Ruthenium-catalyzed Ring-closing Metathesis Research Articles

Construction of indolizine scaffolds from α,ω-alkynoic acids and α,ω-vinylamines via sequential-relay catalysis in "one pot".

A simple and efficient method has been developed for the synthesis of a diverse range of aryl-fused indolizin-3-ones through sequential Au(I)-catalyzed hydrocarboxylation, aminolysis, and cyclization, followed by ruthenium-catalyzed ring-closing metathesis. Moderate to good yields were observed with satisfactory substrate scope and functional group tolerance. The developed protocol represents a practical strategy for the construction of bioactive aryl-fused indolizin-3-ones.

Synthesis and Cytotoxicity Evaluation of Betulin Cycloolefin Derivatives by Ruthenium-Catalyzed Ring-Closing Metathesis.

The combination of ring-closing metathesis with betulin enables the design and synthesis of novel biomolecules representing a library of triterpenoid derivatives for potential pharmacological research. In this work, cyclic olefin betulin derivatives were attempted to be prepared by the combination of ring-closing metathesis with betulin. Dicyclohexyl carbodiimide coupling reaction allowed the transformation of betulin into two types of linear olefin derivatives that have different methylene spacer lengths between the olefin and ester groups. Subsequently, betulin-based cycloolefins were synthesized by ring-closing metathesis using Grubbs first-generation catalyst. The influence of different parameters including solvents, temperature, catalysts, and catalyst loading on ring-closing metathesis was investigated. Cytotoxicity results indicated that these betulin-based olefin derivatives, derived from renewable bioresources, have potential applications in the biomedical field.

Absorption, fluorescence, and two-photon excitation ability of 5-phenyl-13-arylisoindolo[2,1-a]quinolines prepared by one-pot reaction of ring-closing metathesis and 1,3-dipolar cycloaddition

Substituted 5-phenyl-13-aryl-isoindolo[2,1-a]quinoline dyes that exhibit two-photon absorption up to 375 GM have been synthesized via ruthenium-catalyzed ring-closing metathesis in tandem with a 1,3-dipolar cycloaddition reaction.

Origin of the selectivity in the ring-closing metathesis step of the synthesis of (−)-callyspongiolide: Formation of fourteen-versus eight-membered rings

In previous work we reported the formal synthesis of the marine macrolide (−)-callyspongiolide through a synthetic approach in which the generation of the key macrocyclic core relies on a ruthenium-catalyzed ring-closing metathesis reaction. However, besides the predicted macrolactone intermediate, an undesired cyclooctene was observed. We investigate here the mechanism of this critical step through density functional theory calculations. The results indicate that the chemoselectivity is not under kinetic control but ruled by thermodynamics. This conclusion is further confirmed by additional experimental studies.

E/ZSwitchable Ring-Closing Metathesis in 1,1′-Bis(but-3-enyl)ferrocenes: Synthesis and Characterization of Axially Chiralansa[6]-Ferrocenes

A series of ansa[6]-ferrocenes were obtained through the ruthenium-catalyzed ring-closing olefin metathesis in 1,1′-bis(but-3-enyl)ferrocenes. The stereoselectivity of this reaction depended on the structure of substrates, that is, mixtures of (E) and (Z) isomers were obtained for alkyl-substituted 3a–3d while (Z)-isomers only for aryl-substituted 3e and 3f. The ansa[6]-ferrocenes are axially chiral in the solid state according to single-crystal X-ray analysis. In the case of methyl-substituted derivative 4a, spontaneous resolution of the racemate was observed during crystallization. The solution properties of (E) and (Z) isomers are remarkably different; the latter displays inequivalence of the two formally identical parts of the molecule at low temperature.

Ruthenium Metathesis: A Key Step To Access a New Cyclic Tetrasubstituted Olefin Platform.

An rapid and mild synthetic route for the preparation of cyclic tetrasubstituted platforms via ruthenium-catalyzed ring-closing metathesis (RCM) has been developed. This process tolerates a wide range of functionalities such as nitrogen, oxygen, sulfur, silicon, and carbon tethered groups, as well as very challenging fluorine and boron atoms (36 derivatives, up to 96%). This diversity-oriented method was further demonstrated by the postfunctionalization reactions, such as Pd-couplings, N-substitution, and reductive amination introducing a morpholine moiety.

Synthesis of Chiral 1,3-Dienes through Ring-Closing Metathesis of Enantioenriched Enynes: Potential Precursors of Morphane Analogs.

A simple methodology for the synthesis of enynes by indium mediated diastereoselective allylation of aromatic N-tert-butanesulfinylimines bearing alkenyl groups at ortho-position with allyl bromide has been developed. The addition of the allyl indium intermediate to the chiral imine took place with excellent diastereoselectivity. Ruthenium-catalyzed ring-closing metathesis of the resulting enynes provided the expected cyclic 1,3-dienes in good to moderate yields. These chiral dienes are potential precursors of biologically and pharmacologically active morphane derivatives.

ChemInform Abstract: An Approach to the Synthesis of Pyrimido[b]azepines via Ruthenium‐Catalyzed Ring‐Closing Metathesis.

ChemInform Abstract: An Approach to the Synthesis of Pyrimido[b]azepines via Ruthenium‐Catalyzed Ring‐Closing Metathesis.

An enantiocontrolled entry to the tricyclic polar segment of (+)-fusarisetin A

The tricyclic polar segment of fusarisetin A, designed for preparing analogues for structure–activity relationship studies of the aliphatic segment thereof, has been constructed in an enantiocontrolled manner, featuring the Yamamoto asymmetric epoxidation of a homoallylic alcohol, C3-selective ring-opening of a 3,4-epoxy alcohol, stereocontrolled merger of a γ-lactone with Garner’s counterpart, and ruthenium-catalyzed ring-closing metathesis.

An Approach to the Synthesis of Pyrimido[b]azepines via Ruthenium-Catalyzed Ring-Closing Metathesis

A highly efficient approach to the synthesis of a series of pyrimido[b]azepines has been developed with 5-allyl-2,4,6-trichloropyrimidine as the starting material in six or seven steps via a ring-closing metathesis (RCM) reaction. The absolute configuration of the key intermediate pyrimido[4,5-b]azepine was ascertained by X-ray crystal structure analysis.

Ring‐Closing Metathesis of (η5‐Alkenylcyclopentadienyl)(alkenylphosphine)manganese(I) Dicarbonyl Complexes

AbstractThe ruthenium‐catalyzed ring‐closing metathesis (RCM) reactions of various [η5‐(ω‐alkenyl)cyclopentadienyl](ω‐alkenylphosphine)manganese(I) dicarbonyl complexes were examined. The RCM reaction between an η5‐allyl‐ or an η5‐vinyl‐cyclopentadienyl ligand and an allyldiphenylphosphine ligand in the manganese coordination spheres gave the corresponding cyclized products in good to excellent yields. The X‐ray analyses of the two cyclized products revealed the structural differences between the C3‐ and the C4‐bridged complexes. The RCM reactions of the o‐bromo‐substituted manganese complexes were also operative and the cyclized products were obtained in excellent yields of >95%. The preferential formation of the C4‐bridged species over the C3‐bridged analogues in the RCM of the manganese complexes was confirmed by an intramolecular competitive RCM experiment with the [η5‐1‐(methallyl)‐2‐(2‐propenyl)cyclopentadienyl](allyldiphenylphosphine)manganese(I) dicarbonyl complex.magnified image

ChemInform Abstract: Ruthenium‐Catalyzed One‐Pot Ring‐Closing Metathesis/Syn‐Dihydroxylation in the Synthesis of Bicyclic Iminosugars.

Abstract Novel polyhydroxylated derivatives of quinolizidine and decahydropyrido[1,2-a]azepine were prepared starting from a common oxazolidinone. The bicyclic cores were prepared by a ruthenium-catalyzed ring-closing metathesis, followed by re-use of the catalyst in the subsequent syn-dihydroxylation in a one-pot procedure.

Design and Stereoselective Synthesis of ProM-2: A Spirocyclic Diproline Mimetic with Polyproline Type II (PPII) Helix Conformation.

With the aim of developing polyproline type II helix (PPII) secondary-structure mimetics for the modulation of prolin-rich-mediated protein-protein interactions, the novel diproline mimetic ProM-2 was designed by bridging the two pyrrolidine rings of a diproline (Pro-Pro) unit through a Z-vinylidene moiety. This scaffold, which closely resembles a section of a PPII helix, was then stereoselectively synthesized by exploiting a ruthenium-catalyzed ring-closing metathesis (RCM) as a late key step. The required vinylproline building blocks, that is, (R)-N-Boc-2-vinylproline (Boc=tert-butyloxycarbonyl) and (S,S)-5-vinylproline-tert-butyl ester, were prepared on a gram scale as pure stereoisomers. The difficult peptide coupling of the sterically demanding building blocks was achieved in good yield and without epimerization by using 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU)/N,N-diisopropylethylamine (DIPEA). The RCM proceeded smoothly in the presence of the Grubbs II catalyst. Stereostructural assignments for several intermediates were secured by X-ray crystallography. As a proof of concept, it was shown that certain peptides containing ProM-2 exhibited improved (canonical) binding towards the Ena/VASP homology 1 (EVH1) domain as a relevant protein interaction target.

ChemInform Abstract: Enantioselective Syntheses of Bicyclic Lactams Based on Iridium‐Catalyzed Asymmetric Allylic Substitution and Heck Cyclization.

A sequence of reactions that include an iridium-catalyzed regio- and enantioselective allylic amination, the formation of an amide, a ruthenium-catalyzed ring-closing metathesis, and an intramolecular Heck reaction allows for the preparation of [3,3,1]- and [4,3,1]-bicyclic amides. The target compounds have a nitrogen atom at the bridgehead, a nonplanar amide moiety, and a stereogenic center at the one-carbon bridge.

Ruthenium-catalyzed one-pot ring-closing metathesis/syn-dihydroxylation in the synthesis of bicyclic iminosugars

Novel polyhydroxylated derivatives of quinolizidine and decahydropyrido[1,2-a]azepine were prepared starting from a common oxazolidinone. The bicyclic cores were prepared by a ruthenium-catalyzed ring-closing metathesis, followed by re-use of the catalyst in the subsequent syn-dihydroxylation in a one-pot procedure.

Synthesis of substituted styrenes and 3-vinylphenols using ruthenium-catalyzed ring-closing enyne metathesis.

The synthesis of substituted styrenes 3 and 3-vinylphenols 9 was achieved by ring-closing enyne metathesis (RCEM)/dehydration of 7 and RCEM/tautomerization of 8, respectively. Those methods provide selective access to unique aromatic compounds and solve the problem of regioisomer formation.

ChemInform Abstract: Synthesis of Azaheterocyclic Vinylphosphonates by Ring‐Closing Metathesis.

The title compounds were synthesized by ruthenium-catalyzed ring-closing metathesis of N-tosyl-N-(ω-alkenyl)aminomethylvinyl phosphonates, which were obtained from N-(ω-alkenyl)-N-tosylamides. These compounds, in turn, were prepared from unsaturated alcohols through the Mitsunobu reaction. This methodology gives access to five- and six-membered ring compounds. Additionally, chiral phosphonates can be obtained easily.

Stereoselective Synthesis of Functionalized Cyclic Amino Acid Derivatives via a [2,3]-Stevens Rearrangement and Ring-Closing Metathesis

Unnatural cyclic amino acids are valuable tools in biomedical research and drug discovery. A two-step stereoselective strategy for converting simple glycine-derived aminoesters into unnatural cyclic amino acid derivatives has been developed. The process includes a palladium-catalyzed tandem allylic amination/[2,3]-Stevens rearrangement followed by a ruthenium-catalyzed ring-closing metathesis. The [2,3]-rearrangement proceeds with high diastereoselectivity through an exo transition state. Oppolzer's chiral auxiliary was utilized to access an enantiopure cyclic amino acid by this approach, which will enable future biological applications.

Cell-permeable stapled peptides based on HIV-1 integrase inhibitors derived from HIV-1 gene products.

HIV-1 integrase (IN) is an enzyme which is indispensable for the stable infection of host cells because it catalyzes the insertion of viral DNA into the genome and thus is an attractive target for the development of anti-HIV agents. Earlier, we found Vpr-derived peptides with inhibitory activity against HIV-1 IN. These Vpr-derived peptides are originally located in an α-helical region of the parent Vpr protein. Addition of an octa-arginyl group to the inhibitory peptides caused significant inhibition against HIV replication associated with an increase in cell permeability but also relatively high cytotoxicity. In the current study, stapled peptides, a new class of stabilized α-helical peptidomimetics were adopted to enhance the cell permeability of the above lead peptides. A series of stapled peptides, which have a hydrocarbon link formed by a ruthenium-catalyzed ring-closing metathesis reaction between successive turns of α-helix, were designed, synthesized, and evaluated for biological activity. In cell-based assays some of the stapled peptides showed potent anti-HIV activity comparable with that of the original octa-arginine-containing peptide (2) but with lower cytotoxicity. Fluorescent imaging experiments revealed that these stapled peptides are significantly cell permeable, and CD analysis showed they form α-helical structures, whereas the unstapled congeners form β-sheet structures. The application of this stapling strategy to Vpr-derived IN inhibitory peptides led to a remarkable increase in their potency in cells and a significant reduction of their cytotoxicity.

Synthesis of Cyclic 1-Alkenylboronates via Zr-Mediated Double Functionalization of Alkynylboronates and Sequential Ru-Catalyzed Ring-Closing Olefin Metathesis

Synthesis of novel cyclic 1-alkenylboronates is accomplished through the zirconium-mediated regio- and stereoselective double functionalization of 1-alkynylboronates and the subsequent ruthenium-catalyzed ring-closing metathesis (RCM). The obtained substituted cyclic 1-alkenylboronates are transformed into o-terphenyl and triphenylene derivatives.