Direct 18F-Fluorosulfurylation of Phenols and Amines Using an [18F]FSO2+ Transfer Agent Generated In Situ.

We report the direct radiofluorosulfurylation method for the synthesis of 18F-labeled fluorosulfuryl derivatives from phenols and amines using an [18F]FSO2+ transfer agent generated in situ. Nucleophilic radiofluorination is achieved even in a hydrous organic medium, obviating the need for azeotropic drying and the use of cryptands. This unprecedented, operationally simple isotopic functionalization facilitates the reliable production of potential radiotracers for positron emission tomography, rendering facile access to SuFEx radiochemistry.

Nickelocene as an Air- and Moisture-Tolerant Precatalyst in the Regioselective Synthesis of Multisubstituted Pyridines.

Ni(COD)2-catalyzed cycloaddition reactions to access pyridines have been extensively studied. However, this catalyst typically requires drying procedures and inert-atmosphere techniques for the reactions. Herein, we report operationally simple nickel(0) catalysis to access substituted pyridines from various nitriles and 1,6-diynes without the aid of air-free techniques. The Ni-Xantphos-based catalytic manifold is tolerant to air, moisture, and heat while promoting the [2 + 2 + 2] cycloaddition reactions with high reaction yields and broad substrate scope. In addition, we disclose that not only the steric effect but also the frontier molecular orbital interactions can play a critical role in determining the regiochemical outcome of nickel-catalyzed [2 + 2 + 2] cycloaddition for the synthesis of substituted pyridines.

Chemo- and regioselective click reactions through nickel-catalyzed azide-alkyne cycloaddition.

Metal-catalyzed cycloaddition is an expeditious synthetic route to functionalized heterocyclic frameworks. However, achieving reactivity-controlled metal-catalyzed azide-alkyne cycloadditions from competing internal alkynes has been challenging. Herein, we report a nickel-catalyzed [3 + 2] cycloaddition of unsymmetrical alkynes with organic azides to afford functionalized 1,2,3-triazoles with excellent regio- and chemoselectivity control. Terminal alkynes and cyanoalkynes afford 1,5-disubstituted triazoles and 1,4,5-trisubstituted triazoles bearing a 4-cyano substituent, respectively. Thioalkynes and ynamides exhibit inverse regioselectivity compared with terminal alkynes and cyanoalkynes, affording 1,4,5-trisubstituted triazoles with 5-thiol and 5-amide substituents, respectively. Density functional theory calculations are performed for the elucidation of the reaction mechanism. The computed mechanism suggests that a nickellacyclopropene intermediate is generated by the oxidative addition of the alkyne substrate to the Ni(0)-Xantphos catalyst, and the subsequent C-N coupling of this intermediate with an azide is responsible for the chemo- and regioselectivity.

Chemoselective Trifluoroethylation Reactions of Quinazolinones and Identification of Photostability.

Herein, we report chemoselective trifluoroethylation routes of unmasked 2-arylquinazolin-4(3 H)-ones using mesityl(2,2,2-trifluoroethyl)iodonium triflate at room temperature. Homologous C-, O-, and N-functionalized subclasses are accessed in a straightforward manner with a wide substrate scope. These chemoselective branching events are driven by Pd-catalyzed ortho-selective C-H activation at the pendant aryl ring and base-promoted reactivity modulation of the amide group, leveraging the intrinsic directing capability and competing pronucleophilicity of the quinazolin-4(3 H)-one framework. Furthermore, outstanding photostability of the quinazolin-4(3 H)-one family associated with nonradiative decay is presented.

Nickel-Catalyzed Azide-Alkyne Cycloaddition To Access 1,5-Disubstituted 1,2,3-Triazoles in Air and Water.

Transition-metal-catalyzed or metal-free azide-alkyne cycloadditions are methods to access 1,4- or 1,5-disubstituted 1,2,3-triazoles. Although the copper-catalyzed cycloaddition to access 1,4-disubstituted products has been applied to biomolecular reaction systems, the azide-alkyne cycloaddition to access the complementary 1,5-regioisomers under aqueous and ambient conditions remains a challenge due to limited substrate scope or moisture-/air-sensitive catalysts. Herein, we report a method to access 1,5-disubstituted 1,2,3-triazoles using a Cp2Ni/Xantphos catalytic system. The reaction proceeds both in water and organic solvents at room temperature. This protocol is simple and scalable with a broad substrate scope including both aliphatic and aromatic substrates. Moreover, triazoles attached with carbohydrates or amino acids are prepared via this cycloaddition.

An Annulative Synthetic Strategy for Building Triphenylene Frameworks by Multiple C-H Bond Activations.

C-H activation is a versatile tool for appending aryl groups to aromatic systems. However, heavy demands on multiple catalytic cycle operations and site-selectivity have limited its use for graphene segment synthesis. A Pd-catal- yzed one-step synthesis of functionalized triphenylene frameworks is disclosed, which proceeds by 2- or 4-fold C-H arylation of unactivated benzene derivatives. A Pd2 (dibenzylideneacetone)3 catalytic system, using cyclic diaryliodonium salts as π-extending agents, leads to site-selective inter- and intramolecular tandem arylation sequences. Moreover, N-substituted triphenylenes are applied to a field-effect transistor sensor for rapid, sensitive, and reversible alcohol vapor detection.

Covalent Conjugation of Small-Molecule Adjuvants to Nanoparticles Induces Robust Cytotoxic T Cell Responses via DC Activation.

Specific recognitions of pathogen associated molecular patterns by Toll-like receptors (TLRs) initiate dendritic cell (DC) activation, which is critical for coordinating innate and adaptive immune responses. Imidazoquinolines as small-molecule TLR7 agonists often suffer from prompt dissemination and short half-life in the bloodstream, preventing their localization to the corresponding receptors and effective DC activation. We postulated that covalent incorporation of imidazoquinoline moieties onto the surface of biocompatible nanoparticles (∼30 nm size) would enhance their chemical stability, cellular uptake efficiency, and adjuvanticity. The fully synthetic adjuvant-nanocomplexes led to successful DC activation at lower nanomolar doses compared with free small-molecule agonists. Once a model antigen such as ovalbumin was used for immunization, we found that the nanocomplexes promoted an unusually strong cytotoxic T lymphocyte response, revealing their unique immunostimulatory capacity benefiting from multivalency and efficient transport to endosomal TLR7.

A palladium and gold catalytic system enables direct access to O- and S-linked non-natural glyco-conjugates.

Here we report a straightforward cross-coupling method for the synthesis of non-natural glycoamino acids from alkyne-bearing monosaccharides and p-iodophenylalanine. Pd/Au-catalyzed Sonogashira coupling is tolerant to both O- and S-glycosides without any epimerization. In addition, no racemization of the amino acid was observed allowing direct access to the homogeneous glyco-conjugate in a single step. Notably, this Pd/Au catalytic system presents enhanced catalytic activity than conventional Pd/Cu and Pd-only platforms, and it further enables the convergent synthesis of glycodipeptides.

Ferritin protein cage nanoparticles as versatile antigen delivery nanoplatforms for dendritic cell (DC)-based vaccine development.

We utilized ferritin protein cage nanoparticles (FPCN) as antigen delivery nanoplatforms for DC-based vaccine development and investigated DC-mediated antigen-specific immune responses. Antigenic peptides, OT-1 (SIINFEKL) or OT-2 (ISQAVHAAHAEINEAGR) which are derived from ovalbumin, were genetically introduced either onto the exterior surface or into the interior cavity of FPCN. FPCN carrying antigenic peptides (OT-1-FPCN and OT-2-FPCN) were effectively delivered to DCs and processed within endosomes. Delivered antigenic peptides, OT-1 or OT-2, to DCs successfully induced antigen-specific CD8(+) or CD4(+) T cell proliferations both in vitro and in vivo. Naïve mice immunized with OT-1-FPCN efficiently differentiated OT-1 specific CD8(+) T cells into functional effector cytotoxic T cells resulting in selective killing of antigen-specific target cells. Effective differentiation of proliferated OT-2 specific CD4(+) T cells into functional CD4(+) Th1 and Th2 cells was confirmed with the productions of IFN-γ/IL-2 and IL-10/IL-13 cytokines, respectively. FROM THE CLINICAL EDITOR: In this study, the authors utilized ferritin protein cage nanoparticles as antigen delivery nanoplatforms for dendritic cell-based vaccine development and investigated DC-mediated antigen-specific immune responses using strong model antigens derived from ovalbumin, suggesting potential future clinical applicability of this or similar techniques.

Recent advances in earth-abundant transition metal-catalyzed dihydrosilylation of terminal alkynes.

Over the past few years, earth-abundant transition metal-catalyzed hydrosilylation has emerged as an ideal strategy for the synthesis of organosilanes. The success in this area of research has expanded to the advancements of alkyne dihydrosilylation reactions, offering broadened synthetic applications through the selective installation of two silyl groups. In particular, catalysts based on Fe, Co, and Ni have engendered enabling platforms for mild transformations with a range of distinct regioselectivity. This mini-review summarizes recent advances in this research field, highlighting the unique features of each system from both synthetic and mechanistic perspectives.

Isolation and Reactivity of Arylnickel(II) Complexes in Nickel-Catalyzed Borylation of Aryl Fluorosulfates.

Aryl fluorosulfates have emerged as versatile SuFExable substrates, harnessing the reactivity of the S-F bond. In this study, we unveil their alternative synthetic utility in nickel-catalyzed borylation via C-O bond activation. This method highlights mild reaction conditions, a broad substrate scope, and moderate functional group tolerance, rendering it a practical and appealing approach for synthesizing a diverse array of aryl boronate esters. Furthermore, computational analysis sheds light on the reaction pathways, uncovering the participation of LNi(0) and LNi(II)ArX species. This insight is supported by the 31P NMR reaction monitoring along with isolation and single-crystal X-ray structural elucidation of well-defined arylnickel(II) intermediates obtained from the oxidative addition of aryl fluorosulfates. A comprehensive investigation, merging experimental and computational approaches, deepens our understanding of the alternative reactivity of SuFExable substrates.

Electrolyte Design for High-Voltage Lithium-Metal Batteries with Synthetic Sulfonamide-Based Solvent and Electrochemically Active Additives.

Considering practical viability, Li-metal battery electrolytes should be formulated by tuning solvent composition similar to electrolyte systems for Li-ion batteries to enable the facile salt-dissociation, ion-conduction, and introduction of sacrificial additives for building stable electrode-electrolyte interfaces. Although 1,2-dimethoxyethane with a high-donor number enables the implementation of ionic compounds as effective interface modifiers, its ubiquitous usage is limited by its low-oxidation durability and high-volatility. Regulation of the solvation structure and construction of well-structured interfacial layers ensure the potential strength of electrolytes in both Li-metal and LiNi0.8Co0.1Mn0.1O2 (NCM811). This study reports the build-up of multilayer solid-electrolyte interphase by utilizing different electron-accepting tendencies of lithium difluoro(bisoxalato) phosphate (LiDFBP), lithium nitrate, and synthetic 1-((trifluoromethyl)sulfonyl)piperidine. Furthermore, a well-structured cathode-electrolyte interface from LiDFBP effectively addresses the issues with NCM811. The developed electrolyte based on a framework of highly- and weakly-solvating solvents with interface modifiers enables the operation of Li|NCM811 cells with a high areal capacity cathode (4.3 mAh cm-2) at 4.4 V versus Li/Li+.

Iterative SuFEx approach for sequence-regulated oligosulfates and its extension to periodic copolymers.

The synthesis of sequence-regulated oligosulfates has not yet been established due to the difficulties in precise reactivity control. In this work, we report an example of a multi-directional divergent iterative method to furnish oligosulfates based on a chain homologation approach, in which the fluorosulfate unit is regenerated. The oligosulfate sequences are determined by high resolution mass spectrometry of the hydrolyzed fragments, and polysulfate periodic copolymers are synthesized by using oligomeric bisfluorosulfates in a bi-directional fashion. The synthetic utility of this iterative ligation is demonstrated by preparing crosslinked network polymers as synthetic adhesive materials.

Mechanistic evidence for a front-side, SNi-type reaction in a retaining glycosyltransferase.

A previously determined crystal structure of the ternary complex of trehalose-6-phosphate synthase identified a putative transition state-like arrangement based on validoxylamine A 6'-O-phosphate and uridine diphosphate in the active site. Here linear free energy relationships confirm that these inhibitors are synergistic transition state mimics, supporting front-face nucleophilic attack involving hydrogen bonding between leaving group and nucleophile. Kinetic isotope effects indicate a highly dissociative oxocarbenium ion-like transition state. Leaving group (18)O effects identified isotopically sensitive bond cleavages and support the existence of a hydrogen bond between the nucleophile and departing group. Brønsted analysis of nucleophiles and Taft analysis highlight participation of the nucleophile in the transition state, also consistent with a front-face mechanism. Together, these comprehensive, quantitative data substantiate this unusual enzymatic reaction mechanism. Its discovery should prompt useful reassessment of many biocatalysts and their substrates and inhibitors.

Ni-Ion-Chelating Strategy for Mitigating the Deterioration of Li-Ion Batteries with Nickel-Rich Cathodes.

Ni-rich cathodes are the most promising candidates for realizing high-energy-density Li-ion batteries. However, the high-valence Ni4+ ions formed in highly delithiated states are prone to reduction to lower valence states, such as Ni3+ and Ni2+ , which may cause lattice oxygen loss, cation mixing, and Ni ion dissolution. Further, LiPF6 , a key salt in commercialized electrolytes, undergoes hydrolysis to produce acidic compounds, which accelerate Ni-ion dissolution and the interfacial deterioration of the Ni-rich cathode. Dissolved Ni ions migrate and deposit on the surface of the graphite anode, causing continuous electrolyte decomposition and threatening battery safety by forming Li dendrites on the anode. Herein, 1,2-bis(diphenylphosphino)ethane (DPPE) chelates Ni ions dissolved from the Ni-rich cathode using bidentate phosphine moieties and alleviates LiPF6 hydrolysis via complexation with PF5 . Further, DPPE reduces the generation of corrosive HF and HPO2 F2 substantially compared to the amounts observed using trimethyl phosphite and tris(trimethylsilyl) phosphite, which are HF-scavenging additives. Li-ion cells with Ni-rich cathodes and graphite anodes containing DPPE exhibit remarkable discharge capacity retentions of 83.4%, with high Coulombic efficiencies of >99.99% after 300 cycles at 45 °C. The results of this study will promote the development of electrolyte additives.

Alkylation of nucleobases by 2-chloro-N,N-diethylethanamine hydrochloride (CDEAH) sensitizes PARP1-deficient tumors.

Targeting BRCA1- and BRCA2-deficient tumors through synthetic lethality using poly(ADP-ribose) polymerase inhibitors (PARPi) has emerged as a successful strategy for cancer therapy. PARPi monotherapy has shown excellent efficacy and safety profiles in clinical practice but is limited by the need for tumor genome mutations in BRCA or other homologous recombination genes as well as the rapid emergence of resistance. In this study, we identified 2-chloro-N,N-diethylethanamine hydrochloride (CDEAH) as a small molecule that selectively kills PARP1- and xeroderma pigmentosum A-deficient cells. CDEAH is a monofunctional alkylating agent that preferentially alkylates guanine nucleobases, forming DNA adducts that can be removed from DNA by either a PARP1-dependent base excision repair or nucleotide excision repair. Treatment of PARP1-deficient cells leads to the formation of strand breaks, an accumulation of cells in S phase and activation of the DNA damage response. Furthermore, CDEAH selectively inhibits PARP1-deficient xenograft tumor growth compared to isogenic PARP1-proficient tumors. Collectively, we report the discovery of an alkylating agent inducing DNA damage that requires PARP1 activity for repair and acts synergistically with PARPi.

Synthesis of α,ß-unsaturated ketones through nickel-catalysed aldehyde-free hydroacylation of alkynes.

α,ß-Unsaturated ketones are common feedstocks for the synthesis of fine chemicals, pharmaceuticals, and natural products. Transition metal-catalysed hydroacylation reactions of alkynes using aldehydes have been recognised as an atom-economical route to access α,ß-unsaturated ketones through chemoselective aldehydic C-H activation. However, the previously reported hydroacylation reactions using rhodium, cobalt, or ruthenium catalysts require chelating moiety-bearing aldehydes to prevent decarbonylation of acyl-metal-hydride complexes. Herein, we report a nickel-catalysed anti-Markovnikov selective coupling process to afford non-tethered E-enones from terminal alkynes and S-2-pyridyl thioesters in the presence of zinc metal as a reducing agent. Utilization of a readily available thioester as an acylating agent and water as a proton donor enables the mechanistically distinctive and aldehyde-free hydroacylation of terminal alkynes. This non-chelation-controlled approach features mild reaction conditions, high step economy, and excellent regio- and stereoselectivity.

Rapid access to polycyclic N-heteroarenes from unactivated, simple azines via a base-promoted Minisci-type annulation.

Conventional synthetic methods to yield polycyclic heteroarenes have largely relied on metal-mediated arylation reactions requiring pre-functionalised substrates. However, the functionalisation of unactivated azines has been restricted because of their intrinsic low reactivity. Herein, we report a transition-metal-free, radical relay π-extension approach to produce N-doped polycyclic aromatic compounds directly from simple azines and cyclic iodonium salts. Mechanistic and electron paramagnetic resonance studies provide evidence for the in situ generation of organic electron donors, while chemical trapping and electrochemical experiments implicate an iodanyl radical intermediate serving as a formal biaryl radical equivalent. This intermediate, formed by one-electron reduction of the cyclic iodonium salt, acts as the key intermediate driving the Minisci-type arylation reaction. The synthetic utility of this radical-based annulative π-extension method is highlighted by the preparation of an N-doped heptacyclic nanographene fragment through fourfold C-H arylation.

Filled and glycosylated carbon nanotubes for in vivo radioemitter localization and imaging.

Functionalization of nanomaterials for precise biomedical function is an emerging trend in nanotechnology. Carbon nanotubes are attractive as multifunctional carrier systems because payload can be encapsulated in internal space whilst outer surfaces can be chemically modified. Yet, despite potential as drug delivery systems and radiotracers, such filled-and-functionalized carbon nanotubes have not been previously investigated in vivo. Here we report covalent functionalization of radionuclide-filled single-walled carbon nanotubes and their use as radioprobes. Metal halides, including Na(125)I, were sealed inside single-walled carbon nanotubes to create high-density radioemitting crystals and then surfaces of these filled-sealed nanotubes were covalently modified with biantennary carbohydrates, improving dispersibility and biocompatibility. Intravenous administration of Na(125)I-filled glyco-single-walled carbon nanotubes in mice was tracked in vivo using single-photon emission computed tomography. Specific tissue accumulation (here lung) coupled with high in vivo stability prevented leakage of radionuclide to high-affinity organs (thyroid/stomach) or excretion, and resulted in ultrasensitive imaging and delivery of unprecedented radiodose density. Nanoencapsulation of iodide within single-walled carbon nanotubes enabled its biodistribution to be completely redirected from tissue with innate affinity (thyroid) to lung. Surface functionalization of (125)I-filled single-walled carbon nanotubes offers versatility towards modulation of biodistribution of these radioemitting crystals in a manner determined by the capsule that delivers them. We envisage that organ-specific therapeutics and diagnostics can be developed on the basis of the nanocapsule model described here.

Late-Stage 18F/19F Isotopic Exchange for the Synthesis of 18F-Labeled Sulfamoyl Fluorides.

Synthesis of sulfamoyl [18F]fluorides has been a challenging topic owing to the inefficient nucleophilic radiofluorination of sulfamoyl derivatives. Herein, we report an 18F/19F isotopic exchange approach to synthesize various sulfamoyl [18F]fluorides, otherwise inaccessible via direct synthesis from amines, with high radiochemical yields up to 97% (30 examples). This late-stage labeling protocol offers an efficient route to yield functionalized molecules by diversifying the chemical library possessing sulfamoyl functionalities through nucleophilic 18F incorporation within nitrogen-containing sulfur(VI) frameworks.