Theoretical study of rhodium(III)-catalyzed synthesis of benzoxepine and coumarin.

The mechanisms of the rhodium-catalyzed cycloaddition of 2-vinylphenol with diphenylacetylene and carbon monoxide have been studied using density functional theory calculations at the B3LYP/6-31G (d, p) (Lanl2dz for Rh) level of theory. The SMD solvation model was used in MeCN solvents at M06-2X/6-311 ++ G (d, p) (Lanl2dz (f) for Rh) levels using a single-point calculation to consider the solvent effect. The calculation results show that there are two competitive reaction pathways for the cycloaddition reaction of rhodium-catalyzed synthesis of benzohexine and coumarin. Starting from the precursor reaction complex, the reaction channel is more favorable for the carbon atoms of diphenylacetylene and carbon monoxide to attack the Rh-C bond (the barriers of 9.88 and 10.01 kcal/mol) rather than attack the Rh-O bond (the barriers of 15.37 and 30.17 kcal/mol), and carbon monoxide in two different reaction channels has a greater energy difference than diphenylacetylene. The results show that the computational study of the rhodium-catalyzed cycloaddition reaction has a high catalytic activity consistent with the high yield of the experiment of Gulías et al.

Design, Synthesis and Antibacterial Evaluation of Compounds Based on New Benzoxepine-oxime-1,2,3-triazole Hybrid.

BACKGROUND: A library of compounds related to the new benzoxepine-oxime-1,2,3-triazole hybrid was created as probable antibacterial agents. Their synthesis involved a Cu-catalyzed azidealkyne cycloaddition (CuAAC) as a key step to construct the desired 1,2,3-triazole ring. Thus the click reaction between the appropriate alkyne containing the benzoxepine-oxime framework with aryl azides afforded the target compounds in good yields. METHOD: To assess their antibacterial properties all the synthesized compounds were tested using four bacterial strains consisting of one Gram-positive and three Gram-negative species. RESULTS & CONCLUSION: These compounds were generally found to be effective towards gram -ve species and one of them showed selective cytotoxicity against lung cancer cell line.

Total Synthesis of Ovafolinins†A and B: Unique Polycyclic Benzoxepin Lignans through a Cascade Cyclization.

Ovafolinins A and B, isolated from Lyonia ovalifolia var. elliptica, are lignans that contain a unique bridged structure containing a penta- and tetracyclic benzoxepin and an aryl tetralin. We report the first total synthesis of these natural products in which an acyl-Claisen rearrangement was initially utilized to construct the lignan backbone with correct relative stereochemistry. Judicious use of a bulky protecting group placed reactive moieties in the correct orientation, thereby resulting in a cascade reaction to form the bridged benzoxepin/aryl tetralin from a linear precursor in a single step. Modification of this route allowed the enantioselective synthesis of (+)-ovafolinins A and B, which confirmed the absolute stereochemistry, and comparison of optical rotation suggests that these compounds are found as scalemic mixtures in nature.

Design, synthesis, cytotoxicities and DNA cleavage activities of dibenzoxepine and isoquinoline derivatives starting from dehydroabietylamine.

A series of novel hexahydrodibenzoxepine and quinazoline derivatives were designed and synthesized starting from dehydroabietylamine. The cytotoxicities of the compounds against L02 and HepG2 cell lines were investigated. Meanwhile, the plasmid DNA (Escherichia coli) cleavage of several heterocyclic derivatives was studied. These compounds exhibit remarkable activities on plasmid DNA pBR322. Our study provides useful information for developing new and more potent antitumor agents.

Gold-Catalyzed Synthesis of Tropone and Its Analogues via Oxidative Ring Expansion of Alkynyl Quinols.

A new and convenient strategy for the synthesis of functionalized tropone derivatives based on the gold-catalyzed oxidative ring expansion of alkynyl quinols has been developed. The reaction proceeds via gold-catalyzed highly regioselective oxidation followed by 1,2-migration of a vinyl or phenyl group. Extension of this chemistry allows ready access to various seven- or six-membered ring systems such as benzotropones, benzooxepines, phenanthrenes, and quinolin-2(1H)-ones.

Synthesis of New Benzocyclotrimer Analogues: New Receptors for Tetramethylammonium Ion Recognition.

Using a [2 + 2 + 2] cycloaddition/Mitsunobu reaction sequence, a convenient synthesis to access new benzocyclotrimer analogues has been developed. The new receptors have the geometry and functionality capable of recognizing the tetramethylammonium ion in the gas phase and in solution.

Synthesis of targeted dibenzo[b,f]thiepines and dibenzo[b,f]oxepines as potential lead molecules with promising anti-breast cancer activity.

A targeted library of substituted dibenzo[b,f]thiepines and dibenzo[b,f]oxepines (prototypes I, II and III), and structurally analogous to tamoxifen have been synthesized as a new class of anti-breast cancer agents. All the prototype molecules exhibited potential antiproliferative activity against ER + ve and ER-ve breast cancer cell lines. Dibenzo[b,f]thiepine prototypes were found to be more active. Of all the compound tested, 14b exhibited potent in-vitro antiproliferative activity at 1.33 µM and 5 µM concentration in MCF-7 and MDA-MB-231 cell lines and was devoid of any cytotoxicity in normal HEK cells even at 50 µM. Cell cycle analysis showed that the compound 14b inhibited cell proliferation due to G0/G1 arrest in MCF-7 cells. Annexin-V FITC and PI staining experiments confirmed that the cell inhibition was primarily due to apoptosis and not by necrosis, which was also supported by LDH release assay experiment. Molecular docking studies showed better binding interaction of the new dibenzo[b,f]thiepine analogue 14b with the estrogen receptor (ER) as compared to 4-hydroxy-tamoxifen and this enhanced binding might be responsible for its estrogen antagonistic activity that induces cell cycle arrest, apoptosis and inhibition of breast cancer cells.

One-Pot Synthesis of 5-Amino-2,5-dihydro-1-benzoxepines: Access to Pharmacologically Active Heterocyclic Scaffolds.

A one-pot multibond-forming process involving a thermally mediated Overman rearrangement and a ring closing metathesis reaction of allylic trichloroacetimidates bearing a 2-allyloxyaryl group has been developed for the synthesis of 5-amino-substituted 2,5-dihydro-1-benzoxepines. Chemoselective reduction and functionalization of these compounds allowed access to a range of pharmacologically active 5-amino-2,3,4,5-tetrahydro-1-benzoxepine scaffolds.

Convenient one-pot synthesis, anti-mycobacterial and anticancer activities of novel benzoxepinoisoxazolones and pyrazolones.

Series of new benzoxepinoisoxazolones 4a-d and pyrazolones 6a-t were prepared by the cyclocondensation of substituted (E)-ethyl 3-oxo-2,3-dihydrobenzo[b]oxepine-4-carboxylates 3a-d with hydroxylamine hydrochloride and phenylhydrazine hydrochlorides 5a-k. Synthesized compounds were screened for their in vitro anti-mycobacterial activity and anticancer activity. Ten compounds displayed good anti-mycobacterial activity, among these; compound 4d and 6b found to be potent when compared to standard drug isoniazid. Eleven compounds displayed good anticancer activity and compounds 4b-d displayed equipotent activity on HeLa cell lines when compared to standard drug doxorubicin. Activation of caspase-3 and caspase-9 has been measured for compounds 4b-d on HeLa cell lines (apoptosis). This is the first report assigning in vitro anti-mycobacterial, anticancer and structure-activity relationship for this new class of benzoxepinoisoxazolones and pyrazolones.

Total synthesis of the putative structure of xylarinol†B.

The total synthesis of the putative structure of xylarinol B is described and the need to revise its structure is demonstrated. The central benzoxepine skeleton was constructed by employing a cobalt-mediated bimolecular [2+2+2] Reppe-Vollhardt alkyne cycloaddition reaction.

FeCl3-catalyzed synthesis of functionally diverse dibenzo[b,f]oxepines and benzo[b]oxepines via alkyne-aldehyde metathesis.

An efficient synthesis of dibenzo[b,f]oxepines and benzo[b]oxepines via FeCl3-catalyzed alkyne-aldehyde metathesis reaction is described. Structurally diverse dibenzo[b,f]oxepines and benzo[b]oxepines have been achieved in good yields with high regio- and chemoselectivity under mild conditions. Notably, among the various catalysts such as Fe(III), Au(III), In(III), Zn(II), Ag(I) and triflic acid, the alkyne-aldehyde metathesis reaction of 2-(2'-phenylethynyl-phenyloxy)-benzaldehyde is only catalyzed by environmentally friendly and sustainable iron(III) chloride.

A novel approach for C-C, C-N, and C-O bond formation reactions: a facile synthesis of benzophenazine, quinoxaline, and phenoxazine derivatives via ring opening of benzoxepines.

A new one-pot protocol has been developed for the synthesis of benzophenazine, quinoxaline, and phenoxazine derivatives by the reaction of benzoxepine-4-carboxylates with benzene-1,2-diamines, ethane-1,2-diamine, and 2-aminophenols in the presence of Bi(OTf)3 (5 mol %) under mild conditions in very good yields. The present protocol opens a new way for C-C, C-N, and C-O bond-formation reactions in a single-step process. The structural assignment was confirmed by X-ray analysis.

Highly enantioselective synthesis of chiral 7-ring O- and N-heterocycles by a one-pot nitro-Michael-cyclization tandem reaction.

A concise enantioselective approach to synthesise medium-sized 7-ring O- and N-heterocycles has been developed. The synthetic strategy relies on an organocatalytic nitro-Michael-nitrile oxide cycloaddition tandem reaction, leading to the corresponding chiral benzoxe- and benzazepine derivatives containing an additional fused dihydroisoxazoline ring in good yields and excellent enantioselectivities (up to 97% ee).

Synthesis of dibenzoxepine lactams via a Cu-catalyzed one-pot etherification/aldol condensation cascade reaction: application toward the total synthesis of aristoyagonine.

A general synthesis of dibenzoxepine lactams has been developed using a one-pot Cu-catalyzed etherification/aldol condensation cascade reaction. The reaction of 4-hydroxyisoindolin-1-one with a wide range of 2-bromobenzaldehydes in the presence of a copper catalyst provided various aristoyagonine derivatives in good yields.

Photocycloaddition of arenes and allenes.

In this work, we report on a new intramolecular para cycloaddition of arenes with allenes, yielding attractive rigid scaffolds bearing several reactive functionalities to build in further diversity. Bicyclo[2.2.2]octadiene-type products and benzoxepine acetals are formed in this reaction, in ratios and yields depending on the substitution pattern on the aromatic ring, the nature of the chromophore, and the tether. This unprecedented reaction has remarkable features that distinguish it from many other photochemical transformations: it is particularly robust with respect to substituents, it can be scaled up without a notable loss of efficiency, and it can lead to structures with a high degree of complexity in low to good yields. All photochemical precursors could be synthesized readily in three steps. We confirmed the compatibility of the nitrogen atom in the photocycloaddition step, which gives access to a bicyclo[2.2.2]octadiene scaffold with two points that allow further diversification. This reaction was scaled up to multigram quantities without erosion of the typically high yields in photocycloadducts. Sequential deprotection of the N- or C-terminus of bicyclic amino acids gave access to two conformationally constrained unnatural amino acids with different dispositions of the two anchor points.

Discovery of thiazolobenzoxepin PI3-kinase inhibitors that spare the PI3-kinase ß isoform.

A series of suitable five-membered heterocyclic alternatives to thiophenes within a thienobenzoxepin class of PI3-kinase (PI3K) inhibitors was discovered. Specific thiazolobenzoxepin 8-substitution was identified that increased selectivity over PI3Kß. PI3Kß-sparing compound 27 (PI3Kß Ki,app/PI3Kα Ki,app=57) demonstrated dose-dependent knockdown of pAKT, pPRAS40 and pS6RP in vivo as well as differential effects in an in vitro proliferation cell line screen compared to pan PI3K inhibitor GDC-0941. A new structure-based hypothesis for reducing inhibition of the PI3K ß isoform while maintaining activity against α, δ and γ isoforms is presented.

Design, synthesis and anticancer properties of 5-arylbenzoxepins as conformationally restricted isocombretastatin A-4 analogs.

A series of novel benzoxepins 6 was designed and prepared as rigid-isoCA-4 analogs according to a convergent strategy using the coupling of N-tosylhydrazones with aryl iodides under palladium catalysis. The most potent compound 6b, having the greatest resemblance to CA-4 and isoCA-4 displayed antiproliferative activity at nanomolar concentrations against various cancer cell lines and inhibited tubulin assembly at a micromolar range. In addition, benzoxepin 6b led to the arrest of HCT116, K562, H1299 and MDA-MB231 cancer cell lines in the G2/M phase of the cell cycle, and strongly induced apoptosis at low concentrations. Docking studies demonstrated that benzoxepin 6b adopt an orientation similar to that of isoCA-4 at the colchicine binding site on ß-tubulin.

Cis-amide isosteric replacement in thienobenzoxepin inhibitors of PI3-kinase.

Substructural class effects surrounding replacement of a 'cis' N-methyl aniline amide within potent and selective thienobenzoxepin PI3-kinase inhibitors are disclosed. While a simple aryl to alkyl switch was not tolerated due to differences in preferred amide conformation, heterocyclic amide isosteres with maintained aryl substitution improved potency and metabolic stability at the cost of physical properties. These gains in potency allowed lipophilic deconstruction of the arene to simple branched alkyl substituents. As such, overall lipophilicity-neutral, MW decreases were realized relative to the aniline amide series. The improved properties for lead compound 21 resulted in high permeability, solubility and bioavailability.

An efficient approach for the construction of benzazepine and benzoxepine derivatives.

A novel and facile synthetic protocol for the construction of benzazepine and benzoxepine derivatives through a copper(I)-catalyzed reaction of 2-(2-ethynylphenyl)-1-tosylaziridine or 2-(2-ethynylphenyl)oxirane with sulfonyl azides is disclosed. A ketenimine is the key intermediate during the reaction process.

First total synthesis of dioxepine bastadin 3.

The synthesis of dioxepine bastadin 3, a tyrosine-tyramine derivative with a dibenzo-1,3-dioxepine scaffold that is rarely present among natural products, is described. The dibenzo-1,3-dioxepine ring was formed early in the sequence and the (E)-2-(hydroxyimino)-N-alkylamide was generated in the last step by oxidation of the 2-amino-N-alkylamide precursor. The presumably biogenetic late-stage ring formation starting from congener bastadin 3 failed. A new synthesis of this alkaloid was also developed. This new route requires a minimal use of protecting groups and the order of the two key steps was reversed relative to the route to dioxepine bastadin 3.