Fitting the catalysts for effective enantioselective C-X bond forming reactions. Theoretically guided ligand design and mechanistic investigations

La creixent demanda de compostos enantiomèricament purs, ha incrementat l’interès pel desenvolupament de metodologies per l’obtenció d'aquests compostos. Entre elles, la catàlisi asimètrica és la tècnica més emprada. En aquesta metodologia, l'elecció lligand quiral és clau per l'obtenció de elevades activitats i enantioselectivitats. En aquest context, aquesta tesis és centra en la síntesis de diferents famílies de lligands quirals altament modulars a partir de productes de partida d'elevada disponibilitat. Més concretament, s’han sintetitzat diverses famílies de lligands heterodadors P-oxazolina (P= fosfina, fosfinit, fosfit, fosforamidit), P-altres grups N-dadors (P= fosfit, fosforamidit, fosfonit i N= tiazol, sulfoximina, hidrazona, amina, piridina), P-tioèter (P= fosfina, fosfinit, fosfit) i una família de lligands fosfina quiral-fosfit. Aquests lligands s'han aplicat en la reacció d’hidrogenació d’olefines funcionalitzades i mínimament funcionalitzades catalitzada per Rh i Ir, la reacció de substitució al·lílica i la reacció de protonació descarboxilativa d’oxindoles ambdues catalitzades per Pd. A més a més, en alguns casos, s'han dut a terme estudis computacionals en combinació amb assajos experimentals per estudiar l'origen de les enantioselectivitats obtingudes o bé per guiar l'optimització dels lligand.La creciente demanda de compuestos enantioméricamente puros, ha incrementado el interés por el desarrollo de metodologías para la obtención de dichos compuestos. Entre ellas, la catálisis asimétrica es la técnica mas utilizada. En dicha metodología, la elección del ligando quiral es clave para la obtención de elevada actividades i enantioselectividades. En este contexto, esta tesis se centra en la síntesis de diferentes familias de ligandos quirales altamente modulares a partir de productos de partida de elevada disponibilidad. Más concretamente, se ha trabajado en la síntesis de ligandos heterodadores P-oxazoline (P= fosfina, fosfinito, fosfito, fosforamidito), P-otros grupos N-dadores (P= fosfito, fosforamidito, fosfonito y N= tiazol, sulfoximina, hidrazona, amina, piridina), P-tioéter (P= fosfina, fosfinito, fosfito) i una familia de ligandos fosfina quiral-fosfito. Estos ligandos se han aplicado en la reacción de hidrogenación de olefinas funcionalitzadas i mínimamente funcionalitzadas catalizada por Rh i Ir, la reacción de substitución alílica y la reacción de protonación descarboxilativa de oxindolas ambas catalizadas por Pd. Además, en algunos casos, se han realizado cálculos computacionales en combinación con ensayos experimentales para estudiar el origen de las enantioselectividades obtenidas o bien para guiar la optimización de los ligandos.The growing demand on enantiomerically pure compounds has stimulated the interest for the development of methodologies to obtain these compounds. Among them, asymmetric catalysis is one of the most employed tools. In this technic, the choice of the chiral ligand is fundamental to obtain high levels of activity and enantioselectivity. In this context, this thesis is focused on the synthesis of several families of highly modular chiral ligands from readily available starting materials. Particularly, we worked on the synthesis of P-oxazoline (P= phosphine, phosphinite, phosphite, phosphoroamidite), P-other N-donor groups (P= phosphite, phosphoroamidite, phosphonite and N= thiazole, sulfoximine, hydrazone, amine, pyridine), P-thioether (P= phosphine, phosphinite, phosphite) and a family of P*-stereogenic phosphine-phosphite ligands. These ligands have been applied in the Rh- and Ir-catalyzed hydrogenation of functionalized and minimally functionalized olefins, Pd-catalyzed allylic substitution reaction and Pd-catalyzed decarboxylative protonation. Furthermore, in some cases, DFT studies in combination with experimental ones have been performed to better understand the origin of the obtained enantioselectivities or in order to guide the ligand optimization

Desarrollo comunitario en la 20 de noviembre: mediante el ocio y el tiempo libre como herramienta

Treball final de Màster Universitari en Cooperació al Desenvolupament. Codi: SRP531. Curs acadèmic 2016-2017Este trabajo recoge la experiencia de prácticas reflejada en proyecto de acción participativa para el desarrollo comunitario de uno de los barrios de la ciudad de Esmeraldas, Ecuador. El hilo conductor de esta intervención ha sido el ocio y tiempo libre, centrados en el desarrollo de habilidades y capacidades de los y las menores, jóvenes, y personas de edad adulta del barrio 20 de noviembre en Esmeraldas.Ofreciendo oportunidades y un acompañamiento para su empoderamiento y lograr la autogestión Se aprecia en esta experiencia la creación de espacios que den paso al diálogo y a la crítica constructiva, mejora en habilidades sociales y hábitos de la vida cotidiana de los vecinos y vecinas, mayor capacidad de autogestión, capacidad para desarrollar ocio alternativo y sostenible con el medioambiente, un fortalecimiento del tejido social del Barrio 20 de Noviembre en Esmeraldas.This work reflects the experience of practices reflected in a participatory action project for the community development of one of the neighborhoods of the city of Esmeraldas, Ecuador. The driving force behind this intervention has been leisure and free time, focused on the development of skills and abilities of the minors, youth, and adults of the neighborhood November 20 in Esmeraldas. Offering opportunities and accompaniment for their empowerment and self-management. In this experience, the creation of spaces that give way to dialogue and constructive criticism, improvement in social skills and habits of the daily life of neighbors and neighbors, greater capacity for self-management, capacity to develop alternative and sustainable leisure with the environment, A strengthening of the social fabric of Barrio 20 de Noviembre in Esmeraldas

Nonexistence of almost Moore digraphs of degrees 4 and 5 with self-repeats

An almost Moore (d,k)-digraph is a regular digraph of degree d>1, diameter k>1 and order N(d,k)=d+d2+⋯+dk. So far, their existence has only been shown for k=2, whilst it is known that there are no such digraphs for k=3, 4 and for d=2, 3 when k≥3. Furthermore, under certain assumptions, the nonexistence for the remaining cases has also been shown. In this paper, we prove that (4,k) and (5,k)-almost Moore digraphs with self-repeats do not exist for k≥5.Nacho López: Supported in part by grants PID2020-115442RB-I00 and 2021 SGR-00434. Arnau Messegué: Supported in part by grants Margarita Sala and 2021SGR-00434. Josep M. Miret: Supported in part by grants PID2021-124613OB-I00 and 2021 SGR-00434.Peer ReviewedPostprint (published version

Capacidad predictiva de las escalas de valoración de riesgo de úlceras por presión y otras lesiones relacionadas con la dependencia en el paciente crítico

Les úlceres per pressió (UPP) suposen un problema de salut que afecta tots els nivells assistencials i que adquireix una especial rellevància a les Unitats de Cures Intensives on trobem nivells de prevalença molt alts. Històricament el terme "úlcera per pressió" ha estat l'empleat per a denominar tant a aquelles lesions on el mecanisme causal és la pressió, com a aquelles que responen a etiologies diferents. Agrupar sota un únic nom (UPP) a lesions on l'origen és en ocasions molt diferent a la pressió, pot dificultar la tasca preventiva orientada a contrarestar els efectes dels diferents mecanismes causals. Això va portar a García-Fernández et al. al desenvolupament d'una teoria infermera que incloïa la construcció d'un nou model que explica, no només el mecanisme de producció de les UPP, sinó el de fins a set tipus de lesions diferents a les que van denominar Lesions relacionades amb la dependència (LRD). La valoració integral del pacient es planteja com l'element primordial en la prevenció de les UPP i altres LRD i inclou entre d'altres, la valoració del risc mitjançant una escala validada. Com que totes les escales van ser elaborades per pronosticar UPP i no un altre tipus de lesions, aquest estudi de caràcter quantitatiu i dissenyat en dues fases ben diferenciades, es planteja com a objectiu analitzar i comparar la validesa i capacitat predictiva de tres escales (EMINA, EVARUCI i Braden) per pronosticar LRD en una població de pacients crítics. En definitiva, pretén apropar la teoria a la pràctica a la recerca del millor coneixement infermer que condueixi a una millora en la seguretat del pacient.Las ulceras por presión (UPP) suponen un problema de salud que afecta a todos los niveles asistenciales y que adquiere una especial relevancia en las Unidades de Cuidados Intensivos donde encontramos niveles de prevalencia muy altos. Históricamente el término “úlcera por presión” ha sido el empleado para denominar tanto a aquellas lesiones cuyo mecanismo causal es la presión, como a aquellas que responden a etiologías distintas. Agrupar bajo un único nombre (UPP) a lesiones cuyo origen es en ocasiones muy distinto a la presión, puede entorpecer la labor preventiva orientada a contrarrestar los efectos de los diferentes mecanismos causales. Esto llevó a García-Fernández et al. al desarrollo de una teoría enfermera que incluía la construcción de un nuevo modelo que explica, no sólo el mecanismo de producción de las UPP, sino el de hasta siete tipos de lesiones distintas a las que denominaron Lesiones relacionadas con la dependencia (LRD). La valoración integral del paciente se plantea como el elemento primordial en la prevención de las UPP y otras LRD e incluye entre otros, la valoración del riesgo mediante una escala validada. Puesto que todas las escalas fueron elaboradas para pronosticar UPP y no otro tipo de lesiones, este estudio de carácter cuantitativo y diseñado en dos fases bien diferenciadas, se plantea como objetivo analizar y comparar la validez y capacidad predictiva de tres escalas (EMINA, EVARUCI y Braden) para pronosticar LRD en una población de pacientes críticos. En definitiva, pretende acercar la teoría a la práctica en busca del mejor conocimiento enfermero que conduzca a una mejora en la seguridad del paciente.Pressure ulcers (PU) are a health problemthat affects to all care levels and acquires special relevant in Intensive Care Units where we find very high prevalence levels. Historically, the term “pressure ulcers” has been used to name those injuries caused by pressure as well as those related to different etiologies. Enclosing under a unique name (PU) theinjuries which origin is very different to the pressure can hinder the preventive labour oriented to counteract the effects of the different causal mechanisms. This led to García-fernández et al. to the development of a nursing theory that included the construction of a new model that explains, not only the pathophysiology of the PU, but up to seven different lesions that were named Lesions related with the dependency (DRL). The comprehensive evaluation of the patient is proposed as the main element in the prevention of PU and other DRL and includes, among others, the evaluation of the risk through a validated scale. Because all the scales were created to diagnose PU rather than other types of DRL, this quantitative study and designed in two differentiated phases, aims to analyse and compare the validity and predictive capacity of three scales (EMINA, EVARUCI and Braden) to diagnose DRL in critically ill patients. In conclusion, it aims to approach the theory to the clinical practice in the search of the best nursing knowledge that enhances an improvement in patient safety

Environmental exposure to chlorpyrifos during gestation, APOE polymorphism and the risk on autistic-like behaviors

Autism spectrum disorder (ASD) encompasses several neurodevelopmental conditions characterized by communication and social impairment, as well as repetitive patterns of behavior. However, it can co-occur with other mental conditions such as anxiety. The massive use of chlorpyrifos (CPF) has been linked to the increased prevalence of developmental disorders. Likewise, ASD has also been closely linked to a wide variety of genetic factors. The aims of the present investigation are to study how gestational CPF exposure and APOE polymorphism affects communication skills, early development and mid-term anxiety-like behaviors, as well as, changes in gene expression related to the cholinergic system. C57BL/6J and humanized apoE3 and apoE4 homozygous mice were exposed to 0 or 1 mg/kg/day of CPF through the diet, from gestational day (GD) 12-18. In addition, a group of C57BL/6J females were injected subcutaneously with 300 mg/kg/day of valproic acid (VPA) on GD 12 and 13. This group was used as a positive control for studying some core and associated autism-like behaviors. Communication skills by means of ultrasonic vocalizations and physical/motor development were assessed during the preweaning period, whereas locomotor activity, anxiety-like behaviors and the gene expression of cholinergic elements were evaluated during adolescence. Our results showed that C57BL/6J mice prenatally exposed to CPF or VPA showed a decrease in body weight and a delay in eye opening. Communication and anxiety behavior were affected differently depending on treatment, while gene expression was altered by sex and treatment. In addition, none of the parameters evaluated in apoE transgenic mice exposed to CPF were affected, but there were differences between genotypes. Therefore, we suggest that prenatal CPF exposure and VPA produce divergent effects on communication and anxiety. Keywords: APOE genotype; Anxiety; Autism; Chlorpyrifos; Cholinergic system; Development; Ultrasonic vocalizations

Nonexistence of almost Moore digraphs of diameter four

Regular digraphs of degree d > 1, diameter k > 1 and order N(d; k) = d+ +dk will be called almost Moore (d; k)-digraphs. So far, the problem of their existence has only been solved when d = 2; 3 or k = 2; 3. In this paper we prove that almost Moore digraphs of diameter 4 do not exist for any degree dPostprint (published version

The influence of environmental particulate matter exposure during late gestation and early life on the risk of neurodevelopmental disorders: a systematic review of experimental evidences

Particulate matter (PM) is a major component of ambient air pollution (AAP), being widely associated with adverse health effects. Epidemiological and experimental studies point towards a clear implication of AAP on the development of central nervous system (CNS) diseases. In this sense, the period of most CNS susceptibility is early life, when the CNS is maturing. In humans the last trimester of gestation is crucial for brain maturation while in rodents, due to the shorter gestational period, the brain is still immature at birth, and early postnatal development plays a significant role. The present systematic review provides an updated overview and discusses the existing literature on the relationship between early exposure to PM and neurodevelopmental outcomes in experimental studies. We included 11 studies with postnatal exposure and 9 studies with both prenatal and postnatal exposure. Consistent results between studies suggest that PM exposure could alter normal development, triggering impairments in short-term memory, sociability, and impulsive-like behavior. This is also associated with alterations in synaptic plasticity and in the immune system. Interestingly, differences have been observed between sexes, although not all studies included females. Furthermore, the developmental window of exposure seems to be crucial for effects to be observed in the future. In summary, air pollution exposure during development affects subjects in a time- and sex-dependent manner, the postnatal period being more important and being males apparently more sensitive to exposure than females. Nevertheless, additional experimental investigations should prioritize the examination of learning, impulsivity, and biochemical parameters, with particular attention provided to disparities between sexes

Extending the substrate scope in the hydrogenation of unfunctionalized tetrasubstituted olefins with Ir-P stereogenic aminophosphine-oxazoline catalysts

Air stable and readily available Ir-catalyst precursors modified with MaxPHOX-type ligands have been successfully applied in the challenging asymmetric hydrogenation of tetrasubstituted olefins under mild reaction conditions. Gratifyingly, these catalyst precursors are not only able to efficiently hydrogenate a range of indene derivatives (ee's up to 96%) but also 1,2-dihydro-napthalene derivatives and acyclic olefins (ee's up to 99%), which both constitute the most challenging substrates for this transformation

P-Stereogenic Ir-MaxPHOX: A Step toward Privileged Catalysts for Asymmetric Hydrogenation of Nonchelating Olefins

The Ir-MaxPHOX-type catalysts demonstrated high catalytic performance in the hydrogenation of a wide range of nonchelating olefins with different geometries, substitution patterns, and degrees of functionalization. These air-stable and readily available catalysts have been successfully applied in the asymmetric hydrogenation of di-, tri-, and tetrasubstituted olefins (ee′s up to 99%). The combination of theoretical calculations and deuterium labeling experiments led to the uncovering of the factors responsible for the enantioselectivity observed in the reaction, allowing the rationalization of the most suitable substrates for these Ir-catalysts