B(C6F5)3/CPA-Catalyzed Aza-Diels-Alder Reaction of 3,3-Difluoro-2-Aryl-3H-indoles and Unactivated Dienes.

Here we report B(C6F5)3/CPA-catalyzed enantioselective aza-Diels-Alder reaction of 3,3-difluoro-2-Aryl-3H-indoles with unactivated dienes to access chiral 10,10-difluoro-tetrahydropyrido[1,2-a]indoles. This protocol allows the formation of pyrazole-based C2-quaternary indolin-3-ones with high enantioselectivities and regioselectivities. Moreover, gram-scale synthesis of the 10,10-difluoro-tetrahydropyrido[1,2-a]indole skeleton was successfully achieved without any reduction in both yield and enantioselectivity.

Asymmetric Synthesis of Axially Chiral N, N-1,2-Pentatomic Heterobiaryl Diamines by an Organocatalytic Arylation Reaction.

The utilization of axially chiral biaryl diamines has been widely acknowledged as highly advantageous structures for the advancement of chiral catalysts and ligands. This highlights their extensive range of applications in asymmetric catalysis and synthesis. Herein, we devised a direct arylation reactions of 5-aminopyrazoles with azonaphthalenes, utilizing chiral phosphoric acid as the catalyst. This method delivers structurally novel atroposelective N, N-1,2-azole heteroaryl diamines with high yields (up to >98%) and good to excellent enantiomeric ratios while exhibiting a wide range of substrate compatibility.

Electrochemical Dimerization of o-Aminophenols and Hydrogen Borrowing-like Cascade to Synthesize N-Monoalkylated Aminophenoxazinones via Paired Electrolysis.

A novel electrocatalytic dimerization of o-aminphenols and a hydrogen borrowing-like cascade for synthesizing N-monoalkylated aminophenoxazinones have been developed. This electrocatalytic reaction uses a constant current mode in an undivided cell and is free of metal catalysis, open to the air, and eco-friendly. In particular, this protocol exhibits a wide substrate range and provides versatile N-monoalkylated aminophenoxazinones in medium to good yields. The results of our mechanistic research reveal that this protocol involves a cascade of electrochemical cyclocondensation of o-aminphenols and the hydrogen transfer process via paired electrolysis.

Asymmetric aza-Friedel-Crafts Reaction of Cyclic Ketimines with 5-Aminopyrazole Derivatives: Expedient Access to Pyrazole-Based C2-quaternary Indolin-3-Ones.

A chiral phosphoric acid-catalyzed enantioselective aza-Friedel-Crafts reaction of 5-aminopyrazole derivatives with cyclic ketimines attached to a neutral functional group is reported. This protocol allows the formation of pyrazole-based C2-quaternary indolin-3-ones with high enantioselectivities and regioselectivities. Moreover, gram-scale synthesis of the 5-aminopyrazole-based C2-quaternary indolin-3-ones was performed, with no decrease in the yield and enantioselectivity.

Organocatalyzed Enantioselective Aza-Morita-Baylis-Hillman Reaction of Cyclic Ketimine with α,ß-Unsaturated γ-Butyrolactam.

The enantioselective aza-MBH reaction is an efficient strategy for constructing novel carbon-carbon bonds, providing access to multitudinous chiral densely functionalized MBH products. However, the enantioselective aza-MBH reaction of cyclic-ketimines that would generate a versatile synthon is still missing and challenging. Herein, we developed a challenging direct organocatalytic asymmetric aza-MBH reaction involving cyclic ketimines attached to a neutral functional group. Moreover, the α,ß-unsaturated γ-butyrolactam was utilized as a rare nucleophile alkene in this work. The reactions provide enantiomerically enriched 2-alkenyl-2-phenyl-1,2-dihydro-3H-indol-3-ones, bearing with a tetra-substituted stereogenic center. Moreover, this reaction features high α-selectivities, high enantioselectivities (up to 99% ee), and good yields (up to 80%).

Chiral phosphoric acid-catalyzed enantioselective aza-Friedel-Crafts reaction of naphthols and electron-rich phenols with 2-aryl-3H-indol-3-ones.

The enantioselective aza-Friedel-Crafts reaction is one of the most straightforward and efficient strategies for constructing a new carbon-carbon bond bearing quaternary stereocenter in organic synthesis, but the catalytic asymmetric aza-Friedel-Crafts reaction of naphthols/phenols with cyclic-ketimines attached to a neutral functional group remains still relatively unexplored. Herein, a highly enantioselective aza-Friedel-Crafts reaction of cyclic-ketimines and naphthols/phenols has been realized using a chiral phosphoric acid catalyst. A variety of chiral aminonaphthols (chiral indolin-3-ones) containing a quaternary stereocenter at the C2 position were obtained with excellent outcomes (up to 97% yield, 98% ee). Moreover, the synthetic utility of the enantiomerically enriched chiral aminonaphthols was demonstrated in some efficient transformations. According to the experimental results, a possible transition state model has been proposed to rationalize the origin of asymmetric induction.

B(C6F5)3-catalyzed ß-C(sp3)-H alkylation of tertiary amines with 2-aryl-3H-indol-3-ones.

The ß-C-H functionalization of amines is one of the most powerful tools for the synthesis of saturated nitrogen-containing heterocycles in organic synthesis. However, the ß-C-H functionalization of amines via redox-neutral addition with cyclic-ketimines is still unprecedented. Herein, the ß-C-H functionalization of tertiary amines is described, providing the corresponding 1,3-diamines containing the indolin-3-one moiety in high yields via the B(C6F5)3-catalyzed borrowing hydrogen strategy. According to the experimental results, a possible catalytic cycle has been proposed to rationalize the process of this reaction. Notably, the ß-C-H alkylation of amines is external oxidant- and transition-metal-free, which makes a significant contribution to promoting economical chemical synthesis.

Changes in blood pressure, oxygen saturation, hemoglobin concentration, and heart rate among low-altitude migrants living at high altitude (5380 m) for 360 days.

BACKGROUND: This article aimed to study the adjustment and adaptation of resting systolic blood pressure (SBP), diastolic blood pressure (DPB), oxygen saturation (SpO2 ), hemoglobin concentration ([Hb]), and heart rate (HR) in low-altitude migrants during a 1-year stay at high altitude. MATERIALS AND METHODS: Our study enrolled 35 young migrants who were exposed to a hypoxia environment at 5380 m altitude on the Qinghai Tibetan Plateau between June 21, 2017, and June 16, 2018. We set 14-time points (the 1st-10th, 20th, 30th, 180th, and 360th day after arriving at 5380 m) for obtaining the measurements of resting SBP, DBP, HR, SpO2, and [Hb] and compared them with the control values recorded prior to migration. Variables with continuous data were summarized as means (SD). One-way repeated measures ANOVA without assuming sphericity was carried out to test whether the mean values (SBP, DBP, HR, SpO2 , and [Hb]) on different days were different significantly. Furthermore, Dunnett's multiple comparisons test was carried out to determine the time points whose values were significantly different from the control values. RESULTS: SBP and DBP were continually increasing within d1-3 and peaked on the 3rd day, then steadily declined from d3 to d30. SBP fell back to the control values on d10 (p > 0.05), and DBP fell back to the control values on d20 (p > 0.05). A significant decline occurred on d180 (p < 0.05). Both SBP and DBP were lower than the control values on d180 (p < 0.05), and this trend was maintained to d360. There were similar characteristics of HR and BP in the time course at HA. HR on d1-3 was increasing (p < 0.05) compared to the control values, after which it fell back to the control values on d180 (p > 0.05), and this trend was maintained to d360. SpO2 was the lowest on d1 and lower than the control value throughout the study at HA (p < 0.05). [Hb] increased after long-term exposure (180 and 360 days) to HA (p < 0.05). CONCLUSIONS: Our study continuously monitored lowlanders at 5380 m in Tibet, and is perhaps the only longitudinal study of migrants conducted at an altitude above 5000 m during a 1-year period. Our study provides new information on the adjustment and adaptation of [Hb], SpO2 , SBP, DBP, and HR in high-altitude plateau migrants during a 360-day stay at an altitude of 5380 m.

Asymmetric Intramolecular Hydroalkylation of Internal Olefin with Cycloalkanone to Directly Access Polycyclic Systems.

An asymmetric intramolecular hydroalkylation of unactivated internal olefins with tethered cyclic ketones was realized by the cooperative catalysis of a newly designed chiral amine (SPD-NH2 ) and PdII complex, providing straightforward access to either bridged or fused bicyclic systems containing three stereogenic centers with excellent enantioselectivity (up to 99 % ee) and diastereoselectivity (up to >20 : 1 dr). Notably, the bicyclic products could be conveniently transformed into a diverse range of key structures frequently found in bioactive terpenes, such as Δ6 -protoilludene, cracroson D, and vulgarisins. The steric hindrance between the Ar group of the SPD-NH2 catalyst and the branched chain of the substrate, hydrogen-bonding interactions between the N-H of the enamine motif and the C=O of the directing group MQ, and the counterion of the PdII complex were identified as key factors for excellent stereoinduction in this dual catalytic process by density functional theory calculations.

Enantioselective Synthesis of 3,3'-Disubstituted 2-Amino-2'-hydroxy-1,1'-binaphthyls by Copper-Catalyzed Aerobic Oxidative Cross-Coupling.

A challenging direct asymmetric catalytic aerobic oxidative cross-coupling of 2-naphthylamine and 2-naphthol, using a novel CuI /SPDO system, has been successfully developed for the first time. Enantioenriched 3,3'-disubstituted NOBINs were achieved and could be readily derived to divergent chiral ligands and catalysts. This reaction features high enantioselectivities (up to 96 % ee) and good yields (up to 80 %). The DFT calculations suggest that the F-H interactions between CF3 of L17 and H-1,8 of 2-naphthol, and the π-π stacking between the two coupling partners could play vital roles in the enantiocontrol of this cross-coupling reaction.

Resolvin D1 ameliorates cognitive impairment following traumatic brain injury via protecting astrocytic mitochondria.

Cognitive impairment is one of the most common and devastating neuropsychiatric sequelae after traumatic brain injury (TBI), and hippocampal neuronal survival plays a causal role in this pathological process. Resolvin D1 (RvD1), an important endogenous specialized pro-resolving mediator, has recently been reported to exert a potent protective effect on mitochondria. This suggests that RvD1 may suppress neuroinflammation and protect astrocytic mitochondria at the same time to play further neuroprotective roles. C57BL/6 mice subjected to TBI using a controlled cortical impact device were used for in vivo experiments. Cultured primary mouse astrocytes and an N2a mouse neuroblastoma cell line were used for in vitro experiments. In TBI mice, RvD1 significantly ameliorated cognitive impairment, suppressed gliosis and alleviated neuronal loss in the hippocampus. To explore the mechanism underlying this activity, we verified that RvD1 can induce a higher level of mitophagy to remove damaged mitochondria and eliminate extra mitochondria-derived reactive oxygen species (mitoROS) by activating ALX4/FPR2 receptors in astrocytes. In an in vitro model, we further confirmed that RvD1 can protect mitochondrial morphology and membrane potential in astrocytes and thereby enhance the survival of neurons. Meanwhile, RvD1 was also shown to increase the expression of brain-derived neurotrophic factor and glutamate aspartate transporter in the hippocampus following TBI, which indicates a possible way by which RvD1 increases the supportive function of astrocytes. These findings suggest that RvD1 may be a potent therapeutic option for ameliorating cognitive impairment following TBI by controlling neuroinflammation and protecting astrocytic mitochondria.

Zerumbone ameliorates behavioral impairments and neuropathology in transgenic APP/PS1 mice by suppressing MAPK signaling.

BACKGROUND: Alzheimer's disease (AD) is a major clinical problem, but there is a distinct lack of effective therapeutic drugs for this disease. We investigated the potential therapeutic effects of zerumbone, a subtropical ginger sesquiterpene, in transgenic APP/PS1 mice, rodent models of AD which exhibit cerebral amyloidosis and neuroinflammation. METHODS: The N9 microglial cell line and primary microglial cells were cultured to investigate the effects of zerumbone on microglia. APP/PS1 mice were treated with zerumbone, and non-cognitive and cognitive behavioral impairments were assessed and compared between the treatment and control groups. The animals were then sacrificed, and tissues were collected for further analysis. The potential therapeutic mechanism of zerumbone and the signaling pathways involved were also investigated by RT-PCR, western blot, nitric oxide detection, enzyme-linked immunosorbent assay, immunohistochemistry, immunofluorescence, and flow cytometry analysis. RESULTS: Zerumbone suppressed the expression of pro-inflammatory cytokines and induced a switch in microglial phenotype from the classic inflammatory phenotype to the alternative anti-inflammatory phenotype by inhibiting the mitogen-activated protein kinase (MAPK)/nuclear factor-kappa B signaling pathway in vitro. After a treatment period of 20 days, zerumbone significantly ameliorated deficits in both non-cognitive and cognitive behaviors in transgenic APP/PS1 mice. Zerumbone significantly reduced ß-amyloid deposition and attenuated pro-inflammatory microglial activation in the cortex and hippocampus. Interestingly, zerumbone significantly increased the proportion of anti-inflammatory microglia among all activated microglia, potentially contributing to reduced ß-amyloid deposition by enhancing phagocytosis. Meanwhile, zerumbone also reduced the expression of key molecules of the MAPK pathway, such as p38 and extracellular signal-regulated kinase. CONCLUSIONS: Overall, zerumbone effectively ameliorated behavioral impairments, attenuated neuroinflammation, and reduced ß-amyloid deposition in transgenic APP/PS1 mice. Zerumbone exhibited substantial anti-inflammatory activity in microglial cells and induced a phenotypic switch in microglia from the pro-inflammatory phenotype to the anti-inflammatory phenotype by inhibiting the MAPK signaling pathway, which may play an important role in its neuroprotective effects. Our results suggest that zerumbone is a potential therapeutic agent for human neuroinflammatory and neurodegenerative diseases, in particular AD.

Value of the Barthel scale in prognostic prediction for patients with cerebral infarction.

BACKGROUND: This study aims to evaluate the ADL(activity of daily living) of patients with acute cerebral infarction through BI scoring, in order to observe its predictive value in the prognosis of these patients. METHODS: According to the inclusion and exclusion criteria, patients with acute anterior circulation cerebral infarction were included in the present study. Then, the BI scoring was analyzed through five grades, in order to further investigate the dose-response relationship between BI scoring and mortality risk in patients with cerebral infarction. The receiver operating characteristic (ROC) curves for BI-scored patients were drawn, and the predictive authenticity of the Barthel scale in prognostic prediction for patients with cerebral infarction was estimated. RESULTS: The difference in BI scores between the survival group and death group were statistically significant (t = 10.029, P < 0.05), in which the score was lower in the death group than in the survival group. According to the linear trend ×2-test, the decrease in BI score indicates an increase in mortality risk in patients with cerebral infarction. The area under the curve (AUC) of the ROC curve was 0.794 with a P-value of < 0.05. CONCLUSION: BI scoring is a highly valuable scoring system for the prognostic prediction of patients with acute cerebral infarction.

Copper-Complex-Catalyzed Asymmetric Aerobic Oxidative Cross-Coupling of 2-Naphthols: Enantioselective Synthesis of 3,3'-Substituted C1 -Symmetric BINOLs.

A novel chiral 1,5-N,N-bidentate ligand based on a spirocyclic pyrrolidine oxazoline backbone was designed and prepared, and it coordinates CuBr in situ to form an unprecedented catalyst that enables efficient oxidative cross-coupling of 2-naphthols. Air serves as an external oxidant and generates a series of C1 -symmetric chiral BINOL derivatives with high enantioselectivity (up to 99 % ee) and good yield (up to 87 %). This approach is tolerant of a broader substrates scope, particularly substrates bearing various 3- and 3'-substituents. A preliminary investigation using one of the obtained C1 -symmetric BINOL products was used as an organocatalyst, exhibiting better enantioselectivity than the previously reported organocatalyst, for the asymmetric α-alkylation of amino esters.

Lewis acid-promoted cascade reaction for the synthesis of Michael acceptors and its application in a dimerization reaction.

An efficient Lewis acid-promoted cascade reaction with dimethyl sulfoxide as a methylene source for the synthesis of Michael acceptors is reported. The key to developing this procedure is the selection of a mild base to modulate the equilibrium of various intermediates in order to drive the reaction forward to the formation of Michael acceptor and dimeric compound products. Extensive studies were performed to gain insight into a possible reaction mechanism.

[Label-Free and Rapid Detection of Histidine-Rich Peptides in Saliva].

Siliva as a kind of biomarker containing a variety of bioactive components can be used to help disease diagnosis. Compared with the urine and blood, the collection of saliva is more simple and convenient while the collection process is completely non-invasive. Therefore, saliva detection attracts more and more attention in non-invasive disease diagnosis. Histatins are a family of small, cationic, histidine-rich peptides, which secreted by salivary bringing innate defense of the oral cavity. It has been reported that histatins are related to many other diseases, such as HIV and AIDs. Thus the detection of histatins in saliva is significantly important for oral healthy monitoring and disease diagnosis. In this paper, a new label free method for rapid detection of histidine-rich peptides was developed based on the fact that histidine-rich peptides can interact with 3-azidocoumarin through hydrogen bonds which decreases the electron-donating ability of the azido group and results in fluorescence enhancement of the system. The results showed that the fluorescence intensities were dramatically increased when histatin 5 were incubation with 3-azidocoumarin. There is a good relationship with the linear co r of 0.994 between the enhanced fluorescence and histatin 5 concentration ranging from 0.23 to 31.05 µmol·L-1, and the limit of detection is 72 nmol·L-1 (3σ/k). Moreover, the detection of histidine-rich peptides in saliva was successfully achieved by the new developed label free method since amino acids and proteins in saliva will not be interfered with the detection with the recoveries between 96.7%~111.6%. Compared with the existing saliva analysis methods, this method has the advantage of simple, fast and low cost. It might be applied in non-invasive disease diagnosis.

Copper and electrocatalytic synergy for the construction of fused quinazolinones with 2-aminobenzaldehydes and cyclic amines.

A new copper and electrocatalytic synergy strategy for efficiently constructing fused quinazolinones has been developed. In the presence of cupric acetate and oxygen, aryl ketones and 1,2,3,4-tetrahydroisoquinoline can smoothly participate in this transformation, thus providing a variety of substituted quinazolones in an undivided cell. The reaction shows good functional group tolerance and provides universal quinazolinones at a good yield under mild conditions.

Electrochemical-induced solvent-tuned selective C(sp3)-H bond activation towards the synthesis of C3-functionalized chromone derivatives.

An unprecedented solvent-tuned electrochemical method for selective C(sp3)-H bond activation towards the synthesis of C3 functionalized chromone derivatives has been developed. This electrosynthesis protocol provides an efficient and green way to access various C3-functionalized chromones by avoiding traditionally employed transition metals and high temperatures. The swappable chemoselectivity was controlled mainly by altering the solvent and the current. A plausible reaction mechanism has been proposed with the help of radical capture and cyclic voltammetry experiments.

Electrochemical multicomponent [2+2+1] cascade cyclization of enaminones and primary amines towards the synthesis of 4-acylimidazoles.

An electrochemical multicomponent [2+2+1] cascade cyclization of enaminones and primary amines towards the synthesis of 4-acylimidazoles has been developed. In an undivided cell, enaminones and primary amines can smoothly participate in this reaction to provide a series of 1,2-disubstituted 4-acylimidazoles at room temperature. The reaction avoids the use of both transition-metal catalysts and oxidation reagents, which makes it more sustainable and renewable.