Rearrangement Of Epoxides Research Articles

Ti-catalyzed regioselective ring-opening alkynylation of epoxides with haloalkynes

Ti-catalyzed ring-opening alkynylation of epoxides with haloalkynes has been achieved, allowing an efficient and regioselective entry to various propargylic alcohols in moderate to good yields. The developed protocol features extremely mild reaction conditions, broad substrate scope, varied functional group compatibility, and chemospecificity in the rearrangements of epoxides to aldehydes.

Development of chiral bisphosphoric acid/boronic acid co-catalyst system for enantioselective SN2’ reaction

An enantioselective intramolecular SN2’ reaction of geometrically defined allylic substrates was developed by introducing a co-catalyst system composed of chiral bisphosphoric acid and phenylboronic acid. In the enantioselective nucleophilic substitution reaction using chiral phosphoric acids and derivatives (CPAs) as the catalyst, the formation of the corresponding CPA ester, which is afforded through the SN2 reaction of the substrate with the nucleophilic phosphate anion generated during the activation of a leaving group, has been a serious problem because of the catalyst deactivation. The developed co-catalyst system surmounted this fundamental problem by efficiently suppressing the catalyst deactivation process to afford enantioenriched vinyl epoxides in good yields with moderate to high enantioselectivities. Mechanistic elucidation of the present enantioselective intramolecular SN2’ reaction using the co-catalyst system revealed that the leaving group is involved in the enantio-determining transition states, and the anti-SN2’ pathway is considered to be the rational mechanism of the present allylic substitution reaction. In addition, the stereospecific Meinwald rearrangement of the thus-formed enantioenriched vinyl epoxide was aided by an equimolar amount of a Lewis acid, affording the corresponding all-carbon quaternary α-vinyl cyclohexanone without marked loss of enantiomeric purity.

Synthesis of Cardiotonic Steroids Oleandrigenin and Rhodexin B.

This article describes a concise synthesis of cardiotonic steroids oleandrigenin (7) and its subsequent elaboration into the natural product rhodexin B (2) from the readily available intermediate (8) that could be derived from the commercially available steroids testosterone or DHEA via three-step sequences. These studies feature an expedient installation of the β16-oxidation based on β14-hydroxyl-directed epoxidation and subsequent epoxide rearrangement. The following singlet oxygen oxidation of the C17 furan moiety provides access to oleandrigenin (7) in 12 steps (LLS) and a 3.1% overall yield from 8. The synthetic oleandrigenin (7) was successfully glycosylated with l-rhamnopyranoside-based donor 28 using a Pd(II)-catalyst, and the subsequent deprotection under acidic conditions provided cytotoxic natural product rhodexin B (2) in a 66% yield (two steps).

Asymmetric Catalytic Vinylogous Addition Reactions Initiated by Meinwald Rearrangement of Vinyl Epoxides.

The first catalytic asymmetric multiple vinylogous addition reactions initiated by Meinwald rearrangement of vinyl epoxides were realized by employing chiral N,N'-dioxide/ScIII complex catalysts. The vinyl epoxides, as masked β,γ-unsaturated aldehydes, via direct vinylogous additions with isatins, 2-alkenoylpyridines or methyleneindolinones, provided a facile and efficient way for the synthesis of chiral 3-hydroxy-3-substituted oxindoles, α,β-unsaturated aldehydes and spiro-cyclohexene indolinones, respectively with high efficiency and stereoselectivity. The control experiments and kinetic studies revealed that the Lewis acid acted as dual-tasking catalyst, controlling the initial rearrangement to match subsequent enantioselective vinylogous addition reactions. A catalytic cycle with a possible transition model was proposed to illustrate the reaction mechanism.

Asymmetric Catalytic Vinylogous Addition Reactions Initiated by Meinwald Rearrangement of Vinyl Epoxides

AbstractThe first catalytic asymmetric multiple vinylogous addition reactions initiated by Meinwald rearrangement of vinyl epoxides were realized by employing chiral N,N′‐dioxide/ScIII complex catalysts. The vinyl epoxides, as masked β,γ‐unsaturated aldehydes, via direct vinylogous additions with isatins, 2‐alkenoylpyridines or methyleneindolinones, provided a facile and efficient way for the synthesis of chiral 3‐hydroxy‐3‐substituted oxindoles, α,β‐unsaturated aldehydes and spiro‐cyclohexene indolinones, respectively with high efficiency and stereoselectivity. The control experiments and kinetic studies revealed that the Lewis acid acted as dual‐tasking catalyst, controlling the initial rearrangement to match subsequent enantioselective vinylogous addition reactions. A catalytic cycle with a possible transition model was proposed to illustrate the reaction mechanism.

Stereoselective tandem iridium-catalyzed alkene isomerization-cope rearrangement of ω-diene epoxides: efficient access to acyclic 1,6-dicarbonyl compounds.

The Cope rearrangement of 2,3-divinyloxiranes, a rare example of epoxide C–C bond cleavage, results in 4,5-dihydrooxepines which are amenable to hydrolysis, furnishing 1,6-dicarbonyl compounds containing two contiguous stereocenters at the 3- and 4-positions. We employ an Ir-based alkene isomerization catalyst to form the reactive 2,3-divinyloxirane in situ with complete regio- and stereocontrol, which translates into excellent control over the stereochemistry of the resulting oxepines and ultimately to an attractive strategy towards 1,6-dicarbonyl compounds.

Rearrangements of the Betulin Core. Synthesis of Terpenoids Possessing the Bicyclo[3.3.1]nonane Fragment by Rearrangement of Lupane-Type Epoxides.

The rearrangements of dihydrobetulin, dihydrobetulinic acid, and abeo-lupane epoxides under acidic conditions (HCl, montmorillonite K10, and BF3·Et2O) were studied. The treatment of dihydrobetulin with HCl or K10 produced abeo-lupane olefins. Their epoxidation afforded epoxides, which, in the presence of protic or Lewis acids, rearranged to dienes or lupanes bearing a bicyclo[3.3.1]nonane fragment. The structure of final products depended on the nature of the catalyst. The HCl promoted 1,4-elimination of water, whereas in the presence of BF3·Et2O bond migration took place preferentially. Montmorillonite K10 favored cyclization to bicyclononane.

Sustainable catalytic rearrangement of terpene-derived epoxides: towards bio-based biscarbonyl monomers.

Seeking a sustainable and selective approach for terpene modification, a catalyst deconvolution approach was applied to the Meinwald rearrangement of (+)-limonene oxide as a model substrate to yield dihydrocarvone. In order to identify the most suitable catalyst and reaction conditions, different Lewis acids were evaluated. Bismuth triflate proved to be the most active catalyst under mild reaction conditions, with a low catalyst loading (1 mol%) and a relatively short reaction time (3 h). The optimized reaction conditions were subsequently transferred to other terpene-based epoxides, yielding different bio-based biscarbonyl structures, which constitute interesting and valuable substances, e.g. for polymer synthesis or as fragrances. Monoepoxides derived from (R)-(-)-carvone and (+)-dihydrocarvone rearranged to the desired products with high selectivities and yields. γ-Terpinene dioxide could be transformed in a double rearrangement to the respective biscarbonyl in moderate yields. A better result was achieved for limonene dioxide after further adjustment of the protocol to reach acceptable yields with a low catalyst loading of 0.1 mol% using 2-methyl tetrahydrofuran as a sustainable solvent. Compared to many procedures described in the literature, this procedure represents a step towards an increased sustainability in terpene modification by considering several principles of Green Chemistry, such as renewable resources, catalysis and mild reaction conditions for elementary chemical transformations. This article is part of a discussion meeting issue 'Science to enable the circular economy'.

Au(I)-Catalyzed Cyclization of Epoxyalkynes to Allylic Alcohol Containing Spiroketals and Application to the Total Synthesis of (-)-Alotaketal A.

A gold-catalyzed tandem spiroketalization of epoxyalkynes accompanied by epoxide rearrangement into the corresponding allylic alcohol was developed for the construction of functionalized spiroketals. This new synthetic methodology for unsaturated spiroketals warranted a facile total synthesis of alotaketal A from carvone via a corresponding epoxyalkyne precursor.

Reaction Mechanism of the Isomerization of Monoterpene Epoxides with Fe3+ as Active Catalytic Specie: A Computational Approach.

The reaction mechanism of the isomerization of α and β-pinene epoxides with Fe species as catalysts was studied with density functional theory (DFT) calculations and an experimental methodology. β-pinene epoxide can be isomerized into myrtanal and myrtenol in four steps, while in the case of perillyl alcohol, two additional steps are necessary. On the other hand, high selectivity to myrtanal obtained experimentally can be explained by the number of steps and the kind of the hydrogen transference that is easier for this compound in comparison with myrtenol and perillyl alcohol. A thermodynamic analysis showed that transformation into myrtenol, myrtanal, and perillyl alcohol is spontaneous but transformation into myrtanal is the most favorable. In the case of α-pinene epoxide rearrangement, a mechanistic study was carried out toward the optimization of the possible intermediates. Synthesis of campholenic aldehyde and carveol from α-pinene epoxide was carried out through three steps after the coordination of oxygen to iron, showing that in contrast to carveol formation, campholenic aldehyde synthesis is spontaneous. Analysis of ∇2ρ, the total energy density (H = V + G), and the |V|/G ratio evaluated at the bond critical point of the Fe-O bond showed for both epoxides that such interaction is closed shell instead of covalent. Apparently, α-pinene epoxide can be isomerized faster that β-pinene epoxide with Fe3+, which is in agreement with previous experimental results. This is the first report where a reaction mechanism of isomerization of monoterpenes epoxides is studied based on very detailed experimental and computational methodologies.

Brønsted Acid Catalyzed Asymmetric House–Meinwald Rearrangement of p-Hydroxyphenyl Epoxides

Key words House–Meinwald rearrangement - quaternary stereocenters - epoxides - chiral phosphoric acids

Catalytic Enantioselective Pinacol and Meinwald Rearrangements for the Construction of Quaternary Stereocenters.

The development of enantioselective pinacol rearrangement is extremely challenging due to the likelihood involvement of the carbenium intermediate that renders the stereochemical communication between catalyst and substrate difficult to achieve. Herein, we report chiral N-triflyl phosphoramide-catalyzed enantioselective pinacol rearrangement of 1,2-tertiary diols and mechanistically related Meinwald rearrangement of tetrasubstituted epoxides for the synthesis of enantioenriched 2-alkynyl-2-arylcyclohexanones and 2,2-diarylcyclohexanones, respectively. Total synthesis of (+)-mesembrane featuring the catalytic enantioselective pinacol rearrangement as a key strategic step is also documented.

Bimetallic Radical Redox-Relay Catalysis for the Isomerization of Epoxides to Allylic Alcohols.

Organic radicals are generally short-lived intermediates with exceptionally high reactivity. Strategically, achieving synthetically useful transformations mediated by organic radicals requires both efficient initiation and selective termination events. Here, we report a new catalytic strategy, namely, bimetallic radical redox-relay, in the regio- and stereoselective rearrangement of epoxides to allylic alcohols. This approach exploits the rich redox chemistry of Ti and Co complexes and merges reductive epoxide ring opening (initiation) with hydrogen atom transfer (termination). Critically, upon effecting key bond-forming and -breaking events, Ti and Co catalysts undergo proton transfer/electron transfer with one another to achieve turnover, thus constituting a truly synergistic dual catalytic system.

Iron-catalysed regioselective hydrogenation of terminal epoxides to alcohols under mild conditions

The reduction of epoxides has been recognized as an important method for the synthesis of alcohols using stoichiometric amounts of metal hydride reducing agents. However, homogeneous catalysis-enabled hydrogenation processes with molecular hydrogen remain scarce. Here, we present a general methodology for the synthesis of primary alcohols in high yields, selectively and under mild conditions, from aliphatic and aromatic epoxides. Crucial for the hydrogenation of terminal epoxides is the presence of an Fe(BF4)2.6H2O/tetraphos catalyst system. Compared to existing methods, which make use of noble metals, the presented protocol shows broad substrate scope and good functional group tolerance. The generality of this is showcased by transformation of various natural products, including steroids, terpenoids, sesquiterpenoids and drug derivatives, which give the desired alcohols in moderate to excellent yields. Mechanistic studies confirm the distinct feature of the catalyst system, which is active for Meinwald rearrangement of epoxides as well as for carbonyl hydrogenations. Primary alcohols are known for their broad application in life sciences and the chemical industry. Now, Beller and colleagues present a regioselective, iron-catalysed hydrogenation of aliphatic and aromatic epoxides as a general route to primary alcohols under mild conditions

Isomerization of α- and β- pinene epoxides over Fe or Cu supported MCM-41 and SBA-15 materials

Fe and Cu based heterogeneous catalysts were evaluated in the isomerization reaction of α- and β-pinene epoxides. The metals were incorporated on SBA-15 and MCM-41 using incipient wetness impregnation procedure and the materials were characterized by XRD, Raman spectroscopy, BET analysis, NH3-TPD, TEM and XPS. 1.4/Fe-MCM-41 was the catalyst with the highest TON value (364) and α-pinene epoxide conversion (73%) with a campholenic aldehyde selectivity of 59%, while from β-pinene epoxide 1.4/Fe-SBA-15 was the material with the highest TON (299) and selectivity (100%) to myrtanal with a substrate conversion of 60%. Cu based materials presented lowest TON value for the rearrangement of β-pinene epoxide than using α-pinene epoxide as substrate. Besides, it was elucidated that the formation of campholenic aldehyde and myrtanal is function of the presence of metal oxides, mean particle diameter and the strength of acidity; moreover, the most active catalysts did not present leaching under the reaction conditions. 1.4/Fe-MCM-41 can be used until five times without loss of catalytic activity with α pinene epoxide. Based on the characterization and different products synthetized, a reaction mechanism for the rearrangement reaction of α-pinene epoxide is proposed. This is the first report of Cu heterogenized on mesoporous materials for the isomerization reaction of monoterpenes epoxides.

Nucleophilic Organic Base DABCO-Mediated Chemospecific Meinwald Rearrangement of Terminal Epoxides into Methyl Ketones.

Nucleophilic organic base DABCO (1,4-diazabicyclo[2.2.2]octane)-mediated Meinwald rearrangement of various epoxides was investigated. 2-Aryl-, alkenyl-, and alkynylepoxides generate the corresponding methyl ketones chemospecifically in good to excellent yields. The current DABCO-mediated Meinwald rearrangement of epoxides features readily accessible starting materials, a wide substrate scope, a transition-metal- and acid-free environment, and chemospecificity in the isomerization of epoxides.

Synthetic approaches to phomactins: Novel oxidation of homoallylic alcohols using tetra-n-propylammonium perruthenate

Previous studies of a synthesis of phomactin A had resulted in the synthesis of a 15-methylenebicyclo[9.3.1]pentadecadiene. The next step in the synthesis was to be the epoxidation of this methylenecyclohexane that was hoped would lead to a 1-(hydroxymethyl)cyclohexene by rearrangement of the exocyclic epoxide, but the epoxidation was difficult to carry out regioselectively on advanced intermediates. However, oxidation of a 15-methylenebicyclo[9.3.1]pentadeca-3,7-dien-14-ol using tetra-n-propylammonium perruthenate and N-methylmorpholine-N-oxide led to conversion of this homoallylic alcohol into the corresponding 14-oxobicyclo[9.3.1]pentadeca-1(15),3,7-triene-15-carboxaldehyde in one step. Reduction of this using DIBAL-H gave a promising intermediate for a synthesis of a phomactin. The scope of this oxidation of homoallylic alcohols was briefly investigated.

Total Synthesis of ent-Ascospiroketal B.

Ascospiroketal B was isolated from a marine-derived fungus as a structurally unique polyketide possessing a rare tricyclic core including 5,5-spiroketal-γ-lactone. An asymmetric total synthesis of ent-ascospiroketal B was achieved using an original synthetic route. The synthesis included the stereoselective construction of 5,5-spiroketal for ascospiroketal B and stereocontrolled construction of a quaternary asymmetric carbon by rearrangement of a trisubstituted epoxide.

Regio- and chemoselective rearrangement of terminal epoxides into methyl alkyl and aryl ketones.

The development of the highly active pincer-type rhodium catalyst 2 for the nucleophilic Meinwald rearrangement of functionalised terminal epoxides into methyl ketones under mild conditions is presented. An excellent regio- and chemoselectivity is obtained for the first time for aryl oxiranes.

Biocatalytic Formal Anti-Markovnikov Hydroamination and Hydration of Aryl Alkenes

Biocatalytic anti-Markovnikov alkene hydroamination and hydration were achieved based on two concepts involving enzyme cascades: epoxidation–isomerization–amination for hydroamination and epoxidation–isomerization–reduction for hydration. An Escherichia coli strain coexpressing styrene monooxygenase (SMO), styrene oxide isomerase (SOI), ω-transaminase (CvTA), and alanine dehydrogenase (AlaDH) catalyzed the hydroamination of 12 aryl alkenes to give the corresponding valuable terminal amines in high conversion (many ≥86%) and exclusive anti-Markovnikov selectivity (>99:1). Another E. coli strain coexpressing SMO, SOI, and phenylacetaldehyde reductase (PAR) catalyzed the hydration of 12 aryl alkenes to the corresponding useful terminal alcohols in high conversion (many ≥80%) and very high anti-Markovnikov selectivity (>99:1). Importantly, SOI was discovered for stereoselective isomerization of a chiral epoxide to a chiral aldehyde, providing some insights on enzymatic epoxide rearrangement. Harnessing this s...