The Knight route to cyclopiazonic acid: enantioselective synthesis of a key intermediate

The indole alkaloid α-cyclopiazonic acid (CPA) is one of the few known inhibitors of sarco(endo)plasmic reticulum Ca²⁺-ATPase (SERCA) besides thapsigargin and artemisinin. Inhibitors of SERCA hold promise as novel anticancer and antimalarial drugs. Since its structure elucidation three racemic syntheses of α-cyclopiazonic acid have been published. We report now the first enantioselective and high yielding synthesis of a key-intermediate of the Knight synthesis, currently the most efficient route to CPA. Our synthesis is based on a diastereoselective 1,4-cuprate addition followed by an enolate azidation of an indolylacrylic acid modified with the Evans auxiliary.     

A concise synthesis of (S)-(−)-3-(2-carboxy-4-pyrrolyl)-alanine

A convergent synthesis of (S)-(−)-3-(2-carboxy-4-pyrrolyl)-alanine (CPA) 1, a non-proteinogenic amino acid is described starting from a commercially available dimethyl l-aspartate 2 in good overall yield.     

The detection of T-Nos,a genetic element present in GMOs,by cross-priming isothermal amplification with real-time fluorescence

An isothermal cross-priming amplification (CPA) assay for Agrobacterium tumefaciens nopaline synthase terminator (T-Nos) was established and investigated in this work. A set of six specific primers, recognizing eight distinct regions on the T-Nos sequence, was designed. The CPA assay was performed at a constant temperature, 63 °C, and detected by real-time fluorescence. The results indicated that real-time fluorescent CPA had high specificity, and the limit of detection was 1.06?×?10³ copies of rice genomic DNA, which could be detected in 40 min. Comparison of real-time fluorescent CPA and conventional polymerase chain reaction (PCR) was also performed. Results revealed that real-time fluorescent CPA had a comparable sensitivity to conventional real-time PCR and had taken a shorter time. In addition, different contents of genetically modified (GM)-contaminated rice seed powder samples were detected for practical application. The result showed real-time fluorescent CPA could detect 0.5 % GM-contaminated samples at least, and the whole reaction could be finished in 35 min. Real-time fluorescent CPA is sensitive enough to monitor labeling systems and provides an attractive method for the detection of GMO.

An examination of chlorpromazine hydrochloride as indicator and spectrophotometric reagent for the determination of molybdenum(V)

Chlorpromazine hydrochloride (CPA) has been tested as indicator in the titration of molybdenurn(V) with cerium(IV)sulphate at room temperature in sulphuric acid medium. It gives a sharp, reversible colour change from colourless to dark-red at the equivalence point. Chlorpromazine hydrochloride also reacts in acidic media with thiocyanatomolybdenum(V) complexes forming an orange compound with the formula (CPA · H) [MoO(SCN)₄]. This reaction provides a sensitive method for spectrophotometric determination of molybdenum(V). Molybdenum(VI) is reduced with ascorbic acid in hydrochloric acid solution, and complexed with thiocyanate, and the complex formed is extracted with chlorpromazine hydrochloride in chloroform. The molar absorptivity is 1.6 × 10⁴ l mol^-1 cm^-1 at 465 nm. Beer's law is obeyed in the range 0.5–5.0 μg Mo ml^-1.     

Hybrid Palladium Catalyst Assembled from Chiral Phosphoric Acid and Thioamide for Enantioselective β-C(sp3)−H Arylation

A hybrid palladium catalyst assembled from a chiral phosphoric acid (CPA) and thioamide enables a highly efficient and enantioselective β-C(sp³)−H functionalization of thioamides (up to 99 % yield, 97 % ee). A kinetic resolution of unsymmetrical thioamides by intermolecular C(sp³)−H arylation can be achieved with high s-factors. Mechanistic investigations have revealed that stereocontrol is achieved by embedding the substrate in a robust chiral cavity defined by the bulky CPA and a neutral thioamide ligand.     

Application of synergistic β-lactamase inhibitors and antibiotics in the treatment of wounds infected by superbugs

Amoxicillin appears to be clinically drug-resistant due to the presence of β-lactamase in bacteria. Here, we designed and prepared a hollow Prussian Blue (HPB)-based therapeutic nanoplatform that was constructed by encapsulating amoxicillin into polyethyleneimine with β-lactamase inhibitor 4-carboxyphenylboronic acid (4-Cpba) decorated HPB nanoparticles (CPA NPs). The antibacterial effect of the CPA NPs on drug-resistant bacteria was observed by in vitro colony-forming unit, minimum inhibitory concentration, scanning electron microscopy, and fluorescence tests. The results show that amoxicillin effectively inhibited Escherichia coli and Staphylococcus aureus-resistant bacteria in the presence of 4-Cpba. The in vivo experimental results show that the CPA NPs exhibited a synergistic anti-infective effect in vivo, which inhibited the inflammatory response and apoptosis induced by the drug-resistant bacterial infection, and promoted wound healing in mice. The hematoxylin and eosin staining and blood biochemical experiments revealed that the acute toxicity of the material was negligible and it had good biocompatibility. Our results verify our design that CPA NPs can restore the antibacterial activity of amoxicillin.     

Modeling of phase equilibria with CPA using the homomorph approach

For association models, like CPA and SAFT, a classical approach is often used for estimating pure-compound and mixture parameters. According to this approach, the pure-compound parameters are estimated from vapor pressure and liquid density data. Then, the binary interaction parameters, k_ij, are estimated from binary systems; one binary interaction parameter per system. No additional mixing rules are needed for cross-associating systems, but combining rules are required, e.g. the Elliott rule or the so-called CR-1 rule. There is a very large class of mixtures, e.g. water or glycols with aromatic hydrocarbons, chloroform-acetone, esters-water, CO₂-water, etc., which are classified as “solvating” or “induced associating”. The classical approach cannot be used and the cross-association interactions are difficult to be estimated a priori since usually no appropriate experimental data exist, while the aforementioned combining rules cannot capture the physical meaning of such interactions (as at least one of the compounds is non-self-associating). Consequently, very often one or more of the interaction parameters are optimized to experimental mixture data. For example, in the case of the CPA EoS, two interaction parameters are often used for solvating systems; one for the physical part (k_ij) and one for the association part (β^cross). This limits the predictive capabilities and possibilities of generalization of the model. In this work we present an approach to reduce the number of adjustable parameters in CPA for solvating systems. The so-called homomorph approach will be used, according to which the k_ij parameter can be obtained from a corresponding system (homomorph) which has similar physical interactions as the solvating system studied. This leaves only one adjustable parameter for solvating mixtures, the cross-association volume (β^cross). It is shown that the homomorph approach can be used with success for mixtures of water and glycols with aromatic hydrocarbons as well as for mixtures of acid gases (CO₂, H₂S) with alcohols and water. The homomorph approach is less satisfactory for mixtures with fluorocarbons as well as for aqueous mixtures with ethers and esters. In these cases, CPA can correlate liquid-liquid equilibria for solvating systems using two adjustable parameters. The capabilities and limitations of the homomorph approach are discussed.     

Hybrid Palladium Catalyst Assembled from Chiral Phosphoric Acid and Thioamide for Enantioselective β‐C(sp3)−H Arylation

A hybrid palladium catalyst assembled from a chiral phosphoric acid (CPA) and thioamide enables a highly efficient and enantioselective β‐C(sp³)?H functionalization of thioamides (up to 99 % yield, 97 % ee). A kinetic resolution of unsymmetrical thioamides by intermolecular C(sp³)?H arylation can be achieved with high s‐factors. Mechanistic investigations have revealed that stereocontrol is achieved by embedding the substrate in a robust chiral cavity defined by the bulky CPA and a neutral thioamide ligand.     

Palladium(II)‐Catalyzed Enantioselective Arylation of Unbiased Methylene C(sp3)−H Bonds Enabled by a 2‐Pyridinylisopropyl Auxiliary and Chiral Phosphoric Acids

Enantioselective functionalizations of unbiased methylene C(sp³)?H bonds of linear systems by metal insertion are intrinsically challenging and remain a largely unsolved problem. Herein, we report a palladium(II)‐catalyzed enantioselective arylation of unbiased methylene β‐C(sp³)?H bonds enabled by the combination of a strongly coordinating bidentate PIP auxiliary with a monodentate chiral phosphoric acid (CPA). The synergistic effect between the PIP auxiliary and the non‐C₂‐symmetric CPA is crucial for effective stereocontrol. A broad range of aliphatic carboxylic acids and aryl bromides can be used, providing β‐arylated aliphatic carboxylic acid derivatives in high yields (up to 96 %) with good enantioselectivities (up to 95:5 e.r.). Notably, this reaction also represents the first palladium(II)‐catalyzed enantioselective C?H activation with less reactive and cost‐effective aryl bromides as the arylating reagents. Mechanistic studies suggest that a single CPA is involved in the stereodetermining C?H palladation step.     

Preparation and performance evaluation of carboxylic acid containing polyamide incorporated microporous ultrafiltration PES membranes

Improved ultrafiltration membranes were prepared by the phase inversion technique via immersion precipitation of synthesized carboxylic acid containing polyamide (CPA) and polyethersulfone (PES) in dimethylacetamide. The CPA was synthesized and characterized by Fourier transform infrared (FTIR), nuclear magnetic resonance, thermogravimetric analysis, and differential scanning calorimetry analyses. Next, the influence of CPA adding and its different concentrations on the performances and membrane structure were investigated. The obtained membranes were characterized by means of FTIR in the attenuated total reflection mode, scanning electron microscopy, and contact angle. The membrane performance studies revealed that the presence of CPA in the membrane structure increased water permeability while reducing protein fouling. It turned out that the PES/CPA membranes had better porosity, more hydrophilic surface, and more vertically finger‐like pores in comparison with the bare PES membrane. When the CPA concentration in the blending solution reached 1 wt%, the water permeability increased from 7.3 to 153.6 L/m² h¹. The attenuated total reflection‐FTIR analysis confirmed that CPA was captured in the membrane matrix.     

Chemoenzymatic synthesis of [3,9-C]-labeled NeuAc and KDN

The chemoenzymatic synthesis of ¹³C-labeled sialic acid (NeuAc) and 3-deoxy-d-glycero-d-galacto-2-nonulosonic acid (KDN) as useful molecular probes for studying the conformation of sialyl or KDN oligosaccharides attached to proteins was performed by using [6-¹³C]-ManNAc, [6-¹³C]-Man and [3-¹³C]-pyruvic acid sodium salt. In the synthesis of the compounds, 5,6-anhydro intermediates were found to easily provide not only 6-¹³C-labeled but also 5-, and 6-modified NeuAc and KDN analogs. Furthermore, it was demonstrated that identical results are obtained by NMR for both [3,9-¹³C]-NeuAc and 1:1 mixtures of [3-¹³C]- and [9-¹³C]-NeuAc.     

B(C6F5)3/Chiral Phosphoric Acid Catalyzed Ketimine–Ene Reaction of 2-Aryl-3H-indol-3-ones and α-Methylstyrenes

The enantioselective ketimine–ene reaction is one of the most challenging stereocontrolled reaction types in organic synthesis. In this work, catalytic enantioselective ketimine–ene reactions of 2-aryl-3H-indol-3-ones with α-methylstyrenes were achieved by utilizing a B(C₆F₅)₃/chiral phosphoric acid (CPA) catalyst. These ketimine–ene reactions proceed well with low catalyst loading (B(C₆F₅)₃/CPA=2 mol %/2 mol %) under mild conditions, providing rapid and facile access to a series of functionalized 2-allyl-indolin-3-ones with very good reactivity (up to 99 % yield) and excellent enantioselectivity (up to 99 % ee). Theoretical calculations reveal that enhancement of the acidity of the chiral phosphoric acid by B(C₆F₅)₃ significantly reduces the activation free energy barrier. Furthermore, collective favorable hydrogen-bonding interactions, especially the enhanced N−H⋅⋅⋅O hydrogen-bonding interaction, differentiates the free energy of the transition states of CPA and B(C₆F₅)₃/CPA, thereby inducing the improvement of stereoselectivity.     

Synthesis of the unnatural amino acid N-N-(ferrocene-1-acetyl)-l-lysine: A novel organometallic nuclease

The synthesis of a new unnatural amino acid, N^α-N^ε-(ferrocene-1-acetyl)-l-lysine, was achieved by coupling a ferroceneacetic acid molecule onto the side chain amine of a lysine. The structure of the compound provides options for incorporation of the molecule into peptides or large proteins. In addition, N^α-N^ε-(ferrocene-1-acetyl)-l-lysine exhibits nuclease activity. It is expected that incorporation of this ferrocenyl amino acid into any nucleic acid-binding protein will endow the protein with nuclease capability.     

Palladium‐Catalyzed Enantioselective Desymmetrizing Aza‐Wacker Reaction: Development and Application to the Total Synthesis of (−)‐Mesembrane and (+)‐Crinane

Reported is an unprecedented catalytic enantioselective desymmetrizing aza‐Wacker reaction. In the presence of a catalytic amount of a newly developed Pd(CPA)₂(MeCN)₂ catalyst (CPA=chiral phosphoric acid), a pyrox ligand, and molecular oxygen, cyclization of properly functionalized prochiral 3,3‐disubstituted cyclohexa‐1,4‐dienes afforded enantioenriched cis‐3a‐substituted tetrahydroindoles in good yields with excellent enantioselectivities. A cooperative effect between the phosphoric acid and the pyrox ligand ensured efficient transformation. This reaction was tailor‐made for Amaryllidaceae and Sceletium alkaloids as illustrated by its application in the development of the concise and divergent total synthesis of (?)‐mesembrane and (+)‐crinane.     

Criteria for selecting analytical wavelengths for multicomponent mixtures by the CPA matrix method and simultaneous spectrophotometric determination of niobium and tantalum

The reversed matrix representation of the Lambert-Beer law (CPA matrix method) is applied in simultaneous spectrophotometric determinations. Restrictions on the selection of analytical wavelengths in applying the CPA matrix method are investigated experimentally and theoretically. Four criteria for selecting suitable wavelengths are described. A spectrophotometric procedure for niobium and tantalum with salicylfluorone and cetyltrimethylammonium bromide in the presence of tartaric acid was developed and used for the simultaneous determination of niobium and tantalum by the CPA matrix method. The absorption maxima were at 520 and 513 nm, respectively. Measurements at six wavelengths in the range 500–530 nm provided data from which niobium (0.04–0.4 μm ml^?1) and tantalum (0.08–0.8 μg ml^?1) were evaluated, with relative standard deviations of <2.     

An Efficient Synthesis of Optically Active [4-13C] Labelled Quorum Sensing Signal Autoinducer-2

A new synthetic route for the quorum sensing signal Autoinducer-2 (AI-2) is described and used for the preparation of [4-¹³C]-AI-2 starting from [1-¹³C]-bromoacetic acid. The key step in this process was the enantioselective reduction of an intermediate ketone. This synthesis provides, selectively, both enantiomers of the labelled or unlabelled parent compound, (R) or (S)-4,5-dihydroxypentane-2,3-dione (DPD) and was used for an improved synthesis of [1-¹³C]-AI-2.     

Dynamic Kinetic Stereoselective Glycosylation via RhII and Chiral Phosphoric Acid-Cocatalyzed Carbenoid Insertion to the Anomeric OH Bond for the Synthesis of Glycoconjugates

Chemical synthesis of glycoconjugates is essential for studying the biological functions of carbohydrates. We herein report an efficient approach for the stereoselective synthesis of challenging α-linked glycoconjugates via a Rh^II/chiral phosphoric acid (CPA)-cocatalyzed dynamic kinetic anomeric O-alkylation of sugar-derived lactols via carbenoid insertion to the anomeric OH bond. Notably, we observed excellent anomeric selectivity, excellent diastereoselectivity, broad substrate scope, and high efficiency for this glycosylation reaction by exploring various parameters of the cocatalytic system. DFT calculations suggested that the anomeric selectivity was mainly determined by steric interactions between the C2-carbon of the carbohydrate and the phenyl group of the metal carbenoid, while π/π interactions with the C2−OBn substituent on the carbohydrate substrate play a significant role for diastereoselectivity at the newly generated stereogenic center.     

Total synthesis of the potent anti-inflammatory lipid mediator Protectin D1

The total synthesis of the potent anti-inflammatory lipid mediator Protectin D1 derived from docosahexaenoic acid, has been achieved. The chiral hydroxy-groups at C10 and C17 were obtained via a chiral pool strategy from (4R)-4-(2-hydroxyethyl)-2,2-dimethyl-1,3-dioxolane and 3,4-O-isopropylidene-2-deoxy-d-ribose, respectively. Wittig reactions, Takai olefination, Pd⁰/Cu^I Sonogashira coupling, and Zn(Cu/Ag) reduction completed the total synthesis of Protectin D1.     

Asymmetric synthesis of suitably protected γ-hydroxy-aza-β3-homothreonine building blocks

An efficient and easily applicable method for the enantioselective synthesis of γ-Hydroxy aza-β³-homothreonine (aza-β³-Hyht) has been established. The method involves stereoselective reductive amination of glyoxylic acid and the corresponding Fmoc protected chiral hydrazine. A stereoselectivity of 99% was achieved for each step using (R)-2,3-O-isopropylideneglyceraldehyde as the chiral auxiliary. This new synthetic monomer is a useful building block for the solid-phase synthesis of new peptidomimetics.     

Synthesis of a new family of protected 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid derivatives with thioctic acid pending arms

The synthesis and characterization of a new family of ester protected N-substituted [1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (H3DO3A) derivatives containing a pendant thioctic acid (α lipoic acid, LA) are reported. These compounds (DO3A^tBu-NLA, DO3A^tBu-NMeNLA, and DO3A^tBu-NEtNLA) are suitable for the functionalization of gold surfaces with rare-earth complexes.