Academic literature on the topic 'Oxepine'

This paper deals with the synthesis of 2-deoxy-2-C-alkyl/aryl septanosides. A range of such septanoside derivatives was synthesized by using a common bromo-oxepine intermediate, involving C–C bond forming organometallic reactions. Unsaturated, seven-membered septanoside vinyl bromides or bromo-oxepines, obtained through a ring expansion methodology of the cyclopropane derivatives of oxyglycals, displayed a good reactivity towards several acceptor moieties in C–C bond forming Heck, Suzuki and Sonogashira coupling reactions, thus affording 2-deoxy-2-C-alkyl/aryl septanosides. Whereas Heck and Sonogashira coupling reactions afforded 2-deoxy-2-C-alkenyl and -alkynyl derivatives, respectively, the Suzuki reaction afforded 2-deoxy-2-C-aryl septanosides. Deprotection and reduction of the 2-deoxy-2-alkenyl derivative afforded the corresponding 2-deoxy-2-C-alkyl septanoside free of protecting groups. The present study illustrates the reactivity of bromo-oxepine in the synthesis of hitherto unknown septanosides, branching out at C-2, through C–C bond formation with alkyl and aryl substituents.

As part of a project studying the secondary metabolites extracted from the Chilean flora, we report herein three new β-agarofuran sesquiterpenes, namely (1S,4S,5S,6R,7R,8R,9R,10S)-6-acetoxy-4,9-dihydroxy-2,2,5a,9-tetramethyloctahydro-2H-3,9a-methanobenzo[b]oxepine-5,10-diyl bis(furan-3-carboxylate), C27H32O11, (II), (1S,4S,5S,6R,7R,9S,10S)-6-acetoxy-9-hydroxy-2,2,5a,9-tetramethyloctahydro-2H-3,9a-methanobenzo[b]oxepine-5,10-diyl bis(furan-3-carboxylate), C27H32O10, (III), and (1S,4S,5S,6R,7R,9S,10S)-6-acetoxy-10-(benzoyloxy)-9-hydroxy-2,2,5a,9-tetramethyloctahydro-2H-3,9a-methanobenzo[b]oxepin-5-yl furan-3-carboxylate, C29H34O9, (IV), obtained from the seeds of Maytenus boaria and closely associated with a recently published relative [Paz et al. (2017). Acta Cryst. C73, 451–457]. In the (isomorphic) structures of (II) and (III), the central decalin system is esterified with an acetate group at site 1 and furoate groups at sites 6 and 9, and differ at site 8, with an OH group in (II) and no substituent in (III). This position is also unsubstituted in (IV), with site 6 being occupied by a benzoate group. The chirality of the skeletons is described as 1S,4S,5S,6R,7R,8R,9R,10S in (II) and 1S,4S,5S,6R,7R,9S,10S in (III) and (IV), matching the chirality suggested by NMR studies. This difference in the chirality sequence among the title structures (in spite of the fact that the three skeletons are absolutely isostructural) is due to the differences in the environment of site 8, i.e. OH in (II) and H in (III) and (IV). This diversity in substitution, in turn, is responsible for the differences in the hydrogen-bonding schemes, which is discussed.

The absolute structure of the title compound preaustinoid A1 [systematic name: (5aR,7aS,8R,10S,12R,13aR,13bS)-methyl 10-hydroxy-5,5,7a,10,12,13b-hexamethyl-14-methylene-3,9,11-trioxohexadecahydro-8,12-methanocycloocta[3,4]benzo[1,2-c]oxepine-8-carboxylate], C26H36O7, has been determined by resonant scattering using CuKα radiation [Flack parameter = 0.07 (15)]. The structure is consistent with that reported previously [Stierleet al.(2011).J. Nat. Prod.74, 2272–2277], determined by detailed analysis of MS and NMR data. The molecule consists of a fused four-ring arrangement. The seven-membered oxepan-2-one ring has a chair conformation, as do the central cyclohexane rings, while the outer cyclohexa-1,3-dione ring has a boat conformation. In the crystal, molecules are linkedviaO—H...O hydrogen bonds, forming helical chains propagating along [100].

Dimethoxydiphenylamine-substituted dispiro-oxepine derivative DDOF has been synthesized using a facile synthetic route and tested in perovskite solar cells as a hole transporting material exhibiting a remarkable PCE of 19.4%.

Three new diketopiperazine alkaloids, including two oxepine‐containing diketopiperazines, chrysopiperazines A and B (1 and 2), and one quinazoline‐containing diketopiperazine, chrysopiperazine C (5), together with three known analogues (3, 4, and 6), were isolated from the gorgonian-derived Penicillium chrysogenum fungus. The relative and absolute configurations of C-3 and C-15 in 1 and 2, C-3 and C-14 in 5 were established by NOE modified Marfey’s analysis and electronic circular dichroism (ECD) calculations. Particularly, the absolute configurations of C-19 in 1 and 3, which was very challenging to be identified due to the flexible conformation in a short aliphatic chain, were successfully determined by the vibrational circular dichroism (VCD) method, supplying with a reliable and optional method to define the absolute configurations. Additionally, this is the first report on oxepine-containing diketopiperazines from the genus Penicillium.

This work outlines a suitable method for the synthesis of oxepane skeleton using iterative C-glycoside technology on the oxepene intermediate, which was synthesized utilizing Wilkinson’s catalyst [Rh(PPh3)3Cl] to generate the isomerized product in a linear synthetic manner. The central core of the oxepene motif was achieved via an olefin metathesis reaction using the Grubbs second-generation and Schrock catalysts. The synthesis of the functionalized oxepane having the desired adriatoxin E-ring relative stereochemistry was achieved starting from commercially available homopropargylic alcohol.

FeCl₃ catalysed construction of 7 membered ring, oxepine and azepine derivatives by the reaction of 2,3-dichloro N-heterocycles with 2-(1H-indol-2-yl)phenol/aniline. Several of these compounds were found anti-proliferative properties against cancer cell lines.

An efficient access to cis-hydrobenzo[b]oxepine frameworks has been established through rhodium(I)-catalyzed cyclization of cyclohexadienone-tethered o-tolyl-substituted alkynes (1,6-enynes). The cascade process involves regioselective α-arylrhodation of the alkyne, 1,4-rhodium migration, and conjugate addition to cyclohexadienone.

The structure of the title compound, C38H28O, has previously been reported by Hirano, Toyota & Toda [Heterocycles (2004), 62, 749–756]. Since these authors did not publish any coordinates, we present here a redetermination of this structure using new intensity data. The molecule has chemical but not crystallographic C 2 symmetry. The central seven-membered ring adopts a twist-boat conformation.

The first total synthesis of (±)-janoxepin I, an antiplasmodial oxepine-pyrimidinone natural product isolated from the fungus Aspergillus janus is described herein. Chapter 1 provides an introduction to janoxepin I and related natural products that have been reported in the literature. In Chapter 2, the available methods for the synthesis of oxepines and pyrimidinones are reviewed, before the preparation of dihydro-oxepine VI from readily available starting materials II-V is described. The enamine side-chain seen in janoxepin I was introduced by way of aldol-addition to the ketopiperazine ring. The development of methodology to achieve this efficiently, and its application to the synthesis of dihydro-janoxepin VII is described in Chapter 3. The synthesis of janoxepin I was completed by way of a novel dihydro-oxepine elaboration to construct the oxepine ring. This transformation was the subject of much investigation as discussed in Chapter 4. The proposed biosynthesis of janoxepin I from pyrazino[2,1-b]quinazoline-3,6-dione VIII was identified as an alternative strategy for oxepine synthesis. Chapter 5 first briefly reviews pyrazino[2,1-b]quinazoline-3,6-dione-containing natural products and the available methods for their synthesis. It then describes the preparation of the putative biosynthetic precursor of janoxepin VIII with a view to further investigation of biomimetic methods for oxepine synthesis.

La synthèse biomimétique, inspirée par des voies de biosynthèse directes et rapides, est un moyen efficace pour produire des produits complexes. Le travail de cette thèse a porté sur le développement de stratégies collectives à partir d’intermédiaires biomimétiques pour accéder rapidement à trois familles de dikétopipérazines : les gliocladrides (DKPs fonctionnalisés), les quinazolino-DKPs et les oxépino-DKPs. Les fonctionnalisations oxydantes tardives par voies chimiques et biologiques des deux premiers intermédiaires ont été envisagées dans le but d’accéder directement au gliocladride A et aux oxépino-DKPs. Une fonctionnalisation oxydante régiosélective par la DDQ a pu être découverte et offre un accès à la synthèse totale des aurantiomides. Alternativement, pour synthétiser des oxépino-DKPs : une méthodologie de synthèse, via une réaction cascade de cyclopropanation/réarrangement oxa-Cope vers des 2,5-dihydrooxepines, a été développée. Cette méthode a bien été explorée par des études expérimentales et théoriques (DFT) et a été appliquée aux synthèses totales des radulanines. De plus, nous avons démontré que l’utilisation de cette stratégie était possible dans une synthèse totale à finaliser des produits naturels de type cinéreain<br>Biomimetic synthesis, inspired by direct and fast biosynthetic processes, is an efficient way to produce complex natural products. This thesis doctoral work focused on the development of collective strategies, from biomimetic intermediates, to get a quick access to three families of diketopiperazines: gliocladrides (functionalized DKPs), quinazolino-DKPs and oxepino-DKPs. The late-stage chemical oxidation reactions and microbial transformations on the two first intermediates were envisaged to synthesize gliocladrid A and oxepino-DKPs. A regioselective late-stage oxidation operated by DDQ was discovered, bringing new synthetic possibilities to make aurantiomides in a collective manner. An alternative methodology to synthesize oxepino-DKPs was investigated in the meantime. A temperature-controlled tandem cyclopropanation/oxa-Cope rearrangement was developed successfully to prepare 2,5-dihydrooxepines. This method was afterwards elucidated by experimental and computational (DFT) studies and further applied as the key step to finish the intractable total synthesis of radulanins. This oxa-Cope rearrangement approach also led to achieve the installation of 2,5-dihydrooxepine DKP, getting close to the accomplishment of the total synthesis of cinereain

Modified nucleosides form an important class of antiviral and anticancer agents, and nucleic acids bearing modified nucleosides hold great promise as therapeutic agents. Oxepane nucleosides and nucleic acids are members of this important class of compounds. Oxepane nucleosides have a seven-membered carbohydrate ring instead of the canonical five-membered pentafuranose ring. This thesis describes work in the development of new synthetic approaches and routes in the synthesis of oxepane nucleosides. In chapter 2, the synthesis of oxepane nucleosides based on the ring expansion approach is described. Building on previous work in the Damha lab, studies in the synthesis of oxepane nucleosides by a ring expansion approach were carried out. In particular, oxepane nucleosides were synthesized using thioglycoside derivatives. Routes in the modification of the oxepane scaffold were explored, but later abandoned in favor of new synthetic approaches to oxepane nucleosides. In chapter 3, work towards the development of new routes in the synthesis of oxepane nucleosides by ring-closing metathesis is described. This new approach to the synthesis of oxepane nucleosides allows for the use of commercially-available nucleosides and circumvents the difficulties observed in glycosylation reaction employed in the previous approach. In chapter 3, various synthetic routes are examined, and work towards the development of viable routes is described. In particular, the direct addition of Grigard reagents to nucleosides dialdehydes, followed by Grubbs II mediated ring closing metathesis serves as a proof-of-principle of the synthesis of oxepane nucleosides by a ring closing route.<br>Les nucléosides modifiés sont des agents thérapeutiques très efficaces contre le cancer et contre des virus. Les oxepanes font partie de ce groupe important. Au lieu d'avoir un cycle de 5 atomes, les oxepanes ont un cycle modifié de 7 atomes. Cette thèse décrit la recherche sur le développement de nouvelles méthodes pour la synthèse des oxepanes. Dans le deuxième chapitre, la synthèse des oxepanes par la méthode d'expansion de cycle est traitée. Notamment, la synthèse des oxepanes par le biais des hétérosides contenant des thiols est décrite. Dans le troisième chapitre, de nouvelles méthodes pour la synthèse des oxepanes sont étudiées. Toutes ces approches ont pour but ultime d'utiliser la métathèse d'alcènes comme l'étape clé. Notamment, l'addition directe des réactifs de Grignard à des nucléosides contenant deux aldéhydes, suivi d'une métathèse d'alcène, constitue une démonstration de faisabilité de cette approche synthétique.

In the present work, a complete study for the synthesis of 2-deoxy-glycosides is described, applying<br/>a strategy previously developed in our group for the preparation of 2-deoxy-2-iodo-pyranoses. This<br/>strategy, that involves Wittig¨CHorner olefination from fully protected furanoses to give alkenyl sulfides,<br/>electrophilic¨Cinduced cyclization to furnish 2-deoxy-2-iodo-pyranosyl thioglycosides, gives access to a<br/>new type of glycosyl donor that can be used in glycosylation reactions of the desired glycosyl acceptors to<br/>give 2-deoxy-2-iodo-glycosides.<br/>This method is based, on one hand, in the availability of sulfanylmethylphosphine oxides to perform<br/>the olefination reaction over the furanoses. The usual access to these reagents is the Arbuzov reaction,<br/>that requires chloro derivatives as starting materials that are not easy to prepare and in many cases are<br/>unstable. Furthermore, the efficiency of the cyclization is limited by the obtaintion of E/Z alkene mixtures<br/>in the olefination step, because Z alkenes were proved to be reluctant to cyclization.<br/>To increase the efficiency of the whole process, two implementations were studied in this work.<br/>First, a new approach for the preparation of sulfanylmethylphosphine oxides was investigated starting<br/>from (tosyloxymethyl)phosphine oxide. The method was also extended to heteroatomic substituted<br/>methylphosphine oxides (X, Se, Te, NR2, etc).<br/>Application of these novel sulfanylmethylphosphine oxides in the olefination of ribo- and<br/>arabinofuranoses resulted in the formation of the corresponding sulfanyl alkenes with increased E/Z<br/>stereoselectivity.<br/>The sulfanyl ribo and arabino alkenes were investigated in the iodonium¨Cinduced cyclization<br/>reaction. The effect of the bulkiness of the substituent at sulfur was studied and the results of cyclization<br/>compared to that of phenyl at the phenylsulfanyl parent compound. Cyclization of the arabino derivatives<br/>led to 6-endo cyclization products in lower yields whereas the t-butylsulfanyl arabino-1-hex-enitol<br/>proceeded in higher yield. No cyclization took place from 2,6-dimethylphenyl arabino-1-hex-enitol. The<br/>yields in al cases were higher from ribo-hex-enitols than from the corresponding arabino-hex-enitol.<br/>Glycosylation of some of the allopyranoside thioglycosides synthesized were explored and<br/>compared with those obtained from phenylsulfanyl parent thioglycoside. t-Butyl thioglycoside was<br/>reacted with cholesterol to render alloglycoside product as an anomeric mixture in higher yield without<br/>almost affecting the stereoselectivity whereas with 2,6-dimethylphenyl thioglycoside the stereoselectivity<br/>increased but the yield was lower.<br/>The synthesis of septanosides was studied starting from pyranosides with the strategy of Wittig¨C<br/>Horner olefination and subsequent electrophile¨Cinduced cyclization reaction, but the desired 7-endo<br/>cyclization did no work with secondary alcohols. To overcome this problem, starting from<br/>conformationally¨Crestricted 2,3-O-isopropylidenefuranosides, hex-1-enitols with a free primary hydroxyl<br/>function were prepared, from which 7-endo cyclization reaction took place to furnish the desired<br/>oxepanes with moderate yields.<br/>The total syntheses of 2,6-dideoxyoligosaccharides digitoxin and appetite suppressant P57, with<br/>common 2,6-dideoxypyranose units, were explored, applying the three-step (olefination¨Ccyclization¨C<br/>glycosylation) methodology. For the synthesis of common intermediate C, two different permanent<br/>protecting groups for free hydtoxyl group at C-3 were used: benzyl ethers for digitoxin and methyl ethers<br/>for P57. Different silyl groups (TBS, TES and TBDPS) were used for hydroxyl at C-4 that required<br/>temporary protection. Olefination of the different 6-deoxyribofuranoses rendered the corresponding 5-Osilyl<br/>hex-1-enitols (167, 169, and 173) as a consequence of silyl migration from hydroxyl at C-4 to C-5,<br/>altogether with the expected 4-O-silyl hex-1-enitols (164, 168, and 172). These products were analyzed<br/>by 1D and 2D NMR techniques.<br/>5-O-TES, 5-O-TBS or 5-O-TBDPS protected hex-1-enitols were submitted to iodonium¨Cinduced<br/>cyclization reactions to afford exclusively 5-endo cyclization products. Furthermore, 5-endo cyclization<br/>product 2-iodofuranose 189 was formed as a major product by cyclization from the C-4 unprotected enitol<br/>176.<br/>Digitoxin and P57 synthesis will be reconsidered in a near future using other protecting groups that<br/>do not migrate under the basic conditions of the olefination.<br>En este trabajo se describe un estudio completo para la s¨ªntesis de 2-desoxyglicosidos, aplicando la<br/>estrategia desarrollada anteriormente en nuestro grupo de investigaci¨®n para la preparaci¨®n de 2-desoxi-2-<br/>yodo-piranosidos. Este estrategia incluye la olefinaci¨®n de Wittig¨CHorner de furanosas protegidas<br/>completamente para obtener alquenil sulfidos, las ciclaciones inducidas electrofilicamente para conseguir<br/>2-desoxi-2-yodo-piranisil tioglicosidos y permite el acceso a nuevo tipos de glicosil donores que pueden<br/>ser utilizados en glicosilaci¨®n reacciones con aceptores deseados para suministrar 2-desoxi-2-yodoglicosidos.<br/>Esto m¨¦todo se basa, por un lado, en la disponibilidad de sulfanilmetil oxido fosfinas para llevar a<br/>cabo la reacci¨®n de olefinaci¨®n empezando por furanosas. La preparaci¨®n corriente de estos reactivos es a<br/>trav¨¦s de la reacci¨®n de Arbuzov, que requiere derivados cloratos para materiales de partida cuya<br/>obtenci¨®n, en muchas ocasiones, es complicada o no son estables en condiciones est¨¢ndar. Adem¨¢s, la<br/>eficacia de la ciclaci¨®n est¨¢ limitada a la obtenci¨®n de una mezcla de alquenes en una mezcla de E/Z en la<br/>etapa de olefinaci¨®n, porque los Z alquenos resultan de ciclar m¨¢s lento o no ciclan.<br/>Para mejorar la eficacia de todo el proceso se ha investigado el desarrollo para la obtenci¨®n de<br/>sulfanilmetil oxido fosfinas a partir de tosiloximetil oxido fosfina. Este m¨¦todo se podr¨ªa ampliar para la<br/>s¨ªntesis de otras metil oxido fosfinas ¦Á-sustituidas por heteroatomo (X, Se, Te, NR2, etc).<br/>De la aplicaci¨®n de estas nuevas sulfanilmetil oxido fosfinas en reacciones de olefinaci¨®n con riboy<br/>arabinofuranosas result¨® la formaci¨®n de las sulfanil alquenos correspondientes de estereoselectividad<br/>mejorada con una relaci¨®n de E/Z m¨¢s alta.<br/>Los sulfanil alquenos con configuraciones ribo y arabino se investigaron en reacciones de ciclaci¨®n<br/>inducida electrof¨ªlicamente. Se estudi¨® el efecto de voluminosidad del sustituyente en el azufre y los<br/>resultados de las ciclaciones se compararon con el resultado obtenido del fenil sustituyente en el fenil<br/>sulfanil an¨¢logo. La ciclaci¨®n de alqueno con la configuraci¨®n arabino condujo al producto 6-endo<br/>ciclado con menor rendimiento, mientras que con el t-butilsulfanil arabino-1-hex-enitol se consigui¨®<br/>mejorar el rendimiento. El derivado 2,6-dimetilfenil arabino-1-hex-enitol no particip¨® en ciclaci¨®n.<br/>Se ha explorado la glicosilaci¨®n de unos de los tioglicosidos sintetizados y se ha comprobado con lo<br/>obtenido de la tioglicosido piloto con grupo fenil. El tioglicosido con grupo t-butil ha reaccionado con<br/>colesterol para dar el producto glicosilado con mayor rendimiento y selectividad casi inalterada, mientras<br/>con 2,6-dimethilphenil tioglicosido la estereoselectividad ha aumentado pero con menor rendimiento.<br/>Se ha estudiado la s¨ªntesis de los septanosidos empezando por los piranosidos y furanosidos con la<br/>estrategia de olefinaci¨®n de Wittig¨CHorner y posteriormente ciclaci¨®n inducida electrofilicamente pero el<br/>deseado 7-endo ciclaci¨®n no se di¨® con alcoholes secundarios. Para solucionar el problema se decidi¨®<br/>aplicar 2,3-O-isopropilidenefuranosidos con conformaci¨®n restringida como material de partida,<br/>obteniendo hex-1-enitols con alcoholes primarios libres, que se utiliz¨® en 7-endo ciclaci¨®n para dar los<br/>oxepanes deseados con rendimientos moderados.<br/>Se han explorado las s¨ªntesis totales de 2,6-didesoxioligosaccaridos, de la digitoxina y el supresor<br/>del apetito P57, con 2,6-didesoxipiranosa como unidad estructural com¨²n aplicando la metodolog¨ªa de<br/>tres etapas (olefinaci¨®n¨Cciclaci¨®n¨Cglicosilaci¨®n). Para la s¨ªntesis del intermediario com¨²n C, se utilizaron<br/>dos grupos protectores permanentes diferentes en el grupo hidroxil en la posici¨®n C-3: bencil eteres para<br/>la s¨ªntesis de la digitoxina y metil eteres para la de P57. Se estudi¨® la aplicaci¨®n de diversos grupos sililes<br/>(TBS, TES y TBDPS) para la protecci¨®n del grupo hidroxil en la posici¨®n C-4, que requiere un grupo<br/>protector temporal. La olefinaci¨®n de los diferentes 6-desoxiribofuranosas ha dado los 5-O-silil hex-1-<br/>enitoles correspondientes (167, 169, y 173) como consecuencia de la migraci¨®n del grupo silil, desde el<br/>grupo hidroxil C-4 hasta el C-5, conjuntamente con el deseado 4-O-silil hex-1-enitoles (164, 168, y 172).<br/>Se ha analizado y se ha confirmado la estructura de todos estos productos con t¨¦cnicas de 1D y 2D NMR.<br/>Se ha estudiado la ciclaci¨®n de hex-1-enitoles con grupos protectores como 5-O-TES, 5-O-TBS o 5-<br/>O-TBDPS y de estas reacciones inducidas con yodo se ha obtenido exclusivamente productos de 5-endo<br/>ciclos. Adem¨¢s, se ha obtenido como producto mayoritario el producto de 5-endo ciclo 189 con la<br/>ciclaci¨®n de enitol no protegido en posici¨®n C-4 176.<br/>Se reconsidera la s¨ªntesis total de la digitoxina y la P57 en un futuro cercano aplicando otros grupos<br/>protectores que no participan en reacciones de migraci¨®n bajo las condiciones b¨¢sicas de la olefinaci¨®n.

SCH-64874 (5) is a fungal metabolite that inhibits the epidermal growth factor receptor (EGFR), a high-profile oncology target, with an IC50 of 1.0µg/mL. It is of particular interest because it is unlikely to inhibit the protein’s intramolecular kinase domain (as typical chemical EGFR inhibitors do), and may act instead by obstructing the receptor’s ligand binding and/or dimerisation processes.<br>In this work, the epipolythiodiketopiperazine family of natural products is reviewed, leading to a discussion of the probable biosynthetic pathways by which these complex molecules are produced in nature. A laboratory synthesis based on this proposed biosynthesis was subsequently proposed and undertaken.<br>The oxidation of aromatic systems was investigated, which led to the synthesis, for the first time, of complex functionalised arene oxides such as 178. The regioselective epoxidation of 178 was accessed by derivatisation as the Diels-Alder adduct 180. Subsequent epoxidation and manipulation led to the amino alcohol 195b, possessing the exo-epoxide endo-alcohol stereochemistry shown.<br>This stereochemical assignment was based on detailed NMR analysis of the product, and also on AM1 semi-empirical molecular modelling and Ab initio molecular orbital calculations, which were used to evaluate the relative stabilities of the cyclisation products.