Conspectus C-Nucleosides, characterized by a chemically robust C–C glycosidic bond in place of the canonical C–N linkage, represent a distinct class of nucleoside natural products with diverse biological activities. Their close structural similarity to N-nucleosides enables their incorporation into primary metabolic processes, including de novo nucleoside biosynthesis and RNA polymerization. As a result, both natural and synthetic C-nucleosides exhibit potent antibacterial, antiviral, and anticancer activities, making them attractive targets for drug development in medicinal chemistry and chemical biology. Natural product discovery efforts have uncovered a number of C-nucleosides in which C–C glycosidic bond formation generally involves either decarboxylative electrophilic aromatic substitution or Knoevenagel-Mannich condensation. In both cases, C-glycosylation relies on the biosynthesis of highly nucleophilic heterocycles prior to glycosidic bond formation. These nucleophiles arise from distinct precursors, including d-glutamate-derived heterocyclic carboxylates and l-glutamine-derived scaffolds formed via oxidative cyclization. Following C-glycosylation, d-glutamate-derived intermediates undergo pyrimidine elaboration that parallels aminopyrimidine formation in de novo purine biosynthesis, whereas l-glutamine-derived heterocycles undergo oxidative tailoring reactions that ultimately define their final structure and biological function. Thus, C-glycosylation is indeed the central mechanistic feature of C-nucleoside biosynthesis that places requirements on the initial construction of the nucleophilic heterocycle to facilitate C–C bond formation and in the process defines the properties that govern subsequent tailoring reactions.
Conspectus Organic electrosynthesis has re-emerged as an attractive strategy for electrifying chemical industries without stoichiometric redox reagents. However, the practical value of an electrochemical transformation is not determined by yield and selectivity alone. Energy consumption, supporting-electrolyte removal, and downstream separation must also be considered when translating laboratory-scale reactions into chemical production. Solid polymer electrolyte (SPE) electrolyzers, which have been developed extensively in fuel cells and water electrolysis, offer a promising architecture for addressing these practical requirements in organic electrosynthesis. In an SPE electrolyzer, an ion-exchange membrane is sandwiched between electrodes to form a membrane electrode assembly with a zero-gap configuration. This structure shortens the ion-conduction path, lowers ohmic losses, and eliminates the need for dissolved supporting electrolytes. Within the electrode, the electrocatalyst, ionomer, and organic phase form a triple-phase boundary where electron transfer, ion transport, substrate adsorption, and chemical conversion occur in close proximity. Thus, the SPE architecture provides not only energetic and process advantages but also a platform for engineering the local environment in which electrosynthesis takes place. This Account is organized around three general advances enabled by this architecture. First, the zero-gap configuration can lower cell resistance, while supporting-electrolyte-free operation can simplify product isolation. Second, integration of the electrocatalyst and ionomer converts the triple-phase boundary into a tunable interfacial reaction field. The electrocatalyst controls substrate adsorption and the formation and reactivity of surface intermediates, whereas the ionomer governs the local ionic environment. Membrane selection is also important for broadening the range of compatible substrates and electrocatalysts. Together, the ionomer, electrocatalyst, and membrane provide complementary means of controlling activity and selectivity. Third, SPE electrolyzers offer a useful platform for operando characterization because the working ionomer-catalyst interface can be retained during spectroscopic measurements. Operando infrared and X-ray absorption spectroscopies reveal adsorbed hydrogen species, substrate adsorption geometries, and catalyst oxidation states that cannot be reliably inferred from ex situ characterization alone. These observations show that the catalytically relevant interface is dynamic and that rational catalyst and ionomer design must be based on the states present under operating conditions. After outlining the energetic basis and historical development of SPE electrosynthesis, we discuss representative hydrogenation and oxidation studies that establish these design principles. By integrating low-voltage and supporting-electrolyte-free operation with interfacial reaction engineering and operando mechanistic analysis, SPE electrolyzers provide a framework for developing selective organic transformations driven by renewable electricity. Further advances in membrane and ionomer stability, mass transport, reactor durability, and scale-up will be required to translate this framework into broadly applicable chemical manufacturing processes.
Elastomeric materials are used where few other polymeric materials can operate: in components that must deform repeatedly, recover rapidly, and continue to bear load under mechanical or environmental stress. Yet the molecular features that give elastomeric materials high performance often work against sustainability. The same interactions that make an elastomeric material reliable in service often make it difficult to heal or recycle. Weakening the network improves mobility but usually undermines the mechanical integrity that elastomeric materials are expected to provide. Early studies on supramolecular elastomers demonstrated that reversible hydrogen bonding, ionic association, metal-ligand coordination, and other noncovalent motifs could impart thermoreversibility, self-healing capability, and stress relaxation behavior to materials. Covalent-supramolecular networks combine stable covalent backbones with reversible physical associations, allowing mechanical integrity and local molecular mobility to be regulated at different structural levels. Dynamic covalent networks, including vitrimers and other covalent adaptable networks, introduce exchangeable covalent bonds that enable topology rearrangement, reshaping, repair, and reprocessing while maintaining network connectivity. The central design problem is therefore to make network dynamics conditional: active enough to dissipate energy and enable reconstruction, but restrained enough to preserve integrity during service. Our recent work addresses this question through hierarchical energy-dissipating networks (HEDNs). In HEDNs, supramolecular interactions and covalent linkages are not simply combined; they are assigned different mechanical roles and activated at different stages of deformation or processing. Under deformation, weaker interactions dissociate first to dissipate energy, while stronger interactions and covalent frameworks preserve network integrity. During healing, reprocessing, or upcycling, reversible interactions provide the mobility and adaptability needed for network reconstruction and component integration. Thus, hierarchical energy dissipation serves not only as a toughening mechanism, but also as a molecular strategy for coordinating mechanical robustness, structural stability, and sustainable reuse. This Account highlights three roles of this strategy in our studies of supramolecular elastomers and ionogels. In thermoplastic elastomers, staged supramolecular dissociation allows stress to be dissipated without destroying the load-bearing framework, leading to exceptional strength and toughness. In chemically cross-linked elastomers, covalent frameworks and reversible motifs divide the roles of stability and reconfiguration, enabling thermoset-like robustness together with thermal healing and reprocessing. In postservice materials, preinstalled interaction sites further allow discarded elastomers or ionogels to accommodate ionic liquids, carbon nanotubes, and other functional components, turning recycling into functional upcycling. Together, these studies establish HEDNs as a design principle for elastomeric materials that are tough, stable, reprocessable, and upcyclable.
Conspectus Combatting malaria, a disease afflicting more than 250 million people annually according to the World Health Organization (WHO), requires insecticides as part of integrated vector management. Indoor residual spraying (IRS) of crystalline contact insecticides and insecticide-treated bed nets (ITNs) decorated with insecticide crystals are estimated to have reduced malaria mortality in Africa by 60% in the 21st century. However, resistance now threatens malaria control, spurring the development of new insecticides, a process that requires substantial resources, anddiscovery time while posingenvironmental risks. Improving the effectiveness of compounds currently in use may be preferable. This Account provides a brief history of contact insecticides and describes discoveries from our laboratory that suggest paths to faster-acting contact insecticides based on the engineering of solid-state forms, either amorphous or crystalline polymorphs, thereby potentially obviating the need for new chemicals. Contact insecticides are thought to affect insects by absorption through the footpads. Prior to our 2017 report on the structure of a second solid form of DDT, crystal polymorphism was not optimized for contact insecticides. Comparative analysis of knockdown times for flies and mosquitoes against polymorphs of well-known crystalline contact insecticides including DDT and its analogs, as well as lindane, deltamethrin, and imidacloprid, established a link between thermodynamic crystal stability and insect knockdown speed. The relationship between the knockdown by a crystalline contact insecticide and its crystal structure ultimately arises from crystal thermochemistry. Weak intermolecular interactions in complex systems and associated shallow potential energy hypersurfaces readily lead to crystalline polymorphs with different molecular organizations that vary in crystal free energies and associated bioavailabilities. Notably, a new form of deltamethrin was 12 times more active than the commercial form, and the least stable polymorph of imidacloprid was six and nine times more active against susceptible Anopheles and Aedes mosquitoes, respectively, than the commercial, thermodynamically stable form. Some of these metastable polymorphs were found to be stable against transformation to their thermodynamically stable forms for months in an idealized laboratory setting, approaching WHO guidelines for practical use. The observation of differing polymorph effectiveness demonstrates that tarsal absorption of molecules from the crystal surfaces by insects is a key step, and likely a limiting step, in the insecticidal action. Indeed, a persistently amorphous form of deltamethrin dispersed on chalk exhibited dramatically increased efficacy against deltamethrin-resistant Anopheles mosquitoes from Burkina Faso, revealing that an increased rate of insecticide uptake overwhelmed all the resistance mechanisms tested. Collectively, this work argues that manipulation of the solid-state chemistry of contact insecticides is a viable strategy for mitigating insect-borne diseases and one that should be considered along with others in integrated vector management.
Conspectus Antiaromatic molecules are generally reactive and unstable due to their high highest occupied molecular orbital (HOMO) and low lowest unoccupied molecular orbital (LUMO) energy levels, which hinder their handling under ambient conditions and their use in functional materials. Nevertheless, antiaromatic molecules possess unique electronic features, including narrow HOMO–LUMO gaps, stable redox behavior, and distinctive magnetic properties, making them attractive building blocks for advanced functional materials. In this regard, the development of stable antiaromatic π-conjugated molecules is therefore an important challenge in contemporary molecular science. Norcorrole is a porphyrin analogue that lacks two bridging carbon atoms between the pyrrole subunits. Recent advances in norcorrole synthesis have established norcorroles as a unique platform for exploring antiaromaticity. Despite their pronounced antiaromatic character, norcorroles exhibit sufficient stability under ambient conditions and display a range of unusual properties that are different from conventional porphyrins. This Account details the development of the chemistry of norcorroles, focusing mainly on our research journey, covering the synthesis, structural characteristics, electronic properties, reactivity, and emerging functions of norcorrole derivatives. These include stacked-ring aromaticity arising from closely π-stacked architectures, reversible redox behavior for rechargeable batteries, intense near-infrared absorption for efficient photothermal conversion, high single-molecule conductivity, and the ability to form well-defined supramolecular assemblies. Through these investigations, norcorrole derivatives have evolved from fundamental targets in the chemistry of antiaromatic compounds into versatile functional materials for future applications.
Conspectus Azobenzene (Ph-N = N-Ph) and its derivatives are widely studied in many fields owing to their efficient and reversible E⇄Z photoisomerization. However, the parent azobenzene suffers from performance limitations, including incomplete photoconversion, short thermal half-life, low quantum yield, and reliance on UV light excitation. While specific ortho-substitutions can substantially improve these properties, further performance enhancements for advanced applications remain challenging. In recent years, the emergence of heteroaryl azoswitches (Het-N = N-Het/Ph) has brought new development opportunities to this already mature field, benefiting from their tunable scaffolds and the distinct features arising from diverse heteroaryl motifs. Despite their great potential, heteroaryl azoswitches are still at an early stage, and their advancement faces multiple challenges, including the lack of systematic molecular design principles, challenging synthesis, poor solid-state isomerization efficiency, and insufficient focus on practical implementations. In this Account, we introduce our recent efforts toward the development of high-performance heteroaryl azoswitches, outlining constructive strategies from molecular design to functional materials. To begin with, systematic strategies are presented to overcome key performance trade-offs in solution: 1) Through synergistic optimization of spatial and electronic structures, (hetero)arylazopyrazoles overcome the inherent limitations of conventional azobenzenes, enabling (near-)quantitative bidirectional photoconversion and long thermal half-lives up to years. 2) By rationally combining heteroaryl scaffolds with substituent effects, visible/solar-light-driven heteroaryl azoswitches are developed to avoid using harmful UV light while offering high bidirectional photoconversion and prolonged thermal half-lives. Remarkably, leveraging the efficient isomerization in solution as an essential prerequisite, (near-)quantitative bidirectional photoconversion is realized in azobispyrazole crystals. Building on this foundation, the first reversible single-crystal-to-single-crystal photoisomerization of an azo photoswitch is established, challenging the long-held perception that azo isomerization inevitably compromises single crystallinity. Furthermore, the broad application prospects of heteroaryl azoswitches, ranging from energy storage to photoresponsive smart materials, are validated. Finally, we discuss the enduring challenges and future opportunities of this emerging field. We anticipate that these advancements will inspire subsequent exploration of heteroaryl azoswitches and pave the way for their implementation in next-generation functional materials.
Conspectus Cell-selective fluorescent probes have become indispensable tools for visualizing biological complexity, yet their mechanisms of selectivity are still predominantly interpreted through a binding-centric paradigm. This conventional view assumes that selective interaction with a biomolecular target─typically a protein or glycan─is sufficient to achieve cellular specificity. However, a growing body of evidence reveals a fundamental inconsistency: probes with high binding affinity often fail to exhibit cell selectivity, whereas others with poorly defined or weak binding interactions can display remarkable specificity. These observations suggest that cellular selectivity cannot be explained solely by molecular recognition. In this Account, we present a comprehensive mechanistic framework that redefines the origins of cell selectivity of fluorescent probes. Building upon classical protein-oriented live-cell distinction (POLD) and carbohydrate-oriented live-cell distinction (COLD) mechanisms, we expand the conceptual landscape to include gating-oriented live-cell distinction (GOLD), metabolism-oriented live-cell distinction (MOLD), and lipid-oriented live-cell distinction (LOLD) processes. Through representative examples─including CDr3 and TiY (POLD), BacGO and SLY (COLD), CDg16 and CDr17 (GOLD), CDr20 and NeuO (MOLD), CDgB (LOLD), and CDy1 and CDg18 (multilayered)─we demonstrate that diverse physicochemical and biological factors collectively contribute to selective cellular labeling. A central theme emerging from this work is that cell selectivity is inherently multilayered. Rather than being governed by a single dominant mechanism, selectivity arises from the integration of sequential processes: (i) entry into the cell via transporters or endocytic pathways, (ii) intracellular trafficking, (iii) subcellular localization, and (iv) activation of fluorescence. In many high-performance probes, these processes operate cooperatively, forming a “logic-gated” system in which each step acts as a filter that enhances specificity. This multilayered perspective resolves longstanding discrepancies between binding affinity and imaging performance and highlights the importance of nonbinding mechanisms such as membrane permeability, enzymatic transformation, and lipid environment. Moreover, it suggests that cellular selectivity reflects not only molecular identity but also dynamic cellular states, including metabolism, differentiation, and activation. Looking forward, this framework points toward a paradigm shift in probe design. Instead of optimizing single-target interactions, future strategies will increasingly focus on integrating orthogonal mechanisms to construct probes capable of decoding complex biological contexts. Such approaches will enable more precise visualization of subtle cellular phenotypes and may ultimately transform fluorescent probes into tools for interrogating cellular logic itself.
Conspectus Heteroaromatic compounds are ubiquitous structural motifs in pharmaceuticals, natural products, and functional materials. Accordingly, the development of efficient methods for their construction, functionalization, and skeletal transformation has attracted considerable attention. Among the available approaches, electrochemical synthesis has emerged as a sustainable platform that enables the generation of highly reactive intermediates through an electrode-driven electron transfer. Despite these advantages, direct electrolysis often provides limited control over reactivity, because electron transfer occurs directly between the substrate and the electrode surface. To address this limitation, indirect electrolysis employing redox mediators has emerged as a versatile strategy for generating reactive intermediates and expanding the scope of the electrochemical synthesis. Building on these principles, we have developed a range of electrochemical transformations of heteroaromatic compounds that exploit the distinctive reactivity of mediator-derived intermediates. Using both halogen-based and non-halogen mediators, these methods enable the efficient synthesis and skeletal transformation of diverse heteroaromatic frameworks under mild conditions. In this Account, we describe our studies on mediator-controlled electrochemical transformations of heteroaromatic compounds, focusing on halogen-mediated oxidative cyclizations and skeletal transformations as well as DABCO-mediated radical processes. Particular emphasis is placed on the design of reactive intermediates and the mechanistic principles that govern their reactivities. The first section focuses on bromide-mediated electrochemical C–S bond formation for the synthesis of thienoacenes. Electrogenerated electrophilic bromenium ion species, represented as [Br+] equivalents, activate sulfur atoms to form a bromosulfonium intermediate, thereby enabling oxidative cyclization. We then discuss halogen-mediated electrochemical transformations of indole derivatives. Electrophilic [Br+] species selectively activate the C3 position of the indole framework. Furthermore, structurally complex natural product frameworks were accessed through mediator-controlled cyclization reactions, in which the choice of mediator dramatically influenced the reaction pathway and product architecture. In the final section, we describe the DABCO-mediated electrochemical synthesis of benzophosphole oxides. Electrochemically generated DABCO radical cations (DABCO•+) promote hydrogen-atom transfer (HAT) from P–H bonds to generate phosphorus-centered radicals. These reactive intermediates subsequently undergo annulation reactions, providing efficient access to phosphorus-containing heteroaromatic compounds. These studies illustrate how redox mediators can control activation modes under electrochemical conditions and, thereby, unlock distinct reaction pathways. A detailed understanding of the structures and reactivities of electrochemically generated intermediates is essential for the rational design of new transformations. We hope that this Account will stimulate further advances in indirect electrolysis and inspire the development of new electrochemical strategies for molecular construction and skeletal transformations.
SARS-CoV-2 papain-like protease (PLpro) is a compelling but historically underdeveloped antiviral target. Unlike the viral main protease (Mpro), which rapidly became the focus of intensive drug-discovery efforts and yielded clinical candidates and approved drugs, PLpro posed a more challenging medicinal chemistry problem: a shallow, flexible substrate-recognition surface and a mobile BL2 loop. Nevertheless, PLpro is a high-profile drug target because it is vital for viral replication by processing viral polyproteins and suppresses host innate immunity through deubiquitinating and deISGylating activities. These dual functions make PLpro more than a viral protease; it is a multifunctional immune-evasion enzyme whose inhibition could both block virus replication and restore antiviral host responses. This Account summarizes our group's effort to convert PLpro from a challenging target into a tractable antiviral drug-discovery platform. We began by developing and applying orthogonal assays to identify specific PLpro inhibitors and triage false positives. High-throughput screening and drug-repurposing campaigns yielded early hits, including Jun9722, Jun9754, and tropifexor, but also revealed that biochemical inhibition alone was insufficient to predict cellular antiviral activity. This motivated us to develop a FlipGFP cell-based reporter assay as a BSL-2-compatible bridge between enzymology and live-virus studies. In addition, we later developed a fluorescence polarization assay using a fluorescein-labeled PLpro ligand to enable direct, high-throughput quantification of inhibitor binding. Together with FRET enzymatic assays, thermal shift experiments, cellular FlipGFP assays, and antiviral assays, these tools established a rigorous validation framework for PLpro medicinal chemistry. With this platform in place, we pursued structure-based PLpro inhibitor design. Early cocrystal structures showed that potent noncovalent inhibitors engage the BL2 groove and stabilize inhibitor-bound PLpro conformations. A major conceptual advance came from structural analysis of the Jun11313-bound PLpro complex, which revealed that an inhibitor substituent occupied a hydrophobic surface pocket corresponding to the Val70 position of ubiquitin. We designated this newly recognized region the Val70Ub pocket. Exploiting this pocket transformed PLpro inhibitor design by expanding ligand engagement beyond the canonical BL2 groove and enabling substantial gains in enzymatic inhibition and antiviral activity. This design principle led to orally active noncovalent inhibitors, including Jun12682 and the quinoline lead Jun13296, both of which showed potent enzymatic inhibition, cellular antiviral activity, favorable mouse pharmacokinetics, and protection in SARS-CoV-2 mouse infection models. We further extended the Val70Ub-centered recognition strategy to covalent inhibitor design by appending cysteine-reactive warheads (covalent electrophiles) to optimized noncovalent scaffolds, thereby generating compounds that retained BL2 groove and Val70Ub binding while engaging the catalytic Cys111. Finally, resistance studies identified E167, Y268, and Q269 as drug resistance hotspots, highlighting the need to design inhibitors that engage less mutation-sensitive binding sites. Overall, this Account illustrates how integrated assay development, structural biology, medicinal chemistry, pharmacology, virology, and resistance analysis can transform a challenging viral deubiquitinase into a credible antiviral target. The lessons from PLpro should inform future efforts to design broad-spectrum coronavirus PLpro inhibitors and to target other viral protease-deubiquitinase enzymes with shallow, flexible binding surfaces.
Oxidative electrochemistry provides direct access to highly reactive intermediates under mild and sustainable conditions, yet controlling reactivity remains a central challenge in synthesis. In batch electrochemical systems, short-lived radicals, electrophilic oxidants, and cationic intermediates often undergo overoxidation, decomposition, or competing side reactions because of inefficient mass transfer and poor thermal control. Continuous-flow electrochemistry addresses many of these limitations by enabling rapid intermediate generation, efficient mass transport, precise residence-time control, and intensified reaction environments. In this Account, we describe how oxidative flow electrochemistry can serve as a platform for controlling reactive intermediates through selective generation and interception under continuous-flow conditions. Emphasis is placed on oxygen-centered radicals and reactive oxygen species, selenium electrophiles and radicals, electrophilic halogen and hypervalent iodine intermediates, heteroatom-centered oxidative coupling processes, and stereoselective electrochemical transformations through memory of chirality. Across these studies, a common principle emerges in which reaction selectivity is governed not only by the nature of the intermediate itself, but also by how fast and precisely it is generated, transported, and trapped within the flow reactor. Mechanistic investigations, automation strategies, online analysis, and scalable electrochemical platforms further demonstrate how flow electrochemistry enables a transition from empirical oxidative synthesis toward controllable and predictable reactive intermediate chemistry. Collectively, these studies establish oxidative flow electrochemistry as a versatile platform for reaction control and highlight its future potential in sustainable synthesis, asymmetric electrosynthesis, and automated reaction development.
Organic electrosynthesis has emerged as a powerful platform for sustainable molecular synthesis, while continuous-flow electrochemistry is often viewed primarily as a technology for process intensification and scaleup. In our studies, however, we have found that the significance of continuous-flow electrochemistry extends far beyond improved productivity. The unique reaction environments created by single-pass flow electrolysis─including short residence times, spatially evolving electrochemical conditions, efficient mass transfer, and distinctive electrode interfacial microenvironments─can fundamentally alter reaction outcomes and facilitate transformations that are difficult to achieve in conventional batch reactors. In this Account, we summarize our efforts in developing continuous-flow electrosynthesis as a synthetic platform for challenging oxidative molecular transformations. We first show how single-pass flow electrolysis suppresses undesired secondary electrode reactions, enabling selective oxidative cyclizations, C-H oxygenation, and C-H amination reactions. We then discuss how continuous-flow electrolysis expands the accessible reactivity space of electro-oxidation by promoting productive utilization of highly reactive intermediates, exemplified by sulfur-centered radical chemistry and phosphorus radical cation chemistry. Particular emphasis is placed on electrochemical microenvironment engineering, where local ion distributions and acid-base properties within the electric double layer can be exploited to control reactivity. We further demonstrate how these concepts culminate in electro-oxidative asymmetric catalysis, where continuous-flow electrolysis provides an expanded operational window for simultaneously optimizing electrochemical and stereochemical parameters. Finally, we describe the translation of these transformations from laboratory-scale reactions to continuous production through reactor number-up and process integration. We anticipate that the next phase of development in flow electrosynthesis will be driven as much by advances in reactor engineering as by advances in synthetic methodology, ultimately enabling increasingly sophisticated continuous and electrified manufacturing platforms.
Oral bacteriotherapy has given rise to an unprecedented potential in treating a variety of diseases, especially gastrointestinal tract-associated immune and metabolic disorders, through reversing microbial imbalance-induced physiological dysfunctions. However, living therapeutic bacteria are often plagued by unsatisfactory treatment outcomes due to their impaired oral viability, unpredictable intestinal distribution, and undesired in vivo colonization. Controlled delivery of therapeutic bacteria via customized vehicles is able to overcome these difficulties by protecting a bacteria from environmental insults, selectively releasing in the intestine, and/or increasing targeted accumulation at the lesion site. Recently, remarkable efforts have been made on cell surface modification to improve the in vivo delivery of therapeutic bacteria based on specific physiological environments and/or pathological features. Among these purposive modification strategies, the formation of a stimuli-responsive nanocoating represents a versatile platform to introduce bacteria with extra functions, such as enhanced resistance, site-specific exposure, and physiological signal-triggered in situ activation in the gastrointestinal tract, offering a promising approach for precisely delivering therapeutic bacteria for advanced oral bacteriotherapy. In this Account, we summarize the recent advances from our group in manipulating bacterial behaviors through the construction of gastrointestinal stimuli-responsive nanocoatings, with the aim to enable controlled oral delivery of living therapeutic bacteria. First, we report the use of available reactive moieties on the bacterial surface to form diverse stimuli-responsive nanocoatings without affecting bacterial viability. By virtue of abundant intermolecular interactions, such as electrostatic attraction, hydrophobic adsorption, π-π stacking, coordination bonding, or heterogeneous nucleation mineralization, nanocoatings consisting of functional small molecules, polymers, and/or nanoparticles can be formed on the bacterial surface. We describe how these nanocoatings can intelligently respond to specific gastrointestinal stimuli, thereby enabling the controlled oral delivery of modified bacteria. For instance, the introduction of a gastric acid-responsive nanocoating can neutralize acidic insult to enhance bacterial tolerance, ensuring the passage of intact bacteria through the stomach. Additionally, an enteric nanocoating can be triggered to dissolve in response to pH fluctuation, consequently rendering a selective release of therapeutic bacteria in the intestine. Moreover, equipping bacteria with a pathological signal-sensitive nanocoating enables the controllable exposure of therapeutic bacteria at the lesion site, achieving targeted delivery to the lesion site. Then, we show the advantages of stimuli-responsive nanocoating-enabled controlled oral delivery of therapeutic bacteria for disease intervention. Specifically, we highlight the applications involving the treatment of intestinal infections, the alleviation of chemically induced ulcerative mucositis, the synergistic treatment of pathogen-induced colitis, and the prevention of gut microbiota disorder-caused atherosclerosis. Lastly, we discuss the prospects and challenges of using stimuli-responsive nanocoatings to manipulate the functions of therapeutic bacteria for controlled oral delivery and corresponding disease management, particularly the translational potential from laboratory research to clinical implementations. We anticipate that these stimuli-responsive nanocoating-based oral delivery systems proposed in this Account, as well as their tunable interplays with the gastrointestinal environments, will advance the development of next-generation living therapeutics and provide innovative strategies for disease intervention.
Glycans play pivotal roles in cell-cell communication, immune recognition, signal transduction, and pathogen-host interactions. Their versatile functions stem from extraordinary structural diversity, defined by variations in composition, linkage, configuration, and branching. Such structural complexity poses substantial challenges for comprehensive glycan analysis. Complicating matters further, many glycans exist only in trace amounts in biological systems, and their nontemplate-driven biosynthesis precludes amplification. This dual constraint further intensifies the analytical difficulties. Thus, the ability to isolate and structurally determine glycans with high efficiency has become paramount for advancing glycoscience. Given the structural diversity of glycans, biological systems have evolved a repertoire of glycan-binding proteins to decode these complex structures. Lectins represent a prime example; renowned for their specific binding to glycans, they have been used to profile glycans in the form of affinity reagents. Inspired by lectins, we turned to the rational design of glycan-affinity peptides (GAPs) that mimic lectin function. Over the past decade, our group has been dedicated to the development of GAPs, driving their evolution from simple binders to high-specificity, high-affinity recognition elements. These efforts have advanced GAPs from single amino acids and dipeptides to oligopeptides, accompanied by a remarkable affinity enhancement from millimolar to nanomolar levels. In parallel, the design paradigm has shifted from empirical trial-and-error to directed evolution and now to preliminary computational design. As a result, these GAPs have evolved into versatile precision recognition engines powering two complementary analytical frontiers: first, they underpin robust affinity materials for the precision capture of glycosylated targets, including lipopolysaccharides and circulating tumor cells; second, they enable high-resolution nanopore sensors capable of precision identification of specific glycans and glycosides. Overall, it is the evolution of GAPs into reliable recognition platforms that represents a significant advance in glycan analytical capability, moving from broad-spectrum enrichment toward targeted capture, and from bulk measurements toward single-feature resolution. In this Account, we summarize our efforts in GAP design and applications, presenting a unified narrative of how we engineered these affinity engines to decipher the glycan code with high precision. We begin with an overview of the fundamental principles, design strategies, and future trends underpinning GAP evolution. Following this, we detail our advances in GAP-driven precision glycan analyses. We believe this Account will drive the development of a new generation of GAPs and facilitate their broader implementation across glycoscience.
Conspectus A central question in origin-of-life research is how biological macromolecules and cellular structures arose from simple precursors under prebiotic conditions. This review focuses on the chemical evolution model of N-phosphoryl amino acids (NPAAs) and their multifaceted roles in this process. Featuring high-energy P–N bonds, NPAAs enable intramolecular activation via pentacoordinate phosphorus intermediates, facilitating the formation of homochiral peptides and nucleotides under mild aqueous conditions. Moreover, N-amino acid-nucleotide conjugates (N-aa-NMPs) drive peptide formation with chiral selection between amino acids and nucleosides, where the peptide yield for each amino acid is modulated by specific nucleosides, thereby laying a foundation for a proto-genetic code. Additionally, amphiphilic NPAA derivatives spontaneously self-assemble into vesicles and selectively condense peptides at membrane interfaces, whereas the in situ generation of N-fatty acyl amino acids further enhances membrane stability. Collectively, these findings support a phosphorus-centered model for the integrated origin of nucleic acids, proteins, and membranes.
The chemistry of tetracoordinate borons has long been dominated by the classic 1,2-metalate shift, a powerful yet inherently predictable rearrangement where the migrating aptitude is dictated by the electronic bias of the substituents. Breaking free from this paradigm to achieve controllable and diverse migration─beyond 1,2-shift─remains a formidable challenge. In this Account, we describe our systematic efforts to unlock three previously inaccessible dimensions of tetracoordinate boron reactivity: ionic remote migrations, radical remote migrations, and programmable sequential multiple migrations on a single boron center. Across these three manifolds, the feasibility of migration is governed by three common factors: migration distance is constrained by the size of the cyclic transition state (rings of 5-7 members are viable); the aptitude of a migrating group depends on its ability to stabilize developing charge in ionic pathways or radical character in radical pathways; and conformational preorganization is essential for ionic remote migrations, while radical variants are more tolerant due to the extended lifetime of the radical intermediate. Distilled from systematic mechanistic studies, these principles establish a predictive framework for the design of new migrations. Our journey began with the realization that the conventional 1,2-shift is not the only option. By carefully designing the tetracoordinate boron frameworks and the external stimulus, we can direct a substituent to migrate over a longer distance. In the ionic manifold, we developed remote 1,n-metalate shifts (n ≥ 3) in which heteroatoms (hydroxyl, bromine, hydride) and carbon substituents migrate over 1,3-, 1,4-, and even 1,7-distances, enabling stereospecific ketoxime synthesis, enantioselective construction of axially chiral alkenes, skeletal editing of N-heterocycles, a Passerini-type multicomponent reaction, enolate-driven C(sp2)-C(sp3) cross-coupling, and asymmetric indole reduction─all with a level of control unattainable by classical methods. Second, we turned to a completely orthogonal activation mode: radical-induced remote migrations. Under visible-light photoredox conditions, selective cleavage of a C(sp3)-B bond in tetracoordinate boron species generates an alkyl radical that undergoes unprecedented long-distance migration (1,4-, 1,5-, and the first 1,6-radical shift), with the incorporation of both radical and boron moiety into the products with complete atom economy─solving a long-standing problem in photoredox deboronations of alkyl tetracoordinate borons with boron species discarded as waste. Third, we explored the untapped potential of sequential multiple migrations on a single tetracoordinate boron atom. By judicious selection of inducing reagents─identical or distinct electrophiles, bifunctional reagents, or transition-metal catalysts─two or even three successive 1,2- and 1,3-migrations can be programmed in a controlled order, transforming simple boronates into complex, densely functionalized architectures (e.g., tetrasubstituted alkenyl halides, benzothiophenes, polysubstituted alkenes, deuterated allylboronates, 1,1-diarylalkanes, and diarylmethylamines) in a single operation. Collectively, these discoveries demonstrate that tetracoordinate borons are not merely reactive intermediates confined to the classic 1,2-shift, but rather represent a versatile migration platform whose reactivity─distance, mechanism, and sequence─can be rationally controlled. Mechanistic insights from DFT calculations and kinetic studies rationalize the observed migratory aptitudes and offer a predictive framework for designing future migrations. Our work opens a new chapter in organoboron chemistry, where controllable and diverse migration becomes a synthetic reality.
Electrophilic aromatic substitution has long served as a cornerstone for C-H functionalization, yet its catalytic enantioselective variant, especially for sulfenylation, remains largely unexplored. The challenges are multifaceted: the stereogenic element often lies remote from the reaction site, multiple reactive sites compete, and the mechanisms of asymmetric induction vary unpredictably with substrate structure. Overcoming these obstacles requires not only new catalysts but also a deep understanding of the underlying stereochemical properties. In this Account, we summarize our systematic efforts to address these obstacles through chiral Lewis base-catalyzed enantioselective electrophilic C-H sulfenylation of arenes, a metal-free approach that inherently avoids the catalyst poisoning issues common in transition-metal-mediated C-S cross-couplings. Starting from the atroposelective sulfenylation of biaryl phenols, we discovered that a combined desymmetrization/kinetic resolution sequence, enabled by chiral 1,1'-binaphthyl-2,2'-diol (BINOL)-derived selenide catalysts and an achiral sulfonic acid, delivers axially chiral organosulfur products with high enantiocontrol. This work established the feasibility of asymmetric aromatic sulfenylation and laid the groundwork for subsequent expansions. Mechanistic studies, including nuclear magnetic resonance (NMR) titrations, density functional theory (DFT) calculations, and noncovalent interaction (NCI) analysis, revealed that hydrogen-bond networks and π-π interactions play a crucial role in stabilizing the enantiodetermining transition states. The same catalytic logic was then extended to other substrate classes, proving applicable to N-aryl pyrroles and biaryl anilines, with the latter proceeding via sole desymmetrization. For N-aryl aminoquinones, the sulfide catalyst with a more rigid 1,1'-spirobiindane-7,7'-diol (SPINOL) backbone proved superior, affording chiral products with two contiguous C-N axes. In addition to the synthesis of axially chiral organosulfur compounds, we applied the same catalytic platform to construct planar-chiral, helically chiral, inherently chiral, and chiral silicon-stereogenic organosulfur molecules. For planar-chiral cyclophanes, the mechanism switches among dynamic kinetic resolution (DKR), kinetic resolution (KR), and desymmetrization depending on ring size. Helically chiral aza-[5]helicenes were obtained via DKR, and the sulfide products underwent cross-coupling without erosion of chirality. Inherently chiral calix[4]arenes were accessed through a rare example of chemoselective desymmetrization where kinetic N-sulfenylation is reversible and gives way to thermodynamically favored C-sulfenylation. Finally, chiral silicon-stereogenic cyclic diarylsilanes were delivered through a tandem desymmetrization/kinetic resolution sequence, further underscoring the generality of our approach. Across all systems, noncovalent interactions such as C-H···π, π-π, and hydrogen bonding proved to be the dominant stereocontrolling forces. The evolution of catalysts from selenides to sulfides, from binaphthyl to spiro backbones, and the introduction of chiral amine moieties systematically improved both yield and enantioselectivity. This Account thus provides a unified blueprint for asymmetric aromatic C-H sulfenylation, offering both synthetic access to diverse chiral scaffolds and mechanistic insights that should guide future developments in organocatalytic electrophilic functionalization.
Super-resolution microscopy has fundamentally transformed our ability to observe biological structures, allowing nanoscale observation into biological samples such as fixed and live cells and tissues, and has been notably recognized by the 2014 Nobel Prize in Chemistry. Single-molecule localization microscopy (SMLM) stands out as a highly successful and widely accessible method for super-resolution microscopy. However, because SMLM relies on computationally reconstructing a single image from thousands of sparse frames, it suffers from significant algorithmic bottlenecks, particularly when dealing with high emitter densities or three-dimensional data. Deep learning has emerged as an exceptionally effective solution to bypass these computational challenges, enabling fast, parameter-free reconstruction. The application of neural networks for SMLM analysis is uniquely powerful because such networks can be trained entirely on simulated data; since the optical point spread function is well-understood, and SMLM images are fundamentally simple, consisting of a collection of point-spread functions, it is relatively easy to numerically simulate the vast quantities of highly accurate training images required to train reconstruction nets. In this Account, we summarize our contributions to localization microscopy by applying neural nets to address its limitations and bottlenecks. Specific challenges and applications include dense molecule fitting in 2D and in 3D, single-channel multicolor imaging, super spatiotemporal resolution microscopy, optical genome mapping, large field-of-view (FOV) imaging, and accurate background simulation. The fact that the training of the neural net is based on simulated images enables powerful and interesting capabilities. For example, the optical setup itself can be algorithmically designed together with the decoding neural net; we have used this concept for tasks such as designing optimal phase masks for depth encoding, for spectral encoding, and even for both simultaneously.
