Enantioselective Nickel-Electrocatalyzed Reductive Propargylic Carboxylation with CO2.

The exploitation of carbon dioxide (CO2) as a sustainable, plentiful, and harmless C1 source for the catalytic synthesis of enantioenriched carboxylic acids has long been acknowledged as a pivotal task in synthetic chemistry. Herein, we present a current-driven nickel-catalyzed reductive carboxylation reaction with CO2 fixation, facilitating the formation of C(sp3)-C(sp2) bonds by circumventing the handling of moisture-sensitive organometallic reagents. This electroreductive protocol serves as a practical platform, paving the way for the synthesis of enantioenriched propargylic carboxylic acids (up to 98% enantiomeric excess) from racemic propargylic carbonates and CO2. The efficacy of this transformation is exemplified by its successful utilization in the asymmetric total synthesis of (S)-arundic acid, (R)-PIA, (S)-chizhine D, (S)-cochlearin G, and (S,S)-alexidine, thereby underscoring the potential of asymmetric electrosynthesis to achieve complex molecular architectures sustainably.

Atropisomeric Carboxylic Acids Synthesis via Nickel-Catalyzed Enantioconvergent Carboxylation of Aza-Biaryl Triflates with CO2.

Upgrading CO2 to value-added chiral molecules via catalytic asymmetric C-C bond formation is a highly important yet challenging task. Although great progress on the formation of centrally chiral carboxylic acids has been achieved, catalytic construction of axially chiral carboxylic acids with CO2 has never been reported to date. Herein, we report the first catalytic asymmetric synthesis of axially chiral carboxylic acids with CO2, which is enabled by nickel-catalyzed dynamic kinetic asymmetric reductive carboxylation of racemic aza-biaryl triflates. A variety of important axially chiral carboxylic acids, which are valuable but difficult to obtain via catalysis, are generated in an enantioconvergent version. This new methodology features good functional group tolerance, easy to scale-up, facile transformation and avoids cumbersome steps, handling organometallic reagents and using stoichiometric chiral materials. Mechanistic investigations indicate a dynamic kinetic asymmetric transformation process induced by chiral nickel catalysis.

Cu-Catalyzed Asymmetric Dicarboxylation of 1,3-Dienes with CO2.

Dicarboxylic acids and derivatives are important building blocks in organic synthesis, biochemistry, and the polymer industry. Although catalytic dicarboxylation with CO2 represents a straightforward and sustainable route to dicarboxylic acids, it is still highly challenging and limited to generation of achiral or racemic dicarboxylic acids. To date, catalytic asymmetric dicarboxylation with CO2 to give chiral dicarboxylic acids has not been reported. Herein, we report the first asymmetric dicarboxylation of 1,3-dienes with CO2 via Cu catalysis. This strategy provides an efficient and environmentally benign route to chiral dicarboxylic acids with high regio-, chemo-, and enantioselectivities. The copper self-relay catalysis, that is, Cu-catalyzed boracarboxylation of 1,3-dienes to give carboxylated allyl boronic ester intermediates and subsequent carboxylation of C-B bonds to give dicarboxylates, is key to the success of this dicarboxylation. Moreover, this protocol exhibits broad substrate scope, good functional group tolerance, easy product derivatizations, and facile synthesis of chiral liquid crystalline polyester and drug-like scaffolds.

Nickel-Catalyzed Asymmetric Reductive Carbo-Carboxylation of Alkenes with CO2.

Reductive carboxylation of organo (pseudo)halides with CO2 is a powerful method to provide carboxylic acids quickly. Notably, the catalytic reductive carbo-carboxylation of unsaturated hydrocarbons via CO2 fixation is a highly challenging but desirable approach for structurally diverse carboxylic acids. There are only a few reports and no examples of alkenes via transition metal catalysis. We report the first asymmetric reductive carbo-carboxylation of alkenes with CO2 via nickel catalysis. A variety of aryl (pseudo)halides, such as aryl bromides, aryl triflates and inert aryl chlorides of particular note, undergo the reaction smoothly to give important oxindole-3-acetic acid derivatives bearing a C3-quaternary stereocenter. This transformation features mild reaction conditions, wide substrate scope, facile scalability, good to excellent chemo-, regio- and enantioselectivities. The method highlights the formal synthesis of (-)-Esermethole, (-)-Physostigmine and (-)-Physovenine, and the total synthesis of (-)-Debromoflustramide B, (-)-Debromoflustramine B and (+)-Coixspirolactam A; thereby, opening an avenue for the total synthesis of chiral natural products with CO2 .

Analysis and comparison of metabolic processes of salvianolic acid A and salvianolic acid B in rats based on UHPLC-LTQ-Orbitrap MS technology / 中国中药杂志

The metabolites of salvianolic acid A and salvianolic acid B in rats were analyzed and compared by ultra-high-perfor-mance liquid chromatography with linear ion trap-orbitrap mass spectrometry(UHPLC-LTQ-Orbitrap MS). After the rats were administrated by gavage, plasma at different time points and urine within 24 hours were collected to be treated by solid phase extraction(SPE), then they were gradient eluted by Acquity UPLC BEH C_(18) column(2.1 mm×100 mm, 1.7 μm) and 0.1% formic acid solution(A)-acetonitrile(B) mobile phase system, and finally all biological samples of rats were analyzed under negative ion scanning mode. By obtaining the accurate relative molecular mass and multi-level mass spectrometry information of metabolites, combined with the characteristic cleavage law of the reference standard and literature reports, a total of 30 metabolites, including salvianolic acid A and B, were identified. Among them, there were 24 metabolites derived from salvianolic acid A, with the main metabolic pathways including ester bond cleavage, dehydroxylation, decarboxylation, hydrogenation, methylation, hydroxylation, sulfonation, glucuronidation, and their multiple reactions. There were 15 metabolites of salvianolic acid B, and the main biotransformation pathways were five-membered ring cracking, ester bond cleavage, decarboxylation, dehydroxylation, hydrogenation, methylation, sulfonation, glucuronidation, and their compound reactions. In this study, the cross-metabolic profile of salvianolic acid A and B was elucidated completely, which would provide reference for further studies on the basis of pharmacodynamic substances and the exploration of pharmacological mechanism.

Preliminary study of basis of hepatotoxic substance of ripe fruit of Terminalia chebula Retz. var. tomentella Kurtwith high content screening assay / 中国药理学通报

Aim To study the material basis of hepatotoxicity induced by the ripe fruit of Terminalia chebula Retz. var. tomentella Kurt using high content screening. Methods Shikimic acid, benzoic acid, gallic acid, and 1,2,3,4,6-o-pentagalactosyl glucose were applied to HepG2 cells, respectively, and the cells were stained with fluorescent stains such as Hoechst 33342. The imagewas scannedand the collected datawere input into the Assay Template. Finally, the dose-response curves of cell numbers, DNA content, GSH reduction level, ROS content, MMP and other indicators were obtained for different monomers at different concentrations, thereby the hepatotoxicity of the monomers was determined. Results Aspirin and shikimic acid showed negative results. Ticlopidine, benzoic acid, 1,2,3,4,6-o-pentagalloglucose, gallic acid caused a significant decrease in cell number and increase in ROS content. There was a risk of liver-toxicity. Conclusions Gallic acid, benzoic acid, 1,2,3,4,6-o-pentagalactosylglucose have the risk of hepatotoxicity, and the risk of hepatotoxicity caused by gallic acid is the largest. Basically, gallic acid is safer when administered at concentrations below 50 mg·L-1

Analysis of carnosic acid metabolites in rats by UHPLC-Q-Exactive MS / 中国中药杂志

A method of ultra-high performance liquid chromatography coupled with quadrupole/electrostatic field Obitrap high-resolution mass spectrometry(UHPLC-Q-Exactive MS) was established to comprehensively identify the metabolites of carnosic acid in rats. After oral gavage of carnosic acid CMC-Na suspension in rats, urine, plasma and feces samples were collected and pretreated by solid phase extraction(SPE). Acquity UPLC BEH C_(18 )column(2.1 mm×100 mm, 1.7 μm) was used with 0.1% formic acid solution(A)-acetonitrile(B) as the mobile phase for the gradient elution. Biological samples were analyzed by quadrupole/electrostatic field Obitrap high-resolution mass spectrometry in positive and negative ion mode. Based on the accurate molecular mass, fragment ion information, and related literature reports, a total of 28 compounds(including carnosic acid) were finally identified in rat samples. As a result, the main metabolic pathways of carnosic acid in rats are oxidation, hydroxylation, methylation, glucuronide conjugation, sulfate conjugation, S-cysteine conjugation, glutathione conjugation, demethylation, decarbonylation and their composite reactions. The study showed that the metabolism of carnosic acid in rats could be efficiently and comprehensively clarified by using UHPLC-Q-Exactive MS, providing a reference for clarifying the material basis and metabolic mechanism of carnosic acid.

Highly Selective and Catalytic Generation of Acyclic Quaternary Carbon Stereocenters via Functionalization of 1,3-Dienes with CO2.

The catalytic asymmetric functionalization of readily available 1,3-dienes is highly important, but current examples are mostly limited to the construction of tertiary chiral centers. The asymmetric generation of acyclic products containing all-carbon quaternary stereocenters from substituted 1,3-dienes represents a more challenging, but highly desirable, synthetic process for which there are very few examples. Herein, we report the highly selective copper-catalyzed generation of chiral all-carbon acyclic quaternary stereocenters via functionalization of 1,3-dienes with CO2. A variety of readily available 1,1-disubstituted 1,3-dienes, as well as a 1,3,5-triene, undergo reductive hydroxymethylation with high chemo-, regio-, E/Z-, and enantioselectivities. The reported method features good functional group tolerance, is readily scaled up to at least 5 mmol of starting diene, and generates chiral products that are useful building blocks for further derivatization. Systemic mechanistic investigations using density functional theory calculations were performed and provided the first theoretical investigation for an asymmetric transformation involving CO2. These computational results indicate that the 1,2-hydrocupration of 1,3-diene proceeds with high π-facial selectivity to generate an (S)-allylcopper intermediate, which further induces the chirality of the quaternary carbon center in the final product. The 1,4-addition of an internal allylcopper complex, which differs from previous reports involving terminal allylmetallic intermediates, to CO2 kinetically determines the E/Z- and regioselectivity. The rapid reduction of a copper carboxylate intermediate to the corresponding silyl-ether in the presence of Me(MeO)2SiH provides the exergonic impetus and leads to chemoselective hydroxymethylation rather than carboxylation. These results provide new insights for guiding further development of asymmetric C-C bond formations with CO2.

Synergetic iridium and amine catalysis enables asymmetric [4+2] cycloadditions of vinyl aminoalcohols with carbonyls.

Catalytic asymmetric cycloadditions via transition-metal-containing dipolar intermediates are a powerful tool for synthesizing chiral heterocycles. However, within the field of palladium catalysis, compared with the well-developed normal electron-demand cycloadditions with electrophilic dipolarophiles, a general strategy for inverse electron-demand ones with nucleophilic dipolarophiles remains elusive, due to the inherent linear selectivity in the key palladium-catalyzed intermolecular allylations. Herein, based on the switched regioselectivity of iridium-catalyzed allylations, we achieved two asymmetric [4+2] cycloadditions of vinyl aminoalcohols with aldehydes and ß,γ-unsaturated ketones through synergetic iridium and amine catalysis. The activation of vinyl aminoalcohols by iridium catalysts and carbonyls by amine catalysts provide a foundation for the subsequent asymmetric [4+2] cycloadditions of the resulting iridium-containing 1,4-dipoles and (di)enamine dipolarophiles. The former provides a straightforward route to a diverse set of enantio-enriched hydroquinolines bearing chiral quaternary stereocenters, and the later represent an enantio- and diastereodivergent synthesis of chiral hydroquinolines.

Effect of NEU3 on biological behaviors of human prostate cancer DU145 cells / 中国病理生理杂志

AIM:To explore the effects of neuraminidase 3 (NEU3) on the viability, invasion and apoptosis of human prostate cancer DU145 cells and the molecular mechanism.METHODS:The human prostate cancer DU145 cells were divided into blank control group and treatment group.The cells in treatment group were treated with either neuraminidase inhibitor DANA, or NEU3 small interfering RNA (siRNA) to knock down the expression of NEU3.The cell viability was measured by CCK-8 assay.The cell invasion ability was detected by Transwell assay.The effects of the treatments on the mRNA level of Bcl-2 were detected by q PCR.The effects of the treatments on the protein levels of matrix metalloproteinase 2 (MMP2) and apoptotic inhibitory protein Bcl-2 were determined by Western blot.Apoptosis of the cells was analyzed by flow cytometry.RESULTS:The protein level of NEU3 and the apoptotic rate in DANA group were not significantly different from those in blank control group.The viability of DANA-treated DU145 cells was increased, and the invasion ability, MMP2 protein level, and Bcl-2 mRNA and protein levels were all decreased in these cells, compared with blank control group.On the other hand, the levels of NEU3 protein and Bcl-2 mRNA and protein in NEU3 siRNA group were significantly decreased compared with blank control group, while the viability and apoptotic rate of the cells with NEU3 siRNA transfection were increased (P<0.05).However, the protein expression of MMP2 and the invasion ability of the cells were not significantly changed after NEU3 siRNA treatment.CONCLUSION:The inhibition of NEU3 in enzyme activity and expression decreases the viability, and enhances the apoptosis of human prostate cancer DU145 cells.However, it has no obvious effect on the invasion ability of DU145 cells.

Highly Regio- and Enantioselective Copper-Catalyzed Reductive Hydroxymethylation of Styrenes and 1,3-Dienes with CO2.

Herein, we report a highly regio- and enantioselective copper-catalyzed reductive hydroxymethylation of styrenes and 1,3-dienes with 1 atm of CO2. Diverse important chiral homobenzylic alcohols were readily prepared from styrenes. Moreover, a variety of 1,3-dienes also were converted to chiral homoallylic alcohols with high yields and excellent regio-, enantio-, and Z/E-selectivities. The utility of this transformation was demonstrated by a broad range of styrenes and 1,3-dienes, facile product modification, and synthesis of bioactive compounds (R)-(-)-curcumene and (S)-(+)-ibuprofen. Mechanistic studies demonstrated the carboxylation of phenylethylcopper complexes with CO2 as one key step.

Accommodative response and nearwork-induced transient myopia induced by simplified and traditional Chinese characters / 中华实验眼科杂志

Background Epidemiologic studies found that the incidence of myopia is higher in Hong Kong and Taiwan regions of China than that of the mainland.So whether the general reading words with traditional Chinese characters and simplified characters is associated with myopia deserves attention.Objective This study was to test the accommodative responses and the regression levels of nearwork-induced transient myopia (NITM) induced by traditional complex Chinese characters and modern simplified ones in the same size,and to explore the differences and inherent relationship of the accommodative regulations based on the structures of the two types of Chinese character in causing reading triggered myopia.Methods Twenty two volunteers aged 24-29 years were included in this study with informed consent.The corrected vision of both eyes from each subject was ≥ 1.0 with a mean spherical equivalence of (-1.86±2.34)D.Accommodative response was tested with 4 different reading texts using the rapid sequence visual presenting model with the GRAND SEIKO-WV5500 infrared autorefractor,and this procedure was performed after full correction of refractive error.An initial test of looking at a certain distance was performed (as baseline),and then the subjects read intensively at the targets for 10 minutes at 33 cm to calculate the accommodative responses.After a 10 second pause,the ocular refractive status was obtained exactly at 15 seconds,20 seconds.The one-way ANOVA method was used to determine the effects of the different font types and sizes on the adjustive responses and the causation of NITM.Results Accommodative response induced by simplified and traditional Chinese characters showed an accommodative lag of (1.11 ±0.38),(0.95 ±0.43),(1.18 ±0.33) and (1.06±0.28) D,showing a significant difference among the 9 pt and 12 pt simplified and traditional Chinese characters (F =1.62,P =0.19),and significantly different accommodative lag values between 12 pt simplified characters and 9 pt traditional characters was found (t =5.56,P =0.02).NITM induced by the four different targets were (-0.45 ±0.45),(-0.47 ±0.46),(0.45 ±0.82) and (-0.46±0.78) D in the 4 types of characters,without a significant difference among them (F=0.01,P =0.99).Conclusions Near-distance reading causes accommodative lag regardless of the type of reading texts.The target demonstrated stimuli spatial frequency and font size play an impact on accommodative responses.NITM appears when one reads simplified or traditional Chinese for 10 minutes.The accommodative lag and NITM trend might be responsible for the onset or regression of myopia,yet it is not supportive for the hypothesis that reading traditional Chinese causes more strain since there is no difference between the two.