Wagner-Meerwein Rearrangement Research Articles

New Pathways in Transannular Cyclization of Germacrone [Germacra-1(10),4,7(11)-trien-8-one]: Evidence Regarding a Concerted Mechanism

The transannular cyclization of germacrone with HSO(3)Cl at -78 degrees C by means of a concerted and regioselective mechanism gives rise to a bicyclo[6.2.0]decan-2-ylium intermediate ion, which evolves to unusual skeletons through subsequent cyclization and Wagner-Meerwein rearrangements. This novel germacra-1(10),4-diene cyclization could suggest the existence of a new biosynthetic pathway to sesquiterpenes.

Cyclobutanones via Ring Expansion of Allenylcyclopropanols

The gold(I)-catalyzed enantioselective ring expansion of allenylcyclopropanols is described. This protocol provides cyclobutanones with a vinyl-substituted quaternary stereogenic center in good yield and with high enantioselectivity. The proposed mechanism for the reaction involves ring expansion by a Wagner-Meerwein shift and is reported to be the first account of an enantioselective gold-catalyzed 1,2-alkyl migration.

19β,28-Epoxy-18α-olean-3β-ol

The title triterpene, C30H50O2, is an 18α-oleanane derivative prepared by the Wagner–Meerwein rearrangement of betulin with Bi(OTf)3.xH2O (OTF is trifluoromethanesulfonate). There are two symmetry-independent mol­ecules in the asymmetric unit that show no significant differences concerning bond lengths and angles. The conformation of the six-membered rings is close to a chair form, while the five-membered epoxide rings adopt envelope conformations. All rings are trans-fused. In the crystal, mol­ecules are held together by O—H⋯O hydrogen bonds. A quantum-mechanical ab initio Roothan Hartree–Fock calculation on the isolated mol­ecule gives values for bond lengths and valency angles close to the experimental values. The calculations also reproduce well the mol­ecular conformation with calculated puckering parameters that match well the observed values.

Methanetrisulfonic Acid: A Highly Efficient Strongly Acidic Catalyst for Wagner-Meerwein Rearrangement, Friedel-Crafts Alkylation and Acylation Reactions. Examples from Vitamin E Synthesis

Methanetrisulfonic acid had been prepared for the first time over 140 years ago, but it was used only scarcely in chemical transformations. In the course of our activities dealing with key-steps of industrial syntheses of vitamins, e.g. economically important vitamin E (acetate), we found that methanetrisulfonic acid is an extremely effective catalyst in a variety of reactions. Examples of its applications are Wagner-Meerwein rearrangements, Friedel-Crafts alkylations and ring closures, as well as acylation reactions. Use of this catalyst in truly catalytic amounts (0.04-1.0 mol%) resulted in highly selective transformations and yields over 95%. (Remark by the authors: We are describing only one example each for the various types of reactions. Therefore, it would be more appropriate to write (here and in the Introduction and in the Conclusion sections): “Wagner-Meerwein rearrangement, Friedel-Crafts alkylation and ring closure, as well as acylation reactions”)

Bismuth triflate-catalyzed Wagner-Meerwein rearrangement in terpenes. Application to the synthesis of the 18α-oleanane core and A-neo-18α-oleanene compounds from lupanes

The use of bismuth(III) salts as catalysts for the Wagner-Meerwein rearrangement of lupane derivatives with expansion of ring E and formation of an additional O-containing ring is reported. This process has also been extended to other terpenes, such as the sesquiterpene (-)-caryophyllene oxide. When the reaction was performed with oleanonic acid, 28,13beta-lactonization occurred, without Wagner-Meerwein rearrangement. Under more vigorous reaction conditions, dehydration of the 3beta-hydroxyl group and subsequent additional Wagner-Meerwein rearrangement led to the selective synthesis of A-neo-18alpha-oleanene compounds, in very high yields.

Formation of Quaternary Stereogenic Centers by Wagner-Meerwein Rearrangement – Synthesis of Optically Active Cyclopentadienyl Complexes from Borneol and Fenchol

The development of optically active cyclopentadienyl complexes as enantioselective catalysts calls for simple synthetic procedures for cyclopentadienes with optically active alkyl substituents. While exo-bornyl chloride and exo-fenchyl bromide do not react or exclusively eliminate hydrogen halide with cyclopentadienylmetal compounds in ether solvents or ammonia, they undergo Wagner- Meerwein rearrangement and substitution with cyclopentadienylmagnesium chloride in toluene. The bornyl cation yields racemic exo-bornylcyclopentadiene and partially racemized isocamphylcyclopentadiene, but for the fenchyl cation no racemization pathway is available, and the main diastereomer among the lithium salts of the ensuing substituted cyclopentadienes can be isolated in 95% diastereomeric purity by solvent extraction. This material with the IUPAC name lithium (2R)- 2,5,5-trimethylbicyclo[2.2.1]hept-2-ylcyclopentadienide carries an alkyl substituent having no trivial name so far. Exo-norbornylcyclopentadiene could be synthesized in high yield with a similar procedure. The same protocol works with 1-bromoadamantane. The novel alkylcyclopentadienes have been converted to ferrocenes and molybdenum complexes of the type [CpRMo(CO)3CH3]. (2R)- 2,5,5-Trimethylbicyclo[2.2.1]hept-2-ylcyclopentadiene with an optical purity of 78% ee (the optical purity of the starting material fenchol) was converted into an optically active titanocene dichloride and tested in the catalytic hydrogenation of 2-phenyl-1-butene. The hydrogenation product was obtained with 31% ee, which compares favorably with results obtained with other group 4 metallocene dichlorides with one optically active alkyl substituent on each ring ligand. Facile procedures for the synthesis of the starting compounds exo-bornyl chloride and exo-fenchyl bromide based on the tosylate method have been developed with a tosylate melt or with toluene serving as solvents.

Wagner–Meerwein rearrangement in the course of the ozonolysis of a bornene derivative

The ozonolysis of the bicyclo[2.2.1]heptene derivative 1 or 2 gave the octaline derivative 6 (the structure was confirmed by X-ray crystallographic analysis) or 7. The exo-addition of ozone to the double bond of 1 or 2 was followed by the fragmentation in carbonyl oxide and aldehyde. Then, the strong electrophilic character of the carbonyl oxide induces an unexpected Wagner–Meerwein rearrangement to give zwitterion 4. Finally, a fragmentation reaction with elimination of dioxygen gave the tetrasubstituted C–C double bonds of 6 or 7.

A New Chiral Organosulfur Catalyst for Highly Stereoselective Synthesis of Epoxides

AbstractA new chrial organosulfide was synthesized through an unexpected Wagner–Meerwein rearrangement. This organosulfide could catalyze the epoxidation reaction of various aromatic aldehydes smoothly with benzyl bromide to give trans‐diaryl epoxides in satisfactory yields (60–84%) with excellent diastereoselectivities (trans:cis=95:5–100:0) and good to excellent enantioselectivities (86–96% ee).

Palladium-Catalyzed Asymmetric Wagner-Meerwein Shift of Allenylcyclobutanols

The authors demonstrate the first asymmetric Wagner-Meerwein shift of allenylcyclobutanol with palladium catalysts by applying hydropalladation of allenes. This method provides a good way to synthesize highly substituted chiral cyclopentanones with an a-chiral O-tertiary center. They showed a further application of this method by utilizing cyclopentanone products with an ester side chain in a Claisen condensation to produce 5,5-cis and 5,6-cis bicyclic compounds.

Generation and Reaction of a Phenyl-Substituted Cyclopentadienyl Cation Annelated with Two Homoadamantene Frameworks

The generation of the title cation 2(+) and its reaction under solvolytic and non-nucleophilic conditions were investigated. When the precursor chlorocyclopentadiene 5 was reacted with silica gel that contained water or with anhydrous MeOH, the corresponding 5-hydroxy- and 5-methoxycyclopentadienes (7 and 6) were produced in 68 and 81% yields, respectively. This indicates that 2(+) is formed as an intermediate under solvolytic conditions and persists without any rearrangement of the homoadamantane frameworks, at least during the period before capture by the nucleophile. On the other hand, the abstraction of a chloride ion from 5 by Ag(+) in the absence of a nucleophile at -78 degrees C resulted in the quantitative formation of allyl cation 8(+), incorporated in a bicyclo[3.1.0]hexane framework, via the Wagner-Meerwein rearrangement of a homoadamantane framework. Cation 8(+) was isolated as the SbF6(-) salt, and its structure was determined by X-ray crystallography. Quenching this cation with MeOH afforded a methyl ether 14, with a cyclopentadiene structure retained but one of the homoadamantane frameworks had undergone a structural change by a further Wagner-Meerwein rearrangement.

ChemInform Abstract: Reaction of Selenofenchone with Propiolic Acid: First Instance of Wagner—Meerwein Rearrangement in Selone.

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Revealing Phenylium, Phenonium, Vinylenephenonium, and Benzenium Ions in Solution

The 4-methoxyphenylium ion has been generated in the triplet state ((3)An(+)) by photolysis of 4-chloroanisole in polar media and detected by flash photolysis (lambda(max)=400 nm). This is the first detection of a phenylium ion in solution by flash photolysis and the assignment is supported by time-dependent density functional theory (TD-DFT) calculations. In neat solvents, the cation was reduced to anisole, a process initiated by electron transfer from the starting compound ((3)An(+)+AnCl-->An(*)+AnCl(*+), with the radical cation detected at 470 nm, then An(*)-->AnH). Addition of pi nucleophiles to the (3)An(+) cation offers a novel access to a number of other cationic intermediates under mild, nonacidic conditions. Two intermediates are successively formed with alkenes, a diradical cation and the phenonium ion, which are detected at 440 and 320 nm, respectively, by flash photolysis and are in accordance with calculations. Allylanisoles or beta-alkoxyalkylanisoles are the end products, with a small amount of alpha-alkoxyalkylanisoles that arises from a Wagner-Meerwein rearrangement to form benzyl cations. Further intermediates that have been predicted and detected are the phenylvinylium ion, possibly in equilibrium with the vinylenephenonium ion, with 1-hexyne (lambda(max)=340 nm) and the benzenium ion with benzene (lambda(max)=380 nm). The final products were anisylhexyne and methoxybiphenyl (an analogous product and intermediate were detected with thiophene).

Two Novel Skeletal Rearrangements Involving in the C Ring of C19-Diterpenoid Alkaloid Deltaline Derivatives

Treatment of compounds 2 and 5, both from the C19-diterpenoid alkaloid deltaline 1, with 5% NaOH methanol (room temperature, 16 h) and NaOH-N,N-dimethylformamide (reflux, 10 h) led to the two novel skeletal rearrangement products 4 (90%) and 6 (62%), respectively, involving Wagner-Meerwein rearrangement and Grob fragmentation. Their structures were fully characteristized based on 2D NMR and HR-MS data.

Development of a Nazarov Cyclization/Wagner—Meerwein Rearrangement Sequence for the Stereoselective Synthesis of Spirocycles.

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Useful approach to access germanicanes from betulin

A new semisynthetic access to germanicane-type triterpenes was achieved from betulin, a natural triterpene of the lupane family. The Wagner–Meerwein rearrangement of acetylated betulinic acid allowed the formation of the typical ring E of germanicanes and a lactone function. Several germanicane derivatives can be obtained via the lactone ring-opening such as 19β-machaerocerol and 19β-machaeroceric acid. The cytotoxicity of some compounds was evaluated against two cancerous cell lines.

Reaction of selenofenchone with propiolic acid: first instance of Wagner–Meerwein rearrangement in selone

The reaction of selenofenchone ( 3a) with propiolic acid in refluxing chloroform produced selenodioxenone ( 4) along with rearranged product ( 5b), while 5b was obtained in almost quantitative yield under solvent-free conditions. In the presence of Lewis acid, selenofenchone 3a reacted with methyl propiolate to afford corresponding rearranged adduct ( 7).

Synthesis and structure–activity relationship study of cytotoxic germanicane- and lupane-type 3β- O-monodesmosidic saponins starting from betulin

Germanicane-type triterpenes allobetulin ( 3) and 28-oxoallobetulin ( 4) can be obtained by the Wagner-Meerwein rearrangement of the more available lupane-type triterpenes betulin ( 1) and betulinic acid ( 2), respectively. The medical uses of betulinic acid ( 2) and its derivatives are limited because of their poor hydrosolubility and pharmacokinetics properties. In order to overcome this major problem, we synthesized and studied the in vitro anticancer activity of a series of 3β- O-monodesmosidic saponins derived from betulin ( 14– 16), betulinic acid ( 20– 22), allobetulin ( 23– 28) and 28-oxoallobetulin ( 29– 34) based on six different natural sugar residues ( d-glucose, l-rhamnose, d-arabinose, d-galactose, d-mannose and d-xylose). This structure–activity relationship study confirmed that betulinic acid saponins are generally better in vitro anticancer agents than those derived from betulin with the exception of betulin 3β- O-α- d-mannopyranoside ( 15) which exerted a potent cytotoxic activity against lung carcinoma (A-549) and colorectal adenocarcinoma (DLD-1) human cell lines with IC 50 ranging from 7.3 to 10.1 μmol/L. Furthermore, although the synthesis of novel germanicane-type saponins was carried out with success, the bioactivity measured for these glycosides was not as high as we anticipated since only the 3β- O-β- d-glucopyranoside and 3β- O-β- d-galactopyranoside of allobetulin ( 23, 24) showed moderate anticancer activity (IC 50 30–40 μmol/L).

Development of a Nazarov Cyclization/Wagner−Meerwein Rearrangement Sequence for the Stereoselective Synthesis of Spirocycles

A stereoselective Nazarov cyclization/Wagner−Meerwein rearrangement sequence for the synthesis of spirocyclic compounds was developed. While a range of different substrate types engaged in the cyclization/rearrangement sequence, it was found that different substrates underwent different reaction pathways. Depending on the substitution pattern of the substrate, the sequence was terminated by either a hydride shift or the shift of a vinyl or aryl group. It was also possible to install adjacent quaternary stereocenters using this protocol. The efficiency of the Wagner−Meerwein rearrangement was found to be dependent upon both the type and the amount of promoter used to generate the intermediate oxyallyl cation.

Wagner‐Meerwein rearrangement of a [3.3.3]‐ to a [4.3.3]propellane: deuterium tracer and conformational analysis

Formation of (-)-[4.3.3]propellane 4 from (-)-14-hydroxymodhephene (2) proceeds through a Wagner-Meerwein rearrangement via C3--C4 bond-shift to give a stable intermediate, dimethylcyclohexadienyl cation A, which undergoes deprotonation. Herein, this mechanism was investigated by using a deuterium labeled substrate at the C-14 methylene group of (-)-2, which was incorporated into the C-4 position of (-)-[4.3.3]propellane 4. The stereostructure of (-)-4 was investigated by applying a combination of NMR experimental and theoretical approaches.

Theoretical study of the role of solvent H2O in neopentyl and pinacol rearrangements

The neopentyl and the pinacol rearrangements as examples of Wagner-Meerwein rearrangements were investigated by the use of DFT calculations. As the first reaction, a model of neopentyl chloride (1b) and (H2O)12 was employed. In the reaction, the patterns of C--Cl scission, methyl migration, and C--OH formation were analyzed. The calculations have shown that the 2-methyl-2-butanol (6) is formed in two steps with the transient intermediate, neopentyl alcohol (3). The first step is the nucleophilic substitution reaction and is the rate-determining one. The second step is the dual migration of methyl and OH2 groups. The primary and tertiary carbocations were calculated to be absent in the neopentyl rearrangement starting from the hydrolysis. As the second reaction, the pinacol rearrangement of two substrates 2,3-dimethyl-2,3-butanediol (7) and 2,3-diphenyl-2,3-butanediol (12) was investigated. Acidic aqueous solvent was modeled by H3O+ and 12H2O. The reaction paths were promoted by a hydrogen-bond circuit of H3O+(H2O)2 and were determined as completely concerted processes. Protonated species and carbocations as intermediates also do not intervene during the pinacol rearrangement. Active functions of proton relays along the hydrogen bonds in the two rearrangements were demonstrated.