Ring-closing Metathesis Product Research Articles

Synthesis of 3‐Spiro Cycloalkenes Fused 7‐Aza‐2‐indalones from 3,3′‐di‐ or N,3,3′‐tri‐ allyl/homoallyl/pentenyl 7‐Aza‐2‐indalones via Ring Closing Metathesis using Grubbs‐II Catalyst

AbstractA facile and efficient synthesis of 3‐spiro cycloalkene fused 7‐aza‐2‐indalones from 3,3′‐di‐ or N,3,3′‐tri‐ allyl/homoallyl/pentenyl 7‐aza‐2‐indalones via ring‐closing metathesis (RCM) using Grubbs‐II catalyst has been achieved. The scope of the reaction has been demonstrated by synthesizing spiro products of various ring sizes (n=5, 7, and 18), utilizing 2‐indalone/7‐azaindalone and various alkenylation agents such as allyl/homoallyl/pentenyl bromides as substrates. In addition to usual RCM products, a cross metathesis (CM) product was observed when the substrate was N,3,3′‐triallylated derivative from 2‐indalone. Notably, a macrocyclic, 18‐membered bis‐spirodiene of N‐methyl‐7‐azaindalone was observed by means of intermolecular ring‐closing metathesis (RCM‐RCM). Also, Structures of a few representative spiro‐annulated products were evidenced with single crystal XRD analysis. Furthermore, a plausible mechanism for the products is discussed.

Computational Elucidation on the Conformational Control of Selectivity in Intramolecular Ring-Closing Metathesis vs Intermolecular Homometathesis.

The ring-closing metathesis reaction of diene plays an important role in the construction of cyclic compounds. In this research, density functional theory (DFT) calculations were conducted to elucidate the mechanisms and origins of the selectivity of ring-closing metathesis and homometathesis. The computational results suggest that the selectivity is determined by the substrate conformation. For the ester-tethered substrate, the homometathesis is more favorable, due to the planar structure of ester facilitating the conjugative effect of the formed E-homometathesis product. For the amide-tethered substrate, the ring-closing metathesis product is the only observed product because the steric hindrance of N-substituents disfavors homometathesis.

Formation of Seven-Membered Rings by Ring-Closing Metathesis of Vinyl Bromides

AbstractA Grubbs II catalyst mediated ring-closing metathesis (RCM) of monobrominated dienes is reported to proceed in moderate to good yields (40–80%) where the linking chain contains five atoms, leading to carbocyclic and heterocyclic seven-membered bromoolefins. Notably, RCM to form five-, six-, or eight-membered bromoolefins was unsuccessful, with the exception of one example where RCM afforded diethyl 3-bromocyclohex-3-ene-1,1-dicarboxylate. In this case, a bromomethyl-substituted cyclohexene was obtained as a byproduct. The utility of selected bromoolefin RCM products was demonstrated through their participation in Suzuki–Miyaura reactions. Vinylic halide exchange (Br → Cl) was noted as a side reaction under RCM conditions.

Unintended Formation of a 26-Membered Cycle in the Course of a Novel Approach to Myricanol, a Strained [7,0]-Metacyclophane

A convergent approach for the synthesis of (±)-myricanol, a strained diarylheptanoid isolated from Myricacae, was undertaken using a Suzuki–Miyaura coupling followed by a ring-closing metathesis (RCM). Herein, we report the unintentional formation of a 26-membered macrocycle as RCM product resulting from a head-to-tail dimerization of the seco-precursor, even in relay ring-closing metathesis (RRCM) conditions.

Selectivity in Olefin-Intervened Macrocyclic Ring-Closing Metathesis

The ring-closing metathesis (RCM) of α,m,ω-triene was employed for the syntheses of four slightly different EE, EZ, ZE, and ZZ isomers of macrocycles with two greatly separated type I olefins. Kinetic control of the RCM reaction using G1 was achieved, in which secondary metathesis of the initially formed RCM product that usually afforded the thermodynamically favored product was inhibited, and a reliable model was built to differentiate the kinetic or thermodynamic control in the RCM reaction. Kinetic studies of olefin metathesis using the kinetically controlled Z-selective catalyst Cat-Z were conducted to determine its thermodynamic capability to convert (Z)-olefin to (E)-olefin. Finally, the ring size selectivity of α,ω- vs α,m-/m,ω-products in the RCM reaction of α,m,ω-triene revealed that all types of isomeric α,ω-products are favored for the 18-membered ring and above, and α,m-/m,ω-products are predominant for the rings with 14-members and less. For the 15-, 16-, and 17-membered rings, each of the E/Z-selective RCM reactions of starting (mE)- and (mZ)-trienes has a different performance under the optimized conditions. These studies provide insights into the applications of RCM on the synthesis of macrocycles with two separate type I olefins.

Synthesis of Dihydrooxepino[3,2-c]Pyrazoles via Claisen Rearrangement and Ring-Closing Metathesis from 4-Allyloxy-1H-pyrazoles.

Synthesis of novel pyrazole-fused heterocycles, i.e., dihydro-1H- or 2H-oxepino[3,2-c]pyrazoles (6 or 7) from 4-allyloxy-1H-pyrazoles (1) via combination of Claisen rearrangement and ring-closing metathesis (RCM) has been achieved. A suitable catalyst for the RCM of 5-allyl-4-allyloxy-1H-pyrazoles (4) was proved to be the Grubbs second generation catalyst (Grubbs2nd) to give the predicted RCM product at room temperature in three hours. The same reactions of the regioisomer, 3-allyl-4-allyloxy-1H-pyrazoles (5), also proceeded to give the corresponding RCM products. On the other hand, microwave aided RCM at 140 °C on both of 4 and 5 afforded mixtures of isomeric products with double bond rearrangement from normal RCM products in spite of remarkable reduction of the reaction time to 10 min.

A New Synthetic Approach to C2‐Symmetric Octacyclic Cage Diol via Claisen Rearrangement and Ring‐Closing Metathesis as Key Steps

AbstractA simple synthetic strategy to C2‐symmetric bisannulated octacyclic novel cage diol 20 is reported in eight linear steps starting with a readily available 1,4‐hydroquinone 22. Here, an atom economic processes such as Claisen rearrangement, Diels‐Alder reaction, intramolecular [2+2] photocycloaddition and ring‐closing metathesis (RCM) were used as key steps. The synthetic approach demonstrated here opensup new opportunities to assembled highly functionalized complex cage molecules that are difficult to realize by conventional routes. The structure of the RCM product 19 was firmly established on the basis of single‐crystal X‐ray diffraction studies.

Design and Synthesis of Cyclic Mismatch-Binding Ligands (CMBLs) with Variable Linkers by Ring-Closing Metathesis and their Photophysical and DNA Repeat Binding Properties.

Cyclophane-containing bis(2-amino-1,8-naphthyridine) moieties attached to variable linkers at the C2-position (linker B) were synthesized as cyclic mismatch-binding ligands (CMBLs). Ring-closing metathesis (RCM) is used as a key step for the introduction of double bonds at the linker B. Decreasing the size of the linker of the substrate, formation of the RCM products with an increasing trans/cis (E/Z) ratio was observed with moderate to high overall yields. Concentration-dependent fluorescence spectra were observed for CMBLs with longer linkers (n=3), whereas concentration-independent spectra were observed for CMBLs with shorter linkers (n=2 and/or 1) with a marked exception of the E-alkene 6 a. Concomitant changes in the absorption as well as in the fluorescence spectra were also observed for the CMBLs with an increasing hydrophobicity of the solvent. Absorption and fluorescence spectra of the CMBLs in solutions containing 99-100 % methanol resembled to that of the monomer. The binding behavior of these CMBLs with repeat DNA structures was investigated by using a surface plasmon resonance (SPR) assay and circular dichroism (CD) spectra. The cyclic E-alkenes 1 a (n=3) and 3 a (n=2) show an orthogonal binding relationship with d(CCTG)9 and d(CAG)9 . However, the selectivity for the cyclic Z-alkenes increased with decreasing the length of the linker from compound 2 b (n=3) to compound 7 b (n=1). These compounds display a large molecular diversity, which allowed the tuning of the binding affinity and selectivity of the CMBLs by varying the linkers towards various biologically significant repeat DNA structures.

Nonaqueous and Aqueous Emulsion ROMP Reactions Induced by Environment-Friendly Latent Ruthenium Indenylidene Catalyst Bearing Morpholine Substituted Bidentate (N, O) Schiff Bases

In this study, a novel latent ruthenium indenylidene catalyst, bearing morpholine substituted bidentate (N, O) Schiff base is used in nonaqueous emulsion ring-opening metathesis polymerization (ROMP) reactions for the first time. This novel catalyst has unique features such as latency and high silica gel affinity. The performance of the catalyst is tested on ring-closing metathesis (RCM), ROMP reactions, and aqueous emulsion ROMP reactions. In addition, nonaqueous (using immiscible binary organic solvents: n-hexane and dimethylformamide) emulsion ROMP reactions are carried out for the first time using latent ruthenium catalysts. The latency of the catalyst allows us to control the molecular weight of emulsion ROMP polymers by varying HCl/Ru ratio, keeping the nanoparticle sizes stable between 26 and 75 nm in aqueous emulsion and 51 and 208 nm in nonaqueous emulsion ROMP reactions. In addition, high silica gel affinity of the catalyst allows us to synthesize pure RCM products with ruthenium contamination less than 1 ppm.

Development of an Enyne Metathesis/Isomerization/Diels-Alder One-Pot Reaction for the Synthesis of a Novel Near-Infrared (NIR) Dye Core.

N-Alkyl-N-allyl-2-alkynylaniline derivatives undergo a tandem ring-closing enyne metathesis/isomerization/Diels-Alder cycloaddition sequence in the presence of a second-generation Grubbs catalyst and dienophiles. In practice, the acyclic enyne in the presence of the ruthenium alkylidene first undergoes ring-closing metathesis to generate cyclic 4-vinyl-1,2-dihydroquinolines; following diene isomerization and then the addition of a dienophile, these ring-closing metathesis products are selectively converted into a 7-methyl-4H-naphtho[3,2,1-de]quinoline-8,11-dione core. Overall, the reaction sequence converts simple aniline derivatives into π-conjugated small molecules, which have characteristic absorption in the near-infrared region, in a single operation through three unique ruthenium-catalyzed transformations.

Ring‐Closing Metathesis Reactions: Interpretation of Conversion–Time Data

Conversion-time data were recorded for various ring-closing metathesis (RCM) reactions that lead to five- or six-membered cyclic olefins by using different precatalysts of the Hoveyda type. Slowly activated precatalysts were found to produce more RCM product than rapidly activated complexes, but this comes at the price of slower product formation. A kinetic model for the analysis of the conversion-time data was derived, which is based on the conversion of the precatalyst (Pcat) into the active species (Acat), with the rate constant k(act), followed by two parallel reactions: 1) the catalytic reaction, which utilizes Acat to convert reactants into products, with the rate k(cat), and 2) the conversion of Acat into the inactive species (Dcat), with the rate k(dec). The calculations employ two experimental parameters: the concentration of the substrate (c(S)) at a given time and the rate of substrate conversion (-dc(S)/dt). This provides a direct measure of the concentration of Acat and enables the calculation of the pseudo-first-order rate constants k(act), k(cat), and k(dec) and of k(S) (for the RCM conversion of the respective substrate by Acat). Most of the RCM reactions studied with different precatalysts are characterized by fast k(cat) rates and by the k(dec) value being greater than the k(act) value, which leads to quasistationarity for Acat. The active species formed during the activation step was shown to be the same, regardless of the nature of different Pcats. The decomposition of Acat occurs along two parallel pathways, a unimolecular (or pseudo-first-order) reaction and a bimolecular reaction involving two ruthenium complexes. Electron-deficient precatalysts display higher rates of catalyst deactivation than their electron-rich relatives. Slowly initiating Pcats act as a reservoir, by generating small stationary concentrations of Acat. Based on this, it can be understood why the use of different precatalysts results in different substrate conversions in olefin metathesis reactions.

Synthetic studies of the spirocyclic cyclohexene part of versipelostatin, a novel GRP78/Bip molecular chaperone downregulator

The spirocyclic part consisting of an α-acylated tetronic acid and a multisubstituted cyclohexene embedded in versipelostatin, a novel GRP78/Bip molecular chaperone downregulator, has been synthesized in enantiomerically pure form. The asymmetric synthesis of the targeted spiro[4.5]-1-oxa-7-decen-2,4-dione derivative was characterized by (1) stereoselective allylation at the α-carbon of methylmalonate diester, in which one carboxylic acid was esterified with a D-glucose-derived chiral template, (2) construction of the tetrasubstituted cyclohexenone substructure by high-yielding ring-closing metathesis and (3) stereoselective construction of the spirocyclic tetronic acid part starting from the cyclohexenone obtained as the ring-closing metathesis product.

Fast Olefin Metathesis at Low Catalyst Loading

Reactions of the Grubbs 3rd generation complexes [RuCl(2)(NHC)(Ind)(Py)] (N-heterocyclic carbene (NHC)=1,3-bis(2,4,6-trimethylphenylimidazolin)-2-ylidene (SIMes), 1,3-bis(2,6-diisopropylphenylimidazolin)-2-ylidene (SIPr), or 1,3-bis(2,6-diisopropylphenylimidazol)-2-ylidene (IPr); Ind=3-phenylindenylid-1-ene, Py=pyridine) with 2-ethenyl-N-alkylaniline (alkyl=Me, Et) result in the formation of the new N-Grubbs-Hoveyda-type complexes 5 (NHC=SIMes, alkyl=Me), 6 (SIMes, Et), 7 (IPr, Me), 8 (SIPr, Me), and 9 (SIPr, Et) with N-chelating benzylidene ligands in yields of 50-75 %. Compared to their respective, conventional, O-Grubbs-Hoveyda complexes, the new complexes are characterized by fast catalyst activation, which translates into fast and efficient ring-closing metathesis (RCM) reactivity. Catalyst loadings of 15-150 ppm (0.0015-0.015 mol %) are sufficient for the conversion of a wide range of diolefinic substrates into the respective RCM products after 15 min at 50 °C in toluene; compounds 8 and 9 are the most catalytically active complexes. The use of complex 8 in RCM reactions enables the formation of N-protected 2,5-dihydropyrroles with turnover numbers (TONs) of up to 58,000 and turnover frequencies (TOFs) of up to 232,000 h(-1); the use of the N-protected 1,2,3,6-tetrahydropyridines proceeds with TONs of up to 37,000 and TOFs of up to 147,000 h(-1); and the use of the N-protected 2,3,6,7-tetrahydroazepines proceeds with TONs of up to 19,000 and TOFs of up to 76,000 h(-1), with yields for these reactions ranging from 83-92 %.

Probing the Origin of Degenerate Metathesis Selectivity via Characterization and Dynamics of Ruthenacyclobutanes Containing Variable NHCs

The preparation of new phosphonium alkylidene ruthenium metathesis catalysts containing N-heterocyclic carbenes (NHCs) that result in a preference for degenerate metathesis is described. The reaction of the catalysts with ethylene or substrates relevant to ring-closing metathesis (RCM) produced ruthenacyclobutanes that could be characterized by cryogenic NMR spectroscopy. The rate of α/β methylene exchange in ethylene-only ruthenacycles was found to vary widely between ruthenacycles, in some cases being as low as 3.97 s(-1) at -30 °C, suggesting that the NHC plays an important role in degenerative metathesis reactions. Attempts to generate RCM-relevant ruthenacycles resulted in the low-yielding formation of a previously unobserved species, which we assign to be a β-alkyl-substituted ruthenacycle. Kinetic investigations of the RCM-relevant ruthenacycles in the presence of excess ethylene revealed a large increase in the kinetic barrier of the rate-limiting dissociation of the cyclopentene RCM product compared with previously investigated catalysts. Taken together, these results shed light on the degenerate/productive selectivity differences observed for different metathesis catalysts.

Synthetic studies of mycalolide B, an actin-depolymerizing marine macrolide: construction of the tris-oxazole macrolactone using ring-closing metathesis

Tris-oxazole macrolactone 2, a key intermediate of mycalolide B ( 1), which has 13 stereogenic centres, was synthesized through the use of ring-closing metathesis (RCM). The E/ Z ratio of the RCM product 2 was reversed by the use of CH 2Cl 2 and toluene, whereas a cross-metathesis reaction yielded the C1–C35 long-chain compound 19 in a highly E-selective manner. Thus, the loss of flexibility in aliphatic carbon chains and the steric hinderance of β- and γ-substituents of the C20 olefin in the precursor 11 may affect the stereoselectivity in RCM reactions.

A Versatile Access to Calystegine Analogues as Potential Glycosidases Inhibitors

An efficient metathetic strategy and nitrone chemistry have been suitably tethered to construct 8-azabicyclo[3.2.1]octanes as versatile precursors for the synthesis of several calystegine analogues. This synthetic strategy relies on the ability of mannose-derived nitrone to undergo a highly stereoselective nucleophilic addition of various Grignard reagents to access syn orientation of alkenes, which then smoothly undergo ring-closing metathesis (RCM) to provide this framework. These RCM products 18 and 20 have been successfully used as advance precursors to synthesize many calystegine analogues (27, 36, 38, 40, 43, and 44) either by syn-dihydroxylation or by hydrogenation and followed by global deprotection. Interestingly, both compounds 36 and 40 exhibited significant noncompetitive inhibition against alpha-mannosidase and N-acetyl-beta-D-glucosaminidase.

Preparation of Photoreactive Oligomers by ADMET Polymerization of [(C5H4(CH2)8CH═CH2)Mo(CO)3]2

Polymerization of the [(η5-C5H4(CH2)8CH═CH2)Mo(CO)3]2 complex by acyclic diene metathesis polymerization (ADMET) is reported. The polymerization reactions were performed using Schrock’s catalyst, which resulted in formation of a polydisperse oligomer (Mn = 2300 and Mw/Mn = 4.3) with Mo−Mo bonds in the oligomer chain. Under dilute solvent conditions, the reaction was shown to favor the formation of the ring-closing metathesis (RCM) product. The ADMET oligomer was photochemically degradable, and irradiation with λ > 520 nm light in CCl4 resulted in cleavage of the oligomer backbone and formation of the metal chloride complex [μ-C5H4(CH2)8CH═CH(CH2)8C5H4{Mo(CO)3Cl}2]. The RCM product was also irradiated and the photochemical product is identical to that formed by irradiation of the oligomer. Copolymerization of [(η5-C5H4(CH2)8CH═CH2)Mo(CO)3]2 with 1,9-decadiene using Grubbs’ second-generation catalyst resulted in a higher molecular weight oligomer (Mn = 3400, Mw/Mn = 3.9).

Influence of Appended Groups on the Formation of 16-Membered Macrolactone Core Related to the Plecomacrolides via Diene-Ene Ring-Closing Metathesis

A 1,3-diene-ene ring-closing metathesis (RCM) strategy was investigated for assembling the 16-membered macrolactone core of the plecomacrolides. It was found that the desired (10E,12E)-diene unit could be constructed from the fully functionalized C13-C17 homoallyl alcohol fragment and the C1-C12 acid fragment possessing one E double bond at C2-C3 or C3-C4. The functional groups at C2 and C3 resulted in preferential formation of the undesired (12Z)-macrolactone, while additional appended groups at C6-C8 furnished the (12Z)-macrolactone as the sole RCM product.

Design and Synthesis of 1‐Benzazepine Derivatives by Strategic Utilization of Suzuki–Miyaura Cross‐Coupling, Aza‐Claisen Rearrangement and Ring‐Closing Metathesis

AbstractA new and simple methodology has been realized for the synthesis of 7‐substituted 2,3,4,5‐tetrahydro‐1‐benzazepine derivatives with Suzuki–Miyaura cross‐coupling, aza‐Claisen rearrangement and ring‐closing metathesis (RCM) the key steps. Here, o‐allylacetanilide derivatives were obtained by Suzuki–Miyaura cross‐coupling of the corresponding o‐iodoacetanilides. The o‐allylacetanilides, on N‐allylation under phase‐transfter catalysis conditions, provided diallyl derivatives as suitable precursors for RCM. These diallyl derivatives, on treatment with Grubbs' second‐generation catalyst, gave the 1‐benzazepine derivatives in moderate‐to‐good yields. These RCM products were found to be unstable and so they were hydrogenated to provide stable tetahydro‐1‐benzazepine derivatives 25–28. 1H‐1‐Benzazepin‐2‐one derivatives 44 and 45 were synthesized following a similar sequence. In addition, the aza‐Claisen rearrangement was utilized as a key step in the preparation of RCM precursor 17. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

Olefin metathesis catalysts bearing a pH-responsive NHC ligand: a feasible approach to catalyst separation from RCM products

Two novel ruthenium-based olefin metathesis catalysts, H(2)ITap(PCy(3))Cl(2)Ru[double bond, length as m-dash]CH-Ph and H(2)ITapCl(2)Ru[double bond, length as m-dash]CH-(C(6)H(4)-O-iPr) (H(2)ITap = 1,3-bis(2',6'-dimethyl-4'-dimethylaminophenyl)-4,5-dihydroimidazol-2-ylidene), were synthesized bearing a pH-responsive NHC ligand with two aromatic NMe(2) groups. The crystal structures of complexes and were determined via X-ray crystallography. Both catalysts perform ring opening metathesis polymerization (ROMP) of cyclooctene (COE) at faster rates than their commercially available counterparts H(2)IMes(PCy(3))Cl(2)Ru[double bond, length as m-dash]CH-Ph and H(2)IMesCl(2)Ru[double bond, length as m-dash]CH-(C(6)H(4)-O-iPr) (H(2)IMes = 1,3-bis(2',4',6'-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene) and perform at similar rates during ring closing metathesis (RCM) of diethyldiallylmalonate (DEDAM). Upon addition of 2 equiv. of HCl, catalyst is converted into a mixture of several mono and diprotonated Ru-carbene species 12' which are soluble in methanol but degrade within a few hours at room temperature. Catalyst can be protonated with 2 equiv. of HCl and the resulting complex is moderately water-soluble. The complex is stable in aqueous solution in air for >4 h, but over prolonged periods of time shows degradation in acidic media due to hydrolysis of the NHC-Ru bond. Catalysts and perform RCM of diallylmalonic acid in acidic protic media with only moderate activity at 50 degrees C and do not produce polymer in the ROMP of cationic 7-oxanorbornene derivative under the same conditions. Catalyst was used for Ru-seperation studies when RCM of DEDAM or 3,3-diallypentadione (DAP) was conducted in low-polar organic solution and the Ru-species was subsequently precipitated by addition of strong acid. The Ru-species were removed by (1) filtration and (2) filtration and subsequent extraction with water. The residual Ru-levels could be reduced to as far as 11 ppm (method 2) and 24 ppm (method 1) without the use of chromatography or other scavenging methods.