Ring-closing Olefin Metathesis Research Articles

Enantioselective synthesis of spliceostatin E and evaluation of biological activity.

An enantioselective total synthesis of spliceostatin E has been accomplished. The δ-lactone unit A was constructed from readily available (R)-glycidyl alcohol using a ring-closing olefin metathesis as the key reaction. A cross-metathesis of ring A containing δ-lactone and the functionalized tetrahydropyran B-ring provided spliceostatin E. Our biological evaluation of synthetic spliceostatin E revealed that it does not inhibit splicing in vitro and does not impact speckle morphology in cells. Spliceostatin E was reported to possess potent antitumor activity.

Asymmetric synthesis of a functionalized tricyclo[6.2.0.02,6]decane ring system present in kelsoene and poduran

Synthesis of a functionalized tricyclo[6.2.0.02,6]decane derivative in enantiomerically pure form, the core structure present in the natural products kelsoene and poduran, is described. The key steps involve a stereocontrolled copper (I)-catalyzed intramolecular [2 + 2] photocycloaddition of a 1, 6-diene prepared from D-mannitol to form a substituted bicyclo[3.2.0]heptane derivative and a ring closing olefin metathesis involving the vicinal substituents on the five-membered ring of the bicyclo[3.2.0]heptane derivative. An asymmetric synthesis of a functionalized tricyclo[6.2.0.02,6]decane derivative has been described. The key step involves an intramolecular Cu (I)-catalyzed [2 + 2] photocycloaddition of a 1,6-diene derived from D-mannitol to provide a bicyclo[3.2.0]heptane derivative. Annulation of a five-membered ring on to the five-membered ring of this derivative using RCM provided the title compound.

ChemInform Abstract: Synthesis of C‐Spiro‐glycoconjugates from Sugar Lactones via Zinc Mediated Barbier Reaction.

Anomeric gem-diallylation, mono-β-crotylation and mono-β-propargylation of sugar 1,5 and 1,4 lactones have been achieved under Barbier reaction conditions using Zn powder and a catalytic amount of TMSCl as an activator. Ring closing olefin metathesis of the synthesized gem-diallyl derivatives furnished C-spiro cyclopentene glycosides. Finally, the cyclopentene rings were converted into carbohydrate based tricyclic morpholine fused triazole glycoconjugates as potential SGLT2 inhibitors.

A Star of David catenane.

We describe the synthesis of a [2]catenane that consists of two triply entwined 114-membered rings, a molecular link. The woven scaffold is a hexameric circular helicate generated by the assembly of six tris(bipyridine) ligands with six iron(II) cations, with the size of the helicate promoted by the use of sulfate counterions. The structure of the ligand extension directs subsequent covalent capture of the catenane by ring-closing olefin metathesis. Confirmation of the Star of David topology (two rings, six crossings) is provided by NMR spectroscopy, mass spectrometry and X-ray crystallography. Extraction of the iron(II) ions with tetrasodium ethylenediaminetetraacetate affords the wholly organic molecular link. The self-assembly of interwoven circular frameworks of controlled size, and their subsequent closure by multiple directed covalent bond-forming reactions, provides a powerful strategy for the synthesis of molecular topologies of ever-increasing complexity.

The Right Computational Recipe for Olefin Metathesis with Ru-Based Catalysts: The Whole Mechanism of Ring-Closing Olefin Metathesis.

The initiation mechanism of ruthenium methylidene complexes was studied detailing mechanistic insights of all involved reaction steps within a classical olefin metathesis pathway. Computational studies reached a good agreement with the rarely available experimental data and even enabled to complement them. As a result, a highly accurate computational and rather cheap recipe is presented; M06/TZVP//BP86/SVP (PCM, P = 1354 atm).

Lanthanide template synthesis of a molecular trefoil knot.

We report on a complex featuring three 2,6-pyridinedicarboxamide ligands entwined around a lanthanide (Ln(3+)) ion. The ligand strands can be cyclized by ring-closing olefin metathesis to form a molecular trefoil knot in 58% yield. Demetalation with tetraethylammonium fluoride quantitatively generates the wholly organic 81-atom-loop trefoil knot.

One‐Pot Preparation of Chiral Carbacycles from Morita–Baylis–Hillman Carbonates by an Asymmetric Allylic Alkylation/Olefin Metathesis Sequence

AbstractAn operationally simple, one‐pot synthetic protocol for the formation of all‐carbon, highly substituted five‐ and six‐membered rings is described. In this two‐step procedure, an asymmetric allylic alkylation (AAA) of Morita–Baylis–Hillman (MBH) carbonates with allylmalononitrile, catalyzed by a chiral tertiary amine, is followed by a ring‐closing alkene metathesis (RCM) reaction. Products are obtained in high yields, and an excellent level of optical purity of some of the target compounds is achieved after just a single recrystallization.

Efficient synthesis of fused bicyclic ethers and their application in herbicide chemistry

A series of triketones 2 and 3 featuring novel fused bicyclic aryl ethers have been prepared. The syntheses utilized ring-closing olefin metathesis (compounds 2), or oxidative cyclization of allylphenols as the key steps. The herbicidal activity of the targeted triketones 2 and 3 on various grasses and broad-leaved weeds was determined and compared with compound 1. The strength of the novel compounds 2 and 3 is their good herbicidal activity on broad-leaved weeds in post-emergent applications, whereas activity on grasses was inferior compared to 1. In addition, computational methods have been applied to provide a deeper understanding of the SAR found for compounds 2 and 3.

ChemInform Abstract: 9‐Membered Carbocycle Formation: Development of Distinct Friedel—Crafts Cyclizations and Application to a Scalable Total Synthesis of (.+‐.)‐Caraphenol A.

While forming any medium-sized ring requires an approach capable of overcoming significant entropic and enthalpic penalties,[1] the challenge in meeting that requirement is often more pronounced in systems composed only of carbon atoms, such as the 9-membered rings of caraphenol A (1)[2] and α-viniferin (2),[3] two oligomeric forms of the natural product resveratrol (3)[4,5] which are bioactive (including acetylcholinesterase inhibition, anti-inflammatory properties, and potential value as probes for elucidating key pathways in Alzheimer’s disease and drug resistance in tumors).[6] Indeed, without the more obvious and established array of productive cyclization strategies afforded by heteroatoms, only a handful of approaches have proven capable of accessing fully carbocyclic variants. For 9-membered rings, that includes Grob fragmentations (such as 4→5),[7] highly context specific C–C bond constructions such as the acetylide addition leading to enediyne 6,[8] and ring-closing olefin metathesis (not shown).[9] Given this landscape, as well as the unique and sp2-rich patterning of 1 and 2 (and 11 other related molecules)[10] that effectively precludes the application of these three established strategies, we sought to identify additional approaches capable of forging strained, 9-membered carbocycles. Herein, we show that a variety of Friedel–Crafts-type reactions promoted by either Au(III) or Br∅nsted acids are competent in this regard with functionally rich substrates. In addition to providing what we believe is the first example of a 9-exo-dig ring closure, late-stage application of one of the developed approaches has enabled the completion of an efficient and highly scalable total synthesis of caraphenol A (1).

The Total Synthesis of (−)‐Nitidasin

Nitidasin is a pentacyclic sesterterpenoid with a rare 5-8-6-5 carbon skeleton that was isolated from the Peruvian folk medicine "Hercampuri". It belongs to a small class of sesterterpenoids that feature an isopropyl trans-hydrindane moiety fused to a variety of other ring systems. As a first installment of our general approach toward these natural products, we report the total synthesis of the title compound. Our stereoselective, convergent route involves the addition of a complex alkenyl lithium compound to a trans-hydrindanone, followed by chemoselective epoxidation, ring-closing olefin metathesis, and redox adjustment.

Structure-based design and synthesis of tricyclic IAP (Inhibitors of Apoptosis Proteins) inhibitors

The design and synthesis of a series of novel tricyclic IAP inhibitors is reported. Rapid assembly of the core tricycle involved two key steps: Rh-catalyzed hydrogenation of an unsaturated bicyclic ring system and a Ru-catalyzed ring closing alkene metathesis reaction. The final Smac mimetics bind to cIAP1 and XIAP BIR3 domains and elicit the desired phenotype in cellular proliferation assays. Dimeric IAP inhibitors were found to possess nanomolar potency in a cellular proliferation assay and favourable in vitro drug-like properties.

Synthesis, Characterization and Antibacterial Activity of Cyclic Sulfamide Linked to Tetrathiafulvalene (TTF)

We herein describe the synthesis and antibacterial activity of cyclic sulfamide linked to tetrathiafulvalene (TTF). This approach exploits the inherent chemistry of biomolecules and π-donors compounds to generate symmetric bis-trimethyltetrathiafulvalenyl-2-thiophenyl cyclic sulfamides. Two strategies are revealed, one centres on the Ringclosing olefin metathesis using the Grubbs catalyst a second strategy based on the direct alkylation of dibromoalkane derivatives with symmetric sulfamide under basic conditions. All the newly synthesized compounds were screened for their antimicrobial activities and some of them were found to possess good or moderate antimicrobial activity. Keywords: Antibacterial activity, cyclic sulfamides, olefin metathesis, sultams, sulfur heterocycles, tetrathiafulvalenes.

Synthesis of C-spiro-glycoconjugates from sugar lactones via zinc mediated Barbier reaction

Anomeric gem-diallylation, mono-β-crotylation and mono-β-propargylation of sugar 1,5 and 1,4 lactones have been achieved under Barbier reaction conditions using Zn powder and a catalytic amount of TMSCl as an activator. Ring closing olefin metathesis of the synthesized gem-diallyl derivatives furnished C-spiro cyclopentene glycosides. Finally, the cyclopentene rings were converted into carbohydrate based tricyclic morpholine fused triazole glycoconjugates as potential SGLT2 inhibitors.

Synthesis of stabilized alpha-helical peptides.

Stabilized alpha-helical (SAH) peptides are valuable laboratory tools to explore important protein-protein interactions. Whereas most peptides lose their secondary structure when isolated from the host protein, stapled peptides incorporate an all-hydrocarbon "staple" that reinforces their natural alpha-helical structure. Thus, stapled peptides retain their functional ability to bind their native protein targets and serve multiple experimental uses. First, they are useful for structural studies such as NMR or crystal structures that map and better define binding sites. Second, they can be used to identify small molecules that specifically target that interaction site. Third, stapled peptides can be used to test the importance of specific amino acid residues or posttranslational modifications to the binding. Fourth, they can serve as structurally competent bait to identify novel binding partners to specific alpha-helical motifs. In addition to markedly improved alpha-helicity, stapled peptides also display resistance to protease cleavage and enhanced cell permeability. Most importantly, they are useful for intracellular experiments that explore the functional consequences of blocking particular protein interactions. Because of their remarkable stability, stapled peptides can be applied to whole-animal, in vivo studies. Here we describe a protocol for the synthesis of a peptide that incorporates an all-hydrocarbon "staple" employing a ring-closing olefin metathesis reaction. With proper optimization, stapled peptides can be a fundamental, accurate laboratory tool in the modern chemical biologist's armory.

Total Synthesis of Pectenotoxin-2

Pectenotoxin-2 (PTX2) is a shellfish toxin and has a non-anomeric spiroacetal, which is not stabilized by an anomeric effect. The selective construction of the non-anomeric spiroacetal has been a major problem in the synthesis of PTX2. Described herein is the stereoselective total synthesis of PTX2 via the isomerization of anomeric spiroacetal pectenotoxin-2b (PTX2b). The synthesis of PTX2b was achieved by a simple process including sulfone-mediated assembly of spirocyclic and bicyclic acetals and subsequent macrocyclization by ring-closing olefin metathesis. Finally, the selective construction of PTX2 was accomplished by the early termination of a dynamic transition process to equilibrium in the acid-catalyzed isomerization of anomeric PTX2b. [6,6]-Spiroacetal pectenotoxin-2c (PTX2c) was also synthesized from PTX2b. The cytotoxicity assay of the synthetic compounds against HepG2 and Caco2 cancer cells showed a potency of the order: PTX2≫PTX2b>PTX2c.

Total Synthesis of Pectenotoxin-2

Pectenotoxin-2 (PTX2) is a shellfish toxin and has a non-anomeric spiroacetal, which is not stabilized by an anomeric effect. The selective construction of the non-anomeric spiroacetal has been a major problem in the synthesis of PTX2. Described herein is the stereoselective total synthesis of PTX2 via the isomerization of anomeric spiroacetal pectenotoxin-2b (PTX2b). The synthesis of PTX2b was achieved by a simple process including sulfone-mediated assembly of spirocyclic and bicyclic acetals and subsequent macrocyclization by ring-closing olefin metathesis. Finally, the selective construction of PTX2 was accomplished by the early termination of a dynamic transition process to equilibrium in the acid-catalyzed isomerization of anomeric PTX2b. [6,6]-Spiroacetal pectenotoxin-2c (PTX2c) was also synthesized from PTX2b. The cytotoxicity assay of the synthetic compounds against HepG2 and Caco2 cancer cells showed a potency of the order: PTX2≫PTX2b>PTX2c.

Synthesis of fused chromene-1,4-naphthoquinones via ring-closing metathesis and Knoevenagel-electrocyclization under acid catalysis and microwave irradiation

Two complementary methodologies involving olefin ring-closing metathesis and Knoevenagel-electrocyclization were utilized for the synthesis of α-xyloidones and fused chromene-1,4-naphthoquinones 5f–n and 6. The latter methodology was performed under acid catalysis or microwave irradiation allowing the synthesis of α-xyloidones 5f–j in moderate to good yield, which could not be obtained via the Knoevenagel-electrocyclization method. On the other hand, the lawsone bis-alkylation (C and O) then RCM olefin enabled the preparation of simple xyloidone 5m–n and the oxepin-1,4-naphthoquinones 6.

Synthesis of a TREN in Which the Aryl Substituents are Part of a 45 Atom Macrocycle

A substituted TREN has been prepared in which the aryl groups in (ArylNHCH2CH2)3N are substituted at the 3- and 5-positions with a total of six OCH2(CH2)nCH═CH2 groups (n = 1, 2, 3). Molybdenum nitride complexes, [(ArylNCH2CH2)3N]Mo(N), have been isolated as adducts that contain B(C6F5)3 bound to the nitride. Two of these [(ArylNCH2CH2)3N]Mo(NB(C6F5)3) complexes (n = 1 and 3) were crystallographically characterized. After removal of the borane from [(ArylNCH2CH2)3N]Mo(NB(C6F5)3) with PMe3, ring-closing olefin metathesis (RCM) was employed to join the aryl rings with OCH2(CH2)nCH═CH(CH2)nCH2O links (n = 1-3) between them. RCM worked best with a W(O)(CHCMe3)(Me2Pyr)(OHMT)(PMe2Ph) catalyst (OHMT = hexamethylterphenoxide, Me2Pyr = 2,5-dimethylpyrrolide) and n = 3. The macrocyclic ligand was removed from the metal through hydrolysis and isolated in 70-75% yields relative to the borane adducts. Crystallographic characterization showed that the macrocyclic TREN ligand in which n = 3 contains three cis double bonds. Hydrogenation produced a TREN in which the three links are saturated, i.e., O(CH2)10O.

Synthesis and Biological Activity of 7,8,9-Trideoxy- and 7RDesTHP-Peloruside A

The stereoselective syntheses of 7,8,9-trideoxypeloruside A (4) and a monocyclic peloruside A analogue lacking the entire tetrahydropyran moiety (3) are described. The syntheses proceeded through the PMB-ether of an ω-hydroxy β-keto aldehyde as a common intermediate which was elaborated into a pair of diastereomeric 1,3-syn and -anti diols by stereoselective Duthaler-Hafner allylations and subsequent 1,3-syn or anti reduction. One of these isomers was further converted into a tetrahydropyran derivative in a high-yielding Prins reaction, to provide the precursor for bicyclic analogue 4. Downstream steps for both syntheses included the substrate-controlled addition of a vinyl lithium intermediate to an aldehyde, thus connecting the peloruside side chain to C15 (C13) of the macrocyclic core structure in a fully stereoselective fashion. In the case of monocyclic 3 macrocyclization was based on ring-closing olefin metathesis (RCM), while bicyclic 4 was cyclized through Yamaguchi-type macrolactonization. The macrolactonization step was surprisingly difficult and was accompanied by extensive cyclic dimer formation. Peloruside A analogues 3 and 4 inhibited the proliferation of human cancer cell lines in vitro with micromolar and sub-micromolar IC50 values, respectively. The higher potency of 4 highlights the importance of the bicyclic core structure of peloruside A for nM biological activity.

A New Variant of Fused Cyclic Ether Synthesis Based on Ireland-Claisen Rearrangement and RCM

A new variant of fused cyclic ether synthesis based on Ireland-Claisen rearrangement and ring-closing olefin metathesis (RCM) was developed. The Ireland-Claisen rearrangement of a (Z)-3-alkoxyprop-2-en-1-yl glycolate ester having a cyclic ether on the oxygen at C3 of the (Z)-prop-2-en-1-yl group stereoselectively produced an anti-alpha,beta-dialkoxyester, which was successfully transformed to a fused bicyclic ether via a reaction sequence including RCM.