Polyphosphazenes for the Stille reaction: A new type of recyclable stannyl reagents

Producción CientíficaThe random phosphazene copolymer {[N=P((CH2)7-Br)Ph]0,5[N=PMePh]0,5}n (2) and the block copolyphosphazene {[N=P((CH2)7-Br)Ph]25[N=PMePh]20}-b-[N=P(O2C12H8)]55 (5), having a branch with two randomly distributed units, have been synthesized and used as precursors for the stannyl derivatives {[N=P((CH2)7-SnBu2An)Ph]0,5[N=PMePh]0,5}n (3) and {[N=P((CH2)7-SnBu2An)Ph]25[N=PMePh]20}-b-[N=P(O2C12H8)]55 (6, An = p-MeOC6H4). Polymers 3 and 6 were tested as recyclable tin reagents in the Stille cross-coupling reaction with C6H5I, using various Pd catalysts and different experimental conditions. Polymer 6 can be recycled without significant release of tin, but its efficiency decreased after three consecutive cycles. This effect was explained by studying the self-assembly of the polymer under the same conditions used for the catalytic experiments, which evidenced the progressive coalescence of the polymeric vesicles (polymersomes) leading to stable and bigger core-shell aggregates by the attraction of the [N=P(O2C12H8)] rich membranes, thus decreasing the accessibility of the tin active centers.2017-12-15Junta de Castilla y León (programa de apoyo a proyectos de investigación – Ref. VA302U13)Ministerio de Economía, Industria y Competitividad (CTQ2014-56345)Ministerio de Economía, Industria y Competitividad (CTQ2013-48406-P)Universidad de Oviedo (Project UNOV-13-EMERG-GIJON-08

Asymmetric Organocatalysts Supported on Vinyl Addition Polynorbornenes for Work in Aqueous Media

Producción CientíficaIn an effort to identify novel polymer architectures suitable for the covalent supporting of catalysts, L–proline derivatives have been immobilized onto rationally designed vinyl addition polynorbornene (VA-PNB) resins through copper-catalyzed azide-alkyne cycloaddition (CuAAC) reactions. The fully saturated VA-PNB resins have been found to be optimal catalyst supports, the resulting proline-functionalized resins behaving as very active, easily recoverable and highly reusable organocatalysts for the asymmetric direct aldol reaction of benzaldehydes with ketones in aqueous media. The obtained results show that the combination of modular, VA-PNB resins with proline derivatives through triazole linkers represent a promising strategy for the immobilization of organocatalytic species.Ministerio de Economía, Industria y Competitividad (CTQ2013-48406-P)Ministerio de Economía, Industria y Competitividad (CTQ2012-38594-C02-01)Junta de Castilla y León (programa de apoyo a proyectos de investigación – Ref. VA373A11-2)Generalitat de Catalunya (Grant 2014SGR827

Síntesis y funcionalización de polinorbornenos de adición vinílica: soportes poliméricos para una reacción de Stille Limpia

La síntesis mediante adición vinílica de polinorbornenos que posean grupos polares en su esqueleto resulta interesante ya que poseen una estructura muy robusta que puede ser muy útil como soporte de reactivos o catalizadores. En este contexto, se describe la síntesis y caracterización de haloalquil polinorbornenos, de bromofenil polinorborneno y de nuevos polinorbornenos funcionalizados que derivan de éstos. Estos polímeros se pueden preparar con un contenido variable de halógeno y funcionalizar con diferentes grupos polares en su estructura, introducidos mediante reacciones de sustitución nucleofílica y mediante reacciones de acoplamiento catalizadas por paladio. Mediante reacciones CuAAC se han preparado organocatalizadores soportados que son reciclables. A partir de los haloalquil polinorbornenos se han sintetizado nuevos polinorbornenos estannilados. También se han preparado nuevos polifosfacenos estannilados. Estos polímeros actúan como reactivos en la reacción de Stille y proporcionan productos de acoplamiento con contenido de estaño extraordinariamente bajo y pueden ser regenerados y reutilizados.Departamento de Química Inorgánic

Batch Stille Coupling with Insoluble and Recyclable Stannylated Polynorbornenes

[EN] The Stille coupling can be carried out in a batch process using insoluble tin supports. The new type of support consists of stannylated polymers based on the vinylic polynorbornene skeleton that allow one to use a set-up where the tin reagent is immobilized in a column. The immobilized stannylated polymeric reagent can be easily reused. The coupling products are thus obtained by a very simple work-up procedure and have very low levels of tin contamination.Financial support from the Spanish MEC (DGI, grant CTQ2010-18901/BQU; fellowship to N. C.), and the Junta de Castilla y Leon (grant VA373A11-2) is gratefully acknowledged.Martínez-Arranz, S.; Carrera, N.; Albéniz, AC.; Espinet, P.; Vidal Moya, JA. (2012). Batch Stille Coupling with Insoluble and Recyclable Stannylated Polynorbornenes. Advanced Synthesis and Catalysis. 354(18):3551-3560. https://doi.org/10.1002/adsc.201200624S3551356035418Scully, S. S., & Porco, J. A. (2011). 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Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

BackgroundWe previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15-20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in similar to 80% of cases.MethodsWe report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded.ResultsNo gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5-528.7, P=1.1x10(-4)) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR=3.70[95%CI 1.3-8.2], P=2.1x10(-4)). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR=19.65[95%CI 2.1-2635.4], P=3.4x10(-3)), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR=4.40[9%CI 2.3-8.4], P=7.7x10(-8)). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD]=43.3 [20.3] years) than the other patients (56.0 [17.3] years; P=1.68x10(-5)).ConclusionsRare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old

Whole-genome sequencing reveals host factors underlying critical COVID-19

Altres ajuts: Department of Health and Social Care (DHSC); Illumina; LifeArc; Medical Research Council (MRC); UKRI; Sepsis Research (the Fiona Elizabeth Agnew Trust); the Intensive Care Society, Wellcome Trust Senior Research Fellowship (223164/Z/21/Z); BBSRC Institute Program Support Grant to the Roslin Institute (BBS/E/D/20002172, BBS/E/D/10002070, BBS/E/D/30002275); UKRI grants (MC_PC_20004, MC_PC_19025, MC_PC_1905, MRNO2995X/1); UK Research and Innovation (MC_PC_20029); the Wellcome PhD training fellowship for clinicians (204979/Z/16/Z); the Edinburgh Clinical Academic Track (ECAT) programme; the National Institute for Health Research, the Wellcome Trust; the MRC; Cancer Research UK; the DHSC; NHS England; the Smilow family; the National Center for Advancing Translational Sciences of the National Institutes of Health (CTSA award number UL1TR001878); the Perelman School of Medicine at the University of Pennsylvania; National Institute on Aging (NIA U01AG009740); the National Institute on Aging (RC2 AG036495, RC4 AG039029); the Common Fund of the Office of the Director of the National Institutes of Health; NCI; NHGRI; NHLBI; NIDA; NIMH; NINDS.Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care or hospitalization after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes-including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)-in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease