Electrophilic Precursor Research Articles

Substrate-Induced Cooperative Ionic Catalysis: Difunctionalization of Indole Derivatives Employing Dimethyl Carbonate.

The global urge to adopt sustainable chemistry has resulted in the development of more environmentally benign strategies (EBS) that use CO2 and CO2-derived chemicals in a step-economic manner. In this context, we investigated a dual C-H methylation and (C═O)-methoxylation of indole derivatives using dimethyl carbonate (DMC) in the presence of catalytic amounts of Cs2CO3. Mechanistic insights include DMF-assisted, DMC-induced cooperative ionic catalysis, which allows DMC to act as both a nucleophilic and an electrophilic precursor, resulting in (C═O)-methoxylation and C-H methylation of N-benzylindolyl ketones.

Shotgun Proteomic-Based Approach with a Q-Exactive Hybrid Quadrupole-Orbitrap High-Resolution Mass Spectrometer for Protein Adductomics on a 3D Human Brain Tumor Neurospheroid Culture Model: The Identification of Adduct Formation in Calmodulin-Dependent Protein Kinase-2 and Annexin-A1 Induced by Pesticide Mixture.

Pesticides are increasingly used in combinations in crop protection, resulting in enhanced toxicities for various organisms. Although protein adductomics is challenging, it remains a powerful bioanalytical tool to check environmental exposure and characterize xenobiotic adducts as putative toxicity biomarkers with high accuracy, facilitated by recent advances in proteomic methodologies and a mass spectrometry high-throughput technique. The present study aims to predict the potential neurotoxicity effect of imidacloprid and λ-cyhalothrin insecticides on human neural cells. Our protocol consisted first of 3D in vitro developing neurospheroids derived from human brain tumors and then treatment by pesticide mixture. Furthermore, we adopted a bottom-up proteomic-based approach using nanoflow ultraperformance liquid chromatography coupled with a high-resolution mass spectrometer for protein-adduct analysis with prediction of altered sites. Two proteins were selected, namely, calcium-calmodulin-dependent protein kinase-II (CaMK2) and annexin-A1 (ANXA1), as key targets endowed with primordial roles. De novo sequencing revealed several adduct formations in the active site of 82-ANXA1 and 228-CaMK2 as a result of neurotoxicity, predicted by the added mass shifts for the structure of electrophilic precursors. To the best of our knowledge, our study is the first to adopt a proteomic-based approach to investigate in depth pesticide molecular interactions and their potential to adduct proteins which play a crucial role in the neurotoxicity mechanism.

Cooperative Catalyst-Enabled Regio- and Stereodivergent Synthesis of α-Quaternary α-Amino Acids via Asymmetric Allylic Alkylation of Aldimine Esters with Racemic Allylic Alcohols.

We describe cooperative bimetallic catalysis that enables regio-/stereodivergent asymmetric α-allylations of aldimine esters. By employing Et3 B as the key activator, racemic allylic alcohols can be directly ionized to form Pd or Ir-π-allyl species in the presence of achiral Pd or chiral Ir complexes, respectively. The less or more substituted allylic termini of the metal-π-allyl species are amenable to nucleophilic attack by the chiral Cu-azomethine ylide, the formation of which is simultaneously facilitated by Et3 B, affording α-quaternary α-amino acids with high regioselectivity and excellent stereoselectivity. The use of readily available allylic alcohols as electrophilic precursors represents an improvement from an environmental and atom/step economy perspective. Computational mechanistic studies reveal the crucial role of the Et3 B additive and the origins of stereo- and regioselectivities by analyzing steric effects, dispersion interactions, and frontier orbital population.

Cooperative Catalyst‐Enabled Regio‐ and Stereodivergent Synthesis of α‐Quaternary α‐Amino Acids via Asymmetric Allylic Alkylation of Aldimine Esters with Racemic Allylic Alcohols

AbstractWe describe cooperative bimetallic catalysis that enables regio‐/stereodivergent asymmetric α‐allylations of aldimine esters. By employing Et3B as the key activator, racemic allylic alcohols can be directly ionized to form Pd or Ir‐π‐allyl species in the presence of achiral Pd or chiral Ir complexes, respectively. The less or more substituted allylic termini of the metal‐π‐allyl species are amenable to nucleophilic attack by the chiral Cu‐azomethine ylide, the formation of which is simultaneously facilitated by Et3B, affording α‐quaternary α‐amino acids with high regioselectivity and excellent stereoselectivity. The use of readily available allylic alcohols as electrophilic precursors represents an improvement from an environmental and atom/step economy perspective. Computational mechanistic studies reveal the crucial role of the Et3B additive and the origins of stereo‐ and regioselectivities by analyzing steric effects, dispersion interactions, and frontier orbital population.

The diverse functions of isocyanides in phosphorescent metal complexes.

In this Perspective, we highlight many examples of photoluminescent metal complexes supported by isocyanides, with an emphasis on recent developments including several from our own group. Work in this field has shown that the isocyanide can play important structural roles, both as a terminal ligand and as a bridging ligand for polynuclear structures, and can influence the excited-state character and excited-state dynamics. In addition, there are many examples of isocyanide-supported complexes where the isocyanide serves as a chromophoric ligand, meaning the low-energy excited states that are important in the photochemistry are partially or completely localized on the isocyanide. Finally, an emerging trend in the design of luminescent compounds is to use the isocyanide as an electrophilic precursor, converted to an acyclic carbene by nucleophilic addition which imparts certain photophysical advantages. This Perspective aims to show the diverse roles played by isocyanides in the design of luminescent compounds, showcasing the recent developments that have led to a substantial growth in fundamental knowledge, function, and applications related to photoluminescence.

Phosphinic Dehydrodipeptides: Diversification of the P1′ Residue with the Morita–Baylis–Hillman Acetates and Inhibition of Alanyl Aminopeptidases

Activated allyl acetates (the Morita–Baylis–Hillman acetates) were confirmed as convenient electrophilic precursors of the P1′ fragment of phosphinic dehydrodipeptides, and then, their selected saturated analogs were obtained in the subsequent reduction. This approach is particularly appropriate for structurally complex side chains and thus is an alternative to the addition of α-substituted acrylates with aminoalkylphosphinic acids. While phosphinic dehydrodipeptides were found to be good inhibitors of two mammalian alanyl metalloaminopeptidases, the saturated compounds showed higher activities than their structurally constrained counterparts. Docking calculations and molecular modeling showed that conformational freedom allowed for the favorable binding of distinct stereoisomers of phosphinates, while the presence of the double bond was more restrictive.

Strategy for identifying unknown hemoglobin adducts using adductome LC-MS/MS data: Identification of adducts corresponding to acrylic acid, glyoxal, methylglyoxal, and 1-octen-3-one

Electrophilic compounds have the ability to form adducts with nucleophilic sites in proteins and DNA in tissues, and thereby constitute risks for toxic effects. Adductomic approaches are developed for systematic screening of adducts to DNA and blood proteins, with the aim to detect unknown internal exposures to electrophiles. In a previous adductomic screening of adducts to N-terminals in hemoglobin, using LC-MS/MS, 19 unknown adducts were detected in addition to seven previously identified adducts. The present paper describes the identification of four of these unknown adducts, as well as the strategy used to identify them. Using LC-MS data from the screening, hypotheses about adduct identities were formulated: probable precursor electrophiles with matching molecular weights were suggested based on the molecular weights of the modifications and the retention times of the analytes, in combination with comparisons of theoretical Log P calculations and databases. Reference adducts were generated by incubation of blood samples with the hypothesized precursor electrophiles. The four identified precursor electrophiles, corresponding to the observed unknown adducts, were glyoxal, methylglyoxal, acrylic acid and 1-octen-3-one. Possible origins/exposure sources and toxicological information concerning the electrophilic precursors are discussed. The identified adducts could be explored as possible biomarkers for exposure.

Tuning Gelation Time and Morphology of Injectable Hydrogels Using Ketone–Hydrazide Cross-Linking

Injectable, covalently in situ forming hydrogels based on poly(N-isopropylacrylamide) have been designed on the basis of mixing hydrazide-functionalized nucleophilic precursor polymers with electrophilic precursor polymers functionalized with a combination of ketone (slow reacting) and aldehyde (fast reacting) functional groups. By tuning the ratio of aldehyde:ketone functional groups as well as the total number of ketone groups in the electrophilic precursor polymer, largely independent control over hydrogel properties including gelation time (from seconds to hours), degradation kinetics (from hours to months), optical transmission (from 1 to 85%), and mechanics (over nearly 1 order of magnitude) can be achieved. In addition, ketone-functionalized precursor polymers exhibit improved cytocompatibility at even extremely high concentrations relative to polymers functionalized with aldehyde groups, even at 4-fold higher functional group densities. Overall, increasing the ketone content of the precursor copolymers can result in in situ-gellable hydrogels with improved transparency and biocompatibility and equivalent mechanics and stimuli-responsiveness while only modestly sacrificing the speed of gel formation.

Self-Catalyzed Immobilization of GST-Fusion Proteins for Genome-Encoded Biochips

With the surge of proteomic information that has become available in recent years from genome sequencing projects, selective and robust technologies for making protein biochips have become increasingly desirable. Herein, we describe the development of small-molecule SNAr electrophiles (smSNAREs), a new class of capture probes that enables a selective, single-step immobilization for protein biochips. This enzymology-driven approach rides on the binding and catalytic mechanism of SjGST. We have designed and synthesized mechanism-based substrate analogs 3, 4, and 5 as electrophilic precursors for conjugation of glutathione S-transferase (GST) or any of its fusion proteins. Upon evaluating the conjugation of these probes to glutathione in the presence of SjGST via UV–visible spectroscopy (UV–vis) and LC-MS techniques, we found that 3, 4, and 5 were transferable to GSH. Through the anchoring of alkyne 5 as a smSNARE probe on glass surface, we demonstrate the single-step, self-catalyzed immobilization of SjGST. Fluorescence imaging quantitatively revealed an 18-fold increase in selective binding of SjGST over random orientations (due to nonspecific binding) of the protein. Binding between GST and smSNARE surface is robust and does not reverse upon adding up to 100 mM GSH. Further, a 6-fold increase in resolution for the smSNARE surface probe was observed over commonly employed commercially available GSH-epoxy surfaces. Detailed control experiments revealed insights into the reversibility of binding and catalysis of GSH to form conjugation products with 5 in the presence of the enzyme. As an application of this protein capture technology, we printed alkaloid biosynthesis enzyme, isonitrile synthase (IsnA), to result in a biochip. Because proteins bearing a GST-fusion purification tag are commonly created through the pGEX expression system, these findings show broad potential applicability to genome-wide studies and proteomic platforms.

A Fused Donor−Acceptor System Based on an Extended Tetrathiafulvalene and a Ruthenium Complex of Dipyridoquinoxaline

An application of the Horner-Wadsworth-Emmons reaction carried out on a ruthenium compound as the electrophilic precursor is described for the synthesis of fused donor-acceptor system 1 based on an extended tetrathiafulvalene and a ruthenium complex of dipyridoquinoxaline units.

Sequential Ring‐Opening of trans‐1,4‐Cyclohexadiene Dioxide for an Expedient Modular Approach to 6,7‐Disubstituted (.+‐.)‐Hexahydro‐benzo[1,4]oxazin‐3‐ones.

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, please click on HTML or PDF.

Ultrafast dissociation pathways of diphenylmethyl chloride to generate reactive carbo cations

The primary processes in the formation of electrophilic precursor ions are studied on a microscopic scale by quantum chemical and quantum dynamical methods. For the competing reaction channels of heterolysis and homolysis in the photochemically induced dissociation of diphenylmethyl chloride, ab initio data for the ground and excited electronic states are evaluated in the gas phase. Here, the simultaneous formation of ionic and radicalic products can solely be attributed to the existence of conical intersections which are localized and characterized for the first time. The interaction of different electronic states also leads to the initial charge transfer from the phenyl π-system to the σ-bond of the leaving group which is essential for the fast dissociation and is explained by orbital analysis. Quantum dynamical calculations in one and two dimensions suggest that in gas phase the ion pair constitutes the main product despite its higher potential energy. Possible changes in polar solvents, where the ionic fragments are stabilized below the radical channel, are discussed.

Sequential ring-opening of trans-1,4-cyclohexadiene dioxide for an expedient modular approach to 6,7-disubstituted (±)-hexahydro-benzo[1,4]oxazin-3-ones

A modular approach to novel 6-amino-7-hydroxysubstituted hexahydro-benzo[1,4]oxazin-3-ones has been developed. The method involves a sequential ring-opening of trans-1,4-cyclohexadiene dioxide with amino nucleophiles. The resultant mono-epoxide from benzylamine was converted to a general electrophilic precursor, which enables the parallel treatment with amino nucleophiles to obtain a series of cyclohexane-fused morpholin-3-ones.

Positional isomers of thioxylobiose, their synthesis and inducing ability for d-xylan-degrading enzymes in the yeast cryptococcus albidus

Isomeric S-linked-2-thioxylobiose 10, 3-thioxylobiose 17, and 4-thioxylobioise 19 were conveniently prepared by S n2 displacement of suitable triflylglycoses with the sodium salt of 2,3,4-tri- O-acetyl-1-thio-β- d-glucopyranose, either in N,N-dimethylformamide, or in oxolan in the presence of a sodium complexing agent. Allyl 3,5- O-isopropylidene-2- O-trifluoromethanesulfonyl-β- d-lyxofuranoside was a convenient electrophilic precursor for 10, which was smoothly obtained after a short sequence of deprotection involving conversion to the 1-propenyl glycoside. 1,2:5,6-Di- O-isopropylidene-3- O-trifluoromethylsulfonyl-α- d-allofuranose and 1,2,3-tri- O-benzoyl-4- O-trifluoromethylsulfonyl-β- l-arabinopyranose were the respective precursors for 17 and 19. 4-Thioxylobiose has a highly stimulatory effect on the synthesis of enzymes of the xylanolytic system in the yeast Cryptococcus albidus when applied to the cells in the presence of the natural disaccharide inducer (1→4)-β- d-xylobiose.

Interaction of a glutathione S-conjugate with glutathione reductase. Kinetic and X-ray crystallographic studies.

S-Conjugates of glutathione influence the glutathione/glutathione disulfide (GSH/GSSG) status of hepatocytes in at least two ways, namely by inhibition of GSSG transport into the bile [Akerboom et al. (1982) FEBS Lett. 140, 73-76] and by inhibition of the enzyme GSSG reductase (EC 1.6.4.2). The interaction of GSSG reductase with a well-studied conjugate, namely S-(2,4-dinitrophenyl)-glutathione and its electrophilic precursor 1-chloro-2,4-dinitrobenzene are described. For short exposures both compounds are reversible inhibitors of the enzyme, the Ki values being 30 microM and 22 microM respectively. After prolonged incubation, 1-chloro-2,4-dinitrobenzene blocks GSSG reductase irreversibly, which emphasizes the need for rapid conjugate formation in situ. As shown by X-ray crystallography the major binding site of S-(2,4-dinitrophenyl)-glutathione in GSSG reductase overlaps the binding site of the substrate, glutathione disulfide. However, the glutathione moiety of the conjugate does not bind in the same manner as either of the glutathiones in the disulfide.

ChemInform Abstract: SYNTHESIS OF A 6‐METHYLPYRIDOXINE HYDROCHLORIDE DERIVATIVE AS AN ELECTROPHILIC PRECURSOR FOR PYRIDOXAL‐LIKE FUNCTIONALIZATION

Chemischer InformationsdienstVolume 13, Issue 42 Heterocyclic Compounds ChemInform Abstract: SYNTHESIS OF A 6-METHYLPYRIDOXINE HYDROCHLORIDE DERIVATIVE AS AN ELECTROPHILIC PRECURSOR FOR PYRIDOXAL-LIKE FUNCTIONALIZATION M. IWATA, M. IWATASearch for more papers by this authorH. KUZUHARA, H. KUZUHARASearch for more papers by this author M. IWATA, M. IWATASearch for more papers by this authorH. KUZUHARA, H. KUZUHARASearch for more papers by this author First published: October 19, 1982 https://doi.org/10.1002/chin.198242243Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume13, Issue42October 19, 1982 RelatedInformation

Synthesis of a 6-Methylpyridoxine Hydrochloride Derivative as an Electrophilic Precursor for Pyridoxal-like Functionalization

Abstract Through a key step of regioselective rearrangement of 5′-O-acetyl-3,4′-O-isopropylidene-6-methylpyridoxine 1-oxide, stable 5′-deoxy-2′,5′-dichloro-3,4′-O-isopropylidene-6-methylpyridoxine hydrochloride, which is expected to be a strong electrophile in an HCl free form, was synthesized from Dl-alanine in good yield.