Continuous Flow Processes as an Enabling Tool for the Synthesis of Constrained Pseudopeptidic Macrocycles.

Herein we report our efforts to develop a continuous flow methodology for the efficient preparation of pseudopeptidic macrocyclic compounds containing the hexahydropyrrolo-[3,4-f]-isoindolocyclophane scaffold and involving four coupled substitution reactions in the macrocyclization process. Appropriate design of a supported base permitted the continuous production of the macrocycles even at large scales, taking advantage of the positive template effect promoted by the bromide anions. In addition, the use of flow protocols allowed a ca. 20-fold increase in productivity as well as reducing the environmental impact almost 2 orders of magnitude, in comparison with the related batch macrocyclization process.

Rational Design of Simple Organocatalysts for the HSiCl3 Enantioselective Reduction of (E)-N-(1-Phenylethylidene)aniline.

Prolinamides are well-known organocatalysts for the HSiCl3 reduction of imines; however, custom design of catalysts is based on trial-and-error experiments. In this work, we have used a combination of computational calculations and experimental work, including kinetic analyses, to properly understand this process and to design optimized catalysts for the benchmark (E)-N-(1-phenylethylidene)aniline. The best results have been obtained with the amide derived from 4-methoxyaniline and the N-pivaloyl protected proline, for which the catalyzed process is almost 600 times faster than the uncatalyzed one. Mechanistic studies reveal that the formation of the component supramolecular complex catalyst-HSiCl3-substrate, involving hydrogen bonding breaking and costly conformational changes in the prolinamide, is an important step in the overall process.

Chiral Imidazolium Prolinate Salts as Efficient Synzymatic Organocatalysts for the Asymmetric Aldol Reaction.

Chiral imidazolium l-prolinate salts, providing a complex network of supramolecular interaction in a chiral environment, have been studied as synzymatic catalytic systems. They are demonstrated to be green and efficient chiral organocatalysts for direct asymmetric aldol reactions at room temperature. The corresponding aldol products were obtained with moderate to good enantioselectivities. The influence of the presence of chirality in both the imidazolium cation and the prolinate anion on the transfer of chirality from the organocatalyst to the aldol product has been studied. Moreover, interesting match/mismatch situations have been observed regarding configuration of chirality of the two components through the analysis of results for organocatalysts derived from both enantiomers of prolinate (R/S) and the trans/cis isomers for the chiral fragment of the cation. This is associated with differences in the corresponding reaction rates but also to the different tendencies for the formation of aggregates, as evidenced by nonlinear effects studies (NLE). Excellent activities, selectivities, and enantioselectivities could be achieved by an appropriate selection of the structural elements at the cation and anion.

Synergy between supported ionic liquid-like phases and immobilized palladium N-heterocyclic carbene-phosphine complexes for the Negishi reaction under flow conditions.

The combination of supported ionic liquids and immobilized NHC-Pd-RuPhos led to active and more stable systems for the Negishi reaction under continuous flow conditions than those solely based on NHC-Pd-RuPhos. The fine tuning of the NHC-Pd catalyst and the SILLPs is a key factor for the optimization of the release and catch mechanism leading to a catalytic system easily recoverable and reusable for a large number of catalytic cycles enhancing the long-term catalytic performance.

Urea-Based Low-Molecular-Weight Pseudopeptidic Organogelators for the Encapsulation and Slow Release of (R)-Limonene.

Low-molecular-weight compounds containing alkylurea fragments attached to the amino end of different miminalistic pseudopeptidic structures have been shown to be excellent organogelators in a variety of organic solvents and liquid organic compounds of different nature. The formation of gels in this work is defined through rheological measurements for those cases where G' > G''. Both the topology and the symmetry of the corresponding urea compounds play a role in defining their organogelator behavior. This can also be tuned by the presence of additional supramolecular guests, as is the case for suberic acid. These compounds also achieve the gelation of relevant active substances such as terpene natural oils and complex mixtures of flavors and fragrances. This provides a simple and mass-efficient supramolecular system for the quantitative encapsulation of active substances, without the need for any additional solvent or complex processes, and their consequent controlled release.

Rose Bengal Immobilized on Supported Ionic-Liquid-like Phases: An Efficient Photocatalyst for Batch and Flow Processes.

The catalytic activity of Rose Bengal (RB) immobilized on supported ionic liquid (IL)-like phases was evaluated as a polymer-supported photocatalyst. In these systems, the polymer was designed to play a pivotal role. The polymeric backbone adequately modified with IL-like moieties (supported IL-like phases, SILLPs) was not just an inert support for the dye but controlled the accessibility of reagents/substrates to the active sites and provided specific microenvironments for the reaction. The structure of SILLPs could be finetuned to adjust the catalytic efficiency of the RB-SILLP composites, achieving systems that were more active and stable than the related systems in the absence of IL-like units.

Divergent Multistep Continuous Synthetic Transformations of Allylic Alcohol Enabled by Catalysts Immobilized in Ionic Liquid Phases.

Two individual catalytic platforms (metal- and organo-catalyzed) based on the use of an ionic liquid phase were successfully integrated for the synthesis of α-cyano-amine and cyanohydrin trimethylsilyl ethers from allylic alcohol. The right combination of continuous flow processes enabled access to the divergent preparation of two alternative and interesting intermediate compounds from the same starting material.

New porous monolithic membranes based on supported ionic liquid-like phases for oil/water separation and homogenous catalyst immobilisation.

Porous monolithic advanced functional materials based on supported ionic liquid-like phase (SILLP) systems were used for the preparation of oleophilic and hydrophobic cylindrical membranes and successfully tested as eco-friendly and safe systems for oil/water separation and for the continuous integration of catalytic and separation processes in an aqueous-organic biphasic reaction system.

Selective synthesis of partial glycerides of conjugated linoleic acids via modulation of the catalytic properties of lipases by immobilization on different supports.

Lipases B from Candida antarctica (CALB), Rhizomucor miehei (RML) and Thermomyces lanuginosus (TLL) were immobilized on octadecyl methacylate (OM) or octadecyl methacrylate (OMC) beads. Their specific activity and regioselectivity were studied in the synthesis of conjugated linoleic acid (CLA) partial glycerides, which presented nutraceutical properties. TLL derivatives were poor catalysts. Novozym® 435 was much better than Lipozyme® RM IM. RML activity (a GRAS enzyme) was modulated via immobilization. After only 3 h, OM-RML gave the highest CLA conversion (54% at 40 °C with 1:3 M ratio of glycerol to CLA). OM-RML reduced by a factor of 3.12 and 1.16 the activation energy of the reaction with Lipozyme® RM IM and Novozym® 435, respectively. The new GRAS preparation OM-RML brings forth an optimal regioselective preparation of sn-1 mono and sn-1,3 diacylglycerols rich in CLA, with a ratio of sn-1,3/sn-1,2 regioisomers of 21.8, compared to 2.3 for Novozym® 435.

Chiral imidazolium receptors for citrate and malate: the importance of the preorganization.

A family of simple receptors formed by two or three cationic imidazolium arms attached to a central aromatic linkage and displaying different conformational flexibility has been synthesized from the enantiopure (1S,2S)-2-(1-H-imidazol-1-yl)-cyclohexanol. The crystal structures of the corresponding bromides of two of the hosts showed remarkable differences. The tripodal receptor with a trimethylated central benzene ring (1a) showed a cone-type conformation defining an inner anion-binding site, while the bipodal molecule with the central meta-phenylene spacer (m-2a) displayed an extended conformation. The binding properties of the chiral imidazolium hosts toward citrate, isocitrate and the two enantiomers of malate have been studied by (1)H NMR titration experiments in 9:1 CD3CN:CD3OH at 298.15 K. Interestingly, 1a showed a stronger interaction with dianionic malate than with the trianionic citrate or isocitrate, suggesting that the smaller guest is better accommodated in the host cavity. Among this family, 1a proved to be the best receptor due to a combination of a larger number of electrostatic and H-bonding interactions and to a more efficient preorganization in the cone-type conformation. This preorganization effect is also present in solution as confirmed by (1)H NMR spectroscopy.

Chiral triazolium salts and ionic liquids: from the molecular design vectors to their physical properties through specific supramolecular interactions.

An exhaustive experimental study based on X-ray diffraction analysis, NMR, FTIR-ATR (attenuated total reflection), and Raman spectroscopy as well as theoretical calculations is reported in order to understand how the non-covalent intermolecular contacts are fundamental to explain structure-property relationships and allowing us to correlate a basic macroscopic property (i.e., the melting point, T(m)) with the structural variables of a family of enantiopure 1,4-dialkyl-1,2,4-triazolium salts. The effect of different structural vectors such as the ring size, the spatial disposition of the substituent, the substitution on the oxygen atom, the nature of the anion, or the N4 alkylation of the triazole on the intermolecular interactions of these chiral salts of a well-defined 3D structure is reported. The non-covalent intermolecular contacts mainly implicating the triazolium H3 proton are fundamental to explain structure-property relationships and, therefore, the physical properties of these new chiral salts, rather than simple anion-cation interactions. Overall, our findings highlight the importance of the specific supramolecular interactions for the understanding of the physical properties of triazolium salts and ionic liquids.

Hydrolysis of triacetin catalyzed by immobilized lipases: effect of the immobilization protocol and experimental conditions on diacetin yield.

The effect of the immobilization protocol and some experimental conditions (pH value and presence of acetonitrile) on the regioselective hydrolysis of triacetin to diacetin catalyzed by lipases has been studied. Lipase B from Candida antarctica (CALB) and lipase from Rhizomucor miehei (RML) were immobilized on Sepabeads (commercial available macroporous acrylic supports) activated with glutaraldehyde (covalent immobilization) or octadecyl groups (adsorption via interfacial activation). All the biocatalysts accumulated diacetin. Covalently immobilized RML was more active towards rac-methyl mandelate than the adsorbed RML. However, this covalent RML preparation presented the lowest activity towards triacetin. For this reason, this preparation was discarded as biocatalyst for this reaction. At pH 7, acyl migration occurred giving a mixture of 1,2 and 1,3 diacetin, but at pH 5.5, only 1,2 diacetin was produced. Yields were improved at acidic pH values and in the presence of 20% acetonitrile (to over 95%). RML immobilized on octadecyl Sepabeads was proposed as optimal preparation, mainly due to its higher specific activity. Each enzyme preparation presented very different properties. Moreover, changes in the reaction conditions affected the various immobilized enzymes in a different way.

From salts to ionic liquids by systematic structural modifications: a rational approach towards the efficient modular synthesis of enantiopure imidazolium salts.

This paper reports a simple and robust modular synthetic strategy that leads to a large variety of configurationally and structurally diverse imidazole-based chiral ionic liquids (CILs) by lipase-catalyzed resolution. The intimate microscopic interactions of the supramolecular ionic network of these imidazolium chiral salts at the molecular level are investigated both spectroscopically (NMR, FT-IR-ATR) and theoretically, and a topological analysis of the experimental electron densities obtained by X-ray diffraction of single crystals is performed. Our results support the key role played by the relative configuration of the -OR group on the hydrogen-bonding pattern and its strong influence on the final physical properties of the imidazolium salt. We also obtained a reasonable correlation between the observed melting point and the non-covalent interactions. The spectroscopic data and the topological analysis reflect the key role played by hydrogen bonds between the OH and imidazolium C2H groups in both cation-anion and cation-cation interactions, with the presence of an OH group leading to an additional inter-cation interaction. This interaction significantly affects the properties of stereoisomeric salts. Even more interestingly, we also studied the effect of the chirality by comparing enantiopure CILs with their racemic mixtures and found that, with the exception of trans-Cy6-OH-Im-Bn-Br, the melting points of the racemic mixtures are higher than those of the corresponding enantiomerically pure forms. For stereoisomeric examples, we have successfully explained the differences in melting temperatures in light of the corresponding structural data. Chirality should therefore be taken into account as a highly attractive design vector in the preparation of ILs with specifically desired properties.