Ring-closing Metathesis Reaction Research Articles

Exploring the Reactivity of Substituted [(Allyloxy)methyl]phosphonates in Cycloaddition and Coupling Reactions

AbstractThis paper describes the versatility of substituted [(allyl­oxy)methyl]phosphonates to open the way to the synthesis of original phosphonated molecules with heterocyclic architectures. In 1,3-dipolar cycloaddition reactions with nitrile oxides, nitrile imines, and nitrones, these [(allyloxy)methyl]phosphonates react as dipolarophiles to give, regioselectively, the corresponding isoxazolines, pyrazolines, and isoxazolidines. Transition-metal-catalyzed reactions, including inter- or intramolecular Heck coupling, provided access to cinnamyl- and indenyl-linked moieties and phosphonated benzo-fused oxacycles, respectively. Additionally, ring-closing metathesis reactions enabled the synthesis of 2,5-dihydrofurans with the phosphonate group at the anomeric position. In this work, 51 novel phosphorylated heterocyclic compounds, which may find significance in the pharmaceutical and agrochemical fields, were prepared.

Asymmetric Synthesis of the Functionalized A/E-Ring Fragment of C18-Diterpenoid Alkaloids.

A new asymmetric synthesis of the A/E-ring fragment of C18-diterpenoid alkaloids is described. The crucial contiguous stereogenic centers at C4, C5, and C11 were established through an asymmetric Michael addition/allylation sequence. The unique azabicyclo[3.3.1]nonane motif (A/E rings) was assembled by employing ring-closing metathesis and Mitsunobu reaction as key strategies.

Asymmetric Total Synthesis of Pedrolide.

The asymmetric total synthesis of pedrolide (>200 mg) with an unprecedented [5-5-5-6-6-3] hexacyclic core (pedrolane) was achieved. Its unique bicyclo[2.2.1]heptane ring system was efficiently constructed via an enantioselective ene reaction of cyclopentadiene followed by a Wittig reaction, isomerization, and a diastereoselective intramolecular Diels-Alder reaction cascade. The highly oxygenated carane [6-3] ring system was synthesized via a ring-closing metathesis reaction followed by an unusual free carbene cyclopropanation. Furthermore, the 12 contiguous stereocenters of pedrolide were installed diastereoselectively.

Bioinspired Total Synthesis of Bipolarolides A and B.

We have achieved the first total synthesis of bipolarolides A and B, which possess an intriguing and complex 5/6/6/6/5 caged pentacyclic skeleton with seven contiguous stereocenters. The synthesis features a lithium-halogen exchange/intermolecular nucleophilic addition to link two enantioenriched fragments, two ring-closing metathesis reactions to assemble the five- and eight-membered rings, and a bioinspired Prins reaction/ether formation cascade cyclization to construct the 5/6/6/6/5 caged skeleton.

MYC-Targeting Inhibitors Generated from a Stereodiversified Bicyclic Peptide Library.

Here, we present the second generation of our bicyclic peptide library (NTB), featuring a stereodiversified structure and a simplified construction strategy. We utilized a tandem ring-opening metathesis and ring-closing metathesis reaction (ROM-RCM) to cyclize the linear peptide library in a single step, representing the first reported instance of this reaction being applied to the preparation of macrocyclic peptides. Moreover, the resulting bicyclic peptide can be easily linearized for MS/MS sequencing with a one-step deallylation process. We employed this library to screen against the E363-R378 epitope of MYC and identified several MYC-targeting bicyclic peptides. Subsequent in vitro cell studies demonstrated that one candidate, NT-B2R, effectively suppressed MYC transcription activities and cell proliferation.

Chemical recycling of polyolefins via ring-closing metathesis depolymerization.

The current insufficient recycling of commodity polymer waste has resulted in pressing environmental and human health issues in our modern society. In the quest for next-generation polymer materials, chemists have recently shifted their attention to the design of chemically recyclable polymers that can undergo depolymerization to regenerate monomers under mild conditions. During the past decade, ring-closing metathesis reactions have been demonstrated to be a robust approach for the depolymerization of polyolefins, producing low-strain cyclic alkene products which can be repolymerized back to new batches of polymers. In this review, we aim to highlight the recent advances in chemical recycling of polyolefins enabled by ring-closing metathesis depolymerization (RCMD). A library of depolymerizable polyolefins will be covered based on the ring size of their monomers or depolymerization products, including five-membered, six-membered, eight-membered, and macrocyclic rings. Moreover, current limitations, potential applications, and future opportunities of the RCMD approach will be discussed. It is clear from recent research in this field that RCMD represents a powerful strategy towards closed-loop chemical recycling of novel polyolefin materials.

Development of Highly Enantio- and Z-Selective Grubbs Catalysts via Controllable C-H Bond Activation.

Asymmetric olefin metathesis is a powerful strategy for stereocontrolled synthesis that allows the formation of chiral elements in conjunction with carbon-carbon double bonds. Here, we report a new series of cyclometalated stereogenic-at-Ru catalysts that enable highly efficient asymmetric ring opening/cross-metathesis (AROCM) and asymmetric ring-closing metathesis (ARCM) reactions. Single enantiomers of these catalysts with either right-handed or left-handed configurations at the Ru center can be easily accessed via highly stereoselective C-H bond activation-based cyclometalation. Right-handed chiral Ru catalysts enabled the Z- and enantioselective AROCM of a wide range of norbornenes and terminal alkenes, generating densely functionalized cyclopentanes with excellent stereo- and enantioselectivities (99:1 Z/E, up to 99% ee). Left-handed chiral Ru catalysts enabled the facile ARCM of sterically unhindered, all-terminal prochiral trienes, which had not been achieved by previous Ru catalysts, providing simple cyclic ethers and amides with tertiary or quaternary carbon stereocenters with excellent enantioselectivities (up to 99% ee).

Convergent Total Synthesis of (-)-Cyclopamine.

A concise and enantioselective total synthesis of the Veratrum alkaloid cyclopamine is disclosed. This highly convergent synthesis with a 16-step longest linear sequence (LLS) was enabled by a de novo synthesis of the trans-6,5-heterobicycle via a strain-inducing halocyclization process, a key Tsuji-Trost cyclization to construct the fully substituted, spirocyclic THF motif with exquisite diastereocontrol, and a late-stage ring-closing metathesis (RCM) reaction to forge the central tetrasubstituted olefin.

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.

Indole-Based Macrocyclization by Metal-Catalyzed Approaches

This review is dedicated to the different varieties of macrocycles synthesis bearing indole units in their architecture by metal-catalyzed strategies. The progress of the new macrocyclization approaches is persisted be a keen area of research. Macrocycles contain a wide variety of molecules, and among those, heteroaryl motifs are valuable constituents that provide an attractive feature to macrocyclic systems. Indole represents one of the privileged pharmacophores against a variety of targets with various biological applications. Among the nitrogen-based heterocycles, indole plays a prominent role in organic synthesis, medicinal chemistry, pharmaceuticals, natural products synthesis, agrochemicals, dye and fragrances, and drug design. These scaffolds are widely distributed in several bioactive natural products and synthetic macrocycles constructed against a specific biochemical target and the most common constituents of naturally occurring molecules. Due to its immense importance, the progress of novel approaches for the synthesis of indole-based scaffolds has increased steadily. The majority of the macrocycles synthesis proceeds through the macrolactamization and macrolactonization, as well as the C–C bond macrocyclization process described by metal-catalyzed ring-closing metathesis (RCM) and coupling reactions. Among macrocyclizations, metal-catalyzed approaches are considered one of the most powerful tools for synthetic chemists in the design of a variety of macrocycles. This review aims to give a comprehensive insight into the synthesis of varieties of macrocycles bearing indole scaffold catalyzed by various transition metals that emerged in the literature over the last two decades. We hope that this review will persuade synthetic chemists to search for novel strategies for the C–C bond macrocyclization by metal-catalyzed protocols.

Stereoselective total synthesis of Pestalotioprolide C and C7-epi-Pestalotioprolide C

The total synthesis of 14 membered macrolide Pestalotioprolide C and C7-epi- Pestalotioprolide C were accomplished starting from commercially available D-Mannitol by Stereoselective synthetic approach. The key reactions involved are Mitsunobu reaction, Regioselective ring opening of chiral epoxide and ring-closing metathesis reactions (RCM).

Synthesis of lactones from fatty acids by ring-closing metathesis and their biological evaluation

The present study involves the synthesis of macrocyclic lactones by the esterification of unsaturated fatty acids (oleic acid, undecenoic acid, and erucic acid) with unsaturated alcohols (allyl alcohol, prop-2-ene-1-ol, oleyl alcohol, and undecenol) followed by a ring closing metathesis reaction employing Grubbs' second generation catalyst (1.0-1.5 mmol). The structure of the compounds was confirmed by 1H NMR, 13C NMR, FT-IR, and ESI-Mass spectral studies. The antibacterial activity of the synthesised lactones was evaluated. The larger ring-sized lactone, namely, erucic acid lactone, exhibited excellent antibacterial activity against three bacterial cell lines, namely, Staphylococcus aureus, Staphylococcus epidermidis, and Bacillus subtilis. Undecenoic acid-based lactones exhibited excellent antibacterial activity selectively against only Staphylococcus epidermidis. The assay of macrolactones for their in vitro anticancer activity was carried out by MTT for different cancer cell lines, namely, human prostate epithelial cancer cells (ATCC HTB-81), HepG2 derived from hepatic cancer cells (ATCC HB-8065), SKOV3 derived from human ovarian cancer cells (ATCC HTB-77), MDAMB-231 derived from human breast cancer cells (ATCC HTB-26) and Chinese hamster ovarian (CHO-K1) cell lines. The molecules selectively exhibited anticancer activity against Chinese hamster ovarian (CHO-K1) cell lines. Among macrolactones, (E)-oxacyclotridec-11-en-2-one (MALUN) was more active and its activity was much higher compared to others and on par with the reference standard Mitomycin C. This was followed by (E)-oxacyclotricos-14-en-2-one (MOLER) and (E)-oxacyclononadec-10-en-2-one (MOLOH). The fatty acid-based cyclic lactones with selective antibacterial and anticancer activities can be further explored for a variety of pharmaceutical formulations.

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.

Synthesis of protected 1,4-trans-1,5-cis-4,5-diamino-2-cyclopenten-1-ol via stereoselective vinylation of α-amino aldimine

We report the synthesis of diaminocyclitol, protected 1,4-trans-1,5-cis-4,5-diamino-2-cyclopenten-1-ol. The key strategy was stereoselective vinylation of an acyclic chiral α-amino aldimine to construct syn-diamine moiety. The 1,5-cis-amino alcohol moiety was established by stereoselective reduction, and the cyclopentene structure was secured through a ring-closing metathesis reaction.

Enantioselective Synthesis of Fluorinated Indolizidinone Derivatives

The enantioselective synthesis of fluorinated indolizidinone derivatives has been developed. The process involved an enantioselective intramolecular aza-Michael reaction of conjugated amides bearing a pendant α,β-unsaturated ketone moiety, catalyzed by the (S)-TRIP-derived phosphoric acid, followed by dimethyltitanocene methylenation and ring closing metathesis (RCM). Final indolizidine-derived products comprise a fluorine-containing tetrasubstituted double bond generated by the RCM reaction, which is a challenging task. The whole synthetic sequence took place in acceptable overall yields with excellent enantioselectivities.

Synthesis of 5‐spirocycle camptothecin using ring‐closing metathesis strategy

AbstractCamptothecin (CPT) is an important natural product targeting to Topoisomerase I (Topo I). Despite the high antitumor activity, this compound cannot enter clinical trial owing to its high toxicity and low bio‐availability. In this project, the ring‐closing metathesis (RCM) synthesis strategy was employed to introduce spirocycle functional group in the 5‐position of CPT. Thus, in the catalysis of Grubbs II catalyst, 5,5‐diallylcamptothecin underwent RCM reaction to give 5‐spirocycle CPT compound in 73% yield.

Highly Strained Oxygen-Doped Chiral Molecular Belts of the Zigzag-Type with Strong Circularly Polarized Luminescence.

Herein we report a two-directional cyclization strategy for the synthesis of highly strained depth-expanded oxygen-doped chiral molecular belts of the zigzag-type. From the easily accessible resorcin[4]arenes, an unprecedented cyclization cascade generating fused 2,3-dihydro-1H-phenalenes has been developed to access expanded molecular belts. Stitching up the fjords through intramolecular nucleophilic aromatic substitution and ring-closing olefin metathesis reactions furnished a highly strained O-doped C2 -symmetric belt. The enantiomers of the acquired compounds exhibited excellent chiroptical properties. The calculated parallelly aligned electric (μ) and magnetic (m) transition dipole moments are translated to the high dissymmetry factor (|glum | up to 0.022). This study provides not only an appealing and useful strategy for the synthesis of strained molecular belts but also a new paradigm for the fabrication of belt-derived chiroptical materials with high CPL activities.

Transition-Metal-Catalyzed C–C Bond Macrocyclization via Intramolecular C–H Bond Activation

Macrocycles are commonly synthesized via late-stage macrolactamization and macrolactonization. Strategies involving C–C bond macrocyclization have been reported, and examples include the transition-metal-catalyzed ring-closing metathesis and coupling reactions. In this mini-review, we summarize the recent progress in the direct synthesis of polyketide and polypeptide macrocycles using a transition-metal-catalyzed C–H bond activation strategy. In the first part, rhodium-catalyzed alkene–alkene ring-closing coupling for polyketide synthesis is described. The second part summarizes the synthesis of polypeptide macrocycles. The activation of indolyl and aryl C(sp2)–H bonds followed by coupling with various coupling partners such as aryl halides, arylates, and alkynyl bromide is then documented. Moreover, transition-metal-catalyzed C–C bond macrocyclization reactions via alkyl C(sp3)–H bond activation are also included. We hope that this mini-review will inspire more researchers to explore new and broadly applicable strategies for C–C bond macrocyclization via intramolecular C–H activation.

Ruthenium Metathesis Catalysts with Imidazole Ligands

Phosphine-free ruthenium benzylidene complexes containing imidazole ligands are reported. These catalysts are effective for ring-closing metathesis (RCM) and cross-metathesis (CM) reactions at high temperatures, where the more widely used phosphine-containing N-heterocyclic carbene-based ruthenium catalysts show side reactions. This discovery opens up a pathway to develop more selective ruthenium metathesis catalysts for reactions requiring harsh conditions.