Nucleophilic Functionalization Research Articles

ChemInform Abstract: Palladium(0)‐Catalyzed Cyclization of 1,6‐Diyn‐3‐yl Carbonates with a Nucleophilic Functionality: Efficient Synthesis of Polycyclic Benzo[b]fluorene Derivatives via Allene Intermediates.

AbstractA convenient sequential method for the facile and efficient synthesis of the title compounds (II) and (IV) from easily accessible starting materials is developed under mild conditions.

Synthesis of nitroxyl radical by direct nucleophilic functionalization of a C-H bond in the azadiene systems

Cyclic dinitrones underwent nucleophilic substitution of the hydrogen atom in the reaction with a paramagnetic carbanion, the lithium derivative of 4,4,5,5-tetramethyl-4,5-dihydro-1H-imidazol-1-oxyl 3-oxide, to give polyfunctional nitronyl nitroxyls.

Palladium(0)-catalyzed cyclization of 1,6-diyn-3-yl carbonates with a nucleophilic functionality: efficient synthesis of polycyclic benzo[b]fluorene derivatives via allene intermediates

We report in this paper an interesting tandem reaction involving sequential palladium(0)-catalyzed decarboxylation of diynylic carbonates, intramolecular nucleophilic cyclization and Schmittel reaction, which provides a facile method for the synthesis of a variety of polycyclic benzo[b]fluorene derivatives from easily accessible starting materials.

Investigation of Uranyl Nitrate Ion Pairs Complexed with Amide Ligands Using Electrospray Ionization Ion Trap Mass Spectrometry and Density Functional Theory

Ion populations formed from electrospray of uranyl nitrate solutions containing different amides vary depending on ligand nucleophilicity and steric crowding at the metal center. The most abundant species were ion pair complexes having the general formula [UO(2)(NO(3))(amide)(n=2,3)](+); however, singly charged complexes containing the amide conjugate base and reduced uranyl UO(2)(+) were also formed as were several doubly charged species. The formamide experiment produced the greatest diversity of species resulting from weaker amide binding, leading to dissociation and subsequent solvent coordination or metal reduction. Experiments using methyl formamide, dimethyl formamide, acetamide, and methyl acetamide produced ion pair and doubly charged complexes that were more abundant and less abundant complexes containing solvent or reduced uranyl. This pattern is reversed in the dimethylacetamide experiment, which displayed lower abundance doubly charged complexes, but augmented reduced uranyl complexes. DFT investigations of the tris-amide ion pair complexes showed that interligand repulsion distorts the amide ligands out of the uranyl equatorial plane and that complex stabilities do not increase with increasing amide nucleophilicity. Elimination of an amide ligand largely relieves the interligand repulsion, and the remaining amide ligands become closely aligned with the equatorial plane in the structures of the bis-amide ligands. The studies show that the phenomenological distribution of coordination complexes in a metal-ligand electrospray experiment is a function of both ligand nucleophilicity and interligand repulsion and that the latter factor begins exerting influence even in the case of relatively small ligands like the substituted methyl-formamide and methyl-acetamide ligands.

Probing the anticancer mechanism of prospective herbal drug Withaferin A on mammals: a case study on human and bovine proteasomes

BackgroundThe UPP (ubiquitin proteasome pathway) is the major proteolytic system in the cytosol and nucleus of all eukaryotic cells which regulates cellular events, including mitotis, differentiation, signal transduction, apoptosis, and inflammation. UPP controls activation of the transcriptional factor NF-κB (nuclear factor κB), which is a regulatory protein playing central role in a variety of cellular processes including immune and inflammatory responses, apoptosis, and cellular proliferation. Since the primary interaction of proteasomes occurs with endogenous proteins, the signalling action of transcription factor NF-κB can be blocked by inhibition of proteasomes. A great variety of natural and synthetic chemical compounds classified as peptide aldehydes, peptide boronates, nonpeptide inhibitors, peptide vinyl sulfones and epoxyketones are now widely used as research tools for probing their potential to inhibit proteolytic activities of different proteasomes and to investigate the underlying inhibition mechanisms. The present work reports a bio-computational study carried out with the aim of exploring the proteasome inhibition capability of WA (withaferin A), a steroidal lactone, by understanding the binding mode of WA as a ligand into the mammalian proteasomes (X-ray crystal structure of Bos taurus 20S proteasome and multiple template homology modelled structure of 20S proteasome of Homo sapiens) using molecular docking and molecular dynamics simulation studies.ResultsOne possible mode of action which is proposed here for WA to act as a proteasome inhibitor is by suppression of the proteolytic activity which depends on the N-terminal threonine (Thr1) residue hydroxyl group. Docking studies carried out with herbal ligand WA into the structures of bovine and human proteasomes substantiate that WA has the ability to inhibit activity of mammalian 20S proteasomes by blocking the nucleophilic function of N-terminal Thr1. Results from molecular dynamics simulations in water show that the trajectories of both the native human 20S proteasome and the proteasome complexed with WA are stable over a considerably long time period of 4 ns suggesting the dynamic structural stability of human 20S proteasome/WA complex.ConclusionsInhibition of proteasomal activity are promising ways to retard or block degradation of specific proteins to correct diverse pathologies. Though quite a number of selective and efficient proteasomal inhibitors exist nowadays, their toxic side effects limit their potential in possible disease treatment. Thus there is an indispensable need for exploration of novel natural products as antitumor drug candidates. The present work supports the mammalian proteasomes inhibiting activity of WA along with elucidation of its possible mode of action. Since WA is a small herbal molecule, it is expected to provide one of the modest modes of inhibition along with added favours of ease in oral administration and decreased immunogenicity. The molecular docking results suggest that WA can inhibit the mammalian proteasomes irreversibly and with a high rate through acylation of the N-terminal Thr1 of the β-5 subunit.

Enantioselective Halocyclization Reactions for the Synthesis of Chiral Cyclic Compounds

Ground-breaking progress has been made in the synthesis of chiral cyclic compounds from nonchiral unsaturated substrates with a nucleophilic functionality. A number of highly enantioselective electrophilic halocyclizations based on either the interaction of a chiral Lewis acid with an unsaturated substrate or the generation of a chiral electrophilic intermediate in situ from an electrophile and a chiral reagent (see scheme) were developed.

Functionalization of Hyaluronic Acid with Chemoselective Groups via a Disulfide-Based Protection Strategy for In Situ Formation of Mechanically Stable Hydrogels

Functionalization of hyaluronic acid (HA) with chemoselective groups enables in situ (in vivo) formation of HA-based materials in minimally invasive injectable manner. Current methods of HA modification with such groups primarily rely on the use of a large excess of a reagent to introduce a unique reactive handle into HA and, therefore, are difficult to control. We have developed the new protective group strategy based on initial mild cleavage of a disulfide bond followed by elimination of the generated 2-thioethoxycarbonyl moiety ultimately affording free amine-type functionality, such as hydrazide, aminooxy, and carbazate. Specifically, new modifying homobifunctional reagents have been synthesized that contain a new divalent disulfide-based protecting group. Amidation of HA with these reagents gives rise to either one-end coupling product or to intra/intermolecular cross-linking of the HA chains. However, after subsequent treatment of the amidation reaction mixture with dithiothreitol (DTT), these cross-linkages are cleaved, ultimately exposing free amine-type groups. The same methodology was applied to graft serine residues to the HA backbone, which were subsequently oxidized into aldehyde groups. The strategy therefore encompasses a new approach for mild and highly controlled functionalization of HA with both nucleophilic and electrophilic chemoselective functionalities with the emphasis for the subsequent conjugation and in situ cross-linking. A series of new hydrogel materials were prepared by mixing the new HA-aldehyde derivative with different HA-nucleophile counterparts. Rheological properties of the formed hydrogels were determined and related to the structural characteristics of the gel networks. Human dermal fibroblasts remained viable while cultured with the hydrogels for 3 days, with no sign of cytotoxicity, suggesting that the gels described in this study are candidates for use as growth factors delivery vehicles for tissue engineering applications.

Gold-Catalyzed Tandem Cyclizations of 1,6-Diynes Triggered by Internal N- and O-Nucleophiles

Investigations on gold-catalyzed tandem cyclization reactions of 1,6-diynes, tethered to nucleophilic functionalities such as amine, carboxylic acid, amide, and sulfonamide, are reported. The ability of such substrates to undergo tandem cyclization, triggered by internal nucleophiles, has been examined. Depending on the substrate, the catalytic system, and reaction conditions, different regioisomers of monocyclic and bridged bicyclic products were obtained.

Opposite Regiospecific Ring Opening of 2-(Cyanomethyl)aziridines by Hydrogen Bromide and Benzyl Bromide: Experimental Study and Theoretical Rationalization

Ring opening of 1-arylmethyl-2-(cyanomethyl)aziridines with HBr afforded 3-(arylmethyl)amino-4-bromobutyronitriles via regiospecific ring opening at the unsubstituted aziridine carbon. Previous experimental and theoretical reports show treatment of the same compounds with benzyl bromide to furnish 4-amino-3-bromobutanenitriles through ring opening at the substituted aziridine carbon. To gain insights into the regioselective preference with HBr, reaction paths have been analyzed with computational methods. The effect of solvation was taken into account by the use of explicit solvent molecules. Geometries were determined at the B3LYP/6-31++G(d,p) level of theory, and a Grimme-type correction term was included for long-range dispersion interactions; relative energies were refined with the meta-hybrid MPW1B95 functional. Activation barriers confirm preference for ring opening at the unsubstituted ring carbon for HBr. HBr versus benzyl bromide ring opening was analyzed through comparison of the electronic structure of corresponding aziridinium intermediates. Although the electrostatic picture fails to explain the opposite regiospecific nature of the reaction, frontier molecular orbital analysis of LUMOs and nucleophilic Fukui functions show a clear preference of attack for the substituted aziridine carbon in the benzyl bromide case and for the unsubstituted aziridine carbon in the HBr case, successfully rationalizing the experimentally observed regioselectivity.

Competitive Substituent Effects on the Reactivity of Aromatic Rings

We performed second order perturbation theory calculations of gas phase proton affinities for o, m, p-nitroaniline at all positions and attempted correlations of the thermodynamic stability of the products with several reactivity indices: inductive effects from resonance, partial charges, and frontier orbital related indices such as local nucleophilic and electron-donating powers, global hardness of the products, and the substituent push-pull effect. All protonation reactions at ring positions are predicted to be exothermic. Resonance and charge analysis give inconsistent correlations with proton affinities, while the condensed nucleophilic Fukui function, electron-donating power, global hardness, and push-pull effect show promising trends.

Functionalised ionic liquids: synthesis of ionic liquids with tethered basic groups and their use in Heck and Knoevenagel reactions

A simple and efficient synthesis of a novel series of ionic liquids bearing nucleophilic (Me2N) and non-nucleophilic base (iPr2N) functionalities is described. The non-nucleophilic base functionality resembles the structure of the Hünig's base (N,N-diisopropylethylamine), which has been used widely in organic synthesis. A qualitative measure of the basicity of these ionic liquids is presented by utilising their interaction with universal indicator. The basicity of these ionic liquids was found to be dependent on the amine tether and choice of linker between the two nitrogen centres. The relative base strength of these ionic liquids was also probed by using them as catalysts in the Heck and Knoevenagel reactions.

Brostallicin (PNU-166196), a new minor groove DNA binder: preclinical and clinical activity

Brostallicin (PNU-166196), a-bromo-acrylamido tetra-pyrrole derivative, showed high cytotoxic potency and myelotoxicity dramatically reduced compared with other minor groove DNA-binding agents. In the presence of high intracellular glutathione concentrations, which are associated with resistance to chemotherapy, brostallicin performs a DNA minor groove attack leading to alkylation of DNA nucleophilic functions. In preclinical models, the antitumor activity of brostallicin has been tested in ovarian cancer xenografts, L1210 murine leukemia models, renal, colon and prostatic cancer cells and glutathione-S-transferase (GST) transfected human breast carcinoma cells. In clinical setting, the antitumor activity of brostallicin has been tested in ovarian cancer and in soft tissue sarcoma patients. A clear therapeutic advantage is also observed in preclinical models when brostallicin is combined with anticancer agents such as cisplatin (CDDP), doxorubicin, irinotecan and docetaxel. Brostallicin was also tested in combination with gefitinib, imatinib and bevacizumab in in vitro and in vivo studies, documenting a synergistic effect and with cetuximab showing an additive effect. Preliminary results of activity and toxicities of brostallicin in Phase I and II studies will be provided.

ChemInform Abstract: Highly Regio‐ and Stereoselective Synthesis of Nine‐ to Twelve‐Membered Cyclic Compounds by a Pd0‐Catalyzed Cyclization Reaction Between Allenes with a Nucleophilic Functionality and Organic Halides.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Local reactivity descriptors from degenerate frontier molecular orbitals

Conceptual Density Functional Theory (DFT) has proposed a set of local descriptors to measure the reactivity on specific sites of a molecule, as an example dual descriptor has been successfully used in analyzing interesting systems to understand their local reactivity, however under the frozen orbital approximation (FOA), it is defined from non-degenerate frontier molecular orbitals (FMOs). In this work, the degeneration is taken into account to propose approximated expressions to obtain the dual descriptor, nucleophilic and electrophilic Fukui functions in closed-shell systems. The proposed expressions have been tested on molecules presenting degenerate FMOs.

Highly Regio‐ and Stereoselective Synthesis of Nine‐ to Twelve‐Membered Cyclic Compounds by a Pd0‐Catalyzed Cyclization Reaction between Allenes with a Nucleophilic Functionality and Organic Halides

Simple cyclization: A novel method has been developed for the highly regio- and stereoselective synthesis of nine- to twelve-membered cyclic compounds by a Pd0-catalyzed cyclization reaction of allenes with a carbon or nitrogen nucleophilic functionality. Oxidative addition and carbopalladation gave anti-π-allyl palladium intermediates, then an exclusive intramolecular nucleophilic attack at the terminal carbon atom of the allene moiety gave the E product in good yields (see scheme; Ts=tosyl; DMA=N,N-dimethylacetamide).

Chiral Perazamacrocycles: Synthesis and Applications. Part 2

The formation of chiral non-racemic perazamacrocyles containing three or more nitrogen atoms in the form of identical of different functionalities can be achieved by diverse methodologies which usually exploit the sequential formation of carbon-nitrogen bonds by reaction of nucleophilic nitrogen functions with electrophilic compounds. The rigidity and restricted flexibility of the reaction partners is generally a requisite for the successful cyclization, which can be alternatively accomplished by the use of a metal template. The carbon stereocenters in the formed macrocycle are generally present in the starting nitrogen-containing reagent, e.g. amine, diamine, α- aminoacid and their derivatives. Intrinsically chiral porphyrins, lacking carbon stereocenters, have been also prepared. Chiral perazamacrocycles and their metal complexes have found applications in the fields of biomedical research, diagnosis, anion sensing, molecular recognition, enantiomeric discrimination, asymmetric catalysis, and material chemistry. Keywords: Asymmetric catalysis, cyclization, enantioselective recognition, metal complexes, perazamacrocycles, porphyrins, supramolecular chemistry

Liquefaction of rice straw in sub- and supercritical 1,4-dioxane–water mixture

The critical liquefaction of rice straw in sub- and supercritical 1,4-dioxane–water mixture was investigated in a 500 mL autoclave at temperature of 260–340 °C, resistance time of 0–20 min, and volume ratios 0–100 vol.% (1,4-dioxane:mixture). The yields of oil and PA + A (preasphaltene and asphaltene) were in the range of 29.64–57.30 wt.% and 6.42–22.68 wt.%, depending on the temperature, resistance time and volume ratio. The synergistic capability of 1,4-dioxane–water mixture could allow the great decomposition of the tubular structure of lignocelluloses. It was shown by the results that the “oxygen-transfer” reaction, deoxygenation and decarboxylation may occur in the liquefaction of rice straw with 1,4-dioxane–water mixture, while deoxygenation and decarboxylation may be the main reaction. The oil and PA + A fractions obtained at different volume ratios were analyzed by FTIR and GC–MS to investigate the effect of the ratios on the type of the compounds in the liquid products. It is shown that the nucleophilic and hydrolytic functions of water might be weaken at the higher ratio of 1,4-dioxane runs, resulting the lower amount of phenolic, acidic, hydrocarbon and ester derivatives in the oil and PA + A fractions.

A Highly Efficient Macrolactonization Method via Ethoxyvinyl Ester

We present the highly efficient reaction procedure of the macrolactonization method via ethoxyvinyl esters (EVEs). The following procedure was performed: 1) The EVE was prepared from hydroxycarboxylic acid and ethoxyacetylene in the presence of the Ru catalyst [RuCl(2)(p-cymene)](2) in acetone; 2) after filtration of the Ru catalyst through a short-neutral SiO(2) pad and evaporation of acetone, the EVE formed was diluted in 1,2-dichloroethane (DCE) and the solution was slowly added by a syringe pump to the highly diluted DCE solution of pTsOH (10 mol %) at 80 degrees C. Various-sized lactones could be produced by the method described here. It is noteworthy that the method can give 9- to 14-membered macrolactones in good yields. This macrolactonization method via EVEs is useful for acid-/base-sensitive substrates. Furthermore, it was found that EVE formation was possible without loosing activity of the Ru catalyst even for the compounds with nucleophilic amine functions. The characteristic feature of the method was exemplified by the reaction of the compound 14 with many functional groups.

Selective monobromination in the series of quinoid pyrido[1,2-a]benzimidazole derivatives

Bromo-substituted quinoid compounds are widespread in nature (examples are alkaloids discorhabdins, verongiaquinol, components of plant pigments, etc.), and they exhibit pronounced antibacterial activity [1]. Synthetic analogs of natural compounds could also be expected to display various kinds of biological activity. Furthermore, regioselective introduction of bromine atoms into quinoid ring should make further nucleophilic functionalization of the bromination products more unambiguous with a view to obtain compounds having pharmacophoric groups. On the other hand, heterocyclic compounds whose molecules contain quinoid fragments are convenient substrates for various transformations due to their fairly rare ability to undergo functionalization under mild conditions by the action of both nucleophilic and electrophilic reagents, as well as of radical species.

Diastereoselective, Catalytic Pd(II)-Based Allylic Alkylation

The methodology described in this report is one of the first direct catalytic allylic C-H alkylation reactions. White and Young have introduced a novel set of reaction conditions, allowing the reaction to proceed in a truly catalytic fashion. The use of DMSO as an π-acceptor ligand facilitates nucleophilic functionalization of the π-allylPd intermediate, while the combination of sterically bulkier 2,6-dimethylbenzoquinone (DMBQ) and AcOH serves as an oxidant, activating agent of π-allylPd species toward reductive elimination and as a source of catalytic base.