Ring-opening Cross-metathesis Research Articles

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.

Non-Symmetrical Tetrafluoroalkadienes Synthesized by ROCM of 3,3,4,4-Tetrafluorocyclobutene.

As the first known example of ring-opening cross metathesis (ROCM) of polyfluorinated strained cyclobutenes, ROCM of 3,3,4,4-tetrafluorocyclobutene with electronically rich alkenes, catalyzed by Grubbs or Hoveyda-Grubbs 2nd generation precatalysts, gave a small library of non-symmetrical isolated dienes bearing a tetrafluoroethylene spacer between the double bonds. 1-Butoxy-3,3,4,4-tetrafluorohexa-1,5-diene thus formed underwent subsequent regioselective cross metathesis (CM) with a series of styrenes, catalyzed by Hoveyda-Grubbs 2nd generation precatalyst, leading to non-symmetrically substituted dienes. 6,6-Dibutoxy-3,3,4,4-tetrafluorohex-1-ene, formed by regioselective butoxylation of 1-butoxy-3,3,4,4-tetrafluorohexa-1,5-diene, was dihydroxylated and cyclized to the corresponding 3,3,4,4-tetrafluorohexopyranose.

Late-stage Modification of Cage Diones by Tandem Metathesis.

Herein, we report the application of tandem ring-opening cross-metathesis (ROCM) and tandem ring-opening cross-metathesis followed by cross-metathesis (ROCM/CM) in highly strained diastereomeric heptacyclic cage diones (HCCD's) catalyzed by ruthenium catalysts. These caged diastereomeric compounds have a high degree of ring strain as well as steric congestion. Therefore, the present work related to ROCM is unique and intricate as compared to simple norbornene derivatives. It is useful to prepare new hexacyclic cage derivatives suitable for high-energy density materials. The synthetic strategy of starting cage compounds features the Diels-Alder reaction, and [2+2] photocycloaddition as key steps.

Cationic Molybdenum Imido Alkylidene N‐Heterocyclic Carbene Complexes Confined in Mesoporous Silica: Tuning Transition States Towards Z‐Selective Ring‐Opening Cross‐Metathesis

AbstractWe recently reported a method for selective macro(mono)cyclization of dienes utilizing catalysts confined inside the pores of mesoporous silica, which we believe occurs due to suppression of oligomerization due to pore size. We hypothesized, however, that the system of cationic molybdenum imido alkylidene N‐heterocyclic carbene (NHC) catalysts immobilized selectively inside the mesopores of silica materials could address much more subtle selectivity differences, such as E/Z selectivity in ring‐opening/cross‐metathesis (ROCM). Upon investigation, we observed that surface‐bound cationic molybdenum imido alkylidene NHC catalysts indeed display an increased Z‐selectivity, especially during the early stages of the reaction. This effect was present when the catalyst was confined inside a pore, as well as when the catalyst was bound to non‐porous silica, which led us to conclude it is an effect caused by the catalyst being bound directly to the surface of a silica material where the proximity of the catalyst to the surface governs the transition state. Kinetic investigations revealed that significant post‐metathesis olefin isomerization occurs, the amount of which seems to be governed by the rate of diffusion of the product away from the active catalyst, with smaller pore sizes resulting in higher Z‐selectivity at higher conversion, attributable to faster diffusion of the product out of the pore than diffusion back into the pore.

Strain-Induced Regioselective Ring-Opening Cross-Metathesis of Hybrid Cage Propellane Containing both Bicyclo[2.2.1]heptene and Bicyclo[2.2.2]octene Units

AbstractHerein, we report strain-driven regioselective tandem ring-opening cross-metathesis (ROCM) of a linearly fused cage system that contains both bicyclo[2.2.1]heptene and bicyclo[2.2.2]octene units fused to the same cage system. The synthesis of novel cage propellane involves Diels–Alder cycloaddition and [2+2] photocycloaddition as key steps.

A Fischer-Type Ruthenium Carbene Complex as a Metathesis Catalyst for the Synthesis of Enol Ethers.

The Grubbs G-I or G-II catalyst gives the ruthenium ethoxy carbene complex, which catalyzes ring-opening cross metathesis (ROCM) of a strained cyclic alkene to give a diene where one of the two alkene moieties in the product contains an ethoxy substituent. No polymeric products are detected. Hydrocarbons such as parent norbornene or substituted cyclopropenes can proceed with the reaction smoothly. Tertiary amines, N-alkylimides, esters, and aryl or alkyl bromides remain intact under the reaction conditions. In addition to vinyl ethers, vinylic esters can also be used. The time required to reach a 50% yield of the ROCM product t50 varies from 0.01 to 140 h depending on the strain and nucleophilicity of the double bond. Anchimeric participation of an electron-rich group would result in significant enhancement of the reactivity, and the t50 could be as short as several minutes. A similar substrate without such a neighboring group shows a much slower rate. An exo-norborne derivative reacts much faster than the corresponding endo-isomer. Alkenes with poor nucleophilicity are less favored for the ROCM process, so is less strained cyclooctene.

Stereoselective Olefin Ring‐Opening Cross Metathesis Catalyzed by Molybdenum Imido Alkylidene N‐Heterocyclic Carbene Complexes

AbstractThe influence of the structure of cationic molybdenum imido alkylidene N‐heterocyclic carbene (NHC) catalysts, i. e. of [Mo(N‐2‐tert‐butyl‐C6H4) (CHCMe2Ph)(NHC)X+ B(ArF)4−] (NHC=1,3‐di(2‐Pr)imidazol‐2‐ylidene (iPr), 1,3‐dimesitylimidazol‐2‐ylidene (IMes); X=pyrrolide, OCH(CF3)2, B(ArF)4−=tetrakis(3,5‐bis(trifluoromethyl)phenyl)borate) and of [Mo(N‐3,5‐Me2‐C6H3)(CHCMe2Ph)(NHC)(CH3CN)X+ B(ArF)4−] (NHC=1,3‐dimesitylimidazol‐2‐ylidene, 1,3‐dimesitylimidazolin‐2‐ylidene (IMesH2); X=CF3SO3, OCPh(CF3)2) on E/Z‐selectivity in the ring‐opening cross‐metathesis (ROCM) of endo, endo‐2,3‐dicarbomethoxynorborn‐5‐ene (endo, endo‐DCMNBE), exo, exo‐2,3‐dicarbomethoxynorborn‐5‐ene (exo, exo‐DCMNBE), endo, exo‐2,3‐dicarbomethoxynorborn‐5‐ene ((+) DCMNBE) and 2,3‐exo,exo‐bis(acetoxymethyl)‐7‐oxabicyclo[2.2.l]hept‐5‐ene (7‐oxa‐NBE) with 1‐pentene, styrene, allyltrimethylsilane, allyl benzyl ether, allyl phenyl ether and allyl ethyl ether has been studied. With the exception of the ROCM reaction of endo, endo‐DCMNBE with styrene, all other ROCM reactions of endo, endo‐DCMNBE proceeded under thermodynamic control without any post‐metathesis isomerization reactions with full retention of the configuration of the newly formed 1,2‐disubstituted double bond as confirmed by kinetic studies. Similar accounts for selected homometathesis reactions. Catalyst structure‐selectivity correlations based on the buried volume, Vbur, of the N‐imido ligand are presented.magnified image

Consecutive Intermolecular Reductive Amination/Asymmetric Hydrogenation: Facile Access to Sterically Tunable Chiral Vicinal Diamines and N-Heterocyclic Carbenes.

A highly enantioselective iridium- or ruthenium-catalyzed intermolecular reductive amination/asymmetric hydrogenation relay with 2-quinoline aldehydes and aromatic amines has been developed. A broad range of sterically tunable chiral N,N'-diaryl vicinal diamines were obtained in high yields (up to 95 %) with excellent enantioselectivity (up to >99 % ee). The resulting chiral diamines could be readily transformed into sterically hindered chiral N-heterocyclic carbene (NHC) precursors, which are otherwise difficult to access. The usefulness of this synthetic approach was further demonstrated by the successful application of one of the chiral vicinal diamines and chiral NHC ligands in a transition-metal-catalyzed asymmetric Suzuki-Miyaura cross-coupling reaction and asymmetric ring-opening cross-metathesis, respectively.

Hoveyda-Grubbs catalysts with an N→Ru coordinate bond in a six-membered ring. Synthesis of stable, industrially scalable, highly efficient ruthenium metathesis catalysts and 2-vinylbenzylamine ligands as their precursors.

A novel and efficient approach to the synthesis of 2-vinylbenzylamines is reported. This involves obtaining 2-vinylbenzylamine ligands from tetrahydroisoquinoline by alkylation and reduction followed by the Hofmann cleavage. The resultant 2-vinylbenzylamines allowed us to obtain new Hoveyda–Grubbs catalysts, which were thoroughly characterised by NMR, ESIMS, and X-ray crystallography. The utility of this chemistry is further demonstrated by the tests of the novel catalysts (up to 10−2 mol %) in different metathesis reactions such as cross metathesis (CM), ring-closing metathesis (RCM) and ring-opening cross metathesis (ROCM).

One‐pot Synthesis of 1,3‐Butadiene and 1,6‐Hexanediol Derivatives from Cyclopentadiene (CPD) via Tandem Olefin Metathesis Reactions

AbstractA novel tandem reaction of cyclopentadiene leading to high value linear chemicals via ruthenium catalyzed ring opening cross metathesis (ROCM), followed by cross metathesis (CM) is reported. The ROCM of cyclopentadiene (CPD) with ethylene using commercially available 2nd gen. Grubbs metathesis catalysts (1‐G2) gives 1,3‐butadiene (BD) and 1,4‐pentadiene (2) (and 1,4‐cyclohexadiene (3)) with reasonable yields (up to 24 % (BD) and 67 % (2+3) at 73 % CPD conversion) at 1–5 mol % catalyst loading in toluene solution (5 V% CPD, 10 bar, RT) in an equilibrium reaction. The ROCM of CPD with cis‐butene diol diacetate (4) using 1.00 ‐ 0.05 mol % of 3rd gen. Grubbs (1‐G3) or 2nd gen. Hoveyda‐Grubbs (1‐HG2) catalysts loading gives hexa‐2,4‐diene‐1,6‐diyl diacetate (5), which is a precursor of 1,6‐hexanediol (an intermediate in polyurethane, polyester and polyol synthesis) and hepta‐2,5‐diene‐1,7‐diyl diacetate (6) in good yield (up to 68 % or TON: 1180). Thus, convenient and selective synthetic procedures are revealed by ROCM of CPD with ethylene and 4 leading to BD and 1,6‐hexanediol precursor, respectively, as key components of commercial intermediates of high‐performance materials.

GaCl3-Catalyzed Ring-Opening Carbonyl-Olefin Metathesis.

The development of a Lewis acid-catalyzed ring-opening cross-metathesis reaction which enables selective access to acyclic, unsaturated ketones as the carbonyl-olefin metathesis products is described. While catalytic amounts of FeCl3 were previously identified as optimal to catalyze ring-closing metathesis reactions, the complementary ring-opening metathesis between cyclic alkenes and carbonyl functionalities relies on GaCl3 as the superior Lewis acid catalyst.

Norbornene in Organic Synthesis

The norbornene skeleton possesses an alkene functionality with a fixed conformation, and represents unique reactivity. The use of norbornene and analogues as substrates is overviewed; reactivities are discussed as well as the role of norbornenes as ligands assisting modern organic transformations.1 Introduction2 Synthesis of Substituted Norbornenes2.1 Preparation of Functionalized Norbornenes by Deprotonation and Substitution Reactions2.2 Preparation of Functionalized Norbornenes under Palladium-Catalyzed­ Reaction Conditions2.3 Alkylation of Norbornene2.4 Multistep Synthesis3 Synthesis of Substituted Norbornanes3.1 Three-Membered-Ring Formation3.2 Formation of Four-Membered Rings3.3 Five- and Six-Membered Ring Formation3.4 Syntheses of Difunctionalized Norbornanes4 Synthesis of Cyclopentanes4.1 Oxidation Reactions4.2 Ring-Opening Cross Metathesis (ROCM)4.3 Ring-Opening Metathesis Polymerization (ROMP)4.4 Palladium-Catalyzed Ring-Opening of Norbornene5 Norbornene-Mediated Reactions5.1 Palladium Insertion into Carbon–Halide Bonds5.2 Palladium Insertion into N–H and C–H Bonds5.3 Norbornene as Ligand in Mediated Reactions6 Conclusion

Synthesis and Application of Stereoretentive Ruthenium Catalysts on the Basis of the M7 and the Ru–Benzylidene–Oxazinone Design

A series of new stereoretentive ruthenium catalysts bearing the dithiocatecholate ligand was synthesiszed on the basis of the M7 and Ru–benzylidene–oxazinone design. The activity of the catalysts was tested in ring-opening cross-metathesis reactions, ring-closing metathesis reactions, cross-metathesis reactions, and self-metathesis reactions using Z- and E-configured starting materials. The desired metathesis products were obtained with moderate to high yields and with excellent stereoselectivities (>95%). Substrate-dependent reactivity was found by carrying out kinetic studies on internal and terminal olefins.

Design and Synthesis of Spirocycles

In this account we disclose a variety of simple strategies demonstrated in our laboratory in the last two decades for the assembly of diverse and intricate molecular frameworks containing spiro linkage(s) by using various metathesis protocols such as ring‐closing metathesis (RCM), ring‐opening cross‐metathesis (ROCM), ring‐closing enyne metathesis (RCEM) and ring‐rearrangement metathesis (RRM). Also, cycloaddition reactions ([2+2], [4+2] and [2+2+2]) and other key processes such as Claisen rearrangement (CR), Grignard addition, Fischer indolization (FI), Suzuki–Miyaura (SM) cross‐coupling and the retro‐Diels–Alder (rDA) reaction have been used as key steps to construct spirocycles.

Precision Synthesis of Alternating Copolymers via Ring-Opening Polymerization of 1-Substituted Cyclobutenes.

ConspectusInvestigation of complex molecular systems depends on our ability to correlate physical measurements with molecular structure. Interpretation of studies that rely on synthetic polymers is generally limited by their heterogeneity; i.e., there is variation in the number and arrangement of the monomeric building blocks that have been incorporated. Superior physics and biology can be performed with materials and tools that exert precise control over the sequence and spacing of functional groups.An interest in functional ligands combined with a desire to control the orientation and stereochemistry of monomer incorporation led to the design of new substrates for ruthenium-catalyzed ring-opening metathesis polymerization (ROMP). We discovered that ROMP of cyclobutene-1-carboxamides provides uniform and translationally invariant polymers. In contrast, cyclobutene-1-carboxylate esters ring open upon treatment with ruthenium catalyst, but they are stable to homopolymerization. However, in the presence of cyclohexene monomers, they undergo alternating ROMP (AROMP or alt-ROMP) to give copolymers with a precisely controlled sequence.The alternating cyclobutene ester/cyclohexene pair provides access to functional group spacing larger than is possible with homopolymers. This can be desirable; for example, polymers with a regular 8–10 Å backbone spacing of cationic charge and with between four and eight cationic groups were the most effective antibacterial agents and had low cytotoxicity.Moreover, the AROMP chemistry allows alternation of two functional moieties: one associated with the cyclohexene and one attached to the cyclobutene. In the case of antibacterial copolymers, the alternating chemistry allowed variation of hydrophobicity via the cyclohexene while maintaining a constant cation spacing through the cyclobutene. In the case of copolymers that bear donor and acceptor groups, strict alternation of the groups increased intrachain charge transfer.Like cyclobutene-1-carboxylate esters, bicyclo[4.2.0]oct-7-ene-7-carboxylate esters ring open upon treatment with ruthenium catalyst and undergo ring opening cross-metathesis with cyclohexene to form alternating copolymers. The corresponding bicyclo[4.2.0]oct-7-ene-7-carboxyamides isomerize to the bicyclo[4.2.0]oct-1(8)-ene-8-carboxamides before they can ring open. However, the isomerized amides undergo ruthenium-catalyzed ring opening metathesis and rapidly AROMP with cyclohexene.Our alternating copolymer systems allow functionality to be placed along a polymer chain with larger than typical spacing. We have used both homopolymers and alternating copolymers for defining the functional group density required for targeting a cell surface and for the exploration of functional group positioning within a polymer chain. These polymer systems provide access to new materials with previously inaccessible types of nanoscale structures.

Amino acids as chiral anionic ligands for ruthenium based asymmetric olefin metathesis.

Several amino acid ligands were introduced into the Hoveyda-Grubbs 2nd generation complex by a facile anionic ligand exchange. The chiral pre-catalysts obtained displayed enantioselectivity in asymmetric ring-closing and ring-opening cross-metathesis reactions. Reduction of the lability of the carboxylate ligands was found to be cardinal for improving the observed enantiomeric product enrichment.

Sophorolipids: Expanding structural diversity by ring‐opening cross‐metathesis

Lactonic sophorolipids (LSL) are glycolipid biosurfactants produced in large quantity by yeast fermentation. Chemical or enzymatic modification of naturally produced sophorolipids is an effective route to improve their functional properties. For the first time, ring‐opening cross metathesis (RO/CM) was used to convert natural LSL to a unique family of modified sophorolipids. Reaction conditions for RO/CM of LSL with n‐alkyl acrylates, trans‐3‐hexene, 1‐hexene and ethylene were investigated. For the RO/CM of n‐alkyl acrylates with LSL, %‐conversions greater than 95% within 1 h resulted from conducting reactions in THF at 60°C using 5 mol% of Grubbs second generation ruthenium based catalyst (M2). The RO/CM reaction of LSL with ethylene performed at 3 bar under an ethylene atmosphere using Grubbs first generation (G1) (10 mol%) as the catalyst in dichloromethane (room temperature, 5 h) gave complete conversion of LSL to the corresponding ring‐opened product. Ethanolysis of LSL RO/CM products generated a series of medium chain (C10‐C14) SL‐surfactants and fatty acid co‐products. Values of surface tension reduction at the air‐water interface versus Log (C) for modified SLs were measured by the Wilhelmy plate method. Minimum surface tension values varied as a function of the hydrophobic character of modified SLs. The modified SL from RO/CM with 1‐hexene (SL‐14) gave the largest surface tension reduction and lowest CMC (to 34 mN/m and 0.15 mM, respectively) and showed a similar surface tension reduction behavior as n‐dodecyl‐β‐D‐maltoside (Mal‐C12). Increasing the number of carbons in the hydrophobic segment for the homologous series of n‐alkyl sophorosides results in an almost linear decrease in log(CMC), with B = 0.18 ± 0.03. This number is smaller than that of other related surfactants such as alkyl‐β‐D‐glycosides and alkyl‐β‐D‐maltosides.Practical applications: Modified sophorolipids can be used in a wide variety of applications such as stabilization of oil‐in‐water dispersions, antimicrobials and various cleaning operations.Ring‐opening cross‐metathesis was used to expand structural diversity of natural sophorolipid surfactants.

Asymmetric Ring Opening–Cross-Metathesis of Cyclobutene-diols

Asymmetric Ring Opening–Cross-Metathesis of Cyclobutene-diols

Functionalization of β-caryophyllene generates novel polypharmacology in the endocannabinoid system.

The widespread dietary plant sesquiterpene hydrocarbon β-caryophyllene (1) is a CB2 cannabinoid receptor-specific agonist showing anti-inflammatory and analgesic effects in vivo. Structural insights into the pharmacophore of this hydrocarbon, which lacks functional groups other than double bonds, are missing. A structure-activity study provided evidence for the existence of a well-defined sesquiterpene hydrocarbon binding site in CB2 receptors, highlighting its exquisite sensitivity to modifications of the strained endocyclic double bond of 1. While most changes on this element were detrimental for activity, ring-opening cross metathesis of 1 with ethyl acrylate followed by amide functionalization generated a series of new monocyclic amides (11a, 11b, 11c) that not only retained the CB2 receptor functional agonism of 1 but also reversibly inhibited fatty acid amide hydrolase (FAAH), the major endocannabinoid degrading enzyme, without affecting monoacylglycerol lipase (MAGL) and α,β hydrolases 6 and 12. Intriguingly, further modification of this monocyclic scaffold generated the FAAH- and endocannabinoid substrate-specific cyclooxygenase-2 (COX-2) dual inhibitors 11e and 11f, which are probes with a novel pharmacological profile. Our study shows that by removing the conformational constraints induced by the medium-sized ring and by introducing functional groups in the sesquiterpene hydrocarbon 1, a new scaffold with pronounced polypharmacological features within the endocannabinoid system could be generated. The structural and functional repertoire of cannabimimetics and their yet poorly understood intrinsic promiscuity may be exploited to generate novel probes and ultimately more effective drugs.

Olefin Metathesis - Application in the Synthesis of Natural Products and Related Organic Compounds

Exchange of an alkene unit of an olefinic compound with alkene unit of another compound (metathesis) leads to a new olefinic compound. This process takes place in presence of a transition metal alkylidine complex as catalyst. A variety of synthetic operations such as ring closing metathesis, ring opening metathesis, cross metathesis, enyne metathesis and domino processes involving ring opening-ring closing and cross metathesis can be achieved to construct novel molecular architectures that are difficult to make by other reactions. This account presents briefly the contributions mainly from authors’ laboratory on applications of the various metathetic processes for synthesis of natural products and related molecules.