Catalytic enantioselective reductive Eschenmoser-Claisen rearrangements.

An important challenge in enantioselective catalysis is developing strategies for the precise synthesis of neighboring congested all-carbon quaternary stereocenters. The well-defined transition states of [3,3]-sigmatropic rearrangements and their underlying stereospecificity render them powerful tools for the synthesis of such arrays. However, this type of pericyclic reaction remains notoriously difficult to catalyze, especially in an enantioselective fashion. Herein, we describe an enantioselective reductive Eschenmoser-Claisen rearrangement catalyzed by chiral 1,3,2-diazaphospholene-hydrides. This developed transformation enables full control of the two newly formed acyclic stereogenic centers, leading to amides with vicinal all-carbon quaternary-tertiary or quaternary-quaternary carbon atoms.

Reductive Asymmetric Aza-Mislow-Evans Rearrangement by 1,3,2-Diazaphospholene Catalysis.

1,3,2-diazaphospholene hydrides (DAP-H) enable smooth conjugate reduction of polarized double bonds. The transiently formed phosphorus-enolate provides a potential platform for reductive α-functionalizations. In this respect, asymmetric C-heteroatom bond forming processes are synthetically appealing but remain elusive. We report a 1,3,2-diazaphospholene-catalyzed three-step cascade reaction of N-sulfinyl acrylamides comprised of conjugate reduction, [2,3]-sigmatropic aza-Mislow-Evans rearrangement and subsequent S-O bond cleavage. The obtained enantio-enriched α-hydroxy amides are formed in good yields and excellent enantiospecificity. The stereo-defined P-bound N,O-ketene aminal ensures an excellent transfer of chirality from the sulfur stereocenter to α-carbon. The transformation operates under mild conditions at ambient temperature. Moreover, DAP-H is a competent reductant for the cleavage of formed sulfenate ester, eliminating the extra step in traditional Mislow-Evans processes.

Comparative analysis of the daily liver transcriptomes in wild nocturnal bats.

BACKGROUND: Mammals rely on the circadian clock network to regulate daily systemic metabolism and physiological activities. The liver is an important peripheral organ in mammals, and it has a unique circadian rhythm regulation process. As the only mammals that can fly, bats have attracted much research attention due to their nocturnal habits and life histories. However, few research reports exist concerning the circadian rhythms of bat liver gene expression and the relevant biological clock regulation mechanisms in the liver. RESULTS: In this study, the expression levels of liver genes of Asian particolored bats were comparatively analyzed using RNA-seq at four different time points across 24 h. A total of 996 genes were found to be rhythmic, accounting for 65% of the total number of expressed genes. The critical circadian rhythm genes Bmal1, Rev-erbα, Cry, and Ror in the liver exhibited different expression patterns throughout the day, and participated in physiological processes with rhythmic changes, including Th17 cell differentiation (ko04659), antigen processing and presentation (ko04612), the estrogen signaling pathway (ko04915), and insulin resistance (ko04931). In addition, previous studies have found that the peroxisome proliferator-activated receptor (PPAR) metabolic signaling pathway (ko03320) may play a vital role in the rhythmic regulation of the metabolic network. CONCLUSIONS: This study is the first to demonstrate diurnal changes in bat liver gene expression and related physiological processes. The results have thus further enriched our understanding of bats' biological clocks.

Comparative analysis of the daily brain transcriptomes of Asian particolored bat.

Daily rhythms are found in almost all organisms, and they comprise one of the most basic characteristics of living things. Daily rhythms are generated and mainly regulated by circadian clock. Bats have attracted interest from researchers because of their unique biological characteristics. However, little is known about the molecular underpinnings of daily rhythms in bats. In this study, we used RNA-Seq to uncover the daily rhythms of gene expression in the brains of Asian particolored bats over the 24-h day. Accordingly, four collected time points corresponding to four biological states, rest, sleep, wakefulness, and active, were selected. Several groups of genes with different expression levels in these four states were obtained suggested that different physiological processes were active at various biological states, including drug metabolism, signaling pathways, and the circadian rhythm. Furthermore, downstream analysis of all differentially expressed genes in these four states suggested that groups of genes showed daily rhythms in the bat brain. Especially for Per1, an important circadian clock gene was identified with rhythmic expression in the brain of Asian particolored bat. In summary, our study provides an overview of the brain transcriptomic differences in different physiological states over a 24-h cycle.

Trends in Smoking Prevalence and Intensity between 2010 and 2018: Implications for Tobacco Control in China.

BACKGROUND: China is the world's largest producer and consumer of cigarettes. Since 2010, the Chinese government has implemented many policies to combat the tobacco epidemic, yet little is known about their overall impacts. This study aims to investigate the trends in smoking prevalence and intensity between 2010 and 2018. METHODS: We use five waves of data from China Family Panel Studies (CFPS), a nationally representative survey, to examine the trends in smoking prevalence and intensity. We use the chi-square test and t-test to examine differences across waves. Binary logistic regressions and linear regressions are applied to examine the association between smoking behaviors and risk factors. RESULTS: The current smoking prevalence dropped from 30.30% in 2010 (90% CI 29.47-31.31) to 28.69% (90% CI 27.69-29.69) in 2018. As for smoking intensity, the average daily cigarettes consumption decreased steadily from 16.96 cigarettes (90% CI 16.55-17.36) in 2010 to 15.12 cigarettes (90% CI 15.07-15.94) in 2018. Smoking risk factors for men included marriage status, education level, employment status, alcohol consumption, and physical activities. The smoking risk was higher for women with a lower education level, lower household income, unemployment status, and alcohol consumption behavior. CONCLUSIONS: Our study shows declined trends in both smoking prevalence and intensity between 2010 and 2018, suggesting some positive progress in tobacco control in China. Nonetheless, to achieve the goal of reducing smoking prevalence among people aged 15 and above to less than 20% by 2030, the Chinese government needs to take stronger anti-tobacco measures.

Prevalence and associated socioeconomic factors of multimorbidity in 10 regions of China: an analysis of 0.5 million adults.

BACKGROUND: The epidemiology of multiple chronic conditions in China is poorly understood. We investigated the prevalence of multimorbidity among the middle-aged and elderly population in China and analyzed its demographic and socioeconomic correlates. METHODS: Data were obtained from the baseline of the China Kadoorie Biobank Study, which recruited over 0.5 million participants between 2004 and 2008. We calculated the prevalence by the characteristics of multimorbidity. The demographic and socioeconomic correlates were analyzed using a multivariable logistic regression model. RESULTS: 15.9% of the participants were multimorbid. Although the prevalence of multimorbidity increased with age, the absolute number of people with multimorbidity was much higher among middle-aged adults (30-60 years, n = 42 041) than the elderly group (>60 years, n = 38 834). The odd of multimorbidity was higher in males (aOR =1.09, 95% CI: 1.07-1.11) and among those who were unemployed (aOR = 1.58, 95% CI: 1.55-1.62). Those who received the highest level of education were most likely to be multimorbid compared with those with no education (aOR = 1.14, 95% CI: 1.09-1.19). Such an association was similar when treating multimorbidity as multinomial variable. CONCLUSIONS: Multimorbidity is a public health concern, with higher prevalence among the elderly, males and those who belong to a lower socioeconomic stratum. Actions are needed to curb multimorbidity epidemic in China.

ProPhenol Derived Ligands to Simultaneously Coordinate a Main-Group Metal and a Transition Metal: Application to a Zn-Cu Catalyzed Reaction.

A new bifunctional ligand bearing chiral N-heterocyclic carbene (NHC) and prolinol moieties is presented. Utilizing the designed ligand, an in situ formed Cu/Zn hetero-bimetallic complex unlocks the asymmetric allylic alkylation reactions of allyl phosphates with zinc keto-homoenolates, leading to the formation of various γ-vinyl ketones with good regio- and enantio-selectivity. DF sT calculation supports that the chelation of allyl phosphates with catalyst promotes the SN 2' addition and the ligand-substrate steric interactions account for the stereoselective outcome.

Total Synthesis of Kadcoccinic Acid A Trimethyl Ester.

The first total synthesis of the trimethyl ester of kadcoccinic acid A is described. The central structural element of our synthesis is a cyclopentenone motif that allows the assembly of the natural product skeleton. A gold(I)-catalyzed cyclization of an enynyl acetate led to efficient construction of the cyclopentenone scaffold. In this step, optimization studies revealed that the stereochemistry of the enynyl acetate dictates regioisomeric cyclopentenone formation. The synthesis further highlights an efficient copper-mediated conjugate addition, merged with a gold(I)-catalyzed Conia-ene reaction to connect the two fragments, thereby forging the D-ring of the natural product. The synthetic strategy reported herein can provide a general platform to access the skeleton of other members of this family of natural products.

Ruthenium-catalysed multicomponent synthesis of the 1,3-dienyl-6-oxy polyketide motif.

Polyketide natural products are an important class of biologically active compounds. Although substantial progress has been made on the synthesis of repetitive polyketide motifs through the iterative application of a single reaction type, synthetic access to more diverse motifs that require more than one type of carbon-carbon bond connection remains a challenge. Here we describe a catalytic, multicomponent method for the synthesis of the privileged polyketide 1,3-dienyl-6-oxy motif. The method allows for the formation of two new carbon-carbon bonds and two stereodefined olefins. It generates products that contain up to three contiguous sp3 stereocentres with a high stereoselectivity in a single operation and can be used to generate chiral products. The successful development of this methodology relies on the remarkable efficiency of the ruthenium-catalysed alkene-alkyne coupling reaction between readily available vinyl boronic acids and alkynes to provide unsymmetrical 3-boryl-1,4-diene reagents. In the presence of carbonyl compounds, these reagents undergo highly diastereoselective allylations to afford the desired 1,3-dienyl-6-oxy motif and enable complex polyketide synthesis in a rapid and asymmetric fashion.

Electrochemical Oxidative [4+2] Annulation for the π-Extension of Unfunctionalized Heterobiaryl Compounds.

Considering their unique electronic properties and diverse biological activities, regioselective access to fused aromatic compounds is significantly important in the field of organic materials and pharmaceutical science. Herein, we developed electrochemical oxidative [4+2] annulation reactions of heterobiaryl compounds with alkynes or alkenes, leading to the formation of several polycyclic heteroaromatic compounds. This electrosynthetic methodology serves for the straightforward π-extension of unfunctionalized heterobiaryl compounds. The requirements of additional oxidants and prefunctionalization of starting materials are obviated. Through the in situ generation of heterobiaryl radical cation intermediates, various fused aromatic compounds were obtained with good yields and excellent regioselectivity.

Ruthenium-Catalyzed Intermolecular Coupling of Vinylic 1,2-Bisboronates with Alkynes: Stereoselective Access to Boryl-Substituted Homoallylic Alcohols.

The ruthenium catalytic addition of alkenes to alkynes has been demonstrated as a powerful synthetic tool to form diene motifs and widely applied in the synthesis of complex molecules. However, except for the intramolecular coupling, trisubstituted alkenes are unsatisfactory coupling partners with alkynes, presumably due to the increased steric hindrance. Herein, we discovered that substituted vinyl 1,2-bisboronate derivatives can serve as the trisubstituted alkene equivalents to couple with alkynes, generating various boryl-substituted homoallylic alcohol motifs with good stereoselectivity through the sequential allylboration with aldehydes. In contrast to carbon substituents on the double bond, boron substituents accelerate the alkyne coupling.

Electrochemical oxidation induced intermolecular aromatic C-H imidation.

The dehydrogenative aryl C-H/N-H cross-coupling is a powerful synthetic methodology to install nitrogen functionalities into aromatic compounds. Herein, we report an electrochemical oxidation induced intermolecular cross-coupling between aromatics and sulfonimides with high regioselectivity through N-radical addition pathway under external-oxidant-free and catalyst-free conditions. A wide variety of arenes, heteroarenes, alkenes and sulfonimides are applicable scaffolds in this transformation. In addition, aryl sulfonamides or amines (aniline derivatives) can be obtained through different deprotection process. The cyclic voltammetry mechanistic study indicates that the N-centered imidyl radicals are generated via proton-coupled electron transfer event jointly mediated by tetrabutylammonium acetate and anode oxidation process.

Electrochemical Oxidation with Lewis-Acid Catalysis Leads to Trifluoromethylative Difunctionalization of Alkenes Using CF3SO2Na.

The directly external oxidant-free oxytrifluoromethylation and aminotrifluoromethylation of alkenes have been developed through the constant current electrolysis synergizing with a Lewis-acid catalysis protocol. By using sodium trifluoromethanesulfinate as the trifluoromethyl source, the method enabled difunctionalization of C-C double bonds of a wide range of styrene derivatives.

The synergistic effect of self-assembly and visible-light induced the oxidative C-H acylation of N-heterocyclic aromatic compounds with aldehydes.

Constructing carbon-carbon bonds through oxidative cross-coupling between two hydrocarbon compounds is regarded as a foundational issue in green chemistry. High atom-economy and mild conditions are long term pursued goals in this field. Herein, we developed a visible-light mediated direct cross-coupling between N-heterocycles and aldehydes without the requirement of a photocatalyst. Several N-heterocycles afforded the acylation products with aromatic or aliphatic aldehydes in good yields. The reaction can be conducted under room temperature and easily scaled up.

Photoinduced oxidative activation of electron-rich arenes: alkenylation with H2 evolution under external oxidant-free conditions.

The dehydrogenative cross-coupling of arenes and alkenes is a particularly ideal approach for the synthesis of aryl alkenes. Herein, we report a photo-induced C-H/C-H cross-coupling between electron-rich arenes and styrene derivatives using a dual catalytic system containing an acridinium photosensitizer and a cobaloxime proton-reducing catalyst. This catalytic system enables the Csp2-Csp2 bond formation accompanying H2 evolution. Various substituted aryl alkenes can be afforded with good to excellent yields and high ß-regioselectivity.

Oxidative [4+2] annulation of styrenes with alkynes under external-oxidant-free conditions.

The sequenced Diels-Alder/oxidation reaction represents a powerful route for the construction of aromatic compounds in organic synthesis. The oxidative Diels-Alder reaction with H2 evolution would be a more ideal approach that can avoid the additional oxidation procedure and stoichiometric oxidant. Herein, an oxidative [4 + 2] annulation reaction of styrene derivatives with electron-rich dienophiles accompanying the H2 generation has been developed by using the synergistic merger of photoredox and cobaloxime catalyst. With respect to atom and step-economy ideals, this dual catalytic system enables the formation of high-value molecules from feedstock chemicals in a single step under room temperature.

Selective Oxidative [4+2] Imine/Alkene Annulation with H2 Liberation Induced by Photo-Oxidation.

The oxidative [4+2] annulation reaction represents an elegant and versatile synthetic protocol for the construction of six-membered heterocyclic compounds. Herein, a photoinduced oxidative [4+2] annulation of NH imines and alkenes was developed by utilizing a dual photoredox/cobaloxime catalytic system. Various multisubstituted 3,4-dihydroisoquinolines can be obtained in good yields. This method is not only obviated the need of stiochiometric amounts of oxidants but also exhibited excellent atom economy by generating H2 as the only byproduct. Remarkably, high regioselectivity and trans diastereoselectivity can be achieved in this transformation even if the Z/E mixture of alkenes were employed.

Recent Advances in Radical C-H Activation/Radical Cross-Coupling.

Research and industrial interest in radical C-H activation/radical cross-coupling chemistry has continuously grown over the past few decades. These reactions offer fascinating and unconventional approaches toward connecting molecular fragments with high atom- and step-economy that are often complementary to traditional methods. Success in this area of research was made possible through the development of photocatalysis and first-row transition metal catalysis along with the use of peroxides as radical initiators. This Review provides a brief and concise overview of the current status and latest methodologies using radicals or radical cations as key intermediates produced via radical C-H activation. This Review includes radical addition, radical cascade cyclization, radical/radical cross-coupling, coupling of radicals with M-R groups, and coupling of radical cations with nucleophiles (Nu).

Anti-Markovnikov Oxidation of ß-Alkyl Styrenes with H2O as the Terminal Oxidant.

Oxygenation of alkenes is one of the most straightforward routes for the construction of carbonyl compounds. Wacker oxidation provides a broadly useful strategy to convert the mineral oil into higher value-added carbonyl chemicals. However, the conventional Wacker chemistry remains problematic, such as the poor activity for internal alkenes, the lack of anti-Markovnikov regioselectivity, and the high cost and chemical waste resulted from noble metal catalysts and stoichiometric oxidant. Here, we describe an unprecedented dehydrogenative oxygenation of ß-alkyl styrenes and their derivatives with water under external-oxidant-free conditions by utilizing the synergistic effect of photocatalysis and proton-reduction catalysis that can address these challenges. This dual catalytic system possesses the single anti-Markovnikov selectivity due to the property of the visible-light-induced alkene radical cation intermediate.

Visible-light induced oxidant-free oxidative cross-coupling for constructing allylic sulfones from olefins and sulfinic acids.

An oxidant-free dehydrogenative sulfonylation of α-methyl-styrene derivatives was developed for the construction of allylic sulfones by using eosin Y as a photosensitizer in conjunction with a cobaloxime catalyst. The process features a low-cost metal catalyst and atom economy, which provides an appealing strategy for future synthetic chemistry.