Horizons in Asymmetric Organocatalysis: En Route to the Sustainability and New Applications

Nowadays, the development of new enantioselective processes is highly relevant in chemistry due to the relevance of chiral compounds in biomedicine (mainly drugs) and in other fields, such as agrochemistry, animal feed, and flavorings. Among them, organocatalytic methods have become an efficient and sustainable alternative since List and MacMillan pioneering contributions were published in 2000. These works established the term asymmetric organocatalysis to label this area of research, which has grown exponentially over the last two decades. Since then, the scientific community has attended to the discovery of a plethora of organic reactions and transformations carried out with excellent results in terms of both reactivity and enantioselectivity. Looking back to earlier times, we can find in the literature a few examples where small organic molecules and some natural products could act as effective catalysts. However, with the birth of this type of catalysis, new chemical architectures based on amines, thioureas, squaramides, cinchona alkaloids, quaternary ammonium salts, carbenes, guanidines and phosphoric acids, among many others, have been devel-oped. These organocatalysts have provided a broad range of activation modes that allow privileged interactions between catalysts and substrates for the preparation of compounds with high added value in an enantioselective way. Here, we briefly cover the history of this chemistry, from our point of view, including our beginnings, how the field has evolved during these years of research, and the road ahead. © 2022 by the authors. Licensee MDPI, Basel, Switzerland

Hydrogen-Bonding Organocatalysis Enabled Photocatalytic Intramolecular [2+2]-Cycloaddition Reaction

The combination of organocatalytic activation and photocatalysis for enabling the intramolecular [2+2]‐cycloaddition of enone‐ene substrates bearing one Lewis base binding site is reported. While in a variety of solvents a poor conversion or no reaction takes place in the absence of a hydrogen bonding catalyst, the corresponding ring‐fused cyclobutane products could be built in moderate to good yields using a synergistic dual iridium‐urea co‐catalytic system. Control and mechanistic studies supported the postulated interaction between the organocatalyst and the substrate, which proved essential for an efficient energy transfer from the photosensitizer

Enantioselective C-P Bond Formation through C(sp3)-H Functionalization

An enantioselective C−P bond formation has been developed through a C(sp3)−H activation in an oxidation step followed by an organocatalyzed hydrophosphonylation protocol. The asymmetric organocatalytic Pudovik reaction has been achieved following a one‐pot strategy, starting from different benzylic and allylic alcohols and dibenzyl phosphite, using MnO2 as the oxidant and a chiral squaramide as organocatalyst. The scope of the reaction provides enantiomerically enriched α‐hydroxy phosphonates with yields from 40% to >95% and enantioselectivities from 64% to >99%. Furthermore, the use of this methodology has been demonstrated to form a tetrasubstituted carbon stereocenter, generating an acetophenone derivative in situ, using diphenyl phosphite. Therefore, this approach represents an asymmetric strategy for constructing chiral C−P bonds, which are of interest to the pharmaceutical industry

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.This research was funded by Agencia Estatal de Investigación (AEI), project PID2020-117455GB-I00/AEI/10.13039/501100011033; RED2018-102471-T/ AEI/10.13039/501100011033 and Gobierno de Aragón-Fondo Social Europeo (Research Group E07_20R).Peer reviewe

Enantioselective C–P Bond Formation through C(sp3)–H Functionalization

An unprecedented enantioselective C–P bond formation has been developed through a C(sp3)–H activation in an oxidation step followed by an organocatalyzed hydrophosphonylation protocol. The asymmetric organocatalytic Pudovik reaction has been successfully achieved following a one-pot strategy, starting from different benzylic alcohols and dibenzylphosphite, using MnO2 as the oxidant and a chiral squaramide as organocatalyst. The scope of the reaction provides enantiomerically enriched α-hydroxy phosphonates in good to excellent yields (up to >95%) and high enantioselectivities (up to >99%). Furthermore, the use of this methodology has been successfully demonstrated to form a quaternary centre, generating an acetophenone derivative in situ, using diphenyl phosphite. Therefore, this approach represents a highly effective strategy for constructing chiral C–P bonds, which are of significant interest to the pharmaceutical industry. This proof of concept represents a significant breakthrough in the field of chemistry

Synthesis of 1,4-dihydropyridine derivatives and study of their biological properties

Resumen del trabajo presentado al IV Workshop de NanoOncología, celebrado en la Universidad de Zaragoza del 19 al 20 de octubre de 2021.Peer reviewe

Organocatalyzed enantioselective Pudovik reaction of aldehydes in situ generated from alcohols

Resumen del póster presentado a la XXXVIII Reunión Bienal de la Real Sociedad Española de Química, celebrada en el Palacio de Congresos de Granada, del 27 de junio al 30 de junio de 2022.Many organic reactions that initially start from aldehydes lead to products of biological interest. However, aldehydes over time, easily become contaminated with traces of their carboxylic acids. Thus, during the development of our previous Henry protocol, we realized that the presence of these acidic traces could inactivate the organocatalyst. Encouraged by this fact, we explored the possibility of producing in situ the aldehydes by oxidizing the corresponding alcohols. These chemicals are, in general, more convenient than aldehydes, mainly due to their high availability and stability, as well as their easier handling. The transformation of primary and secondary alcohols to obtain the corresponding carbonyl compounds for their subsequent reaction with nucleophiles in an organocatalytic and enantioselective manner has been scarcely explored. The Pudovik reaction is an important C-P bond-forming method in organic synthesis, based on the reaction of phosphorus nucleophiles with aldehydes. Herein, we want to present the first organocatalytic enantioselective Pudovik reaction starting from alcohols and the biological assessment of the final α-hydroxyphosphonates.Peer reviewe

Síntesis organocatalítica de derivados de 1,4-dihidropiridina y estudio de sus propiedades antitumorales

Resumen del trabajo presentado a la 9ª Jornada de Jóvenes Investigadores de Química y Física de Aragón, celebrada el 16 de diciembre de 2021 en la Universidad de Zaragoza.Peer reviewe

1-Benzamido-1,4-dihydropyridine derivatives as anticancer agents: in vitro and in vivo assays

1,4-Dihydropyridine is a privileged scaffold present in many bioactive molecules, from coenzymes to commercially available drugs. Among other interesting properties, it has been found good anticancer activity in some of these 1,4-DHPs, therefore many research groups are trying to develop new compounds based on this structural core.For this purpose, in this work, a family of 23 new 1,4-dihydropyridines has been synthesized using hydrazide and malononitrile derivatives as precursors. This straightforward catalytic process has given rise to the desired products with moderate to excellent yields. All the compounds have been tested against four different cancer cell lines [HeLa (human cervical carcinoma), Jurkat (leukemia), A549 (human lung cancer) and MIA PaCa-2 (pancreatic cancer)] to establish a preliminary structure–activity relationship. From this study, and among the best candidates, we chose 4-chlorophenyl and 4-(trifluoromethyl)phenyl derivatives in the malononitrile ring to synthesize a second generation of molecules with enhanced cytotoxicity, modifying the substituent in the N-heterocyclic position (acylhydrazine moieties). With this second generation of compounds, we successfully decreased the IC50 until 7 µM.An in-depth analysis of their biological properties suggests that these promising compounds trigger a non-conventional cell death mechanism known as paraptosis. Moreover, the tested photophysical properties of these products show in some cases an interesting long wavelength emission and excitation, potentially leading to new biosensors or theragnostic agents.Finally, in vivo assays concerning the acute toxicity in mice of two of the most active compounds (with an alkyl chain of seven carbon atoms in the acylhydrazine moiety) demonstrated that even dosed at thousands fold the corresponding IC50 values (2500 and 3300 times more concentrated than the IC50 values for the two compounds studied), there was no sign of harmful effects on the tested subjects, results that support their use in further studies to discover new anticancer drugs