar cycloaddition of azomethine ylides to ß,ß-disubstituted ß-fluoroacrylates catalyzed by a chiral N,O-ligand/Cu(CH3CN)4BF4 system is reported, affording chiral densely substituted pyrrolidines with four contiguous stereocenters, including one fluorinated quaternary stereocenter at the 3-position, in good to excellent yields (up to 99%), with excellent levels of diastereo- and enantioselectivities (dr >20:1; ee up to 99%).
RESUMO
The first highly diastereoselective and enantioselective catalytic asymmetric Michael addition of cyclic azomethine ylides with nitroalkenes have been developed to diastereodivergently generate either the syn or anti adducts by employing N,O-ligand/Cu(OAc)2 and N,P-ligand/Cu(OAc)2 catalytic systems. Both catalytic systems exhibit broad substrate applicability to afford the corresponding Michael adducts in good to excellent yields, with excellent levels of diastereo- (up to 99:1 diastereomeric ratio) and enantioselectivities (up to >99% enantiomeric excess). Importantly, the chiral 1,7-diazaspiro[4.4]nonane diastereomer derivatives can be easily obtained in good yields through facile NaBH4 reduction of the Michael adducts.
RESUMO
A protocol to access useful 4-aminopyrrolidine-2,4-dicarboxylate derivatives has been developed. A variety of chiral N,O-ligands derived from 2,3-dihydroimidazo[1,2-a]pyridine motifs have been evaluated in the asymmetric 1,3-dipolar cycloaddition of azomethine ylides to α-phthalimidoacrylates. Reactions catalyzed by copper in combination with ligand 7-Cl-DHIPOH provided the highest level of stereoselectivity for the 1,3-dipolar cycloaddition reaction. The reaction tolerates both ß-substituted and ß-unsubstituted α-phthalimidoacrylate as dipolarophiles, affording the corresponding quaternary 4-aminopyrrolidine cycloadducts with excellent diastereo- (>98:2â d.r.) and enantioselectivities (up to 97 %â ee). Removal of the phthalimido protecting group can be accomplished by a simple NaBH4 reduction. Theoretical calculations employing DFT methods show this cycloaddition reaction is likely to proceed through a stepwise mechanism and the stereochemistry was also theoretically rationalized.
RESUMO
Multipotent human bone marrow stromal cells (hBMSCs) potentially serve as a source for cell-based therapy in regenerative medicine. However, in vitro expansion was inescapably accompanied with cell senescence, characterized by inhibited proliferation and compromised pluripotency. We have previously demonstrated that this aging process is closely associated with reduced 20S proteasomal activity, with down-regulation of rate-limiting catalytic ß-subunits particularly evident. In the present study, we confirmed that proteasomal activity directly contributes to senescence of hBMSCs, which could be reversed by overexpression of the ß5-subunit (PSMB5). Knocking down PSMB5 led to decreased proteasomal activity concurrent with reduced cell proliferation in early-stage hBMSCs, which is similar to the senescent phenotype observed in late-stage cells. In contrast, overexpressing PSMB5 in late-stage cells efficiently restored the normal activity of 20S proteasomes and promoted cell growth, possibly via upregulating the Cyclin D1/CDK4 complex. Additionally, PSMB5 could enhance cell resistance to oxidative stress, as evidenced by the increased cell survival upon exposing senescent hBMSCs to hydrogen peroxide. Furthermore, PSMB5 overexpression retained the pluripotency of late-stage hBMSCs by facilitating their neural differentiation both in vitro and in vivo. Collectively, our work reveals a critical role of PSMB5 in 20S proteasome-mediated protection against replicative senescence, pointing to a possible strategy for maintaining the integrity of culture-expanded hBMSCs by manipulating the expression of PSMB5.
Assuntos
Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Complexo de Endopeptidases do Proteassoma/genética , Complexo de Endopeptidases do Proteassoma/metabolismo , Animais , Diferenciação Celular/genética , Diferenciação Celular/fisiologia , Proliferação de Células , Sobrevivência Celular/genética , Sobrevivência Celular/fisiologia , Senescência Celular/genética , Senescência Celular/fisiologia , Ciclina D1/metabolismo , Quinase 4 Dependente de Ciclina/metabolismo , Técnicas de Silenciamento de Genes , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Estresse Oxidativo , Regulação para CimaRESUMO
Bioisosteric silicon replacement has proven to be a valuable strategy in the design of bioactive molecules for crop protection and drug development. Twenty-one novel carboxamides possessing a silicon-containing biphenyl moiety were synthesized and tested for their antifungal activity and succinate dehydrogenase (SDH) enzymatic inhibitory activity. Among these novel succinate dehydrogenase inhibitors (SDHIs), compounds 3a, 3e, 4l, and 4o possessing appropriate clog P and topological polar surface area values showed excellent inhibitory effects against Rhizoctonia solani, Sclerotinia sclerotiorum, Botrytis cinerea, and Fusarium graminearum at 10 mg/L in vitro, and the EC50 values of 4l and 4o were 0.52 and 0.16 mg/L against R. solani and 0.066 and 0.054 mg/L against S. sclerotiorum, respectively, which were superior to those of Boscalid. Moreover, compound 3a demonstrated superior SDH enzymatic inhibitory activity (IC50 = 8.70 mg/L), exhibiting 2.54-fold the potency of Boscalid (IC50 = 22.09 mg/L). Docking results and scanning electron microscope experiments revealed similar mode of action between compound 3a and Boscalid. The new silicon-containing carboxamide 3a is a promising SDHI candidate that deserves further investigation.
Assuntos
Ascomicetos , Desenho de Fármacos , Fungicidas Industriais , Fusarium , Simulação de Acoplamento Molecular , Rhizoctonia , Silício , Succinato Desidrogenase , Fungicidas Industriais/farmacologia , Fungicidas Industriais/química , Fungicidas Industriais/síntese química , Silício/química , Silício/farmacologia , Rhizoctonia/efeitos dos fármacos , Succinato Desidrogenase/antagonistas & inibidores , Succinato Desidrogenase/metabolismo , Fusarium/efeitos dos fármacos , Relação Estrutura-Atividade , Ascomicetos/efeitos dos fármacos , Botrytis/efeitos dos fármacos , Proteínas Fúngicas/antagonistas & inibidores , Proteínas Fúngicas/química , Proteínas Fúngicas/metabolismo , Doenças das Plantas/microbiologia , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/síntese química , Estrutura Molecular , Amidas/química , Amidas/farmacologia , Amidas/síntese químicaRESUMO
The enantioselective allylic alkylation of nitro ketene aminals with racemic allylic alcohols was realized by iridium/acid dual catalysis. An allyl group was installed on the α-position of nitro ketene aminals in a branched-selective manner in high efficiency with excellent enantioselectivities (93-99% ee). The protocol was applied to the late-stage modification of neonicotinoid insecticides, which directly furnished a novel neonicotinoid analogue with good insecticidal activity against Aphis craccivora (LC50 = 6.40 mg/L). On the basis of the control experiment, an aza-ene-type allylic alkylation reaction mechanism was proposed.
RESUMO
The first catalytic enantioselective 1,3-dipolar cycloaddition of azomethine ylides to α-aminoacrylate catalyzed by a AgOAc/ferrocenyl oxazolinylphosphine (FOXAP) system was developed, which exhibits excellent exo- and enantioselectivity (92-99 %â ee). This process provides efficient access to useful 4-aminopyrrolidine-2,4-dicarboxylic acid (APDC)-like compounds containing a unique quaternary α-amino acid unit.
Assuntos
Alanina/análogos & derivados , Aminoácidos/síntese química , Compostos Azo/química , Ácidos Dicarboxílicos/síntese química , Pirrolidinas/síntese química , Tiossemicarbazonas/química , Alanina/química , Aminoácidos/química , Catálise , Reação de Cicloadição , Ácidos Dicarboxílicos/química , Estrutura Molecular , Pirrolidinas/química , EstereoisomerismoRESUMO
An asymmetric cascade allylation/spiroketalization reaction between 2-(1-hydroxyallyl)phenols and 5-methyleneoxazolines is accomplished by using a chiral Ir(I) catalyst derived from commercially available iridium precursor and the Carreira ligand. This protocol furnishes a class of structurally novel and unique oxazoline-spiroketals in up to 86% yield, >99% ee and >20:1 dr. Moreover, control experiments reveal that 4,4-disubstitution on 5-methyleneoxazolines is necessary to avoid the aromatization and for the spiroketalization to occur. On the basis of this, a plausible reaction mechanism is illustrated.
RESUMO
The compounds featuring α-difluorothiomethylated ketone skeleton derivatives are of particular interest in pharmaceuticals and agrochemicals. Herein, we designed novel electrophilic N-difluoromethylthiophthalimide reagents that can be easily prepared with commercially available and economical chemicals. These reagents could smoothly react with various nucleophiles, such as Grignard reagents, boronic acids, ß-keto esters, and anilines, which affords structurally diverse α-difluoromethylthiolated ketones in good to excellent yields. The formal synthesis of active antifungal compounds positively confirmed the practicability of these reagents.
Assuntos
Cetonas , Ftalimidas , Cetonas/química , Catálise , Compostos RadiofarmacêuticosRESUMO
Neonicotinoid insecticides acting on the insect nicotinic acetylcholine receptors (nAChRs) play an essential role in contemporary pest control. In the present study, a series of novel neonicotinoid analogues with conjugated diene were synthesized. Bioassays indicated that compounds A3 and A12 had LC50 values of 1.26 and 1.24 mg/L against Myzus persicae, respectively, which were comparable to that of imidacloprid (IMI, LC50 = 0.78 mg/L). Density functional theory (DFT) calculations were performed to explain the differences in the insecticidal activities of target compounds. Molecular docking results indicate that compounds A3 and A12 interact favorably with Lymnaea stagnalis AChBP. The hydrolysis experiments confirmed that the stability of compounds A3 and A12 was enhanced in water.
Assuntos
Inseticidas , Receptores Nicotínicos , Animais , Inseticidas/farmacologia , Simulação de Acoplamento Molecular , Neonicotinoides , Insetos , Nitrocompostos/farmacologiaRESUMO
Excitatory-inhibitory imbalance (E/I) is a fundamental mechanism underlying autism spectrum disorders (ASD). TRIM32 is a risk gene genetically associated with ASD. The absence of TRIM32 causes impaired generation of inhibitory GABAergic interneurons, neural network hyperexcitability, and autism-like behavior in mice, emphasizing the role of TRIM32 in maintaining E/I balance, but despite the description of TRIM32 in regulating proliferation and differentiation of cultured mouse neural progenitor cells (NPCs), the role of TRIM32 in cerebral cortical development, particularly in the production of excitatory pyramidal neurons, remains unknown. The present study observed that TRIM32 deficiency resulted in decreased numbers of distinct layer-specific cortical neurons and decreased radial glial cell (RGC) and intermediate progenitor cell (IPC) pool size. We further demonstrated that TRIM32 deficiency impairs self-renewal of RGCs and IPCs as indicated by decreased proliferation and mitosis. A TRIM32 deficiency also affects or influences the formation of cortical neurons. As a result, TRIM32-deficient mice showed smaller brain size. At the molecular level, RNAseq analysis indicated reduced Notch signalling in TRIM32-deficient mice. Therefore, the present study indicates a role for TRIM32 in pyramidal neuron generation. Impaired generation of excitatory pyramidal neurons may explain the hyperexcitability observed in TRIM32-deficient mice.
Assuntos
Córtex Cerebral , Células-Tronco Neurais , Células Piramidais , Ubiquitina-Proteína Ligases , Animais , Córtex Cerebral/citologia , Camundongos , Células-Tronco Neurais/citologia , Neurogênese/genética , Neurônios/citologia , Células Piramidais/citologia , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismoRESUMO
An unprecedented iridium-catalyzed asymmetric [4 + 3] cycloaddition of racemic 4-indolyl allylic alcohols with azomethine ylides is reported. The ability of acid promoter zinc triflate to perform multiple roles is the key factor for the success of this strategy. This method provides scalable and efficient access to biologically important azepino[3,4,5-cd] indoles in good yields with generally excellent diastereo- and enantioselectivities (up to >20:1 dr and >99% ee). Mild reaction conditions, easily accessible substrates and chiral catalyst, and broad substrate scope highlight the practicality of this methodology.
RESUMO
An iridium-catalyzed trifluoroacetic acid-promoted asymmetric cascade allylation/Pictet-Spengler cyclization reaction of azomethine ylides with aromatic allylic alcohols is reported. This protocol provides a facile and scalable method for the construction of 1,3,4-trisubstituted tetrahydroisoquinolines containing two stereogenic centers in good yields (up to 96%) with generally excellent diastereo- and enantioselectivities (up to >20:1 dr and >99% ee). Furthermore, a series of aromatic heterocycle-fused piperidines were also obtained with excellent enantiocontrol by this methodology.
RESUMO
The palladium-catalyzed asymmetric [4 + 3] cycloaddition of a sulfonyl-trimethylenemethane (TMM) donor with azadienes furnished various sulfonyl-fused azepines with exclusive regioselectivities and excellent stereoselectivities (up to >20:1 dr, >99% ee) in high yields (up to 93%). Moreover, sulfone, serving as a transient activating group of the TMM species, can be easily removed from the cycloadducts to provide the structurally simple fused azepines with excellent enantioselectivities. This strategy demonstrates sulfonyl-TMM as an effective surrogate of naked TMM with high reactivity, exclusive regioselectivity, and excellent stereoselectivity.
RESUMO
A catalytic asymmetric decarboxylative [3 + 2] annulation via indolyl copper-allenylidene amphiphilic intermediates has been developed. This protocol offers a straightforward method for the synthesis of biologically important pyrrolo[1,2-a]indoles bearing contiguous quaternary and tertiary stereogenic centers with excellent diastereo- and enantioselectivities (up to >20:1 dr and >99% ee). In addition, the diversity-oriented synthesis of pyrrolo[1,2-a]indoles was achieved via versatile transformations of the alkyne-containing cycloadducts.