Oxidative Cyclization Research Articles

Two Cytochrome P450 Enzymes Form the Tricyclic Nested Skeleton of Meroterpenoids by Sequential Oxidative Reactions.

Meroterpenoid clavilactones feature a unique benzo-fused ten-membered carbocyclic ring unit with an α,β-epoxy-γ-lactone moiety, forming an intriguing 10/5/3 tricyclic nested skeleton. These compounds are good inhibitors of the tyrosine kinase, attracting a lot of chemical synthesis studies. However, the natural enzymes involved in the formation of the 10/5/3 tricyclic nested skeleton remain unexplored. Here, we identified a gene cluster responsible for the biosynthesis of clavilactone A in the basidiomycetous fungus Clitocybe clavipes. We showed that a key cytochrome P450 monooxygenase ClaR catalyzes the diradical coupling reaction between the intramolecular hydroquinone and allyl moieties to form the benzo-fused ten-membered carbocyclic ring unit, followed by the P450 ClaT that exquisitely and stereoselectively assembles the α,β-epoxy-γ-lactone moiety in clavilactone biosynthesis. ClaR unprecedentedly acts as a macrocyclase to catalyze the oxidative cyclization of the isopentenyl to the nonterpenoid moieties to form the benzo-fused macrocycle, and a multifunctional P450 ClaT catalyzes a ten-electron oxidation to accomplish the biosynthesis of the 10/5/3 tricyclic nested skeleton in clavilactones. Our findings establish the foundation for the efficient production of clavilactones using synthetic biology approaches and provide the mechanistic insights into the macrocycle formation in the biosynthesis of fungal meroterpenoids.

Total Syntheses of Discoipyrroles A, B, and C, Three Marine Natural Products.

Herein, we describe our efforts culminating in the total syntheses of discoipyrroles A, B, and C in 6, 6, and 7 steps respectively with excellent overall yield. Total syntheses of these unique natural products have been accomplished involving microwave-mediated Paal-Knorr pyrrole synthesis, Pd-catalyzed carbonylative transformation, and MoOPH (Vedejs reagent) oxidation as key reactions to construct the 1,2,3,5-tetrasubstituted pyrrole and oxidative cyclization of highly substituted pyrrole as key steps.

Analysis of Vascular Smooth Muscle Cells from Thoracic Aortic Aneurysms Reveals DNA Damage and Cell Cycle Arrest as Hallmarks in Bicuspid Aortic Valve Patients.

Thoracic aortic aneurysm (TAA) is mainly sporadic and with higher incidence in the presence of a bicuspid aortic valve (BAV) for unknown reasons. The lack of drug therapy to delay TAA progression lies in the limited knowledge of pathophysiology. We aimed to identify the molecular hallmarks that differentiate the aortic dilatation associated with BAV and tricuspid aortic valve (TAV). Aortic vascular smooth muscle cells (VSMCs) isolated from sporadic TAA patients with BAV or TAV were analyzed by mass spectrometry. DNA oxidative damage assay and cell cycle profiling were performed in three independent cohorts supporting proteomics data. The alteration of secreted proteins was confirmed in plasma. Stress phenotype, oxidative stress, and enhanced DNA damage response (increased S-phase arrest and apoptosis) were found in BAV-TAA patients. The increased levels of plasma C1QTNF5, LAMA2, THSB3, and FAP confirm the enhanced stress in BAV-TAA. Plasma FAP and BGN point to an increased inflammatory condition in TAV. The arterial wall of BAV patients shows a limited capacity to counteract drivers of sporadic TAA. The molecular pathways identified support the need of differential molecular diagnosis and therapeutic approaches for BAV and TAV patients, showing specific markers in plasma which may serve to monitor therapy efficacy.

Advances and Challenges in Oxygen Carriers for Chemical Looping Partial Oxidation of Methane

To cope with global warming and increasing carbon emissions, the chemical looping process has attracted attention due to its excellent ability to convert fossil fuel and capture CO2. In this case, chemical looping partial oxidation technology has become the focus of attention due to its advantages in the production of syngas and hydrogen, especially with respect to the design and selection of oxygen carriers, which directly affect the efficiency of the production of syngas and hydrogen. In particular, the conversion of methane can reach 95% in the chemical looping partial oxidation of methane, and the selectivity of syngas, in the range of 700 °C to 900 °C at atmospheric pressure, can reach 99% for twenty or more cycles. In this review, from the perspective of metal oxide selection and structure regarding the chemical looping partial oxidation process, we discuss the role of oxygen carriers in the chemical looping partial oxidation cycle, in which the specific surface area, the lattice oxygen mobility, and the thermal stability are understood as the important factors affecting reactivity. We hope to summarize the design and development of efficient oxygen carriers with high oxygen-carrying capacity and syngas selectivity, as well as contribute to the selection, design, optimization, and redox reaction mechanism of redox catalysts.

An new contribution of Ru to the anti-rumpling characteristics of β-(Ni,Pt)Al coatings during cyclic oxidation at 1150 °C

The thermal cycling behavior of β-(Ni,Pt)Al coatings covered on two different superalloys (one without Ru and one with additional Ru) was investigated at 1150 °C. The results showed that a few β to γ′ phase transitions caused a slight rumpling of β-(Ni,Pt)Al coating on the superalloy doped with Ru. Ru in the superalloy entered the β phase of coating by diffusion and inhibited the diffusion of Al, thereby postponing the transition of the β phase and the subsequent rumpling of the coating.

Direct Oxidative Cyclization of 3-Arylpropionic Acids to 3,4-Dihydrocoumarins: Reinvestigation of the Reaction Mechanism.

Instigated by olfactory analysis of odorant molecules, the constitutions of 3,4-dihydrocoumarins prepared by PIFA-based oxidative cyclizations of 3-arylpropionic acids were revised by means of 2D NMR and X-ray analysis. Supported by computational analysis, the migratory mechanism of intermediate spirolactonic cations has been amended: 1,2-alkyl shifts instead of 1,2-carboxylic shifts were selectively obtained.

Bioinspired Collective Total Synthesis of (±)-Rhynchines A-E.

Herein, we present the first racemic total synthesis of the structurally complex monoterpene indole alkaloids rhynchines A-E, starting from commercially available methyl nicotinate and 3-(2-bromoethyl)-1H-indole. The success of our synthesis is attributed to the utilization of a bioinspired synthetic strategy, which facilitated the rapid construction of the pentacyclic core skeleton of the target molecules through biomimetic skeletal rearrangement and late-stage C-H oxidative cyclization. Additionally, silica-gel-promoted tautomerization played a crucial role as a strategic element in the chemical synthesis of rhynchines A and B.

Thermal barrier coating on Inconel 718: understanding cyclic oxidation kinetics

This study investigates the cyclic oxidation behaviour of a thermal barrier coating (TBC) system applied to Inconel 718 alloy substrates. The TBC comprises a NiCr bond coat and a YSZ top coat, applied using the air plasma spray method. Cyclic oxidation studies involve subjecting the coated samples to repeated heating and cooling cycles, with mass gain measurements taken after each cycle. Vibrational modes and surface morphology are analysed before and after oxidation. Results reveal a gradual increase in mass gain up to the 4th cycle, attributed to interface bonding and diffusion-limited growth. Thermal cycling induces stresses, leading to micro cracking and accelerated oxidation. Oxidation kinetics follows both parabolic and linear laws, with rates decreasing over cycles. Kl values consistently exceed Kp, indicating faster linear growth. The study enhances understanding of TBC behaviour under cyclic oxidation conditions, critical for improving durability in practical applications.

Copper-catalyzed aerobic oxidative dehydrogenative cyclization to construct polycyclic aromatic hydrocarbons

The copper-catalyzed aerobic oxidative dehydrogenative cyclization of benzo[b]thiophene represents an efficient approach for the rapid construction of polycyclic aromatic hydrocarbons (PAHs) containing benzo[b]thiophene groups. However, this remains an underexplored field. Here, we establish a new type of copper-catalyzed aerobic oxidative dehydrogenative cyclization of benzo[b]thiophene that enables the utilization of benzo[b]thiophene functionality to access polycyclic aromatic hydrocarbons. This methodology features mild reaction conditions, high atom economy, and remarkable chemo-selectivity, delivering a diversity of PAHs containing benzo[b]thiophene groups. Mechanistic experiments and DFT calculations demonstrate that the in situ generation of benzothiophenyl radical cation intermediate undergoes the intermolecular cyclization and the capture of H2O to furnish the oxidative cycloaromatization reaction. Labeling experiment disclosed that the carbonyl oxygen atom of the product originates from H2O generated during the reaction.

A comparative study of the effect of chromium on the oxidation resistance of nano-structured cobalt-aluminium coatings deposited by magnetron sputtering

The experiment studied the effect of chromium on the oxidation resistance of nanostructured cobalt-aluminum coatings, deposited on superalloy Superni-718 by magnetron sputtering. For this, the cobalt-aluminium coated superalloy was subjected to similar conditions of cyclic oxidation at 1173 K as the cobalt-alumimium coated samples with chromium. Further, the influence of substrate temperature on the properties of coatings was examined by comparing the coatings deposited at substrate temperatures of 773 and 973 K during magnetron sputtering. Post-cyclic oxidation tests, the examination of the surface morphology and phase formations was carried using X-Ray Diffraction and Field-Emission Scanning Electron Microscope/Energy Dispersive Spectroscopy. The coating containing chromium displayed the maximum resistance to cyclic oxidation in comparison to the coatings without chromium, as is apparent from the variation in mass per unit area of the superalloy. Further it was observed that increasing the substrate temperature in magnetron sputtering significantly augments the high temperature resistance of the coatings.

Total Synthesis of Dragocins A-C through Electrochemical Cyclization.

The first total synthesis of dragocins A-C, remarkable natural products containing an unusual C4' oxidized ribose architecture bridged by a polyhydroxylated pyrrolidine, is presented through a route featuring a number of uncommon maneuvers. Several generations towards the target molecules are presented, including the spectacular failure of a key C-H oxidation on a late-stage intermediate. The final route features rapid, stereocontrolled access to a densely functionalized pyrrolidine and an unprecedented diastereoselective oxidative electrochemical cyclization to forge the hallmark 9-membered ring. Preliminary studies suggest this electrochemical oxidation protocol is generally useful.

A study on the thermal cyclic behavior of NiCrAlY coatings via femtosecond laser remelting with high repetition rate

NiCrAlY coatings are widely applied bond coatings in thermal barrier coating systems to prevent high-temperature oxidation of turbine blades. However, the uncontrollable microstructure design and high surface roughness seriously affect the oxidation resistance. Herein, NiCrAlY coatings fabricated through arc ion plating were subjected to high-repetition-rate femtosecond laser remelting (HRR-FLR) treatment. This study assessed the surface rumpling behavior, residual stress evolution, and thermally grown oxide (TGO) layer growth under thermal cyclic oxidation at 1100 °C to determine their impact on coating lifetime. The results indicated that the HRR-FLR treatment was effective in reducing surface roughness, restructuring microstructures, and redistributing reactive elements. These improvements facilitated the formation of a flat, continuous, and dense alumina layer, enhancing the spallation and rumpling resistance of TGO. Consequently, the efficiency of HRR-FLR technique was proven in significantly improving the lifetime of NiCrAlY coatings, which provides a new application prospect of femtosecond lasers in remelting and polishing of metallic surfaces.

Ligand Field Sensitive Spin Acceleration in the Iron-Catalyzed [2 + 2] Cycloaddition of Unactivated Alkenes and Dienes.

Redox-active pyridine(diimine) (PDI) iron catalysts promote the reversible [2 + 2] cycloaddition of alkenes and dienes to cyclobutane derivatives that have applications ranging from fuels to chemically recyclable polymers. Metallacycles were identified as key intermediates, and spin crossover from the singlet to the triplet surface was calculated to facilitate the reductive coupling step responsible for the formation of the four-membered ring. In this work, a series of sterically and electronically differentiated PDI ligands was studied for the [2 + 2] cycloaddition of ethylene and butadiene to vinylcyclobutane. Kinetic studies revealed that the fastest and slowest turnover were observed with equally electron-deficient supporting ligands that either feature phenyl-substituted imine carbon atoms (MeBPDI) or a pyrazine core (MePZDI). While the oxidative cyclization was comparatively slow for both catalysts, the rate of reductive coupling─determined by stoichiometric 13C2H4 labeling studies─correlated with the turnover frequencies. Two-state density functional theory studies and the distinct electronic structures of related (iPrBPDI) and (iPrPZDI) iron methyl complexes revealed significantly different ligand field strengths due to either diminished ligand σ-donation (MeBPDI) or promoted metal π-backbonding (MePZDI). Spin acceleration, leading to fast reductive coupling and catalytic turnover, was promoted in the case of the weaker ligand field and depends on both the nature and position of the electron-withdrawing group. This study provides strong evidence for the role of two-state reactivity in C(sp3)-C(sp3) bond formation and insights on how ligand design either promotes or inhibits spin acceleration in earth-abundant metal catalysis.

Thermal fatigue failure analysis and life assessment of Ni-based single crystal superalloys with film cooling holes

The transient thermal fatigue behavior of Ni-based single crystal superalloys with film cooling holes under different peak temperatures (25 °C → 980 °C and 25 °C → 1050 °C) were investigated by a combination of test and finite element simulation. The initiation position and propagation direction of thermal fatigue cracks in both single hole and multi-hole specimens exhibit the angles of ± 45° with respect to the horizontal direction at the four corners of the holes. Octahedral slip failure mainly occurred at the crack initiation location and crack tip. The cyclic oxidation around the film cooling hole promotes the initiation and propagation of cracks. Based on the crystallographic theory, the strain–stress constitutive equation of the Ni-based single crystal superalloy under transient thermal shock was established. The location and evolution of thermal stress around the hole at different temperatures were obtained by finite element calculation. The kinetic behavior of cyclic oxidation has been quantitatively characterized. A thermal fatigue crack initiation life model considering heating temperature, transient thermal stress, and cyclic oxidation has been established. The simulation results are in good agreement with the tests.

Stereoselective Total Synthesis of Pyranicin and 4‐Epi‐Pyranicin from Carbohydrate Precursors

AbstractHerein, we describe a simple and efficient pathway for the total synthesis of pyranicin and 4‐epi‐pyranicin by utilizing carbohydrates as chiral raw materials for the first time. The general synthetic strategy involves the formation of two main fragments: Fragment 1 is the central tetrahydropyran core, which was constructed in a total of 10 steps from 2,3,4,6‐tetra‐O‐acetyl D‐glucal via Ferrier‐type rearrangement and oxidative cyclization as the key steps. Fragment 2 is the butenolide fragment, which was obtained in a gram scale with a total of 14 steps from diacetyl‐L‐rhamnal involving a ring contraction strategy.

Copper perchlorate catalyzed oxidative cyclisation of a novel bishydrazone ligand, formation of an unusual copper complex and in vitro biological implications

A novel hexadentate bishydrazone ligand, 1,10-bis(di(2-pyridyl)ketone) adipic acid dihydrazone (H2L1) is synthesized and characterized. With copper perchlorate as a catalytic oxidant, the ligand undergoes oxidative cyclisation and resulted in the formation of an unusual copper complex [Cu(L1a)2Cl]ClO4 (1), where L1a is 3-(2-pyridyl)triazolo[1,5-a]-pyridine. The Cu(II) complex was characterized physicochemically, while the molecular structure was confirmed by single crystal X- ray diffraction. In the complex cation, copper(II) is in a distorted trigonal bipyramidal coordination environment, surrounded by two triazolo nitrogen atoms and two pyridyl nitrogen atoms of L1a and a chloride atom. The relevant non covalent intermolecular interactions of the complex quantified using Hirshfeld surface analysis reveals that the O···H/ H···O (27.2%) contacts has the highest contribution. The solution phase bandgaps of the compounds were calculated using Tauc plot, whereas the solid-state band gaps were calculated by Kubelka-Munk model. DFT studies of the compounds indicate that the theoretical calculations corroborate with the experimental data. DPPH antioxidant activity assay of the synthesized compounds showed that the proligand H2L1 has a lower IC50 value (24.1 μM) than that of complex 1 (29.7 μM). The in vitro antibacterial activity was evaluated against Escherichia coli and Staphylococcus aureus, which revealed that complex 1 have excellent activity against E. coli, much as the standard ciprofloxacin. The cytotoxic efficacy investigation of the compounds against A549 (lung) adenocarcinoma cells suggested that H2L1 has more anticancer activity (IC50 value of 149.08 μM) than that of complex 1(IC50 value of 176.70 μM).

Insight into the role of Sc on microstructure, mechanical properties and high temperature oxidation resistance of NiCoCrAlSiSc alloys

The microstructure and mechanical properties of Ni–20Co–20Cr–2Al–1Si-xSc (x = 0, 0.1, 0.3, 0.5, 1 wt %) alloys were investigated, and the oxidation behavior of the alloys with different Sc contents at 1000°C was studied. The results indicate that NiCoCrAlSi alloy without Sc solidified into coarse columnar grains, with the addition of Sc, the grain size significantly decreased. Sc enriched at the grain boundaries of the alloy and promotes the segregation of Si and Ni towards the grain boundaries, forming the compound NiScSi. Within the range of 0∼1% (wt.%) Sc content, as the Sc content increased, there is an increase in the yield strength (σ0.2) of the alloy, a decrease in elongation, a little variation in tensile strength, and an enhancement in Vickers hardness. After cyclic oxidation at 1000°C and 120 h for alloys with different Sc contents, composite oxide films were formed on the surfaces of the alloys, but the properties and microstructure of the oxide films were significantly different. As the Sc content rised, the integrity of the oxide films was significantly improved, and the oxidation resistance of the alloys gradually enhanced at a high temperature of 1000°C.

Abstract 2092: Genomic and proteomic analysis of glioblastoma recurrences during TTFields exposure

Abstract Glioblastoma (GB) is the most aggressive type of brain tumor, and current treatments are generally ineffective in preventing recurrence. Tumor Treating Fields (TTFields) are an innovative treatment that has been shown to improve patients' life expectancy in the last two decades. TTFields therapy has an antitumoral effect that involves different mechanisms and is an optional add-on to standard maintenance temozolomide. Although TTFields therapy initially slows tumor progression, it does not prevent tumor relapse in most patients. In the present investigation, we run a genomic and proteomic analysis of surgical material from 10 patients treated with TTFields. GB tissues were obtained from the primary tumor mass and from a second surgery after tumor relapse. All the patients, in addition to brain tumor standard therapies, were treated with TTFields for eighteen hours a day, the time span of treatment application was dependent on GB recurrence. Control samples were obtained from primary and secondary surgeries of 5 patients treated with standard therapy alone. The GB tissue extracts were analyzed with an RNAseq routine, and the results from the secondary surgery were compared with the data obtained from tumor specimens of the primary surgery. A common feature of transcripts among all the patients was the alterations of several pathways promoting the increase of intracellular oxidation and cell cycle regulation. In parallel with the analysis of patient specimens, we developed an in vitro GB cell relapse model. This was instrumental in investigating the beneficial contribution of TTFields action during tumor relapse, but also in uncovering the limitation of this therapeutic procedure. GB primary cultures obtained from patients' surgery were exposed for up to 12 days with 200 kHz TTFields stimulation using the inovitro™ system. After 12 days of continuous TTFields application, GB cells showed an average depolarization of the resting membrane potential, increasing oxidation, and acidification of the cytoplasm. Genomic analysis of treated cells compared with wild-type primary culture, denoted an increase of tumor stem cell markers, activation of several metabolic pathways, and upregulation of different ion channel protein transcripts. Our final goal is to identify specific molecular features enhanced by TTFields treatment to be used as a parallel therapy to fight GB recurrence. Citation Format: Francesca Cianci, Guido Rey, Dietmar Krex, Davide Ceresa, Paolo Malatesta, Michele Mazzanti. Genomic and proteomic analysis of glioblastoma recurrences during TTFields exposure [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2092.

Microstructure, hardness, oxidation and corrosion behavior of Cr(VNb)2 Laves containing CrNbTaVW RHEA in 3.5 wt% NaCl and 1 M H2SO4

In this study, CrNbTaVW RHEA was produced via vacuum arc melting. The microstructure, hardness, corrosion and oxidation properties were explored in comparison with the commercial IN718 alloy. The results indicated that CrNbTaVW RHEA exhibited a dendritic microstructure that was segregated into BCC1, BCC2, and Cr(VNb)2 Laves. The CrNbTaVW RHEA has a higher hardness of 688 HV than the IN718 alloy with 301 HV. The higher hardness is due to Laves phase solid solution strengthening and grain refinement. From the corrosion results, CrNbTaVW RHEA had a lower corrosion rate in 3.5 wt% NaCl (0.000097 mm/yr) and 1 M H2SO4 (0.00013 mm/yr) than the commercial IN718 alloy (0.054 mm/yr and 1.12 mm/yr). The cyclic oxidation analysis at 850 °C and 1050 °C after 15 hours confirmed a mass gain of 4.41 mg/cm2 and 10.84 mg/cm2 for IN718 alloy, while CrNbTaVW RHEA exhibited a mass loss of −25.17 mg/cm2 and − 35.91 mg/cm2, respectively, indicating that the IN718 alloy exhibited the best oxidation resistance. Thermal and growth stresses contributed to the pores, voids, cracks, and spallation observed in the CrNbTaVW RHEA.

In vitro β–glucuronidase and in silico molecular docking studies of thiazole-fused-thiadiazole derivatives prepared through molecular-iodine promoted [3+2] oxidative cyclization

As pharmacological medicines and their constituents are vital to human life and global public health, there is a growing need to find safe and efficient inhibitors for the treatment of β-glucuronidase. The present study was aimed to design and synthesize thiazole-fused-thiadiazole derivatives (1–15). The synthesized compounds were spectroscopically characterized through elementary analysis, HREIMS, 1HNMR and 13CNMR. After the confirmation of their structure, the synthesized compounds were tested for their inhibition properties against β-glucuronidase (in vitro) as compared to standard d-saccharic acid-1,4- lactone drug. The tested derivatives exhibited variable inhibitory potential against β-glucuronidase with an IC50 values in the range of 1.20 ± 0.05 to 34.70 ± 0.70 µM. The results were compared with standard drug d-saccharic aci‑1, 4-lactone (48.30 ± 0.50 µM). In particular, derivatives 3, 5, 7, 9, 11, 14 were found to be significantly active, even more active than the standard drug, while the remaining compounds showed moderate to low inhibitory potential compared to the standard drug. Structure-activity relationship (SAR) study was carried out for all analogues based on substitutions pattern around aromatic aryl rings. Similarly, molecular study was conducted to assess the binding interactions of synthesized derivatives with the active sites of target enzyme.