Asymmetric Organocatalyzed Aza-Henry Reaction of Hydrazones: Experimental and Computational Studies.

The first asymmetric catalyzed aza-Henry reaction of hydrazones is presented. In this process, quinine was used as the catalyst to synthesize different alkyl substituted ß-nitrohydrazides with ee up to 77 %. This ee was improved up to 94 % by a further recrystallization and the opposite enantiomer can be obtained by using quinidine as the catalyst, opening exciting possibilities in fields in which the control of chirality is vital, such as the pharmaceutical industry. Additionally, experimental and ab initio studies were performed to understand the reaction mechanism. The experimental results revealed an unexpected secondary kinetic isotope effect (KIE) that is explained by the calculated reaction pathway, which shows that the protonation of the initial hydrazone and the C-C bond forming reaction occur during a concerted process. This concerted mechanism makes the catalysis conceptually different to traditional base-promoted Henry and aza-Henry reactions.

Novel ureido-dihydropyridine scaffolds as theranostic agents.

In this work, the synthesis of interesting urea derivatives 5 based on 1,4-dihydropyridines 3 is described for the first time. Considering that both families exhibit potential as drugs to treat various diseases, their activity as anticancer agents has been evaluated in HeLa (cervix), Jurkat (leukaemia) and A549 (lung) cancer cell lines as well as on healthy mice in vivo. In general, whereas 1,4-dihydropyridines show a moderate cytotoxic activity, their urea analogues cause an extraordinary increase in their antiproliferative activity, specially towards HeLa cells. Because of the chiral nature of these compounds, enantiomerically enriched samples were also tested, showing different cytotoxic activity than the racemic mixture. Although the reason is not clear, it could be caused by a complex amalgam of physical and chemical contributions. The studied compounds also exhibit luminescent properties, which allow performing a biodistribution study in cancer cells. They have emission maxima between 420 and 471 nm, being the urea derivatives in general red shifted. Emission quenching was observed for those compounds containing a nitro group (3e,f and 5e,f). Fluorescence microscopy showed that 1,4-dihydropyridines 3a and 3g localised in the lysosomes, in contrast to the urea derivatives 5h that accumulated in the cell membrane. This different distribution could be key to explain the differences found in the cytotoxic activity and in the mechanism of action. Interestingly, a preliminary in vivo study regarding the acute toxicity of some of these compounds on healthy mice has been conducted, using a concentration up to 7200 times higher than the corresponding IC50 value. No downgrade in the welfare of the tested mice was observed, which could support their use in preclinical tumour models.

First Organocatalytic Asymmetric Synthesis of 1-Benzamido-1,4-Dihydropyridine Derivatives.

Preliminary results concerning the first asymmetric synthesis of highly functionalized 1-benzamido-1,4-dihydropyridine derivatives via the reaction of hydrazones with alkylidenemalononitriles in the presence of ß-isocupreidine catalyst are reported. The moderate, but promising, enantioselectivity observed (40⁻54% ee), opens the door to a new area of research for the asymmetric construction of new chiral 1,4-dihydropyridine derivatives, whose enantioselective catalytic preparation are still very limited. Moreover, the use of hydrazones for the enantioselective construction of chiral 1,4-dihydropyridines has been overlooked in the literature so far. Therefore, our research represents a pivotal example in this field which remains still unexplored.

Synthesis and supramolecular self-assembly of glutamic acid-based squaramides.

We describe the preparation and characterization of two new unsymmetrical squaramide-based organogelators. The synthesis of the compounds was carried out by subsequent amine condensations starting from dimethyl squarate. The design of the gelators involved a squaramide core connected on one side to a long aliphatic chain and on the other side to a glutamic acid residue. The gelator bearing the free carboxylic groups showed a lower gelation capacity than its precursor diester derivative. Some selected gels were further studied by infrared spectroscopy, rheology and electron microscopy. Critical gelation concentrations and gel-to-sol transition temperatures were also determined for each case. In addition, the superior squaramide diester gelator was compared with an analogue triazole-based gelator in terms of critical gelation concentration, gelation kinetics and thermal phase transition.

Optimizing the Accuracy and Computational Cost in Theoretical Squaramide Catalysis: The Henry Reaction.

This study represents the first example where the accuracy of different combinations of density functional theory (DFT) methods and basis sets have been compared in squaramide catalysis. After an optimization process of the precision obtained and the computational time required in the computational calculations, highly precise results were achieved compared to the experimental outcomes while requiring the least amount of time possible. Here, we have explored computationally and experimentally the mechanism of the squaramide-catalyzed Henry reaction. This is a complex reaction of about 100 atoms and a great number of diverse non-covalent interactions. Moreover, this research is one of the scarce examples where the organocatalyst acts in a trifunctional manner and is the first investigation in which a trifunctional squaramide catalyst has been employed. Functional ωB97X-D showed the best results when used with different versions of the 6-311 basis sets, leading to highly accurate calculations of the outcomes of the Henry reaction when using nine aldehydes with different structural characteristics. Furthermore, in these relatively large systems, the use of a split-valence triple-zeta basis set saves a large amount of time compared with using larger basis sets that are sometimes employed in organocatalytic studies, such as the TZV and Def2TZV basis set families.

Asymmetric Organocatalytic Synthesis of Substituted Chiral 1,4-Dihydropyridine Derivatives.

The first cinchona-alkaloid-organocatalyzed enantioselective synthesis of chiral 1,4-dihydropyridine derivatives is described. Bis-cinchona catalyst 3b activates the Michael addition reaction between malononitrile derivatives 2 and enamines 1, affording the appealing and highly substituted 1,4-dihydropyridines 4 with very good results in most cases. This is one of very few examples of the synthesis of chiral 1,4-dihydropyridines by an enantioselective catalytic procedure. The highly substituted final compounds are of interest for their potential biological activity. This efficient protocol opens the door to a new area of research for the asymmetric construction of these skeletons for which enantioselective syntheses are still very limited.

Self-assembled fibrillar networks of a multifaceted chiral squaramide: supramolecular multistimuli-responsive alcogels.

Chiral N,N'-disubstituted squaramide has been found to undergo self-assembly in a variety of alcoholic solvents at low concentrations leading to the formation of novel nanostructured supramolecular alcogels. The gels responded to thermal, mechanical, optical and chemical stimuli. Solubility studies, gelation ability tests and computer modeling of a series of structurally related squaramides proved the existence of a unique combination of non-covalent molecular interactions and favorable hydrophobic/hydrophilic balance in that drive the anisotropic growth of alcogel networks. The results have also revealed a remarkable effect of ultrasound on both the gelation kinetics and the properties of the alcogels.

Fluoride Anion Recognition by a Multifunctional Urea Derivative: An Experimental and Theoretical Study.

In this work we demonstrate the ability of a multifaceted N,N'-disubstituted urea to selectively recognize fluoride anion (F(-)) among other halides. This additional function is now added to its already reported organocatalytic and organogelator properties. The signaling mechanism relies on the formation of a charge-transfer (CT) complex between the urea-based sensor and F¯ in the ground state with a high association constant as demonstrated by absorption and fluorescence spectroscopy. The nature of the hydrogen bonding interaction between the sensor and F¯ was established by ¹H-NMR studies and theoretical calculations. Moreover, the recovery of the sensor was achieved by addition of methanol.

The aminoindanol core as a key scaffold in bifunctional organocatalysts.

The 1,2-aminoindanol scaffold has been found to be very efficient, enhancing the enantioselectivity when present in organocatalysts. This may be explained by its ability to induce a bifunctional activation of the substrates involved in the reaction. Thus, it is easy to find hydrogen-bonding organocatalysts ((thio)ureas, squaramides, quinolinium thioamide, etc.) in the literature containing this favored structural core. They have been successfully employed in reactions such as Friedel-Crafts alkylation, Michael addition, Diels-Alder and aza-Henry reactions. However, the 1,2-aminoindanol core incorporated into proline derivatives has been scarcely explored. Herein, the most representative and illustrative examples are compiled and this review will be mainly focused on the cases where the aminoindanol moiety confers bifunctionality to the organocatalysts.

New Organocatalytic Asymmetric Synthesis of Highly Substituted Chiral 2-Oxospiro-[indole-3,4'- (1',4'-dihydropyridine)] Derivatives.

Herein, we report our preliminary results concerning the first promising asymmetric synthesis of highly functionalized 2-oxospiro-[indole-3,4'-(1',4'-dihydropyridine)] via the reaction of an enamine with isatylidene malononitrile derivatives in the presence of a chiral base organocatalyst. The moderate, but promising, enantioselectivity observed (30%-58% ee (enantiomeric excess)) opens the door to a new area of research for the asymmetric construction of these appealing spirooxindole skeletons, whose enantioselective syntheses are still very limited.

Exploiting molecular self-assembly: from urea-based organocatalysts to multifunctional supramolecular gels.

We describe the self-assembly properties of chiral N,N'-disubstituted urea-based organocatalyst 1 that leads to the formation of hierarchical supramolecular gels in organic solvents at low concentrations. The major driving forces for the gelation are hydrogen bonding and π-π interactions according to FTIR and (1)H NMR spectroscopy, as well as quantum-mechanical studies. The gelation scope could be interpreted based on Kamlet-Taft solvatochromic parameters. TEM, SEM, and AFM imaging revealed that a variety of morphologies including helical, laths, porous, and lamellar nanostructures could be obtained by varying the solvent. Experimental gelation tests and computational structural analysis of various structurally related compounds proved the existence of a unique set of molecular interactions and an optimal hydrophilic/hydrophobic balance in 1 that drive the formation of stable gels. Responses to thermal, mechanical, optical, and chemical stimuli, as well as multifunctionality were demonstrated in some model gel materials. Specifically, 1 could be used for the phase-selective gelation of organic solvent/water mixtures. The gel prepared in glycerol was found to be thixotropic and provided a sensitive colorimetric method for the detection of Ag(I) ions at millimolar concentrations in aqueous solution. Moreover, the gel matrix obtained in toluene served as a nanoreactor for the Friedel-Crafts alkylation of 1H-indole with trans-ß-nitrostyrene.

A Friedel-Crafts alkylation mechanism using an aminoindanol-derived thiourea catalyst.

Computational calculations based on experimental results shed light on the mechanistic proposal for a Friedel-Crafts alkylation reaction between indole and nitroalkenes, catalysed by a chiral aminoindanol-derived thiourea. In our hypothesis both substrates are simultaneously coordinated to the catalyst in a bifunctional mode. This study elucidates the crucial role played by the hydroxyl group of the catalyst in the success of the reaction. The OH group seems to be involved in the preferential attack of the indole over the nitroalkene, affording the major enantiomer and stabilizing the resulting transition state by a concomitant coordination with the nitroolefin. The results obtained with other catalysts from the same family, and other indoles, are reported and discussed. Theoretical calculations are in agreement with the experimental outcomes and with our previously developed mechanism, displaying the pivotal role played by hydrogen bond interactions.

Organocatalytic enantioselective hydrophosphonylation of aldehydes.

We report our results concerning the first squaramide-catalysed hydrophosphonylation of aldehydes. In all cases, the reactions proceeded smoothly and cleanly under mild reaction conditions rendering final α-hydroxy phosphonates in very good yields and high enantioselectivities. It is one of the few organocatalytic examples of this reaction using aldehydes. It is the first time that diphenylphosphite (1e) has been successfully employed in a chiral Pudovik reaction with aldehydes, in contrast to the dialkylphosphites used in previously published procedures, extending the generality of this asymmetric methodology.

Asymmetric organocatalytic Strecker-type reactions of aliphatic N,N-dialkylhydrazones.

The enantioselective organocatalytic Strecker-type reaction of aliphatic N,N-dialkylhydrazones is presented. Using trimethylsilyl cyanide (TMSCN) as the cyanide source, the reaction can be efficiently catalyzed by a tert-leucine-derived bifunctional thiourea to afford the corresponding hydrazino nitriles in good to excellent yields (50-96%) and moderate to good enantioselectivities, up to 86% ee. Further transformations of the nitrile functionality allow access to useful protected hydrazino acids and imidazolidinones. Interestingly, some of the hydrazino nitriles and their derivatives could be recrystallized in high recovery, yielding essentially pure enantiomers.

Heterocycles in Breast Cancer Treatment: The Use of Pyrazole Derivatives.

Among the aromatic heterocycle rings, pyrazole -a five-membered ring with two adjacent nitrogen atoms in its structure has been postulated as a potent candidate in the pharmacological context. This moiety is an interesting therapeutic target covering a broad spectrum of biological activities due to its presence in many natural substances. Hence, the potential of the pyrazole derivatives as antitumor agents has been explored in many investigations, showing promising results in some cases. In this sense, breast cancer, which is already the leading cause of cancer mortality in women in some countries, has been the topic selected for this review, which covers a range of different research from the earliest studies published in 2003 to the most recent ones in 2021.

Thiourea catalyzed organocatalytic enantioselective Michael addition of diphenyl phosphite to nitroalkenes.

Bifunctional thiourea catalyzes the enantioselective Michael addition reaction of diphenyl phosphite to nitroalkenes. This methodology provides a facile access to enantiomerically enriched ß-nitrophosphonates, precursors for the preparation of synthetically and biologically useful ß-aminophosphonic acids. DFT level of computational calculations invoke the attack of the diphenyl phosphite to the nitroolefin by the Re face, this give light to this scarcely explored process update in the literature. The computational calculations support the absolute configuration obtained in the final adducts.

Ultrasound-assisted multicomponent synthesis of 4H-pyrans in water and DNA binding studies.

A simple approach to synthesize new highly substituted 4H-pyran derivatives is described. Efficient Et3N acts as a readily accessible catalyst of this process performed in pure water and with only a 20 mol% of catalyst loading. The extremely simple operational methodology, short reaction times, clean procedure and excellent product yields render this new approach extremely appealing for the synthesis of 4H-pyrans, as potentially biological scaffolds. Additionally, DNA interaction analysis reveals that 4H-pyran derivatives behave preferably as minor groove binders over major groove or intercalators. Therefore, this is one of the scarce examples where pyrans have resulted to be interesting DNA binders with high binding constants (Kb ranges from 1.53 × 104 M-1 to 2.05 × 106 M-1).