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The replacement of aryl rings with C(sp3)-rich structures has garnered significant interest in drug discovery due to the potential for improved pharmacokinetic properties upon substitution. In particular, 1,3-difunctionalized bicyclo[1.1.1]pentanes (BCPs) have been widely adopted as bioisosteres for para-substituted arene rings, appearing in a number of lead pharmaceutical candidates. Due to their medicinal importance, multiple methods have been developed to efficiently synthesize these 1,3-difunctionalized BCPs. However, despite the pharmaceutical value of 2-substituted BCPs as replacements for ortho- or meta-substituted arene rings, general and rapid syntheses of these scaffolds remain elusive. Current approaches to 2-substituted BCPs rely on installation of the bridge substituent prior to BCP core construction, leading to lengthy step counts and often non-modular sequences. While challenging, direct functionalization of the strong bridge BCP C–H bonds would offer a more streamlined pathway to diverse 2-substituted BCPs. Here we report a generalizable synthetic linchpin strategy for bridge functionalization via radical C–H abstraction of the BCP core. Through mild generation of a strong hydrogen atom abstractor, we rapidly synthesize novel 2-substituted BCP synthetic linchpins in one pot. These synthetic linchpins then serve as common precursors to complex 2-substituted BCPs, allowing one step access to a number of previously inaccessible electrophile and nucleophile fragments at the 2-position via two new metallaphotoredox protocols. Altogether, this platform enables the expedient synthesis of four pharmaceutical analogs, all of which show similar or improved properties compared to their aryl-containing equivalents, demonstrating the potential of these 2-substituted BCPs in drug development.

While achieving economic growth, China's cities have also experienced severe environmental pollution problems. To achieve the goal of green production, this paper first measures the green total factor productivity (GTFP) of Chinese prefecture-level cities using the super Slacks-Based Measure and the global Malmquist-Luenberger index (SBM-GML) model and then explores the paths affecting GTFP from the perspective of information infrastructure construction policy (IICP) using a time-varying Difference-in-Difference (time-varying DID) model. The results show that the information infrastructure construction policy significantly contributes to urban GTFP growth overall, and the implementation of the policy leads to an average increase of 0.209 in pilot cities relative to non-pilot cities. The information infrastructure construction policy contributes to urban GTFP growth through green technology diffusion effects and the improvement of employment structure.

The merger of photoredox catalysis with transition metal catalysis, termed metallaphotoredox catalysis, has become a mainstay in synthetic methodology over the past decade. Metallaphotoredox catalysis has combined the unparalleled capacity of transition metal catalysis for bond formation with the broad utility of photoinduced electron- and energy-transfer processes. Photocatalytic substrate activation has allowed the engagement of simple starting materials in metal-mediated bond-forming processes. Moreover, electron or energy transfer directly with key organometallic intermediates has provided novel activation modes entirely complementary to traditional catalytic platforms. This Review details and contextualizes the advancements in molecule construction brought forth by metallaphotocatalysis.

Background: The majority of COVID-19 patients presented persisting symptoms after discharge. We aimed to determine the long-term enteric consequences of SARS-CoV-2 infection, and to identify the risk and the protective factors for gastrointestinal sequelae. Methods: A retrospective cohort of 117 SARS-CoV-2 nucleic acid positive patients hospitalized in 12 hospitals from January 16 to March 7, 2020 were included in this study. Clinical data collected during hospitalization, from return visits and from telephone interviews in 3 months after discharge were reviewed. Multivariable logistic regression was performed to identify the risk and the protective factors for any and individual gastrointestinal sequelae. Findings: In three months after discharge, 53 patients (45%) presented at least one gastrointestinal sequelae. Common gastrointestinal sequelae included loss of appetite (28 patients, 24%), nausea (21 patients, 18%), acid reflux (21 patients, 18%), and diarrhea (17 patients, 15%). Decreased blood oxygen saturation and PPI treatment were risk factors, while enteral nutrition was a protective factor for gastrointestinal sequelae in general. For individual gastrointestinal sequelae, the decreased blood oxygen saturation was a risk factor, while male sex was a protective factor for loss of appetite after discharge. For nausea after discharge, PPI treatment was a risk factor while parenteral nutrition was a protective factor. Decreased blood oxygen saturation, BMI >25, and PPI treatment were risk factors for acid reflux after discharge. And finally, male sex was a risk factor for diarrhea after discharge. Interpretation: At three months after discharge, gastrointestinal sequelae were still common in recovering COVID-19 patients. Decreased blood oxygen saturation, PPI treatment, BMI >25, and male sex are risk factors, while nutritional support and male sex are protective factors, for gastrointestinal sequelae. Our data highlight the importance of gastrointestinal care and nutritional support for discharged COVID-19 patients. Funding: Guangdong Province “Pearl River Talent Plan” Innovation and Entrepreneurship Team Project, National Natural Science Foundation of China, and the National Key Clinical Discipline of China. Declaration of Interests: All authors declare no competing interests. Ethics Approval Statement: This study was approved by the Institutional Review Boards of Sun Yat-sen University and the participating hospitals.

A data set containing 25,083 images of 80 kinds of TCM is constructed in this paper to solve the complications of identifying various traditional Chinese medicines quickly and accurately. Combined with the traditional Convolutional Neural Network, PyTorch and Keras frameworks are employed to manually build a DenseNet model for the recognition of Chinese herbal pieces. Besides, the method of dropout is adopted to solve the problem of overfitting. The highest recognition rate of the traditional DenseNet-based model can reach 96.78%. Therefore, the network model such as densitynet201 is selected for pre-training, and an adaptive average pool layer is added to amplify the receiving field of the kernel, thereby further improving the recognition accuracy and convergence speed of the model, and combining the idea of transfer learning. Finally, the classification output is performed, and the highest recognition rate of the transfer learning-based model can reach 97.34%, which is helpful to further improve the accurate recognition rate of the model, effectively solve the intelligent recognition of Chinese herbal pieces, and lay the theoretical foundation for the intelligentizing of the traditional Chinese medicine industry.

ObjectiveChanges in thyroid function will be accompanied by changes in urinary N-acetyl-β-D-glucosaminidase (uNAG) levels. Therefore, whether thyroid hormones interfere the ability of uNAG in detecting acute kidney injury (AKI) has raised concern in patients with critical illness.DesignA prospectively recruited, observational study was performed.SettingAdults admitted to the intensive care unit of a grade A tertiary hospital in China.ParticipantsA total of 1919 critically ill patients were enrolled in the study.Main outcome measuresTo investigate the variations of the ability of uNAG to detect AKI in patients with critical illness under different thyroid hormones levels (differences in area under the curve (AUC) for uNAG diagnosis and prediction of AKI with different thyroid hormones levels).ResultsThe bivariate correlation analysis revealed that FT3 and TT3 levels were independently associated with uNAG levels (p0.05).ConclusionsEven if uNAG levels varied with FT3 and TT3 levels, these hormones did not interfere with uNAG’s ability to detect AKI in patients with critical illness.

Over the past three decades, considerable progress has been made in the development of methods to construct sp2 carbon-nitrogen (C-N) bonds using palladium, copper or nickel catalysis1,2. However, the incorporation of alkyl substrates to form sp3 C-N bonds remains one of the major challenges in the field of cross-coupling chemistry. Here we demonstrate that the synergistic combination of copper catalysis and photoredox catalysis can provide a general platform from which to address this challenge. This cross-coupling system uses naturally abundant alkyl carboxylic acids and commercially available nitrogen nucleophiles as coupling partners. It is applicable to a wide variety of primary, secondary and tertiary alkyl carboxylic acids (through iodonium activation), as well as a vast array of nitrogen nucleophiles: nitrogen heterocycles, amides, sulfonamides and anilines can undergo C-N coupling to provide N-alkyl products in good to excellent efficiency, at room temperature and on short timescales (five minutes to one hour). We demonstrate that this C-N coupling protocol proceeds with high regioselectivity using substrates that contain several amine groups, and can also be applied to complex drug molecules, enabling the rapid construction of molecular complexity and the late-stage functionalization of bioactive pharmaceuticals.

The functionalization of carbon–hydrogen (C–H) bonds is one of the most attractive strategies for molecular construction in organic chemistry. The hydrogen atom is considered to be an ideal coupling handle, owing to its relative abundance in organic molecules and its availability for functionalization at almost any stage in a synthetic sequence1. Although many C–H functionalization reactions involve C(sp3)–C(sp2) coupling, there is a growing demand for C–H alkylation reactions, wherein sp3 C–H bonds are replaced with sp3 C–alkyl groups. Here we describe a polarity-match-based selective sp3 C–H alkylation via the combination of photoredox, nickel and hydrogen-atom transfer catalysis. This methodology simultaneously uses three catalytic cycles to achieve hydridic C–H bond abstraction (enabled by polarity matching), alkyl halide oxidative addition, and reductive elimination to enable alkyl–alkyl fragment coupling. The sp3 C–H alkylation is highly selective for the α-C–H of amines, ethers and sulphides, which are commonly found in pharmaceutically relevant architectures. This cross-coupling protocol should enable broad synthetic applications in de novo synthesis and late-stage functionalization chemistry.

Tempered glass panels in the point supported glass facade (PSGF) are usually subjected to large in-plane load. In order to investigate the bearing capacity of tempered glass panels against in-plane load, three tests are firstly carried out. Afterwards, finite element method (FEM) is adopted to study stresses around holes under different loading conditions and explore the influence of the in-plane load on the stress distribution of the glass panel. It is concluded that stresses around holes in tempered glass panels are principally affected by the in-plane load, while stresses at centers of the surface and edges are mainly controlled by the out-of-plane load. When the in-plane load is relatively high, the out-of-plane load is probably able to reduce stresses at some points around holes, contributing to the improvement of the load-bearing capacity of tempered glass panels. If the in-plane load is large enough, specimens are bound to experience state transitions which are caused by large plastic deformation of stainless steel bolt fittings and result in the rapid increase of stresses on glass panels. Therefore, by enhancing the shear strength of bolt fittings one can improve the bearing capacity of tempered glass panels in the PSGF against the in-plane load.

A wide array of cross-coupling methods for the formation of C–C bonds from unactivated alkyl electrophiles have been described in recent years. In contrast, progress in the development of methods for the construction of C–heteroatom bonds has lagged; for example, there have been no reports of metal-catalyzed cross-couplings of unactivated secondary or tertiary alkyl halides with silicon nucleophiles to form C–Si bonds. In this study, we address this challenge, establishing that a simple, commercially available nickel catalyst (NiBr_2·diglyme) can achieve couplings of alkyl bromides with nucleophilic silicon reagents under unusually mild conditions (e.g., −20 °C); especially noteworthy is our ability to employ unactivated tertiary alkyl halides as electrophilic coupling partners, which is still relatively uncommon in the field of cross-coupling chemistry. Stereochemical, relative reactivity, and radical-trap studies are consistent with a homolytic pathway for C–X bond cleavage.

Stresses around holes of tempered glass panels are tend to be ignored in the practical design of point supported glass facades. With the intent of investigating the stress distribution around holes in tempered glasses, the experimental and theoretical studies were firstly carried out and the finite element model was subsequently developed using ANSYS software. Afterwards, the theoretical formula was combined with test results to predict the failure stresses in the vicinity of holes and the stress limitations were proposed. It is concluded that the theoretical and numerical results are at least consistent with the chosen test data although they have some uncertainties and limitations in the analyses. The stresses around holes are significantly higher than those on the large area and lateral surface and ought to be the controlling parameter in the design. The maximum principal stress of some random point on the tempered glass panel is proportional to the external load and inversely proportional to the square of the panel thickness if the spacing between this point and the centroid of glass panel is determined. Furthermore, the clamping effect of the button head bolt fitting is more pronounced than that of countersunk bolt fitting and capable of reducing stresses near holes, especially for the thin plate.

Over the last three decades, significant progress has been made in the development of methods to construct sp2 C–N bonds using palladium, copper, or nickel catalysis. However, the incorporation of alkyl substrates to form sp3 C–N bonds remains one of the major challenges in the field of cross-coupling chemistry. Here, we demonstrate that the synergistic combination of copper catalysis and photoredox catalysis can provide a general platform to address this long-standing challenge. This novel cross-coupling system employs naturally abundant alkyl carboxylic acids and commercially available N-nucleophiles as coupling partners, and is applicable to a wide variety of primary, secondary, and tertiary alkyl carboxylic acids (via in situ iodonium activation). At the same time, a vast array of N-nucleophiles, including N-heterocycles, amides, sulfonamides, and anilines, can undergo C–N coupling to provide N-alkyl products in good to excellent efficiency at room temperature and in short order (5 minutes to 1 hour). We have also demonstrated that this C–N coupling protocol can be applied to substrates bearing multiple amines with high regioselectivity, as well as complex drug molecules, enabling the rapid construction of molecular complexity and the late stage functionalization of bioactive pharmaceuticals.

Over the last three decades, significant progress has been made in the development of methods to construct sp2 C–N bonds using palladium, copper, or nickel catalysis1,2. However, the incorporation of alkyl substrates to form sp3 C–N bonds remains one of the major challenges in the field of cross-coupling chemistry. Here, we demonstrate that the synergistic combination of copper catalysis and photoredox catalysis can provide a general platform to address this challenge. This cross-coupling system employs naturally abundant alkyl carboxylic acids and commercially available N-nucleophiles as coupling partners, and is applicable to a wide variety of primary, secondary, and tertiary alkyl carboxylic acids (via iodonium activation). At the same time, a vast array of N-nucleophiles, including N-heterocycles, amides, sulfonamides, and anilines, can undergo C–N coupling to provide N-alkyl products in good to excellent efficiency at room temperature and in short order (5 minutes to 1 hour). We have also demonstrated that this C–N coupling protocol can be applied to substrates bearing multiple amines with high regioselectivity, as well as complex drug molecules, enabling the rapid construction of molecular complexity and the late stage functionalization of bioactive pharmaceuticals.

In this report, we establish that a readily available nickel/bis(oxazoline) catalyst accomplishes a wide array of enantioconvergent cross-couplings of arylzinc reagents with CF_3-substituted racemic secondary alkyl halides, a process that necessitates that the chiral catalyst be able to effectively distinguish between a CF_3 and an alkyl group in order to provide good ee. We further demonstrate that this method can be applied without modification to the catalytic asymmetric synthesis of other families of fluorinated organic compounds.

The development of new approaches to the construction of fluorine-containing target molecules is important for a variety of scientific disciplines, including medicinal chemistry. In this Article, we describe a method for the catalytic enantioselective synthesis of tertiary alkyl fluorides through Negishi reactions of racemic α-halo-α-fluoroketones, which represents the first catalytic asymmetric cross-coupling that employs geminal dihalides as electrophiles. Thus, selective reaction of a C-Br (or C-Cl) bond in the presence of a C-F bond can be achieved with the aid of a nickel/bis(oxazoline) catalyst. The products of the stereoconvergent cross-couplings, enantioenriched tertiary α-fluoroketones, can be converted into an array of interesting organofluorine compounds.

For the first time, the use of metal catalyst NiBr2·diglyme for the title reaction is described to yield a wide range of silylated compounds.

In this report, we establish that a readily available nickel/bis(oxazoline) catalyst accomplishes a wide array of enantioconvergent cross-couplings of arylzinc reagents with CF3-substituted racemic secondary alkyl halides, a process that necessitates that the chiral catalyst be able to effectively distinguish between a CF3 and an alkyl group in order to provide good ee. We further demonstrate that this method can be applied without modification to the catalytic asymmetric synthesis of other families of fluorinated organic compounds.

Silver hexafluroantimonate was identified as a highly efficient agent to reverse the facial selectivity of the titanium chloride-mediated vinylogous Mukaiyama aldol reaction (VMAR), and this unprecedented reaction provides a concise, diastereoselective synthesis of δ-hydroxy-α,γ-dimethyl-α,β-unsaturated carbonyl units from readily available chiral vinylketene silyl N,O-acetal 6 and ethyl glyoxylate 8.

Fluorinated organic molecules are of interest in fields ranging from medicinal chemistry to polymer science. Described herein is a mild, convenient, and versatile method for the synthesis of compounds bearing a perfluoroalkyl group attached to a tertiary carbon atom by using an alkyl–alkyl cross-coupling. A nickel catalyst derived from NiCl_2⋅glyme and a pybox ligand achieves the coupling of a wide range of fluorinated alkyl halides with alkylzinc reagents at room temperature. A broad array of functional groups is compatible with the reaction conditions, and highly selective couplings can be achieved on the basis of differing levels of fluorination. A mechanistic investigation has established that the presence of 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) inhibits cross-coupling under these conditions and that a TEMPO–electrophile adduct can be isolated.

Fluorinated organic molecules are of interest in fields ranging from medicinal chemistry to polymer science. Herein, we describe a mild, convenient, and versatile method for the synthesis of compounds that bear a perfluoroalkyl group attached to a tertiary carbon, via an alkyl–alkyl cross-coupling. Thus, a nickel catalyst derived from commercially available components (NiCl2·glyme and a pybox ligand) achieves the coupling of a wide range of fluorinated alkyl halides with alkylzinc reagents at room temperature. A broad array of functional groups (e.g., alkyne, aryl iodide, carbamate, furan, ketone, nitrile, phosphonate, primary alkyl bromide, and primary alkyl tosylate) are compatible with the reaction conditions, and highly selective couplings can be achieved on the basis of differing levels of fluorination. A mechanistic investigation has established that the presence of TEMPO inhibits cross-coupling under these conditions and that a TEMPO–electrophile adduct can be isolated.

The development of new approaches to the construction of fluorine-containing target molecules is important for a variety of scientific disciplines, including medicinal chemistry. In this Article, we describe a method for the catalytic enantioselective synthesis of tertiary alkyl fluorides through Negishi reactions of racemic α-halo-α-fluoroketones, which represents the first catalytic asymmetric cross-coupling that employs geminal dihalides as electrophiles. Thus, selective reaction of a C–Br (or C–Cl) bond in the presence of a C–F bond can be achieved with the aid of a nickel/bis(oxazoline) catalyst. The products of the stereoconvergent cross-couplings, enantioenriched tertiary α-fluoroketones, can be converted into an array of interesting organofluorine compounds.