Synthesis of Cyclopropylboronates and Allylic Alcohols via Copper-Catalyzed Borylation Reactions

Tesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Química Orgánica. Fecha de lectura: 24-11-2017Esta tesis tiene embargado el acceso al texto completo hasta el 24-05-2019Esta Tesis Doctoral ha sido realizada en el Departamento de Química Orgánica de la Universidad Autónoma de Madrid, bajo la dirección de la Doctora Mariola Tortosa Manzanares. Este trabajo ha sido financiado por el ‘European Research Council’ (ERC-337776), así como por MINECO (CTQ2012-35957)

Stereospecific synthesis of α-hydroxy-cyclopropylboronates from allylic epoxides

This is the peer reviewed version of the following article: Angewandte Chemie - International Edition 58.10 (2019): 3188-03192, which has been published in final form at https://doi.org/10.1002/anie.201812836. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived VersionsWe report a catalytic and stereospecific method for the preparation of enantioenriched α-hydroxy cyclopropylboronates with control in four contiguous stereocenters. The reaction involves the borylation of readily available allylic epoxides using an inexpensive Cu(I) salt and a commercially available phosphine ligand. High diastereocontrol is achieved and different diastereomers can be selectively prepared. Functionalization of the carbon–boron bond provides access to different enantiomerically enriched trisubstituted cyclopropanes from a common intermediateWe thank the European Research Council (ERC-337776) and MINECO (CTQ2016-78779-R) for financial suppor

Harnessing the elusive 1,4-reduction of vinyl epoxides through copper catalysis

This document is the Accepted Manuscript version of a Published Work that appeared in final form in ACS Catalysis, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://pubs.acs.org/doi/10.1021/acscatal.9b02005We present an efficient strategy for the formal 1,4-reduction of vinyl epoxides that does not require superstoichiometric amounts of a strong reductant. Using a readily available copper catalyst and a diboron compound, a wide variety of enantioenriched allylic alcohols have been prepared. Additionally, epoxyenynes have been reduced in a 1,4-manner to selectively afford skipped enynes or skipped dienes.We thank the European Research Council (ERC-337776) and MINECO (CTQ2016-78779-R) for financial suppor

Stereoselective traceless borylation–allenation of propargylic epoxides: dual role of the copper catalyst

This is the peer reviewed version of the following article: Chemistry: A European Journal 23.69 (2017): 17478 –17481, which has been published in final form at http://doi.org/10.1002/chem.201705019. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-ArchivingChiral α-allenols are prepared with high diastereocontrol through an unprecedented and spontaneous β-oxygen elimination of an α-epoxy vinyl boronate. Stochiometric experiments and DFT calculations support a dual role of the copper catalyst, which orchestrates the hydroboration and the syn-elimination stepThe European ResearchCouncil (ERC-337776) and MINECO (CTQ2016-78779-R) for financial support M.T.thanks MICINNfor a RyC contrac

Insight into the copper-catalyzed borylation of strained alkenes

This document is the accepted manuscript version of a published work that appeared in final form in Synlett 2015; 26(04): 494-500, copyright © Georg Thieme Verlag Stuttgart · New York after peer review and technical editing by the publisher. To access the final online work see DOI: 10.1055/s-0034-1379882The copper-catalyzed hydro- and carboboration of strain alkenes is presented. The reaction is highly diastereoselective and affords boronic ester derivatives many of which are difficult to synthesize by known methods. Competition experiments with different alkenes show that high levels of chemoselectivity can be achieved. DFT calculations are in agreement with the observed chemoselectivityWe thank the European Research Council (ERC-337776) and MINECO (CTQ2012-35957 and CTQ2013-43698-P) for financial support. M. T. and S. D.-T thank MINECO for RyC contracts. A. P. thanks MINECO for JyC contrac

Cyclobutene vs 1,3-Diene Formation in the Gold-Catalyzed Reaction of Alkynes with Alkenes : The Complete Mechanistic Picture

The intermolecular gold(I)-catalyzed reaction between arylalkynes and alkenes leads to cyclobutenes by a [2 + 2] cycloaddition, which takes place stepwise, first by formation of cyclopropyl gold(I) carbenes, followed by a ring expansion. However, 1,3-butadienes are also formed in the case of ortho -substituted arylalkynes by a metathesis-type process. The corresponding reaction of alkenes with aryl-1,3-butadiynes, ethynylogous to arylalkynes, leads exclusively to cyclobutenes. A comprehensive mechanism for the gold(I)-catalyzed reaction of alkynes with alkenes is proposed on the basis of density functional theory calculations, which shows that the two pathways leading to cyclobutenes or dienes are very close in energy. The key intermediates are cyclopropyl gold(I) carbenes, which have been independently generated by retro-Buchner reaction from stereodefined 1a,7b-dihydro-1 H -cyclopropa[ a ]naphthalenes

Phase II study of preoperative bevacizumab, capecitabine and radiotherapy for resectable locally-advanced rectal cancer

Background: to evaluate whether the addition of bevacizumab (BVZ) to capecitabine-based chemoradiotherapy in the preoperative treatment of locally advanced rectal cancer (LARC) improves efficacy measured by the pathological complete response (pCR) rate. Methods: a phase II two-step design was performed. Patients received four cycles of therapy consisting of: BVZ 10 mg/kg in first infusion on day 1 and 5 mg/kg on days 15, 29, 43, capecitabine 1800 mg/m2/day 5 days per week during radiotherapy, which consisted of external-beam irradiation (45 Gy in 1.8 Gy dose per session over 5 sessions/week for 5 weeks). Six to eight weeks after completion of all therapies surgery was undergone. To profile the biological behaviour during BVZ treatment we measured molecular biomarkers before treatment, during BVZ monotherapy, and during and after combination therapy. Microvessel density (MVD) was measured after surgery. Results: forty-three patients were assessed and 41 were included in the study. Three patients achieved a pathological complete response (3/40: 7.5%) and 27 (67.5%) had a pathological partial response, (overall pathological response rate of 75%). A further 8 patients (20%) had stable disease, giving a disease control rate of 95%. Downstaging occurred in 31 (31/40: 77.5%) of the patients evaluated. This treatment resulted in an actuarial 4-year disease-free and overall survival of 85.4 and 92.7% respectively. BVZ with chemoradiotherapy showed acceptable toxicity. No correlations were observed between biomarker results and efficacy variables. Conclusion: BVZ with capecitabine and radiotherapy seem safe and active and produce promising survival results in LARC

Repercusión de la actualización del software del monitor 5008 en el volumen convectivo total

Introducción: La hemodiafiltración on-line (HDF-OL) se basa en la administración controlada de grandes volúmenes de sustitución de líquido de diálisis ultrapuro al circuito sanguíneo extracorpóreo de diálisis. Actualmente es la técnica más efectiva para la eliminación de toxinas urémicas de pequeño y gran tamaño. Recientes estudios han observado una asociación en el descenso de la mortalidad en relación directa con el volumen convectivo recibido. La última actualización del software del monitor Fresenius 5008 (5008 CorDiax) permite la automatización del volumen de sustitución sin precisar la introducción de los valores de proteínas totales y hematocrito, con el objetivo optimizar al máximo la convección. Objetivo: El objetivo del estudio fue valorar la reciente versión del software del monitor 5008 comparada con la versión anterior sobre la repercusión en el volumen convectivo total. Material y métodos: Se incluyeron 63 pacientes, 44 varones y 19 mujeres, con una edad media de 65,2 ± 15 años, que se encontraban en programa de HDF-OL. Cada paciente fue analizado en 6 sesiones, 3 con el monitor 5008 y 3 con el monitor 5008 CorDiax. En cada sesión se feterminaron el volumen de sustitución, el volumen convectivo total y los parámetros de diálisis. Resultados: No se observaron diferencias significativas en las presiones arterial, venosa o transmembrana ni aumento en el número de alarmas o coagulación de líneas o dializadores. Se observó un aumento significativo del volumen de sustitución con el uso del software CorDiax al pasar de 27,2 a 31,2 l/sesión. El volumen convectivo total se incrementó de 29,5 a 33,3 l/sesión, representando un aumento del volumen convectivo efectivo del 26 % al 29,6 % de la sangre total depurada. Conclusión: El cambio de software en el monitor de diálisis 5008 ha significado un aumento del volumen convectivo total del 13 %, representando un incremento del 3,5 % de la sangre total depurada

Copper-catalyzed diastereo- and enantioselective desymmetrization of cyclopropenes: Synthesis of cyclopropylboronates

This document is the accepted manuscript version of a Published Work that appeared in final form in Journal of American Chemical Society 136.45, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see DOI: 10.1021/ja510419zA novel Cu-catalyzed diastereo- and enantioselective desymmetrization of cyclopropenes to afford nonracemic cyclopropylboronates is described. Trapping the cyclopropylcopper intermediate with electrophilic amines allows for the synthesis of cyclopropylaminoboronic esters and demonstrates the potential of the approach for the synthesis of functionalized cyclopropanesWe thank the European Research Council (ERC-337776) and MINECO (CTQ2012-35957) for financial support. M. T. and A. P. thank MICINN for RyC and JdC contract

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