Highly Selective Anion Template Effect in the Synthesis of Constrained Pseudopeptidic Macrocyclic Cyclophanes.

Herein, we report the synthesis of a novel family of constrained pseudopeptidic macrocyclic compounds containing the hexahydropyrrolo[3,4-f]isoindolocyclophane scaffold and involving four coupled substitution reactions in the macrocyclization process. Although the increase in the number of steps involved in the macrocyclization could lead to a larger number of possible side products, the optimization of the methodology and the study of the driving forces have made it possible to obtain the desired macrocycles in excellent yields. A thorough computational study has been carried out to understand the macrocyclization process, and the results obtained nicely agree with experimental data. Moreover, the bromide anion had a clear catalytic template effect in the macrocyclization reaction, and surprisingly, the chloride anion had a negative template effect in opposition to the results obtained for analogous macrocycles. The parameters responsible for the specific kinetic template effect observed have been studied in detail.

Chiral catalysts immobilized on achiral polymers: effect of the polymer support on the performance of the catalyst.

Positive effects of the polymeric support on the performance of supported chiral catalysts, in terms of activity, stability and selectivity-enantioselectivity, have been reported when the support is properly selected and optimized opening the way to the design of more efficient catalytic systems.

The interaction of amino acids with macrocyclic pH probes of pseudopeptidic nature.

The fluorescence quenching, by a series of amino acids, of pseudopeptidic compounds acting as probes for cellular acidity has been investigated. It has been found that amino acids containing electron-rich aromatic side chains like Trp or Tyr, as well as Met quench the emission of the probes mainly via a collisional mechanism, with Stern-Volmer constants in the 7-43 M-1 range, while other amino acids such as His, Val or Phe did not cause deactivation of the fluorescence. Only a minor contribution of a static quenching due to the formation of ground-state complexes has been found for Trp and Tyr, with association constants in the 9-24 M-1 range. For these ground-state complexes, a comparison between the macrocyclic probes and an open chain analogue reveals the existence of a moderate macrocyclic effect due to the preorganization of the probes in the more rigid structure.

Macrocycle Synthesis by Chloride-Templated Amide Bond Formation.

A new family of pseudopeptidic macrocyclic compounds has been prepared involving an anion-templated amide bond formation reaction at the macrocyclization step. Chloride anion was found to be the most efficient template in the macrocyclization process, producing improved macrocyclization yields with regard to the nontemplated reaction. The data suggest a kinetic effect of the chloride template, providing an appropriate folded conformation of the open-chain precursor and reducing the energy barrier for the formation of the macrocyclic product.

Cu(2+), Zn(2+), and Ni(2+) Complexes of C2-Symmetric Pseudopeptides with an Aromatic Central Spacer.

Two new tetradentate C2-symmetric pseudopeptidic ligands derived from Val and Phe containing two amino and two amido groups and a central o-substituted aromatic spacer have been prepared. Their complexes with Cu(2+), Zn(2+), and Ni(2+) have been studied by potentiometry, UV-vis spectrophotometry, FT-IR, and ESI-MS. The presence of the aromatic spacer provides Cu(2+) complexes with stability constants several orders of magnitude higher than those observed for related ligands containing aliphatic central spacers. Besides, the formation of [MH-2L] complex species is favored. Crystal structures for the corresponding Cu(2+) and Ni(2+) have been obtained, revealing the metal atom in an essentially square-planar geometry, although, in several instances, the oxygen atom of an amide carbonyl of a second complex species can act as a fifth coordination site. In the case of Zn(2+), the only crystal structure obtained displays a square-pyramidal arrangement of the metal center. Finally, preliminary experiments show the catalytic activity of some of these complexes, in particular, Zn(2+) complexes, for epoxide ring-opening with using aniline as the nucleophile in a ligand accelerated process.

Mechanistic implications of the enantioselective addition of alkylzinc reagents to aldehydes catalyzed by nickel complexes with α-amino amide ligands.

The enantioselective alkylation of aldehydes catalysed by nickel(ii)-complexes derived from α-amino amides was studied by means of density functional theory (DFT) and ONIOM (B3LYP:UFF) calculations. A mechanism was proposed in order to investigate the origin of enantioselectivity. The chirality-determining step for the alkylation was the formation of the intermediate complexes with the involvement of a 5/4/4-fused tricyclic transition state. The predominant products predicted theoretically were of (S)-configuration, in good agreement with experimental observations. The scope of the reaction was examined and high yields and enantioselectivities were observed for the enantioselective addition of Et2Zn and Me2Zn to aromatic and aliphatic aldehydes.

Application of optically active chiral bis(imidazolium) salts as potential receptors of chiral dicarboxylate salts of biological relevance.

A family of chiral bis(imidazolium) salts derived from natural amino acids has been synthesized by a simple synthetic approach and the corresponding bis(trifluoromethylsulfonyl)imide salts have been shown to be room temperature chiral ionic liquids (RTCILs). The structures and self-assembling properties of the resulting salts have been studied by (1)HNMR, ATR-FTIR, DSC, SEM and theoretical calculations. Moreover, these receptors have been applied to the enantiomeric recognition of dicarboxylic amino acids. The supramolecular complexes formed have been studied by (1)HNMR titration experiments, ATR-FTIR and DSC.

The synthesis of new fluorescent bichromophoric compounds as ratiometric pH probes for intracellular measurements.

Three different bichromophoric compounds (1-3) containing an aminomethyl anthracene moiety linked to a second chromophore (pyrene, 4-nitrobenzo-2-oxa-1,3-diazole (NBD) and dansyl) through a valine-derived pseudopeptidic spacer have been prepared and their fluorescent properties studied. The results obtained show that upon irradiation the photophysical behavior of these probes involves electronic energy transfer from the excited anthracene to the second chromophore and also intramolecular photoinduced electron transfer. The X-ray structure obtained for 3 reveals that the folding associated with the pseudopeptidic spacer favours a close proximity of the two chromophores. The emissive response of 3 is clearly dependent on the pH of the medium, hence this bichromophoric compound was shown to be an excellent ratiometric pH fluorescent sensor. The emission intensity due to the anthracene moiety exhibits a decrease at neutral-basic pH values that is concomitant with an increase in the intensity arising from the dansyl fluorophore. These properties make this compound a good candidate for biological pH sensing as has been confirmed by preliminary studies with RAW 264.7 macrophage cells imaged by means of confocal fluorescence microscopy with an average pH estimation of 5.4-5.8 for acidic organelles.

Tight and selective caging of chloride ions by a pseudopeptidic host.

The selective molecular recognition of chloride versus similar anions is a continuous challenge in supramolecular chemistry. We have designed and prepared a simple pseudopeptidic cage (1 a) that defines a cavity suitable for the tight encapsulation of chloride. The interaction of the protonated form of 1 a with different inorganic anions was studied in solution by (1)H NMR spectroscopy and ESI-MS, and in the solid state by X-ray diffraction. The solution binding data showed that the association constants of 1 a to chloride are more than two orders of magnitude higher than to any other tested inorganic anion. Remarkably, 1 a displayed a high selectivity for chloride over other closely related halides such as bromide (selectivity=111), iodide (selectivity=719), and fluoride (selectivity >1000). Binding experiments ((1)H NMR spectroscopy and ESI-MS) suggested that 1 a has a high-affinity (inner) binding site and an additional low-affinity (external) binding site. The supramolecular complexes with F(-), Cl(-), and Br(-) have been also characterized by the X-ray diffraction of the corresponding [1 a⋅nHX] crystalline salts. The structural data show that the chloride anion is tightly encapsulated within the host, in a binding site defined by a very symmetric array of electrostatic H-bonds. For the fluoride salt, the size of the cage cavity is too large and is occupied by a water molecule, which fits inside the cage efficiently competing with F(-). In the case of the bigger bromide, the mismatch of the anion inside the cage caused a geometrical distortion of the host and thus a large energetic penalty for the interaction. This minimalistic pseudopeptidic host represents a unique example of the construction of a simple well-defined binding pocket that allows the highly selective molecular recognition of a challenging substrate.

Recognition of free tryptophan in water by synthetic pseudopeptides: fluorescence and thermodynamic studies.

Pseudopeptidic receptors containing an acridine unit have been prepared and their fluorescence response to a series of amino acids was measured in water. Free amino acids, not protected either at the C or the N terminus, were used for this purpose. The prepared receptors display a selective response to tryptophan (Trp) versus the other assayed amino acids under acidic conditions. The macrocyclic nature of the receptor is important as the fluorescence quenching is higher for the macrocyclic compound than for the related open-chain receptor. Notably, under the experimental acidic conditions used, both the receptor and guest are fully protonated and positively charged; thus, the experimental results suggest the formation of supramolecular species that contain two positively charged organic molecular components in proximity stabilized through aromatic-aromatic interactions and a complex set of cation-anion-cation interactions. The selectivity towards Trp seems to be based on the existence of a strong association between the indole ring of the monocharged amino acid and the acridinium fragment of the triprotonated form of the receptor, which is established to be assisted by the interaction of the cationic moieties with hydrogen sulfate anions.

The role of the amino acid-derived side chain in the preorganization of C2-symmetric pseudopeptides: effect on S(N)2 macrocyclization reactions.

A family of pseudopeptidic macrocycles containing non-natural amino acids have been synthesized. The macrocyclization reaction has been studied experimentally and computationally, demonstrating the key role of both the amino acid side chain and the catalytic bromide anion. The bromide anion acts as an external template assisting the folding of the open-chain precursor in a proper conformation. Computations revealed that in the presence of the anion, the effect of the side chain on the energy barrier for the macrocyclization is very small. However, the effect on the conformational equilibria of the open-chain precursors is very important. Overall, the stabilization of those conformation(s) in which the two reactive ends of the open-chain intermediate are located at short distances from each other with the correct orientation is the critical parameter defining the success of the macrocyclization. The best yield was found for the compound containing cyclohexylalanine, for which the computationally-predicted most stable conformer in the presence of Br(-) has a proper preorganization for cyclization. The remarkable agreement obtained between experiments and theory reveals that the computational approach here considered can be of great utility for the prediction of the behavior of other related systems and for the design of appropriate synthetic routes to new macrocyclic compounds.

Fluorescent macrocyclic probes with pendant functional groups as markers of acidic organelles within live cells.

A new family of acidity sensitive fluorescent macrocycles has been synthesized and fully characterized. Their photophysical properties including emission quantum yield and fluorescence lifetime have been determined. The acid-base properties of the new molecules can be tuned by the incorporation of pendant functional groups. The nature of such functional groups (carboxylic acid or ester) influences dramatically the pKa of the probes, two compounds of which exhibit low values. Preliminary intracellular studies using confocal microscopy together with emission spectra of the probes from the cellular environment have shown that the synthesized fluorescent macrocycles mark the acidic organelles of RAW 264.7 macrophage cells.

New advances in dual stereocontrol for asymmetric reactions.

Achieving dual stereocontrol in asymmetric reactions using a single enantiomer for the building of the chiral catalyst or auxiliary is a very important goal in enantioselective synthesis as it eliminates the need for having available the two enantiomers of the auxiliary or catalyst designed. Recent strategies and advances towards this goal during the last four years will be discussed throughout this review.

Photoluminescence enhancement of CdSe quantum dots: a case of organogel-nanoparticle symbiosis.

Highly fluorescent organogels (QD-organogel), prepared by combining a pseudopeptidic macrocycle and different types of CdSe quantum dots (QDs), have been characterized using a battery of optical and microscopic techniques. The results indicate that the presence of the QDs not only does not disrupt the supramolecular organization of the internal fibrillar network of the organogel to a significant extent, but it also decreases the critical concentration of gelator needed to form stable and thermoreversible organogels. Regarding the photophysical properties of the QDs, different trends were observed depending on the presence of a ZnS inorganic shell around the CdSe core. Thus, while the core-shell QDs preserve their photophysical properties in the organogel medium, a high to moderate increase of the fluorescence intensity (up to 528%) and the average lifetime (up to 1.7), respectively, was observed for the core QDs embedded in the organogel. The results are relevant for the development of luminescent organogels based on quantum dots, which have potential applications as advanced hybrid materials in different fields.

Template effects in S(N)2 displacements for the preparation of pseudopeptidic macrocycles.

Macrocyclisation reactions of C(2)-symmetric pseudopeptides containing central pyridine-derived spacers are affected by the presence of different anions. The selection of the proper anion gives excellent results for the preparation of the corresponding macrocyclic structures. Kinetic studies show that the presence of those anions enhances both the yield and the rate of the reaction. Computational studies at the B3LYP/6-31G* level have allowed us to rationalise the experimental results. The obtained transition states (TSs) show that the interaction between the anion and the open-chain pseudopeptidic chain has a stabilising effect. The anion stabilises the two TSs involved: the first one, which involves the formation of the initial bond between the two subunits and leads to an open-chain intermediate, and the second one, which precedes the formation of the cyclic structure. The optimum anion (Br(-) when the central spacer is derived from 2,6-bis(aminomethyl)pyridine, is able to act as a template, in that it forces the two ends of the open-chain intermediate to approach each other by forming hydrogen bonds with the two amino acid subunits present in the intermediate. This stabilises the second TS to a greater extent than the first one, and thus, favours macrocyclisation over the competing oligomerisation reactions. The computational calculations also allowed us to predict the outcome of new experiments. Accordingly, the synthesis of the pseudopeptidic macrocycle derived from 2,6-diaminopyridine was not successful under the optimised conditions previously used. Nevertheless, calculations predicted that in this case Cl(-) should be more efficient than Br(-), and this was subsequently experimentally confirmed. Interestingly, the presence of different substituents on the constituent amino acids seems to play a minor role in the overall process.

Tuning chloride binding, encapsulation, and transport by peripheral substitution of pseudopeptidic tripodal small cages.

A highly efficient synthesis of small pseudopeptidic cages from simple precursors has been achieved by the triple S(N)2 reaction between tripodal tris(amido amines) and several 1,3,5-tris(bromomethyl)benzene electrophiles. The success of the macrobicyclization strongly depends on the central triamine scaffold, which dictates the correct preorganization of the intermediates. The chloride binding properties of the protonated pseudopeptidic cages have been studied in the solid state (by X-ray diffraction) as well as in solution (by NMR spectroscopy and ESI-MS) and in the gas phase (by collision-induced dissociation (CID)-MS). The crystal structure of the HCl salts of several cages show a chloride partially or completely caged within the cavity of the macrobicycle. Both the amino acid side chain and the substitution at the aromatic tripodal ring have an effect on the chloride binding ability. The cages derived from the 1,3,5-benzene moiety show low affinity, whereas the triple substitution in the ring (either with Me or Et) increases the chloride binding by one order of magnitude. Besides, the cages derived from aliphatic amino acids display a stronger interaction than those derived from phenylalanine. The basis for the different mode of binding depending on the receptor structure is proposed according to the structural data (X-ray and NMR spectroscopy). Finally, the transport of the chloride anion through lipid bilayers has been studied for selected cages. Despite the important differences in the chloride binding, the transport properties are better correlated with the lipophilicity of the molecules. Therefore, the pseudopeptidic cages sharing the same binding motif for chloride rendered very different interaction and transport properties depending on the peripheral substitution.

Fluorescent acridine-based receptors for H2PO4(-).

Two new pseudopeptidic molecules (one macrocyclic and one open chain) containing an acridine unit have been prepared. The fluorescence response of these receptors to a series of acids was measured in CHCl(3). Receptors are selective to H(2)PO(4)(-) versus HSO(4)(-), and an even higher selectivity is found over other anions such as Cl(-), Br(-), CH(3)COO(-), and CF(3)COO(-). We show that the macrocyclic receptor is more selective for H(2)PO(4)(-) than the related open chain receptor. The supramolecular interactions of triprotonated receptors with different anions have been modeled in silico and have been studied by different experimental techniques. Optimized geometries obtained by computational calculations agree well with experimental data, in particular fluorescence experiments, suggesting that the selective supramolecular interaction takes places through coordination of the anions to the triprotonated form of the receptor.

Kinetic analysis for macrocyclizations involving anionic template at the transition state.

Several kinetic models for the macrocyclization of a C2 pseudopeptide with a dihalide through a S(N)2 reaction have been developed. These models not only focus on the kinetic analysis of the main macrocyclization reaction, but also consider the competitive oligomerization/polymerization processes yielding undesired oligomeric/polymeric byproducts. The effect of anions has also been included in the kinetic models, as they can act as catalytic templates in the transition state reducing and stabilizing the transition state. The corresponding differential equation systems for each kinetic model can be solved numerically. Through a comprehensive analysis of these results, it is possible to obtain a better understanding of the different parameters that are involved in the macrocyclization reaction mechanism and to develop strategies for the optimization of the desired processes.

Supercritical synthesis of biodiesel.

The synthesis of biodiesel fuel from lipids (vegetable oils and animal fats) has gained in importance as a possible source of renewable non-fossil energy in an attempt to reduce our dependence on petroleum-based fuels. The catalytic processes commonly used for the production of biodiesel fuel present a series of limitations and drawbacks, among them the high energy consumption required for complex purification operations and undesirable side reactions. Supercritical fluid (SCF) technologies offer an interesting alternative to conventional processes for preparing biodiesel. This review highlights the advances, advantages, drawbacks and new tendencies involved in the use of supercritical fluids (SCFs) for biodiesel synthesis.