Tandem Diastereo- and Enantioselective Preparation of Aryl and Alkyl Cyclopropyl Carbinols with Three Adjacent Stereocenters Using Perhydrobenzoxazines and Diethylzinc

Producción CientíficaThe enantio‐ and diastereoselective one‐pot ethylation/cyclopropanation is efficiently promoted by a chiral perhydrobenzoxazine. The catalytic system tolerates a wide range of di‐ and trisubstituted α,β‐unsaturated aldehydes and has been found to be highly diastereo- and enantioselective. Enals leading to intermediates lacking allylic strain or with either A1,2 or A1,3 strain afford the corresponding syn hydroxycyclopropanes very selectively. While α‐methyl enals are successfully ethylated/cyclopropanated, the presence of bulky substituents at alpha position of the enal constitutes a limitation to the substrate scope. The use of 1,1‐diiodoethane allows the obtention of the corresponding enantioenriched cyclopropylcarbinol, which bears carbon‐substituents at all three positions of the ring, with good enantiocontrol, although moderate diastereoselectivity. A procedure for the asymmetric one‐pot arylation/cyclopropanation of enals is proposed, which involves the use of triarylboroxin, diethylzinc and diiodomethane.Ministerio de Economía, Industria y Competitividad (CTQ 2011-28487)Junta de Castilla y León (programa de apoyo a proyectos de investigación – Ref. VA064U13)Universidad de Valladolid for a pre-doctoral fellowship

7-Endo selenocyclization reactions on chiral 3-prenyl and 3-cinnamyl-2 hydroxymethylperhydro-1,3-benzoxazine derivatives. A way to enantiopure 1,4-oxazepanes

Producción CientíficaEnantiopure 1,4-oxazepanes derivatives have been prepared by selenocyclofunctionalization of chiral 3-prenyl- and 3-cinnamyl-2-hydroxymethyl-substituted perhydro-1,3-benzoxazine derivatives. The 7-endo-cyclization occurs in high yields and diastereoselection. The regio and stereochemistry of the cyclization products was dependent of the substitution pattern of the double bond, the nature of the hydroxyl group and the experimental conditions.Ministerio de Economía, Industria y Competitividad (CTQ2014-59870-P)Junta de Castilla y León (programa de apoyo a proyectos de investigación – Ref. VA064U13)Thanks to Dr. José M. Martín-Álvarez for his assistance in the determination of the X-ray structure

Synthesis of Enantiopure Oxygen- and Nitrogen-Containing Heterocycles by Diastereoselective Ring-Closing Metathesis Reaction in Perhydro-1,3-benzoxazine Derivatives

Producción CientíficaDiastereoselective ring‐closing metathesis reactions on chiral trienic perhydro‐1,3‐benzoxazines derived from (−)‐8‐aminomenthol featuring two diastereotopic olefin chains is described. The diastereochemical outcome of the cyclization appeared to be dependent on the length and position of the olefin chains in perhydro‐1,3‐benzoxazine, the degree of substitution of the double bonds and the ruthenium catalyst used. After separation of the diastereomers, and removal of the chiral auxiliary, enantiopure oxygen‐ and nitrogen‐containing heterocycles were obtained.Ministerio de Economía, Industria y Competitividad (Project FEDER-CTQ2014-59870-P)Junta de Castilla y León (Ref. Project FEDER-VA115P17

Dimethylzinc-Mediated Addition of Phenylacetylene to α-Diketones Catalyzed by Chiral Perhydro-1,3-benzoxazines

Producción CientíficaAn efficient enantioselective Me2Zn-mediated mono addition of phenylacetylene to α-diketones in the presence of a chiral perhydro-1,3-benzoxazine ligand is described. At temperatures higher than -20 ºC a kinetic resolution of the resulting α-hydroxy ketone occurs which greatly improves the enantioselectivity although with moderate chemical yield. The alkynylation of nonsymmetrical aromatic diketones with electronically different substituents on the aromatic rings proceed with high regioselectivity. This procedure allows the preparation of α-hydroxy-α-ynyl-ketones as highly enantioenriched materials.2018-07-07Ministerio de Economía, Industria y Competitividad (Project CTQ2014-59870 P)Junta de Castilla y León (programa de apoyo a proyectos de investigación – Ref. VA064U13

RPAS integration in non segregated airspace: the SESAR approach

Airliners and Remotely Piloted Aircraft Systems (RPAS), with very different performances and features, will have to coexist in a seamless airspace whose definition and technological infrastructure, the Single European Sky ATM Research initiative (SESAR), is currently undertaking. This paper presents the Concept of Operations (CONOPS) of the integration of RPAS in non segregated airspace, from two perspectives that should be harmonized: the first one is the future Air Traffic Management (ATM) system defined by SESAR; and the second is the perspective of the RPAS operator or user. The objective of this paper is to present a well defined context of operations for the RPAS to be integrated in non segregated airspace, describing the basic interfaces which the RPAS user will need for the safe integration of the RPAS operations in non segregated airspace proposed in SESAR concept

Enantioselective synthesis of 3-hydroxy- and 3-amino-3-alkynyl-2-oxindoles by the dimethylzinc-mediated addition of terminal alkynes to isatins and isatin-derived ketimines

Producción CientíficaA common protocol for enantioselective alkynylation of isatins and isatin-derived ketimines using terminal alkynes and Me2Zn in the presence of a catalytic amount of a chiral perhydro-1,3-benzoxazine with moderate to excellent enantioselectivity under mild reaction conditions is described. The additions to ketimines present a novel approach to chiral amines being derivatives of oxindoles. The reaction is broad in scope with respect to aryl- and alkyl-substituted terminal alkynes and isatin derivatives. In isatins, the alkynylation occurs at the Si face of the carbonyl group, whereas in the ketimine derivatives it occurs at the Re face of the imine.Junta de Castilla y León, proyectos FEDER-VA115P17 y VA149G1

Stress coping behaviour, brain connectivity and LPA1 receptor: similarities and differences between the genetic and the pharmacological approach

LPA1 receptor is one of the six characterized G protein-coupled receptors (LPA1-6) through which lysophosphatidic acid acts as an intercellular signalling molecule. It has been recently proposed that this receptor has a key role in controlling depression-like behaviours and in the detrimental consequences of stress. Here, we sought to establish the involvement of the LPA1 receptor in brain activity after an acute stressor. To this end, we examined behavioural despair in mice with a constitutive depletion of the LPA1 receptor (maLPA1-null mice), wild-type mice and mice receiving one single icv dose of the LPA1 receptor antagonist Ki16425 or vehicle. Furthermore, the expression of c-Fos protein in stress-related brain areas and the corticosterone response following acute stress were examined. Our data indicated that, contrary to the knockout model, the antagonism of the LPA1 receptor significantly increased immobility in the Forced Swim Test. However, latency to first immobility was reduced in both experimental conditions. Immunohistochemistry studies revealed an increased in activity in key limbic structures such as medial prefrontal cortex in both the LPA1 antagonist-treated mice and maLPA1-null mice, with an interesting opposed effect on hippocampal activity. Following acute stress, the sole infusion of Ki16425 in the cerebral ventricle increased corticosterone levels. In conclusion, the alteration of LPA1 receptor function, through both genetic deletion or pharmacological antagonism, is involved in behavioural despair and hyperactivity of brain stress systems, thus contributing to explore specific susceptibility mechanisms of stress as targets for therapeutic recovery.Funding by the Andalusian Ministry of Economy, Innovation, Science and Employment (SEJ1863) and the Spanish Ministry of Education, Culture and Sports ( PSI2017 - 83408 - P). Authors RD. M-F and A. N-Q hold a Grant of the Spanish Ministry of Education, Culture and Sports (FPU14/01610 and FPU16/05308, respectively). Author S.T. holds a Grant of the Andalusian Ministry of Economy, Innovation, Science and Employment C. R. (FPDI 2016); Andalucía Tech. I Plan Propio de Investiga ción y Transferencia de la Universidad de Málaga. Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tec

Social avoidance and altered stress axis in a mouse model of anxious depression

Prevalence of stress-related disorders, such as depression, is raising in modern societies. Indeed, current neurobiological research aims to elucidate the link between deregulation of the hypothalamic-pituitary-adrenal (HPA) axis among vulnerable individuals and the onset of depressive symptoms, such as social withdrawal. Herein, we seek to determine the role of LPA1 receptor in social behaviour and the performance of maLPA1-null mice, a model of anxious depression, in the dexamethasone (DEX) suppression test. For that purpose, we used the three-chamber test for social preference. Also, we administered vehicle or DEX 0.1mg/kg to wild-type (WT) mice and maLPA1-null mice, analysed corticosterone (CORT) response by ELISA method and determine glucocorticoid receptor (GR) expression and serum/glucocorticoid regulated kinase 1 (SGK1) in the hippocampus by Western-Blot analysis. We found that maLPA1-null mice lack preference for the social chamber as compared to WT animals. Additionally, mice lacking the LPA1 receptor did not suppress CORT after DEX treatment and increased significantly hippocampal SGK1 expression despite unaltered GR protein levels. These results provide further insight on the role of LPA1 receptors in depressive-like behavior and the pathological intracellular signals involved in stress regulation.Andalusian Regional Ministries of Economy, Innovation, Science and Employment (SEJ1863 to CP and CTS-643 to GE-T) and of Health (Nicolas Monardes Programme to GE-T). Spanish Ministry of Economy and Competitiveness (PSI2013-44901-P to LJS and CP; and co-financed with Funds of the European Commission “FEDER” PSI2017-83408-P to CP). Author AN-Q and RDM-F hold Grants of the Spanish Ministry of Education, Culture and Sports (FPU 16/05308; FPU14/01610, respectively). Author FJG-S held a Grant of the First Research and Transfer Plan of the University of Malaga. University of Malaga, Campus de Excelencia Internacional Andalucía Tech, and I Plan Propio de Investigación y Transferencia of the University of Malaga

Phase angle by electrical bioimpedance is a predictive factor of hospitalisation, falls and mortality in patients with cirrhosis

The phase angle is a versatile measurement to assess body composition, frailty and prognosis in patients with chronic diseases. In cirrhosis, patients often present alterations in body composition that are related to adverse outcomes. The phase angle could be useful to evaluate prognosis in these patients, but data are scarce. The aim was to analyse the prognostic value of the phase angle to predict clinically relevant events such as hospitalisation, falls, and mortality in patients with cirrhosis. Outpatients with cirrhosis were consecutively included and the phase angle was determined by electrical bioimpedance. Patients were prospectively followed to determine the incidence of hospitalisations, falls, and mortality. One hundred patients were included. Patients with phase angle¿=¿4.6° (n¿=¿31) showed a higher probability of hospitalisation (35% vs 11%, p¿=¿0.003), falls (41% vs 11%, p¿=¿0.001) and mortality (26% vs 3%, p¿=¿0.001) at 2-year follow-up than patients with PA¿>¿4.6° (n¿=¿69). In the multivariable analysis, the phase angle and MELD-Na were independent predictive factors of hospitalisation and mortality. Phase angle was the only predictive factor for falls. In conclusion, the phase angle showed to be a predictive marker for hospitalisation, falls, and mortality in outpatients with cirrhosis.Postprint (published version

BIM aplicado al patrimonio cultural

La asociación buildingSMART tiene como principal objetivo fomentar la eficacia en el sector de la construcción a través del uso de estándares abiertos de interoperabilidad con la metodología BIM (Building InformationMode-ling). Para ello, cuenta con una estructura de grupos de trabajo a nivel internacional para abordar diferentes cues-tiones al respecto. Sin embargo, en el ámbito del Patrimonio Cultural, no existe en la actualidad una aproximación internacional sobre el uso de BIM, y es por lo que buildingSMART Spanish Chapter ha puesto en marcha un grupo de trabajo abierto, denominado LEGEND–HBIM, y que está centrado en BIM aplicado al Patrimonio Cultural. De este modo, buildingSMART Spanish Chapter continua la laborde promover el uso de la metodología BIM a través de guías como esta, que supone una continuación de las guías uBIM publicadas en el año 2014