Methoxycarbonylation versus Hydroacylation of Ethene; Dramatic Influence of the Ligand in Cationic Palladium Catalysis

The palladium‐catalysed carbonylation of ethene in methanol shows acute sensitivity towards the diphosphine ligand used. Systems based on 1,3‐bis(di‐t‐butylphosphino)propane afford catalysts for fast, selective methoxycarbonylation to methyl propionate; the corresponding catalyst based on 1,2‐bis(di‐t‐butylphosphino)ethane hydroacylates ethene to diethyl ketone at high rates. The use of less sterically demanding ligands, hydrogen and auxiliary acid are explored and mechanistic implications discussed.     

Development of a Metabolically Stable Neurotensin Receptor 2 (NTS2) Ligand

Subtype‐selective neurotensin receptor 2 (NTS2) ligands can be used as molecular probes to investigate the physiological role of neurotensinergic systems and serve as lead compounds to initiate the development of drugs for the treatment of tonic pain. Starting from our recently described NTS2 ligand 1 , structural variants of type 2 were synthesized to further improve binding affinity and selectivity to gain metabolic stability. The peptide–peptoid hybrid 2 b showed excellent NTS2 binding affinity (K_i=2.8 nM ) and 22 000‐fold selectivity over NTS1, as well as metabolic stability over 32 h in a serum degradation assay. Employing a MAPK‐driven luciferase reporter gene assay and an IP accumulation assay, the neurotensin mimetic 2 b displayed respective inhibitions of constitutive activity exceeding 4.3‐ and 3.9‐fold that of the inverse agonist activity of the endogenous ligand neurotensin.     

Selectivity of Competitive Multivalent Interactions at Interfaces

The development of synthetic, low‐molecular‐weight ligand receptor systems for the selective control of biomolecular interactions remains a major challenge. Binding of oligohistidine peptides to chelators containing Ni²⁺‐loaded nitrilotriacetic acid (NTA) moieties is one of the most widely used and best‐characterised recognition systems. Recognition units containing multiple NTA moieties (multivalent chelator headgroups, MCHs) recognise oligohistidines with substantially increased binding affinities. Different multivalencies both at the level of the MCH and at that of the oligohistidine ligand provide a powerful means to vary the affinity of the interaction systematically. Here we have explored the selectivity for the binding of different oligohistidines to immobilised MCH. Using microarrays of mono‐, bis‐, tris‐ and tetrakis‐NTA chelators spotted at different surface densities, we explored the ability of these binders to discriminate fluorescently labelled hexa‐ and decahistidine peptides. When hexa‐ and decahistidine were tested alone, the discrimination of ligands showed little dependence either on the nature or on the density of the chelator. In contrast, coincubation of both peptides decreased the affinity of hexahistidine, increased the affinity of decahistidine, and made the binding of decahistidine highly dependent on MCH density. Kinetic binding assays by dual‐colour total internal reflection fluorescence spectroscopy revealed active exchange of His₆ by His₁₀ and confirmed the high selectivity towards His₁₀. Our results establish the key role of surface multivalency for the selectivity of multivalent interactions at interfaces.     

Rhodium‐Catalyzed Enantioselective Intramolecular [4+2] Cycloaddition using a Chiral Phosphine‐Phosphite Ligand: Importance of Microwave‐Assisted Catalyst Conditioning

The use of modular α,α,α′,α′‐tetraaryl‐1,3‐dioxolane‐4,5‐dimethanol (TADDOL)‐ and 1,1′‐bi‐2‐naphthol (BINOL)‐derived phosphine‐phosphite ligands (L₂*) in the asymmetric rhodium‐catalyzed intramolecular [4+2] cycloaddition (“neutral” Diels–Alder reaction) of (E,E)‐1,6,8‐decatriene derivatives (including a 4‐oxa and a 4‐aza analogue) was investigated. Initial screening of a small ligand library led to the identification of a most promising, TADDOL‐derived ligand bearing a phenyl group adjacent to the phosphite moiety at the arene backbone. In the course of further optimization studies, the formation of a new, more selective catalyst species during the reaction time was observed. By irradiating the pre‐catalyst with microwaves prior to substrate addition high enantioselectivities (up to 93% ee) were achieved. The new cyclization protocol was successfully applied to all three substrates investigated to give the bicyclic products in good yield and selectivity. ³¹P NMR and ESI‐MS measurements indicated the formation of a [Rh(L₂*)₂]⁺ species as the more selective (pre‐) catalyst.     

Surface layer modification of AEMs by infiltration and photo‐cross‐linking to induce monovalent selectivity

Surface modification of anion exchange membranes (AEMs) by attaching a negatively charged layer is the main method for preparing monovalent anion selective membranes. However, tremendous increase of membrane resistance and poor long‐term stability of the modified membranes face great challenges. In this work, a photosensitive molecule (4,4‐diazostilbene‐2,2‐disulfonic acid disodium salt [DAS]) was infiltrated into the membrane surface and immobilized in the structure by cross‐linking under UV irradiation. This method introduced negative charge to the surface layer of the AEMs without increasing membrane thickness, leading to high performance membrane with high monovalent anion selectivity. The optimized membrane (D‐5) shows the highest perm‐selectivity of 11.21, which is superior to the commercial selective membrane Selemion^® ASV and previously reported monovalent anion selective AEMs. Furthermore, the newly developed membrane exhibits excellent long‐term stability, which can maintain constant selectivity during the 80 h ED experiment. © 2017 American Institute of Chemical Engineers AIChE J, 64: 993–1000, 2018     

Fabrication of ordered microporous styrene‐acrylonitrile copolymer blend imprinted membranes for selective adsorption of phenol from salicylic acid using breath figure method

Highly selective, ordered microporous molecularly imprinted membranes (MIMs) for phenol were synthesized by breath figure (BF) method using styrene‐acrylonitrile copolymer (SAN) as the membrane matrix and molecularly imprinted polymer nanoparticles (nano‐MIPs) as the imprinted nanoparticles. The nano‐MIPs were synthesized by oil‐in‐water emulsion polymerization using 4‐vinyl pyridine (4‐VP), methyl methacrylate (MMA) or cinnamic acid (CA) as the functional monomer, respectively. The prepared nano‐MIPs were characterized by transmission electron microscope (TEM) and Raman, whereas MIMs were characterized by SEM, membrane flux, and selective adsorption experiments. Morphological analysis exhibited that the addition of nano‐MIPs improved the formation of ordered and well‐defined porous membrane morphology. Compared with MMA‐MIM and CA‐MIM, the 4‐VP‐MIM exhibited higher membrane flux, adsorption capacity, and stronger selective binding for phenol as well as excellent permeation selectivity for phenol. Moreover, the selective effect of 4‐VP‐MIM on phenol was strongly affected by the amount of 4‐VP imprinted nanoparticles (nano‐4‐VP‐MIPs). The experimental data revealed that the 4‐VP‐MIM containing 2.0 wt % of nano‐4‐VP‐MIPs exhibited the highest separation selectivity for the template phenol, whose selectivity coefficients for phenol relative to salicylic acid (SA) and p‐hydroxybenzoic acid (p‐HB) were 5.6770 and 5.5433, respectively, which was close to the predicted selectivity coefficient value. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015 , 132, 42350.     

Bio‐inspired synthesis of molecularly imprinted nanocomposite membrane for selective recognition and separation of artemisinin

Inspired from the highly bioadhesive performance of mussel protein, a simple, yet efficient synthetic method for efficiently imprinting of Artemisinin (Ars) was developed to prepare the bio‐inspired molecularly imprinted membranes (MIMs) via atom transfer radical polymerization (ATRP). In this work, attributed to the unique properties of polydopamine (pDA) modified layers and ATRP technology, the uniform recognition sites for efficiently selective extraction of the Ars with high stability could be obtained on the MIMs surfaces. In addition, the maximum adsorption capacity of the MIMs is 158.85 mg g^?1 by the Langmuir isotherm model, which is remarkable higher than NIMs. Additionally, because of the formation of the uniform specific recognition cavities on membrane surfaces, the as‐prepared MIMs exhibited a rapid adsorption dynamics and well‐fitted for the pseudo‐second‐order rate equation, also, possessed an excellent per‐selectivity performance (β_{artemether/Ars} values is 0.18) of template molecule, which clearly demonstrated the potential value of this method in the selective separation and purification of Ars. © 2016 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2016 , 133, 43405.     

Pushing Boundaries—Selective Cooling Crystallization as Tool for Selectivity Compensation and Product Purification Using a Recyclable Pd/Xantphos Catalyst in the Methoxycarbonylation of Methyl 10-Undecenoate

The homogeneously catalyzed methoxycarbonylation of methyl 10-undecenoate allows for the synthesis of dimethyl 1,12-dodecandioate as an interesting bio-based drop-in alternative for 1,12-dodecandioic acid as polymer building block. Although the benchmark catalyst system of Pd/1,2-bis((di-tert-butylphosphino)methyl)benzene and methane sulfonic acid is very active and selective, long-term stability over a potential catalyst recycling is limited. In this work, modifications of this catalyst system in terms of protonation of the ligand and its replenishment during recycling are first investigated, proving that the reaction system is tolerant against minor changes. Finally, the commercially available ligand Xantphos, featuring higher stability but comes with a rather low l:b selectivity of 70:30, is applied. However, through the application of cooling crystallization, 58 g product (52% isolated yield) with an overall purity of 94% is obtained from the crude reaction solution without further treatment and a ∑TON of 4000 after ten reaction runs, while catalyst loss into the product is low. Practical Applications: Selective syntheses on the basis of renewable resources are a powerful tool for the production of value products in terms of green chemistry. Thereby, homogeneous transition metal catalysts are beneficial regarding selectivity. However, their separation and recycling are challenging due to their limited stability. The combination of a stable, commercially available catalyst with a selective purification method allows for isolation and purification from a crude reaction mixture without the need for any auxiliary or further purification steps. In this work, cooling crystallization is applied for subsequent purification of the linear diester dimethyl 1,12-dodecandioate. Thereby, a lower selectivity from the methoxycarbonylation reaction using the stable Xantphos ligand is compensated and combined with recycling of the homogeneous catalyst. Thus, the development of an integrated process covering a stable catalyst system in the reaction, and high selectivity in the purification is the key toward an efficient homogeneous catalyst recycling.     

Separation of water–isopropyl alcohol mixtures with novel hybrid composite membranes

New‐fangled hybrid composite membranes were prepared by the incorporation of 5, 10, and 15 mass % NaY–zeolite particles into blend membranes of carboxymethyl cellulose (CMC)‐g‐acrylamide/sodium alginate (NaAlg) and crosslinked with glutaraldehyde. The pervaporation (PV) separation performance of the hybrid composite membranes was explored for the dehydration of isopropyl alcohol from their aqueous solutions at 30°C. The effect of NaY–zeolite in these blend membranes was investigated in PV dehydration. From the experimental results, we found that NaY particles could be intercalated in the aqueous polymer solution. The obtained results show that both the flux and selectivity increased simultaneously with increasing zeolite content in the membrane. This was explained on the basis of an enhancement of the hydrophilicity, selective adsorption, and molecular sieving action by the creation of pores in the membrane matrix. The membranes were characterized by differential scanning calorimetry, scanning electron microscopy, and Fourier transform infrared spectroscopy. © 2012 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2012     

Impact of the Proline Residue on Ligand Binding of Neurotensin Receptor 2 (NTS2)‐Selective Peptide–Peptoid Hybrids

To investigate the binding mode and structure–activity relationships (SARs) of selective neurotensin receptor 2 (NTS2) ligands, novel peptide–peptoid hybrids that simulate the function of the endogenous ligand were developed. Starting from our recently described NTS2 ligands of type 1 , structural variants of type 2 and the metabolically stable analogues 3 a , b were developed. Replacement of the proline unit by a collection of structural surrogates and evaluation of the respective molecular probes for NTS2 affinity and selectivity indicated similar SARs as described for NT(8–13) derivatives bound to the subtype NTS1. Peptide–peptoid hybrids 2 d , 3 a , b showed substantial NTS2 binding affinity (K_i=8.1–16 nM ) and 2400–8600‐fold selectivity over NTS1. The thiazolidine derivative 3 b showed metabolic stability over 32 h in a serum degradation assay. In an inositol phosphate accumulation assay, the neurotensin mimetics 3 a and 3 b displayed an inhibition of constitutive activity exceeding 1.7–2.0 times the activity of NT(8–13). The fluorinated derivative 3 a could afford attractive opportunities to detect NTS2 by ¹⁹F magnetic resonance imaging.     

An RNA Aptamer That Selectively Inhibits the Enzymatic Activity of Protein Tyrosine Phosphatase 1B in vitro

SELEX was used to create an RNA aptamer targeted to protein tyrosine phosphatase 1B (PTP1B), an enzyme implicated in type 2 diabetes, breast cancer and obesity. We found an aptamer that strongly inhibits PTP1B in vitro with a K_i of less than 600 pM . This slow‐binding, high‐affinity inhibitor is also highly selective, with no detectable effect on most other tested phosphatases and approximately 300:1 selectivity over the closely related TC‐PTP. Through controlled synthesis of truncated variants of the aptamer, we isolated shorter forms that inhibit PTP1B. We also investigated various single‐nucleotide modifications to probe their effects on the aptamer's secondary structure and inhibition properties. This family of aptamers represents an exciting option for the development of lead nucleotide‐based compounds in combating several human cancers and metabolic diseases.     

Pervaporation of organic compounds from aqueous mixtures using polydimethylsiloxane‐containing block copolymer membranes

Pervaporation of aqueous mixtures of ethanol, acetone, butanol, isobutanol, and furfural through polystyrene‐b‐polydimethylsiloxane‐b‐polystyrene (SDS) triblock copolymer membranes is reported. These mixtures are important for biofuel production from lignocellulosic feedstocks. Feedstock depolymerization results in the formation of furfural which must be removed before fermentation. Ethanol, butanol, isobutanol, and acetone are important fermentation biofuels. The membrane selectivity of SDS is about unity over a wide range of concentrations of aqueous ethanol mixtures, similar to the membrane selectivity of crosslinked polydimethylsiloxane (PDMS). The permeabilities of butanol, isobutanol, and furfural are larger than those of ethanol and acetone. The volatile organic compound permeability through SDS is similar to or higher than that through PDMS across a broad range of temperatures and feed concentrations is found. More selective and permeable membranes are needed to lower the cost of biofuel purification. The SDS membranes developed are but one step toward improved membranes. © 2015 American Institute of Chemical Engineers AIChE J, 61: 2789–2794, 2015     

PNA‐Encoded Synthesis (PES) of a 10 000‐Member Hetero‐Glycoconjugate Library and Microarray Analysis of Diverse Lectins

Identification of selective and synthetically tractable ligands to glycan‐binding proteins is important in glycoscience. Carbohydrate arrays have had a tremendous impact on profiling glycan‐binding proteins and as analytical tools. We report a highly miniaturized synthetic format to access nucleic‐acid‐encoded hetero‐glycoconjugate libraries with an unprecedented diversity in the combinations of glycans, linkers, and capping groups. Novel information about plant and bacterial lectin specificity was obtained by microarray profiling, and we show that a ligand identified on the array can be converted to a high‐affinity soluble ligand by straightforward chemistry.     

Biofragments: An Approach towards Predicting Protein Function Using Biologically Related Fragments and its Application to Mycobacterium tuberculosis CYP126

We present a novel fragment‐based approach that tackles some of the challenges for chemical biology of predicting protein function. The general approach, which we have termed biofragments, comprises two key stages. First, a biologically relevant fragment library (biofragment library) can be designed and constructed from known sets of substrate‐like ligands for a protein class of interest. Second, the library can be screened for binding to a novel putative ligand‐binding protein from the same or similar class, and the characterization of hits provides insight into the basis of ligand recognition, selectivity, and function at the substrate level. As a proof‐of‐concept, we applied the biofragments approach to the functionally uncharacterized Mycobacterium tuberculosis (Mtb) cytochrome P450 isoform, CYP126. This led to the development of a tailored CYP biofragment library with notable 3D characteristics and a significantly higher screening hit rate (14 %) than standard drug‐like fragment libraries screened previously against Mtb CYP121 and 125 (4 % and 1 %, respectively). Biofragment hits were identified that make both substrate‐like type‐I and inhibitor‐like type‐II interactions with CYP126. A chemical‐fingerprint‐based substrate model was built from the hits and used to search a virtual TB metabolome, which led to the discovery that CYP126 has a strong preference for the recognition of aromatics and substrate‐like type‐I binding of chlorophenol moieties within the active site near the heme. Future catalytic analyses will be focused on assessing CYP126 for potential substrate oxidative dehalogenation.     

An Efficient Method for the Selective Iridium‐Catalyzed Monoalkylation of (Hetero)aromatic Amines with Primary Alcohols

An efficient multi‐gram scale synthesis protocol of a variety of P,N ligands is described. The synthesis is achieved in a two‐step reaction. First, the amine is deprotonated and subsequently the chlorophosphine is added to yield the corresponding P,N ligand. Deprotonation of the amine is normally achieved with n‐BuLi at low temperature, but for the preparation of ligands with a 2,2′‐dipyridylamino backbone and phosphines with a high steric demand KH has to be employed in combination with reaction temperatures of 110 °C for the salt metathesis step. The reaction of two equivalents of a selected P,N ligand with one equivalent of the iridium complex [IrCl(cod)]₂ (cod=1,5‐cyclooctadiene) affords P,N ligand‐coordinated iridium complexes in quantitative yield. X‐Ray single crystal structure analysis of one of these complexes reveals a monomeric five‐coordinated structure in the solid state. The iridium complexes were used to form catalysts for the N‐alkylation of aromatic amines with alcohols. The catalyst system was optimized by studying 8 different P,N ligands, 9 different solvents and 14 different bases. Systematic variation of the substrate to base and the amine to alcohol ratios as well as the catalyst loading led to optimized catalytic reaction conditions. The substrate scope of the developed catalytic protocol was shown by synthesizing 20 different amines of which 12 could be obtained in isolated yields higher than 90%. A new efficient catalyst system for the selective monoalkylation of primary aromatic and heteroaromatic amines with primary aromatic, heteroaromatic as well as aliphatic alcohols has been established. The reaction proceeds with rather moderate catalyst loadings.     

Mechanism‐Guided Library Design and Dual Genetic Selection of Synthetic OFF Riboswitches

After the recent discovery of bacterial riboswitches, synthetic riboswitches have been engineered by using natural and artificial RNA aptamers. In contrast to natural riboswitches, the majority of synthetic riboswitches in bacteria reported to date are ON switches that activate gene expression in response to the aptamer ligand. In this study, we adopted a mechanism‐guided approach to design libraries predisposed to contain OFF riboswitches that respond to thiamine pyrophosphate (TPP). The first library design exploited a pseudo‐Shine‐Dalgarno (SD) sequence located near the 3′‐end of the TPP aptamer, which would be less accessible to the ribosome when the aptamer is bound to TPP. In the second library, an SD sequence was strategically placed in the aptamer's P1 stem, which is stabilized upon ligand binding. OFF riboswitches were obtained by dual genetic selection of these libraries. The results underscore the importance of effective library design to achieve desired riboswitch functions.     

Development of Tetrachlorophthalimides as Liver X Receptor β (LXRβ)‐Selective Agonists

Liver X receptor (LXR) agonists are candidates for the treatment of atherosclerosis via induction of ABCA1 (ATP‐binding cassette A1) gene expression, which contributes to reverse cholesterol transport (RCT) and to cholesterol efflux from the liver and intestine. However, LXR agonists also induce genes involved in lipogenesis, such as SREBP‐1c (sterol regulatory binding element protein 1c) and FAS (fatty acid synthase), thereby causing an undesirable increase in plasma and hepatic triglyceride (TG) levels. Recent studies indicate that LXRα contributes to lipogenesis in liver, and selective LXRβ activation improves RCT in mice. Therefore, LXRβ‐selective agonists are promising candidates to improve atherosclerosis without increasing plasma or hepatic TG levels. However, the ligand‐binding domains in the two LXR isoforms α/β share high sequence identity, and few LXR ligands show subtype selectivity. In this study we identified a tetrachlorophthalimide analogue as an LXRβ‐selective agonist. Structural development led to (E)‐4,5,6,7‐tetrachloro‐2‐(2‐styrylphenyl)isoindoline‐1,3‐dione ( 24 a ), which shows potent and selective LXRβ agonistic activity in reporter gene assays. In binding assays, compound 24 a bound to LXRβ preferentially over LXRα. It also induced the expression of ABCA1 mRNA but not SREBP‐1c mRNA in cells. Compound 24 a appears to be a promising lead compound for therapeutic agents to treat atherosclerosis without the side effects induced by LXRα/β dual agonists.     

MT1‐Selective Melatonin Receptor Ligands: Synthesis,Pharmacological Evaluation,and Molecular Dynamics Investigation of N‐{[(3‐O‐Substituted)anilino]alkyl}amides

The design of compounds selective for the MT₁ melatonin receptor is still a challenging task owing to the limited knowledge of the structural features conferring selectivity for the MT₁ subtype, and only few selective compounds have been reported so far. N‐(Anilinoalkyl)amides are a versatile class of melatonin receptor ligands that include nonselective MT₁/MT₂ agonists and MT₂‐selective antagonists. We synthesized a new series of N‐(anilinoalkyl)amides bearing 3‐arylalkyloxy or 3‐alkyloxy substituents at the aniline ring, looking for new potent and MT₁‐selective ligands. To evaluate the effect of substituent size and shape on binding affinity and intrinsic activity, both flexible and conformationally constrained derivatives were prepared. The phenylbutyloxy substituent gave the best result, providing the partial agonist 4 a , which was endowed with high MT₁ binding affinity (pK_i=8.93) and 78‐fold selectivity for the MT₁ receptor. To investigate the molecular basis for agonist recognition, and to explain the role of the 3‐arylalkyloxy substituent, we built a homology model of the MT₁ receptor based on the β₂ adrenergic receptor crystal structure in its activated state. A binding mode for MT₁ agonists is proposed, as well as a hypothesis regarding the receptor structural features responsible for MT₁ selectivity of compounds with lipophilic arylalkyloxy substituents.     

Recent developments in fuel‐processing and proton‐exchange membranes for fuel cells

In recent years, great progress has been made in the development of proton‐exchange membrane fuel cells (PEMFCs) for both mobile and stationary applications. This review covers two types of new membranes: (1) carbon dioxide‐selective membranes for hydrogen purification and (2) proton‐exchange membranes; both of these are crucial to the widespread application of PEMFCs. On hydrogen purification for fuel cells, the new facilitated transport membranes synthesized from incorporating amino groups in polymer networks have shown high CO₂ permeability and selectivity versus H₂. The membranes can be used in fuel processing to produce high‐purity hydrogen (with less than 10 ppm CO and 10 ppb H₂S) for fuel cells. On proton‐exchange membranes, the new sulfonated polybenzimidazole copolymer‐based membranes can outperform Nafion^® under various conditions, particularly at high temperatures and low relative humidities. Copyright © 2010 Society of Chemical Industry