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A designed N-heterocyclic carbene (NHC) catalyst was covalently anchored on a range of mesoporous and hierarchical supports, to study the influence of pore size in the benzoin condensation of furfural. The structural and spectroscopic characteristics of the anchored catalysts were investigated, also with the help of molecular dynamics simulations, in order to rationalize the degree of stability and recyclability of the heterogenized organocatalysts. Quantitative yields (99 %) and complete recyclability were maintained after several cycles, vindicating the design rationale.
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Benzoína , Furaldeído , Benzoína/química , Benzimidazóis , Simulação de Dinâmica Molecular , CatáliseRESUMO
The first enantioselective addition of alkyl BODIPYs to Morita-Baylis-Hillman (MBH) carbonates is reported. This is the first reported enantioselective methodology using the methylene position of BODIPYs as a nucleophile. The reaction is efficiently catalyzed by cinchona alkaloids, achieving high enantioselectivities and total diastereoselectivity. The use of cinchona alkaloid pseudo enantiomers (chinine/cinchonine) allows us to obtain both pairs of enantiomers in similar yields and enantioselectivities, a common issue in this type of reaction. The photophysical study of these dyes (absorption and fluorescence) has been performed in order to determine their parameters and explore future possible application in bioimaging. In addition, electronic circular dichroism (ECD) studies supported by time-dependent density functional theory (TD-DFT) calculations were also performed.
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Biological samples are a complex and heterogeneous matrix where different macromolecules with different physicochemical parameters cohabit in reduced spaces. The introduction of fluorophores into these samples, such as in the interior of cells, can produce changes in the fluorescence emission properties of these dyes, caused by the specific physicochemical properties of cells. This effect can be especially intense with solvatofluorochromic dyes, where changes in the polarity environment surrounding the dye can drastically change the fluorescence emission. In this article, we studied the photophysical behavior of a new dye and confirmed the aggregation-induced emission (AIE) phenomenon with different approaches, such as by using different solvent proportions, increasing the viscosity, forming micelles, and adding bovine serum albumin (BSA), through analysis of the absorption and steady-state and time-resolved fluorescence. Our results show the preferences of the dye for nonpolar media, exhibiting AIE under specific conditions through immobilization. Additionally, this approach offers the possibility of easily determining the critical micelle concentration (CMC). Finally, we studied the rate of spontaneous incorporation of the dye into cells by fluorescence lifetime imaging and observed the intracellular pattern produced by the AIE. Interestingly, different intracellular compartments present strong differences in fluorescence intensity and fluorescence lifetime. We used this difference to isolate different intracellular regions to selectively study these regions. Interestingly, the fluorescence lifetime shows a strong difference in different intracellular compartments, facilitating selective isolation for a detailed study of specific organelles.
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Espectrometria de Fluorescência/métodos , Diagnóstico por Imagem/métodos , Micelas , Soroalbumina Bovina/químicaRESUMO
The first stereoselective synthesis of dihydroacridines through synergistic catalysis, achieving the final target compounds with good to excellent yields and good to excellent enantioselectivities and diastereoselectivities, is reported. The synergistic approach consists in the activation of substituted quinolines with a Lewis acid catalyst that react in a cascade fashion with activated enals in the iminium form. Mechanistic calculations support a consecutive Michael-aldol reaction, followed by dehydration.
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In this study, we report a highly stereoselective and versatile synthesis of spiro pyrazolones, promising motifs that are being employed as pharmacophores. The new synthetic strategy merges organocatalysis and metal catalysis to create a synergistic catalysis using proline derivatives and Pd catalysts. This protocol is suitable for late-stage functionalization, which is very important in drug discovery. Additionally, a thorough computational study proved to be very useful to elucidate the function of the different catalysts along the reaction, showing a peculiar feature: the -CPh2OSiMe3 group of the proline catalyst switches its role during the reaction. In the initial Michael reaction, this group plays its commonly-assumed role of bulky blocking group, but the same group generates π-Pd interactions and acts as a directing group in the subsequent Pd-catalyzed Conia-ene reaction. This finding might be very relevant especially for processes with many steps, such as cascade reactions, in which functional groups are assumed to play the same role during all reaction steps.
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Hybrid materials have been synthesized by anchoring a N-heterocyclic carbene (NHC) precursor on different inorganic zeolitic supports with hierarchical porosity, in particular hierarchical HZSM-5 and SAPO-5. Hierarchical porous inorganic supports have been obtained both by top-down and bottom-up approaches and the role of hierarchical porosity has been evaluated. A detailed physico-chemical characterization has been performed on the organic-inorganic hybrids using a multi-technique approach (XRD, volumetric and thermogravimetric analysis, ssNMR and FTIR) in order to establish a structure-property relationship. The hybrids were tested in the benzoin condensation reaction of furfural, a base catalyzed reaction.
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The rapid generation of molecular complexity from simple reactants is a key challenge in organic synthesis. Spiro compounds, underrepresented 3D motifs in chemical libraries, represent a challenge due to the creation of spiro quaternary carbon and the need to control the 3D shape in one step. Herein, we report the first ring contraction/formal [6 + 2] cycloaddition using synergistic Pd(0)/secondary amine catalysis, obtaining [5,5]-spiropyrazolone derivatives in excellent yields and stereoselectivities. We demonstrate that this reaction has a broad scope of early and late stage derivatization that will benefit the creation of highly valuable chemical libraries using spiropyrazolone motifs. We detected the key palladium activated intermediate in its protonated form by mass spectrometry and characterized its structure by infrared spectroscopy and DFT calculations, allowing us to propose a conceivable mechanistic pathway for this reaction.
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The enantioselective synthesis of spirocycles has long been pursued by organic chemists. Despite their unique 3D properties and presence in several natural products, the difficulty in their enantioselective synthesis makes them underrepresented in pharmaceutical libraries. Since the first pioneering reports of the enantioselective construction of spirosilanes by Tamao et al., significant effort has been devoted towards the development of new promising asymmetric methodologies. Remarkably, with the advent of organocatalysis, particularly over six years, the reported methodologies for the synthesis of spirocycles have increased exponentially. The aim of this review is to summarize the latest trends and developments in the enantioselective synthesis of spirocompounds during these last six years.
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Vinyl cyclopropanes are amongst the most useful building blocks in organic synthesis. Their easy opening and capacity to generate dipoles have been exploited for the synthesis of cyclopentanes with good yields and sometimes excellent stereoselectivities. In this review we give an overview of their applications, focusing on the present century.
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A double synergistic cascade reaction is reported, combining transition metal and amine catalysis. The reaction between vinyl cyclopropanes and enals renders the final cyclopentane derivatives in excellent yields and stereoselectivities.
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Herein, we describe the first enantioselective cyclopropanation of enals using benzyl chlorides as bifunctional (nucleophilic and electrophilic) reagents. The reaction is simply catalyzed by chiral secondary amines to afford the formyl cyclopropane derivatives in good yields with moderate to excellent stereoselectivities.
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In the present paper we report our latest efforts in pushing the boundaries of synergistic catalysis. We propose the use of 3 different catalytic cycles working in concert for the formation of cis cyclopropane derivatives of benzoxazoles with excellent stereoselectivities. This is the proof of concept that synergistic catalysis could be successfully used in cascade reactions.
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Stereocontrolled formation of carbon-carbon and carbon-heteroatom bonds through asymmetric organocatalysis is a formidable challenge for modern synthetic chemistry. Among the most significant contributions to this field are the transformations involving the use of acetaldehyde or α-heteroatom-substituted acetaldehydes for constructing valuable synthons (e.g., amino acid derivatives and hydroxycarbonyl). In this Minireview, versatile (enantioselective) organocatalytic transformations are discussed.
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Acetaldeído/química , Aminoácidos/química , Catálise , Estrutura Molecular , EstereoisomerismoRESUMO
The highly enantioselective asymmetric allylic alkylation of Morita-Baylis-Hillman carbonates with anthrones is presented. The reaction is simply catalyzed by cinchona alkaloid derivatives affording the final alkylated products in good yields and excellent enantioselectivities.
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We report a highly diastereoselective synthesis of spiropyrazolones catalyzed by secondary amines. The reported Michael-Aldol cascade reaction affords the desired spiropyrazolones bearing four chiral centers as a single diastereomer in excellent yields.
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Pirazolonas/síntese química , Compostos de Espiro/síntese química , Aminas/química , Catálise , Estrutura Molecular , Pirazolonas/química , Compostos de Espiro/química , EstereoisomerismoRESUMO
Several recurrent copy number variants (CNVs) increasing risk to neuropsychiatric diseases have been identified in recent years. They show variable clinical expressivity, being associated with different disorders, and incomplete penetrance. However, due to its very low frequency, the full variety of clinical outcomes associated with each one of these CNVs is unknown. Current methods for detection of CNVs are labor intensive, expensive or not suitable for high throughput analysis. Quantitative interspecies competitive PCR linked to variant minisequencing and detection by mass-spectrometry may overcome these limitations. Here, we present two multiplex assays based on this method to screen for eleven psychiatric risk CNVs, such as 1q21, 16p11.2, 3q29, or 16p13.11 regions, among others. The assays were tested in our collection of 514 schizophrenia patients. Results were compared with MLPA at two CNVs. Additional positive results were confirmed by exome sequencing. A total of fourteen patients were CNV carriers. The method presents high sensitivity and specificity, showing its utility as a cheap, accurate, high throughput screening tool for recurrent CNVs. The method may be very useful for management of psychiatric patients as well as screening of different collections of samples to better identify the full spectrum of clinical variability.
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Variações do Número de Cópias de DNA , Genoma Humano , Ensaios de Triagem em Larga Escala , Esquizofrenia/genética , Animais , Linhagem Celular , Cromossomos Humanos Par 1/química , Cromossomos Humanos Par 16/química , Cromossomos Humanos Par 3/química , Exoma , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Análise de Sequência com Séries de Oligonucleotídeos , Pan troglodytes/genética , Penetrância , Esquizofrenia/diagnósticoRESUMO
This study further explores the association between schizophrenia and caffeine use by combining two prior published Spanish samples (250 schizophrenia outpatients and 290 controls from the general population) with two Spanish long-term inpatient samples from the same hospital (145 with schizophrenia and 64 with other severe mental illnesses). The specific aims were to establish whether or not, after controlling for confounders including tobacco smoking, the association between schizophrenia and caffeine is consistent across schizophrenia samples and across different definitions of caffeine use. The frequency of caffeine use in schizophrenia inpatients was not significantly higher than that in non-schizophrenia inpatients (77%, 111/145 vs. 75%, 48/64) or controls but was significantly higher than in schizophrenia outpatients. The frequency of high caffeine users among caffeine users in schizophrenia inpatients was not significantly higher than in non-schizophrenia inpatients (45%, 50/111 vs. 52%, 25/48) or controls, but was significantly lower than in schizophrenia outpatients. Smoking was significantly associated with caffeine use across all samples and definitions. Between 2 and 3% of schizophrenia inpatients, schizophrenia outpatients and non-schizophrenia inpatients showed caffeinism (>700 mg/day in smokers). Several of these smoking patients with caffeinism were also taking other inducers, particularly omeprazole. The lack of consistent association between schizophrenia and caffeine use is surprising when compared with the very consistent association between tobacco smoking and caffeine use across all of our analyses (use and high use in users) and all our samples. The confounding effects of tobacco smoking may explain in large part the apparent association between schizophrenia and caffeine use.
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Cafeína/administração & dosagem , Estimulantes do Sistema Nervoso Central/administração & dosagem , Esquizofrenia/epidemiologia , Psicologia do Esquizofrênico , Tabagismo/epidemiologia , Adulto , Idoso , Antipsicóticos/uso terapêutico , Feminino , Hospitais Psiquiátricos , Humanos , Masculino , Pessoa de Meia-Idade , Esquizofrenia/tratamento farmacológico , Espanha , Transtornos Relacionados ao Uso de Substâncias/epidemiologiaRESUMO
A novel catalytic enantioselective methodology based on synergistic catalysis is reported. The strategy involves: 1)â the metal-Lewis-acid activation of alkylazaarenes, and 2)â the secondary-amine activation of enals. Consequently, highly functionalized chiral alkylazaarenes were obtained in good yields and with reasonable stereoselectivity.
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Genome wide association studies (GWAS) has allowed the discovery of some interesting risk variants for schizophrenia (SCZ). However, this high-throughput approach presents some limitations, being the most important the necessity of highly restrictive statistical corrections as well as the loss of statistical power inherent to the use of a Single Nucleotide Polymorphism (SNP) analysis approach. These problems can be partially solved through the use of a polygenic approach. We performed a genotyping study in SCZ using 86 previously associated SNPs identified by GWAS of SCZ, bipolar disorder (BPD) and autistic spectrum disorder (ASD) patients. The sample consisted of 3063 independent cases with DSM-IV-TR diagnosis of SCZ and 2847 independent controls of European origin from Spain. A polygenic score analysis was also used to test the overall effect on the SCZ status. One SNP, rs12290811, located in the ODZ4 gene reached statistical significance (p=1.7×10(-4), Allelic odds ratio=1.21), a value very near to those reported in previous GWAS of BPD patients. In addition, 4 SNPs were close to the significant threshold: rs3850333, in the NRXN1 gene; rs6932590, at MHC; rs2314398, located in an intergenic region on chromosome 2; and rs1006737, in the CACNA1C gene. We also found that 74% of the studied SNPs showed the same tendency (risk or protection alleles) previously reported in the original GWAS (p<0.001). Our data strengthen the polygenic component of susceptibility to SCZ. Our findings show ODZ4 as a risk gene for SCZ, emphasizing the existence of common vulnerability in psychosis.