Transition metal-catalyzed asymmetric allylic dearomatization of beta-naphthols provides efficient access to enantioenriched naphthalenones. However, these reactions generally suffer from limited substrate scope, incompatibility with alkyl-substituted allylic electrophiles, and poor understandings of the reaction mechanism. Herein, we report a rhodium-catalyzed asymmetric allylic dearomatization of beta-naphthols utilizing a bisdihydrobenzooxaphosphole (BIBOP) chiral ligand. This catalytic system displays high yields and enantioselectivity and broad substrate scope, efficiently accommodating both alkyl- and aryl-substituted allylic carbonates. Detailed mechanistic studies reveal that the reaction proceeds through a tandem asymmetric allylic etherification/Claisen rearrangement sequence. This provides critical insights into the fundamental pathways for the asymmetric allylic dearomatization of naphthols.

Chiral alpha-hydroxy amide derivatives are privileged structural motifs in pharmaceuticals and bioactive molecules, yet their catalytic asymmetric synthesis remains challenging, particularly under transition metal-free conditions. Herein, we report the successful merger of photochemical [1,3]-silyl migration (Brook rearrangement) with the organocatalytic asymmetric addition reaction of ketenes, establishing a metal-free paradigm for the enantioselective synthesis of alpha-hydroxy amides. The success of this process hinges on the transient generation of siloxyketenes from alpha-ketoacylsilanes. This transformation features mild reaction conditions, a broad substrate scope, good functional group tolerance, and facile scalability. The method highlights the formal synthesis of the AAK1 inhibitor and BMS-270394. Mechanistic studies, including DFT calculations, provide critical insights into the reaction pathway and stereochemical outcomes.

Cyclization of bicyclo[1.1.0]butanes (BCBs) is an effective way to construct saturated polycyclic 3D structures. Herein we report a visible-light-induced intramolecular dearomative reaction to forge bicyclo[4.1.1] frameworks through (1,3)-cyclization of BCBs. Moreover, the unprecedented (1,2,3)-cyclization of BCBs through 1,4-hydrogen atom transfer (HAT) process was also realized along with the further transformations. The mechanistic studies revealed that the reaction was initially carried out by an energy transfer (EnT) process and the key open-shell singlet biradical intermediate may undergo [4 pi + 2 sigma] cycloaddition or 1,4-HAT process leading to the formation of two products and we found that the selectivity of product is related to the substituents at the BCBs bridgehead position. Our findings are supported by control experiments, deuterium labeling and kinetic studies, cyclic voltammetry, Stern-Volmer experiments, as well as density functional theory (DFT) calculations.

Reformatsky reagents are commonly employed with activated electrophiles, such as aldehydes, ketones, or activated alkyl halides. However, their limited nucleophilicity remains a considerable challenge for direct reactions with unactivated alkyl halides, typically necessitating transition metal catalysis. Here, we present a transition-metal-catalyst-free approach that facilitates direct nucleophilic substitution between Reformatsky reagents and diverse unactivated alkyl halides, which enables formal reductive cross-electrophile coupling via a one-pot process. Mechanistic studies reveal the pivotal role of highly polar solvents and the formation of zincate enolate intermediates containing hindered alkyl groups, which streamlines the SN2 reaction with unactivated alkyl halides via open-frame transition states. The modular nature of the current protocol eliminates the need for strong bases and transition metal catalysts, allowing easy access to esters, amides, and ketones bearing all-carbon quaternary centers with a wide range of functional groups, thereby providing a simple and expedient synthetic avenue to build complex molecules.

Despite the significant applications of fluorinated cyclobutanes in industrial and diagnostic fields, efficient methods for synthesizing these valuable fluorinated structures remain limited. Here, we report a new difluoroalkylating reagent, 2-(difluoromethylene)cyclobutyl sulfonium salts (CB-DFASs). This reagent can be readily synthesized on a gram scale in three steps from readily available cyclobutanone enol silyl ether. CB-DFASs exhibit high reactivity and enable chemodivergent synthesis of structurally diverse difluoroalkylated cyclobutenes using a wide array of nucleophiles, including those based on carbon, oxygen, nitrogen, and sulfur, under mild conditions. The resulting products serve as versatile linchpins for diverse transformations, thereby enabling the synthesis of a variety of difluoroalkylated cyclobutanes. The synthetic utility of CB-DFASs has been demonstrated through the late-stage modification of complex pharmaceuticals and the rapid synthesis of analogues of bioactive molecules, highlighting their potential in drug discovery.

There remains an ongoing challenge to develop facile methods for the preparation of chiral gamma,gamma-difluorinated amines, which are commonly considered a privileged motif in bioactive compounds. In this context, we report a straightforward protocol for the stereoselective nucleophilic difluoro(sulfoximidoyl)methylation of C & boxH;C bonds (considered to be more challenging than the reported C & boxH;O bonds), which exhibits high stereoselectivity and broad substrate scope. The key features of this chemistry include 1) stereoselective addition of the difluoro(sulfoximidoyl)methyl anion to C & boxH;C bonds, although it was considered to be highly unfavorable from the view of hard-soft acid-base (HSAB) theory; 2) intriguing neighboring group participation of the oxygen from the nitro group that was found to play a crucial role in controlling the stereoselectivity and efficiency of the transformation and was supported by mechanistic experiments and DFT calculations. This method has been applied to the late-stage modification of several complex molecules and the preparation of enantioenriched bioactive gamma-fluorinated amines, such as a phytopathogenic fungi inhibitor, TRPC6 and CDK11 inhibitors, and even monofluorinated lorcaserin, which further demonstrated the significance and potential of this approach.

One of the characteristics of actinomycetes, especially streptomycetes, is the high GC content in their genome, which often leads to the failure of heterologous expression in E. coli, and thus hinders in vitro enzyme activity experiments. Therefore, we have developed a precisely regulated and efficient Streptomyces expression system, pTZYp, that relied on the strong promoter stnY and the cmt operon. As tested in three model Streptomyces strains (S. albus J1074, S. coelicolor M1152 and S. lividans TK24), the reporter protein sfGFP was not detected without the addition of the inducer cumate, whereas sfGFP was significantly produced when a certain amount of inducer cumate was added to the medium, demonstrating that the pTZYp expression system can achieve the goal of precise regulation and efficient expression. After optimization of the expression conditions, the maximum sfGFP production was obtained when the inducer was added to the final concentration of 100 mu M and cultivated for about 24 h. pTZYp has also been used to express other six non-model proteins in Streptomyces, and all of them have been successfully expressed. The pTZYp expression system demonstrated robustness, high efficiency (relying on the stnY promotor), precise regulation (relying on cmt operon and moderate production of regulatory protein CymR) and low experimental cost (relying on the lower cost of the inducer cumate), which may be an efficient and widely applicable heterologous expression tool for genes with high GC content in actinomycetes.

Purpose S-palmitic acid-9-hydroxy stearic acid (SP), a newly characterized endogenous lipid with multifaceted biological activities, is poised to shed light on its potential in diabetes-related cognitive disorder (DRCD). This study aims to uncover the effects of SP on DRCD and the underlying mechanisms.Methods C57BL/6 mice were fed with high-fat diet for 5 months to induce type 2 diabetes mellitus (T2DM). Subsequently, they received bilateral hippocampal injections of adeno-associated virus (AAV) carrying carbonic anhydrase III (CAIII) shRNA or control shRNA. Following one-month treatment with SP or vehicle, cognitive function was assessed using the Morris water maze and Y-maze tests. Oxidative stress and apoptosis were measured by Enzyme-linked Immunosorbent Assay (ELISA), and hippocampal neuronal morphology was examined through HE, Nissl, or NeuN staining. RNA sequencing (RNA seq), cell viability, tetramethylrhodamine ethyl ester (TMRE) staining, and mitoSOX assays were also performed in cultured PC12 cells.Results Our findings demonstrated that CAIII played a pivotal role in enhancing cognitive function in T2DM mice by improving spatial memory. SP ameliorated hippocampal injury by CAIII-mediated AMPK/Sirt1/PGC1 alpha pathway, Bcl-2/Bax ratio elevation, and cleaved-Caspase 3 reduction. CAIII participated in various biological processes in the effects of SP on PC12 cells, including cell viability, lactate dehydrogenase (LDH) release, antioxidant enzymes, the maintenance of mitochondrial membrane potential, and the reduction of mitochondrial reactive oxygen species (ROS).Conclusion Our study revealed that CAIII was integral to the effects of SP on DRCD, suggesting its potential as a therapeutic target for DRCD.

Secreted proteins are key mediators of intercellular communication in multicellular organisms. However, progress in secretomics has been hindered by the lack of effective methods for capturing secreted proteins. Here, we present a two-step secretome enrichment method (tsSEM) that integrates unnatural amino acid labeling with click chemistry-based biorthogonal reaction, enabling robust in vitro secretome profiling in the presence of serum. Applying tsSEM, we systematically analyzed the secretome of human induced pluripotent stem cells (iPSCs)-derived astrocytes (iAst) across various disease models and identified a panel of astrocyte-secreted proteins contributing to noncell autonomous neurotoxicity. Among these, we validated two novel neurotrophic factors, FAM3C and KITLG, which enhanced neurite outgrowth, protected neuronal viability, and promoted neural progenitor proliferation. Our findings demonstrate the utility of tsSEM for high-resolution secretome analysis and underscore the potential of iAst-derived secretomes in elucidating disease mechanisms and identifying therapeutic targets.