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.

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.

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.

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.

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.

Zn/Sc bimetallic relay catalysis: one pot cycloisomerization/carbonyl-ene reaction toward oxazole derivatives.

A novel tandem metal relay catalytic system combining Zn(II)-catalyzed cycloisomerization and a Sc(III)-catalyzed carbonyl-ene reaction has been successfully developed. By using this unprecedented Zn/Sc bimetallic relay catalytic system, a variety of oxazole derivatives were obtained from easily available N-(propargyl)arylamides and aldehydes under mild conditions.

Breaking aziridines to construct morpholines with a gold(i)-catalyzed tandem ring-opening and cycloisomerization reaction.

A convenient synthetic method for the construction of morpholine derivatives from easily available aziridines and propargyl alcohols has been successfully developed. A tandem nucleophilic ring-opening of aziridine/6-exo-dig cyclization/double bond isomerization sequence was achieved by using a single gold(i) catalyst under mild conditions. The gold(i) catalyst served as a π acid and also a σ acid to realize the dual activation of both reactants in this reaction. The obtained unsaturated morpholine products could be easily hydrogenated to achieve target morpholine derivatives with good diastereoselectivities in high yields.

Copper(I)-Catalyzed Interrupted Click Reaction: Synthesis of Diverse 5-Hetero-Functionalized Triazoles.

The 5-heterofunctionalized triazoles are important scaffolds in bioactive compounds, but current click reactions (CuAAC) cannot produce these core structures. A copper(I)-catalyzed interrupted click reaction to access diverse 5-functionalized triazoles is reported. Various 5-amino-, thio-, and selenotriazoles were readily assembled in one step in high yields. The reaction proceeds under mild conditions with complete regioselectivity. It also features a broad substrate scope and good functional group compatibility.

Synthesis of Oxazoles by Tandem Cycloisomerization/Allylic Alkylation of Propargyl Amides with Allylic Alcohols: Zn(OTf)2 as π Acid and σ Acid Catalyst.

A Zn(OTf)2-catalyzed tandem cycloisomerization/allylic alkylation of N-(propargyl)arylamides and allylic alcohols to produce oxazole derivatives has been successfully developed. The zinc catalyst served as π acid and also σ acid in this reaction. The target allylic oxazoles have been transformed into multisubstituted diene structures, which are potential aggregation-induced emission active optical materials.

Synthesis of quinolinones with palladium-catalyzed oxidative annulation between acrylamides and arynes.

An unprecedented palladium-catalyzed oxidative annulation of acrylamides with benzyne precursors has been successfully developed. By using this mild "N-H activation/Heck reaction" method, a wide variety of quinolinones were conveniently prepared in one step with high efficiency.

In situ construction of three anion-dependent cu(i) coordination networks as promising heterogeneous catalysts for azide-alkyne "click" reactions.

Three Cu(I) coordination networks, namely, {[Cu2(bpz)2(CN)X]·CH3CN}n, (X = Cl, 1; I, 3), {[Cu6(bpz)6(CH3CN)3(CN)3Br]·2OH·14CH3CN}n, (2, bpz = 3,3',5,5'-tetramethyl-4,4'-bipyrazole), were prepared by using solvothermal method. The cyanide ligands in these networks were generated in situ by cleavage of C-C bond of MeCN under solvothermal condition. The structures of these networks are dependent on halogen anions. Complex 1 is a ladderlike structure with µ2-CN(-) as rung and µ2-bpz as armrest. The Cl(-) in 1 is at terminal position but does not extend the one-dimensional (1D) ladder to higher dimensionalities. Complex 2 is a three-dimensional (3D) framework comprised of novel planar [Cu3Br] triangle and single Cu nodes, which are extended by µ2-bpz and µ2-CN(-) to form a novel (3,9)-connected gfy network. Density functional theory calculations showed that single-electron delocalization of Br atom induces the plane structure of [Cu3Br]. Complex 3 also possesses a similar ladderlike subunit as in 1, but the I(-) acts as bidentate bridge to extend the ladder to 3D framework with a four-connected sra topology. The three networks show notable catalytic activity on the click reaction. The compared catalytic results demonstrate that complex 2 possesses the best catalysis performance among three complexes, which is ascribed to the largest solvent-accessible void (porosity: 2 (29.4%) > 1 (25.7%) > 3 (17.6%)) and the more Cu(I) active sites in 2. The present combined structure-property studies provide not only a new synthetic route to obtain a new kind of catalyst for click reaction but also the new insights on catalyst structure-function relationships.

Design, synthesis and evaluation of XZH-5 analogues as STAT3 inhibitors.

Inhibition of the signaling pathways of signal transducer and activator of transcription 3 (STAT 3) has shown to be a promising strategy to combat cancer. In this paper we report the design, synthesis and evaluation of a novel class of small molecule inhibitors, that is, XZH-5 and its analogues, as promising leads for further development of STAT3 inhibitors. Preliminary SARs was established for XZH-5 and its derivatives; and the binding modes were predicted by molecular docking. Lead compounds with IC50 as low as 6.5µM in breast cancer cell lines and 7.6µM in pancreatic cancer cell lines were identified.

Hydrogels formed by enantioselective self-assembly of histidine-derived amphiphiles with tartaric acid.

Two chiral enantiomers of histidine-derived amphiphilic gelators, (4R,6S)-UIPCA and (4S,6R)-UIPCA, were synthesized through Pictet-Spengler reaction and their gelation behaviors with different organic acids were investigated. Interestingly, the chiral enantiomers of UIPCA showed smart enantioselectivity for gelating tartaric acid enantiomers to form hydrogels with excellent mechanical strength. The TEM and SEM images demonstrated that the hydrogels were composed of networks by physical entanglement of nanofibers with high aspect ratios. The formation of nanofibers was considered to be driven by the interplay of hydrogen bonding, electrostatic attraction, and hydrophobic interaction, which was supported by XRD and FT-IR spectra. The hydrogels exhibited sensitive response to a series of external stimuli, such as temperature, metal ions, and host-guest interactions, to realize the reversible gel-sol transition. The property of the gelation was elaborated and the gelators were expected to find their applications in chiral discrimination.

Tandem metal relay catalysis: from cyclopropene to polysubstituted furan.

Transmetalation is a key step in traditional coupling reactions. Herein we discuss the most recent progress in the metal-metal relay catalysis based on a transmetalation strategy. An efficient synthetic strategy for the formation of polysubstituted furan derivatives from cyclopropenes based on the tandem metal relay catalysis (TMRC reaction) is summarized.

Modular synthesis of all-substituted furans through oxidative carbonylation of cyclopropenes with tandem metal relay catalysis.

A modular synthesis of tetrasubstituted furan carboxylates using a tandem cycloisomerization/oxidative carbonylation sequence of cyclopropenes has been successfully developed. The Tandem Metal Relay Catalysis (TMRC) pathway accounted for the high efficiency of this transformation.

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.

Asymmetric Michael addition of ketones to alkylidene malonates and allylidene malonates via enamine-metal Lewis acid bifunctional catalysis.

Novel enamine-metal Lewis acid bifunctional catalysts were successfully applied to the asymmetric Michael addition of ketones to alkylidene malonates, offering excellent stereoselectivity (up to >99% ee and >99:1 dr). The asymmetric Michael addition of ketones to allylidene malonates was also achieved.

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.