Oxepine Derivatives Research Articles

Synthesis and Study of Building Blocks with Dibenzo[b,f]oxepine: Potential Microtubule Inhibitors.

The synthesis of biphenylmethoxydibenzo[b,f]oxepine or photoswitchable fluorinated dibenzo[b,f]oxepine derivatives with one or three azo bonds, potential microtubule inhibitors, is described. Our studies provide a concise method for constructing derivatives containing the dibenzo[b,f]oxepine skeleton. An analysis of products was run using experimental and theoretical methods. Next, we evaluated the E/Z isomerization of azo-dibenzo[b,f]oxepine derivatives, which could be photochemically controlled using visible-wavelength light.

Selective Synthesis of Tetrahydro Oxepines by Cu‐Catalyzed Condensations of Diazomalonates and gem‐Dialkyl Vinyl Oxetanes

AbstractThanks to an unprecedented gem‐dialkyl substituent effect, an efficient synthesis of tetrahydro oxepine derivatives is achieved by ring expansion of vinyl oxetanes using acceptor(−acceptor) diazo reagents under Cu(II)‐catalysis. A large scope of 2‐vinyl oxetanes and either diazo mono or diester reagents give access to a series of functionalized oxepines.

Oxepin Derivatives Formation from Gas-Phase Catechol Ozonolysis.

Quantum chemical calculations are performed to explore all of the possible pathways for primary ozonide (POZ) formation from gas-phase ozonolysis of catechol. Canonical transition state theory has been used to calculate the rate coefficients of individual steps for the formation of POZ. The calculated rate coefficients for 1,3-cycloaddition of ozone at the (i) unsaturated C(OH)═C(OH) bond and (ii) CH═C(OH) of catechol, respectively, are in good agreement with the experimental rate constant. In general, subsequent decomposition of POZ leads to well-known Criegee Intermediates. This work reveals a parallel pathway by which the endo-addition of ozone at CH═C(OH) of catechol proceeds through oxepin derivatives along with the paths leading to Criegee Intermediates and peroxy acids. The 7-membered heterocyclic oxepin derivatives have lower energies than Criegee Intermediates but similar relative energies with peroxy acids.

Dibenzo[b,f]oxepine Molecules Used in Biological Systems and Medicine.

In this short review, including 113 references, issues related to dibenzo[b,f]oxepine derivatives are presented. Dibenzo[b,f]oxepine scaffold is an important framework in medicinal chemistry, and its derivatives occur in several medicinally relevant plants. At the same time, the structure, production, and therapeutic effects of dibenzo[b,f]oxepines have not been extensively discussed thus far and are presented in this review. This manuscript addresses the following issues: extracting dibenzo[b,f]oxepines from plants and its significance in medicine, the biosynthesis of dibenzo[b,f]oxepines, the active synthetic dibenzo[b,f]oxepine derivatives, the potential of dibenzo[b,f]oxepines as microtubule inhibitors, and perspective for applications of dibenzo[b,f]oxepine derivatives. In conclusion, this review describes studies on various structural features and pharmacological actions of dibenzo[b,f]oxepine derivatives.

Systematic Studies on Anti-Cancer Evaluation of Stilbene and Dibenzo[b,f]oxepine Derivatives.

Cancer is one of the most common causes of human death worldwide; thus, numerous therapies, including chemotherapy, have been and are being continuously developed. In cancer cells, an aberrant mitotic spindle-a microtubule-based structure necessary for the equal splitting of genetic material between daughter cells-leads to genetic instability, one of the hallmarks of cancer. Thus, the building block of microtubules, tubulin, which is a heterodimer formed from α- and β-tubulin proteins, is a useful target in anti-cancer research. The surface of tubulin forms several pockets, i.e., sites that can bind factors that affect microtubules' stability. Colchicine pockets accommodate agents that induce microtubule depolymerization and, in contrast to factors that bind to other tubulin pockets, overcome multi-drug resistance. Therefore, colchicine-pocket-binding agents are of interest as anti-cancer drugs. Among the various colchicine-site-binding compounds, stilbenoids and their derivatives have been extensively studied. Herein, we report systematic studies on the antiproliferative activity of selected stilbenes and oxepine derivatives against two cancer cell lines-HCT116 and MCF-7-and two normal cell lines-HEK293 and HDF-A. The results of molecular modeling, antiproliferative activity, and immunofluorescence analyses revealed that compounds 1a, 1c, 1d, 1i, 2i, 2j, and 3h were the most cytotoxic and acted by interacting with tubulin heterodimers, leading to the disruption of the microtubular cytoskeleton.

Organocatalytic Asymmetric Synthesis of Bridged Tetrahydrobenzo[b]azepines/oxepines.

The asymmetric synthesis of bridged tetrahydrobenzo[b]azepine and oxepine derivatives through chiral Brønsted acid catalyzed asymmetric aza-Piancatelli rearrangement/Michael addition sequence has been developed. The reaction proceeds under mild reaction conditions to afford the final bridged cyclic products in good yields with excellent enantio- and diastereoselectivities.

An Updated Review on Biologically Promising Natural Oxepines.

Benzo-oxepines and dibenzo-oxepines, a unique class of naturally occurring secondary metabolites, are distributed mainly in plants and fungi and have received much attention from phytochemists and biologists based on their fascinating structural features and health-promoting functions. This review summarizes 100 oxepine derivatives comprising three categories: benzo-oxepine, dibenzo-oxepine, and pyrano-oxepine. Studies on various structural features and pharmacological activities of oxepine derivatives promote further in-depth research on these potent natural products. This review portrays the natural occurrence, bioactivity and biosynthesis of oxepines reported from 1984 to 2021.

Synthesis and Study of Dibenzo[b, f]oxepine Combined with Fluoroazobenzenes-New Photoswitches for Application in Biological Systems.

Dibenzo[b, f]oxepine derivatives are an important scaffold in natural, medicinal chemistry, and these derivatives occur in several medicinally relevant plants. Two dibenzo[b, f]oxepines were selected and connected with appropriate fluorine azobenzenes. In the next step, the geometry of E/Z isomers was analyzed using density functional theory (DFT) calculations. Then the energies of the HOMO and LUMO orbitals were calculated for the E/Z isomers to determine the HOMO-LUMO gap. Next, modeling of the interaction between the obtained isomers of the compounds and the colchicine α and β-tubulin binding site was performed. The investigated isomers interact with the colchicine binding site in tubulin with a part of the dibenzo[b, f]oxepine or in a part of the azo switch, or both at the same time. Based on the UV-VIS spectra, it was found that in the case of compounds with an azo bond in the meta position, the absorption bands n→π* for both geometric isomers and their separation from π→π* are visible. These derivatives therefore have the potential to be used in photopharmacology.

The stereoselective synthesis of cis- and trans-fused pyrrolidine containing bicyclic azepine and oxepine derivatives using aza-Cope rearrangement-Mannich cyclization as a key step

The development of novel methods and strategies for the formation of fused five-, six-, and seven-membered ring structures is of utmost importance in organic syntheses.

Exciting progress in the transition metal‐catalyzed synthesis of oxepines, benzoxepines, dibenzoxepines, and other derivatives

AbstractFrom the past decade so far, the synthesis of seven‐membered oxacycles especially natural monocyclic oxepines and their annulated derivatives has received considerable attention. Due to the importance of these valuable scaffolds in natural products, pharmaceuticals, and prospective drugs, as well as their strong potential for use in the biosynthesis and metabolism of monocyclic and polycyclic aromatic compounds, a variety of synthesis strategies have been proposed to afford oxepine moiety. Among the versatile and attractive approaches, this review article focuses on the exciting developments in transition metal‐mediated reactions as the key step in the synthesis of oxepine derivatives from 2010 to early 2021.

Synthesis of two 2,3,4,5‐tetrahydrooxepin‐7‐ylamino)benzoate derivatives as antibacterial agents against Escherichia coli and Staphylococcus aureus

AbstractSome protocols have been used to preparation of oxepine analogs using some substances which require special conditions such as higher‐temperatures or differences in the pH. The objective of this study was to synthesize two new oxepine‐derivatives from a Bicyclo[6.1.0]‐alkyne analog. Besides, the antibacterial effect against Escherichia coli and Staphylococcus aureus was determinate. The results showed that protocols used for synthesis of two oxepine analogs do not require special conditions to give a good yielding. Other data showed that oxepine analogs decreased the growth bacterial of Escherichia coli and Staphylococcus aureus. In conclusion, in this investigation a facile method for the synthesis of two oxepine derivatives is reported; in addition, these compounds could be good candidates as antibacterial reagents.

Synthesis and Investigations of Building Blocks with Dibenzo[b,f] Oxepine for Use in Photopharmacology.

The synthesis of photoswitchable azo-dibenzo[b,f]oxepine derivatives and microtubule inhibitors were described. Subsequently, we examined the reaction of methoxy derivative 3-nitrodibenzo[b,f]oxepine with different aldehydes and in the presence of BF3·OEt2 as a catalyst. Our study provided a very concise method for the construction of the azo-dibenzo[b,f]oxepine skeleton. The analysis of products was run using experimental and theoretical methods. Next, we evaluated the E/Z isomerization of azo-dibenzo[b,f]oxepine derivatives, which could be photochemically controlled using visible-wavelength light.

Sequential Two‐Fold Claisen Rearrangement, One‐Pot Ring‐Closing Metathesis and Cross‐Metathesis as a Route to Substituted Benzo[b]azepine‐2‐one, Benzo[b]azepine and Benzo[b]oxepine Derivatives

AbstractA synthetic protocol involving sequential use of three atom‐economic processes viz. Claisen rearrangement, ring‐closing metathesis and cross metathesis has been developed to access 7‐substituted benzo[b]azepine and benzo[b]oxepine derivatives starting from appropriate aniline or phenol in good overall yield. A one‐pot RCM‐CM protocol has also been developed for the synthesis of benzazepine and benzoxepine derivatives.

Chemical constituents and acetylcholinesterase inhibitory activity from the stems of Bauhinia pentandra

Two steroids (1 and 2), two oxepin derivatives (3 and 4) and seven flavonoids (5–11) were isolated from the stems of Bauhinia pentandra. Their structures were elucidated on the basis of NMR spectroscopic data, and by comparison with data previously reported in the literature. The ethanol extract from the stems of B. pentandra and the compounds, 4, 5, 6, 7, 8 and 11 have been evaluated as acetylcholinesterase inhibitors, and among these, the compound 5 exhibited the strongest activity. In addition, all the isolated compounds are reported for the first time as constituents of B. pentandra.

Synthesis of bis-BN-Naphthalene-Fused Oxepins and Their Photoluminescence Including White-Light Emission.

A series of novel bis-BN-naphthalene-fused oxepin derivatives were synthesized via a Pd-catalyzed tandem reaction from brominated 2,1-borazaronaphthalenes and cis-bis(boryl)alkenes. X-ray crystallographic analysis revealed that bis-BN-naphthalene-fused oxepins feature a planar framework. The electronic and photophysical properties of the novel BN-naphthalene-fused oxepins were investigated by UV-vis and fluorescence spectroscopies and density functional theory (DFT) calculations, which disclosed the distinct electronic and photophysical properties of the analogous hydrocarbon system. Interestingly, dual-fluorescent emissions were observed upon dissolving N-substituted derivatives 10-14 in dimethyl sulfoxide. Tunable emission colors especially for white-light emissions can be achieved by controlling the ratio of solvents, concentration, or temperature using only a single-molecule compound.

The stilbene and dibenzo[b,f]oxepine derivatives as anticancer compounds

In the present study, the synthesis and cytotoxic effect of six stilbenes and three oxepine derivatives against two cancerous – HeLa and U87, and two normal – EUFA30 and HEK293 cell lines has been reported. The results of cytotoxic assay and flow cytometry analysis revealed that compounds 9-nitrobenzo[b]naphtho[1,2-f]oxepine (4), (E)-3,3′,4,4′,5,5′-hexamethoxystilbene (6) and 4-hydroxy-2′,4′-dinitrostilbene (8) were the most active and their interaction with tubulin (crystal structure from PDB) has been analyzed by computer molecular modeling. Molecular docking of these compounds on colchicine binding site of the tubulin indicates the interaction of (4), (6) and (8) with tubulin. The compound (4) could interact stronger with tubulin, relative to colchicine, however, with no selectivity of action against cancer and normal cells. Conversely, compounds (6) and (8) interact more weakly with tubulin, relative to colchicine but they act more selectively towards cancerous versus normal cell lines. Obtained results proved that the compounds that are the most active against cancerous cells operate through tubulin binding.

Gold-catalyzed cyclization in the synthesis of antimitotic 2,3-dihydrobenzo[b]oxepine derivatives of colchicine

New allocolchicine derivatives bearing 2,3-dihydrobenzo[b]oxepine moiety were synthesized via gold-catalyzed cyclization as a key synthetic step. The obtained 2,3-dihydrobenzo[b]oxepine-containing allocolchicinoids possess cytotoxic activity against HEK293, PANC-1, COL0357, HeLa, and Colon26 cancer cell lines at low micromolar range of concentrations.

Green Fabrication of 2D Fe3O4/Mg(OH)2 and 2D Fe3O4/MgO Nanocomposites Using [OMIM]Br Ionic Liquid and Comparing Catalytic Activity with Green Metrics

In this article, Fe3O4 nanoparticles, 2D Fe3O4/Mg(OH)2, and 2D Fe3O4/MgO nanocomposites were synthesized using ionic liquid [OMIM]Br as green designer and stabilizer at ambient pressure. Here, we report a special method for a sandwich like magnetic nanocomposites synthesis. The characterization of these nanocomposites was performed by IR, XRD, SEM, TEM, BET, and VSM techniques. Synthesized nanostructures were employed in the synthesis of 4H-chromene, 4H-pyran, and oxepine derivatives in three-component tandem reactions. Although, Fe3O4/Mg(OH)2 nanocomposite, as magnetically separable heterogeneous catalyst, has showed lower surface area in comparison to Fe3O4/MgO, exhibited a significant enhancement in the yield of the desired products. The described protocol has various advantages including simple work-up, mild reaction condition, green solvent, and the high atomic economy that make attractive procedure. The nanocatalysts exhibited remarkable reusable activity. Also, investigation of green chemistry metrics approved that Fe3O4/Mg(OH)2 nanocomposites play an essential role in the improvement of the reaction yield of 4H-chromene, among other products.

Lewis Base-Catalyzed [4 + 3] Annulation of ortho-Quinone Methides and MBH Carbonates: Synthesis of Functionalized Benzo[ b]oxepines Bearing Oxindole Scaffolds.

A novel Lewis base-catalyzed [4 + 3] annulation process for the construction of benzo[ b]oxepine scaffolds has been developed. 1,4-Diazabicyclo[2.2.2]octane (DABCO) promotes the union of o-QMs and Morita-Baylis-Hillman carbonates in reasonable to excellent yields and good stereoselectivities (dr > 20:1). This straightforward, catalytic approach offers access to a variety of synthetically useful benzo[ b]oxepine derivatives bearing oxindole scaffolds containing all-carbon spiro-quaternary stereocenters.

One-Pot Synthesis of Dibenzo[ b, d]oxepines via Olefinic C-F Bond Functionalization and Intramolecular Pd-Catalyzed C-H Arylation.

We report base-mediated reactions of 1-bromo-2-(2,2-difluorovinyl)benzenes with phenols followed by Pd-catalyzed intramolecular C-H arylation, which offers a novel route to a pharmaceutically relevant class of compounds, oxepines. Construction of these medium-sized ring structures proceeds as a one-pot two-step reaction through diaryl ketene acetals as intermediates. It allows to obtain various dibenz[ b, d]oxepine derivatives in moderate to high yields.