Given the prevalence of nitrogen heterocycles in pharmaceuticals, divergent skeletal editing techniques that enable rapid access to a diverse library of azacycles from a single substrate are highly desirable. Herein, we report a skeletal editing approach that converts abundant saturated primary amines into N-heterocycles, with exceptional functional-group compatibility, broad skeletal diversity, superior regioselectivity, and diastereospecificity (both >20:1). By harnessing the reactivity of hypervalent iodines, an imino ether intermediate is generated through mild iodane-mediated oxidation, facile N-internalization, and methoxy anion addition. This pivotal intermediate serves as a versatile platform capable of interception by a wide spectrum of nucleophiles, thereby enabling the generation of structurally diverse nitrogen heterocycles (>15 classes). Furthermore, this strategy enables challenging site-controlled carbon-to-nitrogen transmutation and ring contraction of natural products through a one-pot, consecutive skeletal editing sequence.

Organometallic electrochemical synthesis (OES) is a rapidly emerging synthetic domain that elegantly merges transition metal catalysis with electrochemistry, offering a powerful and sustainable complement to traditional organic synthesis. At its core, organometallic species serve as versatile molecular electrocatalysts, precisely regulating electron flow at electrode-solution interfaces and orchestrating controllable redox conversions, thereby establishing a unique mechanistic paradigm distinct from conventional organic electrochemistry, which often relies on radical pathways. Our group has long focused on OES-enabled C-H (carbon-hydrogen) and C-X (carbon-halogen) bond functionalization under this innovative theoretical framework, aiming to address long-standing challenges in synthetic efficiency, atom economy, and selectivity.A key advantage of electrochemistry is its ability to achieve precise, real-time modulation of the oxidation states of organometallic intermediates via heterogeneous interfacial electron transfer. This strategy circumvents the major drawbacks of traditional stoichiometric redox reagents, which often interact unfavorably with catalysts and generate large amounts of toxic byproducts or chemical waste. Anodic oxidation, in particular, efficiently activates inert C-H bonds under mild conditions, enabling challenging C-H bond cleavage and stereoselective carbon-carbon (C-C) and carbon-heteroatom (C-Y) framework formation, while maintaining strict control over the reductive elimination process. Through rational design and introduction of custom chiral ligands, we further manipulate stereoselectivity and achieve highly enantioselective asymmetric functionalization, a critical goal in pharmaceutical and fine chemical synthesis. On the other hand, cathodic reduction primarily facilitates the reductive cross-coupling of carbon-halogen bonds. By eliminating the need for extraneous reducing agents, this approach sustains stable catalytic performance and avoids issues related to reagent activation, deactivation, and side reactions. Chiral induction strategies, when integrated into the cathodic catalytic cycle, deliver cross-coupling products with high enantiomeric excess. Beyond single-electrode reactions, we further explore paired electrolysis and photoassisted paired electrolysis, which synergize anodic oxidation and cathodic reduction in one cell, significantly boosting electron transfer efficiency and expanding the scope of synthetically useful transformations.In this Account, we systematically summarize our recent advances covering anodic oxidation mediated C-H functionalization, cathodic reductive cross-coupling, and paired electrolysis enabled chemical transformations. Rational ligand design, electrode optimization, and detailed mechanistic studies have afforded a suite of versatile, user-friendly synthetic protocols. These strategies provide ecofriendly, scalable pathways for the construction of complex molecules and pharmaceutical intermediates, aligning with the global pursuit of green and sustainable chemistry. The unique strengths of OES, accurate redox modulation, controllable reaction selectivity, and robust functional group compatibility, establish it as a field with remarkable growth potential and bright application outlooks in contemporary organic synthesis.

Supercapacitors have emerged as a vital component in electrochemical energy storage, owing to their compelling advantages including high power density, long cycle life, fast charge/discharge capability, wide operating temperature range, high safety, and environmental friendliness. However, the severe self-discharge phenomenon causes spontaneous voltage decay and continuous energy loss under open-circuit conditions, significantly restricting their practical deployment in independent energy storage and long-term reliability scenarios. To address this critical bottleneck, this review first decouples the three dominant self-discharge mechanisms from a fundamental perspective, namely ohmic leakage, parasitic Faradaic reactions, and charge redistribution. Anchored in device architecture, it then systematically summarizes the influence of each component, including the current collector, electrode material, electrolyte, and separator, on self-discharge behavior and the corresponding suppression strategies. This work aims to provide directional guidance for constructing high-energy supercapacitors with ultralow self-discharge.

Combining polymerization-induced branching (PIB) with controlled radical polymerization (CRP) enables regulated and site-specific synthesis of hyperbranched polymers. However, it remains a challenge to apply this strategy to the synthesis of hydrophobic/oil-soluble hyperbranched polymers with important application value. Existing methods are either suitable for hydrophilic systems or suffer from crosslinking/low efficiency/low conversion in hydrophobic systems. Herein, amine-thiourea bifunctional organic catalysts, widely used in small-molecule asymmetric catalysis, are innovatively employed to construct photoinduced reversible complexation mediated polymerization (RCMP) system, realizing convenient, efficient and controlled synthesis of hydrophobic/oil-soluble hyperbranched polymers via one-shot copolymerization of acrylates and alpha-iodoacrylates. Monomer conversion reaches 98%, yielding hyperbranched polyacrylates with moderate dispersities (1.18-1.90) as well as tunable molecular weights (M-n = 40-190 kg/mol) and branching densities. In the bifunctional catalyst, the tertiary amine moiety complexes with the terminal iodine of the dormant species, inducing reversible cleavage of C-I bond to generate active radical species and enable subsequent controlled chain propagation. While the thiourea group anchors the catalyst through interaction with the terminal monomer unit, which is speculated to serve three functions: i) primarily suppressing biradical coupling/termination via shielding macromolecular radicals; ii) assisting in the activation of C-I bond in dormant species via reducing its electron density (bond energy) to promote chain propagation; iii) reducing the difference in reactivity ratios between inibramer and main monomer via hindering the radical addition of the highly reactive but sterically hindered alpha-iodoacrylate. Consequently, this bifunctional RCMP catalytic system avoids the slow rate, low conversion, severe inter-macromolecular coupling and even cross-linking issues in the ATRP and monofunctional RCMP catalytic systems, delivering fast polymerization and high conversion while suppressing cross-linking. The resulting polymer features a high retention degree of terminal functional groups and ease of modification, enabling its use as a high-performance multifunctional lubricant additive to facilitate the high-value utilization of reclaimed base oil, which holds great significance for environmental protection and resource conservation.

Propargylic substitution is a basic transformation model in organic synthesis, which requires the adoption of alkyne substrates bearing a vicinal leaving group. Recently, the exploration of remote-leaving-group-promoted propargylic substitution pioneered by Fang, He and Xu, has gained much attention and provided new possibilities for this classical area. With this design, a series of related studies have been reported and enabled the enantioselective construction of diverse privileged skeletons. This review article provides a detailed summary of the origin, development, mechanisms, limitations and future directions of this nonclassical propargylation model.

Carbenes are highly valued for their broad utility across diverse fields, and their chemistry has consequently been the subject of extensive research. Taming the high reactivity of these divalent carbon intermediates to achieve controllable selectivity for diverse transformations remains a fundamental challenge. This often necessitates bespoke, fine-tuned conditions for each reaction type, limiting generality and efficiency. Here, we report the rational design of a versatile, electrophilic carbene-bis(trifluoromethylthio)carbene (:C(SCF3)(2))-generated from a scalable reagent (BrCH(SCF3)(2), >30 g/batch). We show that this single carbene species efficiently mediates nearly all classic free carbene reactions, including cyclopropanation, skeletal editing, X-H insertion, sulfur ylide-based [2,3]-sigma rearrangement/1,2-migration, and nitrogen ylide-initiated [4+1] cyclization, under one set of mild conditions with high chemoselectivity. This versatility may be attributed to the synergistic design of the -SCF3 substituent, which concurrently provides strong electron withdrawal, a polarizable sulfur atom, and a bulky trifluoromethyl group. Our work establishes a unified synthetic platform that extends beyond specific reaction development, suggesting a potential paradigm for controlling reactive intermediates through rational substituent design, which may help streamline the synthesis of functional molecules.

A novel method for the selective synthesis of perfluoroalkylated thioamides and thioamide S-oxides has been developed through the reaction of perfluoroalkyl sulfoxides with secondary amines. The selectivity of the reaction can be easily modulated by employing different additives. Specifically, PCl3 promotes the formation of thioamides, whereas ZnCl2 facilitates the formation of thioamide S-oxides. This protocol tolerates a broad range of substrates, including aromatic, aliphatic, and cyclic secondary amines, as well as sulfoxides containing different perfluoroalkyl groups. The plausible mechanistic pathways were proposed on the basis of experimental results.

Nonheme iron/alpha-ketoglutarate-dependent dioxygenases (Fe/alpha KGDs) catalyze diverse oxidative transformations, including hydroxylation, desaturation, and ring expansion. Although these reactions are well established, Fe/alpha KGD-catalyzed epimerization remains rare and has not been characterized in ribosomally synthesized and post-translationally modified peptides (RiPPs). Here, we report the RiPP-modifying enzyme YmI, a bifunctional Fe/alpha KGD that catalyzes C beta-hydroxylation of Phe19 and C alpha-epimerization of Ile20 on the precursor peptide YmA toward the formation of YM-216391. The hydroxylation generates (2S,3R)-beta-hydroxyphenylalanine, whose l-threonine-like stereochemistry facilitates subsequent formation of an unusual 5-phenyloxazole moiety. Substrate profiling analyses reveal leader peptide dependence for catalytic activity. Structural and docking studies provide insights into the substrate binding and active site architecture. Deuterium labeling demonstrates that YmI catalyzes Ile epimerization by directly abstracting the C alpha-hydrogen, generating a C alpha radical that is subsequently reprotonated by a nonexchangeable hydrogen source within the enzyme. These results unveil an unprecedented mechanism and novel bifunctionality, markedly expanding the reaction landscape for alpha KG-dependent enzymes in RiPP biosynthesis.

The UGA-independent substitution of methionine (Met) and cysteine (Cys) with their selenium (Se) analogues, selenomethionine (SeMet) and selenocysteine (Sec), represents a non-canonical but widespread pathway for the biosynthesis of selenium-enriched proteins. Although well-documented across prokaryotes and eukaryotes, the associated cellular adaptive strategies and phenotypes remain poorly understood. Here, we investigated these substitution patterns and their functional consequences in Bifidobacterium longum (B. longum), a probiotic bacterium that adapts efficiently to high Se stress. Using high-resolution mass spectrometry, we systematically identified and compared SeMet and Sec incorporation sites within the B. longum proteome under Se-enriched conditions. SeMet incorporation proved extensive, substituting over 90% of Met residues, with limited cellular damage. Ribosomal proteins exhibited the highest SeMet incorporation, which did not significantly alter the translational rate. In contrast, Sec incorporation was markedly restricted, characterized by significantly fewer substitution sites and lower substitution proportions. This restriction, accompanied by severely delayed bacterial growth, indicates a profound state of cellular stress, which was further corroborated by the upregulation of protein quality control machinery and the remodeling of sulfur metabolism pathways. However, a subset of proteins with a high probability of Sec incorporation remained, primarily found in catalytic enzymes, yet not localized within their active sites. Notably, both SeMet and Sec incorporations occurred preferentially in highabundance proteins, without distinct sequence preferences. This work provides the first systematic comparison of SeMet and Sec incorporation patterns in a bacterial proteome, establishing a framework to analyze noncanonical Se incorporation and the specific adaptation strategies bacteria employ against environmental Se challenges.

The widespread emergence of antibiotic resistance necessitates the development of novel agents with unique mechanisms of action. Obafluorin (OB), a natural beta-lactone antibiotic, is a covalent inhibitor of threonyl-tRNA synthetase (ThrRS), but the high conservation of the active site between prokaryote and eukaryote ThrRSs results in minimal selectivity, hindering the therapeutic potential of OB. Here, we report a structure dynamics-based design strategy that transforms OB into a selective antibacterial agent. OB inhibits human and bacterial ThrRSs with nearly equal potency due to identical binding modes. The nitrophenyl moiety of OB is proposed as a 'kinetic sensor' that discriminates between sensitive and resistant ThrRS paralogs. Guided by this insight, we designed a series of OB analogs through rational modification of this moiety. Among them, OB-D4 bearing a para-methoxyphenyl group in place of the nitrophenyl group, exhibited a 241-fold selectivity for bacterial over human ThrRS, along with a markedly improved safety profile with minimal cytotoxicity. In a murine skin infection model, OB-D4 effectively eradicated pathogens, resolving inflammation, and promoting wound healing. Together, this work establishes a 'kinetic sensor' strategy for achieving species selectivity, turning a fundamental challenge in drug discovery-high active-site conservation-into an exploitable opportunity based on dynamic differences.

Background The etiology of Kawasaki disease (KD) remains unclear. Hematopoietic stem and progenitor cells (HSPCs) serve as the precursor cells for a multitude of immune cells. Investigating their initial transcriptional status may help uncover the aberrant immune mechanisms underlying KD.Methods Induced pluripotent stem cells (iPSCs) were reprogrammed from peripheral blood mononuclear cells (PBMCs) isolated from patients with KD and febrile individuals, followed by directed differentiation into HSPCs. We performed bulk RNA-sequencing to compare transcriptomic profiles of iPSC-derived HSPCs between the two groups, with further comparison against integrated HSPC data from public KD single-cell datasets.Results We recruited three patients with KD prior to Intravenous immunoglobulin (IVIG) therapy and three febrile control patients, and successfully established an iPSC-derived HSPCs disease model. Transcriptomic profiling revealed elevated immune and inflammatory response signatures in iPSC-derived HSPCs from patients with KD compared with those from febrile individuals. In addition, in vitro-generated KD iPSC-HSPCs exhibited partial transcriptional features similar to in vivo HSPCs isolated from PBMCs of patients with KD. Gene Set Enrichment Analysis (GSEA) further revealed that gene sets associated with B-cell developmental processes were transcriptionally downregulated in iPSC-derived HSPCs from patients with KD relative to febrile controls.Conclusions iPSC-derived HSPCs from patients with KD display altered immune-inflammatory transcriptional profiles and suppressed B-cell developmental signatures at the transcriptomic level. These preliminary findings suggest that early hematopoietic immune dysregulation may contribute to KD pathogenesis. We propose that these iPSC-derived HSPCs could be a good cellular model for studying the etiology of KD in vitro. These findings are preliminary, constrained by the small sample size and limited to transcriptomic analysis only. Further studies with larger cohorts and functional experiments are needed to verify these results.

The combination of brain glucose hypometabolism and hyperphosphorylated Tau (p-Tau) pathology is the strongest known clinical predictor of imminent cognitive decline, yet how these factors cooperate to drive dementia remains unknown. Here, we show that glucose hypometabolism synergizes with p-Tau to trigger neuronal loss through necroptosis. Under low-glucose conditions, accumulated p-Tau forms a molecular scaffold that directly recruits RIPK1, while concomitant loss of the necroptosis checkpoint A20 removes a critical brake on this death pathway. This dual mechanism thereby precipitates neuronal necroptosis. Restoring A20 expression with acetyl-L-carnitine or preventing the p-Tau-RIPK1 interaction using a RIPK1-derived competitive peptide alleviates neuronal necroptosis and brain atrophy in a Tau transgenic mouse model. Collectively, our findings uncover a previously unrecognized metabolism-driven necroptotic signaling cascade initiated by a p-Tau-RIPK1 hub, providing mechanistic insight into how glucose hypometabolism synergizes with p-Tau to drive neurodegeneration.