Anionic oxy-Cope Rearrangement Research Articles

Synthesis of Functionalized Allylsilanes via the Condensation of α,β-Unsaturated Carbonyl Compounds with γ-Trimethylsilylmethylallylzircocene Followed by Anionic Oxy-Cope Rearrangement

Condensation of α,β-unsaturated carbonyl compounds with y-trimethylsilylmethylallylzircocene followed by anionic oxy-Cope rearrangement provided a novel method for the synthesis of functionalized allylsilanes compounds possessing a carbonyl group in the same molecule, which are versatile intermediates for intramolecular allylsilylation, giving cyclopentanols on treatment with n-Bu 4 NF.

A radical alternative to the anionic oxy-Cope rearrangement.

A radical alternative to the anionic oxy-Cope rearrangement.

Chemoenzymatic total syntheses of the sesquiterpene (–)-patchoulenoneAspects of this work have been reported in preliminary form: M. Banwell and M. McLeod, Chem. Commun., 1998, 1851.

The bicyclo[5.3.1]undec-7(8)-en-3-one 6, which is prepared from the monochiral cis-1,2-dihydrocatechol 4, affords a mixture of products 7, 8 and 9 on exposure to protic acid. Each of compounds 8 and 9 rearranges to congener 7 on treatment with SnCl2 or upon sustained reaction with protic acid. Reaction of the last compound with hydrogen in the presence of palladium on carbon affords a mixture of the saturated diols 10 and 11 with the latter capable of elaboration to (−)-patchoulenone (1) in four simple steps. An alternate and more efficient route to compound 11 involved a radical cyclisation route wherein enone 6 was treated with SmI2 and thiophenol, the latter reagent being employed to ensure efficient reduction. The major product, 12, thus formed was then debenzylated to give the patchoulenone precursor 11. In an even more efficient route to the title sesquiterpene, the bicyclo[2.2.2]octenone 21 was reacted with isopropenyllithium to give the dienol 22, which engaged in an anionic oxy-Cope rearrangement to afford the bicyclo[5.3.1]undec-7(8)-enone 23 and for which an X-ray crystal structure determination has been carried out. Reductive cyclisation of the last compound using SmI2 in the presence of thiophenol then gave, in a stereoselective manner, diol monoether 24, which after subjection to debenzylation, oxidation and dehydration steps afforded (−)-patchoulenone (1).

The anionic oxy-Cope rearrangement: using chemical reactivity to reveal the facile isomerization of the parent substrates in the gas phase.

The rearrangements of 1,5-hexadiene-3-oxide and 3-methyl-1,5-hexadiene-3-oxide have been studied in the gas phase, using both Fourier transform mass spectrometry (FTMS) and the flowing afterglow (FA) technique. Gas-phase studies of ionic rearrangements can be limited by analysis techniques such as collision-induced dissociation, which have the potential of driving the rearrangement prior to fragmentation. In the studies reported here, we have utilized methanol-O-d, methyl nitrite, and dimethyl disulfide as chemical reactivity probes to discern whether rearrangement of either of the alkoxides to their corresponding enolates occurs. Of the three structural probe reagents, dimethyl disulfide has been found to be most ideal, since it reacts efficiently with both alkoxides and enolates to produce a unique product from each. On the basis of the reactions observed between dimethyl disulfide and anions generated from 1,5-hexadien-3-ol and 3-methyl-1,5-hexadien-3-ol, we have found that the gas-phase Cope rearrangement of both tertiary and secondary alkoxides occurs under both FTMS and FA conditions. Use of dimethyl disulfide in the FTMS and evaluation of ion residence time in the FA lead to the establishment of an upper limit on the Delta H(*) of the rearrangement of both the parent secondary and tertiary substrates as approximately 11 kcal mol(-1) at 298 K. This value is consistent with our B3LYP/6-31+G* prediction. The rearrangement is also faster in the gas phase than in solution, in accord with theoretical predictions.

Acid-induced transannular cyclization of 2-methyl- and 10-methyl-5-cyclodecenone

2-Methyl- and 10-methyl-5-cyclodecenone were made by anionic oxy-Cope rearrangement of the corresponding 1,2-divinylcyclohexanols, and their transannular cyclizations were induced using trifluoroacetic acid. In each case, a single diastereomer of a trans fused bicyclo[4.4.0]decan-1-ol with an equatorial methyl group was isolated. The methyl substituent at C2 or C10 of the 5-cyclodecenone did not alter the regio- and stereochemistry previously observed for the parent ring system, ( E)-5-cyclodecenone. The relative stereochemistry of the products was determined spectroscopically from J-value analysis and NOE.

Density Functional Study of the Oxy-Cope Rearrangement

With the goal of explaining the very large rate acceleration in the anion-assisted Cope rearrangement, the behavior of the prototypes of the Cope rearrangements, namely hexa-1,5-diene (4), hexa-1,5-dien-3-ol (5), and the oxy anion 6 of the latter were compared. For this purpose, two-dimensional DFT (hybrid B3LYP functionals with 6-31G* basis set) potential-energy surfaces (PESs) were computed, based on two interatomic distances. As the reliability of DFT/B3LYP-computed energies can not be taken for granted, we first performed model computations on the experimentally well-studied bridged homotropylidenes 1 – 3. Then, the transition states of the Cope rearrangements of 3-methylhexa-1,5-dien-3-ol (7), (2Z,4Z,7Z)-cyclonona-2,4,7-trien-1-ol (9), 1-methoxy-2-endo-vinylbicyclo[2.2.2]oct-5-en-2-exo-ol (11), and (1S,2R)-2-hydroxy-1-methyl-2-vinylbicyclo[4.4.0]dec-6-en-8-one (arbitrary numbering; 13) and of their oxy anions 8, 10, 12, and 14, respectively, were computed by the same method. These examples were chosen because kinetic data have been measured for most of them (except for 13 and 14) and/or because they furnished already important contributions to the discussion of the character of the Cope rearrangement. The computation of ΔG≠ for a given temperature allowed to calculate the rate constants at that temperature for the different rearrangements and to compare them with the experimental data. In the cases of the neutral and anionic oxy-Cope rearrangements, the equation ΔΔG≠=2.3026⋅RT⋅ΔpKa suggested a correlation between the difference in the pKa values of the pair of reactants and the pair of transition states and the change of the two free energies of activation.

Stereocontrol in a one-pot procedure for anionic oxy-Cope rearrangement followed by intramolecular aldol reaction

Racemic β-hydroxycyclohexanones with up to three chiral centres have been synthesized in a stereocontrolled way using the novel anionic oxy-Cope (AOC) rearrangement of acyclic enol ethers. The first examples of compounds containing an aldehyde and an enol ether in a 1,5 relationship are reported. Stereocontrol in the cyclisation of these compounds by a 6-(enolendo)-exo-trig intramolecular aldol reaction has been studied: there is high stereoselectivity for an axial hydroxy group in the product β-hydroxycyclohexanones. AM1 calculations show that there is a stabilising electrostatic attraction between the oxygen atom of the axial C-3 hydroxy group and the electron-poor carbon at C-1 in the intermediate oxonium ions. ≥87% of AOC rearrangement occurs via a chair-like transition state giving rise to the 5,6-anti stereochemistry of the β-hydroxycyclohexanones. Trapping the enolate product of AOC rearrangement with oxygen gives fragmentation via a 1,2-dioxetane.

A chemoenzymatic synthesis of the carbobicyclic core associated with CP-225,917 and CP-263,114 (phomoidrides A and B)

The bromobenzene-derived and enantiopure cis-1,2-dihydrocatechol 3 has been converted, via a reaction sequence involving Diels–Alder cycloaddition, anionic oxy-Cope rearrangement and Wolff ring-contraction steps, into compound 4 and epimer 24, which embody key structural elements associated with the nonadride-type natural products CP-225,917 (1) and CP-263,114 (2).

From Carbohydrates to the Discovery of Pronounced Heteroatomic Effects on Anionically Accelerated [3,3]-Sigmatropic Rearrangements

The (Z)-(iodovinyl)oxetane 12 was prepared from D-glucose and the acyclic analog 18 was obtained from D-mannitol. Following the generation of their lithium derivatives by halogen−metal exchange, coupling to the enantiopure vinyl-substituted norbornanones 20, 23, and 29 proceeded exclusively via endo attack to deliver the targeted exo-carbinols. The anionic oxy-Cope rearrangements of 21 and 24 were seen to differ appreciably in rate. While the sulfur derivative 24 experiences [3,3] sigmatropy with a half-life of less than a minute at −78 °C, its oxygen analogue 21 proved unreactive below −20 °C under entirely comparable conditions. This phenomenon is critically examined in a synthetic context involving 26 and 30, where the heavily functionalized acyclic side chain involved previously is supplanted by an oxetane assembly. In the sulfur example, isomerization occurs very rapidly as before with 100% transfer of chirality. The kinetic response of vinyl ether 26 now proved to be entirely comparable. However, the pathway followed in this instance was intramolecular nucleophilic attack by the “naked” alkoxide at the less substituted C−O bond of the oxetane with ring cleavage and formation of alcohol 28. The global findings provide a glimpse of the subtle way in which [3,3]-sigmatropic transpositions can be modulated by heteroatomic substitution.

Enantiospecific total synthesis of the sarpagine related indole alkaloids talpinine and talcarpine as well as the improved total synthesis of alstonerine and anhydromacrosalhine-methine via the asymmetric Pictet-Spengler reaction.

The enantiospecific total synthesis of talpinine 1 and talcarpine 2 has been accomplished from D-(+)-tryptophan in 13 steps (11 reaction vessels) in 10% and 9.5% overall yields, respectively. Moreover, this synthetic approach has been employed for the improved synthesis of alstonerine 3and anhydromacrosalhine-methine 4 in 12% and 14% overall yield, respectively. A convenient synthetic route for the enantiospecific, stereospecific preparation of the key intermediate (-)-N(a)-H, N(b)-benzyl tetracyclic ketone 15a via the asymmetric Pictet-Spengler reaction on a multihundred-gram scale has been developed. A diastereocontrolled (>30:1) anionic oxy-Cope rearrangement and the intramolecular rearrangement to form ring-E and an N(b)-benzyl/N(b)-methyl transfer reaction also served as key steps. This general approach can now be utilized for the synthesis of macroline/sarpagine related indole alkaloids and their antipodes for biological screening.

Mechanistic Variations and Rate Effects of Alkoxy and Thioalkoxy Substitutents on Anionic Oxy-Cope Rearrangements [J. Am. Chem. Soc. 1999, 121, 11880−11884

ADVERTISEMENT RETURN TO ISSUEPREVAddition/CorrectionNEXTORIGINAL ARTICLEThis notice is a correctionMechanistic Variations and Rate Effects of Alkoxy and Thioalkoxy Substitutents on Anionic Oxy-Cope Rearrangements [J. Am. Chem. Soc.1999, 121, 11880−11884].Fredrik Haeffner, K. N. Houk, Y. Ravindra Reddy, and Leo A. PaquetteCite this: J. Am. Chem. Soc. 2000, 122, 15, 3799Publication Date (Web):March 30, 2000Publication History Published online30 March 2000Published inissue 1 April 2000https://doi.org/10.1021/ja0046463Copyright © 2000 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views359Altmetric-Citations25LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (28 KB) Get e-Alerts Get e-Alerts

Phosphazene bases and the anionic oxy-Cope rearrangement

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.

Unexpected stereoselectivity in the anionic oxy-Cope rearrangement of acyclic enol ethers

The anionic oxy-Cope rearrangement of alkoxides derived from (1 E,5 Z)-4-methyl-5-alkoxy-1-phenyl-1,5-heptadien-3-ols proceeds via a chair-like transition state with the oxyanion axial, even when there is a 3,4- syn-relationship between the methyl group and the oxyanion so that both groups are axial in the transition state of the [3,3]-sigmatropic rearrangement. We believe that this is the first example of chelation control in the AOC rearrangement. The reaction forms the basis of a stereoselective synthesis of β-hydroxycyclohexanones containing four chiral centres.

Mechanistic Variations and Rate Effects of Alkoxy and Thioalkoxy Substituents on Anionic Oxy-Cope Rearrangements

The effects of thiomethoxy and methoxy substituents on the rates and the mechanisms of anionic oxy-Cope rearrangements were investigated with density functional theory (B3LYP/6-31+G*). Thiomethoxy ...

Indium mediated γ-pentadienylation of conjugated aldehydes: synthons for hydrindanes by an oxy-Cope-cycloaddition strategy

The addition of pentadienylindium to unsaturated aldehydes afforded the alcohols 7, from 1,2-addition, substituted with a 1,4-diene unit. Subsequent anionic oxy-Cope rearrangement provided the Michael 1,4-addition product 8. Wittig reaction followed by intramolecular [2+4] cycloaddition afforded the hydrindane skeleton in an enantioselective manner (five steps).

Chemoenzymatic and Enantiodivergent Routes to Highly Functionalised Steroidal Nuclei

The bromobenzene-derived and enantiopure cis-1,2-dihydrocatechol 2 can be elaborated, via Diels-Alder cycloaddition and anionic oxy-Cope rearrangement reactions, to either compound 1 or its enantiomer (ent-1).

Reversible Charge-Accelerated Oxy-Cope Rearrangements

An asymmetric synthesis of the oxetane-containing norbornanone 23 and its coupling to trans-1-propenyllithium to give 24 are reported, in tandem with the preparation of the related alcohols 28 and 30. All three divinyl carbinols undergo anionic oxy-Cope rearrangement very rapidly at low temperature. Quenching of 24-K+ and 28-K+ under these conditions with water or various aqueous salt solutions results in protonation of the alkoxides. If these reaction mixtures are poured instead onto cold (0 °C) silica gel, their sigmatropically related ketones are isolated in very good yield. Whereas the 24-K+ ⇄ 25-K+ equilibrium pair is not reactive to molecular oxygen, 30-K+ is directly converted into an α-hydroperoxy ketone under comparable conditions. These and additional observations are rationalized in the context of atropisomerism involving conversion of oxygen-up enolates, formed reversibly under kinetically controlled conditions, into their thermodynamically favored, more reactive oxygen-down conformers.

Studies Directed toward the Total Synthesis of Cerorubenic Acid-III. 5. A Radical Cyclization Route Leading to the Methyl Ester of the Natural Isomer1

The first total synthesis of cerorubenic acid-III methyl ester is detailed. Enantiopure 4, obtained by anionic oxy-Cope rearrangement of 3, was transformed via diol 11 into lactol 20. Following proper establishment of both side chains as in 25, a 6-exo radical cyclization was employed to set the configuration of the remaining stereogenic centers. This very useful process set the stage for construction of the pendant side chain. The complete route to 2 from 3-methylcyclohexenone required 30 steps (0.3% overall yield) confirmed the initial complex structural assignment and established the absolute configuration of the natural kairomone.

3 + 4] Annulation of α,β-Unsaturated Acylsilanes with Enolates of α,β-Unsaturated Methyl Ketones: Scope and Mechanism

Reactions of the E and Z isomers of (β-(trimethylsilyl)acryloyl)(tert-butyl)dimethylsilanes with lithium enolate of α,β-unsaturated methyl ketones at −80 to −30 °C afford cis-5,6- and trans-5,6-disubstituted 3-cyclohepetenones, respectively. The same [3 + 4] annulation is observed in the reaction of (β-(tri-n-butylstannyl)acryloyl)silanes. The annulation products are readily transformed into 4-cycloheptene-1,3-dione by treatment with NBS or mCPBA. The observed stereospecificity in the annulation is explained by the reaction pathway that involves an anionic oxy-Cope rearrangement of 1,2-divinylcyclopropanediol intermediate generated via Brook rearrangement of the 1,2-adduct of a lithium enolate. Isolation of vinylcyclopropanol derivative from the reaction of (β-(tri-n-butylstannyl)acryloyl)silanes with lithium enolate of 2‘-bromoacetophenone and its transformation into cycloheptenone derivative with LDA provide strong support for the proposed mechanism. Further support is obtained from the reactions of 1,2...

Total Synthesis of Spinosyn A. 1. Enantioselective Construction of a Key Tricyclic Intermediate by a Multiple Configurational Inversion Scheme

The condensation of (+)-7,7-dimethoxynorbornen-2-one with the cerium reagent derived from enantiopure bromide (+)-11 gives rise to an exo carbinol, which readily undergoes highly stereocontrolled anionic oxy-Cope rearrangement. Conversion of the resulting ketone into 20 proceeds with clean epimerization at C-11 (spinosyn numbering) to properly set the absolute configuration at that site. Reduction of 20 with lithium in liquid ammonia serves to introduce two additional stereogenic centers of the perhydro-as-indacene core. In addition, the protocol makes possible the convenient incorporation of a functionalized two-carbon appendage at C-3 and ultimate generation of a cyclohexene double bond after stereochemical inversion at C-7. This scheme leads to 34, a tricyclic compound subsequently shown to be an advanced precursor to the powerful insecticide spinosyn A.