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This Account describes our research related to the development of molecular catalysts for solution phase olefin polymerization. Specifically, a series of constrained geometry and nonmetallocene (imino-amido-type) complexes were developed for high temperature olefin polymerization reactions. We have discovered many highly active catalysts that are capable of operating at temperatures above 120 °C and producing copolymers with a useful range of molecular weights (from medium to ultrahigh depending on precatalyst identity and polymerization conditions) and α-olefin incorporation capability. Constrained geometry catalysts (CGCs) exhibit very high activities and are capable of producing a variety of copolymers including ethylene-propylene and ethylene-1-octene copolymers at high reactor temperatures. Importantly, CGCs have much higher reactivity toward α-olefins than classical Ziegler-Natta catalysts, thus allowing for the production of copolymers with any desired level of comonomer. In search of catalysts with improved performance, we discovered 3-amino-substituted indenyl-based CGCs that exhibit the highest activity and produce copolymers with the highest molecular weight within this family of catalysts. Phenanthrenyl-based CGCs were found to be outstanding catalysts for the effective production of high styrene content ethylene-styrene copolymers under industrially relevant conditions. In contrast to CGC ligands, imino-amido-type ligands are bidentate and monoionic, leading to the use of trialkyl group IV precatalysts. The thermal instability of imino-amido complexes was addressed by the development of imino-enamido and amidoquinoline complexes, which are not only thermally very robust, but also produce copolymers with higher molecular weights, and exhibit improved α-olefin incorporation. Imido-amido and imino-enamido catalysts undergo facile chain transfer reactions with metal alkyls, as evidenced by a sharp decrease in polymer molecular weight when the polymerization reactions were conducted in the presence of diethylzinc, an essential requirement for use in the production of olefin block copolymers via chain shuttling polymerization. Overall, the excellent characteristics of imino-amido-type catalysts, including high catalytic activities and ultrahigh molecular weight capabilities, make them good candidates for high temperature syntheses of block and random ethylene-α-olefin copolymers. Additionally, trialkyl imino-enamido complexes react quickly with various protic and unsaturated organic fragments, leading to a library of dialkyl precatalysts that, in several instances, resulted in superior catalysts. In conjunction with the development of transition metal catalysts, we also synthesized and evaluated activators for olefin polymerization. We found, for example, that, when conducted in coordinating solvents, the reaction between aluminum alkyls and tris(pentafluorophenyl)borane leads to the exclusive formation of alumenium borates, which are excellent activators for CGC complexes. Additionally, we developed a series of highly effective new activators featuring a very weakly coordinating anion composed of two Lewis acids coordinated to an imidazole fragment.
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BACKGROUND: Ensuring the quality of malaria medicines is crucial in working toward malaria control and eventual elimination. Unlike other validated tests that can assess all critical quality attributes, which is the standard for determining the quality of medicines, basic tests are significantly less expensive, faster, and require less skilled labour; yet, these tests provide reproducible data and information on several critical quality attributes, such as identity, purity, content, and disintegration. Visual and physical inspection also provides valuable information about the manufacturing and the labelling of medicines, and in many cases this inspection is sufficient to detect counterfeit medicines. The Promoting the Quality of Medicines (PQM) programme has provided technical assistance to Amazon Malaria Initiative (AMI) countries to implement the use of basic tests as a key screening mechanism to assess the quality of malaria medicines available to patients in decentralized regions. METHODS: Trained personnel from the National Malaria Control Programmes (NMCPs), often in collaboration with country's Official Medicine Control Laboratory (OMCL), developed country- specific protocols that encompassed sampling methods, sample analysis, and data reporting. Sampling sites were selected based on malaria burden, accessibility, and geographical location. Convenience sampling was performed and countries were recommended to store the sampled medicines under conditions that did not compromise their quality. Basic analytical tests, such as disintegration and thin layer chromatography (TLC), were performed utilizing a portable mini-laboratory. RESULTS: Results were originally presented at regional meetings in a non-standardized format that lacked relevant medicines information. However, since 2008 information has been submitted utilizing a template specifically developed by PQM for that purpose. From 2005 to 2010, the quality of 1,663 malaria medicines from seven AMI countries was evaluated, mostly collected from the public sector, 1,445/1,663 (86.9%). Results indicate that 193/1,663 (11.6%) were found not to meet quality specifications. Most failures were reported during visual and physical inspection, 142/1663 (8.5%), and most of these were due to expired medicines, 118/142 (83.1%). Samples failing TLC accounted for 27/1,663 (1.6%) and those failing disintegration accounted for 24/1,663 (1.4%). Medicines quality failures decreased significantly during the last two years. CONCLUSIONS: Basic tests revealed that the quality of medicines in the public sector improved over the years, since the implementation of this type of quality monitoring programme in 2005. However, the lack of consistent confirmatory tests in the quality control (QC) laboratory, utilizing methods that can also evaluate additional quality attributes, could still mask quality issues. In the future, AMI countries should improve coordination with their health authorities and their QC lab consistently, to provide a more complete picture of malaria medicines quality and support the implementation of corrective actions. Facilities in the private and informal sectors also should be included when these sectors constitute an important source of medicines used by malaria patients.
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Antimaláricos/farmacologia , Antimaláricos/normas , Técnicas de Química Analítica , Preparações Farmacêuticas/química , Preparações Farmacêuticas/normas , Antimaláricos/química , Humanos , Malária/tratamento farmacológico , Controle de Qualidade , América do SulRESUMO
A rhodium(I)-xylyl-BINAP catalyzed asymmetric [2 + 2 + 2] cycloaddition of achiral conjugated aryl ynamides with various diynes is described here. This asymmetric cycloaddition provides a series of structurally interesting chiral N,O-biaryls with excellent enantioselectivity along with a modest diastereoselectivity with respect to both C-C and C-N axial chirality.
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Introducción: la yerba mate (Ilex paraguariensis) constituye un recurso alimentario autóctono, formando parte de la tradición y cultura alimentaria del Paraguay. Sin embargo, existen pocos estudios locales sobre los hábitos de consumo y preferencias por los paraguayos. Objetivo: describir los hábitos de consumo de la yerba mate (Ilex paraguariensis) en el Departamento Central en el 2022. Metodología: estudio descriptivo, transversal, con datos primarios, realizado en el Departamento Central de Paraguay. Muestreo no probabilístico en racimos. Instrumento de elaboración propia, diseñado como encuesta digital en la plataforma Google Form® (EE.UU.). Las variables fueron agrupadas en datos demográficos, relacionados al consumo de mate, tereré y cocido, procesados en Microsoft Excel® (EE.UU.) y EPI INFO® 7.0 (EE.UU.). Resultados: participaron 207 personas, la mayoría contaban entre 18 a 40 años, sexo femenino (83,22 %, 119), solteros, universitarios. El consumo más frecuente fue mate+ tereré+ cocido (43,96 %, 91) y tereré + cocido (14,01 %, 29). Todos los encuestados percibían más de dos salarios mínimos, y eran trabajadores de tiempo completo. El 81,64 % (169) consumían tereré, 69,08 % (143) mate, 80,23 % (138) cocido. El tipo de yerba más consumido fue la "compuesta con hierbas medicinales", con un promedio de 1,5 Litros diarios. Conclusión: las formas más consumidas son tereré, cocido y mate, el tipo de yerba es la compuesta con el agregado de hierbas medicinales. Se sugieren realizar estudios poblacionales más amplios sobre el consumo de bebidas a base de yerba mate en Paraguay, así como ampliar estudios sobre las posibles interacciones e inocuidad entre la yerba mate con hierbas medicinales.
Introduction: yerba mate (Ilex paraguariensis) constitutes a native food resource, forming part of the food tradition and culture of Paraguay. However, there are few local studies on the consumption habits and preferences of Paraguayans. Objective: to describe the consumption habits of yerba mate (Ilex paraguariensis) in the Departamento Central in 2022. Methodology: descriptive, cross-sectional study, with primary data, carried out in the Departamento Central of Paraguay. Non-probability cluster sampling. Self-developed instrument, designed as a digital survey on the Google Form® platform (USA). The variables were grouped into demographic data, related to the consumption of mate, tereré and cocido, processed in Microsoft Excel® (USA) and EPI INFO® 7.0 (USA). Results: people participated was 207, the majority were between 18 and 40 years old, female (83.22 %, 119), single, university students. The most frequent consumption was mate + tereré + cooked (43.96 %, 91) and tereré + cooked (14.01 %, 29). All respondents received more than two minimum wages, and were full-time workers. 81.64 % (169) consumed tereré, 69.08 % (143) consumed mate, 80.23 % (138) cooked. The most consumed type of herb was "composed with medicinal herbs", with an average of 1.5 Liters per day. Conclusion: the most consumed forms are tereré, cooked and mate, the type of yerba is the one composed with the addition of medicinal herbs. It is suggested to carry out larger population studies on the consumption of yerba mate-based drinks in Paraguay, as well as expand studies on the possible interactions and safety between yerba mate and medicinal herbs.
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A concise and enantioselective total synthesis of (+)-aigialospirol is described here, featuring the first complex natural product synthesis that employs a cyclic ketal-tethered ring-closing metathesis strategy and an unexpected stereoselective epimerization of a benzylic hydroxyl group. The 15-step synthetic sequence illustrates the proof-of-concept that such an approach can be competitive with the classical spiroketal formation in the natural product synthesis.
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Benzofuranos/síntese química , Benzofuranos/química , Cristalografia por Raios X , Modelos Moleculares , Estrutura Molecular , Estereoisomerismo , Zearalenona/análogos & derivados , Zearalenona/síntese química , Zearalenona/químicaRESUMO
A Rh(I)-catalyzed asymmetric [2 + 2 + 2] cycloaddition of achiral ynamides is described here. This work demonstrates a unique concept of stereochemical control of both the C-C and C-N axial chirality and provides an approach to the synthesis of chiral N,O-biaryls as well as chiral anilides.
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Carbono/química , Nitrogênio/química , Cristalografia por Raios X , Modelos Moleculares , Estrutura Molecular , EstereoisomerismoRESUMO
[reaction: see text] The cis-dihydroxylation of olefin-containing potassium alkyl- and aryltrifluoroborates proceeds readily in moderate to excellent yields. The resulting diols are efficient coupling partners in Suzuki-Miyaura-type reactions with both alkenyl and aryl bromides.
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Boratos/química , Potássio/química , HidroxilaçãoRESUMO
[reaction: see text] Representative B-butyl- and B-methyl-1,3,2-oxazaborolidines derived from ephedrine and norephedrine were prepared in good yield and excellent purity by one-pot treatment of B-H oxazaborolidines with the corresponding organolithium reagent and subsequent hydrolysis of the cyclic borohydride intermediate with anhydrous ammonium chloride.
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Compostos de Boro/síntese química , Efedrina/análogos & derivados , Oxazinas/síntese química , Fenilpropanolamina/análogos & derivados , Alquilação , Boroidretos/química , Compostos de Lítio/química , Estrutura Molecular , EstereoisomerismoRESUMO
Two remarkable epimerization processes were uncovered during our pursuit of an enantioselective synthesis of (+)-aigialospirol featuring a cyclic acetal tethered ring-closing metathesis. Through modeling, we were able to turn these two unexpected epimerizations to our advantage via modeling to ensure a successful and concise total synthesis, thereby firmly establishing cyclic acetal tethered RCM as a powerful strategy in natural product synthesis. Most importantly, calculations allowed us to fully understand the nature and the mechanistic course of these two epimerizations that were imperative to the total synthesis efforts.
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A highly stereoselective synthesis of chiral alpha-amino-beta-lactam through an ynamide-Kinugasa reaction is described. In addition, a mechanistic model is illustrated here to rationalize the observed diastereoselectivity, which depends on both the initial [3 + 2] cycloaddition step and the subsequent protonation for which both are highly selective.
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Alcinos/química , Amidas/química , beta-Lactamas/síntese química , Cristalografia por Raios X , Ciclização , Modelos Químicos , Modelos Moleculares , Estrutura Molecular , Estereoisomerismo , beta-Lactamas/químicaRESUMO
Background: Ensuring the quality of malaria medicines is crucial in working toward malaria control and eventual elimination. Unlike other validated tests that can assess all critical quality attributes, which is the standard for determining the quality of medicines, basic tests are significantly less expensive, faster, and require less skilledlabour; yet, these tests provide reproducible data and information on several critical quality attributes, such asidentity, purity, content, and disintegration. Visual and physical inspection also provides valuable information aboutthe manufacturing and the labelling of medicines, and in many cases this inspection is sufficient to detectcounterfeit medicines. The Promoting the Quality of Medicines (PQM) programme has provided technical assistanceto Amazon Malaria Initiative (AMI) countries to implement the use of basic tests as a key screening mechanism toassess the quality of malaria medicines available to patients in decentralized regions.Methods: Trained personnel from the National Malaria Control Programmes (NMCPs), often in collaboration with countrys Official Medicine Control Laboratory (OMCL), developed country- specific protocols that encompassed sampling methods, sample analysis, and data reporting. Sampling sites were selected based on malaria burden,accessibility, and geographical location. Convenience sampling was performed and countries were recommendedto store the sampled medicines under conditions that did not compromise their quality. Basic analytical tests, suchas disintegration and thin layer chromatography (TLC), were performed utilizing a portable mini-laboratory...(AU)
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Antimaláricos/análise , Antimaláricos/normas , Avaliação de Medicamentos , Controle de QualidadeRESUMO
The stereoselective synthesis of unsaturated organotrifluoroborates by using the Wittig and Horner-Wadsworth-Emmons olefination is described. These reactions were general for both alkyl- and aryltrifluoroborates. The synthesis of di- and trisubstituted olefins was achieved by using formyl- and acetyl-substituted organotrifluoroborates. The products were isolated in moderate to excellent yield. The Wittig reaction with nonstabilized ylides was performed under salt free conditions in most cases to obtain the Z-isomer. The E-isomer was accessed by using preformed stabilized ylides. The Horner-Wadsworth-Emmons reaction also gave the E-isomer as expected.
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Alcenos/química , Boratos/química , Flúor/química , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Organofosfonatos/química , Potássio/químicaRESUMO
Se realizó una evaluación in vivo de la eficacia de la cloroquina para el tratamiento de la malaria por Plasmodium vivax, en elsitio centinela de Palmar Chico, Municipio de Yacuiba, Provincia Gran Chaco, Departamento de Tarija al Sur de Bolivia. Fueronincluidos en el estudio 61 pacientes entre 5 y 59 años de edad que presentaban monoinfección por P. vivax. Todos los pacientesrecibieron una dosis total de cloroquina de 25 mg/Kg en 3 días (10mg/Kg el primer día; 7,5 mg/Kg el segundo y tercer días).De acuerdo al protocolo estandarizado de la OPS/OMS, todos los pacientes fueron seguidos por 28 días (controles clínicos yparasitológicos). Se completó el seguimiento de 60 pacientes, ninguno de los pacientes tuvo recurrencias de la parasitemia opresentó manifestaciones clínicas después del tercer día de tratamiento. Este estudio mostró 100% de sensibilidad de P. vivaxa la cloroquina, lo que justifica su permanencia en la política de medicamentos antimaláricos como la droga más adecuada parael tratamiento de las infecciones por P. vivax en el Sur de Bolivia.
We carried out an evaluation in vivoof the chloroquine efficacy for the treatment of malaria by Plasmodium vivax, in the sentinelsite of Palmar Chico, Municipality of Yacuiba, Province Gran Chaco, Department of Tarija to the South of Bolivia. Sixty one patientsaged between 5 and 59 years that presented monoinfection by P. vivaxwere included in the study. All patient received undersupervision a total dose of chloroquine 25mg/kg over three days (10mg/kg on the first day; 7.5 mg/kg on the second and thirddays). According the standardized protocol of the PAHO/WHO, all patients were followed-up for 28 days (clinical and parasitologicalcontrols). Sixty patients completed the follow-up, none of the patients had recurrences of parasitemia or presented clinicalmanifestations after third day of treatment. This study showed 100% of sensibility from P. vivax to chloroquine, what justifies theirpermanency in the antimalarial drug policy as the most adequate drug for the treatment of the P. vivax infections in the South of Bolivia.