Different reaction modes for the oxidative dimerization of epoxyquinols and epoxyquinones. Importance of intermolecular hydrogen-bonding

An oxidative dimerization reaction, involving the three successive steps of oxidation, 6 pi-electrocyclization, and Diels-Alder reaction, has been experimentally and theoretically investigated for the three 2-alkenyl-3-hydroxymethyl-2-cyclohexen-1-one derivatives epoxyquinol 3, epoxyquinone 6, and cyclohexenone 10. Of the sixteen possible modes of the oxidation/6 pi-electrocylization/Diels-Alder reaction cascade for the epoxyquinone 6, and eight for the cyclohexenone 10, only the endo-anti(epoxide)-anti(Me)-hetero and endo-anti(Me)-hetero modes are, respectively, observed, while both endo-anti(epoxide)-anti(Me)-hetero and exo-anti(epoxide)-anti(Me)-homo reaction modes occur with the epoxyquinol 3. Intermolecular hydrogen-bonding is found to be the key cause of formation of both epoxyquinols A and B with 3, although epoxyquinone 6 and cyclohexenone 10 both gave selectively only the epoxyquinol A-type product. In the dimerization of epoxyquinol 3, two monomer 2H-pyrans 5 interact with each other to afford intermediate complex 28 or 29 stabilized by hydrogen-bonding, from which Diels-Alder reaction proceeds. Theoretical calculations have also revealed the differences in the reaction profiles of epoxyquinone 6 and cyclohexenone 10. Namely, the rate-determining step of the former is the Diels-Alder reaction, while that of the latter is the 6 pi-electrocyclization.     

Enantioselective total synthesis of antiangeogenic pentaketide dimers, epoxyquinols A and B, through an asymmetric aldol approach to their common monomeric precursor

A new enantioselective total synthesis of epoxyquinols A and B possessing unique pentaketide dimeric structures and potent antiangeogenic activity was achieved by oxidative dimerization of a monomeric pentaketide precursor obtained by the Evans asymmetric aldol reaction and a series of operationally simple transformations.     

Total synthesis of the novel, biologically active epoxyquinone dimer (+/-)-torreyanic acid: a biomimetic approach

[reaction: see text] A total synthesis of the complex, biologically active, dimeric natural product (+/-)-torreyanic acid, which is composed of seven rings and laced with dense, variegated oxy-functionalization, has been accomplished from readily available allyl-substituted p-benzoquinone 8. Our synthetic stratagem involves crafting an epoxyquinone monomer for use in a biomimetic cascade process involving tandem a 6pi electrocyclization and a Diels-Alder dimerization.     

Novel synthesis of the ocular age pigment A2-E: new method for substituted pyridine synthesis via azaelectrocyclization

[reaction: see text] The formal synthesis of the ocular age pigment A2-E was achieved by the efficient one-pot preparation of the substituted pyridine, which involves the aza-6pi-electrocyclization of the Schiff base derived from (E)-3-carbonyl-2,4,6-trienal followed by oxidation.     

Synthesis of epoxyquinol A and related molecules: probing chemical reactivity of epoxyquinol dimers and 2H-pyran precursors

Total syntheses of the epoxyquinoid dimers, epoxyquinols A, B, and epoxytwinol A (RKB-3564 D), have been accomplished employing [4 + 2] and [4 + 4] dimerization of 2H-pyran epoxyquinol monomers. Modifications of 2H-pyran precursors have been explored, including alteration of epoxy alcohol and diene stereochemistry. A stable 2H-pyran prepared by alteration of the epoxyquinol 2H-pyran nucleus was evaluated as a diene in Diels-Alder cycloaddition with reactive dienophiles. Extensive studies for improving the [4 + 4] dimerization of selectively protected 2H-pyran monomers to afford the novel epoxyquinoid dimer epoxytwinol A were carried out, and valuable insight regarding competitive [4 + 2] and [4 + 4] dimerization processes has been obtained. In addition, chemical reactivities and structural modifications of epoxyquinol dimers have been evaluated, including [2 + 2] photocycloaddition and [3,3] sigmatropic rearrangement, indicating the possibility for production of novel structural diversity from dimeric epoxyquinoid natural product frameworks.     

Total synthesis of the novel angiogenesis inhibitors epoxyquinols A and B

The synthesis of the recently discovered angiogenesis inhibitors epoxyquinols A and B, having novel polyketide derived dimeric structures, has been accomplished from the readily available Diels-Alder adduct of cyclopentadiene and p-benzoquinone through a short, simple and flexible strategy that is diversity oriented and can be adapted to an asymmetric variant.     

Enantioselective total synthesis of (−)-epoxyquinols A and B. Novel, convenient access to chiral epoxyquinone building blocks through enzymatic desymmetrization

Following our recent total synthesis of the biologically potent natural products epoxyquinols A and B in racemic form, we have now accomplished the total synthesis of the (−)-epoxyquinols A and B, anti-podes of the angiogenesis inhibiting natural products, through a protocol that involves enzymatic desymmetrization of a versatile epoxyquinone derivative, readily available from the Diels-Alder adduct of cyclopentadiene and p-benzoquinone.     

Rapid biomimetic total synthesis of (±)-rossinone B

A biomimetic total synthesis of (±)-rossinone B has been achieved through a highly efficient strategy featuring a series of rationally designed reactions, including a one-pot allylic rearrangement/oxidation reaction to generate the vinyl quinone 27, an intramolecular vinyl quinone Diels-Alder reaction to construct the linear 6-6-5 tricyclic core of 28, and a double conjugate addition/β-elimination cascade to complete the total synthesis of 1.     

Poly-2-vinylfuran,synthesis, characterization,and diels-alder reaction with maleic anhydride

Poly-2-vinylfuran, synthesized by free-radical polymerization of 2-vinylfuran, was characterized by nuclear magnetic resonance (NMR) and infrared (IR) spectroscopy. The pendant furan rings on the polymer backbone were then used as the diene component of a Diels-Alder reaction with maleic anhydride. The juxtaposition of the furan rings at first suggested an “avalanche” Diels-Alder reaction, in which the product of one cyclization would be the reactant of the next. A lack of polymer stereoregularity and the reversibility of the Diels-Alder reaction, however, prevented its formation. On the other hand, when the dienophile was used in a 1:1 molar ratio with respect to furan the smooth reaction produced a new polymer, the maleic anhydride adduct of poly-2-vinylfuran, which characterized by NMR and IR spectroscopy, was air stable and soluble in a number of solvents up to 70% transformation. When heated to 160°C the polymer reverted to maleic anhydride and somewhat decomposed poly-2-vinylfuran.     

Stereoselective total synthesis of ent-EI-1941-2 and Epi-ent-EI-1941-2

The first asymmetric total syntheses of ent-EI-1941-2 and epi-ent-EI-1941-2 have been accomplished, starting from a chiral epoxy iodoquinone 6, a key intermediate in our total syntheses of epoxyquinols A and B. A key step in the preparation of ent-EI-1941-2 is an intramolecular carboxypalladation via a 6-endo cyclization mode, followed by beta-hydride elimination, while carboxymercuration is a key step in the synthesis of epi-ent-EI-1941-2. [reaction: see text]     

Approach to the synthesis of homoinositols,a new class of <Emphasis Type="Italic">myo</Emphasis>-inositol monophosphatase inhibitors

A new class of structural analogues of inositol (polyhydroxycycloheptanes, homoinositols) is proposed. 2,3,4,4-Tetrachloro-8-octabicyclo[3.2.1]octadiene-2,6, the adduct of the Diels-Alder reaction between tetracyclopropene and furan, is suggested as the key compound in homoinositol synthesis. Its modification leads to the selective preparation of homoinositol stereomers and derivatives.     

Total synthesis of spirotenuipesines A and B

Spirotenuipesines A and B, isolated from the entomopathogenic fungus Paecilomyces tenuipes by Oshima and co-workers, have been synthesized. The synthesis features the highly stereoselective construction of two vicinal all-carbon quaternary centers (C(5) and C(6)) via an intramolecular cyclopropanation/radical initiated fragmentation sequence and a diastereoselective intermolecular Diels-Alder reaction between alpha-methylenelactone dienophile 20 and synergistic diene 6a. Installation of the C(9) tertiary alcohol occurred via nucleophilic methylation. An RCM reaction to produce a tetrasubstituted double bond in the presence of free allylic alcohol and homoallylic oxygenated functional group is also described. This route shortened the synthesis of 11 from 9 steps to 3 steps. We have further developed a strategy to gain access to optically active spirotenuipesines A and B through the synthesis of enantioenriched 10 from commercially available R-(-)-epichlorohydrin.     

Total synthesis of (-)-fusarisetin A and reassignment of the absolute configuration of its natural counterpart

The first total synthesis of (-)-fusarisetin A, the enantiomer of naturally occurring acinar morphogenesis inhibitor (+)-fusarisetin A, was accomplished in 13 steps, leading to the reassignment of the absolute configuration of the natural product. The synthesis featured a Lewis acid-promoted intramolecular Diels-Alder reaction, a Pd-catalyzed O→C allylic rearrangement, a chemoselective Wacker oxidation, and a Dieckmann condensation/hemiketalization cascade.     

High-pressure mediated Diels-Alder reaction of di-l-menthyl acetoxy-methylenemalonate with furan: Enantioselective synthesis of β-D-ribofuranosylmalonate,a prospective synthon for C-nucleoside

β-D-Ribofuranosylmalonate [D]-4 has been synthesized through high-pressure Diels-Alder reaction of furan with di-l-menthyl acetoxymethylenemalonate (1b), followed by reductive retrograde aldol CC bond fission. A mechanism accounting for the observed diastereoselectivity in the Diels-Alder reaction is proposed.     

A formal total synthesis of dysidiolide

[structure] A formal total synthesis of the natural product dysidiolide is described. Starting from a Diels-Alder reaction between an enoate and a Rawal diene, the cyclohexenone 4 was synthesized. A subsequent stereospecific methyl cuprate addition established the desired trans configuration in the cyclohexane 3. Wacker oxidation of the pentenyl side chain to the diketone 17 followed by an intramolecular aldol condensation led to the bicyclic enone 2, a key intermediate in a recently reported synthesis of dysidiolide.     

Multicomponent coupling approach to (+/-)-frondosin B and a ring-expanded analogue

[reaction: see text] A recently discovered multicomponent coupling reaction is used to give direct access to a late intermediate in the synthesis of frondosin B. This intermediate can also be efficiently converted to a ring-expanded analogue of frondosin B by sustained heating of the reaction mixture. An unprecedented tandem 1,7-hydrogen shift, 8pi-electrocyclization is proposed to explain the formation of this ring-expanded species.     

Mechanistic twist of the [8+2] cycloadditions of dienylisobenzofurans and dimethyl acetylenedicarboxylate: stepwise [8+2] versus [4+2]/[1,5]-vinyl shift mechanisms revealed through a theoretical and experimental study

Recently, it was reported that both dienylfurans and dienylisobenzofurans could react with dimethyl acetylenedicarboxylate (DMAD) to give [8+2] cycloadducts. Understanding these [8+2] reactions will aid the design of additional [8+2] reactions, which have the potential for the synthesis of 10-membered and larger carbocycles. The present Article is aimed to understand the detailed mechanisms of the originally reported [8+2] cycloaddition reaction between dienylisobenzofurans and alkynes at the molecular level through the joint forces of computation and experiment. Density functional theory calculations at the (U)B3LYP/6-31+G(d) level suggest that the concerted [8+2] pathway between dienylisobenzofurans and alkynes is not favored. A stepwise reaction pathway involving formation of a zwitterionic intermediate for the [8+2] reactions between dienylisobenzofurans that contain electron-donating methoxy groups present in their diene moieties and DMAD has been predicted computationally. This pathway is in competition with a Diels-Alder [4+2] reaction between the furan moieties of dienylisobenzofurans and DMAD. When there is no electron-donating group present in the diene moieties of dienylisobenzofurans, the [8+2] reaction occurs through an alternative mechanism involving a [4+2] reaction between the furan moiety of the tetraene and DMAD, followed by a [1,5]-vinyl shift. This computationally predicted novel mechanism was supported experimentally.     

Synthesis of functionalized allylic sulfoxides and their use in the construction of 2,3,4-trisubstituted furans via a [3 + 2] annulation

A route to 2,3,4-trisubstituted furan derivatives based on a [3 + 2] annulation of functionalized allylic sulfoxides and aldehydes is described. In this strategy, the precursors of allylic sulfoxides 4, allylic sulfides 3, were synthesized via a thiomethylation reaction of an alpha-EWG ketene-S,S-acetal 1 (EWG: electron-withdrawing group), formaldehyde, and a thiol 2 in high to excellent yields. Allylic sulfoxides 4 were prepared by a highly regioselective oxidation of 3, using m-chloroperoxybenzoic acid as oxidant. Thus, starting from these readily available sulfoxides 4, 2-alkylthio-3,4-disubstituted furans 6 were efficiently constructed via the [3 + 2] annulation reaction of 4 with aldehydes 5 under mild conditions. Further replacement of the 2-alkylthio group of 6 with amines led to the formation of 2-amino-3,4-disubstituted furan derivatives 7.     

Domino 6pi-electrocyclization/Diels-Alder reactions on 1,6-disubstituted (E,Z,E)-1,3,5-hexatrienes: versatile access to highly substituted tri- and tetracyclic systems

The (E,Z,E)-1,3,5-hexatrienes 1a, 2a,b and 3b undergo 6pi-electrocyclization within 15-30 min upon heating to 200-215 degrees C. While the cyclohexene-annelated products 8a,b were stable, the analogous cyclopentene- and cycloheptene-annelated derivatives 7a and 9b easily underwent dehydrogenation to the corresponding aromatic compounds 10a and 12b during the work-up. The cyclohexadiene derivatives 8a,b were employed in thermal Diels-Alder reactions with 4-phenyl-3H-1,2,4-triazoline-3,5-dione (PTAD) and tetracyanoethylene (TCNE) to give the expected [4+2] cycloadducts 13a and 14a in good yields (60 and 78%). The initially formed cycloadduct of 8a and dimethyl acetylenedicarboxylate (DMAD) underwent a subsequent retro-Diels-Alder reaction to give the tetrahydronaphthalene 11b (47%). Under high pressure (10 kbar), the cycloadduct 15a was formed at room temperature and could be isolated in 44% yield. TCNE and N-phenylmaleimide with 8a under high pressure also led to the [4+2] cycloadducts 14a and 16a in good yields (60 and 77%). The 6pi-electrocyclization and subsequent Diels-Alder reaction, when performed as a one-pot domino process, provided direct access to Diels-Alder products of intermediately formed 6pi-electrocyclization products, for example from the 1,3,5-hexatrienes 1a,b, 2a,b, 3b and TCNE to the corresponding tricyclic products 17a,b, 14a,b, 18b in moderate to good yields (27-80%) depending on the nature of the alkoxycarbonyl group. Such sequential reactions with N-phenylmaleimide, maleic anhydride, dimethyl maleate and fumarodinitrile, the latter two under high pressure (10 kbar), worked as well to yield 16b (70%), 19a,b (19, 32%) and 20b (39%) and 21b (76%), respectively. With PTAD, however, the hexatrienes 2a,b reacted at ambient temperature without 6pi-electrocyclization to give the formal [4+2] cycloadducts 27a,b (48 and 46%), most probably via zwitterionic intermediates 23a,b and 25a,b.