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MicroRNAs (miRNAs) are noncoding RNAs with 18–26 nucleotides; they pair with target mRNAs to regulate gene expression and produce significant changes in various physiological and pathological processes. In recent years, the interaction between miRNAs and their target genes has become one of the mainstream directions for drug development. As a large-scale biological database that mainly provides miRNA–target interactions (MTIs) verified by biological experiments, miRTarBase has undergone five revisions and enhancements. The database has accumulated >2 200 449 verified MTIs from 13 389 manually curated articles and CLIP-seq data. An optimized scoring system is adopted to enhance this update’s critical recognition of MTI-related articles and corresponding disease information. In addition, single-nucleotide polymorphisms and disease-related variants related to the binding efficiency of miRNA and target were characterized in miRNAs and gene 3′ untranslated regions. miRNA expression profiles across extracellular vesicles, blood and different tissues, including exosomal miRNAs and tissue-specific miRNAs, were integrated to explore miRNA functions and biomarkers. For the user interface, we have classified attributes, including RNA expression, specific interaction, protein expression and biological function, for various validation experiments related to the role of miRNA. We also used seed sequence information to evaluate the binding sites of miRNA. In summary, these enhancements render miRTarBase as one of the most research-amicable MTI databases that contain comprehensive and experimentally verified annotations. The newly updated version of miRTarBase is now available at https://miRTarBase.cuhk.edu.cn/.

A regiodivergent nickel-catalyzed hydrocyanation of 1-aryl-4-silyl-1,3-diynes is reported. When appropriate bisphosphine and phosphine-phosphite ligands are applied, the same starting materials can be converted into two different enynyl nitriles with good yields and high regioselectivities. The DFT calculations unveiled that the structural features of different ligands bring divergent alkyne insertion modes, which in turn lead to different regioselectivities. Moreover, the synthetic value of the cyano-containing 1,3-enynes has been demonstrated with several downstream transformations.

Selective oxidation is one of the most important and challenging transformations in both academic research and chemical industry. Recently, a highly selective and efficient way to synthesize biologically active γ-hydroxy-α,β-unsaturated molecules from Cu-catalyzed vinylogous aerobic oxidation of α,β- and β,γ-unsaturated compounds has been developed. However, the detailed reaction mechanism remains elusive. Herein, we report a density functional theory study on this Cu-catalyzed vinylogous aerobic oxidation of γ,γ-disubstituted α,β- and β,γ-unsaturated isomers. Our computational study unveils detailed mechanism for each elementary step, i.e. deprotonation, O2 activation, and reduction. Besides, the origin of regioselectivity, divergent reactivities of substrates as well as reducing agents, and the byproduct generation have also been investigated. Notably, the copper catalyst retains the + 2 oxidation state through the whole catalytic cycle and plays essential roles in multiple steps. These findings would provide hints on mechanistic studies and future development of transition metal-catalyzed aerobic oxidation reactions.

A highly regioselective nickel-based catalyst system for the isomerization/hydrocyanation of aliphatic internal olefins is described. This benign tandem reaction provides facile access to a wide variety of aliphatic nitriles in good yields with excellent regioselectivities. Thanks to Lewis acid-free conditions, the protocol features board functional groups tolerance, including secondary amine and unprotected alcohol groups.

A regiodivergent nickel-catalyzed hydrocyanation of a broad range of internal alkenes involving a chain-walking process is reported. When appropriate diastereomeric biaryl diphosphite ligands are applied, the same starting materials can be converted to either linear or branched nitriles with good yields and high regioselectivities. DFT calculations suggested that the catalyst architecture determines the regioselectivity by modulating electronic and steric interactions. In addition, moderate enantioselectivities were observed when branched nitriles were produced.

A nickel-catalyzed cross-electrophile coupling reaction between (hetero)aryl bromides and 2,2-difluorovinyl tosylate is presented. This protocol provides facile incorporation of the gem-difluorovin...

Summary The asymmetric radical-initiated difunctionalization of internal alkenes, which creates two vicinal stereocenters, has been a significant synthetic challenge despite the tremendous progress achieved for terminal alkenes. This is attributable to the common stepwise mechanism that involves an initial free radical addition to the alkene in a nonstereoselective fashion. We report here the first asymmetric radical 1,2-oxysulfonylation of both terminal and internal aryl alkenes in β,γ-unsaturated ketoximes in the presence of copper(I)-cinchona alkaloid-based sulfonamide catalyst. The experimental and computational mechanistic studies collectively support a CuII-CuI mechanism featuring fast, reversible addition of sulfonyl radicals to alkenes and subsequent rate- and stereo-determining C–O bond formation, namely, a scenario under Curtin-Hammett kinetic control. The method provides a robust platform for collective synthesis of a diverse array of valuable chiral sulfonyl-containing building blocks.

Herein, we report that merging palladium catalysis with hydrogen atom transfer (HAT) photocatalysis enabled direct arylations and alkenylations of aldehyde C–H bonds, facilitating visible light-cat...

A new type of coupling between unactivated olefins and nonstabilized alkyl radicals was achieved, which enabled the first intermolecular Heck-type reaction of cycloketone oxime esters and unactivated alkenes. This directing-group-based strategy was compatible with various unactivated alkenes and cyclobutanone-, cyclopentanone-, and cyclohexanone-derived oxime esters. Density functional theory calculations showed that both excellent regioselectivities and good diastereoselectivities could be ascribed to the 2-butanol-assisted concerted H-OBz elimination of the conformationally strained metallacyclic transition state.

Disruption of copper homeostasis is associated with a number of severe diseases including Alzheimer’s disease (AD), Parkinson’s disease (PD), Wilson’s disease, and Menkes syndrome. Given this association, the detection and capture of Cu2+ in biological fluids and tissues may provide a new direction for the diagnosis and treatment of related disorders. The current analytical approaches, however, are challenging due to the high cost, complexity, and long time required to prepare and analyze samples. Here, we report a novel salen ligand, namely N,N’-(1,2-phenylene)bis(1-(1H-imidazol-4-yl)methanimine) (pimi), which can readily detect and concurrently capture Cu2+ from aqueous as well as biological mediums. Pimi can selectively and specifically detect Cu2+ from biofluid and cellular samples with rapid ccresponse time (

Enzymatic stereoselectivity has typically been unrivalled by most chemical catalysts, especially in the conversion of small substrates. According to the ‘lock-and-key theory’1,2, enzymes have confined active sites to accommodate their specific reacting substrates, a feature that is typically absent from chemical catalysts. An interesting case in this context is the formation of cyanohydrins from ketones and HCN, as this reaction can be catalysed by various classes of catalysts, including biological, inorganic and organic ones3–7. We now report the development of broadly applicable confined organocatalysts for the highly enantioselective cyanosilylation of aromatic and aliphatic ketones, including the challenging 2-butanone. The selectivity (98:2 enantiomeric ratio (e.r.)) obtained towards its pharmaceutically relevant product is unmatched by any other catalyst class, including engineered biocatalysts. Our results indicate that confined chemical catalysts can be designed that are as selective as enzymes in converting small, unbiased substrates, while still providing a broad scope.

The dianthracene-based rhomboidal organoplatinum(II) metallacycle 1 was successfully obtained via coordination-driven self-assembly involving the combination of diplatinum(II) acceptor 2 and dipyri...

It has been known for many years that the peroxidase activity of cyclooxygenase 1 and 2 (COX-1 and COX-2) can be reactivated in vitro by the presence of phenol, which serves as a reducing compound, but the underlying mechanism is still poorly understood. In the present study, we use phenol as a model compound to investigate the mechanism by which the peroxidase activity of human COXs is reactivated after each catalytic cycle. Molecular docking and quantum mechanics calculations are carried out to probe the interaction of phenol with the peroxidase site of COXs and the reactivation mechanism. It is found that the oxygen atom associated with the Fe ion in the heme group (i.e., the complex of Fe ion and porphyrin) of COXs can be removed by addition of two protons. Following its removal, phenol can readily bind inside the peroxidase active sites of the COX enzymes, and directly interact with Fe in heme to facilitate electron transfer from phenol to heme. This investigation provides theoretical evidence for several intermediates formed in the COX peroxidase reactivation cycle, thereby unveiling mechanistic details that would aid in future rational design of drugs that target the peroxidase site.

A highly regio- and stereoselective hydrocyanation of 1,3-enynes was implemented by nickel/diphosphine catalysts. A wide range of highly regio- and stereoselective alkenyl nitriles were efficiently prepared. In this transformation, both the tethered alkene and the ligand play key roles in the reactivity and selectivity. The origin of regioselectivity was understood preliminarily by DFT studies.

Molecular dynamics (MD) simulations have been performed to study the dynamic behavior of noncovalent enzyme carbocation complexes involved in the cyclization of geranylgeranyl diphosphate to taxadiene catalyzed by taxadiene synthase (TXS). Taxadiene and the observed four side products originate from the deprotonation of carbocation intermediates. The MD simulations of the TXS carbocation complexes provide insights into potential deprotonation mechanisms of such carbocations. The MD results do not support a previous hypothesis that carbocation tumbling is a key factor in the deprotonation of the carbocations by pyrophosphate. Instead water bridges are identified which may allow the formation of side products via multiple proton transfer reactions. A novel reaction path for taxadiene formation is proposed on the basis of the simulations. © 2018 Wiley Periodicals, Inc.

The selective deoxygenation of polyols has emerged as an attractive approach to transform biomass-derived polyols into valuable building blocks. Herein, we present a theoretical study on the boron-catalyzed selective deoxygenation of terminal 1,2-diols. The computational results explain the different product distributions obtained with different silanes and unveil the critical role of the cyclic siloxane intermediate. Compared to noncyclic pathways, the cyclic pathway facilitates the initial deoxygenation process because the cyclic structure minimizes the steric repulsions between the reagents. It avoids overreduction because the generated bulky disiloxane moiety hinders the second deoxygenation.

An efficient one-pot cascade process via unprecedented quadruple cleavage of BrCF2COOEt with primary amines to afford valuable fluorine-containing heterocycles is described, in which BrCF2COOEt plays a dual role as a C1 synthon and a difluoroalkylating reagent for the first time. Mechanistic studies supported by DFT calculations suggest that a base plays an active role in the formation of the key intermediate isocyanides generated in situ from primary amines and difluorocarbene.

A catalytic pinacol-type reductive rearrangement reaction of internal 1,2-diols is reported herein. Several scaffolds not usually amenable to pinacol-type reactions, such as aliphatic secondary-secondary diols, undergo the transformation well without the need for prefunctionalization. The reaction uses a simple boron catalyst and two silanes and proceeds through a concerted, stereoinvertive mechanism that enables the preparation of highly enantiomerically enriched products. Computational studies have been used to rationalize the preference for migration over direct deoxygenation.

Novel ion imprinted nano-fluorescent probes (IIP–fluorescein) based on polyethyleneimine (PEI) were obtained via simple imprinting and grafting with fluorescein, and used for high recognition, detection and adsorption of Cu2+, Zn2+ and Cr3+ in aqueous solution. The selectivity of PEI is adjustable through an imprinting process for Cu2+, Zn2+or Cr3+, which have a strong affinity for the amino group. Each probe reveals specific selectivity to and recognition of the relevant template metal ion over seven other common metal ions. The three probes exhibit a large linear detection range, high accuracy and strong adsorption capacity for Cu2+, Zn2+ and Cr3+. The sensitive and selective detection, as well as the removal of Cu2+, Zn2+ and Cr3+ by using IIP–fluorescein was further demonstrated in polluted tap and river water, indicating their potential application in environmental monitoring and treatment. Additionally, the sensing mechanism of IIP–fluorescein for metal ions was investigated through Gaussian 09. The synergistic effect of photo-induced electron transfer (PET) and intramolecular charge transfer (ICT) was demonstrated in the sensing process for metal ions. The design concept might propose a method for developing and studying other fluorescent probes with similar systems (containing amino groups, mercapto groups or cyano groups).

Mechanistic studies are of great importance for the understanding, optimization, and design of chemical reactions, especially catalysis. In recent years, the combination of mass spectrometry and computational chemistry has been proven to be powerful and effective for the exploration of reaction mechanisms. The former provides information of possible reaction intermediates, which are difficult to obtain using other experimental methods, while the latter gives detailed structural information of reaction intermediates and explores reaction energy profiles. This review covers applications of the combined method and highlights its strengths in mechanistic studies. Representative works are discussed to demonstrate the complementarity and synergy of mass spectrometry and computational chemistry. Some challenges in mechanistic studies with these tools and their possible solutions, as well as the trend for future developments are also discussed.

We describe the design and development of the first catalytic asymmetric vinylogous Prins cyclization. This reaction constitutes an efficient approach for highly diastereo- and enantioselective synthesis of tetrahydrofurans (THFs) and is catalyzed by a confined chiral imidodiphosphoric acid (IDP). Aromatic and heteroaromatic aldehydes react with various 3,5-dien-1-ols to afford 2,3-disubstituted THFs in excellent selectivity (d.r. > 20:1, e.r. up to 99:1). Aliphatic aldehydes react with similarly excellent results when a highly acidic imidodiphosphorimidate (IDPi) catalyst is used. With a racemic dienyl alcohol, the reaction proceeds via a kinetic resolution. DFT calculations suggest an explanation for unusually high stereoselectivity.

This chapter introduces a detailed computational study on two Cu-catalyzed sp3-C–H cross-dehydrogenative coupling (CDC) reactions using O2 and tert-butyl hydroperoxide (TBHP) as oxidant, respectively. Plausible reaction mechanisms including the single electron transfer (SET) mechanism, a novel mechanism which O2 directly involves in C–H bond cleavage, CuIII mechanism and radical mechanism were considered. Benchmark studies were performed to select a reliable computational method to describe the SET process.

This chapter presents a mechanistic study on Pd/MPAA(mono-N-protected amino acid)-catalyzed meta- and ortho-C–H activation reactions by a combined mass spectrometry and density functional theory (MS/DFT) method. A novel model for C–H activation was established which reveals the role of MPAA in promoting reactivity by favorably forming bidentate coordination with Pd and serving as the proton acceptor in C–H activation. It opens a new avenue for ligand and template design.

A combined ion-mobility mass spectrometry (IM-MS) and DFT study has been carried out to investigate Pd/MPAA(mono-N-protected amino acid)-catalyzed direct asymmetric C–H activation reactions of several prochiral substrates. The IM-MS experiments reveal that the activation of C–H bond can be achieved in PdII(MPAA)(substrate) complex which supports that the N-protecting group acts as proton acceptor. DFT studies lead to the establishment of a chirality relay model which successfully explains the enantioselectivity for all the relevant reactions studied. The enantioselectivity originates from the rigidity of the bidentate MPAA and rigid coordination of the substrate. The effect of bulkiness of the N-protecting group on enantioselectivity is also discussed.

This chapter describes a comprehensive computational study on the template-assisted and Pd(OAc)2-catalyzed meta-selective C–H olefination reaction. The reaction mechanism, the active form of catalyst, the potential role of silver salt and the origin of meta-selectivity were investigated in this work. The computational results demonstrated that the conventionally proposed monomeric Pd(OAc)2 model predicts ortho-selectivity, instead novel dimeric Pd2(OAc)4 and Pd–Ag(OAc)3 models successfully reproduce the experimentally observed meta-selectivity.

A mild and efficient dual-mode Lewis acid induced Diels-Alder (DA)/carbocyclization cascade cyclization reaction has been developed for construction of the tricyclic core of ent-kaurenoids in one pot with the aid of a theoretical study on the π,σ-Lewis acidities of a variety of Lewis acids. With ZnBr2 as the dual-mode Lewis acid, a series of substituted enones and dienes underwent DA/carbocyclization cascade cyclization reaction smoothly at room temperature and provided the tricyclic cyclized products in one pot with good yields and high diastereoselectivity. The tricyclic cyclized product has been successfully utilized as a common intermediate for formal syntheses of (±)-platensimycin and (±)-platencin.

A detailed computational study of a copper-catalyzed aerobic cross-dehydrogenative coupling reaction has been conducted. To select a reliable method to describe the thermochemistry of a single electron transfer (SET) process, benchmark calculations have been performed. M06/6-311+g(d,p) is appropriate to evaluate the thermochemistry of the SET process for the system involving iminium species. The computational results support an SET mechanism, but also uncover an alternative mechanism in which O2 is directly involved in a hydrogen-abstracting step. A comparative study with tert-butylhydroperoxide (TBHP) as the oxidant has also been performed. The computations reveal several competitive pathways, including a radical pathway, a CuIII pathway, and an SET mechanism for the Cu/TBHP system.

A combined mass spectrometric and computational study of the Pd/mono-N-protected amino acid (MPAA)-catalyzed vinyl–vinyl coupling reactions is reported. Computational study reveals that the reaction is initiated by C–H activation of the styrene followed by the insertion of acrylate. This is supported by mass spectrometry. The MPAA ligand facilitates the cross-coupling reaction between monosubstituted alkenes by stabilizing the active palladium catalyst and offering the N-protecting group as a stronger base than acetate. The E/Z selectivity is attributed to the stronger d−π interaction between the catalyst and the substrate in the transition state leading to E product.

Understanding the mechanisms of chemical reactions, especially catalysis, has been an important and active area of computational organic chemistry, and close collaborations between experimentalists and theorists represent a growing trend. This Perspective provides examples of such productive collaborations. The understanding of various reaction mechanisms and the insight gained from these studies are emphasized. The applications of various experimental techniques in elucidation of reaction details as well as the development of various computational techniques to meet the demand of emerging synthetic methods, e.g., C–H activation, organocatalysis, and single electron transfer, are presented along with some conventional developments of mechanistic aspects. Examples of applications are selected to demonstrate the advantages and limitations of these techniques. Some challenges in the mechanistic studies and predictions of reactions are also analyzed.

A combined ion-mobility mass spectrometry (IM-MS) and DFT study has been employed to investigate the mechanism and the origin of selectivity of palladium/mono-N-protected amino acid (MPAA)-catalyzed enantioselective CH activation reactions of several prochiral substrates. We captured the [Pd(MPAA)(substrate)] complex at different stages, and demonstrated that the CH bond can be activated in the absence of an external base. DFT studies lead to the establishment of a significantly modified relay mechanism invoking a key conformational effect to account for the origin of enantioselectivity. This relay mechanism successfully accounts for the enantioselectivity for all the relevant reactions reported. The enantioselectivity originates from the rigid square-planar Pd coordination in the CH activation transition state: Bidentate MPAA and substrate coordination.

The cyano group at the prochiral center plays a key role for the high enantioselectivity of the copper-catalyzed intramolecular N-arylation reactions to give tetrahydroquinoline and tetrahydrobenzoazepine derivatives.

Understanding the mechanisms of chemical reactions, especially catalysis, has been an important and active area of computational organic chemistry, and close collaborations between experimentalists and theorists represent a growing trend. This Perspective provides examples of such productive collaborations. The understanding of various reaction mechanisms and the insight gained from these studies are emphasized. The applications of various experimental techniques in elucidation of reaction details as well as the development of various computational techniques to meet the demand of emerging synthetic methods, e.g., C–H activation, organocatalysis, and single electron transfer, are presented along with some conventional developments of mechanistic aspects. Examples of applications are selected to demonstrate the advantages and limitations of these techniques. Some challenges in the mechanistic studies and predictions of reactions are also analyzed.

The enantioselective construction of all-carbon quaternary stereocenters is one of the most challenging fields in asymmetric synthesis. An asymmetric desymmetrization strategy offers an indirect and efficient method for the formation of all-carbon stereocenters. An enantioselective formation of cyano-bearing all-carbon quaternary stereocen- ters in 1,2,3,4,-tetrahydroquinolines and 2,3,4,5-tetrahydro-1H- benzo(b)azepines by copper-catalyzed desymmetric N-aryla- tion is demonstrated. The cyano group at the prochiral center plays a key role for the high enantioselectivity and works as an important functional group for further transformations. DFT studies provide a model which successfully accounts for the origin of enantioselectivity. All-carbon quaternary stereocenters are prevalent motifs in a variety of bioactive natural products, pharmaceuticals, and chiral ligands. The enantioselective construction of all-carbon quaternary stereocenters is of great interest to organic chemists because of the features of such structures and the innate synthetic challenge they imply for stereocontrol. (1, 2)

A combined experimental/computational study on the amino acid ligand-assisted Pd-catalyzed C–H bond activation reveals a mechanism in which the amino acid acts as both a dianionic bidentate ligand and a proton acceptor. This new model explains the effects of amino acids on reactivity and selectivity and unveils the dual roles of amino acids: stabilizing monomeric Pd complexes and serving as the internal base for proton abstraction.

Density functional theory investigations have elucidated the mechanism and origins of meta-regioselectivity of Pd(II)-catalyzed C-H olefinations of toluene derivatives that employ a nitrile-containing template. The reaction proceeds through four major steps: C-H activation, alkene insertion, β-hydride elimination, and reductive elimination. The C-H activation step, which proceeds via a concerted metalation-deprotonation (CMD) pathway, is found to be the rate- and regioselectivity-determining step. For the crucial C-H activation, four possible active catalytic species-monomeric Pd(OAc)2, dimeric Pd2(OAc)4, heterodimeric PdAg(OAc)3, and trimeric Pd3(OAc)6-have been investigated. The computations indicated that the C-H activation with the nitrile-containing template occurs via a Pd-Ag heterodimeric transition state. The nitrile directing group coordinates with Ag while the Pd is placed adjacent to the meta-C-H bond in the transition state, leading to the observed high meta-selectivity. The Pd2(OAc)4 dimeric mechanism also leads to the meta-C-H activation product but with higher activation energies than the Pd-Ag heterodimeric mechanism. The Pd monomeric and trimeric mechanisms require much higher activation free energies and are predicted to give ortho products. Structural and distortion energy analysis of the transition states revealed significant effects of distortions of the template on mechanism and regioselectivity, which provided hints for further developments of new templates.

A detailed computational study of a copper-catalyzed aerobic cross-dehydrogenative coupling reaction has been conducted. To select a reliable method to describe the thermochemistry of a single electron transfer (SET) process, benchmark calculations have been performed. M06/6-311+g(d,p) is appropriate to evaluate the thermochemistry of the SET process for the system involving iminium species. The computational results support an SET mechanism, but also uncover an alternative mechanism in which O