Ring-closing Metathesis Research Articles

A convergent total synthesis of resorcylic acid lactones zeaenol and cochliomycin A

A convergent approach for the stereoselective total synthesis of zeaenol and cochliomycin A is reported. The key steps involved are alkyne generation using Ohira-Bestmann reagent onto sugar lactol, NaH mediated one-pot esterification and acetonide deprotection, Trost’s protocol of hydrosilylation followed by protodesilylation to get exclusively E-olefin from internal alkyne and ring closing metathesis (RCM) reaction. Readily accessible d-lyxose has been utilized as the chiron substrate for generation of aliphatic chain fragment and 2,4,6-trihydroxybenzoic acid has been used for the synthesis of vinylated arene fragment.

Ring-closing metathesis in flavonoid synthesis, part 1: flavenes

Ring-closing metathesis in flavonoid synthesis, part 1: flavenes

Tandem Macrolactone Synthesis: Total Synthesis of (-)-Exiguolide by a Macrocyclization/Transannular Pyran Cyclization Strategy.

Tetrahydropyran-containing macrolactones were synthesized by integrating Meyer-Schuster rearrangement, macrocyclic ring-closing metathesis, and transannular oxa-Michael addition under gold and ruthenium catalysis. Single-step access to a variety of 14- to 20-membered macrolactones containing a tetrahydropyran ring was possible from readily available linear precursors in good yields and with moderate to excellent diastereoselectivity. A 13-step synthesis of (-)-exiguolide, an anticancer marine macrolide, showcased the feasibility of our tandem reaction sequence for macrolactone synthesis and also demonstrated the power of transannular reactions for rapid assembly of the tetrahydropyran rings of the target natural product.

Modular Approach to Benzofurans, 2H-Chromenes and Benzoxepines via Claisen Rearrangement and Ring-Closing Metathesis: Access to Phenylpropanoids.

Benzofurans, 2H-chromenes and benzoxepines are key structural elements present in several natural products and pharmaceuticals. Here, we describe an easy-to-execute strategy for the synthesis of benzofurans, 2H-chromenes and benzoxepines, by employing Claisen rearrangement and ring-closing metathesis as key steps. A variety of phenols were converted into useful oxacycles in good to excellent yields. The ring-closing metathesis approach has been used to produce phenylpropanoid natural products. Examples described here include, the naturally occurring benzofurans such as 7-methoxywutaifuranal, 7-methoxywutaifuranol, 7-methoxywutaifuranate and the O-prenylated natural products like boropinic acid, boropinols A and C.

Synthesis of 6,7-benzene-fused tropane derivatives from isoindoline-aminal hybrid compound

Herein, the synthesis of 6,7-benzene-fused tropane derivatives from isoindoline-aminal hybrid compound has been reported. In the present synthetic study, ring-closing metathesis (RCM) was employed to construct the 6,7-benzene-fused tropene skeleton. To obtain the desired cis-1-allyl-3-stylylisoindoline precursor for the RCM reaction, the diastereoselective aza-Hosomi-Sakurai allylation and functional group transformations of isoindoline-aminal hybrid compound were performed. Using the synthesized 6,7-benzene-fused tropene derivative as a versatile precursor, synthesis of several 6,7-benzene-fused tropane derivatives was demonstrated by the transformations of the internal alkene moiety.

Synthesis of spiro chromanone sandwiched 15,16,18 membered (Z)-dioxo cycloalkenes by ring closing metathesis and homodimers of 8-allyl-7-((6-bromoalkyl) oxy) spirochroman-4-ones by cross metathesis

Novel spiro chromanone sandwiched 15,16,18 membered (Z)-1,7-dioxo cycloalkenes by Ring Closing Metathesis (RCM) and homodimers of 8-allyl-7-((6-bromo alkyl)oxy) spirochroman-4-ones by Cross Metathesis (CM) were synthesized from simple starting materials 2,4 dihydroxy acetophenone, allyl bromide, and dibromo alkanes. Spiro chromanone is chosen as the core moiety to be incorporated owing to its medicinal and pharmacophoric properties. The concept of molecular hybridization was adopted for the synthesis of compounds 18–26 using Ring Closing Metathesis as a key step. Intermediates 6,7,8 were alkylated with dibromo alkanes to obtain the substrates for RCM and CM, respectively. The dimer dienes 9–17 were made to undergo RCM and the bromo alkyl intermediates 27–34 were made to undergo CM to get homodimers 35–42.

Vernier template synthesis of molecular knots.

Molecular knots are often prepared using metal helicates to cross the strands. We found that coordinatively mismatching oligodentate ligands and metal ions provides a more effective way to synthesize larger knots using Vernier templating. Strands composed of different numbers of tridentate 2,6-pyridinedicarboxamide groups fold around nine-coordinate lanthanide (III) ions to generate strand-entangled complexes with the lowest common multiple of coordination sites for the ligand strands and metal ions. Ring-closing olefin metathesis then completes the knots. A 3:2 (ditopic strand:metal) Vernier assembly produces +31#+31 and -31#-31 granny knots. Vernier complexes of 3:4 (tetratopic strand:metal) stoichiometry selectively form a 378-atom-long trefoil-of-trefoils triskelion knot with 12 alternating strand crossings or, by using opposing stereochemistry at the terminus of the strand, an inverted-core triskelion knot with six alternating and six nonalternating strand crossings.

Highly Substrate‐Selective Macrocyclic Ring Closing Metathesis

AbstractA selective ring‐closing metathesis (RCM) reaction for the formation of large macrocycles by using latent sulfur chelated ruthenium iodide benzylidenes, readily activated by thermal and photochemical (UV‐A and visible light) stimuli, is reported. For dienes having one terminal alkene and one internal double bond, the specific affinity of diiodo ruthenium alkylidenes for the unhindered terminus, combined with their reluctance to react with internal olefins, favors RCM over oligomerization, providing high macrocyclic yields even at relatively high concentrations. Alternatively, for substrates containing two internal double bonds, a sacrificial methylene donor can be used to obtain the desired products. With this methodology, lactones, lactams, and macrocyclic ketones ranging from 13‐ to 22‐membered rings could be synthesized in moderate to high yields. In addition, synthetic applications for a one‐pot cyclization/reduction sequence to produce Exaltolide, a natural macrolide (commercial musk), Dihydrocivetone, and other saturated macrocycles have been explored. Thus, we disclose herein an important advantage for diiodo ruthenium benzylidene catalysts over their less selective dichloro counterparts and provide a more profound understanding of the mechanisms that provide the enhanced cyclization outcome.magnified image

Vanadium Imido NHC Complexes for Ring-Closing Olefin Metathesis Reactions

Vanadium bis-phosphine imido and oxo chloride alkylidenes have been extensively applied in the ring-closing metathesis of various acyclic olefins. However, their reactions involving ethylene have shown limited productivity due to rapid decomposition. The primary degradation pathway involving V bis-phosphine imido complexes is β-H elimination at an unsubstituted metallacyclobutane. In contrast, β-H elimination is disfavored for V oxo species, but bimolecular decomposition precludes its high productivity. Herein, we present the synthesis of V imido NHC complexes that are the most productive V catalysts toward various terminal olefins in ring-closing metathesis reactions. Experimental and computational studies suggest that β-H elimination and bimolecular decomposition are disfavored for V imido NHC complexes.

Chiron Approach for the Total Synthesis of Brevipolide M

AbstractAn efficient stereoselective synthesis of brevipolide M was established in 13 linear steps and 17.8% overall yields based on chiron approach. The key steps of our synthesis involved tandem Wittig olefination–tetrahydrofuran cyclization and sequential ring-closing metathesis (RCM)–double-bond migration in one-pot processes.

Recent Advances in Macrocyclic Drugs and Microwave-Assisted and/or Solid-Supported Synthesis of Macrocycles.

Macrocycles represent attractive candidates in organic synthesis and drug discovery. Since 2014, nineteen macrocyclic drugs, including three radiopharmaceuticals, have been approved by FDA for the treatment of bacterial and viral infections, cancer, obesity, immunosuppression, etc. As such, new synthetic methodologies and high throughput chemistry (e.g., microwave-assisted and/or solid-phase synthesis) to access various macrocycle entities have attracted great interest in this chemical space. This article serves as an update on our previous review related to macrocyclic drugs and new synthetic strategies toward macrocycles (Molecules, 2013, 18, 6230). In this work, I first reviewed recent FDA-approved macrocyclic drugs since 2014, followed by new advances in macrocycle synthesis using high throughput chemistry, including microwave-assisted and/or solid-supported macrocyclization strategies. Examples and highlights of macrocyclization include macrolactonization and macrolactamization, transition-metal catalyzed olefin ring-closure metathesis, intramolecular C–C and C–heteroatom cross-coupling, copper- or ruthenium-catalyzed azide–alkyne cycloaddition, intramolecular SNAr or SN2 nucleophilic substitution, condensation reaction, and multi-component reaction-mediated macrocyclization, and covering the literature since 2010.

E-Selective Ring-Closing Metathesis in α-Helical Stapled Peptides Using Carbocyclic α,α-Disubstituted α-Amino Acids.

We present an E-selective ring-closing metathesis reaction in α-helical stapled peptides at positions i and i + 4. The use of two chiral carbocyclic α,α-disubstituted α-amino acids, (1S,3S)-Ac5c3OAll and (1R,3S)-Ac5c3OAll, provides a high E-selectivity of a ≤59:1 E:Z ratio, while mixtures with E:Z ratios of 2.1-0.5:1 were produced with standard acyclic (S)-(4-pentenyl)alanine amino acids. A stapled octapeptide composed of (1S,3S)- and (1R,3S)-Ac5c3OAll amino acids showed a right-handed α-helical crystal structure.

Synthesis of cationic cobaltocenophane monomers: Isomerization and ring-opening metathesis polymerization

We report the synthesis of cyclic cobaltocenium olefins (cationic cobaltocenophane or ansa-cobaltocenium). This cyclic cobaltocenium is prepared by ring-closing metathesis (RCM) of diallyl cobaltocenium, which isomerizes into two different cobaltocenium dienes. The isomerization of the terminal alkene at higher temperature results in thermodynamically more stable internal alkene, which is supported by the computational calculation. RCM of these isomers produces two different cyclic cobaltocenium monomers [3]- and [4]-ansa-cobaltocenium, which are further evaluated as monomers for ring-opening metathesis polymerization (ROMP). The results indicate that both ansa-cobaltocenium monomers can be copolymerized with cyclooctene derivatives towards main-chain cobaltocenium-containing copolymers.

Preussochromone Puzzle: Structural Revision of Preussochromones E and F by Total Synthesis

A stereoselective synthesis of the proposed and actual structures of the natural products preussochromones E and F is reported. The key step is a ring-closing metathesis to close the five-membered ring and install the trans configuration of the annulated five-six ring system. The analysis of the 3J NMR couplings of the isolated natural product with the synthesized compound revealed its real structure with a cis annulation, which could also be synthesized using an intramolecular aldol reaction of a vic-tricarbonyl compound.

Backbone Hydrocarbon-Constrained Nucleic Acids Modulate Hybridization Kinetics for RNA.

The binding affinity of therapeutic oligonucleotides (ONs) for their cognate RNA is determined by the rates of association (ka) and dissociation (kd). Single-stranded ONs are highly flexible and can adopt multiple conformations in solution, some of which may not be conducive for hybridization. We investigated if restricting rotation around the sugar-phosphate backbone, by tethering two adjacent backbone phosphonate esters using hydrocarbon bridges, can modulate hybridization kinetics of the modified ONs for complementary RNA. Given the large number of possible analogues with different tether lengths and configurations at the phosphorus atoms, we employed molecular dynamic simulations to optimize the size of the hydrocarbon bridge to guide the synthetic efforts. The backbone-constrained nucleotide trimers with stereodefined configurations at the contiguous backbone phosphorus atoms were assembled using a ring-closing metathesis reaction, then incorporated into oligonucleotides by an in situ synthesis of the phosphoramidites followed by coupling to solid supports. Evaluation of the modified oligonucleotides revealed that 15-membered macrocyclic-constrained analogues displayed similar or slightly improved on-rates but significantly increased off-rates compared to unmodified DNA ONs, resulting in reduced duplex stability. In contrast, LNA ONs with conformationally preorganized furanose rings showed similar on-rates to DNA ONs but very slow off-rates, resulting in net improvement in duplex stability. Furthermore, the experimental data generally supported the molecular dynamics simulation results, suggesting that this strategy can be used as a predictive tool for designing the next generation of constrained backbone ON analogues with improved hybridization properties.

Unprotected peptide macrocyclization and stapling via a fluorine-thiol displacement reaction

We report the discovery of a facile peptide macrocyclization and stapling strategy based on a fluorine thiol displacement reaction (FTDR), which renders a class of peptide analogues with enhanced stability, affinity, cellular uptake, and inhibition of cancer cells. This approach enabled selective modification of the orthogonal fluoroacetamide side chains in unprotected peptides in the presence of intrinsic cysteines. The identified benzenedimethanethiol linker greatly promoted the alpha helicity of a variety of peptide substrates, as corroborated by molecular dynamics simulations. The cellular uptake of benzenedimethanethiol stapled peptides appeared to be universally enhanced compared to the classic ring-closing metathesis (RCM) stapled peptides. Pilot mechanism studies suggested that the uptake of FTDR-stapled peptides may involve multiple endocytosis pathways in a distinct pattern in comparison to peptides stapled by RCM. Consistent with the improved cell permeability, the FTDR-stapled lead Axin and p53 peptide analogues demonstrated enhanced inhibition of cancer cells over the RCM-stapled analogues and the unstapled peptides.

A New Organocatalytic Desymmetrization Reaction Enables the Enantioselective Total Synthesis of Madangamine E.

The enantioselective total synthesis of madangamine E has been completed in 30 steps, enabled by a new catalytic and highly enantioselective desymmetrizing intramolecular Michael addition reaction of a prochiral ketone to a tethered β,β′-disubstituted nitroolefin. This key carbon–carbon bond forming reaction efficiently constructed a chiral bicyclic core in near-perfect enantio- and diastereo-selectivity, concurrently established three stereogenic centers, including a quaternary carbon, and proved highly scalable. Furthermore, the pathway and origins of enantioselectivity in this catalytic cyclization were probed using density functional theory (DFT) calculations, which revealed the crucial substrate/catalyst interactions in the enantio-determining step. Following construction of the bicyclic core, the total synthesis of madangamine E could be completed, with key steps including a mild one-pot oxidative lactamization of an amino alcohol, a two-step Z-selective olefination of a sterically hindered ketone, and ring-closing metatheses to install the two macrocyclic rings.

Convergent Synthesis of the WXYZA′B′C′D′E′F′ Ring Segment of Maitotoxin

Abstract Synthesis of the WXYZA′B′C′D′E′F′ ring segment of maitotoxin, a ladder-shaped polyether produced by the dinoflagellate Gambierdiscus toxicus, was achieved based on a convergent strategy via α-cyano ethers developed in our laboratory. The WXYZ ring aldehyde and the C′D′E′F′ diol were combined through the construction of the B′ ring via ring-closing metathesis and the A′ ring via O,S-acetal formation followed by radical reduction. Introduction of a terminal olefin in the side chain culminated in the convergent synthesis of the WXYZA′B′C′D′E′F′ ring segment in 16 steps.

Synthetic prodrug design enables biocatalytic activation in mice to elicit tumor growth suppression

Considering the intrinsic toxicities of transition metals, their incorporation into drug therapies must operate at minimal amounts while ensuring adequate catalytic activity within complex biological systems. As a way to address this issue, this study investigates the design of synthetic prodrugs that are not only tuned to be harmless, but can be robustly transformed in vivo to reach therapeutically relevant levels. To accomplish this, retrosynthetic prodrug design highlights the potential of naphthylcombretastatin-based prodrugs, which form highly active cytostatic agents via sequential ring-closing metathesis and aromatization. Structural adjustments will also be done to improve aspects related to catalytic reactivity, intrinsic bioactivity, and hydrolytic stability. The developed prodrug therapy is found to possess excellent anticancer activities in cell-based assays. Furthermore, in vivo activation by intravenously administered glycosylated artificial metalloenzymes can also induce significant reduction of implanted tumor growth in mice.

Transition-Metal-Mediated Chemo- and Stereoselective Total Synthesis of (−)-Galanthamine

An asymmetric synthetic route to (-)-galanthamine (1), a pharmacologically active Amaryllidaceae alkaloid used for the symptomatic treatment of early onset Alzheimer's disease, was successfully established with very high levels of stereocontrol. The key to achieving high chemo- and stereo-selectivity in this approach was the use of transition-metal-mediated reactions, namely, enyne ring-closing metathesis, Heck coupling, and titanium-based asymmetric allylation.