Novel aminocatalytic and photochemical reactions

L’aminocatàlisi asimètrica ha permès desenvolupar la reacció de Diels-Alder de manera catalítica i asimètrica, mitjançant la generació in situ d’intermedis orto-quinodimetà. La ruta del indol-2,3-quinodimetà pot realitzar-se ara catalíticament utilitzant una amina secundària quiral. Així, aquesta estratègia pot ser utilitzada per a la síntesi d’una gran varietat de compostos nitrogenats i derivats de tetrahidrocarbazols que contenen espirooxindols amb rendiments elevats i excel•lents estereoselectivitats. El potencial d’aquesta ruta aminocatalítica permet la seva aplicació en una amplia varietat de dienòfils. La implementació d’una seqüència multicatalítica de la reacció Diels-Alder/benzoí “one-pot”, basada en la combinació, sense precedents, de trienamina i catàlisi de carbens ha permès la preparació de derivats de tetrahidrocarbazols complexes amb una elevada estereoselectivitat. La reacció aza-Michael organocatalítica asimètrica mitjançant l’activació del nitrogen nucleòfil de dienamines també ha estat estudiada. Organocatalitzadors “self-assembly” com la combinació de (R)-àcid 2-indolincarboxílic i 9-epi-quinina derivada de la esquaramida han estat reconeguts com el millor sistema catalític per a aquesta desafiant adició. El indazol ha estat escollit per la seva habilitat per la formació d'una dienamina centrada en l'àtom de nitrogen. La reacció β-aldòlica directa entre cetones cícliques y cetones aromàtiques s’ha aconseguit a través de la combinació sinèrgica de la catàlisi fotoreductora i l’organocatàlisi. Radicals diaril oximetil o alquil-aril oximetil, transitòriament generats a través de la reducció d’un sol electró de precursors cetònics, es combinen fàcilment amb espècies radicalàries β-enaminil-5πe, generades mitjançant l’oxidació fotoinduïda de enamines, per a produir adductes de γ-hidroxicetona. Finalment, s’ha desenvolupat un protocol per a la perfluoroalquilació aromàtica directa i la trifluorometilació de α-ciano arilacetats. Aquesta estratègia en absència de metall, que es produeix a temperatura ambient i sota irradiació de llum visible, és impulsada per l’activitat fotoquímica de complexos electrònics dador-acceptor (EDA) formats in situ per la interacció de enolats generats transitòriament i iodurs de perfluoroalquil.La aminocatálisis asimétrica ha permitido desarrollar la reacción de Diels-Alder de manera catalítica y asimétrica, a través de la generación in situ de intermedios orto-quinodimetano. La ruta del indol-2,3-quinodimetano, puede realizarse ahora catalíticamente utilizando una amina secundaria quiral. Así, esta estrategia puede ser utilizada para la síntesis de una gran variedad de compuestos nitrogenados y derivados de tetrahidrocarbazoles con rendimientos elevados y excelentes estereoselectividades. El potencial de esta ruta aminocatalítica permite su aplicación en una amplia variedad de dienófilos. La implementación de una secuencia multicatalítica de la reacción Diels-Alder/benzoino “one-pot”, basada en la combinación, sin precedentes, de trienamina y catálisis de carbenos ha permitido la preparación de derivados de tetrahidrocarbazoles complejos con una elevada estereoselectividad. La reacción aza-Michael organocatalítica asimétrica mediante activación del nitrógeno nucleófilo de dienaminas ha sido estudiada. Organocatalizadores “self-assembly” como la combinación de (R)-ácido-2-indolincarboxílico y 9-epi-quinina derivada de la escuaramida han sido reconocidos como el mejor sistema catalítico para esta desafiante adición. El indazol fue elegido por su habilidad por la formación de una dienamina centrada en el átomo de nitrógeno. La reacción β-aldólica directa entre cetonas cíclicas y cetonas aromáticas se ha logrado a través de la combinación sinérgica de la catálisis fotoreductora y la organocatálisis. Radicales diaril oximetil o alquilo-arilo oximetil, transitoriamente generados a través de la reducción de un solo electrón de precursores cetónicos, se combinan fácilmente con especies radicalarias β-enaminil-5πe, generadas por la oxidación fotoinducida de enaminas, para producir aductos de γ-hidroxicetona. Finalmente, se ha desarrollado un protocolo simple para la perfluoroalquilación aromática directa y la trifluorometilación de α-ciano arilacetatos. Esta estrategia en ausencia de metal, que se produce a temperatura ambiente y bajo irradiación de luz visible, es impulsada por la actividad fotoquímica de complejos electrónicos dador-aceptor (EDA) formados in situ por la interacción de enolatos generados transitoriamente y yoduros de perfluoroalquilo.Asymmetric aminocatalysis has allowed to develop the hitherto elusive catalytic asymmetric Diels-Alder reaction of in situ generated ortho-quinodimethane intermediates. The indole-2,3-quinodimethane strategy, originally conceived for the straightforward synthesis of indole alkaloids more than 30 years ago, can now be made catalytic with a chiral secondary amine. This strategy can then be used to synthesize a structurally diverse range of complex nitrogen-contain compounds and spirooxindole-containing tetrahydrocarbazoles with high chemical yields and excellent stereoselectivities. The potential of aminocatalytic indole-2,3-quinodimethane strategy can be expanded to include a variety of different dienophiles. The implementation of a multicatalytic, one-pot Diels-Alder/benzoin reaction sequence, based upon the unprecedented combination of trienamine and carbene catalysis, led to the highly stereoselective preparation of complex tetrahydrocarbazole derivatives. The asymmetric organocatalytic aza-Michael reaction via dienamine activation of the nucleophilic nitrogen has been studied. Self-assembly organocatalysts, such as the combination of (R) 2-indoline carboxylic acid and 9-epi-quinine squaramide derivative, was recognized as the best catalytic system for this challenging addition. Indazole was chosen as model nucleophilic partner due to its acidity and ability to form the N-centered dienamine. The direct β-aldol reaction between cyclic ketones with aryl ketones has been achieved via the synergistic combination of photoredox catalysis and organocatalysis. Diaryl oxymethyl or aryl−alkyl oxymethyl radicals, transiently generated via single-electron reduction of ketone precursors, readily combine with β-enaminyl 5πe– radical key species, generated by photon-induced enamine oxidation, to produce γ-hydroxyketone adducts. Finally, an operationally simple protocol for the direct aromatic perfluoroalkylation and trifluoromethylation of α-cyano arylacetates has been reported. This metal-free approach, which occurs at ambient temperature and under visible-light irradiation, is driven by the photochemical activity of electron donor–acceptor (EDA) complexes, formed in situ by the interaction of transiently generated enolates and perfluoroalkyl iodides

Catalytic C(sp3)-H bond activation in tertiary alkylamines.

The development of robust catalytic methods to assemble tertiary alkylamines provides a continual challenge to chemical synthesis. In this regard, transformation of a traditionally unreactive C-H bond, proximal to the nitrogen atom, into a versatile chemical entity would be a powerful strategy for introducing functional complexity to tertiary alkylamines. A practical and selective metal-catalysed C(sp3)-H activation facilitated by the tertiary alkylamine functionality, however, remains an unsolved problem. Here, we report a Pd(II)-catalysed protocol that appends arene feedstocks to tertiary alkylamines via C(sp3)-H functionalization. A simple ligand for Pd(II) orchestrates the C-H activation step in favour of deleterious pathways. The reaction can use both simple and complex starting materials to produce a range of multifaceted γ-aryl tertiary alkylamines and can be rendered enantioselective. The enabling features of this transformation should be attractive to practitioners of synthetic and medicinal chemistry as well as in other areas that use biologically active alkylamines

Risk factors associated with adverse fetal outcomes in pregnancies affected by Coronavirus disease 2019 (COVID-19): a secondary analysis of the WAPM study on COVID-19.

Objectives To evaluate the strength of association between maternal and pregnancy characteristics and the risk of adverse perinatal outcomes in pregnancies with laboratory confirmed COVID-19. Methods Secondary analysis of a multinational, cohort study on all consecutive pregnant women with laboratory-confirmed COVID-19 from February 1, 2020 to April 30, 2020 from 73 centers from 22 different countries. A confirmed case of COVID-19 was defined as a positive result on real-time reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assay of nasal and pharyngeal swab specimens. The primary outcome was a composite adverse fetal outcome, defined as the presence of either abortion (pregnancy loss before 22 weeks of gestations), stillbirth (intrauterine fetal death after 22 weeks of gestation), neonatal death (death of a live-born infant within the first 28 days of life), and perinatal death (either stillbirth or neonatal death). Logistic regression analysis was performed to evaluate parameters independently associated with the primary outcome. Logistic regression was reported as odds ratio (OR) with 95% confidence interval (CI). Results Mean gestational age at diagnosis was 30.6+/-9.5 weeks, with 8.0% of women being diagnosed in the first, 22.2% in the second and 69.8% in the third trimester of pregnancy. There were six miscarriage (2.3%), six intrauterine device (IUD) (2.3) and 5 (2.0%) neonatal deaths, with an overall rate of perinatal death of 4.2% (11/265), thus resulting into 17 cases experiencing and 226 not experiencing composite adverse fetal outcome. Neither stillbirths nor neonatal deaths had congenital anomalies found at antenatal or postnatal evaluation. Furthermore, none of the cases experiencing IUD had signs of impending demise at arterial or venous Doppler. Neonatal deaths were all considered as prematurity-related adverse events. Of the 250 live-born neonates, one (0.4%) was found positive at RT-PCR pharyngeal swabs performed after delivery. The mother was tested positive during the third trimester of pregnancy. The newborn was asymptomatic and had negative RT-PCR test after 14 days of life. At logistic regression analysis, gestational age at diagnosis (OR: 0.85, 95% CI 0.8-0.9 per week increase; pPeer reviewe

Penilaian Kinerja Keuangan Koperasi di Kabupaten Pelalawan

This paper describe development and financial performance of cooperative in District Pelalawan among 2007 - 2008. Studies on primary and secondary cooperative in 12 sub-districts. Method in this stady use performance measuring of productivity, efficiency, growth, liquidity, and solvability of cooperative. Productivity of cooperative in Pelalawan was highly but efficiency still low. Profit and income were highly, even liquidity of cooperative very high, and solvability was good

Juxtaposing BTE and ATE – on the role of the European insurance industry in funding civil litigation

One of the ways in which legal services are financed, and indeed shaped, is through private insurance arrangement. Two contrasting types of legal expenses insurance contracts (LEI) seem to dominate in Europe: before the event (BTE) and after the event (ATE) legal expenses insurance. Notwithstanding institutional differences between different legal systems, BTE and ATE insurance arrangements may be instrumental if government policy is geared towards strengthening a market-oriented system of financing access to justice for individuals and business. At the same time, emphasizing the role of a private industry as a keeper of the gates to justice raises issues of accountability and transparency, not readily reconcilable with demands of competition. Moreover, multiple actors (clients, lawyers, courts, insurers) are involved, causing behavioural dynamics which are not easily predicted or influenced. Against this background, this paper looks into BTE and ATE arrangements by analysing the particularities of BTE and ATE arrangements currently available in some European jurisdictions and by painting a picture of their respective markets and legal contexts. This allows for some reflection on the performance of BTE and ATE providers as both financiers and keepers. Two issues emerge from the analysis that are worthy of some further reflection. Firstly, there is the problematic long-term sustainability of some ATE products. Secondly, the challenges faced by policymakers that would like to nudge consumers into voluntarily taking out BTE LEI

Severe early onset preeclampsia: short and long term clinical, psychosocial and biochemical aspects

Preeclampsia is a pregnancy specific disorder commonly defined as de novo hypertension and proteinuria after 20 weeks gestational age. It occurs in approximately 3-5% of pregnancies and it is still a major cause of both foetal and maternal morbidity and mortality worldwide1. As extensive research has not yet elucidated the aetiology of preeclampsia, there are no rational preventive or therapeutic interventions available. The only rational treatment is delivery, which benefits the mother but is not in the interest of the foetus, if remote from term. Early onset preeclampsia (<32 weeks’ gestational age) occurs in less than 1% of pregnancies. It is, however often associated with maternal morbidity as the risk of progression to severe maternal disease is inversely related with gestational age at onset2. Resulting prematurity is therefore the main cause of neonatal mortality and morbidity in patients with severe preeclampsia3. Although the discussion is ongoing, perinatal survival is suggested to be increased in patients with preterm preeclampsia by expectant, non-interventional management. This temporising treatment option to lengthen pregnancy includes the use of antihypertensive medication to control hypertension, magnesium sulphate to prevent eclampsia and corticosteroids to enhance foetal lung maturity4. With optimal maternal haemodynamic status and reassuring foetal condition this results on average in an extension of 2 weeks. Prolongation of these pregnancies is a great challenge for clinicians to balance between potential maternal risks on one the eve hand and possible foetal benefits on the other. Clinical controversies regarding prolongation of preterm preeclamptic pregnancies still exist – also taking into account that preeclampsia is the leading cause of maternal mortality in the Netherlands5 - a debate which is even more pronounced in very preterm pregnancies with questionable foetal viability6-9. Do maternal risks of prolongation of these very early pregnancies outweigh the chances of neonatal survival? Counselling of women with very early onset preeclampsia not only comprises of knowledge of the outcome of those particular pregnancies, but also knowledge of outcomes of future pregnancies of these women is of major clinical importance. This thesis opens with a review of the literature on identifiable risk factors of preeclampsia

Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR)25–75 mL/min per 1·73 m 2 of body surface area, and a urine albumin-to-creatinine ratio (UACR)of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders)were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days)or end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure)in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325)or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%)of 1325 patients in the atrasentan group and 105 (7·9%)of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR]0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%)of 1325 patients in the atrasentan group and 34 (2·6%)of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%)patients in the atrasentan group and 52 (3·9%)in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding: AbbVie

Azimuthal anisotropy of charged jet production in root s(NN)=2.76 TeV Pb-Pb collisions

We present measurements of the azimuthal dependence of charged jet production in central and semi-central root s(NN) = 2.76 TeV Pb-Pb collisions with respect to the second harmonic event plane, quantified as nu(ch)(2) (jet). Jet finding is performed employing the anti-k(T) algorithm with a resolution parameter R = 0.2 using charged tracks from the ALICE tracking system. The contribution of the azimuthal anisotropy of the underlying event is taken into account event-by-event. The remaining (statistical) region-to-region fluctuations are removed on an ensemble basis by unfolding the jet spectra for different event plane orientations independently. Significant non-zero nu(ch)(2) (jet) is observed in semi-central collisions (30-50% centrality) for 20 <p(T)(ch) (jet) <90 GeV/c. The azimuthal dependence of the charged jet production is similar to the dependence observed for jets comprising both charged and neutral fragments, and compatible with measurements of the nu(2) of single charged particles at high p(T). Good agreement between the data and predictions from JEWEL, an event generator simulating parton shower evolution in the presence of a dense QCD medium, is found in semi-central collisions. (C) 2015 CERN for the benefit of the ALICE Collaboration. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).Peer reviewe

Forward-central two-particle correlations in p-Pb collisions at root s(NN)=5.02 TeV

Two-particle angular correlations between trigger particles in the forward pseudorapidity range (2.5 2GeV/c. (C) 2015 CERN for the benefit of the ALICE Collaboration. Published by Elsevier B. V.Peer reviewe