Syntheses of Enantiomerically Pure 2‐Substituted Pyrrolidin‐3‐ones via Lithiated Alkoxyallenes – An Auxiliary‐Based Synthesis of both Enantiomers of the Antibiotic Anisomycin

The hydrochlorides of both enantiomers of the antibiotic anisomycin were prepared starting with the ‘diacetone‐fructose’‐substituted allene 1 and the N‐Boc‐protected imine precursor 2a . Addition of an excess of lithiated 1 to 2a provided a 2 : 1 mixture 3a of diastereoisomers, which were cyclized to 4a under base promotion (Scheme 2). The two diastereoisomers of 4a were separated and converted into enantiomerically pure pyrrolidin‐3‐ones (2R)‐ 5a and (2S)‐ 5a . A similar sequence yielded the N‐Tos‐protected compounds (2R)‐ 5b and (2S)‐ 5b . Compounds 5a were converted into silyl enol ethers 6 and by subsequent regio‐ and stereoselective hydroboration into pyrrolidine derivatives 7 (Scheme 3). Straightforward functional‐group transformations led to the hydrochlorides 9 of anisomycin (Scheme 3). The (2R) series provided the hydrochloride (2R)‐ 9 of the natural occurring enantiomer, whereas the (2S) series furnished the antipode (2S)‐ 9 . The overall sequence to the natural product involved ten steps with eight purified intermediates and afforded an overall yield of 8%. Our stereochemically divergent approach to this type of hydroxylated pyrrolidines is highly flexible and should easily allow preparation of many analogues.     

Xanthone Receptors as Oxyanion‐Hole Mimics in Artificial Enzymes

Different xanthone‐based receptors ( 2 – 10 ) for lactones and lactams have been prepared, and the feasibility of these compounds to mimic the known enzymatic ‘oxyanion‐hole’ structure is discussed. The self‐association of the receptors was found to pose a serious drawback for complex formation. X‐Ray crystal structures of receptor dimers allowed us to understand the reasons for their self‐association and to improve the design of the catalysts. The catalytic activity of the receptors has been tested towards the nucleophilic addition of pyrrolidine to unsaturated lactones. Since the resulting complexes were very weak in organic solvents, new receptors were developed for lactams, which showed better stabilities, and their catalytic activities were studied.     

Systematic Exploration of the Synthetic Parameters for the Production of Dynamic VO2(M1)

Thermochromic dynamic cool materials present a reversible change of their properties wherein by increasing the temperature, the reflectance, conductivity, and transmittance change due to a reversible crystalline phase transition. In particular, vanadium (IV) dioxide shows a reversible phase transition, accompanied by a change in optical properties, from monoclinic VO₂(M1) to tetragonal VO₂(R). In this paper, we report on a systematic exploration of the parameters for the synthesis of vanadium dioxide VO₂(M1) via an easy, sustainable, reproducible, fast, scalable, and low-cost hydrothermal route without hazardous chemicals, followed by an annealing treatment. The metastable phase VO₂(B), obtained via a hydrothermal route, was converted into the stable VO₂(M1), which shows a metal–insulator transition (MIT) at 68 °C that is useful for different applications, from energy-efficient smart windows to dynamic concrete. Within this scenario, a further functionalization of the oxide nanostructures with tetraethyl orthosilicate (TEOS), characterized by an extreme alkaline environment, was carried out to ensure compatibility with the concrete matrix. Structural properties of the synthesized vanadium dioxides were investigated using temperature-dependent X-ray Diffraction analysis (XRD), while compositional and morphological properties were assessed using Scanning Electron Microscopy, Energy Dispersive X-ray Analysis (SEM-EDX), and Transmission Electron Microscopy (TEM). Differential Scanning Calorimetry (DSC) analysis was used to investigate the thermal behavior.     

Entry to nitrogen-containing heterocycles by based-promoted heterocyclization on allenylamides of l-α-aminoacids

Allenylamides of Boc-protected α-aminoacids easily gave in basic medium heterocyclic products arising from attack of the NH group on the inside C-C double bond of the 1,2-diene moiety, namely imidazolidinones, pyrazinones, and a pyrrole compound. The microwave-assisted heterocyclization occurred cleanly at C-β of the allenyl group with formation of pyrazin-2-ones having an endo- or exocyclic double bond.     

Human serum albumin unfolding pathway upon drug binding: A thermodynamic and spectroscopic description

The interest on phenothiazine drugs has been increased during last years due to their proved utility in the treatment of several diseases and biomolecular processes. In the present work, the binding of the amphiphilic phenothiazines promazine and thioridazine hydrochlorides to the carrier protein human serum albumin (HSA) has been examined by ζ-potential, isothermal titration calorimetry (ITC), fluorescence and circular dichorism (CD) spectroscopies, and dynamic light scattering (DLS) at physiological pH with the aim of analyzing the role of the different interactions in the drug complexation process with this protein. The ζ-potential results were used to check the existence of complexation. This is confirmed by a progressive screening of the protein charge up to a reversal point as a consequence of drug binding. On the other hand, binding causes alterations on the tertiary and secondary structures of the protein, which were observed by fluorescence and CD spectroscopies, involving a two-step, three-state transition. The thermodynamics of the binding process was derived from ITC results. The binding enthalpies were negative, which reveal the existence of electrostatic interactions between protein and drug molecules. In addition, increases in entropy are consistent with the predominance of hydrophobic interactions. Two different classes of binding sites were detected, viz. Binding to the first class of binding sites is dominated by an enthalpic contribution due to electrostatic interactions whereas binding to a second class of binding sites is dominated by hydrophobic bonding. In the light of these results, protein conformational change resembles the acid-induced denaturation of HSA with accumulation of an intermediate state. Binding isotherms were derived from microcalorimetric results by using a theoretical model based on the Langmuir isotherm. On the other hand, the population distribution of the different species in solution and their sizes were determined through dynamic light scattering (DLS). Aggregation of drug/protein complexes was found as a result of a possible expansion of protein structure induced at high drug concentrations. In addition, the presence of free drug aggregates at concentrations below the drug critical micelle concentration was also detected.     

Development of a Stability-Indicating LC Assay Method for Determination of Chloroquine

A simple and rapid development of a stability-indicating LC method for determination of chloroquine diphosphate in the presence of its hydrolysis, oxidative and photolysis degradation products is described. Stress testing showed that chloroquine diphosphate was degraded under basic conditions and by photolytic treatment but was stable under the other stress conditions investigated. Separation of the drug from its degradation products was achieved with a Nova Pack C18 column, 0.01 M PIC B7 and acetonitrile (40:60 v/v) pH 3.6, as mobile phase. Response was linear over the range 0.08–5.70 μg mL⁻¹ (r = 0.996), with limits of detection and quantification (LOD and LOQ) of 0.17 and 0.35 μg mL⁻¹, respectively.

     

The structured distance to normality of banded Toeplitz matrices

Spectral properties of normal (2k+1)-banded Toeplitz matrices of order n, with k≤⌊ n/2⌋, are described. Formulas for the distance of (2k+1)-banded Toeplitz matrices to the algebraic variety of similarly structured normal matrices are presented.     

Ultrasound energy focused in a glass probe: An approach to the simultaneous and fast extraction of trace elements from sediments

The 3051 USEPA method (or alternatively, the 3051A) can be considered nowadays as a reference method to extract metals from sediments. However, after microwave heating, the sample must be allowed to cool down, which results in a considerable lengthening of the whole analytical process. Microwave ovens and their maintenance are, in addition, expensive, and its use is relatively dangerous. The use of ultrasound focused energy to assist the extraction of chemicals from solid samples is a safe and relatively cheap technique. In this work we propose a new method to extract simultaneously several elements from sediments using ultrasound energy focused in a glass probe to accelerate the process, and check its possibilities to become an alternative to the EPA3051(A) approach. The optimised procedure allows extracting 13 elements in only 6 min, with similar recoveries and, in general, better repetitivities than the EPA3051. In addition, the suspension is only slightly heated during the leaching process.     

Development and NMR validation of minimal pharmacophore hypotheses for the generation of fragment libraries enriched in heparanase inhibitors

A combined strategy based on the development of pharmacophore hypotheses and NMR approaches is reported for the identification of novel inhibitors of heparanase, a key enzyme involved in tumor metastasis through the remodeling of the subepithelial and subendothelial basement membranes, resulting in the dissemination of metastatic cancer cells. Several pharmacophore hypotheses were initially developed from the most active heparanase inhibitors known to date and, after their application to a pool of 27 known heparanase inhibitors and a database of 1,120 compounds approved by the FDA, a four-point pharmacophore model was selected as the most predictive. This model was subsequently applied to a database of 686 chemical fragments, and a subset of 100 fragments accomplishing completely or partially the four-point model was selected to perform nuclear magnetic resonance experiments to validate the hypothesis. The experimental studies confirmed the reliability of our pharmacophore model, its applicability to in silico databases in order to reduce the number of compounds to be experimentally screened, and the possibility of generating fragment libraries enriched in heparanase inhibitors. Rafael Gozalbes and Silvia Mosulén contributed equally to this work.     

IR and NMR time-resolved studies on the hydrolysis and condensation of methacryloxyalkylsilanes

The sol–gel reactions of the two methacrylate-modified silanes methacryloxymethyltriethoxysilane (MAMTES) and methacryloxypropyltrimethoxysilane (MAPTMS) were followed by using two independent time-resolved spectroscopic methods, viz., IR ATR and NMR with the aim to optimise their pre-hydrolysis times and consequently their use as precursors for hybrid materials. Time resolved measurements were carried out on the two systems under sol–gel conditions. Whereas the hydrolysis of both siloxanes is very fast, condensation proceeds gradually and is not completely finished within 5 h.