Coupling Cascade Research Articles

Calcium Imaging and Analysis in Beta Cells in Acute Mouse Pancreas Tissue Slices.

Ca2+ ions play a central role in the stimulus-secretion coupling cascade of pancreatic beta cells. The use of confocal microscopy in conjunction with the acute pancreas tissue slice technique offers valuable insights into changes in theintracellular calcium concentration following stimulation by secretagogues. This allows the study of beta cells on a single cell level, as well as their behavior on a multicellular scale within an intact environment. With the use of advanced analytical tools, this approach offers insight into how single cells contribute to the functional unit of islets of Langerhans and processes underlying insulin secretion. Here we describe a comprehensive protocol for the preparation and utilization of acute pancreas tissue slices in mice, the use of high-resolution confocal microscopy for observation of glucose-stimulated calcium dynamics in beta cells, and the computational analysis for objective evaluation of calcium signals.

Electron Donor‐Acceptor (EDA) Complex Enabled C−C Cross‐Coupling Reactions of α‐Amino Radicals

AbstractElectron‐donor acceptor (EDA) complex has been an integral part of visible‐light photocatalysis and is different from the traditional photoredox catalysis, which requires an exogenous photocatalyst, typically a colored compound to initiate the photocatalytic cycle. Interestingly, the EDA‐complex photochemistry has found profound use in activating the inert α‐C−H bonds of amines. The strategy relied upon the formation of colored EDA‐complex between the donor (amine) and acceptor (Lewis acid), which upon harvesting light energy perform a SET process to generate radical cation and anion intermediates. The radical cation then loses the activated acidic proton (because of the SET, the acidity of α‐proton increases by lowering the BDE) to form α‐amino radical, which then participates in various C−C coupling cascades. In this review, different conceptual approaches for the generation of α‐amino radicals and their coupling for the C−C bond‐forming reaction under EDA‐complex triggered photocatalysis will be discussed with particular emphasis on the reaction mechanism from 2018 onwards.

Total Synthesis of Ganoderma Meroterpenoids Cochlearol B and Its Congeners Driven by Structural Similarity and Biological Homology.

Secondary metabolites that have the same biological origin must share some relationship in their biosynthesis. Exploring this relationship has always been a significant task for synthetic biologists. However, from the perspective of synthetic chemists, it is equally important to propose, prove, or refute potential biosynthetic pathways in order to elucidate and understand the biosynthesis of homologous secondary metabolites. In this study, driven by the high structural similarity between the homologous Ganoderma meroterpenoids cochlearol B and ganocin B, two chemically synthetic strategies were designed and investigated sequentially for the synthesis of cochlearol B from ganocin B. These strategies include intramolecular metal-catalyzed hydrogen atom transfer (MHAT) and intramolecular photochemical [2+2] cycloaddition. The aim was to reveal their potential biosynthetic conversion relationship using chemical synthesis methods. As a result, a highly efficient total synthesis of cochlearol B, cochlearol T, cochlearol F, as well as the formal total synthesis of ganocins A-B, and ganocochlearins C-D, has been achieved. Additionally, a novel synthetic approach for the synthesis of 6,6-disubstituted 6H-dibenzo[b,d]pyran and its analogues has been developed through palladium(II)-catalyzed Wacker-type/cross-coupling cascade reactions.

Asymmetric three-component Tsuji-Trost allylation reaction enabled by chiral aldehyde/palladium combined catalysis.

Despite the long-standing exploration of the catalytic asymmetric Tsuji-Trost allylation reaction since the mid-20th century, most reported instances have adhered to a two-component approach. Here, we present a remarkably efficient three-component asymmetric allylation reaction enabled by the collaborative action of chiral aldehyde and palladium. A diverse array of NH2-unprotected amino acid esters, aryl or alkenyl iodides, and allyl alcohol esters exhibit robust participation in this reaction, resulting in the synthesis of structurally diverse non-proteinogenic α-amino acid esters with favorable experimental outcomes. Mechanistic investigations reveal the dominance of the allylation/Heck coupling cascade in reactions involving electron-rich aryl iodides, while the Heck coupling/allylation cascade emerges as the dominant pathway in reactions involving electron-deficient aryl iodides. This chiral aldehyde/palladium combining catalytic system precisely governs the chemoselectivity of C-allylation and N-allylation, the regioselectivity of linear and branched allylation, and the enantioselectivity of C-allylation products.

Nitrogen-interrupted halo-Prins/halo-Nazarov fragment coupling cascade for the synthesis of indolines.

The nitrogen-interrupted Nazarov cyclization can be a powerful method for the stereocontrolled synthesis of sp3-rich N-heterocycles. However, due to the incompatibility between the basicity of nitrogen and the acidic reaction conditions, examples of this type of Nazarov cyclization are scarce. Herein, we report a one-pot nitrogen-interrupted halo-Prins/halo-Nazarov coupling cascade that joins two simple building blocks, an enyne and a carbonyl partner, to furnish functionalized cyclopenta[b]indolines with up to four contiguous stereocenters. For the first time, we provide a general method for the alkynyl halo-Prins reaction of ketones, thus enabling the formation of quaternary stereocenters. Additionally, we describe the outcomes of secondary alcohol enyne couplings, which exhibit helical chirality transfer. Furthermore, we investigate the impact of aniline enyne substituents on the reaction and evaluate the tolerance of different functional groups. Finally, we discuss the reaction mechanism and demonstrate various transformations of the prepared indoline scaffolds, highlighting their applicability in drug discovery campaigns.

Investigation of EfficientTerahertz Wave Generation by Coupled Cascade Difference Frequency Generation

Investigation of EfficientTerahertz Wave Generation by Coupled Cascade Difference Frequency Generation

Visible-light-induced intramolecular C–S bond formation for practical synthesis of 2,5-disubstituted 1,3,4-thiadiazoles

A general and facile visible-light mediated protocol for the synthesis of 2-arylamino-5-aryl-1,3,4- thiadiazoles via one-pot condensation and intramolecular C–S coupling cascade reaction has been developed. This protocol is mild, practical, metal-free and exogenous oxidant-free, and only involves Eosin Y as photocatalyst using oxygen as the sole terminal oxidant. This protocol exhibits synthetic simplicity, broad scope of substrates, and excellent functional group compatibility. Gram-scale synthesis can be also facilitated with a satisfactory yield, which opens up the possibility of practical applications.

Nickel-Catalyzed Radical Heck-Type C(sp3)-C(sp2) Coupling Cascades Enabled by Bromoalkane-Directed 1,4-Aryl Shift: Access to Olefinated Arylalanines.

A bromoalkane-directed radical 1,4-aryl shift strategy for nickel-catalyzed reductive Heck-type C(sp3)-C(sp2) coupling cascades of α-amino-β-bromocarboxylic acid esters with α-trifluoromethyl alkenes for producing gem-difluorinated arylalanines is presented. The α-aminoalkyl radicals generated from neophyl-type aryl migration function as robust coupling partners to allow for further Giese-type addition with electron-deficient α-trifluoromethyl alkenes and vinyl sulfones, thereby realizing a new radical cascade for the simultaneous installation of an aromatic ring and olefin motif into amino acid backbones.

Successive Cleavage and Reconstruction of Lignin β‐O‐4 Models and Polymer to Access Quinoxalines

The construction of N-heterocyclic compounds from lignin remains a great challenge due to the complex lignin structure and the involvement of multiple steps, including the cleavage of lignin C-O linkages and the formation of heterocyclic aromatic rings. Herein, the first example of KOH mediated sustainable synthesis of quinoxaline derivatives from lignin β-O-4 model compounds in a one-pot fashion under transition-metal-free conditions has been achieved. Mechanistic studies suggested that this transformation includes highly coupled cascade steps of cleavage of C-O bonds, dehydrative condensation, sp3 C-H bond oxidative activation, and intramolecular dehydrative coupling reaction. With this protocol, a wide range of functionalized quinoxalines, including an important drug compound AG1295, were synthesized from lignin β-O-4 model compounds and β-O-4 polymer, showcasing the application potential of lignin in pharmaceutical synthesis.

STRAIGHT-IN enables high-throughput targeting of large DNA payloads in human pluripotent stem cells

SummaryInserting large DNA payloads (>10 kb) into specific genomic sites of mammalian cells remains challenging. Applications ranging from synthetic biology to evaluating the pathogenicity of disease-associated variants for precision medicine initiatives would greatly benefit from tools that facilitate this process. Here, we merge the strengths of different classes of site-specific recombinases and combine these with CRISPR-Cas9-mediated homologous recombination to develop a strategy for stringent site-specific replacement of genomic fragments at least 50 kb in size in human induced pluripotent stem cells (hiPSCs). We demonstrate the versatility of STRAIGHT-IN (serine and tyrosine recombinase-assisted integration of genes for high-throughput investigation) by (1) inserting various combinations of fluorescent reporters into hiPSCs to assess the excitation-contraction coupling cascade in derivative cardiomyocytes and (2) simultaneously targeting multiple variants associated with inherited cardiac arrhythmic disorders into a pool of hiPSCs. STRAIGHT-IN offers a precise approach to generate genetically matched panels of hiPSC lines efficiently and cost effectively.

Asymmetric Synthesis of Spiro[Azetidine-3,3'-Indoline]-2,2'-Diones via Copper(I)-Catalyzed Kinugasa/C-C Coupling Cascade Reaction.

Spiro[azetidine-indolines] are important scaffolds in diverse bioactive compounds. Current efforts to synthesize spiro[azetidine-indolines] are limited to chiral spiro[azetidine-2,3'-indolines]. Asymmetric synthesis of structurally similar chiral spiro[azetidine-3,3'-indolines] remains unexplored. In this work, the first copper(I)-catalyzed asymmetric Kinugasa/aryl C-C coupling cascade reaction is described. This provides a straightforward access to densely functionalized chiral spiro[azetidine-3,3'-indoline]-2,2'-diones in good yields and with high enantioselectivity.

Asymmetric Synthesis of Spiro[Azetidine‐3,3′‐Indoline]‐2,2′‐Diones via Copper(I)‐Catalyzed Kinugasa/C−C Coupling Cascade Reaction

AbstractSpiro[azetidine‐indolines] are important scaffolds in diverse bioactive compounds. Current efforts to synthesize spiro[azetidine‐indolines] are limited to chiral spiro[azetidine‐2,3′‐indolines]. Asymmetric synthesis of structurally similar chiral spiro[azetidine‐3,3′‐indolines] remains unexplored. In this work, the first copper(I)‐catalyzed asymmetric Kinugasa/aryl C−C coupling cascade reaction is described. This provides a straightforward access to densely functionalized chiral spiro[azetidine‐3,3′‐indoline]‐2,2′‐diones in good yields and with high enantioselectivity.

Synthesis of gem-Disulfonyl Enamines via an Iminyl-Radical-Mediated Formal 1,3-HAT/Radical Coupling Cascade.

We herein report the first example of an iminyl-radical-mediated formal 1,3-HAT/radical coupling cascade of vinyl azides leading to the synthesis of tetrasubstituted gem-disulfonyl enamines. It is possible to employ a variety of vinyl azides and sulfinate salt coupling elements without sacrificing effectiveness and scalability. The combination of experimental studies and DFT calculations showed that this reaction proceeds via a radical addition/formal 1,3-HAT/radical coupling mechanism.

Synthesis of β-Thiolated-α-arylated Ketones Enabled by Photoredox and N-Heterocyclic Carbene-Catalyzed Radical Relay of Alkenes with Disulfides and Aldehydes.

β-Thiolated-α-arylated ketones are perversive in bioactive molecules and serve as potential bidentate ligands for catalysis. Herein, a straightforward protocol to access β-thiolated ketones from aldehydes, alkenes, and disulfides enabled by the combination of photocatalysis and N-heterocyclic carbene catalysis is reported. The sequential radical addition to alkenes and subsequent radical-radical coupling cascade process simultaneously forge C-S and C-C bonds. The mild conditions allow for radical relay coupling with a broad functional group tolerance.

λ3-Iodane/Lewis Acid Mediated Intramolecular Cross-Nucleophile Coupling of β-Amino Acrylates: Chemodivergent Syntheses of Indole Alkaloidal Frameworks.

Herein, we report an unprecedented intramolecular cross-nucleophile coupling strategy of indole tethered β-amino acrylates using a catalyst system combining λ3-iodanes and Lewis acids to achieve the chemodivergent synthesis of three unique alkaloid skeletons. It was worth noting that the acquisition of spiroindolenines and azepino[4,5-b]indoles derivatives was switchable with choice of the Lewis acids. Moreover, the polycyclic spiroindolines containing a lactone fragment could also be accessed for the first time via cross-nucleophile coupling cascade intramolecular condensation sequence.

Visible-Light-Promoted Cross Dehydrogenative/Decarboxylative Coupling Cascades of Glycine Ester Derivatives and β-Keto Acids.

A visible-light-induced dehydrogenative/decarboxylative coupling reaction of arylglycine derivatives and β-keto acids is described. This photocatalyst- and additive-free protocol can be applied in the efficient synthesis of γ-keto glycine derivatives under ambient conditions. Further uses of this methodology and a plausible mechanism are also demonstrated.

A design of broadband bandpass frequency selective surface

AbstractIn this paper, a broadband frequency selective surface (FSS) based on a multilayer coupling cascade is presented. The overall structure consists of three metallic layers and two dielectric substrates. In addition, a crosspatch terminated with an E‐shaped structure and a gradient cross structure with a slot is introduced in the middle metallic layer to control the transmission zero and extent of the current path, respectively. The unit cell periodicity is about 0.27 , and the overall thickness of the dielectric layer is about 0.087 . Prototypes of the proposed FSS are designed and simulated, and an equivalent circuit model is developed to explain the mechanism further. Finally, the FSS prototype works at the center frequency of 12.2 GHz with a relative −0.5 dB bandwidth of 70% and a relative −3dB bandwidth of 104%. The frequency responses are relatively stable with the variation of incidence angles from 0° to 60°.

Temperature, stress, refractive index and humidity multi parameter highly integrated optical fiber sensor

Multi parameter measurement based on optical fiber sensor has been a research hotspot in recent years. In this work, four kinds of optical fiber sensors, LPFG, FBG, PMF and SMS are used. The transmission characteristics and sensing characteristics of each sensor are analyzed in detail. Based on the modulation of resonance wavelength by environmental variables, the accurate and synchronous real-time detection of temperature, stress, refractive index and humidity is realized. We use all-optical coupling cascade and wavelength division multiplexing (WDM) technology to prepare a highly integrated sensing device. The problem of signal crosstalk of each sensor is solved, and the cost of signal transmission and reception is greatly reduced. It is of great significance for monitoring a variety of environmental variables under extreme conditions.

Photocatalytic aldehydes/alcohols/toluenes oxidative amidation over bifunctional Pd/MOFs: Effect of Fe-O clusters and Lewis acid sites

Heterogeneous photocatalytic organic synthesis is fascinating because of the utilization of ubiquitous solar light for chemical transformations. Here, three Fe-MOFs with different Fe-O clusters, Lewis acid sites and morphologies were synthesized through coordination structure engineering. Pd/Fe-MOFs nanocomposites were used to challenge the amide bond green synthesis with visible light. Pd/MIL-101(Fe) exhibited the best photocatalytic performance due to the easily excited Fe3-μ3-oxo clusters for light absorption, the efficient photogenerated carriers separation and migration, the large amount of Lewis acid sites based aldehydes and amines condensation promotion and the efficient O2 reduction to superoxide radicals over photogenerated electron-rich Pd NPs. Various aldehydes, alcohols and toluenes could be transformed to amide compounds with amines over Pd/MIL-101(Fe) with just oxygen or air as the green oxidant and water as the by-product. One-pot CC cross-coupling and photo-redox CN coupling cascade reactions could also be achieved over Pd/MIL-101(Fe). This work shed light on the efficient and sustainable amide bonds synthesis.

The Role of cAMP in Beta Cell Stimulus-Secretion and Intercellular Coupling.

Pancreatic beta cells secrete insulin in response to stimulation with glucose and other nutrients, and impaired insulin secretion plays a central role in development of diabetes mellitus. Pharmacological management of diabetes includes various antidiabetic drugs, including incretins. The incretin hormones, glucagon-like peptide-1 and gastric inhibitory polypeptide, potentiate glucose-stimulated insulin secretion by binding to G protein-coupled receptors, resulting in stimulation of adenylate cyclase and production of the secondary messenger cAMP, which exerts its intracellular effects through activation of protein kinase A or the guanine nucleotide exchange protein 2A. The molecular mechanisms behind these two downstream signaling arms are still not fully elucidated and involve many steps in the stimulus–secretion coupling cascade, ranging from the proximal regulation of ion channel activity to the central Ca2+ signal and the most distal exocytosis. In addition to modifying intracellular coupling, the effect of cAMP on insulin secretion could also be at least partly explained by the impact on intercellular coupling. In this review, we systematically describe the possible roles of cAMP at these intra- and inter-cellular signaling nodes, keeping in mind the relevance for the whole organism and translation to humans.