Cross-metathesis Reaction Research Articles

Selective Cross-Metathesis Versus Ring-Closing Metathesis of Terpenes, Taking the Path Less Travelled.

A diiodo ruthenium olefin metathesis pre-catalyst was employed to achieve remarkably selective cross-metathesis reactions of prenylated 1,6-dienes, effectively overcoming the entropically favored intramolecular ring-closing metathesis. This reaction was investigated using Density Functional Theory (DFT) computations and fine-tuned through the application of a Design of Experiments (DoE) approach. The potential of this innovative process was demonstrated through the unprecedented functionalization of various terpene natural products via cross-metathesis, resulting in the synthesis of new derivatives in a single step.

Chiron approach toward the synthesis of the fused tricyclic core of epi-parvistemonine A

A stereoselective synthesis of fused tricyclic framework of epi-parvistemonine A from D-glucono-δ-lactone is described. The synthetic strategic is based on the stereoselective construction of the 7-membered cyclic skeleton via a cross-metathesis reaction followed by a Michael type cyclization promoted by Tf2O.

Exploring the ring-opening metathesis polymerization process by kinetic Monte Carlo simulation

Investigating the kinetics of polymerization reactions is a powerful tool to obtain information for the engineering design of such processes. It provides insights into how the relative rates of elementary reactions which influence both the kinetics of the reactions and thus characteristics of the products as well, particularly when the reaction parameters of these reactions are unknown. Among polymerization processes, ring-opening metathesis polymerization (ROMP) has gained broad academic and industrial interest, due to its mild conditions to obtain a wide range of polymer products. In this study, kinetic Monte Carlo simulation was applied to reveal the effect of the elementary reactions of ROMP on the kinetics and product distribution. Both the propagation and the cross-metathesis reactions were considered, with the latter leading to the formation of various types of macrospecies whose population levels were also monitored. Relevant tendencies were observed regarding how the variations in the reaction parameters of the elementary reactions of this polymerization process, such as reaction probabilities, monomer addition method, catalyst-to-monomer ratio, and reaction time, affect the kinetics of the polymerization process and the product distributions. These variations also influence the key macromolecular parameters of the resulting polymeric materials, including chain length distribution (CLD), population levels, and polymer functionalities. The results of this study indicate that this simulation technique is a valuable tool for mapping the tailoring possibilities of modifying the reaction parameters of ROMP to achieve desired properties. These properties include number average molecular weight, polydispersity, chain end functionality, and macrocycle-free products.

Concise and Stereospecific Total Synthesis of Arenastatin A and Its Segment B Analogs.

A novel and concise synthetic method for arenastatin A, a cytotoxic cyclic depsipeptide of marine origin, was developed in this study. The convergent assembly of the four segments, including the cross-metathesis reaction, gave a cyclization precursor, and Fmoc deprotection caused simultaneous macrocyclization. The Corey-Chaykovsky reaction using a chiral sulfur ylide afforded arenastatin A with complete stereoselectivity in the longest linear sequence of seven reaction steps from the known compound. Using this synthetic method, some analogs of segment B were prepared through a late-stage diversification strategy. The simple SN2 reaction of the thiolate toward the tosylate precursor, prepared using almost the same synthetic method as described above, provided the desired sulfide analogs.

Total Syntheses and Stereochemical Assignment of Acremolides A and B.

The absolute stereochemical configurations of acremolides A and B were predicted by a biochemistry-based rule and unambiguously confirmed through their total syntheses. The features of the total syntheses include sequential Krische's Ir-catalyzed crotylation, Brown's borane-mediated crotylation, Mitsunobu esterification reaction, and cross-metathesis reaction. The efficient total synthesis enabled clear validation of the predicted stereochemistry for acremolides A and B.

Versatile fabrication of palygorskite/diene-based rubber nanocomposites via autogenous-modification and sulfur co-vulcanization strategy

The dispersion and stability of nanofillers in polymer matrices are the main challenges in polymer nanocomposites, especially the rubber nanocomposites. Here, autogenous-modification of nanofillers was proposed for a good dispersion, and therefore a good stability could be achieved via sulfur co-vulcanization with rubber matrix. With the palygorskite (Pal)/nitrile-butadiene rubber (NBR) nanocomposite as an example, NBR chains could be introduced onto the Pal nanorods via surface cross-metathesis reaction, and then the resultant NBR grafted Pal nanorods (NBR-Pal) could be co-vulcanized with NBR matrix. The incorporation of the Pal nanorods in the crosslinked network was revealed by the X-ray photoelectron spectroscopy (XPS) analysis after de-vulcanization. The proposed strategy is expected to impel the mass production and practical application of high-performance diene-based rubber nanocomposites.

Synthesis and Ring‐Closing Reactions of Aminocyclohexane Derivatives Bearing Unsaturated Side Chains at C2: Stereocontrolled Approaches to cis‐ and trans‐Fused Perhydro‐indoles and ‐Quinolines

AbstractTwo epimeric pairs of N‐Ts‐protected cyclohexylamines that incorporate an unsaturated side‐chain at the C2 position have been prepared. Contrary to expectations, none of these underwent clean, photochemically‐induced intramolecular hydroamination reactions to give the corresponding perhydro‐indole or ‐quinolines. However, they did participate in efficient olefin cross metathesis (OCM) reactions with methyl crotonate. Three of the four acrylates so‐formed engaged in base‐promoted and completely diastereoselective, intramolecular aza‐Michael addition (cyclization) reactions to give the isomeric and C2‐substituted perhydro‐indoles or ‐quinolines with the structures of these being confirmed by single‐crystal X‐ray analyses. DFT calculations generated results consistent with the observed diastereoselectivities and the proposed transition states. Manipulation of the ester groups associated with the cyclization products allowed for their conversion, inter alia, into the corresponding n‐propyl residues and thus providing novel analogues of neurotoxic alkaloids such as pumiliotoxin C.

An efficient approach towards highly chemically stable poly(norbornene) membrane for alkaline polyelectrolyte fuel cells

The chemical stability of alkaline polymer electrolytes (APEs) is paramount for ensuring the long-term durability of alkaline polyelectrolyte fuel cells. Convenient methods for acquiring highly stable polymers are pivotal for fuel cell commercialization. Herein, we propose a novel strategy involving post-polymerization and grafting via cross-metathesis reaction to yield highly alkaline-stable quaternary ammonium polynorbornenes (QAPNBs). This method boasts mild reaction conditions, high yields, and cost-effective reactants. The yields have increased from less than 40 % to an impressive 80 %. Upon comparing the alkaline stability of APEs with different side chain structures, it was observed that the presence of unsaturated double bonds in the side chain adversely affected the cations, while saturated APEs retained over 90 % of the cations during stability tests at 80 °C and 1 M KOH for 4800 h. Employing the QAPNBs in fuel cells resulted in a peak power density of 2.32 W cm−2 and a durability of 200 h at 600 mA cm−2.

Sphaeropsidin A C15-C16 Cross-Metathesis Analogues with Potent Anticancer Activity.

We recently discovered that sphaeropsidin A (SphA), a fungal metabolite from Diplodia cupressi, overcomes apoptosis resistance in cancer cells by inducing cellular shrinkage by impairing regulatory volume increase. Previously, we prepared a pyrene-conjugated derivative of SphA by a cross-metathesis reaction involving the phytotoxin's C15,C16-alkene. This derivative's evaluation in a cancer cell panel revealed a significant increase in potency, with the IC50 values 5-10× lower than those displayed by the original natural product. Herein, we describe the preparation and anticancer evaluation of fifteen novel C15,C16-alkene cross-metathesis analogues in which the pyrene moiety was replaced with other aromatic or non-aromatic hydrophobic groups. The idea for this replacement was to prepare a family of compounds that would not be predicted to be mutagenic compared with the original pyrene analogue. We predict several of our new compounds to be non-mutagenic, while retaining the high potency of the original pyrene-containing analogues. Examples of these potential lead compounds included those containing pentamethylphenyl and triphenylethylene pendant groups. As an additional feature of the current investigation, we prepared several deuterated pyrene-containing compounds to overcome intellectual property issues associated with non-patentability of the original pyrene derivative.

Synthesis and structural affirmation of pubesamides A and B, monoterpene N-benzoyltyramides from white sapote (Casimiroa pubescens)

Pubesamides A and B are structurally unusual monoterpene N-benzoyltyramides isolated from Casimiroa pubescens, a tropical fruiting tree with known psychotropic properties. Herein we report the structural affirmation of both natural products through a chemical synthesis that features a Lewis-acid assisted cross-metathesis reaction between a 1,1-disubstituted alkene and a dienone in the presence of the Hoveyda-Grubbs second generation catalyst. Stereochemically pure samples of pubesamide A and B isomerise upon standing, suggesting they are both genuine natural products.

Alkene Cross-Metathesis with 2,5-Dimethyl-2,4-Hexadiene Enables Isobutylenyl/Prenyl Functionalizations and Rubber Valorization.

2,5-Dimethyl-2,4-hexadiene is a readily available and easily managable compound, whose symmetric and polymethylated dienic structure should be prone to engage in cross-metathesis reactions with other alkenes, but this has not been apparently exploited so far. Here we show that this reactant enables the easy synthesis of tri- and tetra-susbtituted alkenes (i. e. isobutylenyl and prenyl groups) from simple alkenes under mild reaction conditions, not only with the conventional 2nd generation Grubbs catalyst but also with other Grela-type catalyts such as StickyCat,TM AquaMetTM and GreenCatTM. The use of liquid and low volatile 2,5-dimethyl-2,4-hexadiene avoids the use of gaseous alkene reactants and, besides, showcases the reactivity of polyisoprene (rubber), thus allowing to optimize the reaction conditions for rubber upcycling, after metathesis reaction of the pristine or used polymer with simple alkenes. These results bring low volatile isoprene-type compounds as privileged poly-substituted reactants for alkene cross-metathesis reactions.

Recent Synthesis of Nucleoside Phosphonate Analogs Using Olefin Cross-metathesis.

Nucleotide analogs known as acyclic and cyclic nucleoside phosphonates (ANPs and CNPs, respectively) have a variety of biological properties, including antibacterial, antiviral, antiparasitic, antineoplastic, and immunomodulatory. A strong reaction that has emerged in the last several decades has fundamentally changed our knowledge of the chemistry of nucleoside phosphonates. In particular, Olefin cross-metathesis (CM) has been a potent and practical synthesis route to produce functionalized olefins from essential alkene precursors. This review describes recent synthesis examples of ANPs and CNPs analogs using the Ru-catalyzed olefin cross-metathesis reactions. Olefin cross-metathesis reactions are performed in the olefinic parts of nucleoside and phosphonate produced by Grubbs, Hoveyda-Grubbs, and Nolan. This review presents a synthetic overview of a few chosen nucleosides with biological significance. Their biological activity results are briefly discussed.

Cyclic (amino)(barrelene)carbene Ru-complexes: synthesis and reactivity in olefin metathesis.

The synthesis of ruthenium-complexes with cyclic (amino)(barrelene)carbenes (namely CABCs) as ligands is reported. Isolated in moderate to good yields, these new complexes showed impressive thermal stability at 110 °C over several days. Good catalytic performances were demonstrated in various ring-closing metathesis (RCM), macrocyclic-RCM, ring-closing enyne metathesis (RCEYM), cross-metathesis (CM), and ring-opening cross metathesis (ROCM) reactions.

Double strain-release enables formal C-O/C-F and C-N/C-F ring-opening metathesis.

Metathesis reactions have been established as a powerful tool in organic synthesis. While great advances were achieved in double-bond metathesis, like olefin metathesis and carbonyl metathesis, single-bond metathesis has received less attention in the past decade. Herein, we describe the first C(sp3)-O/C(sp3)-F bond formal cross metathesis reaction between gem-difluorinated cyclopropanes (gem-DFCPs) and epoxides under rhodium catalysis. The reaction involves the formation of a highly electrophilic fluoroallyl rhodium intermediate, which is capable of reacting with the oxygen atom in epoxides as weak nucleophiles followed by C-F bond reconstruction. The use of two strained ring substrates is the key to the success of the formal cross metathesis, in which the double strain release accounts for the driving force of the transformation. Additionally, azetidine also proves to be a suitable substrate for this transformation. The reaction offers a novel approach for the metathesis of C(sp3)-O and C(sp3)-N bonds, presenting new opportunities for single-bond metathesis.

Stereoselective convergent total synthesis of oxylipins.

We synthesized stereoselectively four stereoisomers of oxylipins (1a-d) by a convergent approach based on chiral catalysis. The synthetic approach involved sequential assembly of two key fragments - ene-diol and allyl alcohol - for an intended convergent cross-metathesis reaction to join these fragments. The key steps include Sharpless kinetic resolution, asymmetric dihydroxylation and Grubbs cross-metathesis. The characterization of the synthesized oxylipins revealed spectroscopic data that were consistent with previously reported values.

Synthetic studies toward Swinhoeisterol A: Synthesis of the 6/6/5/7 tetracyclic core

6/6/5/7 Tetracyclic core of Swinhoeisterol A was constructed starting from Wieland-Miescher ketone and silylated ethyl 5–hydroxyvalerate. After modification, the bicyclic and linear subunits were assembled by means of cross-metathesis reaction. Then, cyclopentane C ring was formed by the intramolecular aldol condensation. C17-stereocenter was constructed using Claisen rearrangement followed by the decarbonylation step. Finally, ene reaction was applied for the simultaneous formation of cycloheptane d-ring and tetrasubstituted double bond between rings B and C.

Taking Olefin Metathesis to the Limit: Stereocontrolled Synthesis of Trisubstituted Alkenes.

ConspectusIn this Account, we share the story of the development of catalytic olefin metathesis processes that efficiently deliver a wide range of acyclic and macrocyclic E- or Z-trisubstituted alkenes. The tale starts with us unveiling, in collaboration with Richard Schrock and his team, the blueprint in 2009 for the design of kinetically controlled Z-selective olefin metathesis reactions. This paved the way for the development of Mo-, W-, and Ru-based catalysts and strategies for synthesizing countless linear and macrocyclic Z-olefins. Six years later, in 2015, we found that abundant Z-alkene feedstocks, such as oleic acid, can be directly transformed to high-value and more difficult-to-access alkenes through a cross-metathesis reaction promoted by a Ru-catechothiolate complex that we had developed; the approach, later coined stereoretentive olefin metathesis, was extended to the synthesis of E-alkenes.It was all about disubstituted alkenes until when in 2017 we addressed the challenge of accessing stereodefined Z- and E-trisubstituted alkenes, key to medicine and materials research. These transformations can be most effectively catalyzed by Mo monoaryloxides pyrrolide (MAP) and chloride (MAC) complexes. A central aspect of the advance is the merging of olefin metathesis, which delivered trisubstituted alkenyl fluorides, chlorides, and bromides with cross-coupling. These catalytic and stereoretentive transformations can be used in various combinations, thereby enabling access to assorted Z- or E-trisubstituted alkene. Ensuing work led to the emergence of other transformations involving substrates that can be purchased with high stereoisomeric purity, notably E- and Z-trihalo alkenes. Trisubstituted olefins, Z or E, bearing a chemoselectively and stereoretentively alterable F,Cl-terminus or B(pin),Cl-terminus may, thus, be easily and reliably synthesized. Methods for stereoretentive preparation of other alkenyl bromide regioisomers and α,β-unsaturated carboxylic and thiol esters, nitriles, and acid fluorides followed, along with stereoretentive ring-closing metathesis reactions that afford macrocyclic trisubstituted olefins. Z- and E-Macrocyclic trisubstituted olefins, including those that contain little or no entropic support for cyclization (minimally functionalized) and/or are disfavored under substrate-controlled conditions, can now be synthesized. The utility of this latest chapter in the history of olefin metathesis has been highlighted by applications to the synthesis of several biologically active compounds, as well as their analogues, such as those marked by one or more site-specifically incorporated fluorine atoms or more active but higher energy and otherwise unobtainable conformers.The investigations discussed here, which represent every stereoretentive method that has been reported thus far for preparing a trisubstituted olefin, underscore the inimitable power of Mo-based catalysts. This Account also showcases a variety of mechanistic attributes─some for the first time, and each instrumental in solving a problem. Extensive knowledge of mechanistic nuances will be needed if we are to address successfully the next challenging problem, namely, the development of catalysts and strategies that may be used to synthesize a wide range of tetrasubstituted alkenes, especially those that are readily modifiable, with high stereoisomeric purity.

Ruthenium-catalyzed Olefin Metathesis in Water using Thermo-responsive Diblock Copolymer Micelles

Abstract: Ruthenium-catalyzed olefin metathesis reactions were conducted in water with thermoresponsive block copolymers forming micelles. The block copolymers were prepared by living radical polymerization and consisted of a thermo-responsive and hydrophilic segments. The former segment included poly(N-isopropylacrylamide) or poly(N,N-diethylacrylamide), and the latter poly(sodium 4-styrene sulfonate), poly(sodium 2-acrylamido-2-methylpropanesulfonate) or poly(ethylene glycol). Homometathesis, cross-metathesis and ring-closing metathesis reactions proceeded to afford the products in moderate to good yields. Extraction efficiency from the reaction mixture was also studied.

Synthesis of trans-Tetrafluoro(trifluoromethyl)-λ6-sulfanyl (CF3SF4)-Containing Olefins via Cross Metathesis.

The cross-metathesis reactions of trans-tetrafluoro(trifluoromethyl)-λ6-sulfanyl (CF3SF4)-containing olefins expand the repertoire of synthetic transformations of CF3SF4-substituted molecules. Treatment of a primary alkene and 3-CF3SF4-propene with a second-generation Hoveyda-Grubbs catalyst yielded the cross-metathesis product in good yield under very mild conditions (room temperature). CF3SF4-propene undergoes cross metathesis with substrates containing electron-withdrawing groups or electron-donating groups at room temperature or under dichloromethane reflux. The formation of the CF3SF4-propene homodimer and the utility of that dimer to undergo selective cross-metathesis reactions are described.

ONE-POT SYNTHESIS OF NORBORNENE-CYCLOOCTENE COPOLYMERS

The one-pot synthesis of random multiblock copolymers of norbornene and cyclooctene has been performed for the first time. It is shown that the first generation Grubbs Ru-carbene complex makes it possible to obtain these copolymers directly from monomers. In the course of one-pot synthesis, the metathesis polymerization of norbornene, which has a markedly higher ring strain, occurs first. Then, cyclooctene polymerizes and simultaneously an interchain cross-metathesis reaction takes place, during which the block structure of the copolymer is formed. Compared to the previously studied interaction of polynorbornene and polycyclooctene, the one-pot method makes it possible to obtain copolymers with a higher molar mass at a lower catalyst consumption.