Ring-closing Metathesis Research Articles

Polyhydroxylated Cyclopentane β-Amino Acids Derived from d-Mannose and d-Galactose: Synthesis and Protocol for Incorporation into Peptides.

A stereoselective synthesis of polyhydroxylated cyclopentane β-amino acids from hexoses is reported. The reaction sequence comprises, as key steps, ring-closing metathesis of a polysubstituted diene intermediate followed by the stereoselective aza-Michael functionalization of the resulting cyclopent-1-ene-1-carboxylic acid ester. Examples of synthesis of polysubstituted 2-aminocyclopentanecarboxylic acid derivatives starting from protected d-mannose and d-galactose are presented. A general protocol for the incorporation of these highly functionalized alicyclic β-amino acids into peptides is also reported.

Design and Synthesis of Hetero-Steroids Via Ring-Closing Metathesis: Biological Studies Towards in Vitro Anticancer Activity

Design and Synthesis of Hetero-Steroids Via Ring-Closing Metathesis: Biological Studies Towards in Vitro Anticancer Activity

Ten-step asymmetric total syntheses of potent antibiotics anthracimycin and anthracimycin B.

The increase in antibiotic resistance calls for the development of novel antibiotics with new molecular structures and new modes of action. However, in the past few decades only a few novel antibiotics have been discovered and progressed into clinically used drugs. The discovery of a potent anthracimycin antibiotic represents a major advance in the field of antibiotics. Anthracimycin is a structurally novel macrolide natural product with an excellent biological activity profile: (i) potent in vitro antibacterial activity (MIC 0.03-1.0 μg mL-1) against many methicillin-resistant Staphylococcus aureus (MRSA) strains, Bacillus anthracis (anthrax), and Mycobacterium tuberculosis; (ii) low toxicity to human cells (IC50 > 30 μM); (iii) a novel mechanism of action (inhibiting DNA/RNA synthesis). While the first total synthesis of anthracimycin was elegantly accomplished by Brimble et al. with 20 steps, we report a 10-step asymmetric total synthesis of anthracimycin and anthracimycin B (first total synthesis). Our convergent strategy features (i) one-pot sequential Mukaiyama vinylogous aldol/intramolecular Diels-Alder reaction to construct trans-decalin with high yield and excellent endo/exo selectivity and (ii) Z-selective ring-closing metathesis to forge the 14-membered ring. In vitro antibacterial evaluation suggested that our synthetic samples exhibited similar antibacterial potency to the naturally occurring anthracimycins against Gram-positive strains. Our short and reliable synthetic route provides a supply of anthracimycins for further in-depth studies and allows medicinal chemists to prepare a library of analogues for establishing structure-activity relationships.

Synthesis and development of seven-membered constrained cyclic urea based PSMA inhibitors via RCM

Intramolecular ring-closing metathesis on an N,N-diallyl Glu-urea-Gly substrate affords 7-membered cyclic ureas as inhibitors of prostrate specific membrane antigen (PMSA).

Relay ring-closing metathesis strategies towards the synthesis of the ABC tricycle of Taxol

Two synthetic routes towards the ABC tricycle of Taxol are presented. They both involve a relay ring-closing metathesis reaction to make the central B ring in a convergent fashion. In the first approach, the extender arm is positioned on the A ring, and the C ring bears the relay tether in the second route. Metathesis precursors with diverse extender arms were efficiently synthesised; unfortunately, the crucial metathesis reactions failed to deliver the target compounds in all cases.

Formation of medium-ring heterocyclic compounds by two-directional ring-closing metathesis reaction

A synthetic method based on the tandem application of two-directional ring-closing metathesis reaction as key-steps has been established for the synthesis of medium ring heterocyclic compounds.

Total Synthesis of Palodesangrens A and C.

Palodesangrens A and C along with the common tetracyclic core are prepared from simple benzaldehyde and acetophenone derivatives in a 10-step longest linear sequence which featured the Diels-Alder reaction forming the cyclohexene moiety, LiAlH4 isomerization, stereoselective acid-catalyzed cyclization forming the chroman moiety, regioselective iodination/vinyl Suzuki cross-coupling reaction, and ring-closing metathesis (RCM) forming the 2H-pyran-2-one. Overall, the desired palodesangrens A and C are obtained in 6.1% and 6.4% yields, respectively.

Development of New Synthetic Methods for Carbazole Compounds Aimed at Drug Discovery and Exploratory Research on Pharmaceutical Materials

We are developing the synthesis of biologically interesting carbazole compounds, including natural products by tandem cyclic reactions. In this report, we describe the new synthesis of carbazole-1,4-quinones as follows; 1) the synthesis of carbazole-1,4-quinones using a tandem ring closing metathesis (RCM) -dehydrogenation reaction, 2) a novel one-pot synthesis of carbazole-1,4-quinone by consecutive Pd-catalyzed cyclocarbonylation, desilylation, and oxidation reactions. Two new synthetic strategies were applied to the synthesis of carbazole-1,4-quinone alkaloids and ellipticine quinones, and then the antiproliferative activity against HCT-116 and HL-60 cells of the synthesized compounds were evaluated.

Synthesis of highly stable dual-site immobilized ruthenium olefin metathesis catalyst without ru leaching

The tri-block copolymer is used as a carrier to simultaneously immobilize the N-heterocyclic and benzylidene ligands precursor of the Ru-based catalyst to form a dual-site immobilized catalyst. The dual-site immobilized catalyst can catalyze ring-opening metathesis polymerization, ring-closing metathesis and self-metathesis. The dual-site immobilized catalyst shows good heterogeneity in dichloromethane, which simplifies the purification of product and recovery of catalyst. The dual-site immobilized catalyst exhibits excellent activity and recycling performance. The excellent recyclability can be attributed to the capture of ruthenium by the excess ligands precursor on carrier. Importantly, ruthenium residues are not detected in product.

Olefin Metathesis in Continuous Flow Reactor Employing Polar Ruthenium Catalyst and Soluble Metal Scavenger for Instant Purification of Products of Pharmaceutical Interest.

In recent years, the development of continuous-flow reactors has attracted growing attention from the synthetic community. Moreover, findings in the precise control of the reaction parameters and improved mass/heat transfer have made the flow setup an attractive alternative to batch reactors, both in academia and industry, enabling safe and easy scaling-up of synthetic processes. Even though a majority of the pharmaceutical industry currently rely on batch reactors or semibatch reactors, many are integrating flow technology because of easier maintenance and lower risks. Herein, we demonstrate an operationally simple flow setup for homogeneous ring-closing metathesis, which is applicable to the synthesis of active pharmaceutical ingredients precursors or analogues with high efficiency, low residence time, and in a green solvent. Furthermore, through the addition of a soluble metal scavenger in the subsequent step within the flow system, the level of ruthenium contamination in the final product can be greatly reduced (to less than 5 ppm). To ensure that this method is applicable for industrial usage, an upscale process including a 24 h continuous-flow reaction for more than 60 g of a Sildenafil analogue was achieved in a continuous-flow fashion by adjusting the tubing size and flow rate accordingly.

Synthetic Approaches to Crinipellin Based Tetraquinanes via Ring‐Rearrangement Metathesis and Ring‐Closing Metathesis

AbstractHerein, we have studied the synthetic approaches to tetraquinanes that are present in crinipellin type natural products by employing ring‐rearrangement metathesis (RRM) and ring‐closing metathesis (RCM) as key steps. These studies involve finding the suitable alkylation sequence to prepare desired RRM/RCM precursors. Methyl‐tetraquinane has been assembled by employing a regio‐, and stereoselective methylation followed by allylation sequence. Whereas, allyl‐tetraquinane was constructed by following the allylation‐RRM sequence. Interestingly, spiro‐quinanes rearranges to fused‐quinanes when olefinic moiety is present adjacent to the spiro‐ring under RRM conditions. Additionally, several di‐, and triquinane derivatives reported during this study were also found in diverse polyquinane natural products. The present strategy utilizes the vinyl derivative of exo‐dicyclopentadiene‐1‐one, and produce several intricate polycyclic systems. Our strategy may be useful to design various medicinally important “drug‐like” molecules.

Application of Sequential Ring‐Opening, and Ring‐Closing Metathesis or Ring‐Rearrangement Metathesis to Design Oxacycles and Azacycles

AbstractWe report a concise and simple synthetic approach to oxacycles, azacycles and aza‐propellanes starting with endo/exo‐nadic anhydride via olefin metathesis as a key step. This methodology relies on the usage of Lewis acid mediated allylation of the hydroxy derivatives followed by ring‐opening metathesis (ROM) and ring‐closing metathesis (RCM) to assemble fused oxacycles and azacycles. Moreover, this methodology generates diverse skeletons such as propellanes, highly fused azacycles. Interestingly, some of these heterocyclic frames constitute the basic core of biologically active natural products.

Macrocyclic BACE1 inhibitors with hydrophobic cross-linked structures: Optimization of ring size and ring structure

Based on the X-ray crystallography of recombinant BACE1 and a hydroxyethylamine-type peptidic inhibitor, we introduced a cross-linked structure between the P1 and P3 side chains of the inhibitor to enhance its inhibitory activity. The P1 and P3 fragments bearing terminal alkenes were synthesized, and a ring-closing metathesis of these alkenes was used to construct the cross-linked structure. Evaluation of ring size using P1 and P3 fragments with various side chain lengths revealed that 13-membered rings were optimal, although their activity was reduced compared to that of the parent compound. Furthermore, the optimal ring structure was found to be a macrocycle with a dimethyl branched substituent at the P3 β-position, which was approximately 100-fold more active than the non-substituted macrocycle. In addition, the introduction of a 4-carboxymethylphenyl group at the P1′ position further improved the activity.

Total Synthesis of Thiocladospolide A and Its C2-Epimer

AbstractThe first total synthesis of the recently isolated natural product thiocladospolide A, along with its C2-epimer, is achieved in nine straightforward linear steps and 12% overall yield. The key feature of the synthesis is the construction of the macrocyclic ring via a late-stage ring-closing metathesis reaction followed by alkene reduction.

Design and synthesis of C3-symmetric molecules containing oxepine and benzofuran moieties via Metathesis

• We demonstrated a simple synthetic strategy to assemble C 3 -symmetric star-shaped phenyl and triazine central core based oxepine and benzofuran derivatives. • The key steps involved are Claisen rearrangement, double-bond isomerization and cyclo-trimerization. • We introduced oxepine and furan ring systems in C 3 -symmetric star-shaped phenyl and triazine core derivatives using olefin metathesis. • We studied photophysical properties of prepared molecules by fluorescence spectroscopic data. We report a new synthetic strategy to C 3 -symmetric star-shaped phenyl and triazine central cores bearing oxepine and benzofuran ring systems. In this regard, we have explored the application of metathetic strategy to construct C 3 -symmetric molecules starting with commercially available p -hydroxy acetophenone and p -hydroxy benzonitrile through cyclotrimerization, double bond isomerization, and ring-closing metathesis as key steps. We also studied photophysical properties of these molecules by fluorescence spectroscopic data. All compounds except 1 and 2 exhibit strong fluorescence.

Reversibly Photoswitchable Catalysts for Olefin Metathesis Reactions

Azobenzene-bearing photoswitchable ruthenium catalysts were developed for olefin metathesis reactions. These catalysts exhibited an on–off switching ability in ring-closing metathesis depending on UV irradiation (>99% conversion without UV vs <1% with UV). Photoswitching phenomena have been observed in various types of olefin metathesis reactions, such as ring-opening metathesis, cross-metathesis, and ethenolysis. The photoswitching feature is also reversible, as the ring-closing metathesis reaction can repeatedly be turned on and off by switching the UV light source. Photoisomerization of azobenzene-bearing cyclic(alkyl)(amino)carbene (azo-CAAC) ligands and the corresponding ruthenium catalysts was observed by UV–vis spectroscopy.

Ruthenium-alkylidene Initiated Cyclopolymerization and Tandem Ringopening/ Ring-closing Metathesis (RO/RCM) Polymerization: Facile Access to Cycloolefin-based Polymers

Synthesis of cycloolefin-based polymers via metathesis-accompanied cyclopolymerization and tandem Ring-Opening/Ring-Closing Metathesis (RO/RCM) polymerization are undergoing exciting developments and emerging as an area of great interest in the field of polymer synthesis. Among the conventional polymerization techniques, both cyclopolymerization and tandem polymerization give access to highly functional cycloolefin ring-based polymers. This review provides an overview of the synthesis of such cycloolefin-based conjugated and non-conjugated polymers following cyclopolymerization and tandem RO/RCM polymerization methodologies.

Synthesis and Catalytic Properties of a Very Latent Selenium-Chelated Ruthenium Benzylidene Olefin Metathesis Catalyst.

Herein, we describe a study of the synthesis, characterization, and catalytic properties of a cis-dichlorido seleno-chelated Hoveyda–Grubbs type complex (Ru8). Such a complex has been obtained through a straightforward and high-yielding synthetic protocol in three steps from the commercially available 2-bromobenzaldehyde in good overall yield (54%). The catalytic profile, especially the latency of this complex, has been probed through selected olefin metathesis reactions such as ring-closing metathesis (RCM), self-cross-metathesis (self-CM) and ring-opening metathesis polymerization (ROMP). In addition to its high latency, the selenium Hoveyda-type complex Ru8 exhibits a switchable behavior upon thermal activation. Of interest, while the corresponding sulfur-chelated Hoveyda type catalyst is reported to be only activated by heat, the selenium analogue was found to be active upon both heat and light irradiation.

Diastereoselective Synthesis of the ABCD Ring System of Rubriflordilactone B

AbstractA novel nine-step diastereoselective route to the ABCD ring system of the natural product rubriflordilactone B is reported. Use of an α-substituted butenolide derived from maleic anhydride facilitated a 1,4-conjugate addition to provide a diene. The order in which a ring-closing metathesis and enolate oxidation were performed on this compound dictated the relative stereochemistry of the target. The final product exhibited anisotropic effects during room-temperature NMR studies, requiring elevated-temperature experiments to confirm its identity.

Protecting-Group-Free Total Synthesis of Anticancer (±)-Melotenine A

AbstractMelotenine A, isolated from Melodinus tenuicaudatus, possesses significant anticancer activity against several human cancer cell lines. The synthesis of (±)-melotenine A was achieved without the use of any protecting groups in 11 steps with an overall yield of 6.7%. The key steps of our strategy were a Diels–Alder reaction to construct the tetracyclic framework and ring-closing metathesis to form the seven-membered ring of (±)-melotenine A.