Organocatalysis in total synthesis

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Synthesis of interesting β-nitrohydrazides through a thiourea organocatalysed aza-Michael addition

The synthesis of antimicrobial β-nitrohydrazides, as the target product of our reaction, is reached for the first time under organocatalytic enantioselective conditions. We accomplish this goal by using a thiourea organocatalysed aza-Michael addition reaction of hydrazide to nitroalkenes, furnishing final products with good yields and good enantiomeric ratios. The developed methodology is one of the rare examples of catalytic reactivity using hydrazide where the reaction proceeds through its N2 atom. Our developed strategy extends the generality of this area of research due to the difficulties of designing new nitrogen nucleophiles with high activity, and in addition, this is one of the scarce examples where nitroalkenes and chiral thioureas have been used in asymmetric organocatalytic aza-Michael addition reactions. © 2014 The Royal Society of Chemistry.We thank the Spanish Ministry of Economía y Competitividad (MICINN. Madrid. Spain. Project CTQ2010-19606) and the Government of Aragón (Zaragoza. Spain. Research Group E-10) for financial support of our research.Peer Reviewe

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

Thiourea-catalyzed addition of indoles to aliphatic β,γ-unsaturated α-ketoesters

Communication.A thiourea-catalyzed addition reaction with indoles to aliphatic β,γ-unsaturated α-ketoesters has been developed. The easily accessible thiourea aminoindanol derivative makes this approach an interesting alternative for the use of these aliphatic substrates, very scarcely employed in previously reported procedures, highlighting the complementarity of the strategy presented here. The final adducts, which are valuable intermediates for synthesizing the corresponding α-amino acid or α-hydroxy acid derivatives, are obtained in good yields and enantiomeric excess under mild reaction conditions.We thank the Ministry of Science and Innovation (MICINN. Madrid. Project CTQ2013-44367-C2-1-P) and the University of Zaragoza (JIUZ-2014-CIE-07) for financial support of our research.Peer reviewe

Organocatalytic Enantioselective Henry Reactions

This is an open access article distributed under the Creative Commons Attribution License.A large number of interesting organocatalytic enantioselective protocols have been explored and successfully applied in the last decade. Among them, the Henry (nitroaldol) reaction represents a powerful carbon-carbon bond-forming procedure for the preparation of valuable synthetic intermediates, such as enantioenriched nitro alcohols, which can be further transformed in a number of important nitrogen and oxygen-containing compounds. This area of research is still in expansion and a more complex version of this useful process has recently emerged, the domino Michael/Henry protocol, affording highly functionalized cycles with multiple stereogenic centers.We thank the Spanish Ministry of Science and Innovation (Projects CTQ2009-09028 and CTQ2010-19606) and the Government of Aragón (Project PI064/09 and Research Groups, E-10) for financial support of our research. E. M.-L. thanks CSIC for a JAE-Doc postdoctoral contract. R. P. H. thanks the Aragón I + D Foundation for her permanent position.Peer Reviewe

Synthesis of squaramides and their application in organocatalysis: computational and experimental studies

Las escuaramidas han resultado ser compuestos de marcado interés en distintas ramas de la química. El uso de las escuaramidas quirales como organocatalizadores es interesante ya que, usando la escuaramida adecuada, se crean entornos quirales ideales para la obtención de productos enriquecidos enantioméricamente mediante la formación de enlaces de hidrógeno con los sustratos. Una de las líneas principales de investigación de nuestro grupo es la síntesis y la aplicación organocatalítica de este tipo de compuestos, lo que nos ha llevado a desarrollar durante esta tesis doctoral reacciones quirales poco exploradas anteriormente en esta área.En primer lugar, es muy importante disponer de un método eficaz de síntesis de escuaramidas, motivos estructurales centro de investigaciones posteriores. La síntesis tradicional de escuaramidas consta de dos reacciones independientes de adición de aminas. Sin embargo, a través del diseño de un método de síntesis one-pot, conseguimos sintetizar las escuaramidas empleando un único reactor, con las ventajas asociadas de ahorro de tiempo, energía, dinero, menor generación de residuos, etc.Una de nuestras mayores prioridades dentro de esta tesis ha sido el desarrollo de reacciones organocatalíticas usando escuaramidas que dan lugar a productos enantioméricamente enriquecidos con potencial actividad biológica. A lo largo de esta tesis doctoral, desarrollamos la reacción de Henry catalizada por escuaramidas, obteniéndose los correspondientes β-nitroalcoholes con muy buenos rendimientos y enantioselectividades. Además, en algunos casos la carga catalítica requerida fue de tan sólo 0.25 mol%, siendo la más baja conocida para esta reacción en el campo de la organocatálisis.Asimismo, también estudiamos el mecanismo de la reacción de Henry catalizada por una escuaramida que contiene un grupo NOBIN. Para ello, realizamos distintos estudios computacionales en combinación con los propios datos experimentales. Además, exploramos distintas combinaciones de métodos y conjuntos de funciones de base para averiguar cuál de ellas llevaba a los mejores resultados. En este trabajo, la combinación más precisa fue la formada por el funcional ωB97X-D y el conjunto de funciones 6-311G(d). Este análisis representa el primer ejemplo en el cual se compara la eficiencia de distintas aproximaciones computacionales en la catálisis con escuaramidas.Además, se observó que en esta reacción existe un modo de interacción peculiar que nunca antes se había visto en catálisis, llamado “push-pull π+/π-”. Este modo consiste en dos interacciones π creadas por los anillos aromáticos de un grupo naftilo del catalizador con dos átomos del grupo aldehído, uno δ+ (su átomo de hidrógeno) y el otro δ- (su átomo de oxígeno).<br /

Optimizing 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 has 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 using the least amount of time as possible. Here, we have explored computationally and experimentally the mechanism of 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 ¿B97X-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 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 to using larger basis sets that are sometimes employed in organocatalytic studies, such as the TZV and Def2TZV basis set families

Metal-organic frameworks (MOFs) bring new life to hydrogen-bonding organocatalysts in confined spaces

Hydrogen-bonding organocatalysis has emerged as a promising biomimetic alternative to Lewis acid catalysis. Urea, thiourea and squaramide moieties represent the most common hydrogen-bond donors used for the preparation of these catalysts. However, their significant tendency to undergo self-quenching (self-aggregation) often decreases their solubility and reactivity. Recently, scientists have found a promising way around this problem by immobilizing the hydrogen-bonding organocatalysts on metal–organic frameworks (MOFs). Along with advantageous modular synthesis and recycling properties, the tunable porosity and topology of MOFs also allows fast mass transport and/or interactions with substrates. Herein, we highlight the existing examples dealing with the fabrication and testing of hydrogen-bonding organocatalyst-containing MOFs, providing also our vision for further advances in this area. The results derived from these studies will likely serve as inspiration for the future development of superior hydrogen-bonding organocatalysts to accomplish in confined spaces chemical transformations that are either slow or unaffordable under standard homogeneous conditions

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)

Contaminación lumínica en el Anillo verde de Vitoria-Gasteiz

Este trabajo ha consistido en tomar mediciones de la cantidad de iluminación que reciben distintos ecosistemas alrededor de la ciudad de Vitoria-Gasteiz, para posteriormente analizar y valorar esas mediciones. En primer lugar, se hizo una valoración medioambiental de los distintos espacios, haciendo referencia a los servicios ambientales que prestan y a la flora y fauna presente. En segundo lugar, se tomaron mediciones de la contaminación lumínica de los distintos espacios para así poder comparar y analizar posibles diferencias existentes. Posteriormente se han expuesto los efectos adversos de la contaminación lumínica sobre la salud y el medio ambiente. Por último, se han propuesto actuaciones para mitigar la contaminación lumínica y así contribuir al ahorro energético.<br /