Expeditious preparation of ß-sec-alkyl vicinal amino alcohols used for chiral ligand synthesis.

An economical route providing quick access to chiral ß-amino alcohols bearing one ß-sec-alkyl group was developed. This protocol starts with commercially available and cheap chiral sources such as derivatives of L-serine and L-threonine. A series of vicinal amino alcohols with high optical purity were prepared in good yields through 4 or 6 operationally simple steps. Two different strategies (three routes) were designed for the synthesis of amino alcohols bearing ß-sec-alkyl groups with various steric hindrance.

Catalytic Asymmetric Synthesis of Axially Chiral Diaryl Ethers through Enantioselective Desymmetrization.

Axially chiral diaryl ethers are a type of unique atropisomers bearing two potential axes, which have potential applications in a variety of research fields. However, the catalytic enantioselective synthesis of these diaryl ether atropisomers is largely underexplored when compared to the catalytic asymmetric synthesis of biaryl or other types of atropisomers. Herein, we report a highly efficient catalytic asymmetric synthesis of diaryl ether atropisomers through an organocatalyzed enantioselective desymmetrization protocol. The chiral phosphoric acid-catalyzed asymmetric electrophilic aromatic aminations of the symmetrical 1,3-benzenediamine type substrates afforded a series of diaryl ether atropisomers in excellent yields and enantioselectivities. The facile construction of heterocycles by the utilizations of the 1,2-benzenediamine moiety in the products provided access to a variety of structurally diverse and novel azaarene-containing diaryl ether atropisomers.

Enantioselective Synthesis of Planar-Chiral Macrocycles through Asymmetric Electrophilic Aromatic Amination.

An efficient approach for asymmetric synthesis of planar-chiral macrocycles (paracyclophanes) has been disclosed through enantioselective electrophilic aromatic aminations with azodicarboxylates enabled by chiral phosphoric acid catalysis. A wide range of chiral macrocycles bearing varied ring sizes (16 to 23-membered) and functional group-containing ansa chains were readily afforded using this method, with excellent yields and high enantioselectivities (23 examples, up to 99.5 : 0.5 er). Experimental studies and DFT calculations were performed to elucidate the mechanism and origin of stereoselectivities of these reactions. Preliminary utilization of the planar-chiral macrocycle as chiral organocatalyst showcased the potential applications of these novel chiral skeletons.

Asymmetric Synthesis of Hydroquinolines with α,α-Disubstitution through Organocatalyzed Kinetic Resolution.

The first kinetic resolution of hydroquinoline derivatives with α,α-disubstitution has been achieved through asymmetric remote aminations with azodicarboxylates enabled by chiral phosphoric acid catalysis. Mechanistic studies suggest a monomeric catalyst pathway proceeding through rate- and enantio-determining electrophilic attack promoted by a network of attractive non-covalent interactions between the substrate and catalyst. Facile subsequent removal and transformations of the newly introduced hydrazine moiety enable these protocols to serve as powerful tools for asymmetric synthesis of N-heterocycles with α,α-disubstitution.

Endoplasmic Reticulum Stress Induces HRD1 to Protect Alveolar Type II Epithelial Cells from Apoptosis Induced by Cigarette Smoke Extract.

BACKGROUND/AIMS: Cigarette smoking is a major risk factor of chronic obstructive pulmonary disease. This study aimed to examine the effects of cigarette smoke extract (CSE) on alveolar type II epithelial cells (AECII) and investigate the underlying mechanism. METHODS: Primary AECII were isolated from rat lung tissues and exposed to CSE. Apoptosis was detected by flow cytometry. Protein expression was detected by Western blot analysis. RESULTS: Primary rat AECII maintained morphological and physiological characteristic after 3 passages. CSE increased the expression of ER specific pro-apoptosis factors CHOP and caspase 12, and the phosphorylation of JNK in AECII. CSE activated ER stress signaling and increased the phosphorylation of PERK, eIF2α and IRE1. Furthermore, CSE induced the expression of Hrd1, a key factor of ER-associated degradation, in AECII. Knockdown of Hrd1 led to more than 2 fold increase of apoptosis, while overexpression of Hrd1 attenuated CSE induced apoptosis of AECII. CONCLUSIONS: Our results suggest that ER stress induces HRD1 to protect alveolar type II epithelial cells from apoptosis induced by CSE.

Ag(i)-Catalyzed oxidative decarboxylation of difluoroacetates with activated alkenes to form difluorooxindoles.

A silver-catalyzed oxidative decarboxylative gem-difluoromethylenation of difluoroacetates with activated alkenes under mild reaction conditions has been developed. This radical cascade reaction provides a new method for the construction of a variety of gem-difluoromethylenated oxindoles.

Iron-Catalyzed Direct Diazidation for a Broad Range of Olefins.

Reported herein is a new iron-catalyzed diastereoselective olefin diazidation reaction which occurs at room temperature (1-5 mol% of catalysts and d.r. values of up to >20:1). This method tolerates a broad range of both unfunctionalized and highly functionalized olefins, including those that are incompatible with existing methods. It also provides a convenient approach to vicinal primary diamines as well as other synthetically valuable nitrogen-containing building blocks which are difficult to obtain with alternative methods. Preliminary mechanistic studies suggest that the reaction may proceed through a new mechanistic pathway in which both Lewis acid activation and iron-enabled redox-catalysis are crucial for selective azido-group transfer.

[Regulatory mechanism of Siah1 in the pathogenesis of rat hypoxic pulmonary hypertension].

OBJECTIVE: To explore the regulatory mechanism of Siahl in the pathogenesis of hypoxic pulmonary hypertension (HPH) in rats. METHODS: According to the random number table, 40 adult male Wistar rats were randomly divided into 5 groups (n = 8 each). And the animals were exposed to normoxia or hypoxia for 3, 7, 14 or 21 days respectively. The HPH model was established by normobaric intermittent hypoxia. Mean pulmonary arterial pressure (mPAP), ratio of vascular wall area to total vascular area (WA%), ratio of vascular lumen area to total vascular area (LA%) and right ventricle hypertrophy index (RVHI) were measured. The mRNA and protein relative levels of hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) were detected by in situ hybridization and immunohistochemistry respectively. Reverse transcriptase-polymerase chain reaction ( RT-PCR) and in situ hybridization were used to determine the relative expressions of mRNA of hypoxia-inducible factor-1 (FIH) and Siahl. Immunohistochemistry and Western blot were employed to determine the relative expressions of proteins of FIH and Siahl. RESULTS: The levels of mPAP, WA% and LA% were significantly higher after 7-day hypoxia than those in normoxic control (21. 3 1. 6) vs (15. 9 ± 1. 3) mmHg (1 mmHg = 0. 133 kPa), (41.4 ± 2.8)% vs (35.0 ± 2.2)%, (58.6 ± 2.8)% vs (65.0 ± 2.2)%, all P <0.05). The level of RVHI was significantly higher after 14-day hypoxia than that in normoxic control ((27. 0 ± 1. 8) % vs (3. 2 ± 2. 1) %, P <0. 05). The relative expression of HIF-1α mRNA was significantly higher after 14-day hypoxia than that in normoxic control (0. 188 ± 0. 014 vs 0. 150 ± 0. 014, P < 0. 05). The relative expression of HIF-1α protein was significantly higher after 3-day hypoxia than that in normoxic control (0. 186 ± 0.014 vs 0. 067 ± 0.008, P <0.05). The relative levels of VEGF mRNA and protein were significantly higher after 7-day hypoxia than those in normoxic control (0. 152 ± 0. 019 vs 0. 057 ± 0. 007, 0. 176 ± 0. 017 vs 0. 083 ± 0. 010, both P <0. 05). The relative expression of FIH mRNA had little changes after exposure to hypoxia compared with normoxia. However the related expression of FIH protein was markedly lower after 7-day hypoxia than that in normoxic control (0. 166 ± 0. 015 vs 0. 200 ± 0. 017, P < 0. 05). The relative levels of Siahl mRNA and protein were markedly higher after 7-day hypoxia than those in normoxic control (0. 144 ± 0. 014 vs 0. 067 ± 0. 010, 0. 136 ± 0. 017 vs 0. 084 ± 0. 019, both P <0. 05). Linear correlation analysis showed that HIF-1α protein was positively correlated with the relative levels of VEGF mRNA and VEGF protein (r = 0. 545, 0. 523, both P <0. 01) while FIH protein was negatively correlated with the relative levels of VEGF mRNA and VEGF protein (r = -0. 785, -0. 788, both P < 0. 01). There was a positive correlation between the relative levels of Siahi mRNA and Siahl protein (r = 0. 823, P <0. 01) while a negative correlation existed between the relative levels of Siahl protein and FIH protein (r = -0. 671, P <0. 01). CONCLUSIONS: Under chronic hypoxia, Siahl is transcriptionally induced in pulmonary arterioles and it facilitates the degradation and decline of FIR in rats. And deceased FIH protein in pulmonary arterioles under hypoxia may attenuate its inhibitory effect on the transactivational activity of HIF-l a and promote the transactivation of such HIF-1α target gene as VEGF. Thus it is probably implicated in the pathogenesis of HPH.

Bis(pinacolato)diboron-Enabled Ni-Catalyzed Reductive Arylation/Vinylation of Alkyl Electrophiles.

Herein, the use of economically and environmentally friendly bis(pinacolato)diboron (B2Pin2) is described as a non-metallic reductant in mediating Ni-catalyzed C(sp3)-C(sp2) reductive cross-coupling of alkyl electrophiles with aryl/vinyl halides. This method exhibits excellent suitability for heteroaryl halides and alkyl halides/Katritzky salts. The present study is compatible with an in situ halogenation of alcohol method, allowing for selective mono-functionalization of diols and bio-relevant alcohols (e.g., carbohydrates). The use of B2Pin2 shows potential for easy scalability without introducing additional metal impurities into the products. It is observed for the first time in the realm of cross-electrophile coupling chemistry that B2Pin2 can sever as a reductant to reduce NiII to Ni0. This mechanistic insight may inspire the development of new reductive bond-forming methodologies that can otherwise be difficult to achieve with a metal reductant.

Silver-mediated oxidative C-H/P-H functionalization: an efficient route for the synthesis of benzo[b]phosphole oxides.

A Ag-mediated C-H/P-H functionalization reaction of arylphosphine oxides with internal alkynes was described for the direct preparation of benzo[b]phosphole oxides with a high yield. An unusual aryl migration on the P-atom derived from a C-P bond cleavage and a new C-P bond formation was also observed and demonstrated to proceed via the radical process.

Simvastatin Reduces NETosis to Attenuate Severe Asthma by Inhibiting PAD4 Expression.

Objective: Patients with severe asthma respond poorly to corticosteroids, and their care accounts for more than 60% of the total costs attributed to asthma. Neutrophils form neutrophil extracellular traps (NETs), which play a crucial role in severe asthma. Statins have shown anti-inflammatory effects by reducing NETosis. In this study, we investigate if simvastatin can attenuate severe asthma by reducing NETosis and the underlying mechanism. Methods: Mice were concomitantly sensitized with ovalbumin (OVA), house dust mite (HDM), and lipopolysaccharide (LPS) during sensitization to establish a mouse model of severe asthma with neutrophil predominant inflammation (OVA+LPS mice) and treated with or without simvastatin. In inflammatory response, proportions of Th2, Th17, and Treg cells in lung tissue were detected by flow cytometry, and the levels of cytokines, dsDNA, and MPO-DNA in bronchoalveolar lavage fluid (BALF) were analyzed by ELISA. Citrullinated histone H3 (CitH3) and peptidyl arginine deiminase 4 (PAD4) in lung tissue were determined by Western blot and immunofluorescence imaging. PAD4 mRNA was determined by quantitative PCR (qPCR). HL-60 cells were differentiated into neutrophil-like cells by 1.25% DMSO. The neutrophil-like cells were treated with or without LPS, and simvastatin was then stimulated with PMA. CitH3 and PAD4 expressions were determined. Results: Sensitization with OVA, HDM, and LPS resulted in neutrophilic inflammation and the formation of NETs in the lungs. Simvastatin treatment reduced the inflammation score, cytokine levels, total cells, and neutrophil counts in the BALF and reduced proportions of Th2 and Th17 but increased Treg cells in lungs of OVA+LPS mice. Simvastatin-treated OVA+LPS mice show reduced NET formation in BALF and lung tissue compared to control mice. Adoptive transfer of neutrophils was sufficient to restore NETosis and neutrophilic inflammation in simvastatin-treated OVA+LPS mice. Simvastatin reduced PAD4 mRNA and protein expression in lung tissues and neutrophils isolated from lungs of OVA+LPS mice and consequent NET formation. In vitro, simvastatin reduced LPS-induced PAD4 upregulation and NETosis in HL-60-differentiated neutrophil-like cells. Furthermore, PAD4-overexpressed lentiviral transduction was sufficient to restore PAD4 protein expression and NETosis in simvastatin-treated HL-60-differentiated neutrophil-like cells. Conclusions: Simvastatin reduces Th17-mediated neutrophilic inflammation and airway hyperreactivity by reducing PAD4 expression and inhibiting NETosis in a mouse model of severe asthma. Severe asthmatic patients with high levels of circulating NETs or sputum NETs may show improved responses to statin treatment.

Ti-Catalyzed Dehydroxylation of Tertiary Alcohols.

Herein we report a Ti-catalyzed direct dehydroxylation of tertiary aliphatic alcohols under mild reaction conditions, forging Barton-type deoxygenation products. This protocol tolerates a wide range of functional groups, including primary alkyl chloride and carbonyl groups. It allows for selective dehydroxylation of tertiary alcohols in diols and the formation of deuterated products with moderate deuterium incorporation. The efficient modification of several drugs and natural products (or their derivatives) highlights the synthetic utility of this method.

Asymmetric synthesis of aryl/vinyl alkyl carbinol esters via Ni-catalyzed reductive arylation/vinylation of 1-chloro-1-alkanol esters.

We report herein an asymmetric Ni-catalyzed cross-electrophile coupling approach to prepare enantioenriched aryl/vinyl alkyl carbinol esters through arylation/vinylation of easily accessible racemic 1-chloro-1-alkanol esters with aryl/vinyl electrophiles. The method features a broad substrate scope as demonstrated by more than 60 examples including the challenging chiral allylic esters. It tolerates a wide array of functional groups including alkenyl, carbonyl and free hydroxyl groups that may not survive in conventional carbonyl reduction and addition methods. The synthetic utility of the present work was showcased by facile preparation of a few key intermediates and the modification of chiral drugs and naturally occurring compounds. Finally, we describe an efficient one-pot procedure for this method.

Silver-Promoted Decarboxylative Difluoromethylenation of α,ß-Unsaturated Carboxylic Acids for the Synthesis of Allylic Difluorides.

An efficient silver-promoted decarboxylative gem-difluoromethylenation of aryl- or alkyl-substituted α,ß-unsaturated carboxylic acids with readily available benzo-1,3-diazolic difluoromethyl bromides has been developed. This convenient transformation demonstrated good functional-group tolerability and broad substrate scope, and afforded the allylic difluorides in good to excellent yields with exclusive E-stereoselectivity under mild reaction conditions.

Exploring the Effects of Different Bacteria Additives on Fermentation Quality, Microbial Community and In Vitro Gas Production of Forage Oat Silage.

Bacterial inoculants are considered as a good choice for successful ensiling, playing a key role in improving the silage quality. However, the potential of different bacteria, especially the propionic acid bacteria, in forage oat ensiling is yet to be explored. Therefore, the purpose of this study was to investigate the regulation effects of different bacterial additives on the fermentation quality of forage oat silage. Four additives (Lactiplantibacillus plantarum F1, LP; Lacticaseibacillus 0rhamnosus XJJ01, LR; Lacticaseibacillus paracasei XJJ02, LC; and Propionibacterium acidipropionici 1.1161, PP; without additives, CK) were inoculated in forage oat silage, and the fermentation quality and organic compounds were determined after 60 days of ensiling. Notably, LR showed higher dry matter preservation compared to other additives and CK. In addition, LP and LR showed strong lactic acid synthesis capacity, resulting in lower pH compared to other additives and CK. The treatments of PP and LC increased the bacterial diversity in silage, while the bacterial community in the LR group was different from that in other groups. In addition, the PP- and LC-treated oat silage showed significantly lower total in vitro gas production and a lower methane content. These results suggest that LP is more favorable for producing high-quality oat silage than LR, LC, or PP. Both the PP- and LC- treated oat silage may reduce rumen greenhouse gas emissions.

Kinetic Resolution of 2,2-Disubstituted Dihydroquinolines through Chiral Phosphoric Acid-Catalyzed C6-Selective Asymmetric Halogenations.

A novel kinetic resolution of 2,2-disubstituted dihydroquinolines was achieved by regioselective asymmetric halogenations enabled by chiral phosphoric acid catalysis. A series of dihydroquinolines bearing 2,2-disubstitutions were well-tolerated in these reactions, generating both the recovered dihydroquinolines and C-6-brominated products with high enantioselectivities, with s-factors up to 149. In addition, this kinetic resolution protocol is also applicable for 2,2-disubstituted tetrahydroquinoline and asymmetric iodonation reaction.

Good's syndrome with diffuse panbronchiolitis as the prominent manifestation: A case and literature review.

Good's syndrome (GS) is characterized by thymoma combined with adult-onset immunodeficiency. Diffuse panbronchiolitis (DPB) is a chronic inflammatory airway disease, which predominantly affects East Asians. Japanese scholars have reported extensively about GS combined with DPB or DPB-like pulmonary manifestation. However, such reports are rare in China. We report here a case of GS in China with DPB as the prominent manifestation and carry out a literature review accordingly. Our review indicates that in adults with DPB-like clinical manifestations, thymic lesions should be excluded and related immune function tests should be performed to exclude GS to avoid missed diagnosis and misdiagnosis.

Alkenylation and Arylation of Peptides via Ni-Catalyzed Reductive Coupling of α-C-Tosyl Peptides with Csp2 Triflates/Halides.

A Ni-catalyzed reductive cross-coupling between α-C-tosyl peptides and Csp2 triflates/halides has been developed. This protocol enables the formation of various unnatural di- and tripeptides containing vinyl and aryl side chains, and it expands the applications of Ni-catalyzed reductive cross-coupling in late-stage diversification of peptides.

Kinetic resolution of N-aryl ß-amino alcohols via asymmetric aminations of anilines.

An efficient kinetic resolution of N-aryl ß-amino alcohols has been developed via asymmetric para-aminations of anilines with azodicarboxylates enabled by chiral phosphoric acid catalysis. Broad substrate scope and high kinetic resolution performances were afforded with this method. Control experiments supported the critical roles of the NH and OH group in these reactions.