Intermolecular Cross Research Articles

Enantioselective Synthesis, Crystal Structures, and Stereoisomerism of Substituted o,m,o,p-Tetraphenylenes.

We have achieved the enantioselective synthesis of highly strained, substituted o,m,o,p-tetraphenylenes (≤98% ee) via the cationic Rh(I)/(R)-H8-BINAP complex-catalyzed chemo-, regio-, and enantioselective intermolecular cross-[2+2+2] cycloaddition of teraryl diynes with dimethyl acetylenedicarboxylate. X-ray crystallographic analyses demonstrate the highly bent structures of the para-substituted benzene moieties, and density functional theory calculations reveal the large local strain of the paraphenylene unit. 1H nuclear magnetic resonance analyses and theoretical calculations elucidate the stereoisomerism, indicating that the nonrotatable ortho-disubstituted biphenyl structure results in cis and trans isomers.

Insights into dynamic properties of water in lipidic cubic phases by 2D nuclear Overhauser effect (NOE) NMR spectroscopy

Two-dimensional NOE (nuclear Overhauser effect) NMR spectroscopy was employed to investigate the dynamic properties of water within lyotropic bicontinuous lipidic cubic phases (LCPs) formed by monoolein (MO). Experiments observed categorically different effective residence times of water molecules: (i) in proximity to the glycerol moiety of MO, and (ii) adjacent to the hydrophobic chain towards the hydrocarbon tail of MO, as evidenced by the opposite signs of intermolecular NOE cross peaks between protons of water and those of MO in 2D 1H–1H NOESY spectra. Spectroscopic data delineating the different effective residence times of water molecules within both the gyroid (QIIG) and diamond (QIID) phase groups corresponding to hydration levels of 35 and 40 wt%, respectively, are presented. Additionally, an increase in effective residence time of water molecules in proximity to the glycerol moiety of MO in LCPs was observed upon storage at ambient temperature and in the presence of an additive lipid, cholesterol. Atom-specific NOE build-up curves for protons of water and those of MO are also given. The results presented herein provide new insight into the physicochemical properties and behaviour of water in LCPs, and demonstrate an additional avenue for experimental study of water–lipid interactions and hydration dynamics in model membranes and nanomaterials using 2D NOE NMR spectroscopy.

Biophysical and nuclear magnetic resonance spectroscopic studies of the binding of baicalein to DNA sequence d(CACGTG)2 and its cytotoxicity evaluation

This paper reports the interaction of baicalein with a hexamer nucleic acid sequence d(CACGTG)2, present in the promoter region of various transcription factors, using biophysical techniques and nuclear magnetic resonance spectroscopy. UV–Visible absorption and fluorescence titration data implied partial intercalative binding of baicalein with a binding constant of 105 M−1. Continuous variation analysis using fluorescence data revealed a 1:1 stoichiometry of the baicalein and DNA in the solution. Circular dichroism data displayed a structural change of DNA upon baicalein binding. Thermal denaturing studied using circular dichroism showed that the melting temperature of the system does not significantly vary with the addition of baicalein. The spectral features suggest a partial intercalation of baicalein. Differential scanning calorimetric data exhibited two two-state transitions for alone DNA and its 1:1 complex with subtle changes in the melting temperatures supporting the non-intercalative binding of baicalein. Nuclear magnetic resonance data showed baicalein binding to the region near the C3pG4 base step, evidenced by the intermolecular nuclear overhauser effect cross peaks. Distance restrained molecular dynamics was employed to obtain the lowest energy structure. Biological evaluation of the effect of baicalein displayed excellent apoptotic effect on different cancer cell lines. IC50 values of 72.55, 79.9 and 96.7 µM were obtained in MCF-7, DU-145 and HCT-15 cell lines. The results uphold its chemotherapeutic potential.

Chemical reactions in poly(acrylonitrile-co-itaconic acid) during stabilization as revealed by solid-state NMR spectroscopy and 13C isotope labeling

Understanding and controlling chemical reactions of atactic-Poly(acrylonitrile) (PAN) and its copolymer during thermal heat-treatment under air are critical subjects to produce PAN-based carbon-fibers. Copolymerization of PAN with itaconic acid (IA) monomers effectively lowers initial chemical reaction temperature and thus promote chemical reactions during stabilization. In this work, detailed chemical structure of PAN and poly(acrylonitrile-co-itaconic acid) (PAI) stabilized under air atmosphere were studied by combined use of solid-state (ss) NMR spectroscopy and 13C isotope labeling. By applying 13C–13C INADEQUATE and fully relaxed 13C DPMAS NMR spectra, it was elucidated that 2% cyclized structure can be initially formed in PAI during stabilization. Moreover, five elemental reactions including cyclization, aromatization, oxidization, dehydrogenation, and intermolecular cross-linking were identified and corresponding structures were quantitatively analyzed in both PAN and PAI as a function of stabilization temperature. It was revealed that all the reactions concertedly occur in PAN in the narrow temperature range (290–340 °C). For PAI, it was demonstrated that cyclization and aromatization are dominant in the low temperature range (180–270 °C, regime I), dehydrogenation and intermolecular cross linking are promoted in the high temperature range (270–340 °C, regime II), and oxidization occurs across two regimes. The sensitivity enhanced ssNMR study not only provides fundamental understanding of the chemical reactions in PAN and PAI during stabilization but also guide ones to potentially control the stabilized structures from one dimensional structure to two dimensional one for PAI by choosing a proper temperature and time.

Recent Developments in Intermolecular Cross-Rauhut-Currier Reactions.

Intermolecular cross Rauhut-Currier reactions have gained much importance in recent years. It has proved its importance through procedures involving various catalysts and resulting in complex structures with good regio- as well as stereo- selectivity. This review highlights the recent developments of these reactions, published in current years, involving both achiral and chiral catalysts to give products, having various utilities. In addition, the detailed mechanistic studies of the above-mentioned reactions are also presented.

Molybdenum-Catalyzed Intermolecular Deoxygenative Cross-Coupling Reactions of 1,2-Diketones with α-Ketoamides

Here we describe the Mo-catalyzed intermolecular deoxygenative cross coupling of the bench stable and readily accessible1,2-diketones with α-ketoamides, in which three of the four carbonyl oxygen atoms were eliminated along with the formations of a carbon–nitrogen bond and a carbon–carbon double bond in one step under Mo-catalysis. Various pyrrol-2-ones were secured in up to 96% yield by utilizing a commercial Mo-catalyst. The synthetic potential of the current methodology is additionally demonstrated by synthetic transformations, a gram-scale synthesis, and derivatization of several natural products and drug molecules. The preliminary mechanistic investigation suggest this cascade process might be initiated via the formal intermolecular N–H insertion and followed by the intramolecular carbonyl–carbonyl olefination reaction, in which both steps were catalyzed by a single Mo-catalyst.

Silver-Catalyzed Intermolecular Cross- and Homo-Coupling Reactions of Silyl Enol Ethers

Silver-Catalyzed Intermolecular Cross- and Homo-Coupling Reactions of Silyl Enol Ethers

Design, Synthesis and Application of Multifunctional Chiral Aminophosphine Catalyst for Asymmetric Intermolecular Cross Rauhut‐Currier Reaction

Comprehensive SummaryA series of structurally novel multifunctional chiral aminophosphine catalysts were developed through a concise synthetic strategy from easily available starting materials. The highly enantioselective intermolecular cross Rauhut‐Currier reactions of vinyl ketones with 3‐acyl acrylates and 2‐ene‐1,4‐diones catalyzed by (S,S)‐5a were well realized, generating a wide range of the structurally important chiral multicarbonyl products in good to excellent yields with high stereocontrol (up to 97% yield, 99% ee). In addition, a series of 31P NMR experiments were carried out to further investigate the catalytic process.

Photo-induced catalytic C−H heteroarylation of group 8 metallocenes

Possessing a characteristic sandwich-type structure, metallocenes have been widely used by the chemistry community. However, the direct catalytic C−H heteroarylation of metallocenes still remains underexplored. Here, we report an efficient catalytic protocol for C−H heteroarylation of group 8 metallocenes (M = Fe, Ru) under light irradiation. This intermolecular cross coupling features directing group free, mild conditions and a wide substrate scope. Preliminary mechanistic studies suggest that the newly formed C−C bond is constructed through electrophilic radical substitution of the metallocene with a heteroaryl radical, which is generated via an oxidative quenching pathway.

The spike-ACE2 interaction underlying SARS-CoV-2 infection and inhibition is enhanced by intermolecular cross linking

The interaction between the SARS-CoV-2 spike trimer with the host dimeric angiotensin-converting enzyme 2 (ACE2) receptor is the first step in virus entry. Consequently, efforts aimed at therapeutic intervention have focused on blocking spike-ACE2 binding by designing ACE2-based decoys. The multivalency of ACE2 and spike is fundamental to our understanding of the molecular mechanism underlying ACE2-spike affinity, manifested by the observation of much tighter binding of dimeric ACE2 to spike compared with monomeric ACE2.

A NMR study of binding the metabolite of SN38 derivatives to a model nicked DNA decamer mimicking target of Topo I inhibitors

In this account we present NMR based results of the interaction of 7-ethyl-9-hydroxymethyl-10-hydroxycamptothecin (1), a derivative of SN38, with a model nicked DNA decamer mimicking the wild type DNA target of Topoisomerase I inhibitors from the camptothecin family. The title compound 1 can be considered a main metabolite of phase I in the metabolic pathway of camptothecin derivatives bearing the alkylamino substituent. Therefore, its pharmacodynamic properties are of interest. It was established by DOSY (Diffusion Ordered Spectroscopy) that compound 1 forms a fairly stable molecular complex with a model nicked DNA decamer with affinity constant Ka 3.02 mM−1. The analysis of NOESY experiments revealed intermolecular cross peaks and mutual induced shifts on both interacting components allowing the conclusion that guest molecule 1 is stacking the nitrogen bases inside the nick. MD (Molecular Dynamics) analysis of four possible inclusions of 1 inside the nick allows establishing the detailed geometry of a complex. Two conformations are suggested as the ones best representing the results of molecular modeling reconciled with experimental NOESY results. The aromatic core of both structures is stacking the nitrogen bases in a nick facing the unbroken strand with ring A. The protons in ring E interact with ribose protons of edge bases of a nick. In conclusion, it can be asserted that SN38 derivative 1 can effectively bind the molecular target of Topo I enzyme and play a role as a Topo I inhibitor.

Influence of hydrophobic interfaces and shear on ovalbumin amyloid-like fibril formation in oil-in-water emulsions

Animal proteins are widely used because of their good techno-functional (e.g. emulsification) properties. However, the large ecological impact of animal-derived proteins is often debated and therefore alternatives are evaluated in which animal proteins with increased functionality are employed. Amyloid fibrils are a distinct type of protein fibrils characterized by an intermolecular cross β-sheet structure, mostly studied because of concerns regarding their role in certain human diseases. However, they have also been detected in processed food proteins such as heated ovalbumin (OVA) and other egg proteins. Previous work also mentioned superior emulsification properties of amyloid-like fibrils. Here, the effect of different shear conditions during the emulsification of oil in water emulsions stabilized by heated OVA was investigated. Emulsification with intensive shear treatment (using both an ultra-turrax and a microfluidizer) resulted in submicron sized droplets, whilst ultra-turrax only gave rise to rapidly creaming emulsions (>10 μm). Thioflavin T (ThT) fluorescence, used as an indicator of cross β-sheets, did significantly increase for submicron emulsions, whereas supermicron emulsions showed a similar fluorescence as the aqueous phase used for emulsification. The increase in ThT fluorescence in submicron emulsions was in line with a higher amount of larger fibrillar structures, which showed high ThT fluorescence, measured using size exclusion-HPLC and transmission electron microscopy images. Similar observations were also made for unheated OVA, suggesting that high-shear emulsification induced amyloid-like fibril formation. In contrast, shearing of aqueous solutions without the creation of interfaces did not show increased fibril formation. Therefore, it is claimed that the large specific surface area induced amyloid-like fibril formation or maturation as a result of a better interaction between hydrophobic amyloid-like fibril fragments. In this work, we were able to characterize the protein fibrillar structures present in emulsions by considering commonly used techniques for the study of fibril formation. This creates opportunities towards the implementation of these protein mixtures in food applications.

Phosphine Catalyzed Enantioselective Cascade Reaction Initiated by Intermolecular Cross Rauhut‐Currier Reaction of Electron‐Deficientortho‐Formyl Styrenes

AbstractThe Rauhut‐Currier reaction generally employs α,β‐unsaturated carbonyl compounds and nitroalkenes as the substrates. Here we develop an enantioselective formal [4+2] annulation reaction, which is initiated by an intermolecular cross Rauhut‐Currier reaction between electron‐deficientortho‐formyl‐styrenes and 2‐benzoyl‐acrylonitriles catalyzed by anL‐phenylglycine‐derived phosphine, followed by a cascade aldol/acyl transfer/elimination process. A series of enantioenriched dialin frameworks with an unusualexo‐double bond are furnished in fair to good yields with moderate to excellent enantioselectivity, and the architectures with higher molecular complexity can be constructed via simple transformations.

Peptides from diatoms and grasses harness phosphate ion binding to silica to help regulate biomaterial structure

Many life forms generate intricate submicron biosilica structures with various important biological functions. The formation of such structures, from the silicic acid in the waters and in the soil, is thought to be regulated by unique proteins with high repeats of specific amino acids and unusual sidechain modifications.Some silicifying proteins are characterized by high prevalence of basic amino acids in their primary structures. Lysine-rich domains are found, for instance, in diatom silaffin proteins and in the sorghum grass siliplant1 protein. These domains exhibit catalytic activity in silica chain condensation, owing to molecular interactions of the lysine amine groups with the forming mineral. The use of amine chemistry by two very remote organisms has motivated us to seek other molecular biosilicification processes that may be common to the two life forms.In diatom silaffins, domains rich in phosphoserine residues are thought to assist the assembly of silaffin molecules into an organic supra-structure which serves as a template for the silica to precipitate on. This mold, held by salt bridges between serine phosphates and lysine amines, dictates the shape of the silica particles formed. Yet, silica synthesized with the dephosphorylated silaffin in phosphate buffer showed similar morphology to the one prepared with the native protein, suggesting that a defined spatial arrangement of serine phosphates is not required to generate silica with the desired shape. Concurrently, free phosphates enhanced the activity of siliplant1 in silica formation.It is therefore beneficial to characterize the involvement of these anions as co-factors in regulated silicification by functional peptides from the two proteins and to understand whether they play similar molecular role in the mechanism of mineralization.Here we analyze the molecular interactions of free phosphate ions with silica and the silaffin peptide PL12 and separately with silica and siliplant1 peptide SLP1 in the two biomimetic silica products generated by the two peptides. MAS NMR measurements show that the phosphate ions interact with the peptides and at the same time may be forming bonds with the silica mineral. This bridging capability may add another avenue by which the structure of the silica material is influenced. A model for the molecular/ionic interactions at the bio-inorganic interface is described, which may have bearings for the role of phosphorylated residues beyond the function as intermolecular cross linkers or free phosphate ions as co-factors in regulation of silicification. Statement of SignificanceThe manuscript addresses the question how proteins in diatoms and plants regulate the biosilica materials that are produced for various purposes in organisms. It uses preparation of silica in vitro with functional peptide derivatives from a sorghum grass protein and from a diatom silaffin protein separately to show that phosphate ions are important for the control that is achieved by these proteins on the final shape of the silica material produced. It portrays via magnetic resonance spectroscopic measurements, in atomic detail, the interface between atoms in the peptide, atoms on the surface of the silica formed and the phosphate ions that form chemical bonds with atoms on the silica as part of the mechanism of action of these peptides.

Catalytic Enantiodivergent Michael Addition by Subtle Adjustment of Achiral Amino Moiety of Dipeptide Phosphines.

SummaryOver the past decades, asymmetric catalysis has been intensely investigated as a powerful tool for the preparation of numerous chiral biologically active compounds. However, developing general and practical strategies for preparation of both enantiomers of a chiral molecule via asymmetric catalysis is still a challenge, particularly when the two enantiomers of a chiral catalyst are not easily prepared from natural chiral sources. Inspired by the biologic system, we report herein an unprecedented catalytic enantiodivergent Michael addition of pyridazinones to enones by subtle adjustment of achiral amino moiety of dipeptide phosphine catalysts. These two dipeptide phosphine catalysts, P5 and P8, could deliver both enantiomers of a series of N2-alkylpyridazinones in good yields (up to 99%) with high enantioselectivities (up to 99% ee) via the catalyst-controlled enantiodivergent addition of pyridazinones to enones.

Double Thiol-Chiral Brønsted Base Catalysis: Asymmetric Cross Rauhut-Currier Reaction and Sequential [4 + 2] Annulation for Assembly of Different Activated Olefins.

A double catalytic system combining 2-mercaptobenzoic acid and a chiral phase transfer substance was disclosed for the intermolecular cross Rauhut-Currier reaction of 2-cyclopentenone and isatin-based alkylidene malononitriles. The resulting chiral adducts were sequentially assembled with diverse electron-deficient olefins to furnish highly enantioenriched cyclohexane derivatives (up to 96:4 er, >19:1 dr). A similar catalytic system of 2-mercaptobenzoic acid and quinine was further developed for the reaction of 2-cyclopentenone and α-cyano chalcones (up to 96.5:3.5 er).

Visible-Light Photoredox Enables Ketone Carbonyl Alkylation for Easy Access to Tertiary Alcohols

Being a handle for synthesizing quaternary carbon centers and olefins, together with ubiquitous appearance in organic building blocks, makes tertiary alcohols valuable targets in synthesis. However, traditional syntheses of these alcohols have faced several challenges including the employment of functionalized reactive reagents, undesirable side reactions, and decomposition of the alcohol products under harsh conditions. The paucity of a synthetic approach to bulky tertiary alcohols prompts our interest to develop a benign catalytic protocol to tackle the current issues. Here, we have successfully demonstrated the use of ketyl radicals in intermolecular cross radical–radical coupling, which has opened a different door for accessing complex tertiary alcohols. On the other hand, by starting from feedstock and naturally derived chemicals without any pre-activation, it would be superior to traditional methodologies in the industrial context.

Regio- and Diastereoselective Iron-Catalyzed [4+4]-Cycloaddition of 1,3-Dienes.

A family of single-component iron precatalysts for the [4+4]-cyclodimerization and intermolecular cross-[4+4]-cycloaddition of monosubstituted 1,3-dienes is described. Cyclooctadiene products were obtained with high regioselectivity, and catalyst-controlled access to either cis- or trans-diastereomers was achieved using 4-substituted diene substrates. Reactions conducted either with single-component precatalysts or with iron dihalide complexes activated in situ proved compatible with common organic functional groups and were applied on multigram scale (up to >100 g). Catalytically relevant, S = 1 iron complexes bearing 2-(imino)pyridine ligands, (RPI)FeL2 (RPI = [2-(2,6-R2-C6H3-N═CMe)-C5H4N] where R = iPr or Me, L2 = bis-olefin), were characterized by single-crystal X-ray diffraction, Mößbauer spectroscopy, magnetic measurements, and DFT calculations. The structural and spectroscopic parameters are consistent with an electronic structure description comprised of a high spin iron(I) center ( SFe = 3/2) engaged in antiferromagnetically coupling with a ligand radical anion ( SPI = -1/2). Mechanistic studies conducted with these single-component precatalysts, including kinetic analyses, 12C/13C isotope effect measurements, and in situ Mößbauer spectroscopy, support a mechanism involving oxidative cyclization of two dienes that determines regio- and diastereoselectivity. Topographic steric maps derived from crystallographic data provided insights into the basis for the catalyst control through stereoselective oxidative cyclization and subsequent, stereospecific allyl-isomerization and C-C bond-forming reductive elimination.

Cover Picture: Collective Synthesis of Schilancidilactones A, B and Schilancitrilactones A, B, C, 20‐epi‐Schilancitrilactone A (Chin. J. Chem. 3/2019)

The cover picture shows Schilancidilactones A, B and Schilancitrilactones A, B, C all belong to schinortriterpenoid. Preliminary bioassay shows some of them possess fascinating bioactivities, such as antitumor, antihepatitis, and anti‐HIV‐1 activities. The total synthesis of Schilancidilactones A, B and Schilancitrilactones A, B, C has been accomplished from the common intermediates for the first time by Tang group. An intramolecular radical cyclization, late‐stage halogenation and AIBN‐mediated or Ni‐catalyzed intermolecular radical cross coupling reaction were employed as the key steps. More details are discussed in the article by Tang et al. on page 255–268. image

Collective Synthesis of Schilancidilactones A, B and Schilancitrilactones A, B, C, 20‐epi‐Schilancitrilactone A

Summary of main observation and conclusionSchisandraceae triterpenoids are novel natural products that contain highly fused ring systems bearing multiple chiral centers surrounding. Some of them exhibit promising bioactivities, such as antitumor, anti‐HIV, etc. In this article, we describe our efforts to the collective total synthesis of schilancidilactones A, B, schilancitrilactones A, B, C, and 20‐epi‐schilancitrilactone A from common precursors. An intramolecular radical cyclization, late‐stage halogenation and AIBN‐mediated or Ni‐catalyzed intermolecular radical cross coupling reaction were employed as the key steps.