Nanoarchitectonics of bacteriophage-based click fluorescent biosensing platform for detection of Pseudomonas fluorescens.

Synergistic catalysis of cellulose acetate-poly(ionic liquid) composite catalysts toward CO2 cycloaddition reaction

The topoisomerase 1 (TOP1) enzymatic inhibition and antiproliferative activity of phosphorated indenoquinoline derivatives were investigated. First, the preparation of new hybrid quinoline and tetrahydroquinoline structures with a phosphine oxide group was performed by a two-step Povarov type [4 + 2]-cycloaddition reaction between the corresponding phosphorated aldimines with indene in the presence of BF3·Et2O, affording corresponding 1,2,3,4-tetrahydroindeno[2,1-c]quinolinylphosphine oxides 9, 7H-indeno[2,1-c]quinolinylphosphine oxides 10 and 7-oxoindeno[2,1-c]quinolinylphosphine oxides 11 with good yields. The synthesized derivatives were evaluated as TOP1 inhibitors, showing that some derivatives (9f, 9g, 9l, and 11m) show better or similar activity to the reference compound (CPT) at 1 min. The synthesized derivatives were screened for their antiproliferative activity in different cancerous cell lines, and all of them present a higher selective cytotoxicity in the human lung adenocarcinoma cell line (A549), than in the others. In contrast, almost none of the synthesized phosphorated compounds exhibited antiproliferative activity toward nonmalignant lung fibroblasts MCR5. These results suggest that phosphine oxide-substituted quinoline derivatives have important properties as TOP1 inhibitors and show an interesting cytotoxicity against six different cancerous cell lines.

Cyclobutenes are found in natural products and medicinal chemistry and can be readily functionalized. Herein is presented a straightforward, transition-metal-free [2 + 2] cycloaddition reaction of readily available ynimines with N,N-dimethyl cinnamamides to access fully substituted cyclobutenes. It is proposed that the ynimine is deprotonated, and the resulting allenyl anion undergoes conjugate addition to the cinnamamide followed by ring closure to afford the cyclobutene products. This reaction has good scope, proceeds in 40-83% yield, and is atom economical.

A facile and efficient DBU-mediated [3 + 3] cycloaddition reaction of N-2,2,2-trifluoroethylisatin ketimines with diazo esters for the synthesis of trifluoromethyl dihydro-1,2,4-triazine-spirooxindole derivatives has been developed. The reaction proceeds under mild conditions with a broad substrate scope, tolerating various electronically and sterically diverse substituents to afford moderate to excellent yields. Furthermore, a one-pot cycloaddition/oxidation strategy is established to achieve efficient synthesis of trifluoromethyl-1,2,4-triazine-spirooxindoles. This study not only enriches the structural diversity of spirooxindoles but also provides a valuable synthetic tool for developing novel bioactive molecules in medicinal chemistry.

ABSTRACT A mild, regio‐ and stereoselective synthesis of a series of highly substituted cyclopropanes was accomplished via mono‐ and bis(2 + 1) cycloaddition reactions of α,β,γ,δ‐ unsaturated carbonyl compounds with α‐halomalonates. The reactions proceeded in good yields (up to 90% yields), displaying excellent regio‐ and diastereoselectivity (up to > 25:1 dr). The resulting products which obtained as single stereoisomers, possess two contiguous stereocenters including a quaternary carbon center in monocyclopropanation or four contiguous stereocenters bearing three quaternary carbon center in dicyclopropanation, from readily accessible starting materials using simple operational procedures. Additionally, the novel polysubstituted cyclopropanes exhibit potential anticancer activity, as evidenced by a molecular docking study. The structural framework and relative configuration of the products were determined through spectroscopic techniques as well as single‐crystal X‐ray diffraction analysis.

The development of new carbon (CO2) capture materials has emerged as a top-priority transdisciplinary research field. Ideally, CO2 is not only captured and stored (CCS), but also transformed into more valuable organic compounds, because CO2 itself is a cheap, abundant, non-flammable gas and thus an attractive C1 building block. However, activation of this thermodynamically rather stable molecule requires high activation energies. To overcome this energy barrier, activation of the CO double bond is routinely achieved by exploiting a synergetic metal-ligand cooperativity. The most promising candidates from academia or industry revolve around amino-functionalized materials or components featuring metal-nitrogen bonds. Given their natural abundance, low prices and nontoxicity, environmentally friendly materials should ultimately involve light metals. Recently, we found that the cerium pyrazolate [Ce+IV(pzMe2)4]2 is able to insert CO2 exhaustively and reversibly. In general, such nitrogen-rich azolato ligands comprising pyrazolato, triazolato and tetrazolato derivatives exhibit five-membered aromatic ring systems with nucleophilic nitrogen coordination sites. Azolato ligands adopt a wide variety of coordination modes and especially light metal pyrazolates are a well-established class of compounds. Aiming at higher CO2 uptake capacities, the conceptual approach, developed for the heavy metal cerium, has been consequently adapted to the light metals magnesium, aluminium, scandium and titanium. This review gives an overview of light metal pyrazolates and their CO2 insertion behaviour as well as their catalytic activity in the cycloaddition reaction of CO2 and epoxides to cyclic carbonates. In addition, consideration is given to immobilized variants as well as exemplary complexes and metal-organic framework materials derived from nitrogen-richer azoles/azolates.

Reducing anthropogenic CO2 emissions is crucial, and converting CO2 into value-added chemicals offers a sustainable solution. In this work, a series of metal-substituted CeO2 catalysts were synthesized for the cascade synthesis of glycerol carbonate via cycloaddition and transesterification reactions using CO2, propylene oxide, and glycerol. XRD and FE-SEM analyses confirmed the formation of core-hollow nanospheres architecture, while complementary physicochemical characterizations verified their structural and surface properties. Among the catalysts, the Mg-substituted CeO2 (CHNS-Mg/CeO2) exhibited the highest catalytic activity under solvent and additive-free conditions, achieving a 96% glycerol carbonate yield at 160 °C and 20 bar CO2 after 8 h, along with moderate yields of propylene carbonate and propylene glycol. Systematic studies revealed that the incorporation of Mg into the CeO2 lattice enhanced Lewis basic sites and oxygen vacancies, as evidenced by XPS analysis, thereby improving the levels of CO2 activation and reactants adsorption. The CHNS-Mg/CeO2 catalyst demonstrated excellent recyclability, maintaining both structural integrity and activity over 10 cycles. Comparative evaluations with other monometallic and bimetallic oxide/hydroxide catalysts confirmed its superior performance. A plausible multistep mechanism, supported by experimental data and DFT calculations, highlights the synergistic role of Ce and O lattice sites as Lewis's acid and base centers in activating CO2, glycerol, and propylene oxide. Overall, this study establishes a robust and scalable catalytic system for efficient CO2 utilization and glycerol valorization, combining experimental evidence and theoretical validation to advance sustainable carbon conversion technologies.

The discovery of new chemical transformations is central to advancing modern chemistry, yet conventional approaches often require months or years of extensive experimental screening. Here, we present a machine-learning-assisted and expert-guided pipeline for reaction discovery applied to the search for atom-economic cycloaddition reactions. Candidate reactions were generated from publicly available quantum chemical data, filtered through unsupervised machine learning, and clustered to reduce redundancy. A digital co-expert then enabled rapid prioritization, after which human expertise provided final selection and experimental validation. This hybrid workflow is fully compatible with current laboratory infrastructure and addresses the most time-consuming stage of reaction discovery, accelerating the expert screening bottleneck by approximately 180-fold (from>1200 days to 7 days). Within ∼1 week, two novel cycloaddition reactions were identified and experimentally confirmed, yielding previously undescribed products. While fully autonomous robotic platforms represent a long-term vision, their high cost and limited availability restrict immediate application. In contrast, our approach demonstrates the practicality of human-AI collaboration for reaction discovery, combining computational screening, machine learning and expert knowledge to efficiently expand the accessible chemical space.

The dimensionless Marcus coefficients, β and γ, derived from the Marcus equation for activation free energy, are fundamentally connected to both reaction free energy and intrinsic activation free energy. Their introduction establishes a novel metric for classifying chemical reactions by defining reaction spaces that rationalize reactions based on the underlying energetic characteristics. This study extends beyond mere classification, introducing a comprehensive framework for representing chemical reactions within a parametric {β, γ} space, uniquely accommodating any reaction within a normalized range [0,1]. Through analysis of a data set comprising 5,269 dipolar [3 + 2] cycloaddition reactions, we demonstrate the framework's applicability, uncovering novel patterns and behaviors. These findings enhance the understanding of linear and quadratic free energy relationships, providing chemists with a powerful tool for reaction categorization and design, thereby advancing computational chemistry and reaction design methodologies.

The accuracy of reference data is pivotal, especially when they are used to benchmark modern density functional approximations (DFAs) that approach chemical accuracy. This work re-examines a recent benchmark study on an ambimodal cycloaddition reaction. Using canonical coupled-cluster theory with single, double, and perturbative triple excitations [CCSD(T)] as a rigorous reference, we demonstrate that the performance ranking of leading DFAs is highly sensitive to the quality of the reference energies. Among the tested DFAs, the XYG3-type doubly hybrid (xDH) functional XYG7 emerges as the top performer against this robust benchmark. For strongly correlated subsets (GB1 > 12), CASPT2 is employed as a complementary reference to canonical CCSD(T). The renormalized doubly hybrid functional R-xDH7-SCC15 shows consistent performance across both reference frameworks. This cross-validation highlights the limitations of relying exclusively on single-reference benchmarks and underscores the urgent need for high-accuracy multireference reference data to properly evaluate next-generation density functionals.

Novel coumarin-oxazepane hybrids 3a–b, 4a–b, 5a–b have been synthesized via a cycloaddition reaction strategy. The newly synthesized compound was confirmed based on 1H NMR, Mass and IR spectroscopic analysis techniques. Further, titled compounds were subjected to in vitro anti-microbial screening against various bacterial strains, such as Pseudomonas aeruginosa, Escherichia coli, Staphylococcus aureus and Bacillus subtilis. Among these, all compounds were found to be most active, equally potent against Escherichia coli and Staphylococcus aureus as compared to the standard drug penicillin. Each compound has a bioavailability score of 55% and a pain assay score of zero, complies with Lipinski’s rule of five, and has high gastrointestinal (GI) absorption. Compounds 5a and 5b show the best docking scores with (PDB IDs: 3ERD and 2DXT), ranging from −10.1 to −10.5 kcalmol−1 compared to standard Warfarin and Adriamycin and potency against HL-60 and MCF-7 cell lines in vitro.

ConspectusFour-membered nitrogen-containing heterocycles, azetidines and azetines, have recently garnered interest as attractive targets in the discovery of new compounds for pharmaceutical applications. Despite this, the full potential of these heterocycles has not yet been realized due to a dearth of general, mild synthetic methods to access them. The aza Paternò-Büchi reaction, which is the photochemical [2 + 2]-cycloaddition of imines and alkenes, provides a simple, yet powerful method for accessing azetidines. However, this transformation has historically remained limited due to inherent challenges in capturing the excited state reactivity of imines - photoexcited imines can undergo radiationless decay to the ground state through E/Z-isomerization, which precludes productive cycloaddition reactivity. For this reason, the first few decades of progress for the aza Paternò-Büchi reaction relied on cyclic imine substrates to restrict isomerization and extend the excited state lifetime of the substrate. Recently, triplet energy transfer photocatalysis has emerged as a synthetic tool for generating reactive triplet state intermediates using mild visible light irradiation and commercially available catalysts. We saw an opportunity to use triplet energy transfer to access the excited states of imines and alkenes, thus allowing for access to unprecedented classes of transformations.In this Account, we present our body of work on visible-light-mediated imine-based [2 + 2]-cycloadditions, which rely on a key design principle of energy transfer photocatalysis - careful matching of the triplet energies of the photosensitizer and substrate for selective substrate sensitization. By virtue of using visible light irradiation, this limits sensitization to activated (i.e., conjugated) alkenes and certain types of imines, and renders unactivated (i.e., unconjugated) alkenes and alkynes inaccessible. Relying on this principle, we have developed six distinct strategies (Types I-VI reactions) for accessing azetidines and azetines. These strategies differentiate intra- and intermolecular transformations and the reactivity of three distinct substrate classes: activated alkenes, unactivated alkenes, and alkynes.First, we present an intramolecular aza Paternò-Büchi reaction of acyclic oximes and hydrazones with activated alkenes (Type I). Mechanistically, this relies on selective alkene sensitization to mitigate undesired reactivity that can arise from direct excitation of the imine, meaning that this strategy is not amenable to productively engaging unactivated alkenes. To enable access to this class of substrates, we harnessed the triplet state reactivity of 2-isoxazoline-3-carboxylates in intra- (Type II) and intermolecular (Type III) aza Paternò-Büchi reactions with unactivated alkenes. We also developed a set of intermolecular reactions relying on acyclic imines and activated alkenes (Type IV), providing direct access to monocyclic azetidines for the first time under visible light conditions. Next, we present an extension of the reactivity of 2-isoxazoline-3-carboxylates with untethered (Type V) and tethered (Type VI) alkynes in intermolecular [2 + 2]-cycloadditions to generate 1- and 2-azetines. Lastly, we demonstrate the synthetic and industrial applications of our azetidine compounds: Type I products can be subjected to Ru-catalyzed oxidative β-elimination to access 1-azetines (Type VII), while Type II and III products can be synthetically modified to access nitroazetidines that have potential applications as novel energetic materials.

The [3 + 2] dipolar cycloaddition reaction between cyclopropene and N,N-cyclic azomethine imine is reported, offering an efficient protocol for the construction of the diazabicyclo[3.1.0]hexane skeleton. This method features good yields, robust functional group tolerance (62 examples), and diastereoselectivity. In vitro antiproliferative activity screening of the product library against five strains of tumor cell lines (HL-60, A549, HepG2, MDA-MB-231, and SW480) showed that the scaffold exhibits promising proliferation inhibitory effects. Among them, the HL-60 cell line is the most sensitive with IC50 values being as low as 8.05 ± 0.40 μM. An SAR analysis of these compounds is presented.

Mechanistic study of the steric effect of Lewis acids AlCl3 and TiBr4 on the asynchronous [4+2] cycloaddition reaction of isoprene with Aryl acid: MEDT study.

Fluorine-activated and -directed allene cycloadditions with nitrile oxide: Exploration of selectivities, reactivities, energetic aspects, and molecular mechanism.

Synthesis of polysubstituted cyclopropanes via [2 + 1] cycloaddition reaction of acyclic α,β-unsaturated imines with α-bromomalonate

In the search for new antifungal agents, a series of isoxazoles (D) and isoxazolines (E) analogs were designed and synthesized. The 2,3-dihydro-2,2-dimethyl-7-benzofuranol was used as the raw material, and the chalcone derivatives were obtained by methylation, acetylation, and hydroxyaldol condensation. Notably, the isoxazoles (D) and isoxazolines (E) were obtained via a one-pot [3 + 2] cycloaddition reaction for the first time, and the reaction mechanism was explored preliminarily. The synthesized compounds were verified using 1H NMR, 13C NMR and HRMS. The antifungal activity results showed that the isoxazoles and isoxazolines both have good activity against Pseudoperonospora cubensis. Among them, compounds D2 and E2 have excellent inhibitory activities of 80% and 95% at 100mg/L, respectively, which are almost comparable to the positive control fluopicolide.

Alternative methods for the preparation of naïve libraries for SELEX experiments are in dire need, particularly when hydrophobic, bulky, and complex modification patterns are considered. Here, we explore the first steps toward the preparation of libraries equipped with ruthenium polypyridyl complexes using strain-promoted azide-alkyne cycloaddition (SPAAC) reactions. We demonstrated that dsDNA products can be efficiently equipped with dibenzocyclooctyne (DIBAC) moieties using a suitable modified nucleoside triphosphate and primer extension (PEX) reactions or PCR. The resulting dsDNA products can then be further modified using SPAAC and ruthenium polypyridyl complexes equipped with azide moieties, permitting the installation of >10 complexes. Finally, dsDNA can be efficiently converted into the corresponding modified ssDNA using magnetoseparation. These results offer the possibility of producing longer oligonucleotides equipped with complex modification patterns and open the way to SPAAC-click-SELEX methodologies.

Collinolactone, featuring a 7/10/6 tricyclic core, has been proposed to be biosynthesized via a transannular [6 + 4] cycloaddition reaction. Besides its intriguing architecture, collinolactone holds pharmaceutical promises due to its ability to disrupt amyloid-β (Aβ) and tau aggregation, which are specifically found as disease culprits in the brains of Alzheimer's disease (AD) patients and are key targets in current drug discovery efforts. However, challenges associated with its acquisition from a natural source and limited pharmacokinetic properties have hampered its further studies. Herein, we report the design, synthesis, and biologicalevaluation of 3-desoxycollinoketone B, a collinolactone derivative with improved pharmacokinetics for AD treatment. A stereoselective transannular [6 + 4] cycloaddition efficiently constructs the tricyclic core, allowing its scalable synthesis. AI-assisted binding prediction and simulations not only indicate superior binding of 3-desoxycollinoketone B to Aβ and tau aggregates to collinolactone, but also suggest a mechanistic basis for fibril destabilization. In vitro studies confirm its inhibition and dissociation of Aβ and tau fibrils, while in vivo experiments in AD mouse models show substantial amelioration of cognitive functions and Aβ/tau-associated pathology.