The Dimerization and Oligomerization of Alkenes Catalyzed with Transition Metal Complexes: Catalytic Systems and Reaction Mechanisms.

Dimers and oligomers of alkenes represent a category of compounds that are in great demand in diverse industrial sectors. Among the developing synthetic methods, the catalysis of alkene dimerization and oligomerization using transition metal salts and complexes is of undoubted interest for practical applications. This approach demonstrates substantial potential, offering not only elevated reaction rates but also precise control over the chemo-, regio-, and stereoselectivity of the reactions. In this review, we discuss the data on catalytic systems for alkene dimerization and oligomerization. Our focus lies in the analysis of how the activity and chemoselectivity of these catalytic systems are influenced by various factors, such as the nature of the transition metal, the ligand environment, the activator, and the substrate structure. Notably, this review particularly discusses reaction mechanisms, encompassing metal complex activation, structural and dynamic features, and the reactivity of hydride intermediates, which serve as potential catalytically active centers in alkene dimerization and oligomerization.

Catalytic Properties of Zirconocene-Based Systems in 1-Hexene Oligomerization and Structure of Metal Hydride Reaction Centers.

Despite large-scale investigations of homogeneous single-site metallocene catalysts and systems based on them, there are still unsolved problems related to the control of their activity and chemo- and stereoselectivity. A solution to these problems is required to develop efficient methods for the synthesis of practically useful products of alkene transformations, such as dimers, oligomers, and polymers. Here we studied the catalytic activity of structurally diverse zirconocenes (L2ZrCl2, L = Cp, C5Me5, Ind, L2 = Me2CCp2, Me2SiCp2, Me2C2Cp2, rac-Me2CInd2, rac-H4C2Ind2, BIPh(Ind)2, H4C2[THInd]2), and co-catalysts activating the system, namely HAlBui2, MMAO-12, and (Ph3C)[B(C6F5)4], at low activator/Zr ratios in a 1-hexene oligomerization reaction. The influence of catalyst structure and system composition on the alkene conversion, the type of products, and the reaction stereoselectivity were investigated. The composition of hydride intermediates formed in the L2ZrCl2-HAlBui2-activator system (L2 = ansa-Me2CCp2, Ind) was studied by NMR spectroscopy. Participation of the bis-zirconium hydride complex as the precursor of catalytically active sites of the alkene dimerization reaction was shown.

A Commercial Extract of Cyanotis arachnoidea Roots as a Source of Unusual Ecdysteroid Derivatives with Insect Hormone Receptor Binding Activity.

Ecdysteroids act as molting hormones in insects and as nonhormonal anabolic agents and adaptogens in mammals. A wide range of ecdysteroid-containing herbal extracts are available worldwide as food supplements. The aim of this work was to study such an extract as a possible industrial source of new bioactive ecdysteroids. A large-scale chromatographic isolation was performed from an extract of Cyanotis arachnoidea roots. Ten ecdysteroids (1-10) including eight new compounds were isolated and characterized by extensive nuclear magnetic resonance studies. Highly unusual structures were identified, including a H-14ß (1, 2, 4, and 10) moiety, among which a 14ß(H)17ß(H) phytosteroid (1) is reported for the first time. Compounds with an intact side chain (4-10) and 11 other natural or semisynthetic ecdysteroids (11-21) were tested for insect ecdysteroid receptor (EcR) binding activity. Two new compounds, i.e., 14-deoxydacryhainansterone (5) and 22-oxodacryhainansterone (6), showed strong EcR binding activity (IC50 = 41.7 and 380 nM, respectively). Six compounds were identified as EcR agonists and another two as antagonists using a transgenic ecdysteroid reporter gene assay. The present results demonstrate that commercial C. arachnoidea extracts are rich in new, unusual bioactive ecdysteroids. Because of the lack of an authentic plant material, the truly biosynthetic or artifactual nature of these compounds cannot be confirmed.

In vitro adjuvant antitumor activity of various classes of semi-synthetic poststerone derivatives.

Various classes of semi-synthetic analogs of poststerone, the product of oxidative cleavage of the C20-C22 bond in the side chain of the phytoecdysteroid 20-hydroxyecdysone, were synthesized. The analogs were obtained by reductive transformations using L-Selectride and H2-Pd/C, by molecular abeo-rearrangements using the DAST reagent or ultrasonic treatment in the NaI-Zn-DMF system, and by acid-catalyzed reactions of poststerone derivatives with various aldehydes (o-FC6H4CHO, m-CF3C6H4CHO, CO2Me(CH2)8CHO). The products were tested on a mouse lymphoma cell line pair, L5178 and its ABCB1-transfected multi-drug resistant counterpart, L5178MDR, for their in vitro activity alone and in combination with doxorubicin, and for the ability to inhibit the ABCB1 transporter. Among the tested compounds, new 2,3-dioxolane derivatives of the pregnane ecdysteroid were found to have a pronounced chemosensitizing activity towards doxorubicin and could be considered as promising candidates for further structure optimization for the development of effective chemosensitizing agents.

Photoluminescence and mechanoluminescence of solid-state zirconocene dichlorides.

Spectral-luminescence properties of 23 samples of zirconium complexes were studied. Mechanoluminescence spectra of 10 complexes were obtained. The solid-state component of the mechanoluminescence spectrum, that is the luminescence of the crystal itself, coincided with the photoluminescence spectra of these complexes, which indicated identical emission from the same excited states in mechanoluminescence and photoluminescence, despite the different ways of excitation. The luminescence maximum was red shifted as substituents appeared in the ligand, in particular in the presence of a bridging group connecting π-ligands (ansa-complexes) and also for a substituted bis-indenyl complex rac-Me2 Si(2-Me-4-Ph-5-OMe-6-But -Ind)2 ZrCl2 ). It was found that mechanical destruction of the rac-isomer of complex Mе2 С(2-Me-4-But -C5 H2 )2 ZrCl2 , unlike that of the meso-isomer, was accompanied by a more than a 10-fold increase in intensity and by a shift in the mechanoluminescence spectrum to longer wavelengths.

Ti Group Metallocene-Catalyzed Synthesis of 1-Hexene Dimers and Tetramers.

1-Hexene transformations in the catalytic systems L2MCl2-XAlBui2 (L = Cp, M = Ti, Zr, Hf; L = Ind, rac-H4C2[THInd]2, M = Zr; X = H, Bu i) and [Cp2ZrH2]2-ClAlR2 activated by MMAO-12, B(C6F5)3, or (Ph3C)[B(C6F5)4] in chlorinated solvents (CH2Cl2, CHCl3, o-Cl2C6H4, ClCH2CH2Cl) were studied. The systems [Cp2ZrH2]2-MMAO-12, [Cp2ZrH2]2-ClAlBui2-MMAO-12, or Cp2ZrCl2-HAlBui2-MMAO-12 (B(C6F5)3) in CH2Cl2 showed the highest activity and selectivity towards the formation of vinylidene head-to-tail alkene dimers. The use of chloroform as a solvent provides further in situ dimer dimerization to give a tetramer yield of up to 89%. A study of the reaction of [Cp2ZrH2]2 or Cp2ZrCl2 with organoaluminum compounds and MMAO-12 by NMR spectroscopy confirmed the formation of Zr,Zr-hydride clusters as key intermediates of the alkene dimerization. The probable structure of the Zr,Zr-hydride clusters and ways of their generation in the catalytic systems were analyzed using a quantum chemical approach (DFT).

Bimetallic Zr,Zr-Hydride Complexes in Zirconocene Catalyzed Alkene Dimerization.

Being valuable precursors in the production of adhesives, lubricants, and other high-performance synthetic compounds, alkene dimers and oligomers can be obtained using homogeneous zirconocene catalytic systems. Further advances in such systems require precise control of their activity and chemoselectivity, increasing both the purity and yield of the products. This relies on the process mechanism usually built around the consideration of the hydride complexes as active intermediates in the alkene di- and oligomerization; however, the majority of studies lack the direct evidence of their involvement. Parallel studies on a well-known Cp2ZrCl2-AlR3 or HAlBui2 and a novel [Cp2ZrH2]2-ClAlR2 (R = Me, Et, Bui) systems activated by methylaluminoxane (MMAO-12) have shown a deep similarity both in the catalytic performance and intermediate composition. As a result of the NMR studies, among all the intermediates considered, we proved that new Zr,Zr- hydride complexes having the type x[Cp2ZrH2∙Cp2ZrHCl∙ClAlR2]∙yMAO appear to be specifically responsible for the alkene dimerization with high yield.

Biocompatible Organic Coatings Based on Bisphosphonic Acid RGD-Derivatives for PEO-Modified Titanium Implants.

Currently, significant attention is attracted to the problem of the development of the specific architecture and composition of the surface layer in order to control the biocompatibility of implants made of titanium and its alloys. The titanium surface properties can be tuned both by creating an inorganic sublayer with the desired morphology and by organic top coating contributing to bioactivity. In this work, we developed a composite biologically active coatings based on hybrid molecules obtained by chemical cross-linking of amino acid bisphosphonates with a linear tripeptide RGD, in combination with inorganic porous sublayer created on titanium by plasma electrolytic oxidation (PEO). After the addition of organic molecules, the PEO coated surface gets nobler, but corrosion currents increase. In vitro studies on proliferation and viability of fibroblasts, mesenchymal stem cells and osteoblast-like cells showed the significant dependence of the molecule bioactivity on the structure of bisphosphonate anchor and the linker. Several RGD-modified bisphosphonates of ß-alanine, γ-aminobutyric and ε-aminocaproic acids with BMPS or SMCC linkers can be recommended as promising candidates for further in vivo research.

Synthesis of fusidane triterpenoid Mannich bases as potential antibacterial and antitumor agents.

Mannich bases (8 examples) were synthesized via aminomethylation of fusidane propargyl esters. In vitro antimicrobial screening against key ESKAPE pathogens showed that the fusidic acid based Mannich products exhibit a high antimicrobial effect against Gram-positive bacteria Staphylococcus aureus and the fungus Cryptococcus neoformans. Moreover, the cytotoxic effect of fusidic acid and its analogs, which showed high antibacterial activity, was determined by MTT assay on cancer HepG2, HCT-116, SH-SY5Y, MCF-7, A549 and conditionally normal cells HEK293. A remarkable cytotoxic activity of fusidic acid propargyl ester and its aminomethylene derivatives against cancer and nontumoral HEK293 cells with IC50 values within 4.2-25 µM was found.

3-Amino-Substituted Analogues of Fusidic Acid as Membrane-Active Antibacterial Compounds.

Fusidic acid (FA) is an antibiotic with high activity against Staphylococcus aureus; it has been used in clinical practice since the 1960s. However, the narrow antimicrobial spectrum of FA limits its application in the treatment of bacterial infections. In this regard, this work aims both at the study of the antimicrobial effect of a number of FA amines and at the identification of their potential biological targets. In this way, FA analogues containing aliphatic and aromatic amino groups and biogenic polyamine, spermine and spermidine, moieties at the C-3 atom, were synthesized (20 examples). Pyrazinecarboxamide-substituted analogues exhibit a high antibacterial activity against S. aureus (MRSA) with MIC ≤ 0.25 µg/mL. Spermine and spermidine derivatives, along with activity against S. aureus, also inhibit the growth and reproduction of Gram-negative bacteria Escherichia coli, Acinetobacter baumannii, and Pseudomonas aeruginosa, and have a high fungicidal effect against Candida albicans and Cryptococcus neoformans. The study of the membrane activity demonstrated that the spermidine- and spermine-containing compounds are able to immerse into membranes and disorder the lipidsleading to a detergent effect. Moreover, spermine-based compounds are also able to form ion-permeable pores in the lipid bilayers mimicking the bacterial membranes. Using molecular docking, inhibition of the protein synthesis elongation factor EF-G was proposed, and polyamine substituents were shown to make the greatest contribution to the stability of the complexes of fusidic acid derivatives with biological targets. This suggests that the antibacterial effect of the obtained compounds may be associated with both membrane activity and inhibition of the elongation factor EF-G.

Effect of Fusidic Acid and Some Nitrogen-Containing Derivatives on Liposomal and Mitochondrial Membranes.

The paper assesses the membranotropic action of the natural antibiotic fusidic acid (FA) and its derivatives. It was found that a FA analogue with ethylenediamine moiety (derivative 2), in contrast to native FA and 3,11-dioxime analogue (derivative 1), is able to increase the mobility of the lipid bilayer in the zone of lipid headgroups, as well as to induce permeabilization of lecithin liposome membranes. A similar effect of derivative 2 is also observed in the case of rat liver mitochondrial membranes. We noted a decrease in the microviscosity of the mitochondrial membrane and nonspecific permeabilization of organelle membranes in the presence of this agent, which was accompanied by a decrease in mitochondrial Δψ and OXPHOS efficiency. This led to a reduction in mitochondrial calcium retention capacity. The derivatives also reduced the production of H2O2 by mitochondria. The paper considers the relationship between the structure of the tested compounds and the observed effects.

Synthesis, modification, and biological activity of propargylated methyl dihydroquinopimarates.

The introduction of the alkynyl moiety to the abietane diterpenic core by modification of the cycle E of methyl dihydroquinopimarate is described. The arylpropargyl, aminopropargyl, and 1,2,3-triazole derivatives are synthesized via Sonogashira reaction, Mannich reaction and click-chemistry, correspondingly. The antitumor effect towards the NCI-60 cancer cell line panel and antimicrobial activity against key ESKAPE pathogens of the synthesized compounds were studied in vitro. The cytotoxicity and hemolytic activity of the abietane derivatives was tested using HEK293 human embryonic kidney cell line and the human red blood cells, correspondingly. The methyl dihydroquinopimarate propargyl analogs showed high antitumor activity against leukemia (CCRF-CEM; SR), non-small cell lung cancer (NCI-H522), melanoma (LOX IMVI; MALME-3M), ovarian cancer (IGROV1), and renal cancer (786-0; UO-31) cell lines. The Mannich's diterpene bases with pyrrolidine and diethylamine fragments exhibited fungicidal activity towards Cr. neoformans (MIC= 16 µg/ml), while possessing low toxicity. The described modifications of the abietane diterpenoids have great potential for further development of new cytotoxic and fungicidal compounds.

Modeling of Biological Activity of PEO-Coated Titanium Implants with Conjugates of Cyclic RGD Peptide with Amino Acid Bisphosphonates.

Titanium is considered to be the most essential metal in the field of implantology. The main factors determining metal biocompatibility, among others, include the morphology and chemical composition of the titanium surface. Therefore, the aim of this work was to develop approaches to control the biological activity of the titanium surface by creating coatings that combine both an inorganic phase with a given morphology and organic molecules containing an integrin-selective peptide that regulate cell adhesion and proliferation. As such, we synthesized new c(RGDfC) derivatives of amino acid bisphosphonates (four examples) with different bisphosphonate anchors and maleimide linkers. These molecules were deposited on a highly developed porous surface obtained via the plasma electrolytic oxidation (PEO) of coarse-grained and nanostructured titanium. In vitro studies demonstrated the increase in the viability degree of mesenchymal stem cells and fibroblasts on the surface of coarse-grained or nanostructured titanium modified with PEO and a c(RGDfC) derivative of ε-aminocaproic acid bisphophonate with an SMCC linker. As a result, the use of conjugates of amino acid bisphosphonates with a cyclic RGD peptide for the modification of PEO-coated titanium opens the ways for the effective control of the biological activity of the metal implant surface.

Effect of Modified Levopimaric Acid Diene Adducts on Mitochondrial and Liposome Membranes.

This paper demonstrates the membranotropic effect of modified levopimaric acid diene adducts on liver mitochondria and lecithin liposomes. We found that the derivatives dose-dependently reduced the efficiency of oxidative phosphorylation of mitochondria due to inhibition of the activity of complexes III and IV of the respiratory chain and protonophore action. This was accompanied by a decrease in the membrane potential in the case of organelle energization both by glutamate/malate (complex I substrates) and succinate (complex II substrate). Compounds 1 and 2 reduced the generation of H2O2 by mitochondria, while compound 3 exhibited a pronounced antioxidant effect on glutamate/malate-driven respiration and, on the other hand, caused ROS overproduction when organelles are energized with succinate. All tested compounds exhibited surface-active properties, reducing the fluidity of mitochondrial membranes and contributing to nonspecific permeabilization of the lipid bilayer of mitochondrial membranes and swelling of the organelles. Modified levopimaric acid diene adducts also induced nonspecific permeabilization of unilamellar lecithin liposomes, which confirmed their membranotropic properties. We discuss the mechanisms of action of the tested compounds on the mitochondrial OXPHOS system and the state of the lipid bilayer of membranes, as well as the prospects for the use of new modified levopimaric acid diene adducts in medicine.

Zirconocene dichlorides as catalysts in alkene carbo- and cyclometalation by AlEt3: intermediate structures and dynamics.

A series of zirconocenes L2ZrCl2 (23 examples) were studied as catalysts in the reaction of alkenes with AlEt3. The catalyst activity and reaction chemoselectivity were found to depend on the ligand structure in the complex and the nature of the solvent. The alkyl exchange in the triethylaluminum dimer was studied by NMR spectroscopy; a solvent effect on the alkyl exchange parameters was established. In the reaction between L2ZrCl2 and AlEt3, the formation of intermediates L2ZrEtCl, L2Zr(µ-Cl)CH2CH2AlEt2, L2Zr(µ-H)CH2CH2AlEt2, and L2Zr(µ-Cl)CH2CH(AlEt2)2 was shown; the ratio of the intermediates depends on the ligand structure in the initial complex and the solvent. The exchange in the ethanediyl bridge ZrCH2CH2Al, proceeding via zirconocenecyclopropane structures, was demonstrated for the first time for five-membered bimetallic complexes L2Zr(µ-Cl)CH2CH2AlEt2 with ansa-ligands (L2 = Me2SiCp2, H2CInd2, Me2CInd2, Me2SiInd2, and C2H4Ind2). Five-membered bimetallic complexes were shown to participate in the formation of cyclic organoaluminum products - 3-substituted alumolanes.

New quaternized pyridinium derivatives of betulin: Synthesis and evaluation of membranotropic properties on liposomes, pro- and eukaryotic cells, and isolated mitochondria.

The present study describes the synthesis of pyridinium derivatives of betulin, including new 4-methyl- and 3,5-methyl-pyridinium analogs, their effect on artificial membrane systems (liposomes), cytotoxicity in models of prokaryotic (E. coli K-12 MG1655) and eukaryotic cells (rat thymocytes), as well as their effect on the functioning of membrane systems of rat liver mitochondria. We have shown that the presence of methyl groups in the pyridine ring of compounds determines the ability of the derivatives to effectively permeabilize the artificial membrane of lecithin liposomes for the fluorescent probe sulforhodamine B. The 4-methyl- and 3,5-methyl-pyridinium analogs inhibit the growth of E. coli K-12 MG1655 and, at the same time, did not have a cytotoxic effect on rat thymocytes. However, in the latter case, we noted a decrease in the mitochondrial potential of cells. The studied compounds reduced the functional activity of mitochondria, suppressing the activity of complexes of the respiratory chain and reducing the membrane potential. In addition, compounds containing methyl groups in the p- and m-positions of the pyridine ring were also able to permeabilize the inner membrane of mitochondria, causing them to swell. In this case, the most lipophilic compound containing two methyl substituents at the m-position of the pyridine fragment was most effective and had a protonophore effect on mitochondria. The paper discusses the dependence of the membranotropic and biological actions of the quaternized pyridine derivatives of betulin on their structure and lipophilicity.

Sonochemically assisted 2,3-dideoxygenation and skeletal rearrangement of ecdysteroid derivatives.

Sonochemical 2,3-dideoxygenation of ecdysteroids with the Δ 2(3)-bond generation and activation of the C-C bonds of the steroid core in the poststerone derivatives, that causes the skeletal rearrangement have been carried out for the first time. Thus, the ultrasonically assisted reaction of 2,3-dimesyloxy derivatives of ecdysteroids with the NaI-Zn-DMF system gives rise to their 2,3-dideoxy-Δ2(3)-analogues with yields 70-92%. In the case of 2,3-dimesyloxypoststerone as the initial ecdysteroid substrate the reaction is accompanied by the activation of the allyl moiety and semipinacol rearrangement, resulting in the C13-C14 bond migration with C/D rings contraction/expansion and providing novel short chain (8R)-13(14 → 8)-abeo-isomer.

Synthesis of New Dihydroquinopimaric Acid Analogs with Nitrile Groups as Apoptosis-Inducing Anticancer Agents.

BACKGROUND: Cyan-containing compounds are of great interest as potential anticancer agents. Terpenoids can severe as a natural matrix for the development of promising derivatives with antitumor activity. METHODS: The 2-cyanoethoxy methyl dihydroquinopimarate derivatives (5-9) were synthesized by the reaction of the intermediates (1-4) with acrylonitrile in the presence of alkali (30% KOH solution) using triethylbenzylammonium chloride. The cytotoxicity evaluation was carried out according to the National Cancer Institute (NCI) Protocol, while apoptosis was studied by flow cytometric analysis of Annexin V and 7-aminoactinomycin D staining and cell cycle was analyzed using the method of propidium iodide staining. RESULTS: Synthesis of new dihydroquinopimaric acid derivatives with nitrile groups was carried out. The obtained cyanoethyl derivatives were converted into tetrazole, amine, oxadiazole and amidoxime analogs. The primary screening for antitumor activity showed the highest cytotoxic potency of the cyanoethyl-substituted compounds. The introduction of cyanoethyl groups at C-1, C-4 and C-1, C-4, C-20 positions of dihydroquinopimaric acid methyl ester provided antiproliferative effect towards the Jurkat, K562, U937, and HeLa tumor cell cultures (CC50=0.045-0.154µM). These nitrile derivatives are effective inducers of tumor cell apoptosis affecting the S and G2 phases of the cell cycle in a dose-dependent manner. CONCLUSION: The cyanoethyl analogs of dihydroquinopimaric acid reported herein are apoptosis inducers and cytotoxic agents. These findings will be useful for the further design of more potent cytotoxic agents based on natural terpenes.

Molecular rearrangements of poststerone derivative steroid core with formation of unique D-homostructures of pregnane and androstane series.

20R-Hydroxy short-chain ecdysteroids were synthesized by chemo- and stereoselective reduction of poststerone acetonide with L-Selectride or LiAlH4. The same reaction with the excess of L- Selectride followed by the treatment of the reaction mixture with hydrochloric acid is accompanied by (8R)-13(14 → 8)abeo- rearrangements, which resulted in the contraction/expansion of C/D pregnane rings. The reaction of 20R-hydroxy poststerone analogs with (diethylamino)sulfur trifluoride (DAST) proceeds through intramolecular rearrangements and provides D-homo- or 13,14-seco- androstane structures.

Ligand exchange processes in zirconocene dichloride-trimethylaluminum bimetallic systems and their catalytic properties in reaction with alkenes.

Ligand exchange processes in the systems L2ZrCl2-AlMe3 (L2ZrCl2: Cp2ZrCl2, (CpMe)2ZrCl2, (C5Me5)2ZrCl2, Me2SiCp2ZrCl2, Me2Si(C5Me4)2ZrCl2, rac-Me2C(2-Me-4-But-Cp)2ZrCl2, meso-Me2C(2-Me-4-But-Cp)2ZrCl2, rac-Me2C(3-But-Cp)2ZrCl2, Ind2ZrCl2, rac-H2C(Ind)2ZrCl2, rac-Me2C(Ind)2ZrCl2, rac-Me2Si(Ind)2ZrCl2, rac-C2H4(Ind)2ZrCl2, rac-C2H4(THInd)2ZrCl2, rac-Me2Si(THInd)2ZrCl2) and Cp2ZrMeCl2-n-AlMe3 (n = 1, 2) were studied by NMR spectroscopy with the goal to establish the structures and dynamic features of probable intermediates in the zirconocene-catalyzed reactions of alkenes with AlMe3. The effect of solvent, the organoaluminum compound concentration and the addition of (ClAlMe2)2 on the activation parameters of the alkyl exchange in the trimethylaluminum dimer was studied as well. The constants and activation parameters of the methyl group exchange in the monoalkyl-substituted ansa-complexes L2ZrMeCl (L2 = rac-Me2C(2-Me-4-But-Cp)2, rac-Me2C(3-But-Cp)2, rac-H2CInd2, rac-Me2CInd2, rac-Me2SiInd2, rac-H4C2Ind2) were established for the first time. The catalytic activity and chemoselectivity of zirconocenes in the reaction of alkenes with AlMe3 were evaluated and compared with the exchange and equilibrium constants of ligand exchange processes. A mechanism of the reaction was proposed.