Generation Hoveyda-Grubbs Catalyst Research Articles

Cover Feature: Stability of a Silica‐Supported Second Generation Hoveyda‐Grubbs Catalyst Under Atmospheric Conditions: Experimental and Computational Studies (ChemCatChem 10/2023)

The Cover Feature illustrates the crucial role of storage conditions of silica-gel-supported 2nd generation Hoveyda-Grubbs catalyst. The glass shield on the spaceship protects the catalyst from air and moisture. In their Research Article, C. R. Apesteguía, S. E. Vaillard and co-workers show that after exposure to atmospheric conditions, O2 and H2O degrade the immobilized catalyst, compromising its applicability in olefin metathesis reactions. In order to retain long term stability the catalyst should be stored under controlled conditions. More information can be found in the Research Article by C. R. Apesteguía, S. E. Vaillard and co-workers.

Investigating a new C2-symmetric testosterone dimer and its dihydrotestosterone analog: Synthesis, antiproliferative activity on prostate cancer cell lines and interaction with CYP3A4

The synthesis of a 17α-linked C2-symmetric testosterone dimer and its dihydrotestosterone analog is reported. The dimers were synthesized using a short five-step reaction sequence with 28% and 38% overall yield for the testosterone and dihydrotestosterone dimer, respectively. The dimerization reaction was achieved by an olefin metathesis reaction with 2nd generation Hoveyda-Grubbs catalyst. The dimers and their corresponding 17α-allyl precursors were tested for the antiproliferative activity on androgen–dependent (LNCaP) and androgen–independent (PC3) prostate cancer cell lines. The effects on cells were compared with that of the antiandrogen cyproterone acetate (CPA). The results showed that the dimers were active on both cell lines, with an increased activity towards androgen–dependent LNCaP cells. However, the testosterone dimer (11) was fivefold more active than the dihydrotestosterone dimer (15), with an IC50 of 11.7 μM vs. 60.9 μM against LNCaP cells, respectively, and more than threefold more active than the reference drug CPA (IC50 of 40.7 μM). Likewise, studies on the interaction of new compounds with drug-metabolizing cytochrome P450 3A4 (CYP3A4) showed that 11 was a fourfold stronger inhibitor than 15 (IC50 of 3 μM and 12 μM, respectively). This suggests that changes in the chemical structure of sterol moieties and the manner of their linkage could largely affect both the antiproliferative activity of androgen dimers and their crossreactivity with CYP3A4.

Predicting initiation rates of Hoveyda-Grubbs complexes containing an electron-withdrawing group in four possible positions of the benzylidene ring

The initiation rate of ruthenium metathesis catalysts is one of their most important characteristics from the applicational point of view due to the fact, that initiation is often the rate-limiting step of the entire catalytic cycle. Such initiation rate can be adjusted by introducing various modifications to the commonly used Grubbs-like and Hoveyda-Grubbs-like catalysts. Using a DFT approach, we predicted the initiation rates of the 2nd generation Hoveyda-Grubbs catalyst analogues substituted with electron-withdrawing –NO, –NO2, and –SO2C4F9 groups in all positions of the phenyl ring in the benzylidene part. We show that some of the modifications should result in very fast-initiating catalysts. In particular, the –SO2C4F9-substitued derivatives are predicted to be the fastest-initiating in the series. We also found correlations between the selected computed parameters such as the Gibbs free energy barrier for initiation and ruthenium-oxygen bond strengths which, combined with distortion energy analysis, allowed us to provide an explanation of the main driving force behind fast initiation.

Selectively Depolymerizable Polyurethanes from Unsaturated Polyols Cleavable by Olefin Metathesis

Inside Cover: In article number 2000571 by Brad H. Jones and coworkers, linear and crosslinked polyurethanes are prepared from traditional isocyanates and new polyols containing unsaturated moieties designed to favor ring-closing olefin metathesis and concomitant cleavage of the molecule. These polyurethanes are found to be efficiently depolymerized upon exposure to second generation Hoveyda–Grubbs catalyst under ambient conditions. The depolymerization products are multi-vinyl/cycloalkene species that can be re-polymerized.

Preparation and activity of ruthenium catalyst based on β-cyclodextrin for ring-opening metathesis polymerization

Inspired by substrates-recognition of enzymes, we prepared supramolecular catalyst (Ru-βCD Cat) for ring-opening metathesis polymerization (ROMP) by modifying second generation Grubbs catalyst® (M204) with β-cyclodextrin (βCD) derivative (VPhe-βCD). The ROMP activity of Ru-βCD Cat was demonstrated using 7-oxanorbornene-2,3-dicarboxylic acid dimethyl ester (ONorCOOMe). The VPhe-βCD cavity recognized the ONorCOOMe monomer and attached to catalytic metal center of Ru-βCD Cat to grow poly(ONorCOOMe) with higher yield and molecular weight (Mn) in aqueous medium. The yield and Mn were higher than those of poly(ONorCOOMe) obtained by second generation Hoveyda-Grubbs catalyst® (M720). 1-Adamantanol hindered ONorCOOMe from occupying the βCD cavity, acting as a competitive guest molecule. The inhibition caused lower polymer yield and Mn. These results showed that molecular recognition of ONorCOOMe by the cavity of Ru-βCD Cat is important to increase the polymer yield and Mn of poly(ONorCOOMe).

Synthesis of Stilbene and Chalcone Inhibitors of Influenza A Virus by SBA-15 Supported Hoveyda-Grubbs Metathesis

Stilbene and chalcone derivatives with biological activity against influenza A virus have been synthesized by self-, cross-, and ring-closing metathesis procedures. The reactions were performed under environmentally friendly conditions using the second generation Hoveyda-Grubbs catalyst Aquamet SiPr after immobilization on Santa Barbara Amorphous mesoporous silicate SBA-15. Irrespective from the experimental conditions, the heterogeneous catalyst showed activity and selectivity comparable than the homogeneous counterpart for at least six successive runs without appreciable leaching of the active species. An appreciable antiviral activity against influenza A virus for some of the novel derivatives were observed, mainly involving the early stage of the virus-replication life-cycle.

Synthesis of β-1,3-glucan mimics by β-1,3-glucan trisaccharyl monomer polymerization

β-1,3-Glucans are important as immunostimulating agents in living organisms. The multivalent binding of β-1,3-glucans to dectin-1, a cell surface receptor, activates immunological defenses. To study artificial immunostimulating agents, glycopolymers carrying β-1,3-glucan trisaccharides as artificial ligands were synthesized. The β-1,3-glucan trisaccharide, defined as an active unit of β-1,3-glucan, was constructed from D-glucose by glycosylation. A norbornene group was introduced as a polymerizable group into the trisaccharide derivative at the aglycone. The prepared endo/exo norbornene stereoisomers of the monomers were separated by silica gel chromatography and identified by NMR spectroscopy and mass spectrometry. The synthesized glycosyl monomers were polymerized and copolymerized with norbornene using 2nd generation Hoveyda-Grubbs catalyst, deprotected, and purified by gel filtration to prepare water-soluble glycopolymers of varied compositions and high molecular weights. These polymers will have the potential for multivalent binding to dectin-1 to activate immune response and facilitate studies to understand the binding mechanisms of β-1,3-glucans with dectin-1.

Kinetics of Dicyclopentadiene Polymerization in the Presence of the Second Generation Hoveyda-Grubbs Catalyst with N-Chelating Ligand

This article considers the thermodynamic aspects, thermo- and rheokinetics of endo-dicyclopentadiene polymerization in the presence of the original metathesis second Hoveyda-Grubbs catalyst with an N-chelating ligand. The activation energy of endo-dicyclopentadiene polymerization was determined as 88.9–89.2 kJ/mol. The thermal effect of the ring-opening metathesis endo-dicyclopentadiene polymerization reaction reaches 52.7 kJ/mol. This is lower than the values for molybdenum- and tungsten-containing catalysts reported in the literature, which can be explained by a different microstructure of the polymer produced in the presence of ruthenium-based metathesis catalysts.

Metathesis reaction from bio-based resources: Synthesis of diols and macrodiols using fatty alcohols, β-citronellol and natural rubber

Diols and macrodiols (hydroxytelechelic compounds) were synthesized via metathesis from fatty alcohols and terpenes derivatives using [(1,3-bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene) dichloro (o-isopropoxyphenylmethylene) ruthenium] (second generation Hoveyda-Grubbs catalyst) as catalyst. The unsaturated diols: octadec-9-ene-1,18-diol, icos-10-ene-1,20-diol and 3,10-dimethyl-dodec-6-ene-1,12-diol were obtained with yields of 45–98% using mild conditions reaction, in absence of solvent. In other hand, macrodiols with high yields (>97%) and Fn ≈ 2 were synthetized in one-pot reaction by cross-metathesis degradation from the natural rubber (NR) and the cis-1,4-polybutadiene (PB), using the unprotected free alcohols, 9-decen-1-ol (9de), 10-undecen-1-ol (10un) and β-citronellol (βc), as chain transfer agents (CTA's). The results suggest that 9de, 10un and βc were effective CTA's in such metathesis reactions. The molecular weights were changed in a wide range (297 g/mol to 13,650 g/mol) controlling the rubber/CTA ratio and were in good agreement with their theoretical values.

Synthesis of a tyrosinase inhibitor by consecutive ethenolysis and cross-metathesis of crude cashew nutshell liquid.

A convenient and sustainable three-step synthesis of the tyrosinase inhibitor 2-hydroxy-6-tridecylbenzoic acid was developed that starts directly from the anacardic acid component of natural cashew nutshell liquid (CNSL). Natural CNSL contains 60–70% of anacardic acid as a mixture of several double bond isomers. The anacardic acid component was converted into a uniform starting material by ethenolysis of the entire mixture and subsequent selective precipitation of 6-(ω-nonenyl)salicylic acid from cold pentane. The olefinic side chain of this intermediate was elongated by its cross-metathesis with 1-hexene using a first generation Hoveyda–Grubbs catalyst, which was reused as precatalyst in a subsequent hydrogenation step. Overall, the target compound was obtained in an overall yield of 61% based on the unsaturated anacardic acid content and 34% based on the crude CNSL.

Helicenes as Chirality-Inducing Groups in Transition-Metal Catalysis: The First Helically Chiral Olefin Metathesis Catalyst.

Helical chirality is a novel enantioselectivity-inducing property in transition-metal-catalyzed transformations. The principle is illustrated herein for the example of asymmetric olefin metathesis. This work reports the synthesis of the first helically chiral Ru-NHC alkylidene complex from an aminohelicene-derived imidazolium salt, which was ligated to the first generation Hoveyda-Grubbs catalyst. Kinetic data were acquired for benchmark test reactions and compared to an achiral catalyst. The helically chiral Ru-catalyst was evaluated in asymmetric ring-closing metathesis (RCM) and ring-opening metathesis-cross-metathesis (ROM/CM) reactions, which proceeded with promising levels of enantioselectivity. Extensive NMR-spectroscopic investigations and a DFT geometry optimization were performed. These results led to a topographic steric map and calculation of percent-buried-volume values for each quadrant around the metal center.

Ring opening metathesis polymerization (ROMP) of five‐ to eight‐membered cyclic olefins: Computational, thermodynamic, and experimental approach

ABSTRACTRing opening metathesis polymerization (ROMP) of a series of low‐strain cyclic olefins and their hydroxyl derivatives using second generation Hoveyda–Grubbs catalyst has been investigated. Additionally, density functional theory (DFT) calculations were performed to evaluate the ring strain energies of the cyclic olefins and their hydroxyl derivatives, coupled with kinetic studies for the ROMP reactions. It was found that among different ring size monomers, Cy8 having a relatively moderate ring strain energy in comparison with the other cyclic olefins, exhibited the highest monomer conversion. The effect of temperature (0, 10, 15, and 25 °C) and monomer concentration (1 M; 2.5 M and 5 M for Cy5; and 1 M and 5 M for Cy7) for the cyclic olefins Cy5 and Cy7 were investigated. In general, the experimental results for the kinetic ROMP studies obtained using complex HG2 correlate really well with the DFT calculations determined for the ring strain energies of the cyclic olefins. For comparison, DFT calculations predicted the following trend for the ring strain energies Cy8 > Cy5 > Cy7 > Cy6, and the polymerizations carried out experimentally followed the same trend in terms of monomer conversion, with the exception of Cy5 and Cy7 at lower concentrations, which followed this trend Cy8 > Cy7 > Cy5 > Cy6. © 2017 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2017, 55, 3137–3145

Remarkably Efficient Microwave-Assisted Cross-Metathesis of Lipids under Solvent-Free Conditions.

Catalytic transformation of renewable feedstocks into fine chemicals is in high demands and olefin metathesis is a sophisticated tool for biomass conversion. Nevertheless, the large-scale viability of such processes depends on the conversion efficiency, energy efficiency, catalytic activity, selective conversion into desired products, and environmental footprint of the process. Therefore, conversions of renewables by using simple, swift, and efficient methods are desirable. A microwave-assisted ethenolysis and alkenolysis (using 1,5-hexadiene) of canola oil and methyl esters derived from canola oil (COME) and waste/recycled cooking oil (WOME) was carried out by using ruthenium-based catalytic systems. A systematic study using 1st and 2nd generation Grubbs and Hoveyda-Grubbs catalysts was carried out. Among all ruthenium catalysts, 2nd generation Hoveyda-Grubbs catalyst was found to be highly active in the range of 0.002-0.1 mol % loading. The conversions proved to be rapid providing unprecedented turnover frequencies (TOFs). High TOFs were achieved for ethenolysis of COME (21 450 min-1 ), direct ethenolysis of canola oil (19 110 min-1 ), for WOME (15 840 min-1 ) and for cross-metathesis of 1,5-hexadiene with COME (10 920 min-1 ). The ethenolysis of commercial methyl oleate was also performed with a TOF of 8000 min-1 under microwave conditions.

E- and Z-Selective Transfer Semihydrogenation of Alkynes Catalyzed by Standard Ruthenium Olefin Metathesis Catalysts.

Selective transfer semihydrogenation of alkynes to yield alkenes was achieved with commercial first and second generation Hoveyda-Grubbs catalysts and formic acid as a hydrogen donor. This catalytic system is distinguished by its selectivity and compatibility with many functional groups (halogens, cyano, nitro, sulfide, alkenes). The metathetic activity of the ruthenium catalysts may be utilized in tandem sequences of olefin metathesis plus alkyne reduction.

ChemInform Abstract: Asymmetric Transfer Hydrogenation of Ketones with Modified Grubbs′ Metathesis Catalysts: On the Way to a Tandem Process.

AbstractUpon addition of a chiral amine ligand, an alcohol and a base, the 1st generation Hoveyda—Grubbs catalyst is in situ transformed into an asymmetric transfer hydrogenation catalyst, promoting the enantioselective reduction of acetophenone to 1‐phenylethanol.

ChemInform Abstract: One‐Pot Olefin Isomerization/Aliphatic Enamine Ring‐Closing Metathesis/Oxidation/1,3‐Dipolar Cycloaddition for the Synthesis of Isoindolo[1,2‐a]isoquinolines.

N-Alkyl-N-(2-vinylbenzyl)prop-2-en-1-amine derivatives undergo a one-pot olefin isomerization/aliphatic enamine ring-closing metathesis (RCM)/oxidation/1,3-dipolar cycloaddition sequence with the ruthenium complex, Ru(CO)HCl(PPh3)3, a second generation Hoveyda–Grubbs catalyst, and a 1,3-dipolarophile. Overall, in a single operation the reaction sequence converts simple benzylamine derivatives into isoindolo[1,2-a]isoquinolines with a π-conjugated four-ring system, through three unique ruthenium-catalyzed transformations.

Asymmetric Transfer Hydrogenation of Ketones with Modified Grubbs Metathesis Catalysts: On the Way to a Tandem Process

AbstractHerein, we report the successful transformation of a 1st generation Grubbs metathesis catalyst into an asymmetric transfer hydrogenation (ATH) catalyst. Upon addition of a chiral amine ligand, an alcohol and a base, the 1st generation Hoveyda–Grubbs catalyst (HG‐I) was found to promote the enantioselective reduction of acetophenone to 1‐phenylethanol. After optimizing the order of addition and the reaction conditions, the substrate scope was assessed leading to enantiomeric excesses up to 97% ee. NMR experiments were run in order to get information about the in situ‐generated ATH catalyst. Furthermore, the possibility to perform olefin metathesis and ketone transfer hydrogenation sequentially in one pot was demonstrated, and the first tandem olefin metathesis–ketone asymmetric transfer hydrogenation was carried out.magnified image

One‐Pot Olefin Isomerization/Aliphatic Enamine Ring‐Closing Metathesis/Oxidation/1,3‐Dipolar Cycloaddition for the Synthesis of Isoindolo[1,2‐a]isoquinolines

AbstractN‐Alkyl‐N‐(2‐vinylbenzyl)prop‐2‐en‐1‐amine derivatives undergo a one‐pot olefin isomerization/aliphatic enamine ring‐closing metathesis (RCM)/oxidation/1,3‐dipolar cycloaddition sequence with the ruthenium complex, Ru(CO)HCl(PPh3)3, a second generation Hoveyda–Grubbs catalyst, and a 1,3‐dipolarophile. Overall, in a single operation the reaction sequence converts simple benzylamine derivatives into isoindolo[1,2‐a]isoquinolines with a π‐conjugated four‐ring system, through three unique ruthenium‐catalyzed transformations.magnified image

Effective α-Helix Stabilization via Hexenyl Propionate Cross-Link

In this study we examined two ester-containing cross-links, hex-2-enyl acetate and hex-2-enyl propionate, as new cross-linking systems for helix stabilization of short peptides. We demonstrated that these hexenyl ester cross-links can be readily installed via a ruthenium-mediated ring-closing metathesis reaction of L-aspartic acid 4-allyl ester or L-glutamic acid 5-allyl ester at position i and (S)-2-(4'-pentenyl)alanine at position i+4 using second generation Hoveyda-Grubbs catalyst at 60 o C. Between these two cross-links, we found that the hex-2enyl propionate significantly stabilizes the α-helical conformations of short model peptides. The helixstabilizing effects of the hex-2-enyl propionate tether appear to be as powerful as Verdine’s i,i+4 allhydrocarbon stapling system, which is one of the most widely used and the most potent helix-stabilizing crosslinking systems. Furthermore, the hex-2-enyl propionate bridge is reasonably robust against non-enzymatic hydrolytic cleavage at a physiological pH. While extended studies for probing its chemical scopes and biological applications are needed, we believe that this new helix-stabilizing system could serve as a useful chemical tool for understanding protein folding and designing conformationally-constrained peptide drugs.

Alkynol polymerization catalysed by Grubbs-type and Hoveyda–Grubbs ruthenium alkylidene complexes: A computational study

Density functional theory has been applied to study the mechanism of alkynol (3-butyn-2-ol) polymerization by the third generation Grubbs catalyst and the second generation Hoveyda–Grubbs catalyst. Besides typical linear products that can immediately undergo the next insertion step, cyclic products can be also formed, by oxygen-chelation to the ruthenium centre or as less stable rutenacyclobutene species. The initiation stage is predicted to be faster for the Grubbs-type catalyst, compared to the Hoveyda–Grubbs initiator. It is shown that α-insertion is always kinetically preferred over the β-insertion path. On the other hand, the NMR calculations indicate that the experimentally observed 1H NMR signals can be assigned to alkylidene protons of ruthenium species formed in minor amounts by β-insertion. The choice of the DFT method affects significantly the theoretical values of the 1H NMR chemical shifts. The general conclusions about the kinetic preferences do not depend on the density functional used, although the calculated energy profiles are strongly influenced. The simulation of the solvent effect is less significant.