Marta C. Corvo

Asymmetric synthesis of N-aryl aziridines

Abstract The reactions of a variety of N-arylhydroxamates as nitrogen transfer reagents to acryloyl derivatives of (−)-8-phenylmenthol, (−)-quinine and (−)-Oppolzers sultam acting as Michael acceptors was studied. Poor to modest diastereoselection was observed in the formation of aziridines. The absolute structure of one of the pure diastereomers secured from Oppolzers auxiliary was established by X-ray crystallography and hence the absolute configuration of the derived methyl-N-phenylaziridine-2-carboxylate could be assigned. Whilst only poor facial selectivity was observed for chiral hydroxamic acid prepared from dehydroabietic acid, moderate to good enantioselection of aziridines could be achieved with the chiral quaternary salts based on cinchona alkaloids, especially with that of cinchonine. A model is presented to explain the origin of enantioselection and a mechanism is proposed for the aziridination reaction.

Solvation of Carbon Dioxide in [C4mim][BF4] and [C4mim][PF6] Ionic Liquids Revealed by High-Pressure NMR Spectroscopy†

Where is CO2 ? The intermolecular interactions of [C4 mim]BF4 and [C4 mim]PF6 ionic liquids and CO2 have been determined by high-pressure NMR spectroscopy in combination with molecular dynamic simulations. The anion and the cation are both engaged in interactions with CO2 . A detailed picture of CO2 solvation in these ILs is provided. CO2 solubility is essentially determined by the microscopic structure of the IL.

Binding of Ibuprofen, Ketorolac, and Diclofenac to COX-1 and COX-2 Studied by Saturation Transfer Difference NMR

Saturation transfer difference NMR (STD-NMR) spectroscopy has emerged as a powerful screening tool and a straightforward way to study the binding epitopes of active compounds in early stage lead discovery in pharmaceutical research. Here we report the application of STD-NMR to characterize the binding of the anti-inflammatory drugs ibuprofen, diclofenac, and ketorolac to COX-1 and COX-2. Using well-studied COX inhibitors and by comparing STD signals with crystallographic structures, we show that there is a relation between the orientations of ibuprofen and diclofenac in the COX-2 active site and the relative STD responses detected in the NMR experiments. On the basis of this analysis, we propose that ketorolac should bind to the COX-2 active site in an orientation similar to that of diclofenac. We also show that the combination of STD-NMR with competition experiments constitutes a valuable tool to address the recently proposed behavior of COX-2 as functional heterodimers and complements enzyme activity studies in the effort to rationalize COX inhibition mechanisms.

A radical approach towards indolizidine 167B

Abstract The alkaloids (+)- and (−)-indolizidine 167B were synthesized via radical addition of a carbon radical to a chiral acrylamide. Further cyclization in the presence of BBr 3 , treatment with ‘nickel boride’ and stereospecific hydrogenation over palladium/carbon in acetic acid were other key steps in this synthesis.

A Rational Approach to CO2 Capture by Imidazolium Ionic Liquids: Tuning CO2 Solubility by Cation Alkyl Branching

Branching at the alkyl side chain of the imidazolium cation in ionic liquids (ILs) was evaluated towards its effect on carbon dioxide (CO2 ) solubilization at 10 and 80 bar (1 bar=1×10(5)  Pa). By combining high-pressure NMR spectroscopy measurements with molecular dynamics simulations, a full description of the molecular interactions that take place in the IL-CO2 mixtures can be obtained. The introduction of a methyl group has a significant effect on CO2 solubility in comparison with linear or fluorinated analogues. The differences in CO2 solubility arise from differences in liquid organization caused by structural changes in the cation. ILs with branched cations have similar short-range cation-anion orientations as those in ILs with linear side chains, but present differences in the long-range order. The introduction of CO2 does not cause perturbations in the former and benefits from the differences in the latter. Branching at the cation results in sponge-like ILs with enhanced capabilities for CO2 capture.

The impact of available experimental data on the prediction of 1H NMR chemical shifts by neural networks.

Two different ways were explored to incorporate new available experimental data into previously trained ensembles of feed-forward neural networks, for the structure-based prediction of (1)H NMR chemical shifts of organic compounds. One approach used the new data as the memory of an associative neural network (ASNN) system. For an independent prediction set of 952 cases, a mean average error of 0.19 ppm was achieved (0.13 ppm for 90% of the cases). This approach advantageously avoids retraining the networks, and the predictions compared favorably with those obtained by available commercial software packages. Excellent predictions could also be achieved by retraining the networks with the new data, but only if the training sets were selected so as to be balanced or if the retraining started with the weights of the previously trained networks.

Application of HR-MAS NMR in the solid-phase synthesis of a glycopeptide using Sieber amide resin.

The solid‐phase synthesis (SPS) of a structurally complex glycopeptide, using Sieber amide resin, was monitored by high resolution magic angle spinning NMR, demonstrating the further application of this technique. A synthetic peptidoglycan derivative, a precursor of a biologically active PGN, known to be involved in the cellular recognition, was prepared by SPS. The synthesis involved the preparation of an N‐alloc glucosamine moiety and the synthesis of a simple amino acid sequence L‐Ala‐D‐Glu‐L‐Lys‐D‐Ala‐D‐Ala. Last step consisted the coupling, on solid‐phase, of the protected muramyl unit to the peptide chain. Proton spectra with good suppression of the polystyrene signals in swollen resin samples were obtained in DMF‐d7 as a solvent and by using a nonselective 1D TOCSY/DIPSI‐2 scheme, thus allowing to follow the SPS without losses of compound and cleavage from the resin. The assignment of the proton spectra of the resin‐bound amino acid sequence and of the bound glycopeptide was achieved through the combination of MAS COSY, TOCSY and NOESY. Copyright

Developments in the Reactivity of 2-Methylimidazolium Salts

Unexpected and unusual reactivity of 2-methylimidazolium salts toward aryl-N-sulfonylimines and aryl aldehydes is here reported. Upon reaction with aryl-N-sulfonylimines, the addition product, arylethyl-2-imidazolium-1-tosylamide (3), is formed with moderate to good yields, while upon reaction with aldehydes, the initial addition product (6) observed in NMR and HPLC-MS experimental analysis is postulated by us as an intermediate to the final conversion to carboxylic acids. Studies in the presence and absence of molecular oxygen allow us to conclude that the imidazolium salts is crucial for the oxidation. A detailed mechanistic study was carried out to provide insights regarding this unexpected reactivity.

Molecular order and dynamics of water in hybrid cellulose acetate–silica asymmetric membranes

ABSTRACT In this work 2H NMR spectroscopy and 1H NMR relaxometry and diffusometry were used to characterise water order and dynamics in cellulose acetate/silica asymmetric membranes. Two hydrated membranes were characterised allowing the identification of extra ordering of the water molecules and the presence in each membrane of up to two spectral components with different degrees of order and different values. The mechanism behind this order increase was ascribed to the rapid exchange of the water molecules between the pore walls and its interior. relaxometry dispersions allowed for the identification of the relevant mechanisms of pore-confined water motion, with rotations mediated by translational displacements (RMTD) as the dominant mechanism in the low frequency region. Using the RMTD low cut off frequency along with the in situ directly measured diffusion constant it was possible do determine characteristic lengths of correlated water motion in both membranes studied, which fall in ranges compatible with typical pore dimensions in similar membranes. GRAPHICAL ABSTRACT

1H NMR Relaxometry and Diffusometry Study of Magnetic and Nonmagnetic Ionic Liquid-Based Solutions: Cosolvent and Temperature Effects

In this work, 1H NMR relaxometry and diffusometry as well as viscometry experiments were carried out as a means to study the molecular dynamics of magnetic and nonmagnetic ionic liquid-based systems. In order to evaluate the effect of a cosolvent on the superparamagnetic properties observed for Aliquat-iron-based magnetic ionic liquids, mixtures comprising different concentrations, 1% and 10% (v/v), of DMSO-d6 were prepared and studied. The results for both magnetic and nonmagnetic systems were consistently analyzed an suggest that, when at low concentrations, DMSO-d6 promotes more structured ionic arrangements, thus enhancing these superparamagnetic properties. Furthermore, the analysis of temperature and water concentration effects allowed to conclude that neither one of these variables significantly affected the superparamagnetic properties of the studied magnetic ionic liquids.