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An efficient installation of a 3,7-dimethylocta-2,6-dien-1-yl (geranyl or neryl) side chain at the C(1) position of a xanthone core by utilizing an anion-accelerated aromatic oxy-Cope rearrangement is described. Experiments revealed that this uncommon rearrangement takes place in a stereospecific manner through a chair-like transition-state structure. An application to the syntheses of the natural xanthone fuscaxanthone F, possessing a geranyl side chain, and its neryl analogue is also described.

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.

Tandem anionic oxy-Cope rearrangement/radical oxygenation reactions provide δ,ϵ-unsaturated α-(aminoxy) carbonyl compounds, which serve as convenient precursors to diverse compound classes. Functionalized carbocycles are accessible by very rare all-carbon 5-endo-trig cyclizations, but also common 5-exo-trig radical cyclizations, based on the persistent radical effect. The tandem reactions can be further extended by highly diastereoselective allylation or reduction steps to give complex scaffolds.

Diaddition of alkenyllithium to 1,2-diones induce dianionic oxy-Cope rearrangements. As 1,2-diones some 1,2-diarylethane-1,2-diones were treated with (4,5-dihydrofuran-2-yl)lithium. The reaction, which took place at -78 °C, stereoselctively afforded meso-3,3'-coupled bis(tetrahydrofurans), which, in contrast to their 2,2' counterparts, have so far hardly been investigated. Two of the reaction products were characterized by crystal structure analyses. Subsequent intramolecular aldol addition gave a highly substituted octahydro-2H-cyclopenta[1,2-b:4,3-b']difuran, whose constitution and relative configuration were determined by NMR including NOE measurements.

The first total synthesis of elliptoxanthone A, a naturally occurring isoprenylated xanthone, has been accomplished in 28% overall yield in 12 steps from commercially available 3′,4′-difluoroacetophenone by utilizing the novel C-isoprenylation of xanthone skeleton via the anion-accelerated aromatic oxy-Cope rearrangement.

An effective method for the installation of isoprenyl moiety at the C1 position of xanthone has been developed. Addition of isoprenyl Grignard reagent to 1-fluoroxanthone derivatives proceeded γ-selectively, and the obtained tertiary alcohols underwent aromatic oxy-Cope rearrangement and subsequent elimination of fluoride anion under mild conditions to give 1-isoprenylxanthones in high yields.

Since the isolation of unique tricyclic diterpenoid vinigrol, its promising biological activities and complex framework have resulted in numerous synthetic efforts to the total synthesis of this venerable molecule for the past two and half decades. This mini review highlights the significance of various synthetic strategies towards this structurally unique and challenging natural product. (C) 2018 Elsevier Ltd. All rights reserved.

Bis(iodozincio)methane, prepared from diiodomethane and zinc metal in the presence of a lead catalyst, is capable of performing several unique molecular transformations. It can operate not only as a dianion, but also as a bidentate Lewis acid. In this ­account, the methylenation of carbonyl compounds, nucleophilic cyclopropanation reactions, 1,4-addition reactions of bis(iodozincio)methane, and reduction reactions of π-allylpalladium are discussed, along with the associated density functional theory calculations. 1 Introduction 2 Methylenation of Carbonyl Compounds 3 Nucleophilic Cyclopropanation 3.1 Cyclopropanation of 1,2-Diketones 3.2 Asymmetric Construction of Quaternary Carbon Atoms by Stereospecific Cyclopropanation 4 1,4-Addition Reactions of Bis(iodozincio)methane 4.1 Three-Atom Ring-Contraction Reaction 4.2 Enolate–Homoenolate Intermediates and Their Reactions 5 Reduction of π-Allylpalladium Derivatives 6 Conclusions and Outlook

The stereoselective syntheses of the tricyclic core structure of vinigrol and highly functionalized polycyclic molecules from 5-bromo-2-methoxyphenol in five synthetic steps are reported. Intramolecular and intermolecular Diels–Alder reactions and tandem oxy-Cope/ene reactions are the key steps in the synthesis.

An effective method for the installation of isoprenyl moiety at the C1 position of xanthone has been developed. Addition of isoprenyl Grignard reagent to 1-fluoroxanthone derivatives proceeded γ-selectively, and the obtained tertiary alcohols underwent aromatic oxy-Cope rearrangement and subsequent elimination of fluoride anion under mild conditions to give 1-isoprenylxanthones in high yields.

The oxy-Cope rearrangement of aldol products has been studied both experimentally and theoretically to gain insight into the aspects that are responsible for the exceptional rate and diastereoselectivity of this process. Kinetic studies as well as DFT calculations convincingly show that the activation barrier of this process is mainly dependent on the electronic nature of the oxy-substituent, with electron-withdrawing O-substituents raising this barrier. The diastereoselectivity, however, remains uniformly high for all derivatives investigated and steric factors are proposed to account for the selectivity to a large extent. The poor diastereoselectivity in the case of the anti-aldols was also found in our calculations and it appears to result from unfavorable gauche interactions between the oxy and carboximide groups in the transition state.

An effective, asymmetric total synthesis of the antitumor antibiotic (-)-okilactomycin (1), as well as assignment of the absolute configuration, has been achieved exploiting a convergent strategy. Highlights of the synthesis include a diastereoselective oxy-Cope rearrangement/oxidation sequence to install the C(1) and C(13) stereogenic centers, a Petasis-Ferrier union/rearrangement to construct the highly functionalized tetrahydropyranone inscribed within the 13-membered macrocycle ring, employing for the first time a sterically demanding acetal, an intramolecular chemoselective acylation to access an embedded bicyclic lactone, and an efficient ring-closing metathesis (RCM) reaction to generate the macrocyclic ring.

The synthesis of a series of bicyclo[4.2.2]octenones and bicyclo[3.2.2]heptenones by 1,3- or 1,2-migration reaction from 2-vinylbicyclo[2.2.2]octenols is reported. These ring-expansion reactions were accomplished under basic or neutral conditions. Whether 1,3- or 1,2-migration takes place depends on endo- or exocyclic olefin displacement in the substrates.

Treatment of dinaphthyl diols of 1,10‐phenanthroline (1) and acenaphthene (2) with nonnucleophilic base gave bicyclic ketones (3) and (4), respectively. The formation of (3) and (4) involves aromat...

(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.

Polycyclic compounds have been prepared by aromatic dianionic oxy-Cope rearrangements involving the π bonds of two phenyl rings in a [3,3] sigmatropic rearrangement.

Catalytic antibodies are very interesting not only because of the rate enhancement of the reactions that they catalyze but also because of the selectivities they can achieve that are sometimes not present in natural enzyme processes. We have selected the study of the stereoselectivity of the matured AZ28 that catalyzes an oxy-Cope rearrangement. For this particular case, the presence of a chiral center in the substrate provokes the existence of two different enantiomers, R and S. Furthermore, it is also possible to locate two different orientations for the hydroxyl group in the central ring of the substrate in the transition state, equatorial and axial, rendering two different conformers. In this paper we present the free energy profiles obtained for different substrate isomers in the cavity created by the matured catalytic antibody. Our simulations have reproduced the stereoselectivity of the matured AZ28, differentiating between the axial or equatorial orientations and preferentially stabilizing the S forms, at a qualitative level. Finally, the inclusion of the substrate-CA interactions in a flexible molecular model has allowed us to observe the different pattern of interactions that are related to different interaction energies, which seem to be crucial in the stereoselectivity behavior of the catalytic antibody.

Both enantiomers of ( P )-(+)-2- and ( M )-(−)-2-acetoxy-11,14-dimethyl[5]helicenes 8 were synthesized by asymmetric aromatic oxy-Cope rearrangement of the corresponding chiral bridged bicyclic compounds, which were obtained by enzymatic resolution. The absolute configurations of 8 were assigned by their circular dichroism spectra.

The oxy-Cope rearrangement reaction in the antibody AZ28 is investigated using ab initio molecular orbital calculations and molecular mechanical molecular dynamics simulations. This antibody, AZ28, is known as one of the few systems where the mature catalytic antibody shows a negative correlation between the transition state analogue (TSA) binding affinity and the catalytic rate of the oxy-Cope rearrangement compared to the germ line catalytic antibody. The ab initio optimized structure shows that the transition state structure has a more planar configuration than the TSA. The favorable electrostatic interactions between AZ28 and the transition state analogue overcome the unfavorable van der Waals interactions; thus, AZ28 shows higher binding affinity for the TSA than the germ line. However, the AZ28 is not flexible enough to accept the relatively planar transition state structure. Because the lower flexibility causes poorer antibody-hapten interaction energies, the activation free energy of the oxy-Cope rearrangement becomes larger in the mature antibody than the germ line. We show that the differences in flexibility between the germ line and the mature form and the differences in structure between TSA and the transition state are the origin of the negative correlation in AZ28-catalyzed oxy-Cope rearrangement. The mutation of residue 34 of the light chain, 34(L), affects the binding free energies through the interresidue interaction because it is the closest to the hapten among the six mutatable residues. However, it does not affect the negative correlation.

The π bonds of the two heteroaromatic rings act as a 1,5-hexadiene system necessary for the oxy-Cope rearrangement.

Post Graduate and Research Department of Chemistry, The New College, Affiliated to the University of Madras, Chennai-600 014, India E-mail : drmdabdulhuq@yahoo.com Manuscript received 19 September 2012, revised 04 February 2013, accepted 07 May 2013 Novel heterocyclic compounds (2), (4) and (6) have been prepared by a tandem oxy-Cope rearrangement/SN displacement reaction, a tandem dianionic oxy-Cope rearrangement/nucleophilic substitution at carbonyl carbon and a tandem anionic oxy-Cope rearrangement/transannular reaction respectively. The oxy-Cope rearrangement involves the 𝝅 bonds of the pyridyl rings which forms the 1,5-hexadiene system necessary for a [3,3]-sigmatropic rearrangement.

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.

The sequential ester dienolate [2,3]-Wittig/oxy-Cope rearrangement/carbonyl ene reaction has been investigated. Acyclic α,β-unsaturated α-allyloxy-substituted esters 1a−j were transformed into cyclopentane- or cyclohexanecarboxylates 6a−f and 7a−7d. This study presents a domino ester dienolate [2,3]-Wittig/oxy-Cope rearrangement or a domino oxy-Cope rearrangement/carbonyl ene reaction, depending on the substrate structure. The thermal intramolecular type-I carbonyl ene reaction as the terminating ring-closing reaction proceeds with high simple diastereoselectivity, but low induced diastereoselectivity. The corresponding type-II ene reaction afforded the cyclohexanecarboxylates 7a−d in high yield with complete simple and induced diastereoselectivity. Unfortunately, an attempted auxiliary-controlled enantioselective sequence was inefficient.

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.

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.

Dianionic oxy Cope rearrangements have been shown to take place at low temperature upon syn double addition of alkenyllithium derivatives to cyclobutanedione compounds such as benzocyclobutenedione chromium complex 1 or squaric acid esters. In order to obtain some insight into the more general applicability of this type of reaction sequence beyond these special cases, a number of 1,2-diketones were treated with vinyllithium. The diketones tested include benzil derivatives, aliphatic acyclic 1,2-diketones, ortho-quinones, and cyclic aliphatic 1,2-diketones. With benzil and heterobenzil derivatives, the desired double addition/dianionic oxy Cope rearrangement was found to take place at low temperature, leading to 1,6-diketones and their intramolecular aldol adducts in up to 80% overall yield. With acyclic aliphatic 1,2-diketones as substrates, this reaction sequence was also found, albeit with somewhat lower yields and requiring higher temperatures than in the benzil cases. A brief investigation of the intramolecular aldol adduct/1,6-hexanedione equilibrium indicated that the preferential formation of intramolecular aldol adducts at lower temperatures and at shorter reaction times appears to be the result of kinetic reaction control, whereas the preference for 1,6-diketones at higher temperatures is caused by thermodynamic reaction control. ortho-Quinones reacted with vinyllithium only by addition; no dianionic oxy Cope rearrangement was observed. This was also the case for most aliphatic cyclic diketones; however, in the case of 1,2-indanedione, rearrangement products were obtained in moderate yield at elevated reaction temperatures.

1 Introduction 2 Rearrangements of Allenes and Cumulenes 3 Rearrangements of Conjugated Dienes and Polyenes 4 Rearrangements of Non-Conjugated Dienes and Polyenes Keywords: diene and polyene rearrangements; allene and cumulene rearrangements; vinylcyclopropanes and related systems; cyclic polyenes; circumambulatory rearrangements; carbocation rearrangements of cyclodienes and polyenes; non-conjugated diene and polyene rearrangement; oxy-Cope rearrangement

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.

The anionic oxy-Cope rearrangement of alkoxides derived from (1E,5Z)-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.

[(6-Methyl-1-oxa-4-thiaspiro[4.5]dec-6-en-7-yl)(allyl)methanols were subjected to anion-accelerated oxy-Cope rearrangement in solvents such as THF, benzene and DME to assess the π-facial selectivity caused by the acetal function. The diastereomeric pairs 17a and 17b (R = Ph) furnished the same two diastereomeric products 18a and 18b, differing only in the relative preponderance. The reaction of 17a turned from mostly syn to oxygen (18a∶18b = 1∶4) in THF to moderately syn to sulfur (18a∶18b = 2.2∶1) in DME. The reaction was completely nonselective in benzene. The effect of solvent on the reaction of 17b was even more interesting. The reaction turned from completely nonselective (18a∶18b = 1∶1) in THF to highly syn to sulfur (18a∶18b = 5.4∶1) in DME. The selectivity in benzene was somewhere in between (18a∶18b = 2.7∶1). Likewise, the reaction of 17b (R = H) turned from moderately syn to oxygen in THF (18a∶18b = 1∶2) to nearly nonselective in DME (18a∶18b = 1∶1.1). The rotation around the bond between the methanol carbon and the adjacent ring-carbon is restricted to allow rearrangement only syn to sulfur in 17a and syn to oxygen in 17b. The considerable erosion in the observed diastereoselectivity is due to a radical and/or ionic retroaldol–recombination process. The radical pathway, however, is more prevalent than the ionic alternative. The recombination favors somewhat the addition of the allyl radical to the cogenerated 7-benzoyl-6-methyl-1-oxa-4-thiaspiro[4.5]dec-6-ene on the face syn to the sulfur. As a result of such dissociation and recombination, the oxy-Cope rearrangement does not appear suitable as a probe for the study of diastereofacial selectivity.

The aromatic oxy-Cope rearrangement including a benzene ring took place when 1-methoxy-2-aryl-bicyclo[2.2.2]oct-5-en-2- exo -ols and 2-(2-methoxyphenyl)-bicyclo[2.2.2]oct-5-en- exo -2-ols were treated with KH in THF.

Ethynyl alcohol 4 was synthesised from (1)-menthone by the reaction sequence-hydroxyformylation, C-methylation, Wittig-olefination and addition of lithium acetylide to CO. The concerted thermally allowed oxy-Cope rearrangement of the optically active substrate 4 is reported.