Copper-catalyzed functionalization of enynes Dherbassy, Quentin; Manna, Srimanta; Talbot, Fabien J. T ...
Chemical science (Cambridge),
10/2020, Letnik:
11, Številka:
42
Journal Article
Recenzirano
Odprti dostop
The copper-catalyzed functionalization of enyne derivatives has recently emerged as a powerful approach in contemporary synthesis. Enynes are versatile and readily accessible substrates that can ...undergo a variety of reactions to yield densely functionalized, enantioenriched products. In this perspective, we review copper-catalyzed transformations of enynes, such as boro- and hydrofunctionalizations, copper-mediated radical difunctionalizations, and cyclizations. Particular attention is given to the regiodivergent functionalization of 1,3-enynes, and the current mechanistic understanding of such processes.
The copper-catalyzed functionalization of enynes is a powerful approach to yield densely functionalized products. This review covers various transformations, such as boro- and hydrofunctionalizations, copper-mediated radical difunctionalizations, and cyclizations.
An interrupted Pummerer/nickel‐catalysed cross‐coupling strategy has been developed and used in the elaboration of styrenes. The operationally simple method can be carried out as a one‐pot process, ...involves the direct formation of stable alkenyl sulfonium salt intermediates, utilises a commercially available sulfoxide, catalyst, and ligand, operates at ambient temperature, accommodates sp‐, sp2‐, and sp3‐hybridised organozinc coupling partners, and delivers functionalised styrene products in high yields over two steps. An interrupted Pummerer/cyclisation approach has also been used to access carbo‐ and heterocyclic alkenyl sulfonium salts for cross‐coupling.
Feel free to interrupt: Styrenes were activated under metal‐free conditions by an interrupted Pummerer process. The resulting stable alkenyl sulfonium salts underwent nickel‐catalysed cross‐coupling under simple, mild conditions. The versatile sequence could be carried out as a one‐pot process with a range of organozinc partners to form di‐, tri‐, and tetrasubstituted alkene products.
Copper‐catalyzed borylative multicomponent reactions (MCRs) involving olefins and C−N electrophiles are a powerful tool to rapidly build up molecular complexity. The products from these reactions ...contain multiple functionalities, such as amino, cyano and boronate groups, that are ubiquitous in medicinal and process chemistry programs. Copper‐catalyzed MCRs are particularly attractive because they use a relatively abundant and non‐toxic catalyst to selectively deliver high‐value products from simple feedstocks such as olefins. In this Minireview, we explore this rapidly emerging field and survey the borylative union of allenes, dienes, styrenes and other olefins, with imines, nitriles and related C−N electrophiles.
Copper‐catalyzed borylative multicomponent couplings, involving olefins and C−N electrophiles, constitute an efficient approach to high‐value amine and nitrile products. This Minireview assesses the progress in this rapidly emerging field and surveys the borylative union of allenes, dienes, styrenes, and related olefins, with imines, nitriles, and related electrophiles.
Highlights ► As part of the “inflammaging” process, innate immune processes may not only be ineffective, they may result in harmful inflammatory responses to infection. ► Increased levels of “bGrzB” ...activity associated with CMV, may be a common thread between immune dysfunction and the risk for cardiovascular complications of influenza. ► The IFN-γ:IL-10 ratio and GrzB activity in influenza-challenged PBMC can be used as biomarkers to firmly establish vaccine-mediated protection/failure. ► Adding specific adjuvants may further enhance vaccine responses even in the face of a suboptimal immune system. ► Reliance on antibody titers as a sole predictor of vaccine efficacy is a major barrier to the development of more effective influenza vaccines, which remains an unmet need.
Microvascular muscle transfer is the gold standard for reanimation following chronic facial nerve paralysis, however, despite the regenerative capacity of peripheral motor axons, poor reinnervation ...often results in sub-optimal function. We hypothesized that injection of alginate hydrogels releasing growth factors directly into donor tissue would promote reinnervation, muscle regeneration, and function. A murine model of sciatic nerve ligation and neurorrhaphy was first used to assess the ability of gel delivery of vascular endothelial growth factor (VEGF) and insulin-like growth factor-1 (IGF-1) to promote functional reinnervation. VEGF + IGF-1 gel delivery to aged mice resulted in prolonged ability to control toe movement, increased toe spreading, and improved static sciatic index score, indicative of improved sciatic nerve and neuromuscular junction function. Further, a 26% increase in muscle fiber area, and 2.8 and 3.0-fold increases in muscle contraction force and velocity, respectively, were found compared to blank alginate in the murine model. This strategy was subsequently tested in a rabbit model of craniofacial gracilis muscle transplantation. Electromyography demonstrated a 71% increase in compound muscle action potential 9 weeks after transplantation following treatment with VEGF + IGF-1 alginate, compared to blank alginate in the rabbit model. Improving functional innervation in transplanted muscle via a hydrogel source of growth factors may enhance the therapeutic outcomes of facial palsy treatments and, more broadly, muscle transplantations.
Hydrogen atom transfer‐mediated intramolecular C−C coupling reactions between alkenes and nitriles, using PhSiH3 and catalytic Fe(acac)3, are described. This introduces a new strategic bond ...disconnection for ring‐closing reactions, forming ketones via imine intermediates. Of note is the scope of the reaction, including formation of sterically hindered ketones, spirocycles and fused cyclic systems.
Hydrogen atom transfer (HAT) methodology has been expanded to an intramolecular C−C coupling reaction between alkenes and nitriles, using PhSiH3 and catalytic Fe(acac)3. This introduces a new strategic bond disconnection for ring‐closing reactions, forming ketones via imine intermediates.
AbstractObjectivesTo characterize the clinical severity of covid-19 associated with the alpha, delta, and omicron SARS-CoV-2 variants among adults admitted to hospital and to compare the ...effectiveness of mRNA vaccines to prevent hospital admissions related to each variant.DesignCase-control study.Setting21 hospitals across the United States.Participants11 690 adults (≥18 years) admitted to hospital: 5728 with covid-19 (cases) and 5962 without covid-19 (controls). Patients were classified into SARS-CoV-2 variant groups based on viral whole genome sequencing, and, if sequencing did not reveal a lineage, by the predominant circulating variant at the time of hospital admission: alpha (11 March to 3 July 2021), delta (4 July to 25 December 2021), and omicron (26 December 2021 to 14 January 2022).Main outcome measuresVaccine effectiveness calculated using a test negative design for mRNA vaccines to prevent covid-19 related hospital admissions by each variant (alpha, delta, omicron). Among patients admitted to hospital with covid-19, disease severity on the World Health Organization’s clinical progression scale was compared among variants using proportional odds regression.ResultsEffectiveness of the mRNA vaccines to prevent covid-19 associated hospital admissions was 85% (95% confidence interval 82% to 88%) for two vaccine doses against the alpha variant, 85% (83% to 87%) for two doses against the delta variant, 94% (92% to 95%) for three doses against the delta variant, 65% (51% to 75%) for two doses against the omicron variant; and 86% (77% to 91%) for three doses against the omicron variant. In-hospital mortality was 7.6% (81/1060) for alpha, 12.2% (461/3788) for delta, and 7.1% (40/565) for omicron. Among unvaccinated patients with covid-19 admitted to hospital, severity on the WHO clinical progression scale was higher for the delta versus alpha variant (adjusted proportional odds ratio 1.28, 95% confidence interval 1.11 to 1.46), and lower for the omicron versus delta variant (0.61, 0.49 to 0.77). Compared with unvaccinated patients, severity was lower for vaccinated patients for each variant, including alpha (adjusted proportional odds ratio 0.33, 0.23 to 0.49), delta (0.44, 0.37 to 0.51), and omicron (0.61, 0.44 to 0.85).ConclusionsmRNA vaccines were found to be highly effective in preventing covid-19 associated hospital admissions related to the alpha, delta, and omicron variants, but three vaccine doses were required to achieve protection against omicron similar to the protection that two doses provided against the delta and alpha variants. Among adults admitted to hospital with covid-19, the omicron variant was associated with less severe disease than the delta variant but still resulted in substantial morbidity and mortality. Vaccinated patients admitted to hospital with covid-19 had significantly lower disease severity than unvaccinated patients for all the variants.
Copper-catalyzed coupling of readily available ketiminoesters, allenes, and a diboron affords densely functionalized quaternary α-amino esters bearing adjacent stereocenters and versatile vinyl ...boronate motifs. The method utilizes a commercially available copper(I) catalyst, operates at ambient temperature, and features a catalytic allyl cupration of ketiminoesters.
Abstract
The variability in the response to antipsychotic medication in schizophrenia may reflect between-patient differences in neurobiology. Recent cross-sectional neuroimaging studies suggest that ...a poorer therapeutic response is associated with relatively normal striatal dopamine synthesis capacity but elevated anterior cingulate cortex (ACC) glutamate levels. We sought to test whether these measures can differentiate patients with psychosis who are antipsychotic responsive from those who are antipsychotic nonresponsive in a multicenter cross-sectional study. 1H-magnetic resonance spectroscopy (1H-MRS) was used to measure glutamate levels (Glucorr) in the ACC and in the right striatum in 92 patients across 4 sites (48 responders R and 44 nonresponders NR). In 54 patients at 2 sites (25 R and 29 NR), we additionally acquired 3,4-dihydroxy-6-18Ffluoro-l-phenylalanine (18F-DOPA) positron emission tomography (PET) to index striatal dopamine function (Kicer, min−1). The mean ACC Glucorr was higher in the NR than the R group after adjustment for age and sex (F1,80 = 4.27; P = .04). This was associated with an area under the curve for the group discrimination of 0.59. There were no group differences in striatal dopamine function or striatal Glucorr. The results provide partial further support for a role of ACC glutamate, but not striatal dopamine synthesis, in determining the nature of the response to antipsychotic medication. The low discriminative accuracy might be improved in groups with greater clinical separation or increased in future studies that focus on the antipsychotic response at an earlier stage of the disorder and integrate other candidate predictive biomarkers. Greater harmonization of multicenter PET and 1H-MRS may also improve sensitivity.
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