Oxepane Ring Research Articles

Synthesis of Oxepane Ring Containing Monocyclic, Conformationally Restricted Bicyclic and Spirocyclic Nucleosides from d-Glucose: A Cycloaddition Approach

Carbohydrate-derived substrates having (i) C-5 nitrone and C-3-O-allyl, (ii) C-4 vinyl and a C-3-O-tethered nitrone, and (iii) C-5 nitrone and C-4-allyloxymethyl generated tetracyclic isoxazolidinooxepane/-pyran ring systems upon intramolecular nitrone cycloaddition reactions. Deprotection of the 1,2-acetonides of these derivatives followed by introduction of uracil base via Vorbrüggen reaction condition and cleavage of the isooxazolidine rings as well as of benzyl groups by transfer hydrogenolysis yielded an oxepane ring containing bicyclic and spirocyclic nucleosides. The corresponding oxepane based nucleoside analogues were prepared by cleavage of isoxazolidine and furanose rings, coupling of the generated amino functionalities with 5-amino-4,6-dichloropyrimidine, cyclization to purine rings, and finally aminolysis.

Intramolecular 1,3‐Dipolar Nitrone and Nitrile Oxide Cycloaddition of 2‐ and 4‐O‐Allyl and Propargyl Glucose Derivatives: A Versatile Approach to Chiral Cyclic Ether Fused Isoxazolidines, Isoxazolines and Isoxazoles.

Abstract 2- O - and 4- O -Allyl and -propargyl glucose and the corresponding oxime derivatives were prepared from readily available glucose dithioacetals. Intramolecular 1,3-dipolar cycloaddition of the N -benzyl and N -methyl nitrones of the above acyclic 2- O -allyl glucose derivatives led to the diastereoselective formation of chiral isoxazolidines incorporating the tetrahydrofuran ring. The EI mass spectra revealed a characteristic cleavage of the C-alkyl group adjacent to the furan oxygen atom. An enantiopure trisubstituted tetrahydrofuran was obtained by the reductive cleavage of the isoxazolidine ring of one of the cycloadducts. In contrast, the nitrile oxide cycloaddition of the 2- O -allyl derivatives afforded diastereomeric mixtures of the corresponding dihydroisoxazolines, the stereochemistry of which was tentatively assigned on the basis of the principle of optical superposition. The exclusive formation of a tetrahydrofuran ring from pentaallyl nitrone or nitrile oxide demonstrated the preferred formation of a five-membered ring to that of six or seven-membered rings. The nitrile oxide generated from a 3,4,5,6,7-pentaallyloxy-1-nitroheptane derivative obtained from pentaallylglucose underwent diastereoselective cycloaddition to give an isoxazoline fused to a pyran ring. Enantiopure isoxazoles containing tetrahydrofuran and oxepane rings were also prepared in good yields by the nitrile oxide cycloaddition of the 2- O - and 4- O -propargyl derivatives.

Intramolecular 1,3-dipolar nitrone and nitrile oxide cycloaddition of 2- and 4- O-allyl and propargyl glucose derivatives: a versatile approach to chiral cyclic ether fused isoxazolidines, isoxazolines and isoxazoles

2- O- and 4- O-Allyl and -propargyl glucose and the corresponding oxime derivatives were prepared from readily available glucose dithioacetals. Intramolecular 1,3-dipolar cycloaddition of the N-benzyl and N-methyl nitrones of the above acyclic 2- O-allyl glucose derivatives led to the diastereoselective formation of chiral isoxazolidines incorporating the tetrahydrofuran ring. The EI mass spectra revealed a characteristic cleavage of the C-alkyl group adjacent to the furan oxygen atom. An enantiopure trisubstituted tetrahydrofuran was obtained by the reductive cleavage of the isoxazolidine ring of one of the cycloadducts. In contrast, the nitrile oxide cycloaddition of the 2- O-allyl derivatives afforded diastereomeric mixtures of the corresponding dihydroisoxazolines, the stereochemistry of which was tentatively assigned on the basis of the principle of optical superposition. The exclusive formation of a tetrahydrofuran ring from pentaallyl nitrone or nitrile oxide demonstrated the preferred formation of a five-membered ring to that of six or seven-membered rings. The nitrile oxide generated from a 3,4,5,6,7-pentaallyloxy-1-nitroheptane derivative obtained from pentaallylglucose underwent diastereoselective cycloaddition to give an isoxazoline fused to a pyran ring. Enantiopure isoxazoles containing tetrahydrofuran and oxepane rings were also prepared in good yields by the nitrile oxide cycloaddition of the 2- O- and 4- O-propargyl derivatives.

Total synthesis of natural (+)-(2's,3'r)-zoapatanol.

[reaction: see text] (+)-Zoapatanol was synthesized by using four key-steps: a Suzuki cross-coupling to prepare a (Z)-alpha,beta-unsaturated ester followed by an enantioselective dihydroxylation to control the C2' and C3' stereocenters, an intramolecular Horner-Wadsworth-Emmons olefination to construct the oxepane ring, and a chemoselective nucleophilic addition/Birch reduction process of a Weinreb amide to introduce simultaneously the beta,gamma-unsaturated ketone on the side-chain and regenerate alcohols from benzyl ethers.

Enantioselective Total Synthesis of Briarellins E and F: The First Total Syntheses of Briarellin Diterpenes

Enantioselective total syntheses of briarellin E (4) and briarellin F (5) have been achieved starting with (S)-(+)-carvone and (S)-(-)-glycidol. These total syntheses are the first of briarellin diterpenes. The central step in these syntheses is acid-promoted condensation of cyclohexadienyl diol 15 and (Z)-alpha,beta-unsaturated aldehyde 16 to form, with complete stereocontrol, the hexahydroisobenzofuran core and six stereocenters of these coral metabolites. These syntheses also feature stereospecific photolytic deformylation of beta,gamma-unsaturated aldehyde 17 to remove the extraneous carbon introduced in the Prins-pinacol step, chemo- and stereoselective hydroxyl-directed epoxidation of dienyl alcohol 18 to incorporate the C3 oxygen stereocenter, regio- and stereoselective rearrangement of epoxy ester 19 to install the C4 oxygen substituent, efficient dehydrative cyclization of a 1,6-diol intermediate to form the oxepane ring, and diastereoselective Nozaki-Hiyama-Kishi cyclization of vinyl iodide aldehyde 25 to forge the oxacyclononane ring and the C6 hydroxyl stereocenter. These total syntheses establish the absolute configurations of 4 and 5, define a concise strategy for the total synthesis of briarellin diterpenes, and provide additional illustrations of the uncommon utility of pinacol-terminated cationic cyclizations for stereocontrolled synthesis of complex oxacyclic natural products.

Intramolecular radical cyclization-ring-closing metathesis approach to fused polycyclic ethers. Convergent synthesis and conformational analysis of the (E)FGH ring system of ciguatoxin.

A convergent synthetic route to the (E)FGH ring system 4 of ciguatoxins, the causative toxins for ciguatera fish poisoning, has been developed. The synthesis features convergent coupling to form dioxane acetal, regioselective acetal cleavage by diethylaluminum phenylthiolate or diisobutylaluminum phenylselenolate followed by intramolecular radical cyclization to construct the oxepane ring G, and a ring-closing metathesis reaction to form the hexahydrooxonine ring F. The hexahydrooxonine ring F of tetracyclic model system 4 existed as a 5:1 equilibrium mixture of two conformers (UP and DOWN conformers), with the UP one predominating. This is the first illustration that reproduces the preference for the UP conformer over the DOWN one, which preference was observed for natural ciguatoxins.

Efficient strategy for the iterative synthesis of trans-fused polycyclic ether via SmI 2-induced reductive intramolecular cyclization

A highly efficient strategy for the iterative synthesis of a trans-fused polycyclic ether ring system has been developed. The new iterative method involves SmI 2-induced reductive intramolecular cyclization of an aldehyde and a β-alkoxy acrylate as the key step, producing a 2,3- trans-tetrahydropyran or oxepane ring. The syntheses of trans-fused 6,6,6-tricyclic, 6,7,6-tricyclic, and 6,7,7,6-tetracyclic ethers were effectively achieved based on the newly developed method.

Hypertricone, a Constituent with a Novel Skeleton, Isolated fromHypericum geminiflorum

A novel compound containing an oxepane ring, hypertricone (1), was isolated from the leaves of Hypericum geminiflorum. Its structure, including the relative configuration, was elucidated from spectroscopic data and a computer-generated plot for the 3D structure.

Stereocontrolled Synthesis of the JKLM Ring Fragment of Ciguatoxin

A highly stereocontrolled synthesis of the JKLM ring fragment of ciguatoxin has been achieved. The present synthesis starts with methyl 4,6-O-benzylidene-2-deoxy-2-C-methyl-α-d-altropyranoside, whose configurations and substituents at C2−C5 correspond to those at C46−C49 of ciguatoxin, and involves as the key step base-induced 7-endo selective cyclization of a hydroxy epoxide for the efficient construction of the fully substituted oxepane ring K. Construction of the spiroether ring M was achieved by introduction of an allyl group to the ring L lactone followed by asymmetric dihydroxylation to install the C54 stereogenic center and acid-induced spiroketalization to furnish the protected KLM ring system. Finally, ring J was constructed by the method of Nicolaou to complete the synthesis of the JKLM ring fragment. The synthesis of a carboxylic acid derivative and its conjugation to carrier proteins to give an artificial antigen for development of an immunoassay system for the parent toxin molecule are also r...

Synthesis of the FGH ring fragment of ciguatoxin

Stereoselective synthesis of the FGH ring fragment of ciguatoxin is described. The key steps in the present synthesis are an intramolecular radical cyclization to construct oxepane ring G and ring-closing metathesis reaction to construct hexahydrooxonin ring F.

Formal Total Synthesis of Hemibrevetoxin B by an Oxiranyl Anion Strategy.

The synthesis of the tetracyclic structure of hemibrevetoxin B (1) was achieved through a linear approach involving sequential coupling of three kinds of sulfonyl-stabilized oxiranyl anions, 5b, 6b, and 7b, to the monocyclic tetrahydropyran 4 containing the requisite substituents. Two iterations of alkylation of an oxiranyl anion and 6-endo cyclization provided the 6,6,6-tricyclic ring system 34, which was efficiently transformed into the 6,6,7-ring system 35 by ring expansion using trimethylsilyldiazomethane. Installation of the final oxepane ring into 38 was carried out using a combination of the oxiranyl anion methodology and ring enlargement just described. Stereoselective introduction of a tertiary methyl group into 41 provided the tetracyclic compound 42a, which contains all the asymmetric centers of 1. Elaboration of 42a to the known compound 2, which was already transformed into hemibrevetoxin B, completed the formal total synthesis of the natural product.

ChemInform Abstract: Convergent and Stereoselective Method for Synthesis of O‐Linked Oxepane Ring System by Intramolecular Radical Cyclization.

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Convergent and stereoselective method for synthesis of O -linked oxepane ring system by intramolecular radical cyclization

A new strategy for the construction of O -linked oxepane ring system is described. The present method involves regioselective acetal cleavage by i -Bu 2 AlSePh and intramolecular radical cyclization by use of β-alkoxyacrylate. Graphic

Three 2,5-Disubstituted 9-Oxabicyclo[4.2.1]nonanes. Transannular O-Heterocyclization Products of Cycloocta-1,5-diene

The crystal structures of endo, endo-2,5-dibromo-9-oxabicyclo­[4.2.1]nonane, (I), C8H12Br2O, endo, endo-2,5-bis(phenylthio)-9-oxabicyclo[4.2.1]nonane, (II), C20H22OS2, and 9,10-dioxatricyclo[4.2.1.12,5]decane, (III), C8H12O2, were determined and the conformations of these transannular O-heterocyclization products of cycloocta-1,5-diene were defined. The structure determinations reveal a tetrahydrofuran ring having an envelope conformation and an oxepane ring with a twisted chair-conformation in each of (I) and (II), with the two bulky substituents quasi-equatorial or quasi-axial, respectively, both in a trans-position in relation to the ring O atom. The tricyclic compound (III) consists of two five-membered envelopes and a 1,4-dioxane chair. The cylooctane moiety has a twisted chair-conformation in both (I) and (II), whereas it is a chair in (III).

Synthetic studies on zoapatanol: Construction of oxepanes via an intramolecular 1,3-dipolar cycloaddition strategy

Abstract The nitrones derived from β-allyloxyaldehydes with a β-quaternary centre cyclized to give six- instead of seven-membered O -heterocycles exclusively whereas a nitrile oxide derived from a γ-allyloxyaldehyde with a γ-quaternary center cyclized to yield an oxepane ring as the sole product. Using the latter intramolecular nitrile oxide cycloaddition as the key step, optically active oxepane 5 , which is a suitable intermediate for a synthesis of zoapatanol 1 , has been constructed from d -glucose.

Total Synthesis of Brevetoxin B. 1. First Generation Strategies and New Approaches to Oxepane Systems

The fust generation strategies toward the total synthesis of brevetoxin B (1) are presented and the syntheses of the key intermediates 3, 4, 5, 67, 83, and 94-98 required for the projected construction are described. The earliest and most convergent strategy required the application of the hydroxy epoxide cyclization and the intramolecular conjugate addition as key reactions for the construction of the fused tetrahydropyran ring systems (4) [ABC], (7) [FG], and (8) [UK]. The oxocene ring (H) was formed via a Wittig reaction followed by a hydroxy dithioketal cyclization to produce the hexacyclic fragment [FGHIJK] (6 5). The 12-membered dithionolactone 18 was envisioned as the precursor of the dioxepane system of the molecule via a projected bridging reaction, to construct simultaneously both oxepane rings. However, the dithionation of dilactone 17 proved unsuccessful. In a subsequently evolved strategy, a new photolytic approach toward the dioxepane region was developed, starting from the acyclic dithiono progenitor 20 (20 23). Application of this reaction to the brevetoxin B skeleton afforded the desired oxepene (96 97), which after deprotection produced oxepanone 98. A specifically designed reductive hydroxy ketone cyclization (98 99) was then employed in an attempt to close the remaining ring [E], but, again, without success. The novel rearrangement of hydroxy ketone 87 to the pentacyclic system 89 was observed in a less elaborate skeleton. The scope and generality of these silicon-induced reductive cyclizations are also described.

Synthetic Studies toward Ciguatoxin. Stereocontrolled Construction of the KLM Ring Fragment

The first stereoselective synthesis of the KLM ring fragment of ciguatoxin is reported including as a key step 7-endo selective cyclization of epoxy alcohol to construct a fully substituted oxepane ring (12→13)

Total synthesis of hemibrevetoxin B and (7a.alpha.)-epi-hemibrevetoxin B

The total synthesis of hemibrevetoxin B (1) and (7aα)-epi-hemibrevetoxin B (2) is described. The synthesis of the epimer (2) was achieved through a convergent approach involving coupling of the carboxylic acid 17 carrying the bicyclic pyran system with the hydroxy compound 31 containing the monocyclic pyran system, thionation of the resulting diester 32 to the dithionoester 33, photolytic closure to the oxepane enol ether 34, and hydroxy ketone cyclization to the dioxepane system 40. The Z-diene system was established using a selenyl-Wittig reaction followed by syn elimination of the selenoxide to the diene. The α-vinyl functionality was installed using the Eschenmoser's salt methodology. The synthesis of hemibrevetoxin B (1) was achieved through a linear approach involving sequential formation of the oxepane rings (65 → 67 → 73) using the method of thionolactone formation followed by nucleophilic addition and regio/stereoselective hydroboration (67 → 68, 75 → 76). Elaboration of the side chains was carried out in a similar fashion as described for the epimer. The streochemistry of the ring junctures in 1 and 2 and intermediates leading to them was established by X-ray cristallographic analysis carried out on compounds 45 and 54

Model Studies Directed Towards Microalga Polyether Toxins

AbstractIn view of the described results in acid‐induced polyepoxide cyclizations, the biosynthesis of fused polyether toxins may be better explained by a stepwise mechanism through oxonium ion intermediates acting on the enzyme‐bonded polyepoxide precursor. A new synthetic strategy for the regio‐ and stereospecific synthesis of heterosubstituted oxolane and oxane rings involving intramolecular iodoetherification of 2,3‐epoxy‐cycloalken‐1‐ols was studied. Cyclization/solvolysis of 2,3‐epoxy‐cycloalk‐5‐en‐1‐ols proceed with complete regio‐ and stereoselectivity to yield cis‐2,6‐dialkyl‐3,5‐oxygenated oxane rings and thus assemble in two steps the key structural units present in marine syn‐trans fused polyether toxins. A highly efficient cyclization reaction of 2,3‐epoxycyclonon‐6‐en‐1‐one leading to the oxepane system is described. The silver(I)‐induced solvolysis occurs in high yield under mild conditions and the resulting cyclic system may be manipulated via oxidative carbon‐carbon bond cleavage leading to a functionalized α, α′‐dialkyl β,β′‐oxygenated oxepane ring with defined cis‐syn‐cis stereochemistry.

A synthetic approach to zoapatanol and related bicyclic analogues

A Ni0-catalysed coupling of MeMgBr with dihydrofuran (4) and addition of Grignard reagent (7) to a butyne-1,4-diol derivative (8) were key steps in the highly stereoselective construction of the trisubstituted double bonds in (10) which is a precursor to the oxepane ring system (12) of zoapatanol (1); subsequent elaboration of (12) gave (1R*,4S*,5R*)-4-[5-oxo-8-methylnon-7-enyl]-3,8-dioxabicyclo[3.2.1]octane-1-acetic acid (18), a demethyl analogue of the potent antigestational agent ORF 13811 (2).