Sustainable and cost-effective development of chiral metal-catalysts for C-H and C-X bond forming reactions

L’obtenció de compostos enantiomèricament purs ha esdevingut una necessitat que ha conduit a un important progrés en la catàlisi asimètrica, principalment usant compostos organometàl•lics quirals. Entre les diferents estratègies en l’optimització dels catal•litzadors per aconseguir elevades selectivitats i activitats, el disseny i correcta selecció de lligands quirals, modificant-ne les seves propietats és fonamental i la més utilitzada. Que un lligand sigui fàcil de sintetitzar a partir de compostos de partida accessibles i que aquests lligands siguin estables i fàcils de manipular, tenen un elevat interès en la industria. En aquest context, el principal objectiu d’aquesta tesi és la síntesi de diferents famílies de lligands quirals, acomplint els requisits prèviament esmentats, i la seva posterior aplicació a diverses reaccions asimètriques d’elevat interès industrial: hidrogenació d’olefines funcionalitzades i no funcionalitzades catalitzada per Rh i Ir, hidrogenació de cetones catalitzada per Ir, reaccions de substitució al•lílica catalitzades per Pd i reaccions de substitució propargílica catalitzada per Cu. S’han sintetitzat diverses famílies fosfit/fosfinit-tioèter/selenoèter, carbè-tioèter, amino-fosfit/fosfinit/fosfina, i varies famílies de lligands tridentats.La obtención de compuestos enantioméricamente puros se ha convertido una necesidad que ha conducido a un importante progreso en la catálisis asimétrica, principalmente usando compuestos organometalicos quirales. Entre las diferentes estrategias en la optimización de los catalizadores para conseguir elevadas selectividades y actividades, el diseño y la correcta selección de ligandos quirales, modificando sus propiedades es fundamental y la más utilizada. Que un ligando sea fácil de sintetizar a partir de compuestos de partida accesibles y que estos ligandos sean estables y fáciles de manipular, tienen un elevado interés en la industria. En este contexto, el principal objetivo de esta tesis es la síntesis de distintas familias de ligandos quirales, cumpliendo con los requisitos previamente mencionados, y su posterior aplicación en distintas reacciones asimétricas de alto interés industrial: hidrogenación de alquenos funcionalizados y no funcionalizados catalizados por Rh y Ir, hidrogenación de cetonas catalizada por Ir, reacciones de substitución alílica catalizada por Pd y reacciones de substitución propargílica catalizada por Cu. Se han sintetizado diferentes familias de ligandos Fosfito/fosfinito-tioéter/selenoéter, carbeno-tioéter, amino-fosfito/fosfinito/fosfina, y varias familias de ligandos tridentados.The obtaining of enantiomerically pure compounds has become a need that led to an important progress in asymmetric catalysis, mainly using organometallic chiral compounds. Among different strategies to optimize catalysts in order to obtain high selectivities and activities, the design and the correct selection of chiral ligands, modifying their properties, is fundamental and the most used strategy. Ligands easy to synthesize from readily accessible starting material and stable and easy to manipulate ligands, have a high interest in the industry. In this context, the main objective of this thesis is the synthesis of different chiral ligand families, according to the previously mentioned requirements, and their application in different asymmetric reactions with high industrial interest: Rh- and Ir-catalyzed hydrogenation of functionalized and minimally functionalized olefins; Ir-catalyzed hydrogenation of simple ketones; Pd-catalyzed asymmetric substitution of allylic acetates and Cu-catalyzed propargylic substitution. There have been synthesized different phosphite/phosphinite-thioether/selenoether, carbene-thioether, amino-phosphite/phosphinite/phosphine and various tridentated ligand families

Density Functional Theory-Inspired Design of Ir/P,S-Catalysts for Asymmetric Hydrogenation of Olefins

In silico-based optimization of Ir/P,S-catalysts for the asymmetric hydrogenation of unfunctionalized olefins using (E)-1-(but-2-en-2-yl)-4-methoxybenzene as a benchmark olefin has been carried out. DFT calculations revealed that the thioether group has a major role in directing the olefin coordination. This, together with the configuration of the biphenyl phosphite group, has an impact in maximizing the energy gap between the most stable transition states leading to opposite enantiomers. As a result, the optimized catalyst proved to be efficient in the hydrogenation of a range of alkenes with the same substitution pattern and olefin geometry as the benchmark olefin, regardless of the presence of functional groups with different coordination abilities (ee values up to 97%). Appealingly, further modifications at the thioether groups and at the biaryl phosphite moiety allowed the highly enantioselective hydrogenation of olefins with different substitution patterns (e.g., α,β-unsaturated lactones and lactams, 1,1′-disubstituted enol phosphinates, and cyclic β-enamides; ee values up to >99%).We gratefully acknowledge financial support from the Spanish Ministry of Science and Innovation (PID2019-104904GB-I00, PGC2018-100780-B-I00, and PGC2018-096616-B-I00), European Regional Development Fund (AEI/FEDER, UE), the Catalan Government (2017SGR1472), and the University of Alicante (VOGROB-316FI). M.B. also thanks the URV for generous support

The economic burden of disease of epithelial ovarian cancer in Spain: the OvarCost study

bjective: To assess the economic burden of epithelial ovarian cancer (EOC) in incident patients and the burden by disease stage in Spain. Methods: We developed a Markov model from a social perspective simulating the natural history of EOC and its four stages, with a 10-year time horizon, 3-week cycles, 3% discount rate, and 2016 euros. Healthcare resource utilization and costs were estimated by disease stage. Direct healthcare costs (DHC) included early screening, genetic counselling, medical visits, diagnostic tests, surgery, chemotherapy, hospitalizations, emergency services, and palliative care. Direct non-healthcare costs (DNHC) included formal and informal care. Indirect costs (IC) included labour productivity losses due to temporary and permanent leaves, and premature death. Epidemiology data and resource use were taken from the literature and validated for Spain by the OvarCost group using a Delphi method. Results: The total burden of EOC over 10 years was 3102 mill euros: 15.1% in stage I, 3.9% in stage II, 41.0% in stage III, and 40.2% in stage IV. Annual average cost/patient was 24,111 and it was 8,641; 14,184; 33,858, and 42,547 in stages I-IV, respectively. Of total costs, 71.2% were due to DHC, 24.7% to DNHC, and 4.1% to IC. Conclusions: EOC imposes a significant economic burden on the national healthcare system and society in Spain. Investment in better early diagnosis techniques might increase survival and patients' quality of life. This would likely reduce costs derived from late stages, consequently leading to a substantial reduction of the economic burden associated with EOC

TFG 2012/2013

Amb aquesta publicació, EINA, Centre universitari de Disseny i Art adscrit a la Universitat Autònoma de Barcelona, dóna a conèixer el recull dels Treballs de Fi de Grau presentats durant el curs 2012-2013. Voldríem que un recull com aquest donés una idea més precisa de la tasca que es realitza a EINA per tal de formar nous dissenyadors amb capacitat de respondre professionalment i intel·lectualment a les necessitats i exigències de la nostra societat. El treball formatiu s’orienta a oferir resultats que responguin tant a paràmetres de rigor acadèmic i capacitat d’anàlisi del context com a l’experimentació i la creació de nous llenguatges, tot fomentant el potencial innovador del disseny.Con esta publicación, EINA, Centro universitario de diseño y arte adscrito a la Universidad Autónoma de Barcelona, da a conocer la recopilación de los Trabajos de Fin de Grado presentados durante el curso 2012-2013. Querríamos que una recopilación como ésta diera una idea más precisa del trabajo que se realiza en EINA para formar nuevos diseñadores con capacidad de responder profesional e intelectualmente a las necesidades y exigencias de nuestra sociedad. El trabajo formativo se orienta a ofrecer resultados que respondan tanto a parámetros de rigor académico y capacidad de análisis, como a la experimentación y la creación de nuevos lenguajes, al tiempo que se fomenta el potencial innovador del diseño.With this publication, EINA, University School of Design and Art, ascribed to the Autonomous University of Barcelona, brings to the public eye the Final Degree Projects presented during the 2012-2013 academic year. Our hope is that this volume might offer a more precise idea of the task performed by EINA in training new designers, able to speak both professionally and intellectually to the needs and demands of our society. The educational task is oriented towards results that might respond to the parameters of academic rigour and the capacity for contextual analysis, as well as to considerations of experimentation and the creation of new languages, all the while reinforcing design’s innovative potential

Sustainable and cost-effective development of chiral metal-catalysts for C-H and C-X bond forming reactions

L’obtenció de compostos enantiomèricament purs ha esdevingut una necessitat que ha conduit a un important progrés en la catàlisi asimètrica, principalment usant compostos organometàl•lics quirals. Entre les diferents estratègies en l’optimització dels catal•litzadors per aconseguir elevades selectivitats i activitats, el disseny i correcta selecció de lligands quirals, modificant-ne les seves propietats és fonamental i la més utilitzada. Que un lligand sigui fàcil de sintetitzar a partir de compostos de partida accessibles i que aquests lligands siguin estables i fàcils de manipular, tenen un elevat interès en la industria. En aquest context, el principal objectiu d’aquesta tesi és la síntesi de diferents famílies de lligands quirals, acomplint els requisits prèviament esmentats, i la seva posterior aplicació a diverses reaccions asimètriques d’elevat interès industrial: hidrogenació d’olefines funcionalitzades i no funcionalitzades catalitzada per Rh i Ir, hidrogenació de cetones catalitzada per Ir, reaccions de substitució al•lílica catalitzades per Pd i reaccions de substitució propargílica catalitzada per Cu. S’han sintetitzat diverses famílies fosfit/fosfinit-tioèter/selenoèter, carbè-tioèter, amino-fosfit/fosfinit/fosfina, i varies famílies de lligands tridentats.La obtención de compuestos enantioméricamente puros se ha convertido una necesidad que ha conducido a un importante progreso en la catálisis asimétrica, principalmente usando compuestos organometalicos quirales. Entre las diferentes estrategias en la optimización de los catalizadores para conseguir elevadas selectividades y actividades, el diseño y la correcta selección de ligandos quirales, modificando sus propiedades es fundamental y la más utilizada. Que un ligando sea fácil de sintetizar a partir de compuestos de partida accesibles y que estos ligandos sean estables y fáciles de manipular, tienen un elevado interés en la industria. En este contexto, el principal objetivo de esta tesis es la síntesis de distintas familias de ligandos quirales, cumpliendo con los requisitos previamente mencionados, y su posterior aplicación en distintas reacciones asimétricas de alto interés industrial: hidrogenación de alquenos funcionalizados y no funcionalizados catalizados por Rh y Ir, hidrogenación de cetonas catalizada por Ir, reacciones de substitución alílica catalizada por Pd y reacciones de substitución propargílica catalizada por Cu. Se han sintetizado diferentes familias de ligandos Fosfito/fosfinito-tioéter/selenoéter, carbeno-tioéter, amino-fosfito/fosfinito/fosfina, y varias familias de ligandos tridentados.The obtaining of enantiomerically pure compounds has become a need that led to an important progress in asymmetric catalysis, mainly using organometallic chiral compounds. Among different strategies to optimize catalysts in order to obtain high selectivities and activities, the design and the correct selection of chiral ligands, modifying their properties, is fundamental and the most used strategy. Ligands easy to synthesize from readily accessible starting material and stable and easy to manipulate ligands, have a high interest in the industry. In this context, the main objective of this thesis is the synthesis of different chiral ligand families, according to the previously mentioned requirements, and their application in different asymmetric reactions with high industrial interest: Rh- and Ir-catalyzed hydrogenation of functionalized and minimally functionalized olefins; Ir-catalyzed hydrogenation of simple ketones; Pd-catalyzed asymmetric substitution of allylic acetates and Cu-catalyzed propargylic substitution. There have been synthesized different phosphite/phosphinite-thioether/selenoether, carbene-thioether, amino-phosphite/phosphinite/phosphine and various tridentated ligand families

Sustainable and cost-effective development of chiral metal-catalysts for C-H and C-X bond forming reactions

L’obtenció de compostos enantiomèricament purs ha esdevingut una necessitat que ha conduit a un important progrés en la catàlisi asimètrica, principalment usant compostos organometàl•lics quirals. Entre les diferents estratègies en l’optimització dels catal•litzadors per aconseguir elevades selectivitats i activitats, el disseny i correcta selecció de lligands quirals, modificant-ne les seves propietats és fonamental i la més utilitzada. Que un lligand sigui fàcil de sintetitzar a partir de compostos de partida accessibles i que aquests lligands siguin estables i fàcils de manipular, tenen un elevat interès en la industria. En aquest context, el principal objectiu d’aquesta tesi és la síntesi de diferents famílies de lligands quirals, acomplint els requisits prèviament esmentats, i la seva posterior aplicació a diverses reaccions asimètriques d’elevat interès industrial: hidrogenació d’olefines funcionalitzades i no funcionalitzades catalitzada per Rh i Ir, hidrogenació de cetones catalitzada per Ir, reaccions de substitució al•lílica catalitzades per Pd i reaccions de substitució propargílica catalitzada per Cu. S’han sintetitzat diverses famílies fosfit/fosfinit-tioèter/selenoèter, carbè-tioèter, amino-fosfit/fosfinit/fosfina, i varies famílies de lligands tridentats.La obtención de compuestos enantioméricamente puros se ha convertido una necesidad que ha conducido a un importante progreso en la catálisis asimétrica, principalmente usando compuestos organometalicos quirales. Entre las diferentes estrategias en la optimización de los catalizadores para conseguir elevadas selectividades y actividades, el diseño y la correcta selección de ligandos quirales, modificando sus propiedades es fundamental y la más utilizada. Que un ligando sea fácil de sintetizar a partir de compuestos de partida accesibles y que estos ligandos sean estables y fáciles de manipular, tienen un elevado interés en la industria. En este contexto, el principal objetivo de esta tesis es la síntesis de distintas familias de ligandos quirales, cumpliendo con los requisitos previamente mencionados, y su posterior aplicación en distintas reacciones asimétricas de alto interés industrial: hidrogenación de alquenos funcionalizados y no funcionalizados catalizados por Rh y Ir, hidrogenación de cetonas catalizada por Ir, reacciones de substitución alílica catalizada por Pd y reacciones de substitución propargílica catalizada por Cu. Se han sintetizado diferentes familias de ligandos Fosfito/fosfinito-tioéter/selenoéter, carbeno-tioéter, amino-fosfito/fosfinito/fosfina, y varias familias de ligandos tridentados.The obtaining of enantiomerically pure compounds has become a need that led to an important progress in asymmetric catalysis, mainly using organometallic chiral compounds. Among different strategies to optimize catalysts in order to obtain high selectivities and activities, the design and the correct selection of chiral ligands, modifying their properties, is fundamental and the most used strategy. Ligands easy to synthesize from readily accessible starting material and stable and easy to manipulate ligands, have a high interest in the industry. In this context, the main objective of this thesis is the synthesis of different chiral ligand families, according to the previously mentioned requirements, and their application in different asymmetric reactions with high industrial interest: Rh- and Ir-catalyzed hydrogenation of functionalized and minimally functionalized olefins; Ir-catalyzed hydrogenation of simple ketones; Pd-catalyzed asymmetric substitution of allylic acetates and Cu-catalyzed propargylic substitution. There have been synthesized different phosphite/phosphinite-thioether/selenoether, carbene-thioether, amino-phosphite/phosphinite/phosphine and various tridentated ligand families

IKKα kinase regulates the DNA damage response and drives chemo-resistance in cancer

Phosphorylated IKKalpha(p45) is a nuclear active form of the IKKalpha kinase that is induced by the MAP kinases BRAF and TAK1 and promotes tumor growth independent of canonical NF-¿B signaling. Insights into the sources of IKKalpha(p45) activation and its downstream substrates in the nucleus remain to be defined. Here, we discover that IKKalpha(p45) is rapidly activated by DNA damage independent of ATM-ATR, but dependent on BRAF-TAK1-p38-MAPK, and is required for robust ATM activation and efficient DNA repair. Abolishing BRAF or IKKalpha activity attenuates ATM, Chk1, MDC1, Kap1, and 53BP1 phosphorylation, compromises 53BP1 and RIF1 co-recruitment to sites of DNA lesions, and inhibits 53BP1-dependent fusion of dysfunctional telomeres. Furthermore, IKKalpha or BRAF inhibition synergistically enhances the therapeutic potential of 5-FU and irinotecan to eradicate chemotherapy-resistant metastatic human tumors in vivo. Our results implicate BRAF and IKKalpha kinases in the DDR and reveal a combination strategy for cancer treatment.This work was funded by grants from Instituto de Salud Carlos III FEDER (PIE15/00008 and PI16/00437), Generalitat de Catalunya 2017SGR135, and the “Xarxa de Bancs de Tumors” sponsored by Pla Director d’Oncologia de Catalunya (XBTC). C.C. is supported by FPI BES-2014-068451 and the EMBO Short-Term Fellowship (na7084). P.M. is supported by funding from the European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement #702430. The Boulton lab is supported by The Francis Crick Institute, which receives its core funding from Cancer Research UK (FC0010048), the UK Medical Research Council (FC0010048), and the Wellcome Trust (FC0010048). S.J.B. is funded by European Research Council (ERC) Advanced Investigator Grants (TelMetab) and a Wellcome Trust Senior Investigator Grant. The Centre de Regulació Genòmica/Universitat Pompeu Fabra Proteomics Unit is part of the “Plataforma de Recursos Biomoleculares y Bioinformáticos (ProteoRed)” supported by grant PT13/0001 of Instituto de Salud Carlos III from the Spanish government and “Secretaria d’Universitats i Recerca del Departament d’Economia i Coneixement de la Generalitat de Catalunya” (2014SGR678). We acknowledge support from the Spanish Ministry of Economy and Competitiveness and “Centro de Excelencia Severo Ochoa 2013-2017” (SEV-2012-0208)

IKKα kinase regulates the DNA damage response and drives chemo-resistance in cancer

Phosphorylated IKKalpha(p45) is a nuclear active form of the IKKalpha kinase that is induced by the MAP kinases BRAF and TAK1 and promotes tumor growth independent of canonical NF-¿B signaling. Insights into the sources of IKKalpha(p45) activation and its downstream substrates in the nucleus remain to be defined. Here, we discover that IKKalpha(p45) is rapidly activated by DNA damage independent of ATM-ATR, but dependent on BRAF-TAK1-p38-MAPK, and is required for robust ATM activation and efficient DNA repair. Abolishing BRAF or IKKalpha activity attenuates ATM, Chk1, MDC1, Kap1, and 53BP1 phosphorylation, compromises 53BP1 and RIF1 co-recruitment to sites of DNA lesions, and inhibits 53BP1-dependent fusion of dysfunctional telomeres. Furthermore, IKKalpha or BRAF inhibition synergistically enhances the therapeutic potential of 5-FU and irinotecan to eradicate chemotherapy-resistant metastatic human tumors in vivo. Our results implicate BRAF and IKKalpha kinases in the DDR and reveal a combination strategy for cancer treatment.This work was funded by grants from Instituto de Salud Carlos III FEDER (PIE15/00008 and PI16/00437), Generalitat de Catalunya 2017SGR135, and the “Xarxa de Bancs de Tumors” sponsored by Pla Director d’Oncologia de Catalunya (XBTC). C.C. is supported by FPI BES-2014-068451 and the EMBO Short-Term Fellowship (na7084). P.M. is supported by funding from the European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement #702430. The Boulton lab is supported by The Francis Crick Institute, which receives its core funding from Cancer Research UK (FC0010048), the UK Medical Research Council (FC0010048), and the Wellcome Trust (FC0010048). S.J.B. is funded by European Research Council (ERC) Advanced Investigator Grants (TelMetab) and a Wellcome Trust Senior Investigator Grant. The Centre de Regulació Genòmica/Universitat Pompeu Fabra Proteomics Unit is part of the “Plataforma de Recursos Biomoleculares y Bioinformáticos (ProteoRed)” supported by grant PT13/0001 of Instituto de Salud Carlos III from the Spanish government and “Secretaria d’Universitats i Recerca del Departament d’Economia i Coneixement de la Generalitat de Catalunya” (2014SGR678). We acknowledge support from the Spanish Ministry of Economy and Competitiveness and “Centro de Excelencia Severo Ochoa 2013-2017” (SEV-2012-0208)