Anionic oxy-Cope Rearrangement Research Articles

Approach to the Core Structure of Signermycin B.

Among the natural tetramic acids with a decalinoyl part, signermycin B is unique because it contains a cis-decalin. In this paper, we demonstrate that the cis-decalin section of signermycin B can be accessed by an anionic oxy-Cope rearrangement. The substrate, a tricyclic dienol was prepared by an intramolecular Diels-Alder reaction of a masked ortho-benzoquinone, generated by oxidation of an α-methoxyphenol in presence of cis-2-hexenol. After a superfluous bromine on the cycloadduct was removed, reaction of the tricyclic ketone with isopropenylmagnesium bromide led to the tricyclic trienol that underwent the oxy-Cope rearrangement to a cis-decalinone. While we could show, that introduction of the 4-ethyl substituent (signermycin B numbering) is possible by enolate alkylation, the 4-epi-isomer was formed.

Synthetic study toward tridachiapyrone B.

A convergent approach to the skeleton of tridachiapyrone B is described taking advantage of the desymmetrization of α,α'-dimethoxy-γ-pyrone leading to α-crotyl-α'-methoxy-γ-pyrone in one step. To construct the quaternary carbon of the 2,5-cyclohexadienone of the target, a strategy based on the Robinson-type annulation of an aldehyde derived from α-crotyl-α'-methoxy-γ-pyrone was applied. The grafting of the simplified target's side chain was demonstrated through an oxidative anionic oxy-Cope rearrangement of the tertiary alcohol arising from the 1,2-addition of a 1,3-dimethylallyl reagent to 2,5-cyclohexadienone connected to the α'-methoxy-γ-pyrone motif.

Bi(OAc)3/Chiral Phosphoric Acid-Catalyzed Enantioselective 1,2- and Formal 1,4-Allylation Reaction of β,γ-Unsaturated α-Ketoesters.

A highly efficient asymmetric 1,2-allylation reaction of β,γ-unsaturated α-ketoesters was realized by using a Bi(OAc)3/chiral phosphoric acid catalyst system under mild conditions. Meanwhile, using this combined strategy of enantioselective 1,2-allylation and subsequent anionic oxy-Cope rearrangement, the asymmetric formal 1,4-allylation reaction was achieved by a one-pot process. These reactions offer rapid access to an array of homoallylic tertiary alcohols and γ-allyl-α-ketoesters with good yields and excellent enantioselectivities. Density functional theory calculations were conducted to interpret the high enantioselectivity.

Enantioselective Catalysis of an Anionic Oxy-Cope Rearrangement Enabled by Synergistic Ion Binding.

Charge-accelerated rearrangements present interesting challenges to enantioselective catalysis, due in large part to the competing requirements for maximizing reactivity (ion-pair separation) and stereochemical communication. Herein, we describe application of a synergistic ion-binding strategy to catalyze the anionic oxy-Cope rearrangement of a symmetric bis-styrenyl allyl alcohol in up to 75:25 e.r. Structure-reactivity-selectivity relationship studies, including linear free-energy-relationship analyses, with bifunctional urea catalysts indicate that H-bonding and cation-binding interactions act cooperatively to promote the chemo- and enantioselective [3,3]-rearrangement. Implications for catalyst designs applicable to other transformations involving oxyanionic intermediates are discussed.

Asymmetric Total Synthesis of (-)-Erogorgiaene and Its C-11 Epimer and Investigation of Their Antimycobacterial Activity.

A short, nine-step, highly enantioselective synthesis of (-)-erogorgiaene and its C-11 epimer is reported. The key stereochemistry controlling steps involve catalytic asymmetric crotylation, anionic oxy-Cope rearrangement and cationic cyclisation. (-)-Erogorgiaene exhibited promising antitubercular activity against multidrug-resistant strains of Mycobacterium tuberculosis.

Catalytic asymmetric crotylation of aldehydes: application in total synthesis of (-)-elisabethadione.

A new, highly efficient Lewis base catalyst for a practical enantio- and diastereoselective crotylation of unsaturated aldehydes with E- and Z-crotyltrichlorosilanes has been developed. The method was employed as a key step in a novel asymmetric synthesis of bioactive serrulatane diterpene (-)-elisabethadione. Other strategic reactions for setting up the stereogenic centers included anionic oxy-Cope rearrangement and cationic cyclization. The synthetic route relies on simple, high yielding reactions and avoids use of protecting groups or chiral auxiliaries.

Synthesis of mulinane diterpenoids.

The mulinane class of diterpenoids is a set of tricyclic (5-6-7), biologically active natural products whose members exhibit a variety of oxidation states. Herein, we report the inaugural synthesis of four mulinanes employing a divergent approach that relies on a diastereoselective anionic oxy-Cope rearrangement to set the relative configuration of the C8 stereocenter and an unprecedented vinylogous Saegusa dehydrogenation reaction to address C-ring functionality.

ChemInform Abstract: Total Synthesis of the Congested Propellane Alkaloid (‐)‐Acutumine

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Total synthesis of the congested propellane alkaloid (-)-acutumine.

The enantioselective total synthesis of (-)-acutumine is described. The synthetic strategy was inspired by the premise that the cyclohexenone ring could be derived from an aromatic precursor. After successful construction of a propellane model system, an initial attempt to prepare the spirocyclic subunit was thwarted by incorrect regioselectivity in a radical cyclization. A second-generation approach involving a radical-polar crossover reaction was successful, and the chemistry developed in the aforementioned model system was then applied to synthesize the natural product. Key reactions included a phenolic oxidation, a diastereoselective ketone allylation utilizing Nakamura's chiral allylzinc reagent, an anionic oxy-Cope rearrangement, an acid-promoted cyclization of a secondary amine onto an α,β-unsaturated ketal, and a regioselective methyl enol etherification of a 1,3-diketone.

Enantioselective Conjugate Allylation of Cyclic Enones

Enantioselective organocatalytic 1,2-allylation of a cyclic enone followed by anionic oxy-Cope rearrangement delivered the ketone as a mixture of diastereomers. This appears to be a general method for the net enantioselective conjugate allylation of cyclic enones.

Enantioselective Total Synthesis and Confirmation of the Absolute and Relative Stereochemistry of Streptorubin B

The enantioselective total synthesis of the pyrrolophane natural product streptorubin B is described. Key steps in the concise route include the application of a one-pot enantioselective aldol cyclization/Wittig reaction and an anionic oxy-Cope rearrangement to forge the crucial 10-membered ring. Comparisons between CD spectra of synthetic and natural samples of streptorubin B coupled with X-ray crystallography allowed for the determination of the absolute stereochemistry of this natural product for the first time. These studies also provided unambiguous proof of the relative configuration between the butyl side chain and the bispyrrole subunit. Additional studies revealed a novel atropstereoselective Paal-Knorr pyrrole condensation and provided fundamental experimental insight into the barrier for atropisomerization of the natural product.

Fast Oxy-Cope Rearrangements of Bis-alkynes: Competition with Central C−C Bond Fragmentation and Incorporation in Tunable Cascades Diverging from a Common Bis-allenic Intermediate

Fast anionic oxy-Cope rearrangements of 1,5-hexadiyn-3,4-olates can be incorporated into cascade transformations which rapidly assemble densely functionalized cyclobutenes or cyclopentenones via a common bis-allenic intermediate. The competition between fragmentation, 4π-electrocyclic closure, and aldol condensation can be efficiently controlled by the nature of the acetylenic substituents. The rearrangement of bis-alkynes with two hydroxyl substituents opens a conceptually interesting entry in the chemistry of ε-dicarbonyl compounds and suggests a new approach to analogues of rocaglamide/aglafolin.

ChemInform Abstract: Sequential Vinylcyclopropylcarbene and Anionic Oxy-Cope Rearrangements: An Expedient Synthesis of Nine-Membered Rings.

Abstract 5-Alkenyl-2-methoxy-2-cyclopentenones, readily available from thermolysis of 2-alkenylcyclopropylcarbene-chromium complexes, can be converted to nine-membered rings by treatment with vinylcerium reagents and subsequent anionic oxy-Cope rearrangement.

ChemInform Abstract: Relevance of Oxyanion Stereochemistry to Chirality Transfer in Anionic Oxy-Cope Rearrangements.

Geometrically and optically pure (3R,5E)- and (3R,5Z)-1,5-heptadien-3-ols undergo anionic oxy-Cope rearrangement under the exclusice control of oxyanion orientation with a 58-64% preference for equatorial oxygen. Six semicyclic dienols have also been synthesized where the preferred oxyanion-driven sigmatropic rearrangement pathway is obligatorily pitted against π-facial biases offered by 4-tert-butylcyclohexenyl, norbornenyl, and camphenyl rings. These rearrangements therefore offer especially stringent tests of those factors that control the level and direction of chirality transfer. The data show the oxyanion to disfavor becoming involved in 1,3-diaxial relationships

ChemInform Abstract: Intramolecularly Competitive Anionic Oxy-Cope Rearrangements.

Abstract Two examples of the title reaction are described. While the kinetically preferred pathway for 2 utilizes the vinyl substituent, that for 16 skirts this option completely. To a great extent, these biases are a function of the structural features inherent to these alochols.

ChemInform Abstract: Phosphazene Bases and the Anionic Oxy-Cope Rearrangement.

Abstract Compounds containing a 1,5-hexadien-3-ol system undergo anionic oxy-Cope rearrangement when treated with the phosphazene super-base, P 4 - t -Bu. The [3,3] sigmatropic rearrangement occurs in hexane as well as in THF. The weaker phosphazene base, P 2 -Et fails to induce rearrangement. This is the first example of the use of a metal-free base to induce anionic oxy-Cope rearrangement.

Enantioselective Total Synthesis of (−)-Acutumine

An account of the total synthesis of the tetracyclic alkaloid (-)-acutumine is presented. A first-generation approach to the spirocyclic subunit was unsuccessful as a result of incorrect regioselectivity in a radical cyclization. However, this work spawned a second-generation strategy in which the spirocycle was fashioned via a radical-polar crossover reaction. This process merged an intramolecular radical conjugate addition with an enolate hydroxylation and created two stereocenters with excellent diastereoselectivity. The reaction was promoted by irradiation with a sunlamp, and a ditin reagent was required for aryl radical formation. These facts suggest that the substrate may function as a sensitizer, thereby facilitating homolytic cleavage of the ditin reagent. The propellane motif of the target was then installed via annulation of a pyrrolidine ring onto the spirocycle. The sequence of reactions used included a phenolic oxidation, an asymmetric ketone allylation mediated by Nakamura's chiral allylzinc reagent, an anionic oxy-Cope rearrangement, a one-pot ozonolysis-reductive amination, and a Lewis acid promoted cyclization of an amine onto an alpha,beta-unsaturated dimethyl ketal. Further studies of the asymmetric ketone allylation demonstrated the ability of the Nakamura reagent to function well in a mismatched situation. A TiCl(4)-catalyzed regioselective methyl enol etherification of a 1,3-diketone completed the synthesis.

Total Synthesis of (−)-Acutumine

The first total synthesis of the tetracyclic alkaloid (-)-acutumine is described. Key reactions include an asymmetric ketone allylation mediated by Nakamura's chiral allylzinc reagent, an anionic oxy-Cope rearrangement, and the Lewis acid-promoted cyclization of an amine onto an alpha,beta-unsaturated dimethyl ketal.

Synthesis of Isohasubanan Alkaloids via Enantioselective Ketone Allylation and Discovery of an Unexpected Rearrangement

A synthesis of the hasubanan alkaloids hasubanonine, runanine, and aknadinine via a unified route was attempted. Construction of key phenanthrene intermediates by a Suzuki coupling-Wittig olefination-ring-closing metathesis sequence allowed a convergent and flexible approach. Conversion of the phenanthrenes into the target structures was projected to involve six steps including phenolic oxidation, ketone allylation, anionic oxy-Cope rearrangement, and acid-promoted cyclization. The final step was thwarted by a pinacol-like rearrangement that delivered the unnatural isohasubanan alkaloid skeleton. The structures of the products were established by exhaustive NMR experiments and confirmed by GIAO (13)C NMR calculations of runanine, isorunanine, and three other isomers. These computations revealed some inconsistencies with the benzene solvent correction which suggest that caution should be used in employing this algorithm. The racemic synthesis of isohasubanonine was transformed into an enantioselective synthesis by the discovery that Nakamura's chiral bisoxazoline-ligated allylzinc reagent mediates the enantioselective allylation of ketone 19 in 93% ee. This method could be extended to three other structurally related ketones (92-96% ee), and the enantioselective syntheses of two other isohasubanan alkaloids, isorunanine and isoaknadinine, were accomplished. Racemic isohasubanonine was found to be an ineffective analgesic agent.

Substituted 16α,17α-cyclohexanopregnanes: the anionic oxy-Cope rearrangement of 3β-tert-butyldimethylsilyloxy-19-hydroxy-19-vinyl-16α,17α-cyclohexapregn-5-en-20-one

(19R)-and (19S)-tert-Butyldimethylsilyl (TBS) ethers of 19-hydroxy-19-vinyl-16α,17α-cyclohexanopregn-5-en-20-ones were synthesized. These compounds containing the 1,5-oxydienoic motif were subjectedto the anionic oxy-Cope rearrangement to obtain 3β-TBS ether of 6β-(3-oxopropyl)-16α,17α-cyclohexano-19-norpregn-5(10)-en-20-one. The structures of the compounds synthesized were confirmed by the analysis of their 1H and 13C NMR spectra.