Wagner-Meerwein Rearrangement Research Articles

Single-Carbon Insertion into Single C-C Bonds with Diazirines.

A novel platform for the skeletal editing of single C-C bonds via a single-carbon insertion has been developed using diazirines. This strategy involves the photogeneration of arylchlorocarbenes as carbynoid species that undergo site-selective carbene insertion into tertiary C-H bonds and a subsequent Wagner-Meerwein rearrangement promoted by a silver salt. Our skeletal editing strategy based on a formal selective carbyne C-C bond insertion has been demonstrated in six core-to-core conversions, including linear and cyclic benzylic substrates, alkanes and late-stage functionalizations.

4+1] Heteroannulation to Form 1‐Pyrrolines through Alder‐Ene Reaction of in situ Generated Ynimines: Development and Application in Total Synthesis of Borrecapine

AbstractWe report in this paper a novel Cu‐catalyzed synthesis of polysubstituted 1‐pyrrolines. The reaction of β,γ‐unsaturated oxime esters 4 with terminal alkynes 5 in the presence of a catalytic amount of Cu(OAc)2 and 2,2′‐biquinoline affords the corresponding 1,6‐enynimines, which undergo a highly stereoselective Alder‐ene reaction to afford 1‐pyrrolines with concomitant generation of a quaternary carbon and a 2‐azadiene motif. It represents an unusual [4+1] heteroannulation reaction wherein terminal alkynes act as a one carbon donor and are 1,1‐difunctionalized. Mechanistic studies suggest that the allylic hydrogen trans to the oxime ester main chain is selectively transferred to the electron‐rich alkyne during the pericyclic reaction. The resulting 1‐pyrrolines undergo facile acid‐catalyzed regioselective Wagner–Meerwein rearrangement to provide 2H‐pyrroles in excellent yields. The 2H‐pyrroles are also accessible from 4 and 5 in a one‐pot manner without isolation of the 1‐pyrrolines. Leveraging this heteroannulation reaction as a key step, the first total synthesis of borrecapine, a 2,3,3,5‐tetrasubstituted pyrrolidine, is accomplished.

4+1] Heteroannulation to Form 1-Pyrrolines through Alder-Ene Reaction of in situ Generated Ynimines: Development and Application in Total Synthesis of Borrecapine.

We report in this paper a novel Cu-catalyzed synthesis of polysubstituted 1-pyrrolines. The reaction of β,γ-unsaturated oxime esters 4 with terminal alkynes 5 in the presence of a catalytic amount of Cu(OAc)2 and 2,2'-biquinoline affords the corresponding 1,6-enynimines, which undergo a highly stereoselective Alder-ene reaction to afford 1-pyrrolines with concomitant generation of a quaternary carbon and a 2-azadiene motif. It represents an unusual [4+1] heteroannulation reaction wherein terminal alkynes act as a one carbon donor and are 1,1-difunctionalized. Mechanistic studies suggest that the allylic hydrogen trans to the oxime ester main chain is selectively transferred to the electron-rich alkyne during the pericyclic reaction. The resulting 1-pyrrolines undergo facile acid-catalyzed regioselective Wagner-Meerwein rearrangement to provide 2H-pyrroles in excellent yields. The 2H-pyrroles are also accessible from 4 and 5 in a one-pot manner without isolation of the 1-pyrrolines. Leveraging this heteroannulation reaction as a key step, the first total synthesis of borrecapine, a 2,3,3,5-tetrasubstituted pyrrolidine, is accomplished.

Selectfluor and alcohol-mediated synthesis of bicyclic oxyfluorination compounds by Wagner-Meerwein rearrangement.

Herein, we report the first environmentally friendly systematic fluoroalkoxylation reactions in bicyclic systems. New oxyfluorination products were obtained with excellent yields (up to 98%) via Wagner-Meerwein rearrangement using benzonorbornadiene and the chiral natural compound (+)-camphene as bicyclic alkenes, selectfluor as an electrophilic fluorine source, and water and various alcohols as nucleophile sources. The structure of bicyclic oxy- and alkoxyfluorine compounds was determined by NMR and QTOF-MS analyses.

Dauresorcinols A and B, two pairs of merosesquiterpenoid enantiomers with new carbon skeletons from Rhododendron dauricum

Five pairs of new merosesquiterpenoid enantiomers, named dauresorcinols A−E (1−5), were isolated from the leaves of Rhododendron dauricum. Their structures were elucidated by comprehensive spectroscopic data analysis, quantum chemical calculations, Rh2(OCOCF3)4-induced ECD, and single-crystal X-ray diffraction analysis. Dauresorcinols A (1) and B (2) possess two new merosesquiterpene skeletons bearing an unprecedented 2,6,7,10,14-pentamethyl-11-oxatetracyclo[8.8.0.02,7.012,17]octadecane and a caged 15-isohexyl-1,5,15-trimethyl-2,10-dioxatetracyclo[7.4.1.111,14.03,8]pentadecane motif, respectively. Plausible biosynthetic pathways of 1−5 are proposed involving key oxa-electrocyclization and Wagner−Meerwein rearrangement reactions. (+)/(−)-1 and 3−5 showed potent α-glucosidase inhibitory activity, 3 to 22 times stronger than acarbose, an antidiabetic drug targeting α-glucosidase. Docking results provide a basis to design and develop merosesquiterpenoids as potent α-glycosidase inhibitors.

Forging the Tetracyclic Core Framework of Rhodomolleins XIV and XLII: A Ring-Distortion Approach.

A ring distortion approach for the synthesis of an advanced intermediate en route to rhodomolleins XIV and XLII was described, which led to successful construction of the 5/8/5/5 tetracyclic core framework of the kalmane diterpenoids. Key steps of the strategy include an oxidative dearomatization-induced (ODI)-Diels-Alder cycloaddition, a Dowd-Beckwith rearrangement, and a bioinspired Wagner-Meerwein rearrangement.

Catalytic Enantioselective Wagner–Meerwein Rearrangement of Alkenyl Cycloalkanes

Catalytic Enantioselective Wagner–Meerwein Rearrangement of Alkenyl Cycloalkanes

Exploiting 3-Oxidopyraziniums toward Diazabicyclo[3.2.1]octanes and Their Conversion into Diazabicyclo[2.2.2]octanes and Tricyclic Lactone-Lactams.

3-Oxidopyraziniums are azomethine ylides derived from 2(1H)-pyrazinones that can undergo 1,3-dipolar cycloadditions with acrylate and acrylic acid derivatives. The cycloaddition of 1-(4-methoxybenzyl)-5,6-dimethyl-3-oxidopyrazinium with methyl and tert-butyl acrylate and with methyl crotonate afforded a 3,8-diazabicyclo[3.2.1]octane in 51-73% yield together with traces of the 2,5-diazabicyclo[2.2.2]octane. In contrast, cycloaddition of this 3-oxidopyrazinium with methyl 2-phenyl acrylate provided the [2.2.2] product in 40% yield. Herein, we show that the 2,5-diazabicyclo[2.2.2]octanes were formed from the [3.2.1] compounds via a Wagner-Meerwein rearrangement. Remarkably, when acrylic acid and 2-phenylacrylic acid were employed as dipolarophiles, novel tricyclic fused lactone-lactam systems were obtained in 71% and 50% yields, respectively. The formation of these tricyclic compounds can be rationalized via the mechanism described above followed by lactonization of the 2,5-diazabicyclo[2.2.2]octane.

Catalytic condensation of α-pinene with formaldehyde

While synthesis of hydroxymethyl derivatives of common terpenes by a reaction with formaldehyde (FA) has been commercialized, no open data are available on the preparation of such α-pinene derivatives. Here, an approach for the renewable (–)-α-pinene catalytic utilization by its condensation with FA into a novel terpenoid 8-acetoxy-6-hydroxymethyllimonene is proposed. Both common homogeneous acids and aluminosilicates (halloysite nanotubes pretreated with H3PO4 and HCl, montmorillonite K-10, zeolite H-Beta-25) have been investigated. The solids were characterized by SEM, EDX, 27Al and 29Si MAS NMR, as well as FTIR with pyridine and N2 adsorption–desorption methods. Traditional Lewis and Brønsted acids (ZnCl2, FeCl3, H3PO4 etc.) catalyzed the desired condensation although selectivity did not exceed 24 % in the case of phosphoric acid due to the side reactions, including opening of the α-pinene cyclobutane ring, as well as skeletal rearrangements of its bicyclic structure. On aluminosilicates with a weak to moderate Lewis and Brønsted acidity (45–104 µmol/g), the products of a direct substrate protonation (up to 52.8 %) were predominantly formed. In the presence of strongly acidic H-Beta-25 (301 µmol/g) and phosphoric acid, selectivity to α-pinene addition products with formaldehyde (32.3–35.3 %) and substrate direct protonation (30.0–36.8 %) were comparable. However, with H3PO4 the content of borneol derivatives formed via the Wagner-Meerwein rearrangement was the smallest (13.5 %) giving subsequently the largest selectivity to the desired 8-acetoxy-6-hydroxymethyllimonene. Higher selectivity to the target product was observed at lower reaction temperature and a larger formaldehyde amount. The reaction mechanism has been proposed and elucidated using kinetic and quantum chemical approaches. The developed kinetic model adequately describes the experimental results. The DFT calculations showed that in the presence of H3PO4 there are no significant differences between the energy of the intermediates formed due to formaldehyde addition to α-pinene or its direct protonation. Synthesis of 8-acetoxy-6-hydroxymethyllimonene was performed on 22 g scale. This compound can be considered as a chiral platform for further utilization, including synthesis of heterocyclic compounds.

Catalytic asymmetric cationic shifts of aliphatic hydrocarbons

Asymmetric catalysis is an advanced area of chemical synthesis, but the handling of abundantly available, purely aliphatic hydrocarbons has proven to be challenging. Typically, heteroatoms or aromatic substructures are required in the substrates and reagents to facilitate an efficient interaction with the chiral catalyst. Confined acids have recently been introduced as tools for homogenous asymmetric catalysis, specifically to enable the processing of small unbiased substrates1. However, asymmetric reactions in which both substrate and product are purely aliphatic hydrocarbons have not previously been catalysed by such super strong and confined acids. We describe here an imidodiphosphorimidate-catalysed asymmetric Wagner–Meerwein shift of aliphatic alkenyl cycloalkanes to cycloalkenes with excellent regio- and enantioselectivity. Despite their long history and high relevance for chemical synthesis and biosynthesis, Wagner–Meerwein reactions utilizing purely aliphatic hydrocarbons, such as those originally reported by Wagner and Meerwein, had previously eluded asymmetric catalysis.

ГЕТЕРОЦИКЛИЧЕСКИЕ ТИОПРОИЗВОДНЫЕ КАМФЕНА С ФРАГМЕНТОМ ФЕНИЛТЕТРАЗОЛА

It is known that the tetrazole ring is an important pharmacophore fragment included in the structure of drugs with more than 20 types of biological activity. In order to obtain new biologically active thioterpenoids with heterocyclic fragments, we set the task of combining the natural terpene skeleton and the nitrogen-containing heterocyclic function through the biogenic sulfur atom. We have used thiylation and sulfenylchlorination of (+)-camphene and its derivatives, which are difficult to obtain synthetically (cyclopropene and allene), with 1-phenyltetrazole-5-thiol and 1-phenyltetrazole-5-sulfenyl chloride. Studying the structure of hetarene sulfide obtained by the reaction of camphene with 1-phenyltetrazole-5-thiol in the presence of a Lewis acid (boron trifluoride etherate), allowed us to conclude that during the reaction a Wagner-Meerwein rearrangement occurs. The rearrangement leads to isomerization of the initial camphane structure with the formation of a terpene sulfide of bornane structure with an exo-position of the sulfide group relative to the bicyclic skeleton of the molecule. In non-catalytic sulfenylchlorination reactions isomerization of the camphene skeleton is not observed. 2,2-Dimethylnorbornane-3-spirocyclopropene forms the product of the “normal” addition of 1-phenyltetrazole-5-sulphenyl chloride to the double bond of cyclopropene. A mixture of two regioisomers with a trans-position of the sulfide group and a chlorine atom is observed. In this case, the chlorine atom is located on the endo side of the cyclopropane ring relative to the gem-dimethyl group, while the sulfide group is on the exo side. Sulfenylchlorination of 2,2-dimethyl-3-ethenylidenenorbornane occurs regio- and stereospecifically at a sterically less hindered double bond, with the sulfide group located at the C-10 atom and the chlorine atom at the C-11 atom.

Thermal reaction products and formation pathways of two monoterpenes under in situ thermal desorption conditions that mimic vaping coil temperatures

Vaping has become more popular and different brands and types of vaping devices have rapidly emerged. However, little is known about the potential health risks of human inhalation exposures to the volatile chemicals in the vapour, which includes both directly vaporised components of vaping liquid and their reaction products formed during vaping processes. This study investigated reaction products of two monoterpenes (α-pinene and terpinolene) that are used as flavouring agents in vaping liquids with a focus on the identification of reaction products and their formation pathways. The thermal desorption was conducted under an in situ condition that is in the range of heating coil temperature in vaping by thermally desorbing the chemicals at a temperature range of 100–300 °C. Additional clean air was introduced during the thermal desorption. 36 and 29 reaction products were identified from α-pinene and terpinolene, respectively, at a relative concentration of 0.01% and greater in the desorbed mixture. 3-Carene was the dominant reaction product of α-pinene, while reaction products of terpinolene was dominated by p-isopropenyltoluene. Several reaction pathways including ring opening, allylic oxidation, cyclo-etherification, Wagner–Meerwein rearrangement, epoxidation, cleavage and removal of partial structure, and dehydration were involved in the formation of various reaction products. These pathways and resulting relative concentrations of residual parent compound and reaction products were influenced by both temperature and amount of air present during thermal desorption. The study results demonstrate possible existence of reaction products from thermally labile chemicals like monoterpenes in vaping aerosols and can help inform policies regulating vaping devices and products to protect public health.

Stereoselective Synthesis and Antiproliferative Activity of Steviol-Based Diterpene 1,3-Aminoalcohol Regioisomers.

A series of novel diterpene-type 1,3-aminoalcohols and their regioisomers have been synthesised from natural stevioside in a stereoselective manner. The key intermediate β-keto alcohol was prepared using Wagner-Meerwein rearrangement of the epoxide derived from steviol methyl ester. The primary aminoalcohol was formed via Raney-nickel-catalysed hydrogenation of an oxime, and a versatile library of aminoalcohols was synthesised using a Schiff base with the primary amines. The aminoalcohol regioisomers were prepared from the mesylate of the β-keto alcohols. The corresponding primary aminoalcohol was formed via the palladium-catalysed hydrogenation of hydroxyl-azide, and click reactions of the latter were also carried out. The new compounds were characterised using 1D- and 2D-NMR techniques and HRMS measurements. The in vitro investigations showed high inhibition of cell growth in human cancer cell lines (HeLa, SiHa, A2780, MCF-7 and MDA-MB-231) in the case of naphthalic N-substituted derivatives. The antiproliferative effects were assayed using the MTT method.

Catalyst‐Controlled Divergent Generations and Transformations of α‐Carbonyl Cations from Alkynes**

Abstractα‐Carbonyl cations are the umpolung forms of the synthetically fundamental α‐carbonyl carbanions. They are highly reactive yet rarely studied and utilized species and their precursors were rather limited. Herein, we report the catalyst‐controlled divergent generations of α‐carbonyl cations from single alkyne functionalities and the interception of them via Wagner–Meerwein rearrangement. Two chemodivergent catalytic systems have been established, leading to two different types of α‐carbonyl cations and, eventually, two different types of products, i.e. the α,β‐ and β,γ‐unsaturated carbonyl compounds. Broad spectrum of alkynes including aryl alkyne, ynamide, alkynyl ether, and alkynyl sulfide could be utilized and the migration priorities of different groups in the Wagner–Meerwein rearrangement step was elucidated. Density functional theory calculations further supported the intermediacy of α‐carbonyl cations via the N−O bond cleavage in both the two catalytic systems. Another key feature of this methodology was the fragmentation of synthetically inert tert‐butyl groups into readily transformable olefin functionalities. The synthetic potential was highlighted by the scale‐up reactions and the downstream diversifications including the formal synthesis of nicotlactone B and galbacin.

Catalyst-Controlled Divergent Generations and Transformations of α-Carbonyl Cations from Alkynes.

α-Carbonyl cations are the umpolung forms of the synthetically fundamental α-carbonyl carbanions. They are highly reactive yet rarely studied and utilized species and their precursors were rather limited. Herein, we report the catalyst-controlled divergent generations of α-carbonyl cations from single alkyne functionalities and the interception of them via Wagner-Meerwein rearrangement. Two chemodivergent catalytic systems have been established, leading to two different types of α-carbonyl cations and, eventually, two different types of products, i.e. the α,β- and β,γ-unsaturated carbonyl compounds. Broad spectrum of alkynes including aryl alkyne, ynamide, alkynyl ether, and alkynyl sulfide could be utilized and the migration priorities of different groups in the Wagner-Meerwein rearrangement step was elucidated. Density functional theory calculations further supported the intermediacy of α-carbonyl cations via the N-O bond cleavage in both the two catalytic systems. Another key feature of this methodology was the fragmentation of synthetically inert tert-butyl groups into readily transformable olefin functionalities. The synthetic potential was highlighted by the scale-up reactions and the downstream diversifications including the formal synthesis of nicotlactone B and galbacin.

Discovery of neo-Clerodane Diterpenoids from Ajuga campylantha as Neuroprotective Agents against Ferroptosis and Neuroinflammation.

Twelve new neo-clerodane diterpenoids, eight undescribed methoxy/ethoxy acetal analogues, and one new nor-iridane monoterpenoid were isolated from Ajuga campylantha. Their structures were elucidated using a combination of spectroscopic data, quantum chemical calculations, and X-ray crystallography. This research reveals the distinctive structural features of A. campylantha diterpenes, including distinct C rings and 4,18-double bonds, distinguishing them from diterpenes of other plants in the Ajuga genus. Compound 2 represents the first example of a 19(5→6)-abeo-clerodane formed through a Wagner-Meerwein rearrangement. The isolated compounds were assessed for their neuroprotective effects against RSL3-induced ferroptosis in HT22 cells and LPS-induced neuroinflammation in BV-2 cells. Notably, compound 7 inhibits ferroptosis (EC50 = 10 μM) with a potentially new mechanism of action. The preliminary structure-activity relationship studies revealed that the furan-clerodane diterpenoids possess potential ferroptosis inhibitory activity, while the lactone-clerodanes do not. This study represents the first report of furan-containing clerodanes within the Ajuga genus, providing fresh insights into the phytochemistry and pharmacological potential of A. campylantha.

Cobalt‐Catalyzed Wagner–Meerwein Rearrangements with Concomitant Nucleophilic Hydrofluorination

AbstractWe report a cobalt‐catalyzed Wagner–Meerwein rearrangement of gem‐disubstituted allylarenes that generates fluoroalkane products with isolated yields up to 84 %. Modification of the counteranion of the N‐fluoropyridinium oxidant suggests the substrates undergo nucleophilic fluorination during the reaction. Subjecting the substrates to other known metal‐mediated hydrofluorination procedures did not lead to observable 1,2‐aryl migration. Thus, indicating the unique ability of these cobalt‐catalyzed conditions to generate a sufficiently reactive electrophilic intermediate capable of promoting this Wagner–Meerwein rearrangement.

Cobalt-Catalyzed Wagner-Meerwein Rearrangements with Concomitant Nucleophilic Hydrofluorination.

We report a cobalt-catalyzed Wagner-Meerwein rearrangement of gem-disubstituted allylarenes that generates fluoroalkane products with isolated yields up to 84 %. Modification of the counteranion of the N-fluoropyridinium oxidant suggests the substrates undergo nucleophilic fluorination during the reaction. Subjecting the substrates to other known metal-mediated hydrofluorination procedures did not lead to observable 1,2-aryl migration. Thus, indicating the unique ability of these cobalt-catalyzed conditions to generate a sufficiently reactive electrophilic intermediate capable of promoting this Wagner-Meerwein rearrangement.

Progress toward the asymmetric de novo synthesis of lanostanes: A counter biomimetic cucurbitane-to-lanostane type transformation

An oxidative rearrangement has been established that enables a cucurbitane-to-lanostane type rearrangement that is counter to known biomimetic transformations that proceed in an opposite direction by way of a lanostane-to-cucurbitane transformation. Here, an oxidative dearomatization/Wagner–Meerwein rearrangement with a substrate bearing the characteristic cucurbitane triad of quaternary centers at C9, C13 and C14, and possessing an alkene at C11–C12, proceeds in a manner that selectively shifts the methyl group at C9 to C10 in concert with the establishment of a sterically hindered allylic cation. The major product isolated from this transformation is formed by trapping of the allylic cation by addition of acetate to C12, rather than termination of the cascade by loss of a proton at C8. While proceeding by way of a unique sequence of bond-forming reactions that begins by oxidative dearomatization, this process achieves what we believe is an unprecedented cucurbitane-to-lanostane transformation, generating a product that contains the characteristic lantostane triad of quaternary centers at C10, C13 and C14 while also delivering a functionalized C-ring.

Synthesis and Structure of N-(1-(Bromomethyl)-7,7-dimethylbicyclo[2.2.1]heptan-2-yl)benzenesulfonamide

A new bicyclic sulfonamide derivative, N-(1-(bromomethyl)-7,7-dimethylbicyclo[2.2.1]heptan-2-yl)benzenesulfonamide, was synthesized in the reaction of benzenesulfonamide and camphene in the presence of N-bromosuccinimide in acetonitrile. The proposed mechanism of investigated reaction involves the Wagner–Meerwein rearrangement stage. 3-(Bromomethylene)-2,2-dimethylbicyclo[2.2.1]heptane was isolated as a minor product. The products were characterized by IR, NMR spectroscopy, X-ray diffraction analysis, HRMS and elemental analysis data.