Metathesis Approach Research Articles

A Concise Ring Closing Enyne Metathesis Approach for the Preparation of Functionalized Proline‐Derived Azabicycloalkane Amino Acids

AbstractHerein we report the preparation of C4‐functionalized proline‐derived azabicycloalkane (Aba) amino acids by exploiting a direct ring closing enyne metathesis reaction of readily accessible dipeptide precursors. The reverse‐turn inducing properties of the newly synthesized constrained dipeptide mimics were assessed by computational studies. Furthermore, the desired Aba derivatives, carrying a synthetically versatile diene moiety, were subjected to post‐functionalization reactions to validate their potential application in peptide/peptidomimetic chemistry and drug discovery.

Benign-by-Design SAHA Analogues for Human and Animal Vector-Borne Parasitic Diseases.

The search for new drugs fulfilling One Health and Green Chemistry requirements is an urgent call. Here, for the first time, we envisaged developing SAHA analogues by starting from the cashew nutshell liquid (CNSL) agro-industrial waste and employing a metathesis approach. This sustainable combination (comprising principles #7 and #9) allowed a straightforward synthesis of compounds 13-20. All of them were found to not be toxic on HepG2, IMR-32, and L929 cell lines. Then, their potential against major human and animal vector-borne parasitic diseases (VBPDs) was assessed. Compound 13 emerged as a green hit against the trypomastigote forms of T. b. brucei. In silico studies showed that the T. b. brucei HDAC (TbDAC) catalytic pocket could be occupied with a similar binding mode by both SAHA and 13, providing a putative explanation for its antiparasitic mechanism of action (13, EC50 = 0.7 ± 0.2 μM).

Chromium Complexes with Benzanellated N-Heterocyclic Phosphenium Ligands-Synthesis, Reactivity and Application in Catalytic CO2 Reduction.

A chromium complex carrying two benzanellated N-heterocyclic phosphenium (bzNHP) ligands was prepared by a salt metathesis approach. Spectroscopic studies suggest that the anellation enhances the π-acceptor ability of the NHP-units, which is confirmed by the facile electrochemical reduction of the complex to a spectroscopically characterized radical anion. Co-photolysis with H2 allowed extensive conversion into a σ-H2-complex, which shows a diverse reactivity towards donors and isomerizes under H-H bond fission and shift of a hydride to a P-ligand. The product carrying phosphenium, phosphine and hydride ligands was also synthesized independently and reacts reversibly with CO and MeCN to yield bis-phosphine complexes under concomitant Cr-to-P-shift of a hydride. In contrast, CO2 was not only bound but reduced to give an isolable formato complex, which reacted with ammonia borane under partial recovery of the metal hydride and production of formate. Further elaboration of the reactions of the chromium complexes with CO2 and NH3BH3 allowed to demonstrate the feasibility of a Cr-catalyzed transfer hydrogenation of CO2 to methanol. The various complexes described were characterized spectroscopically and in several cases by XRD studies. Further insights in reactivity patterns were provided through (spectro)electrochemical studies and DFT calculations.

A Catalytic Intramolecular Aldehyde–Alkyne Metathesis Approach to Azepino[1,2‐a]indoles

Reported herein is a method for the construction of azepino[1,2‐a]indoles via an intramolecular aldehyde–alkyne metathesis of 1‐(5‐aryl‐4‐pentynyl)indole‐2‐carbaldehydes. This Sc(OTf)3‐catalyzed reaction has several remarkable features, such as ready accessibility of the starting materials, broad substrate scope, operational simplicity, and high yields. The practicality of the process and the synthetic potential of the products were demonstrated with an upscaling experiment and downstream synthetic derivatizations of the obtained products. We have also extended this methodology to synthesize a 6,7‐dihydropyrido[1,2‐a]indole derivative.

N-Heterocyclic germylenes supported by bulky dianionic N,N-chelating ligands

In this contribution, three novel diamine pro-ligands, incorporating sterically bulky aryl and aliphatic N-substituents, have been developed; viz. (NCNTCHP)H2 (NCNTCHP = {(TCHP)NCH2}2CH2, TCHP = 2,4,6-tricyclohexylphenyl), (NONTCHP)H2 (NONTCHP = {(TCHP)NSiMe2}2O), and (NONAd)H2 (NONAd = {(Ad)NSiMe2}2O; Ad = 1-adamantyl). Through salt metathesis or transamination synthetic approaches, the N-heterocyclic germylenes, [:Ge(NCNTCHP)], [:Ge(NONTCHP)], and [:Ge(NONAd)], have been prepared and crystallographically characterized. The electronic structure of each germylene was studied by DFT calculations. The steric profile of the germanium-bound ligands was also assessed using computational models, and the results compared to those for structurally similar compounds. Significant steric crowding of the germanium centre (>70 % ligand coverage) was observed for [:Ge(NCNTCHP)] and [:Ge(NONTCHP)], while [:Ge(NONAd)] exhibited substantially less steric saturation at the metal centre (∼62 % ligand coverage). Through these studies, we have shown the potential suitably of the developed ligands to stabilise other low-valent main-group species.

A metal-catalysed functional group metathesis approach to the carbon isotope labelling of carboxylic acids.

The distribution, metabolism and ultimate fate of molecules within the body is central to the activity of pharmaceuticals. However, the introduction of radioisotopes into the metabolically stable carbon sites on drugs to probe these features typically requires toxic, radioactive gases such as [14C]CO and [14C]CO2. Here we describe an approach to directly carbon-label carboxylic-acid-containing pharmaceuticals via a metal-catalysed functional group exchange reaction, forming 14C-labelled carboxylic-acid-containing drugs without radioactive gases, in one pot, using an easily available and handled carboxylic acid 14C source. To enable this process, a functional group metathesis of carbon-carbon covalent bonds in acid chloride functionalities is developed, exploiting the ability of nickel catalysts to both reversibly activate carbon-chloride bonds and exchange functionalities between organic molecules. The drug development applicability is illustrated by the direct incorporation of the 14C label or 13C label into an array of complex aryl, alkyl, vinyl and heterocyclic carboxylic acid drugs or drug candidates without gases or a special apparatus, at ambient conditions and without loss of the radiolabel.

An Intramolecular Enyne Metathesis Approach for the Synthesis of Cyclic 3‐Substituted Unsaturated Sulfones

AbstractStudies into the ring‐closing enyne metathesis of a series of nine sulfone containing enynes is described. The readily accessible sulfone substrates were shown to undergo cyclisation to form 3‐subsituted 2,5‐dihydrothiophene 1,1‐dioxides (sulfolenes) and one 3,6‐dihydro‐2H‐thiopyran 1,1‐dioxide. The success of this process depended on the substrate's substitution pattern. Moderate to good yields of the products were obtained when the ene component was monosubstituted and it was found that the reactions proceeded most efficiently using the 2nd generation Grubbs catalysts, at elevated temperatures.

Ring‐Rearrangement Metathesis Approach to Fused [5/5/6/5/5] and [6/5/5/5/5/6] Carbocyclic Derivatives.

AbstractHere, we have developed a simple synthetic approach towards synthesis of [5/6/5] and [5/5/5] fused carbocyclic frameworks from bis‐adducts of norbornadiene and cyclohexadiene derivatives with 1,2,3,4‐tetrachloro‐5,5‐dimethoxycyclopentadiene by employing atom‐economic ring‐rearrangement metathesis as a key step and these ring systems are core units in natural products. Here, we have designed highly congested polycyclic frameworks and introduced molecular complexity in a minimum number of steps. These targets contain up to seven stereo centres. Hence, this strategy can be used to design many different drug‐like molecules valuable in medicinal chemistry.

Molecular Acrobatics in Polycyclic Frames: Synthesis of "Kurmanediol" via Post-synthetic Modification of Cage Molecules by Olefinic Metathesis.

We report late-stage ring-opening metathesis (ROM), ring-rearrangement metathesis (RRM), and ring-closing metathesis (RCM) approaches to generate expanded pentacycloundecane (PCUD) cage derivatives. These higher-order intricate polycyclic cage systems are aesthetically pleasing and structurally intriguing. Their assembly maintains molecular symmetry during the entire synthetic sequence. To this end, metathesis-based catalysts are used to execute the ROM, RRM, and RCM strategies. The synthetic approach to these cage polycycles involves the Diels-Alder reaction, [2 + 2] photocycloaddition, RRM, ROM, and RCM as key steps.

The morphosyntax of imperative agreement in Amharic

Abstract Discontinuous agreement has been the focus of considerable research, especially within the Afroasiatic language family. However, most previous work has focused on how discontinuous agreement is generated and has relied on data from verbs with relatively basic tense, aspect and mood. In this paper, I investigate a different kind of discontinuous agreement puzzle in an atypical kind of verb, namely, why and how the agreement prefix (but not the agreement suffix) is lacking from imperative verbs in Amharic. I argue that the agreement prefix undergoes morphological haplology because it repeats the second person features found in the imperative head. I then demonstrate how a haplology approach decides between two different analyses of discontinuous agreement: it furnishes evidence against a Linearization analysis (Harbour 2008a, 2016, this issue) and in favor of a Metathesis analysis (Hewett 2022, this issue). Overall, this paper develops a novel approach to imperative inflection, supports a Metathesis approach to discontinuous agreement, and advances our understanding of morphological haplology.

Stereoselective Synthesis of Highly Substituted O-Heterocycles via Matteson Homologation: A Ring-Closing Metathesis Approach

Matteson homologations of chiral boronic esters with the aid of unsaturated nucleophiles are powerful for gaining access to a range of different O-heterocycles via subsequent ring-closing metatheses. Using this protocol, six- to eight-membered rings become available and almost any position of the ring can be substituted and/or functionalized.

Sterically controlled isodesmic late-stage C-H iodination of arenes.

Aryl iodides are key motifs in organic chemistry due to their versatility as linchpins in metal-mediated cross-coupling reactions for synthesis and drug discovery. These scaffolds are typically prepared indirectly from prefunctionalized starting materials or via electrophilic aromatic iodination protocols. These methods are limited to specific regioisomers by their inherent selectivities and/or the availability of the required starting materials. Herein, we describe the sterically controlled iodination of arenes through an isodesmic C-H/C-I bond metathesis approach enabled by our dual ligand-based catalysts for arene-limited nondirected C-H activation. The protocol gives direct access to a complementary product spectrum with respect to traditional methods. Its synthetic utility is demonstrated by a broad scope and the suitability for late-stage modification.

Ultrahigh strength and negative thermal expansion and low thermal conductivity in graphyne nanosheets confirmed by machine-learning interatomic potentials

After several decades of experimental endeavors, most recently large-area γ-graphyne layered materials have been synthesized via a reversible dynamic alkyne metathesis approach (Nature Synthesis (2022) 1, 449–454). Motivated by the aforementioned accomplishment and highly appealing physics of the nanoporous sp–sp2-hybridized carbon allotropes, herein we explore the thermal and mechanical properties of six different graphyne lattices, via machine-learning interatomic potentials (MLIPs). To this aim, by employing a computationally efficient passive-training approach, the thermal and mechanical properties are evaluated with ab-initio level of accuracy using the classical molecular dynamics simulations. Analysis of mechanical properties at room temperature reveal that graphyne nanosheets depending on the atomic structure and loading direction can show remarkably high ultimate tensile strengths up to around 90 GPa. The graphyne nanomembranes are however predicted to show by around two orders of magnitude suppressed lattice thermal conductivity than graphene. Graphyne nanoporous networks are also predicted to show ultrahigh negative thermal expansion coefficients, one order of magnitude higher than that of the graphene. The presented MLIP-based results provide a critical vision on the structure and thermo-mechanical property relationships in sp–sp2-hybridized graphyne allotropes, which can be useful for the design of novel nanodevices using this important class of nanomaterials.

Dicationic Bis-Pyridinium Hydrazone-Based Amphiphiles Encompassing Fluorinated Counteranions: Synthesis, Characterization, TGA-DSC, and DFT Investigations.

Quaternization and metathesis approaches were used to successfully design and synthesize the targeted dicationic bis-dipyridinium hydrazones carrying long alkyl side chain extending from C8 to C18 as countercation, and attracted to halide (I-) or fluorinated ion (PF6-, BF4-, CF3COO-) as counteranion. Spectroscopic characterization using NMR and mass spectroscopy was used to establish the structures of the formed compounds. In addition, their thermal properties were investigated utilizing thermogravimetric analyses (TGA), and differential scanning calorimetry (DSC). The thermal study illustrated that regardless of the alkyl group length (Cn) or the attracted anions, the thermograms of the tested derivatives are composed of three stages. The mode of thermal decomposition demonstrates the important roles of both anion and alkyl chain length. Longer chain length results in greater van der Waals forces; meanwhile, with anions of low nucleophilicity, it could also decrease the intramolecular electrostatic interaction, which leads to an overall interaction decrease and lower thermal stability. The DFT theoretical calculations have been carried out to investigate the thermal stability in terms of the Tonset. The results revealed that the type of the counteranion and chain length had a substantial impact on thermal stability, which was presumably related to the degree of intermolecular interactions. However, the DFT results illustrated that there is no dominant parameter affecting the thermal stability, but rather a cumulative effect of many factors of different extents.

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.

Expanding the Protecting Group Scope for the Carbonyl Olefin Metathesis Approach to 2,5-Dihydropyrroles.

Chiral pyrrolidine derivatives are important building blocks for natural product synthesis. Carbonyl olefin metathesis has recently emerged as a powerful tool for the construction of such building blocks from chiral amino acid derivatives. Here, we demonstrate that the supramolecular resorcinarene catalyst enables access to chiral 2,5-dihydropyrroles under Brønsted acid catalysis. Moreover, this catalytic system even tolerated Lewis-basic-protecting groups like mesylates that are not compatible with alternative catalysts. As expected for conversion inside a closed cavity, the product yield and selectivity depended on the size of the substrates.

Synthetic approach to oxa-triquinanes via olefin metathesis as a key step

Earlier, a simple synthetic approach to cis , syn , cis- triquinanes and propellanes from exo -nadic anhydride through metathesis approach had been demonstrated. In the present work is discussed a distinct course of observations when this methodology has been extended to oxygenated exo -nadic anhydride derivatives and the importance of stereochemistry and the role of hetero atom in the outcome of olefin metathesis has been demonstrated.

Greener and Additive‐Free Ring Opening of Epoxides by All‐in‐One Choline Systems

AbstractAdaptation of all‐in‐one ionic systems with ionic liquids (ILs) serving as solvent, reactant, and catalyst is an innovative approach in the organic synthesis. Mild and bio clean choline based ILs as all‐in‐one systems (solvent, reagent, and catalyst) were developed via a simple metathesis approach and were applied on the ring‐opening reaction of epoxides. Sustained transformation of various epoxides using choline cyanide, azide, and hydroxide ILs delivered a neat, efficient and convenient protocol for the synthesis of β‐substituted alcohols in moderate to high yields (64‐97 %) with excellent activity and selectivity as confirmed by nuclear magnetic resonance (NMR) spectroscopic data.

Ring-Closing Metathesis Approaches towards the Total Synthesis of Rhizoxins.

Efforts are described towards the total synthesis of the bacterial macrolide rhizoxin F, which is a potent tubulin assembly and cancer cell growth inhibitor. A significant amount of work was expanded on the construction of the rhizoxin core macrocycle by ring-closing olefin metathesis (RCM) between C(9) and C(10), either directly or by using relay substrates, but in no case was ring-closure achieved. Macrocycle formation was possible by ring-closing alkyne metathesis (RCAM) at the C(9)/C(10) site. The requisite diyne was obtained from advanced intermediates that had been prepared as part of the synthesis of the RCM substrates. While the direct conversion of the triple bond formed in the ring-closing step into the C(9)-C(10) E double bond of the rhizoxin macrocycle proved to be elusive, the corresponding Z isomer was accessible with high selectivity by reductive decomplexation of the biscobalt hexacarbonyl complex of the triple bond with ethylpiperidinium hypophosphite. Radical-induced double bond isomerization, full elaboration of the C(15) side chain, and directed epoxidation of the C(11)-C(12) double bond completed the total synthesis of rhizoxin F.

A Ring Closing Metathesis Approach to the Formal Synthesis of (+)‐Callyspongiolide

AbstractAn enantioselective synthesis of macrocyclic core of (+)‐callyspongiolide is described, constituting a formal synthesis of this natural product. The synthetic strategy constructs the 14‐membered macrocyclic domain via Yamaguchi esterification followed by a challenging ring‐closing metathesis (RCM) to effect the final formation of the macrolactone.