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Dearomative functionalization of heteroaromatics, a readily available chemical feedstock, is one of the most straightforward approaches for the synthesis of three-dimensional, chiral heterocyclic systems, important synthetic building blocks for both synthetic chemistry and drug discovery. Despite significant efforts, direct nucleophilic additions to heteroaromatics have remained challenging because of the low reactivity of aromatic substrates associated with the loss of aromaticity, as well the regio- and stereoselectivities of the reaction. Here we present a catalytic system that leads to unprecedented, high-yielding dearomative C-4 functionalization of quinolines with organometallics with nearly absolute regio- and stereoselectivities and with a catalyst turnover number (TON) as high as 1000. The synergistic action of the chiral copper catalyst, Lewis acid, and Grignard reagents allows us to overcome the energetic barrier of the dearomatization process and leads to chiral products with selectivities reaching 99% in most cases. Molecular modeling provides important insights into the speciation and the origin of the regio- and enantioselectivity of the catalytic process. The results reveal that the role of the Lewis acid is not only to activate the substrate toward a potential nucleophilic addition but also to subtly control the regiochemistry by preventing the C-2 addition from happening.
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Here we report that readily available silyl- and boron-based Lewis acids in combination with chiral copper catalysts are able to overcome the reactivity issues of unactivated enamides, known as the least reactive carboxylic acid derivatives, toward alkylation with organomagnesium reagents. Allowing unequaled chemo-reactivity and stereocontrol in catalytic asymmetric conjugate addition to enamides, the method is distinguished by its unprecedented reaction scope, allowing even the most challenging and synthetically important methylations to be accomplished with good yields and excellent enantioselectivities. This catalytic protocol tolerates a broad temperature range (-78 °C to ambient) and scale up (10 g), while the chiral catalyst can be reused without affecting overall efficiency. Mechanistic studies revealed the fate of the Lewis acid in each elementary step of the copper-catalyzed conjugate addition of Grignard reagents to enamides, allowing us to identify the most likely catalytic cycle of the reaction.
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Ubiquitin-proteasome system (UPS) plays a crucial role in many cellular processes such as cell cycle, proliferation and apoptosis. Aberrant activation of UPS may result in cellular transformation or other altered pathological conditions. Previous studies have shown that metal-based complexes could inhibit proteasome activity and induce apoptosis in certain human cancer cells. In the current study, we report that the cadmium and copper complexes with heterocycle-ornithine Schiff base are potent inhibitors of proteasomal chymotrypsin-like (CT-like) activity, leading to induction of apoptosis in cancer cells. Two novel copper-containing complexes and two novel cadmium-containing complexes with different heterocycle-ornithine Schiff base structures as ligands were synthesized and characterized. We found that complexes Cu1, Cd1 and Cd2 show proteasome-inhibitory activities in human breast cancer MDA-MB-231 and human prostate cancer LNCaP cells, resulting in the accumulation of p27, a natural proteasome substrate and other ubiquitinated proteins, followed by the induction of apoptosis. Our results suggest that metal complexes with heterocycle-ornithine Schiff base have proteasome-inhibitory capabilities and have the potential to be developed into novel anticancer drugs.
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Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Complexos de Coordenação/farmacologia , Inibidores de Proteassoma/farmacologia , Antineoplásicos/química , Cádmio/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Complexos de Coordenação/química , Cobre/química , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Concentração Inibidora 50 , Ornitina/química , Complexo de Endopeptidases do Proteassoma/química , Inibidores de Proteassoma/química , Bases de SchiffRESUMO
ß-Bi2O3 is an efficient visible-light photocatalyst, however, it is unable to split water to produce hydrogen because of the positive conduction band minimum (CBM). In this paper, using hybrid density functional theory (DFT) calculations, we demonstrated that by doping indium in ß-Bi2O3, the CBM shifts upward because of the orbital hybridization of Bi, In and O. In-doped ß-Bi2O3 photocatalysts synthesized using a precipitation method can photocatalytically split water to produce hydrogen in experiments. In-doping also causes the morphological change of ß-Bi2O3 from the hierarchical bulk assembled by nano-sheets to a spongy-like brick. Furthermore, In-doping induces the formation of electric dipoles along the tunnel in the crystal and decreases the effective mass of the electrons, favouring the separation of electron-hole pairs and electron mobility. Therefore, In-doped ß-Bi2O3 has much better performance than that of the pristine ß-Bi2O3 for photocatalytically decomposing methyl orange (MO) solution. This idea of simply incorporating an isovalent single element into photocatalysts to elevate the CBM and tune the local crystal structure is anticipated to be very useful for designing efficient photocatalysts.
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The rapid growth of urban instant delivery, facilitated by digital platforms and characterized by on-demand, short-term, task-based labor, has raised concerns about safety, particularly with the increasing frequency of instant delivery crashes (IDCs). This study addresses knowledge gaps in understanding injury patterns and risk factors associated with IDCs. Utilizing data extracted from judicial verdicts on IDC disputes in China, encompassing demographic, contextual, crash, and injury information, the research employs ordered logit regression to identify significant factors affecting injury patterns, the number of injuries per person (IPP), and injury severity. Overall, traffic injuries related to instant delivery services have gradually improved since 2020, as evidenced by the severity of individual accidents, the number of injuries, and the economic losses. Analysis of 648 injuries among 448 non-fatal victims reveals a prevalence of lower extremity injuries, followed by external, upper extremity, and head injuries. While the majority of victims suffered a single injury, approximately 22 % experienced major injuries. Female delivery riders exhibited higher injury ratios across various body regions. Rider risk behavior, type of delivery vehicles, and the mode of transport of non-delivery travelers emerged as significant influencers of injury patterns. Notably, functional and physical intersection areas exhibited the highest injury ratios among facility types. Contrary to conventional wisdom, older riders and travelers aged above 50 were associated with higher injury severity, challenging the perception of young age as the primary risk factor. The prominence of lower extremity injuries underscores the necessity for heightened protective measures for delivery riders. Major injuries among victims emphasize potential long-term consequences and associated costs. The significance of gender, age, and risk behavior as determining factors highlights the need for targeted safety interventions. These findings offer crucial insights for stakeholders, guiding the formulation of precise safety measures and informed policy initiatives within the dynamic landscape of instant delivery safety.
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Acidentes de Trânsito , Ferimentos e Lesões , Humanos , Feminino , Fatores de Risco , Masculino , China/epidemiologia , Acidentes de Trânsito/estatística & dados numéricos , Ferimentos e Lesões/epidemiologia , Pessoa de Meia-Idade , Adulto , Assunção de Riscos , População Urbana/estatística & dados numéricos , Adulto JovemRESUMO
Here, we present a synthetic route towards γ-amino alcohols with continuous stereocenters based on a copper-catalyzed asymmetric conjugate addition/CO2-trapping tandem reaction of α,ß-unsaturated amide, followed by a reduction of the generated α-carboxyl amide. This strategy provides a green route for the transformation of CO2 into valuable chiral organic molecules.
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We present a catalytic strategy for converting lignin into various pharmaceutical intermediates based on a highly selective lignin depolymerization method and a green benzylic oxidation method employing O2. Selective depolymerization of lignin first afforded 4-ethylphenol, which then efficiently generates several pharmaceutical intermediates with a simple 5-step process, resulting in substantial economic benefits. The study provides an innovative solution for the efficient utilization of lignin and the green acquisition of pharmaceutical intermediates.
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The contributions of the amino and imino resonance forms to the ground-state structures of 2-amino-4-methylpyridinium nitrate, C(6)H(9)N(2)(+)·NO(3)(-), and the previously reported 2-amino-5-methylpyridinium nitrate [Yan, Fan, Bi, Zuo & Zhang (2012). Acta Cryst. E68, o2084], were studied using a combination of IR spectroscopy, X-ray crystallography and density functional theory (DFT). The results show that the structures of 2-amino-4-methylpyridine and 2-amino-5-methylpyridine obtained upon protonation are best described as existing largely in the imino resonance forms.
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Cristalografia por Raios X , Nitratos/química , Compostos de Piridínio/química , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Estrutura Molecular , Teoria QuânticaRESUMO
Titanium (Ti) and its alloys have been widely employed in aeronautical, petrochemical, and medical fields owing to their fascinating advantages in terms of their mechanical properties, corrosion resistance, biocompatibility, and so on. However, Ti and its alloys face many challenges, if they work in severe or more complex environments. The surface is always the origin of failure for Ti and its alloys in workpieces, which influences performance degradation and service life. To improve the properties and function, surface modification becomes the common process for Ti and its alloys. The present article reviews the technology and development of laser cladding on Ti and its alloys, according to the cladding technology, cladding materials, and coating function. Generally, the laser cladding parameters and auxiliary technology could influence the temperature distribution and elements diffusion in the molten pool, which basically determines the microstructure and properties. The matrix and reinforced phases play an important role in laser cladding coating, which can increase the hardness, strength, wear resistance, oxidation resistance, corrosion resistance, biocompatibility, and so on. However, the excessive addition of reinforced phases or particles can deteriorate the ductility, and thus the balance between functional properties and basic properties should be considered during the design of the chemical composition of laser cladding coatings. In addition, the interface including the phase interface, layer interface, and substrate interface plays an important role in microstructure stability, thermal stability, chemical stability, and mechanical reliability. Therefore, the substrate state, the chemical composition of the laser cladding coating and substrate, the processing parameters, and the interface comprise the critical factors which influence the microstructure and properties of the laser cladding coating prepared. How to systematically optimize the influencing factors and obtain well-balanced performance are long-term research issues.
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In the title salt, C(6)H(9)N(2) (+)·NO(3) (-), the 2-amino-5-methyl-pyridinium cation and the nitrate anion are cyclically linked through pyridinium and amine N-Hâ¯O hydrogen bonds [graph set R(4) (3)(12)]. These units are extended into a zigzag chain structure lying parallel to the a axis, through a second cyclic R(2) (2)(8) association involving amine N-Hâ¯O and aromatic C-Hâ¯O hydrogen bonds to nitrate O-atom acceptors.
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Traditional village dwellings in China consisting of timber frames with mud and stone infill walls represent an important part of cultural heritage and civilization. Due to the lack of an effective link between the wood frame and the infill and the poor cohesiveness of clay, the masonry infill can collapse during an earthquake, whereas the wood frame suffers minimal damage. In this study, current retrofitting techniques for village buildings were investigated and discussed. A method using polypropylene (PP) band mesh and cement mortar to retrofit the timber frame with a mud and stone infill was proposed and the connection construction details were designed. In-plane static cyclic tests were conducted on two full-scale wood-stone hybrid walls reinforced on one side with different grid sizes of the PP band mesh. The failure behaviors of the reinforced and non-reinforced sides of the specimens were compared, and the failure mechanics and seismic capacity of the two specimens, i.e., the strength, stiffness, ductility, and energy dissipation, were investigated. The results were also compared with those of a previous frame with stone infill without pebbles and no reinforcement. The study indicated that the retrofitting method strengthened the integrity and lateral resistance of the hybrid structure and prevented the collapse of the stone infill of the reinforced surface in a plane earthquake. The grid size of the PP band mesh substantially affected the lateral performance of the reinforced specimens. The hybrid wall with the narrow PP band mesh grid (150 mm × 150 mm) had a higher lateral stiffness (79%) and lateral capacity (50%) than the wall with the wide grid (250 mm × 250 mm). However, the narrow PP band mesh resulted in a lower ductility of the wall than the wide PP band mesh. The involvement of pebbles in the stone infill led to collapses sooner and a weaker lateral resistance than in the structure without pebble infill.
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Cruising for parking creates a moving queue of cars that are waiting for vacated parking spaces, but no one can see how many cruisers are in the queue because they are mixed with normal cars. In order to mitigate the influence of cruising for parking on normal cars, the simulation framework based on VISSIM was proposed for reproducing the cruising vehicles and normal traffic flows. The car-following model of cruising vehicles was calibrated by the GPS and video data. The scenarios under different cruising ratios were analyzed to evaluate the influence of cruising for parking on traffic efficiency and emissions. Finally, the layout optimization changing the parking locations and positions of entrance-exit gates were discussed to mitigate the negative effect. The results indicated that cruising for parking deteriorates the traffic congestion and emissions on the road sections, intersections and network. The closer distances the intersections and sections are to the parking lot, the greater the negative impact is. But the negative effect after the 30% proportion on traffic performance only illustrates the slight deterioration, because the carrying capacity of the network is reached. The research results provide a quantitative method for the hidden contribution of cruising for parking on traffic congestion and emissions.
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Automóveis , Modelos Teóricos , Emissões de Veículos , Simulação por Computador , Emissões de Veículos/análiseRESUMO
This article aims to analyze the factors affecting the LOS (level of service) of non-motorized vehicles crossing the signalized intersection and to construct an appropriate method to evaluate the LOS. Aiming at the mixed non-motorized traffic flow of electric vehicles and bicycles in the Chinese metropolis, the delay model in the highway capacity manual (HCM) was modified by taking two new factors into account: the pedestrian traffic rule compliance rate and the fuzzy perception of arrival rate in reality. The results show that the data obtained by the modified model are more consistent with the actual one. Next, a comparison was established between the linear regression method and cumulative logistic regression to determine the variables that affect the LOS, and finally, a LOS evaluation index system based on threshold schemes was defined. The recommended LOS model can provide corresponding references for traffic engineers who seek to improve the level of service in urban intersections.
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Acidentes de Trânsito , Pedestres , Ciclismo , Planejamento Ambiental , Humanos , Modelos Logísticos , PercepçãoRESUMO
The purpose of this paper is to analyze the complex coupling relationships among accident factors contributing to the automobile and two-wheeler traffic accidents by establishing the Bayesian network (BN) model of the severity of traffic accidents, so as to minimize the negative impact of automobile to two-wheeler traffic accidents. According to the attribution of primary responsibility, traffic accidents were divided to two categories: the automobile and two-wheeler traffic as the primary responsible party. Two BN accident severity analysis models for different primary responsible parties were proposed by innovatively combining the Kendall correlation analysis method with the BN model. A database of 1560 accidents involving an automobile and two-wheeler in Guilin, Guangxi province, were applied to calibrate the model parameters and validate the effectiveness of the models. The result shows that the BN models could reflect the real relationships among the influential factors of the two types of traffic accidents. For traffic accidents of automobiles and two-wheelers as the primary responsible party, respectively, the biggest influential factors leading to fatality were weather and visibility, and the corresponding fluctuations in the probability of occurrence were 32.20% and 27.23%, respectively. Moreover, based on multi-factor cross-over analysis, the most influential factors leading to fatality were: {Off-Peak Period â Driver of Two-Wheeler: The elderly â Driving Behavior of Two-Wheeler: Parking} and {Drunk Driving Two-Wheeler â Having a License of Automobiles â Visibility: 50 m~100 m}, respectively. The results provide a theoretical basis for reducing the severity of automobile to two-wheeler traffic accidents.
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Condução de Veículo , Automóveis , Acidentes de Trânsito , Idoso , Teorema de Bayes , China/epidemiologia , HumanosRESUMO
Antioxidant intervention is considered to inhibit reactive oxygen species (ROS) and alleviate hyperglycemia. Paradoxically, moderate exercise can produce ROS to improve diabetes. The exact redox mechanism of these two different approaches remains largely unclear. Here, by comparing exercise and antioxidant intervention on type 2 diabetic rats, we found moderate exercise upregulated compensatory antioxidant capability and reached a higher level of redox balance in the liver. In contrast, antioxidant intervention achieved a low-level redox balance by inhibiting oxidative stress. Both of these two interventions could promote glucose catabolism and inhibit gluconeogenesis through activation of hepatic AMP-activated protein kinase (AMPK) signaling; therefore, ameliorating diabetes. During exercise, different levels of ROS generated by exercise have differential regulations on the activity and expression of hepatic AMPK. Moderate exercise-derived ROS promoted hepatic AMPK glutathionylation activation. However, excessive exercise increased oxidative damage and inhibited the activity and expression of AMPK. Overall, our results illustrate that both exercise and antioxidant intervention improve blood glucose control in diabetes by promoting redox balance, despite different levels of redox state(s). These results indicate that the AMPK signaling activation, combined with oxidative damage markers, could act as sentinel biomarkers, reflecting the threshold of redox balance that is linked to effective glucose control in diabetes. These findings provide theoretical evidence for the precise management of diabetes by antioxidants and exercise.
Molecules known as reactive oxygen species or ROS play vital roles in healthy cells. However, ROS can act as a double-edged sword: if their levels become too high, they can be harmful and interfere with many physiological processes. Indeed, diabetes, high blood pressure and many other chronic diseases are associated with imbalances in the levels of ROS in the body. To counter high ROS levels, cells have antioxidant mechanisms that reduce the excess ROS in the cell and keep the 'redox' (from reduction and oxidation) balance of the cell. Exercise and antioxidant nutritional supplements have attracted much attention as drug-free interventions for diabetes. Both strategies alter the levels of ROS in the body, with exercise increasing the levels of ROS, and antioxidant supplements reducing them. Individuals with diabetes and other metabolic health issues have different ROS levels depending on the severity of the disease, age, genetics and other factors, leading to different redox states in their cells. Thus, approaches that can accurately evaluate the redox balance status of individuals are necessary for clinicians to identify what types of exercise and antioxidant supplements are beneficial and which treatments are most appropriate for each patient. Wu, Zhao, Yan, Gao et al. examined the effects of exercise and antioxidant supplements on rats with diabetes, with the aim of identifying molecules also known as biomarkers that reflect the bodies' redox balance. They found that moderate exercise increased the levels of ROS in the liver, which, in turn, compensated by increasing the production of antioxidants to protect against the higher levels of ROS. This resulted in a healthy 'high-level' redox balance, in which both ROS and antioxidants levels were high in the rats. On the other hand, giving the rats antioxidant supplements decreased their levels of ROS, leading to a healthy low-level redox balance with low levels of ROS. These findings indicate that regular moderate exercise may be appropriate for people with pre-diabetes symptoms to restore a healthy redox balance. This is because the compensatory antioxidant mechanisms that kick in during exercise may be enough to counteract the excessive levels of ROS in these people. For patients with mild diabetes, exercise, antioxidant supplements, or a combination of both may be appropriate treatment, depending on their levels of ROS. Finally, patients with severe diabetes, who already have high levels of ROS, may benefit from antioxidant supplements to help reduce their excessive levels of ROS. In the future, the biomarkers identified by Wu, Zhao, Yan, Gao et al. may be used to monitor and assess the change in the redox balance status of various populations and guide personalized interventions to maintain health. Additionally, these findings provide a new strategy for precision prevention and treatment of diabetes and other metabolic diseases.
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Antioxidantes , Diabetes Mellitus Experimental , Ratos , Animais , Antioxidantes/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Controle Glicêmico , Oxirredução , Estresse Oxidativo , Fígado/metabolismo , Biomarcadores/metabolismoRESUMO
As three resources that are necessary for human survival and production, water, energy and food are increasingly closely linked. In recent years, the water-energy-food nexus has attracted special attention from international organizations and academic circles. However, due to the lack of research on its internal mechanisms, there is still controversy on whether the water-energy-food nexus can be used as a new policy basis. The internal mechanisms of the water-energy-food nexus were analysed from the perspective of industrial linkages in this paper and empirically verified by constructing an SVAR (structuralvectorautoregression) model using China's data. The results showed that there were two forms of conduction in China's water-energy-food nexus: the water-energy-food nexus with nuclear power participation and that with natural gas participation. The characteristics of China's water-energy-food nexus were derived. For the interactions of the water-energy segment in China's water-energy-food nexus, the conduction from energy to water was consistent for different types of energy, while that from water to energy varied depending on the type of energy. Food production always had a negative impact on energy production, while the conduction from energy to food varied for different types of energy. The conduction between food and the water supply was not as significant as was generally considered. Especially, the impact of the water supply on food production was weak. The order of strength intensity and the duration were also available for reference. Accordingly, a new policy basis was presented under the framework of China's water-energy-food nexus. Both our research design and research findings are significant in contributing to understanding the internal mechanisms of the water-energy-food nexus, and the policy implications are also helpful for achieving better policy effects.
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With the strengthening of environmental awareness, the government pays much more attention to environmental protection and thus implements carbon trading schemes to promote the reduction of global carbon dioxide emissions. The carbon Generalized System of Preferences (GSP) is an incentive mechanism for citizens to value their energy conservation and carbon reduction. Individual travel needs to rely on various means of transportation, resulting in energy consumption. Carbon tax or subsidy can only be carried out after carbon GSP accurately measures individual carbon emissions. The big data acquired from the smart cards of passengers' travels provide the possibility for carbon emission accounting of individual travel. This research proposes a carbon emission measurement of individual travel. Through establishing the network model of the Nanjing metro with a complex method, the shortest path of the passengers' travels is obtained. Combined with the origination-destination (OD) records of the smart cards, the total distance of the passengers' travels is obtained. By selecting the operation table to estimate the carbon emissions generated by the daily operation of the subway system, the carbon emissions per kilometer or per time of passenger travel are finally obtained. With the accurate tracking of carbon emissions for individual travel, the government may establish a comprehensive monitoring system so as to establish a carbon tax and carbon supplement mechanism for citizens.
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Meios de Transporte , Viagem , Dióxido de Carbono/análise , Conservação dos Recursos NaturaisRESUMO
To identify and quantify the factors that influence the risky riding behaviors of electric bike riders, we designed an e-bike rider behavior questionnaire (ERBQ) and obtained 573 valid samples through tracking surveys and random surveys. An exploratory factor analysis was then conducted to extract four scales: riding confidence, safety attitude, risk perception, and risky riding behavior. Based on the exploratory factor analysis, a structural equation model (SEM) of electric bike riding behaviors was constructed to explore the intrinsic causal relationships among the variables that affect the risky e-bike riding behavior. The results show that the relationship between riding confidence and risky riding behavior is mediated by risk perception and safety attitudes. Safety attitude was found to be significantly associated with risky riding behaviors. Specifically, herd mentality is most closely related to safety attitudes, which means that those engaged in e-bike traffic management and safety education should pay special attention to riders' psychological management and education. Risk perception has a direct path to risky riding behaviors. Specifically, stochastic evaluation and concern degree are significantly related to e-bike riders' risk perception. The findings of this study provide an empirical basis for the creation of safety interventions for e-bike riders in China.
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Ciclismo , Conhecimentos, Atitudes e Prática em Saúde , Assunção de Riscos , Acidentes de Trânsito , Adolescente , Adulto , Atitude , China , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Motocicletas , SegurançaRESUMO
This paper systematically investigates the biomedical performance of selective laser melted (SLM) porous Ti6Al4V ELI scaffolds for bone implantation through in vitro and in vivo experiments. Scaffolds with pore sizes of 500⯵m, 600⯵m and 700⯵m and porosities of 60% and 70% were manufactured in order to explore the optimum pore size and porosity. Rat bone marrow mesenchymal stem cells (rBMMSCs) were used in the in vitro experiments. Cell Counting Kit-8, live/dead staining and scanning electron microscope were used to assess the cytotoxicity of the porous scaffolds. DNA content quantification was performed to investigate cell proliferation on the porous scaffolds. The osteogenic differentiation of cells was measured by alkaline phosphatase (ALP) activity and osteogenic gene expressions, including bone morphogenetic protein-2 (BMP-2), collagen type 1α1 (COL-1), osteocalcin (OCN), osteopontin (OPN) and runt-related transcription factor-2 (RUNX-2). The Sprague-Dawley (SD) rat models with distal femoral condyles defect were used in the in vivo experiments. Micro-CT analysis and histological analysis were performed after implantation surgery to reveal the bone ingrowth into the porous scaffolds. All in vitro data were analyzed by one-way ANOVA followed by Tukey post hoc tests, in vivo data were analyzed using Kruskall-Wallis ANOVA and Conover-Inman post-hoc test. Based on the in vitro and in vivo experiments, it is found that the porous scaffolds manufactured by SLM did not induce a cytotoxic effect. Among all the porous scaffolds, the scaffold with a pore size of 500⯵m and porosity of 60% showed the best cell proliferation and osteogenic differentiation (in vitro experiments) and bone ingrowth (in vivo experiments).
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Diferenciação Celular , Proliferação de Células , Osteogênese , Alicerces Teciduais/química , Titânio/química , Ligas , Animais , Células da Medula Óssea/citologia , Osso e Ossos/diagnóstico por imagem , Osso e Ossos/patologia , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Fraturas Ósseas/terapia , Lasers , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Osteocalcina/genética , Osteocalcina/metabolismo , Osteogênese/efeitos dos fármacos , Porosidade , Ratos , Ratos Sprague-Dawley , Engenharia Tecidual , Titânio/toxicidade , Microtomografia por Raio-XRESUMO
Conjugate addition of organometallics to carbonyl based Michael acceptors is a widely used method that allows the building of new carbon-carbon (C-C) bonds and the introduction of chirality in a single step. However, conjugate additions to the simplest Michael acceptors, namely unprotected, unsaturated carboxylic acids, are considered to be prohibited by the fact that acid-base reactions overpower any other type of reactivity, including nucleophilic addition. Here we describe a transient protecting group strategy that allows efficient catalytic asymmetric additions of organomagnesium reagents to unprotected α,ß-unsaturated carboxylic acids. This unorthodox pathway is achieved by preventing the formation of unreactive carboxylate salts by means of a reactive intermediate, allowing modifications of the carbon chain to proceed unhindered, while the stereochemistry is controlled with a chiral copper catalyst. A wide variety of ß-chiral carboxylic acids, obtained with excellent enantioselectivities and yields, can be further transformed into valuable molecules through for instance catalytic decarboxylative cross-coupling reactions.