Sequential Metathesis Research Articles

Enantioselective Total Synthesis of (-)-Himalensine A via a Palladium and 4-Hydroxyproline Co-catalyzed Desymmetrization of Vinyl-bromide-tethered Cyclohexanones.

Herein, we describe the convergent enantioselective total synthesis of himalensine A in 18 steps, enabled by a highly enantio- and diastereoselective construction of the morphan core via a palladium/hydroxy proline co-catalyzed desymmetrization of vinyl-bromide-tethered cyclohexanones. The reaction pathway was illuminated by density functional theory calculations, which support an intramolecular Heck reaction of an in situ-generated enamine intermediate, where exquisite enantioselectivity arises from intramolecular carboxylate coordination to the vinyl palladium species in the rate- and enantio-determining carbopalladation steps. The reaction tolerates diverse N-derivatives, all-carbon quaternary centers, and trisubstituted olefins, providing access to molecular scaffolds found in a range of complex natural products. Following large-scale preparation of a key substrate and installation of a β-substituted enone moiety, the rapid construction of himalensine A was achieved using a highly convergent strategy based on an amide coupling/Michael addition/allylation/ring-closing metathesis sequence which allowed the introduction of three of the five rings in only three synthetic steps (after telescoping). Moreover, our strategy provides a new enantioselective access to a known tetracyclic late-stage intermediate that has been used previously in the synthesis of many Daphniphyllum alkaloids.

Synthesis of 1,3‐cis‐Fused Tricyclic System through Regio‐ and Stereoselective Epoxidation and Ring‐Rearrangement Metathesis: Access To Basic Core of Presilphiperfolanols

AbstractHere, we report a new synthetic approach to a highly strained 1,3‐fused cis‐cis‐cis‐5/5/6 tricyclic system that appeared among the presilphiperfolanol analogues. The cis‐fusion of six‐membered ring to a diquinane moiety is accomplished by substrate‐controlled regio‐ and stereoselective epoxidation, and ring‐rearrangement metathesis (RRM) sequence. In this regard, both early‐, and late‐stage epoxidation and RRM reactions were studied. The target compound, cis‐cis‐cis‐5/5/6 tricyclic ketone with an α,β‐oxirane ring can serve as a key building block to produce various presilphiperfolanol analogues. The cis‐cis‐cis‐5/5/6‐tricyclic‐α,β‐epoxyketone can also act as masked enone and therefore useful for various chemical transformations in organic synthesis. The short synthetic sequence disclosed here may be useful to design various biologically important molecules. The newly reported molecules are well‐characterized by NMR, HRMS, and IR spectral data.

Design and Synthesis of Amino Acid Derivatives via Diethyl Acetadimalonate and Late‐Stage Modification by Chemical Methods

AbstractWe report various unusual amino acid derivatives containing heterocycles and heteroatoms (S, O, N) via diethyl acetadimalonate as a glycine equivalent and carried out further chemical transformations to modify these unusual amino acid derivatives. Sulfur‐containing halo and alkene derivatives are prepared, and these substrates are further modified by Suzuki‐Miyaura cross‐coupling reaction, cross metathesis sequence and selective formation of sulfoxide and sulfone derivatives. We also report oxazole‐containing amino acid derivative by using TosMIC.

Synthesis of Angular Triquinane and [4.3.3]Propellane Derivatives via Ring‐Rearrangement Olefin Metathesis

AbstractHerein, a simple and useful approach to angular triquinane and [4.3.3]propellane moieties is described via olefin metathesis starting from exo and endo Diels‐Alder (DA) adducts containing norbornene unit. This approach involves DA reaction, and ring‐rearrangement metathesis (RRM) as key steps. Strained norbornene derivatives on allylation at bridgehead position(s) followed by ring‐opening metathesis and ring‐closing metathesis sequence delivered angular triquinane and also stereochemically different propellane derivatives.

An Alkyne-Metathesis-Based Approach to the Synthesis of the Anti-Malarial Macrodiolide Samroiyotmycin A.

We report the first total synthesis of samroiyotmycin A (1), a C2‐symmetric 20‐membered anti‐malarial macrodiolide isolated from Streptomyces sp. The convergent synthetic strategy orchestrates bisalkyne fragment‐assembly using an unprecedented Schöllkopf‐type condensation on a substituted β‐lactone and an ambitious late‐stage one‐pot alkyne cross metathesis–ring‐closing metathesis (ACM–RCAM) reaction. The demanding alkyne metathesis sequence is achieved using the latest generation of molybdenum alkylidynes endowed with a tripodal silanolate ligand framework. Subsequent conversion to the required E‐alkenes uses contemporary hydrometallation chemistry catalysed by tetrameric cluster [{Cp*RuCl}4].

An Alkyne‐Metathesis‐Based Approach to the Synthesis of the Anti‐Malarial Macrodiolide Samroiyotmycin A

AbstractWe report the first total synthesis of samroiyotmycin A (1), a C2‐symmetric 20‐membered anti‐malarial macrodiolide isolated from Streptomyces sp. The convergent synthetic strategy orchestrates bisalkyne fragment‐assembly using an unprecedented Schöllkopf‐type condensation on a substituted β‐lactone and an ambitious late‐stage one‐pot alkyne cross metathesis–ring‐closing metathesis (ACM–RCAM) reaction. The demanding alkyne metathesis sequence is achieved using the latest generation of molybdenum alkylidynes endowed with a tripodal silanolate ligand framework. Subsequent conversion to the required E‐alkenes uses contemporary hydrometallation chemistry catalysed by tetrameric cluster [{Cp*RuCl}4].

Unified Total Synthesis of (-)-Enigmazole A and (-)-15-O-Methylenigmazole A.

The total synthesis of cytotoxic marine phosphomacrolides, (-)-enigmazole A and (-)-15-O-methylenigmazole A, is described in detail. The 2,6-cis-substituted tetrahydropyran ring was efficiently elaborated by using a tandem olefin cross-metathesis/intramolecular oxa-Michael addition reaction. The 18-membered macrolactone skeleton was forged via a Au-catalyzed propargylic benzoate rearrangement/macrocyclic ring-closing metathesis sequence. Late-stage diversification of a common intermediate enabled unified total synthesis of (-)-enigmazole A and (-)-15-O-methylenigmazole A.

Domino Relay Olefin Metathesis of Triallyl Oxindole and Indole Precursors to Access Cyclic Indoxyls and Carbazoles

AbstractWe herein disclose domino relay metathesis sequences using triallyl 3‐oxindole and indole precursors to access C2‐quaternary cyclic pseudooxindole and carbazole ring systems. Triallyl 3‐oxindoles undergo domino ring closing metathesis (RCM) and cross metathesis (CM) to provide C2‐spirocyclic 3‐oxindoles. Intriguingly, a catalyst specific relay metathesis sequence involving ring closing‐ring opening‐ring closing and cross metathesis (RC‐RO‐RC‐CM) of these trienes is established to provide fused bicyclic indoxyl dimers in high yields. Further, the CM of indoxyl dimer with methyl acrylate affords a new class of fused monomeric 3‐oxindole derivative. Moreover, a domino RCM‐CM process of triallyl indoles is demonstrated, enabling a quick access to dihydro‐carbazoles and carbazoles.

Catalytic C-C Cleavage/Alkyne-Carbonyl Metathesis Sequence of Cyclobutanones.

A ring-opening/alkyne-carbonyl metathesis sequence of alkyne-tethered cyclobutanones catalyzed by AgSbF6 is realized for the first time to furnish multisubstituted naphthyl ketones under mild conditions. A range of substrates decorated with various substituents at different positions were all well accommodated. Preliminary mechanistic studies show that silver salt acted as a Lewis acid to facilitate both C-C cleavage of the cyclobutanone moiety and the subsequent metathesis between C═O and C≡C bonds.

Synthesis of Substituted β‐Functionalised Styrenes by Microwave‐Assisted Olefin Cross‐Metathesis and Scalable Synthesis of Apremilast

AbstractPreparation of diversely substituted β‐functionalised styrenes by microwave‐assisted olefin cross‐metathesis (CM) is described. This method can be also employed in the synthesis of β‐deuterated α,β‐unsaturated sulfones from inexpensive allylbenzenes, though unprecedented one‐pot isomerisation/deuteration/cross‐metathesis sequence. One of such obtained CM products has been utilised in a new scalable synthesis of Apremilast (6), a potent and orally active phosphodiesterase 4 and tumour necrosis factor‐α inhibitor. The same strategy was used in synthesis of an optical antipode of 6, ent‐Apremilast.

Synthesis and Preliminary Biophysical and Cellular Evaluation of Some Ring-Enlarged Analogues of the Anti-Tumor Plant Alkaloid Acronycine

Three oxepinoacridine analogues of the important anti-cancer pyranoacridine natural product acronycine have been synthesized using a combined Claisen rearrangement ring-closing metathesis sequence as key steps to install the oxacyclic ring. Preliminary biophysical studies of these proposed oxepino analogues revealed that they interact with ct-DNA in a manner similar to the pyranoacridones but not possibly as intercalators. Cellular evaluations of these analogues in two human leukemic cell lines have also been carried out. These studies indicate that the ring-enlarged analogues have somewhat lower activity than the naturally occurring ones in the cell lines studied.

Design and synthesis of C 3-symmetric molecules bearing propellane moieties via cyclotrimerization and a ring-closing metathesis sequence.

We have developed an efficient synthetic strategy to assemble C3-symmetric molecules containing propellane moieties as end groups and a benzene ring as a central core. The synthesis of these C3-symmetric molecules involves simple starting materials. Our approach to C3-symmetric compounds relies on a Diels–Alder reaction, cyclotrimerization and ring-closing metathesis as key steps.

Studies on the Synthesis of Endocyclic Enol Lactones via a RCM of Selected Vinyl Esters.

The novel and efficient approach toward the synthesis of endocyclic enol lactones was devised based on ring-closing metathesis of unsaturated carboxylic acids vinyl esters. Systematic studies revealed that vinyl esters are suitable substrates for RCM reaction. The developed methodology offers an easy route for synthetically challenging target molecules with different functional groups and substitution. We have also demonstrated that vinyl esters of cyclic carboxylic acids can be successfully applied for domino ring-opening ring-closing metathesis sequences.

An asymmetric synthesis of febrifugine, halofuginone and their hemiketal isomers

A new synthesis of both enantiomers of naturally occurring febrifugine (1) and its analogue halofuginone (3) are reported. This robust route relies on an enzymatic kinetic resolution (EKR)-cross metathesis (CM) sequence, performed on allylic alcohol 8. A diastereoselective Lewis acid-mediated cyclisation of resultant enone 6 affords piperidine 12. In relation to its enantiomeric excess, values of 87 and 88% e.e were obtained for both enantiomers of 12 and for (−)-12 this was increased to 98% e.e by conducting the resolution process twice. A bromination (featuring an in situ temporary alcohol protection), alkylation and amino-deprotection sequence finally afforded the target compounds (+)- and (−)-1, and (+)- and (−)-3. Studies demonstrate that, as their ammonium salts, the compounds are stereochemically stable. However, as their free-bases, particularly in chloroform, C-2 isomerisation occurs. This isomerisation has been taken advantage of synthetically to provide enantioenriched (+)-isofebrifugine (2) and both enantiomers of isohalofuginone (14).

Pd(0)–CMC@Ce(OH)4 organic/inorganic hybrid as highly active catalyst for the Suzuki–Miyaura reaction

A very easy sequential metathesis for the synthesis of Pd(II)–CMC@Ce(OH)4 organic/inorganic hybrid and its application as effective pre-catalyst for the Suzuki–Miyaura reaction have been reported. It was found that the Pd nanoparticles (Pd NPs) were formed in situ in the course of the Suzuki–Miyaura couplings when Pd(II)–CMC@Ce(OH)4 was used as a pre-catalyst. The activity of the Pd NPs in the reaction was enhanced synergistically by the unique redox properties (Ce3+/Ce4+) of Ce(OH)4 and coordination with carboxyl groups as well as free hydroxyl groups of the hybrid of CMC@Ce(OH)4. The results exhibit the Pd(0)–CMC@Ce(OH)4 is super over Pd(II)@CMC, Pd(II)@CeO2, and Pd(II)@Ce(OH)4 catalysts in the Suzuki–Miyaura reaction. Moreover, the catalyst could be easily separated by simple filtration and reused at least seven runs without losing its activity.

Isomerization and functionalization of 2:1 Diels–Alder adducts of cyclopentadiene and p-benzoquinone: Applications to polycycles via ring-closing metathesis and ring-opening metathesis as key steps

Five stereochemically different 2:1 Diels–Alder adducts were prepared starting with cyclopentadiene and p-benzoquinone. Separately, these adducts were treated with an excess amount of base and allyl bromide to deliver two different tetra-allylated products. These allyl derivatives gave the corresponding mono-propellane derivatives on metathesis sequence. Five Diels–Alder adducts on treatment with Grubbs ruthenium catalysts delivered the corresponding mono- and di-ring-opened metathesis products. Structures of three functionalized adducts were determined by single-crystal X-ray diffraction studies.

Metathesis Strategy for the Immobilization of Copper(II) onto Carboxymethylcellulose/Fe3O4 Nanohybrid Supports: Efficient and Recoverable Magnetic Catalyst for the CuAAC Reaction

To overcome the inherent obstacles facing the traditional surface modification of Fe3O4 magnetic nanoparticles with appropriate capping agents to anchor the catalytically active complexes, a novel retrievable copper(II) catalyst immobilized on carboxymethylcellulose/Fe3O4 nanoparticles (CuII–CMC–Fe3O4) magnetic hybrid materials was successfully prepared through three steps of sequential metathesis and one step of oxidation. First, ferrous carboxymethylcellulose (CMC–FeII) was prepared by ionic exchange of ferrous chloride and sodium carboxymethylcellulose (CMC–Na). Second, the resulting CMC–FeII was treated with NaOH solution to form the corresponding hybrid material Na–CMC–Fe(OH)2, which proceeded to be exposed to the air to afford the Na–CMC–Fe3O4. Finally, the as-prepared Na–CMC–Fe3O4 was immersed in copper sulfate solution to self-assembly-fabricate the CuII–CMC–Fe3O4 hybrid catalyst by ionic exchange of Cu(II) with Na–CMC–Fe3O4. The morphology and structural feature of the catalyst were characterized...

Asymmetric Allylation/RCM-Mediated Synthesis of Fluorinated Benzo-Fused Bicyclic Homoallylic Amines As Dihydronaphthalene Derivatives.

Enantiomerically enriched fluorinated benzo-fused bicyclic homoallylic amines have been synthesized through an asymmetric allylation/ring closing metathesis (RCM) sequence. This sequence has been carried out using α-trifluoromethylstyrene derivatives as key intermediates, synthesized by microwave radiation. The great deactivating effect exerted by such substituents has been brought to light by a comparative study.

Design and synthesis of oxacycles from norbornene derivatives via ring-opening metathesis and ring-rearrangement metathesis

Norbornene derivatives containing oxygen atom(s) are found to undergo ring-rearrangement metathesis sequence to deliver cyclic ethers. Here, we have established a simple, efficient and an atom-economic process for the synthesis of fused and spiro-oxacyclic compounds starting with cyclopentadiene. Compounds prepared in this study are difficult to assemble by conventional retrosynthetic routes.

ChemInform Abstract: Target Specific Tactics in Olefin Metathesis: Synthetic Approach to cis‐syn‐cis‐Triquinanes and ‐Propellanes.

A concise and simple synthetic approach to cis-syn-cis-triquinanes and -propellanes has been demonstrated via olefin metathesis starting with exo-nadic anhydride. This approach involves a ring-opening and ring-closing metathesis sequence of norbornene derivatives using Grubb’s catalyst. Early-stage diallylation of norbornene derivatives is demonstrated followed by ring-closing metathesis that delivers propellanes exclusively. Surprisingly, ring-opening metathesis, late-stage diallylation, followed by ring-closing metathesis delivers triquinane as well as propellane derivatives.