Stereodivergent Synthesis of Pyridyl Cyclopropanes via Enzymatic Activation of Pyridotriazoles.

Hemoproteins have recently emerged as powerful biocatalysts for new-to-nature carbene transfer reactions. Despite this progress, these strategies have remained largely limited to diazo-based carbene precursor reagents. Here, we report the development of a biocatalytic strategy for the stereoselective construction of pyridine-functionalized cyclopropanes via the hemoprotein-mediated activation of pyridotriazoles (PyTz) as stable and readily accessible carbene sources. This method enables the asymmetric cyclopropanation of a variety of olefins, including electron-rich and electrodeficient ones, with high activity, high stereoselectivity, and enantiodivergent selectivity, providing access to mono- and diarylcyclopropanes that incorporate a pyridine moiety and thus two structural motifs of high value in medicinal chemistry. Mechanistic studies reveal a multifaceted role of 7-halogen substitution in the pyridotriazole reagent toward favoring multiple catalytic steps in the transformation. This work provides the first example of asymmetric olefin cyclopropanation with pyridotriazoles, paving the way to the exploitation of these attractive and versatile reagents for enzyme-catalyzed carbene-mediated reactions.

Transition-Metal-Catalyzed Denitrogenative Annulation to Access High-Valued N-Heterocycles.

Over the past few years, the development of efficient methods to construct high-valued N-heterocyclic molecules have received massive attention owing to their extensive application in the areas of medicinal chemistry, drug discovery, natural product synthesis and so on. To access those high-valued N-heterocycles, many methods have been developed. In this context, transition-metal-catalyzed denitrogenative annulation of 1,2,3-triazoles and 1,2,3,4-tetrazoles has appeared as a powerful synthetic tool because it offers a step- and atom-economical route for the preparation of the nitrogen-rich molecules. Compared with the denitrogenative annulation of various 1,2,3-triazole frameworks, annulation of 1,2,3,4-tetrazole remains more challenging due to the inertness of the tetrazole moiety. This Review summarizes the significant achievements made in the field of denitrogenative annulation of various 1,2,3-triazoles and 1,2,3,4-tetrazoles including some pioneering examples in this area of research. We anticipate that this denitrogenative annulation reaction will find broad applications in the pharmaceutical industry, drug discovery and other fields of medicinal chemistry.

Iron-Catalyzed Intermolecular Amination of Benzylic C(sp3)-H Bonds.

A catalytic system for intermolecular benzylic C(sp3)-H amination is developed utilizing 1,2,3,4-tetrazole as a nitrene precursor via iron catalysis. This method enables direct installation of 2-aminopyridine into the benzylic and heterobenzylic position. The method selectively aminates 2° benzylic C(sp3)-H bond over the 3° and 1° benzylic C(sp3)-H bonds. Experimental studies reveal that the C(sp3)-H amination undergoes via the formation of a benzylic radical intermediate. This study reports the discovery of new method for 2-pyridine substituted benzylamine synthesis using inexpensive, biocompatible base metal catalysis that should have wide application in the context of medicinal chemistry and drug discovery.

Road Map for the Construction of High-Valued N-Heterocycles via Denitrogenative Annulation.

The pursuit for the discovery of new and powerful synthetic methods to access high-value N-heterocycles has been at the forefront of organic chemistry research for more than a century. Considering the importance of N-scaffolds in modern science, over the past few decades, great research efforts have been made to develop efficient synthetic methods for the construction of nitrogen-rich molecules. Among many efforts, transition metal catalyzed denitrogenative annulation reaction has emerged as a cornerstone due to its innate versatility and wider scope of application.The denitrogenative annulation approach offers clear advantages over many existing methods, as it enables effective, single-step interconversion of easily available feedstocks into a variety of other important N-containing heterocyclic frameworks. Recently, transition metal catalyzed denitrogenative annulation reaction of the 1,2,3-triazole via a metal carbene intermediate sparked significant interest in the application of various important heterocycle syntheses. Denitrogenative annulation reaction of 1,2,3-triazoles proceeds via an ionic mechanism. Recently, we demonstrated a new concept for the denitrogenative reaction of triazoles with alkenes and alkynes via in situ generated 2-(diazomethyl)pyridines. The method takes advantage of the inherent properties of a Co(III)-carbene radical intermediate and is the first report of the denitrogenative annulation/cyclopropanation by a radical-activation mechanism.On the other hand, in contrast to the denitrogenative annulation of 1,2,3-triazole, annulation reaction of 1,2,3,4-tetrazole (a surrogate of azide having an important pyridyl unit) via metal nitrene remains a big challenge. Previously, flash vacuum pyrolysis studies had been used for nitrene-nitrene rearrangement of 1,2,3,4-tetrazole at high temperature. This Account summarizes our recent efforts in developing transition metal catalyzed denitrogenative annulation of 1,2,3-triazoles via a radical mechanism and 1,2,3,4-tetrazoles via metal nitrene to access important nitrogen-rich molecules. We demonstrated that the 1,2,3,4-tetrazole under Ir-catalyzed reaction conditions can produce a productive Ir-nitrene intermediate that can successfully be employed for the construction of a wide number of α-carbolines and 7-azaindoles. Moreover, we developed an iron-based unique strategy for the intermolecular denitrogenative annulation reaction between tetrazoles and alkynes. The reaction overcomes the traditional click reaction and proceeds via an unprecedented metalloradical activation mechanism. Furthermore, we used our understanding of tetrazole reactivity to design an iron-catalyzed intramolecular denitrogenative C(sp3)-H amination reaction of primary, secondary, and tertiary centers by using a metalloradical activation concept. At the same time, we also developed a general catalytic method to enable two distinct reactions (1,3-cycloaddition and denitrogenative annulation) using Mn(TPP)Cl that afforded two different classes of nitrogen heterocycles. Mechanistic studies showed that although the click reaction likely proceeds through an ionic mechanism and the denitrogenative annulation reaction likely proceeds via an electrophilic metallonitrene intermediate rather than a metallonitrene radical intermediate. Finally, we report an iron-catalyzed rearrangement reaction (ring expansion/migration) that proceeded with an unprecedented level of selectivity, reactivity, and functional group tolerance offering rapid access to numerous complex N-heterocycles. We believe that our continuous efforts in this field would be beneficial for pharmaceutical industries, drug discovery, and other fields of medicinal chemistry.

Silver Nanodot Decorated Dendritic Copper Foam As a Hydrophobic and Mechano-Chemo Bactericidal Surface.

The present work investigates the time-dependent antibacterial activity of the silver nanodot decorated dendritic copper foam nanostructures against Escherichia coli (Gram-negative) and Bacillus subtilis (Gram-positive) bacteria. An advanced antibacterial and antifouling surface is fabricated utilizing the collective antibacterial properties of silver nanodots, chitosan, and dendritic copper foam nanostructures. The porous network of the Ag nanodot decorated Cu foam is made up of nanodendrites, which reduce the wettability of the surface. Hence, the surface exhibits hydrophobic nature and inhibits the growth of bacterial flora along with the elimination of dead bacterial cells. The fabricated surface exhibits a water contact angle (WCA) of 158.7 ± 0.17°. Specifically, we tested the fabricated material against both the Gram-positive and Gram-negative bacterial models. The antibacterial activity of the fabricated surface is evident from the growth inhibition percentage of bacterial strains of Escherichia coli (72.30 ± 0.60%) and Bacillus subtilis (48.30 ± 1.71%). The micrographs obtained from scanning electron microscopy (SEM), transmission electron microscopy (TEM), and atomic force microscopy (AFM) of the treated cells show the damaged cellular structures of the bacteria, which is strong evidence of successful antibacterial action. The antibacterial effect can be attributed to the synergistic mechano-chemo mode of action involving mechanical disruption of the bacterial cell wall by the nanoprotrusions present on the Cu dendrites along with the chemical interaction of the Ag nanodots with vital intracellular components.

Dual Reactivity of 1,2,3,4-Tetrazole: Manganese-Catalyzed Click Reaction and Denitrogenative Annulation.

A general catalytic method using a Mn-porphyrin-based catalytic system is reported that enables two different reactions (click reaction and denitrogenative annulation) and affords two different classes of nitrogen heterocycles, 1,5-disubstituted 1,2,3-triazoles (with a pyridyl motif) and 1,2,4-triazolo-pyridines. Mechanistic investigations suggest that although the click reaction likely proceeds through an ionic mechanism, which is different from the traditional click reaction, the denitrogenative annulation reaction likely proceeds via an electrophilic metallonitrene intermediate rather than a metalloradical intermediate. Collectively, this method is highly efficient and offers several advantages over other methods. For example, this method excludes a multi-step synthesis of the N-heterocyclic molecules described and produces only environmentally benign N2 gas a by-product.

Iron-Catalyzed Radical Activation Mechanism for Denitrogenative Rearrangement Over C(sp3 )-H Amination.

An iron-catalyzed denitrogenative rearrangement of 1,2,3,4-tetrazole is developed over the competitive C(sp3 )-H amination. This catalytic rearrangement reaction follows an unprecedented metalloradical activation mechanism. Employing the developed method, a wide number of complex-N-heterocyclic product classes have been accessed. The synthetic utility of this radical activation method is showcased with the short synthesis of a bioactive molecule. Collectively, this discovery underlines the progress of radical activation strategy that should find wide application in the perspective of medicinal chemistry, drug discovery and natural product synthesis research.

Iron-Catalyzed Amination of Strong Aliphatic C(sp3)-H Bonds.

A concept for intramolecular denitrogenative C(sp3)-H amination of 1,2,3,4-tetrazoles bearing unactivated primary, secondary, and tertiary C-H bonds is discovered. This catalytic amination follows an unprecedented metalloradical activation mechanism. The utility of the method is showcased with the short synthesis of a bioactive molecule. Moreover, an initial effort has been embarked on for the enantioselective C(sp3)-H amination through the catalyst design. Collectively, this study underlines the development of C(sp3)-H bond functionalization chemistry that should find wide application in the context of drug discovery and natural product synthesis.

USP36 protects proximal tubule cells from ischemic injury by stabilizing c-Myc and SOD2.

Acute kidney injury (AKI) is a progressive renal injury with high morbidity and mortality, however, the mechanism is far from being clarified and effective clinical interventions are lacking. USP36 is a deubiquitination enzyme involved in a variety of cellular biological processes, but its involvement in renal cell apoptosis and kidney disease is largely unknown. In the present study, we confirmed the decreased expression of USP36 both in vivo in mouse and human AKI samples and in vitro ischemic human renal proximal tubular cells, which are extremely sensitive to the damage of ischemic injury. Importantly, we found that overexpression of USP36 markedly decreased ischemia-induced apoptosis and oxidative stress in HK-2 cells, which was accompanied by elevated c-Myc and SOD2 protein levels with alleviated ischemia-induced ubiquitination of both proteins. Our findings revealed a novel role of USP36 in inhibiting apoptosis of human renal tubular cells induced by ischemia, and provided a potential therapeutic target for AKI treatment.

Iron(II)-Based Metalloradical Activation: Switch from Traditional Click Chemistry to Denitrogenative Annulation.

A unique concept for the intermolecular denitrogenative annulation of 1,2,3,4-tetrazoles and alkynes was discovered by using a catalytic amount of Fe(TPP)Cl and Zn dust. The reaction precludes the traditional, more favored click reaction between an organic azide and alkynes, and instead proceeds by an unprecedented metalloradical activation. The method is anticipated to advance access to the construction of important basic nitrogen heterocycles, which will in turn enable discoveries of new drug candidates.

Ir-Catalyzed Intramolecular Transannulation/C(sp2)-H Amination of 1,2,3,4-Tetrazoles by Electrocyclization.

An efficient strategy for the intramolecular denitrogenative transannulation/C(sp2)-H amination of 1,2,3,4-tetrazoles bearing C8-substituted arenes, heteroarenes, and alkenes is described. The process involves the generation of the metal-nitrene intermediate from tetrazole by the combination of [Cp*IrCl2]2 and AgSbF6. It has been shown that the reaction proceeds via an unprecedented electrocyclization process. The method has been successfully applied for the synthesis of a diverse array of α-carbolines and 7-azaindoles.

Cobalt(II)-based Metalloradical Activation of 2-(Diazomethyl)pyridines for Radical Transannulation and Cyclopropanation.

A new catalytic method for the denitrogenative transannulation/cyclopropanation of in-situ-generated 2-(diazomethyl)pyridines is described using a cobalt-catalyzed radical-activation mechanism. The method takes advantage of the inherent properties of a CoIII -carbene radical intermediate and is the first report of denitrogenative transannulation/cyclopropanation by a radical-activation mechanism, which is supported by various control experiments. The synthetic benefits of the metalloradical approach are showcased with a short total synthesis of (±)-monomorine.

Stereoselective Construction of ß-, γ-, and δ-Lactam Rings via Enzymatic C-H Amidation.

Lactam rings are found in many biologically active natural products and pharmaceuticals, including important classes of antibiotics. Methods for the asymmetric synthesis of these molecules are therefore highly desirable, particularly through the selective functionalization of unreactive aliphatic C-H bonds. Here we show the development of a strategy for the asymmetric synthesis of ß-, γ-, and δ-lactams via hemoprotein-catalysed intramolecular C-H amidation reaction with readily available dioxazolone reagents. Engineered myoglobin variants serve as excellent biocatalysts for this transformation yielding the desired lactam products in high yields, high enantioselectivity, and on preparative scale. Mechanistic and computational studies elucidate the nature of the C-H amination and enantiodetermining steps and provide insights into protein-mediated control of regioselectivity and stereoselectivity. Additionally, an alkaloid natural product and a drug molecule were synthesized chemoenzymatically in much fewer steps (7-8 vs. 11-12) than previously reported, further demonstrating the power of biosynthetic strategy for the preparation of complex bioactive molecules.

Biocatalytic strategy for the construction of sp3-rich polycyclic compounds from directed evolution and computational modelling.

Catalysis with engineered enzymes has provided more efficient routes for the production of active pharmaceutical agents. However, the potential of biocatalysis to assist in early-stage drug discovery campaigns remains largely untapped. In this study, we have developed a biocatalytic strategy for the construction of sp3-rich polycyclic compounds via the intramolecular cyclopropanation of benzothiophenes and related heterocycles. Two carbene transferases with complementary regioisomer selectivity were evolved to catalyse the stereoselective cyclization of benzothiophene substrates bearing diazo ester groups at the C2 or C3 position of the heterocycle. The detailed mechanisms of these reactions were elucidated by a combination of crystallographic and computational analyses. Leveraging these insights, the substrate scope of one of the biocatalysts could be expanded to include previously unreactive substrates, highlighting the value of integrating evolutionary and rational strategies to develop enzymes for new-to-nature transformations. The molecular scaffolds accessed here feature a combination of three-dimensional and stereochemical complexity with 'rule-of-three' properties, which should make them highly valuable for fragment-based drug discovery campaigns.

Stereoselective Construction of ß-, γ-, and δ-Lactam Rings via Enzymatic C-H Amidation.

Lactam rings are found in many biologically active natural products and pharmaceuticals, including important classes of antibiotics. Given their widespread presence in bioactive molecules, methods for the asymmetric synthesis of these molecules, in particular through the selective functionalization of ubiquitous yet unreactive aliphatic C-H bonds, are highly desirable. In this study, we report the development of a novel strategy for the asymmetric synthesis of 4-, 5-, and 6-membered lactams via an unprecedented hemoprotein-catalyzed intramolecular C-H amidation reaction with readily available dioxazolone reagents. Engineered myoglobin variants serve as excellent biocatalysts for this transformation producing an array of ß-, γ-, and δ-lactam molecules in high yields, with high enantioselectivity, and on preparative scale. Mechanistic and computational studies elucidate the nature of the C-H amination and enantiodetermining steps in these reactions and provide insights into protein-mediated control of regioselectivity and stereoselectivity. Using this system, it was possible to accomplish the chemoenzymatic total synthesis of an alkaloid natural product and a drug molecule in much fewer steps (7-8 vs. 11-12) than previously possible, which showcases the power of this biosynthetic strategy toward enabling the preparation of complex bioactive molecules.

An iron(ii)-based metalloradical system for intramolecular amination of C(sp2)-H and C(sp3)-H bonds: synthetic applications and mechanistic studies.

A catalytic system for intramolecular C(sp2)-H and C(sp3)-H amination of substituted tetrazolopyridines has been successfully developed. The amination reactions are developed using an iron-porphyrin based catalytic system. It has been demonstrated that the same iron-porphyrin based catalytic system efficiently activates both the C(sp2)-H and C(sp3)-H bonds of the tetrazole as well as azide-featuring substrates with a high level of regioselectivity. The method exhibited an excellent functional group tolerance. The method affords three different classes of high-value N-heterocyclic scaffolds. A number of important late-stage C-H aminations have been performed to access important classes of molecules. Detailed studies (experimental and computational) showed that both the C(sp2)-H and C(sp3)-H amination reactions involve a metalloradical activation mechanism, which is different from the previously reported electro-cyclization mechanism. Collectively, this study reports the discovery of a new class of metalloradical activation modes using a base metal catalyst that should find wide application in the context of medicinal chemistry, drug discovery and industrial applications.

Low Operating Voltage Organic Field-Effect Transistors with Gelatin as a Moisture-Induced Ionic Dielectric Layer: The Issues of High Carrier Mobility.

We have developed low-voltage (<2 V) flexible organic field-effect transistors (OFETs) with high carrier mobility using gelatin as a moisture-induced ionic gate dielectric system. Ionic concentration in the gelatin layer depends on the relative humidity condition during the measurement. The capacitance of the dielectric layer used for the calculation of field-effect carrier mobility for the OFETs crucially depends on the frequency at which the capacitance was measured. The results of frequency-dependent gate capacitance together with the anomalous bias-stress effect have been used to determine the exact frequency at which the carrier mobility should be calculated. The observed carrier mobility of the devices is 0.33 cm2/Vs with the capacitance measured at frequency 20 mHz. It can be overestimated to 14 cm2/Vs with the capacitance measured at 100 kHz. The devices can be used as highly sensitive humidity sensors. About three orders of magnitude variation in device current have been observed on the changes in relative humidity (RH) levels from 10 to 80%. The devices show a fast response with a response and recovery times of ∼100 and ∼110 ms, respectively. The devices are flexible up to a 5 mm bending radius.

Organic Field-Effect Transistor-Based Ultrafast, Flexible, Physiological-Temperature Sensors with Hexagonal Barium Titanate Nanocrystals in Amorphous Matrix as Sensing Material.

Organic field-effect transistors (OFETs) with hexagonal barium titanate nanocrystals (h-BTNCs) in amorphous matrix as one of the bilayer dielectric systems have been fabricated on a highly flexible 10 µm thick poly(ethylene terephthalate) substrate. The device current and mobility remain constant up to a bending radius of 4 mm, which makes the substrate suitable for wearable e-skin applications. h-BTNC films are found to be highly temperature-sensitive, and the OFETs designed based on this material showed ultraprecision measurement (∼4.3 mK), low power (∼1 µW at 1.2 V operating voltage), and ultrafast response (∼24 ms) in sensing temperature over a range of 20-45 °C continuously. The sensors are highly stable around body temperature and work at various extreme conditions, such as under water and in solutions of different pH values and various salt concentrations. These properties make this sensor unique and highly suitable for various healthcare and other applications, wherein a small variation of temperature around this temperature range is required to be measured at an ultrahigh speed.