Asymmetric rhodium-catalyzed click cycloaddition to access C-N axially chiral N-triazolyl indoles.

The copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction is regarded as a prime example of "click chemistry", but the asymmetric click cycloaddition of internal alkynes still remains challenging. A new asymmetric Rh-catalyzed click cycloaddition of N-alkynylindoles with azides was developed, providing atroposelective access to C-N axially chiral triazolyl indoles, a new type of heterobiaryl, with excellent yields and enantioselectivity. This asymmetric approach is efficient, mild, robust and atom-economic, and features very broad substrate scope with easily available Tol-BINAP ligands.

Synthesis of Benzofuran Derivates via a Gold-Catalyzed Claisen Rearrangement Cascade.

A novel method toward a facile synthesis of diverse benzofuran derivates from easily obtained quinols and alkynyl esters has been reported. A gold-catalyzed intermolecular alkoxylation/Claisen rearrangement/condensation cascade was involved. The introduction of difluorodiphenylsilane as a water-trapping reagent in the reaction leads to a higher yield.

Asymmetric Azide-Alkyne Cycloaddition with Ir(I)/Squaramide Cooperative Catalysis: Atroposelective Synthesis of Axially Chiral Aryltriazoles.

An Ir(I)/squaramide cooperative catalytic strategy for atroposelective synthesis of axially chiral aryltriazoles has been developed for the first time. Diverse structurally novel aryltriazole skeletons that cannot be accessed by traditional click reactions were synthesized in good yields with excellent enantioselectivity. Both enantiomers were easily obtained from a pair of diastereoisomeric natural quinidine- and quinine-derived squaramides. A significant Ir(I)/squaramide coordination activation, but no self-quenching phenomenon was observed in this metal/organo cooperative catalytic system.

Modular Synthesis of α-Quaternary Chiral ß-Lactams by a Synergistic Copper/Palladium-Catalyzed Multicomponent Reaction.

An asymmetric multicomponent, interrupted Kinugasa allylic alkylation (IKAA) reaction has been developed with a synergistic Cu-catalyzed Kinugasa system and a Pd-catalyzed allylic alkylation reaction. This unprecedented reaction provides in high yields and with high stereoselectivity a synthesis of α-quaternary chiral ß-lactams, which cannot be produced with existing synthetic methods. Stereoselective coupling of two catalytic amounts of transient organometallic intermediates formed in situ is an important feature of this reaction.

Astragaloside IV Protects 6-Hydroxydopamine-Induced SH-SY5Y Cell Model of Parkinson's Disease via Activating the JAK2/STAT3 Pathway.

OBJECTIVES: Astragaloside IV (AS-IV), the main active component of Astragalus membranaceus, bears anti-inflammatory, antioxidant, and neuroprotective activity. Parkinson's disease (PD) is a common neurodegenerative disease. This study explored the protective effect of AS-IV on the cell model of PD. MATERIALS AND METHODS: SH-SY5Y cells were incubated with different concentrations (10, 50, 100, 150, and 200 µM) of 6-hydroxydopamine (6-OHDA) for 0, 3, 6, 12, 24, and 48 h to establish the PD cell model. Different concentrations (0, 25, 50, 100, 150, and 200 µM) of AS-IV or 15 mM JAK2/STAT3 pathway inhibitor SC99 was added for intervention 2 h before 6-OHDA treatment. The viability and morphological damage of 6-OHDA-treated SH-SY5Y cells were measured using MTT assay and Hoechst 33258 staining. The expression of microtubule associated protein 2 (MAP2) was detected by immunofluorescence staining. The levels of inflammation and oxidative stress were measured using ELISA. Apoptosis of 6-OHDA-treated SH-SY5Y cells was detected using flow cytometry, and phosphorylation level of JAK2 and STAT3 were detected using Western blot analysis. RESULTS: The survival rate of SH-SY5Y cells treated with 100 µM 6-OHDA for 24 h was about 50%. AS-IV (25-100 µM) significantly improved the viability (all p < 0.01), increased MAP2 expression, and repaired the morphological damage induced by 6-OHDA. AS-IV inhibited IL-1ß, IL-6, and TNF-α level (all p < 0.05), reduced MDA and ROS content and increased SOD concentration, thereby reducing inflammation and oxidative stress (all p < 0.01) in 6-OHDA-treated SH-SY5Y cells. Moreover, AS-IV decreased apoptosis rate and Bax/Bcl-2 ratio induced by 6-OHDA (all p < 0.05). Mechanically, AS-IV significantly increased the phosphorylation of JAK2 and STAT3 (p < 0.01); the addition of SC99 decreased the cell viability, increased the apoptosis rate, enhanced the levels of inflammatory factors and oxidative stress. CONCLUSION: AS-IV enhanced the cell viability, and inhibited apoptosis, inflammation and oxidative stress of 6-OHDA-treated SH-SY5Y cells via activating the JAK2/STAT3 signaling pathway. This study may confer novel insights for the management of PD.

Copper(I)-Catalyzed Asymmetric Interrupted Kinugasa Reaction: Synthesis of α-Thiofunctional Chiral ß-Lactams.

A copper(I)-catalyzed asymmetric, three-component interrupted Kinugasa reaction has been developed. Diverse chiral sulfur-containing chiral ß-lactams with two consecutive stereogenic centers were synthesized in one step from readily available starting materials in good yields and with excellent diastereo- and enantioselectivity. The key is the interception of in situ formed chiral four membered copper(I) enolate intermediate with sulfur electrophiles.

Kinetically Controlled Radical Addition/Elimination Cascade: From Alkynyl Aziridine to Fluorinated Allenes.

A kinetically controlled radical addition/elimination reaction generating fluorinated allenes was developed. This strategy offers a route to a facile synthesis of diverse trifluoromethyl, difluoromethylene, and perfluoroalkyl functionalized allenes from readily available fluoroalkyl halides and alkynyl aziridines under visible-light irradiation. Density functional theory calculation of this radical clock type of reaction revealed a kinetically controlled C-N bond cleavage overcoming the alternative thermodynamically controlled C-C bond cleavage process.

Astragaloside IV Alleviates Cerebral Ischemia-Reperfusion Injury by Activating the Janus Kinase 2 and Signal Transducer and Activator of Transcription 3 Signaling Pathway.

Astragaloside IV (AS-IV) is an active component extracted from the traditional Chinese herbal medicine. AS-IV is a neuroprotective component in cerebral ischemic models. However, roles of AS-IV in cerebral ischemia-reperfusion (I/R) injury and the underlying mechanisms are rarely investigated. The role of AS-IV in oxygen - glucose deprivation reoxygenation (OGD/R)-induced cell proliferation and apoptosis assays were analyzed by Cell Counting Kit-8 and Flow cytometric. Western Blot assays were performed to measure the related expression levels in SH-SY5Y cells. Meanwhile, activities of reactive oxygen species (ROS), superoxide dismutase (SOD), and malondialdehyde (MDA) in OGD/R-induced cells were determined by relative commercial kits. AS-IV was also used in cerebral I/R rat model, aimed to investigate the effects on cerebral infarct. The results indicated that OGD/R suppressed viability, enhanced apoptosis, which could be reversed by AS-IV treatment. Compared with the control group, the expression of p-JAK2 and p-STAT3 was significantly increased by AS-IV (60 µg/mL) under the OGD/R condition. Furthermore, AS-IV (60 µg/mL) treatment markedly increased SOD activity, whereas significantly decreased MDA activity and production of ROS in OGD/R-induced cells. The protective effects of AS-IV mentioned above were weaken or abolished while adding JAK2 inhibitor AG490. In addition, the effects of AS-IV on Janus kinase 2 and signal transducer and activator of transcription 3 (JAK2/STAT3) signaling in cerebral I/R injury were also verified in vivo. AS-IV protected against cerebral I/R injury and reversed by AG490. Therefore, in vitro and in vivo analyses suggested that AS-IV may protect against cerebral I/R injury partly mediated by JAK2/STAT3 signaling pathway and antioxidative effects. AS-IV may serve as a novel therapeutic regimen for cerebral I/R injury.

Asymmetric Synthesis of a Fused Tricyclic Hydronaphthofuran Scaffold by Desymmetric [2+2+2] Cycloaddition.

A rhodium(I)-BINAP-catalyzed highly enantioselective [2+2+2] cycloaddition of enynes with alkynes has been developed. Diverse fused tricyclic hydronaphthofuran scaffolds with three consecutive stereogenic centers were constructed in one step from easily available materials with excellent chemo-, regio-, diastereo-, and enantioselectivity. Notable features of these reactions include 100 % atom economy, very broad scope, and mild reaction conditions.

Hydroalkynylative cyclization of 1,6-enynes with terminal alkynes.

A rhodium-catalyzed highly regio- and enantioselective hydroalkynylation, generating cis-hydrobenzofuranone-tethered enynes has been developed. The reaction proceeds with a selective head-to-head insertion and symmetry breaking Michael addition cascade. One product was produced from tens of possible isomers through precise control of chemo-, regio-, and stereoselectivities using a single rhodium catalyst. Notable features of this method include 100% atom-economy, mild reaction conditions and a very broad substrate scope.

Morphological and clinical risk factors for the rupture of posterior communicating artery aneurysms: significance of fetal-type posterior cerebral artery.

BACKGROUND: Posterior communicating artery (PcomA) aneurysm can be classified into sidewall or bifurcation types based on the anatomical variation of fetal-type posterior cerebral artery (fPCA). The aims of this study were to investigate the significance of fPCA as an independent risk factor for the rupture of PcomA aneurysm and to evaluate other associated morphological and clinical risk factors. METHODS: We retrospectively reviewed clinical and radiological findings of 255 patients with PcomA aneurysms, which were treated in a single tertiary institute between January 2009 and December 2016. Univariate and multivariate analyses were performed to evaluate the associations between morphological and clinical variables and rupture status. Subgroup analysis was also performed based on the aneurysms with and without fPCA. RESULTS: Fifty-five out of 255 PcomA aneurysms (21.6%) were associated with fPCA. Multivariate logistic regression analysis showed that the superior direction of aneurysm dome (OR 9.106, p = 0.007), the presence of a bleb (OR 4.780, p < 0.001), a high aspect ratio (OR 1.878, p = 0.045), and fPCA (2.101, p = 0.040) were significantly associated with PcomA aneurysm rupture. In the fPCA group, only the presence of a bleb varied significantly between ruptured and unruptured PcomA aneurysms. However, in the non-fPCA group, larger aneurysms, the superior direction of dome, the presence of a bleb, and a high aspect and dome-to-neck ratio were significantly higher in the ruptured aneurysm group than in the unruptured aneurysm group. CONCLUSIONS: The results demonstrate that fPCA may be an independent risk factor for rupture, especially together with the presence of a bleb.

Divergent synthesis of chiral cyclic azides via asymmetric cycloaddition reactions of vinyl azides.

Vinyl azides, bearing conjugated azide and alkene functional groups, have been recognized as versatile building blocks in organic synthesis. In general vinyl azides act as 3-atom (CCN) synthons through the fast release of molecular nitrogen and have been extensively utilized in the construction of structurally diverse N-heterocycles. Keeping the azide moiety intact in organic transformations to synthesis chiral azides is an important but challenging task. Herein, we report an enantioselective copper(II)/BOX-catalyzed cycloaddition of vinyl azides, generating diverse chiral cyclic azides. α-Aryl substituted vinyl azides react with unsaturated keto esters through an inverse-electron-demand hetero-Diels-Alder reaction to afford chiral azido dihydropyrans with excellent enatioselectivities. In contrast, cyclohexenyl azides undergo a diastereo- and enantio-selective Diels-Alder reaction giving important azido octahydronaphthalenes with three continuous stereogenic centers. Notable features of these reactions include a very broad scope, mild reaction conditions and 100% atom economy.

Diastereoselective Synthesis of Polysubstituted Spirocyclopenta[ c]furans by Gold-Catalyzed Cascade Reaction.

With the synergistic activation of alkynyl alcohols and alkynyl enones by a single gold catalyst, diverse multisubstituted spirocyclopenta[ c]furans were synthesized in good to excellent yields under mild conditions. Three rings were constructed efficiently in one pot from easily available acyclic starting materials.

Copper-Catalyzed Oxidative Trifunctionalization of Olefins: An Access to Functionalized ß-Keto Thiosulfones.

Aerobic oxidative trifunctionalization of olefins for the synthesis of functionalized ß-keto thiosulfones has been described. The transformation proceeds through molecular oxygen activation under copper catalysis and forms the two new C-S bonds in a single operation using mild conditions. A novel Cu-catalyzed sulfonyl radical addition/oxidation/funtionalization relay mechanism was proposed for the discovered reaction.

Cu-Catalyzed Electrophilic Disulfur Transfer: Synthesis of Unsymmetrical Disulfides.

An efficient electrophilic persulfuration reaction leading to unsymmetrical disulfides and polysulfides has been developed. Various nucleophiles, including aryl boronic acids, ß-keto esters, and thiols, can be used as substrates. The notable features of this method include very simple and practical conditions, general scope, and inexpensive copper catalysts.

Copper(I)-Catalyzed Three-Component Click/Persulfuration Cascade: Regioselective Synthesis of Triazole Disulfides.

A copper(I)-catalyzed three-component CuAAC/persulfuration reaction providing rapid access to asymmetric triazole disulfides has been developed. The interrupted click reaction shows broad substrate scope, complete regioselectivity, and excellent functional group tolerability.

Synthesis of Spiroketals by Synergistic Gold and Scandium Catalysis.

An ultrafast synthesis of spiroketals by synergistic gold(I) and Sc(III) catalysis has been reported. Diverse 5,6-benzannulated spiroketals were rapidly constructed by the diastereoselective [4 + 2] cycloaddition between gold-generated enol ether and Sc(III)-catalyzed o-quinone methide intermediates. Ultrafast reaction rate, ambient reaction temperature, general scope, high yields, excellent diastereoselectivity, and good scalability are attractive features of this method.

Dual gold and photoredox catalysis: visible light-mediated intermolecular atom transfer thiosulfonylation of alkenes.

Regioselective difunctionalization of alkenes has attracted significant attention from synthetic chemists and has the advantage of introducing diverse functional groups into vicinal carbons of common alkene moieties in a single operation. Herein, we report an unprecedented intermolecular atom transfer thiosulfonylation reaction of alkenes by combining gold catalysis and visible-light photoredox catalysis. A trifluoromethylthio group (SCF3) and other functionalized thio groups together with a sulfonyl group were regioselectively introduced into alkenes in the most atom economical manner. A detailed mechanism study indicated that a synergistic combination of gold catalysis and photoredox catalysis is crucial for this reaction.

Bench-Stable 5-Stannyl Triazoles by a Copper(I)-Catalyzed Interrupted Click Reaction: Bridge to Trifluoromethyltriazoles and Trifluoromethylthiotriazoles.

Metalated triazoles are the key reactive intermediate of the current click reaction (CuAAC). Bench-stable 5-stannyl triazoles are obtained by a copper-catalyzed interrupted click reaction of easily available terminal alkynes. Subsequent palladium-catalyzed cross-coupling reactions, electrophilic trifluoromethylthiolation and trifluoromethylation, generate diverse 1,4,5-trisubstituted triazoles efficiently, which the traditional click reaction is unable to do.

Gold-Catalyzed Cycloisomerization/1,5-H Migration/Diels-Alder Reaction Cascade: Synthesis of Complex Nitrogen-Containing Heterocycles.

An unprecedented gold-catalyzed cycloisomerization/1,5-H migration/Diels-Alder reaction cascade has been developed that enables the rapid construction of complex nitrogen polycyclic compounds. This one-pot, three-step cascade reaction offers good yields of the products and is promoted by a single gold catalyst under very mild conditions.