Conspectus Difluoroalkylated compounds play a remarkably important role in life and materials sciences because of the unique characteristics of the difluoromethylene (CF2) group. In particular, ...precise introduction of a CF2 group at the benzylic position can dramatically improve the biological properties of the corresponding molecules. As a consequence, difluoroalkylation of aromatic compounds has become a powerful strategy in modulating the bioactivities of organic molecules. However, efficient strategies to selectively synthesize difluoroalkylated arenes had been very limited before 2012. Traditional synthetic methods in this regard suffer from either harsh reaction conditions or narrow substrate scope, significantly restricting their widespread applications, particularly for late-stage difluoroalkylation of bioactive molecules. To overcome these limitations, a straightforward route to access these valuable difluoroalkylated skeletons is the direct introduction of the difluoroalkylated group (CF2R) onto aromatic rings through transition-metal-catalyzed cross-coupling. However, because of the instability of some difluoroalkylated metal species, which are prone to protonation, dimerization, and/or generation of other unknown byproducts, it is difficult to selectively control the catalytic cycle to suppress these side reactions. In this context, we proposed the use of low-cost and widely available difluoroalkyl halides as fluoroalkyl sources for transition-metal-catalyzed difluoroalkylation reactions via cross-coupling. In this Account, we summarize our major efforts on copper-, palladium-, and nickel-catalyzed difluoroalkylations of aromatics with low-cost and widely available difluoroalkyl halides as fluoroalkyl sources. Four modes of catalytic difluoroalkylation reactions, including nucleophilic difluoroalkylation, electrophilic difluoroalkylation, radical difluoroalkylation, and metal–difluorocarbene coupling (MeDiC), have been demonstrated through careful modulation of the catalytic systems. Among these reactions, the MeDiC reaction represents a new mode of fluoroalkylation. These processes enable difluoroalkylation of a variety of aryl halides and arylboron reagents under mild reaction conditions. A wide range of difluoroalkyl halides, including activated difluoroalkyl halides (Cl/BrCF2R, R = π system), unactivated difluoroalkyl halides (BrCF2R, R = alkyl, H), and especially the inert and inexpensive industrial chemical chlorodifluoromethane (ClCF2H), are applicable to these reactions, providing straightforward and facile routes to a diverse range of difluoroalkylated (hetero)arenes. These difluoroalkyl halide-based strategies can also be applied to prepare difluoroalkylated alkenes, alkynes, and alkanes and feature impressive advantages over conventional methods for the synthesis of difluoroalkylated compounds in terms of synthetic efficiency, functional group tolerance, and structural diversity. In particular, the late-stage difluoroalkylation of bioactive molecules through these processes offers good opportunities for the synthesis and development of new medicinal agents without the need for multistep de novo syntheses.
A generalized nonlinear Schrödinger system is investigated, which can be used to describe the optical pulse propagation in inhomogeneous optical fibers with the fourth- and third-order dispersions ...operators. The Darboux transformation method is extended to construct a mixed breather and rogue wave solution for the system. The interaction behaviors between the breather and rogue wave are studied. As a novel result, the energy transition between the breather and rogue wave is observed. Furthermore, the impacts of the different operators on the mixed solution are analyzed.
Although iron‐catalyzed cross‐coupling of Grignard reagents with alkyl halides has been well established, the adoption of the reaction for fluoroalkylations has not been reported because traditional ...catalytic systems often lead to defluorination reactions. Described herein is the investigation of an iron‐catalyzed cross‐coupling between arylmagnesium bromides and difluoroalkyl bromides with modified N,N,N′,N′‐tetramethyl‐ethane‐1,2‐diamine (TMEDA) as a ligand. The use of this bulky diamine, in which a butylene is substituted at one carbon atom of the ethylene backbone in TMEDA, enables the iron‐catalyzed difluoroalkylation under mild reaction conditions with a wide range of difluoroalkyl bromides, including vulnerable bromodifluoromethane, thus providing a general and cost‐efficient route for applications in medicinal chemistry.
Ligand design: An iron‐catalyzed cross‐coupling between arylmagnesium bromides and difluoroalkyl bromides, with modified N,N,N′,N′‐tetramethyl‐ethane‐1,2‐diamine (TMEDA) as a ligand, is described. The combination of iron(II) salts with L enables the difluoroalkylations with a wide range of difluoroalkyl bromides, thus providing general and cost‐efficient access to difluoroalkylated arenes that are of great interest in the life sciences.
Conspectus Metal carbene plays a vital role in modern organic synthesis. The neutral divalent carbon of metal carbene renders it an active intermediate throughout a range of reactions. In ...experiments, diverse metal carbene-related transformation reactions have been established, including transition-metal-catalyzed cross-coupling reactions using N-heterocyclic carbenes as ligands, metal carbene insertion into σ bonds, cyclopropanations, ylide formation, and so forth. The remarkable progress achieved in synthetic chemistry, in turn, has increased the demand for mechanistic studies of carbene chemistry. A thorough understanding of reaction mechanisms can extend the application scope of metal carbene compounds and inspire the rational design of new carbene transformation reactions. Density functional theory (DFT) calculations have been performed in our group to gain more mechanistic insights into metal carbene-related reactions. This account focuses on computational studies of transition-metal-catalyzed carbene transformation reactions with nucleophiles. The generation of metal carbene or metal-ligated free carbene and subsequent carbene transformation pathways is discussed. According to our mechanistic studies of carbene transformation with nucleophiles, three generalized reaction models are summarized, including the intramolecular migratory insertion of metal carbene, intermolecular nucleophilic addition toward metal carbene, and outer-sphere nucleophilic addition to the metal-ligated free carbene. In general, the intermolecular nucleophilic addition mechanism is commonly proposed since metal carbene has an electrophilic carbene carbon. From a mechanistic point of view, the intramolecular migratory insertion mechanism is also widely used because metal carbene insertion into σ bonds formally occurs through this mechanism. An outer-sphere nucleophilic addition mechanism is proposed for reactions that form a metal-ligated free carbene complex instead of the commonly proposed metal carbene. The metal-ligated free carbene complex contains a naked carbene carbon that is not coordinated with the metal center. In this case, a transition-metal catalyst is used only as a Lewis acid, and nucleophilic addition occurs directly at the free carbene carbon. Our computational results suggested that outer-sphere nucleophilic addition is a facile step because metal ligation could stabilize the transition state as well as the generated intermediate. The intramolecular migratory insertion mechanism also has a low energy barrier due to the lack of an entropy penalty. Carbene formation from carbene precursors is usually the rate-determining step, except in intermolecular nucleophilic addition, and the reactivity of nucleophiles has a significant influence on the overall reaction rate. We can also envision that the weak nucleophilicity of nucleophiles would suppress outer-sphere nucleophilic addition. These computational studies showcase the characteristics of three carbene transformation models, and we hope that it will spur the development of mechanistic studies of carbene chemistry.
Ru-Catalyzed aromatic C-H bond activation and functionalization have emerged as important topics because they have resulted in remarkable progress in organic synthesis. Both experimental and ...theoretical studies of their mechanisms are important for the design of new synthetic methodologies. In this review, a mechanistic view of the Ru-mediated C-H bond cleavage step is first given to reveal the C-H bond activation modes, including oxidative addition, metathesis and base-assisted deprotonation. In this process, directing groups play an important role in determining the reactivity of the C-H bond. The C-H bond activation generally leads to the formation of a Ru-C bond, which is further functionalized in the subsequent steps. The mechanisms of Ru-catalyzed arylation, alkylation, and alkenylation of arenes are summarized, and these transformations can be categorized into cross-coupling with electrophiles or oxidative coupling with nucleophiles. In addition, the mechanism of
ortho
-ruthenation-enabled remote C-H bond functionalization is also discussed.
This review summarized recent advances in the mechanistic study of Ru-catalyzed C-H bond functionalization from a theoretical perspective.
The palladium‐catalyzed difluoroalkylation of aryl boronic acids with bromodifluoromethylphosphonate, bromodifluoroacetate, and further derivatives has been developed. This method provides a facile ...and useful access to a series of functionalized difluoromethylated arenes (ArCF2PO(OEt)2, ArCF2CO2Et, and ArCF2CONR1R2) that have important applications in drug discovery and development. Preliminary mechanistic studies reveal that a single electron transfer (SET) pathway may be involved in the catalytic cycle.
Palladium does it: The palladium‐catalyzed difluoroalkylation of aryl boronic acids with bromodifluoromethylphosphonate, bromodifluoroacetate, and further derivatives has been developed (see scheme). Preliminary mechanistic studies reveal that a single electron transfer (SET) pathway may be involved in the catalytic cycle.
In this paper, we develop a new extended Kadomtsev–Petviashvili (eKP) equation. We use the Painlevé analysis to confirm the integrability of the eKP equation. We derive the bilinear form, multiple ...soliton solutions and lump solutions via using the Hirota’s direct method. Moreover, the soliton, breather and lump interaction solutions for this model are also obtained as well. Graphs are drawn to illustrate the abundant dynamical behaviors of the obtained solutions.
Virtual reality (VR) is not only attracting the attention of the information and computer technology (ICT) industry (Shirer & Torchia, 2017), especially in the production of consumer VR hardware, but ...also that of educators. One of the important features of VR is immersion, which enhances the situated experience of users. The sensation of being there no longer necessitates a physical presence (Flower, 2015). This aspect allows second language (L2) and foreign language (FL) learners to combine learning an additional language with an intercultural experience beyond geographical limitations with no need to step out of the classroom or leave their home countries (Wang, Petrina, & Feng, 2017). Another important feature supported by VR applications is interaction, which provides users with a special channel of interpersonal communication (Ip et al., 2016). Given the importance of situated and contextual learning to FL learning, the specific features of VR of immersion and interaction are also of great interest to language educators. This article reviews previous studies of the application of VR for FL learning, introduces the present-day advanced developments in VR technology that have considerable potential for FL learning, and describes the research trends of VR in this area.
MicroRNA (miR)-155 is a critical player in both innate and adaptive immune responses. It can influence CD4(+) T cell lineage choice. To clarify the role of miR-155 in CD4(+) CD25(+) regulatory T ...(Treg)/T helper (Th)17 cell differentiation and function, as well as the mechanism involved, we performed gain-and loss-of-function analysis by transfection pre-miR-155 and anti-miR-155 into purified CD4(+) T cells. The results showed that miR-155 positively regulated both Treg and Th17 cell differentiation. It also induced the release of interleukin (IL)-17A by Th17 cells, but not the release of IL-10 and transforming growth factor (TGF)-β1 by Treg cells. Furthermore, we found that miR-155 reacted through regulating Janus kinase/signal transducer and activator of transcription (JAK/STAT) rather than TGF-β/mothers against decapentaplegic homolog (SMAD) signaling pathway in the process of Treg and Th17 cells differentiation. This may because suppressors of cytokine signaling (SOCS)1, the important negative regulator of JAK/STAT signaling pathway, was the direct target of miR-155 in this process, but SMAD2 and SMAD5 were not. Therefore, we demonstrated that miR-155 enhanced Treg and Th17 cells differentiation and IL-17A production by targeting SOCS1.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The draining of brain interstitial fluid (ISF) to cerebrospinal fluid (CSF) and the subsequent draining of CSF to meningeal lymphatics is well‐known. Nonetheless, its role in the development of ...glioma is a remarkable finding that has to be extensively understood. The glymphatic system (GS) collects CSF from the subarachnoid space and brain ISF through aquaporin‐4 (AQP4) water channels. The glial limiting membrane and the perivascular astrocyte‐end‐feet membrane both have elevated levels of AQP4. CSF is thought to drain through the nerve sheaths of the olfactory and other cranial nerves as well as spinal meningeal lymphatics via dorsal or basal lymphatic vessels. Meningeal lymphatic vessels (MLVs) exist below the skull in the dorsal and basal regions. In this view, MLVs offer a pathway to drain macromolecules and traffic immunological cells from the CNS into cervical lymph nodes (CLNs), and thus can be used as a candidate curing strategy against glioma and other associated complications, such as neuro‐inflammation. Taken together, the lymphatic drainage system could provide a route or approach for drug targeting of glioma and other neurological conditions. Nevertheless, its pathophysiological role in glioma remains elusive, which needs extensive research. The current review aims to explore the lymphatic drainage system, its role in glioma progression, and possible therapeutic techniques that target MLVs in the CNS.
The lymphatic drainage system in the brain consists of a brain‐wide glymphatic pathway, which includes the perivasal spaces as well as glymphatic CSF‐ISF flow in the brain parenchyma, and cerebrospinal fluid (CSF) drainage routes, which include dural‐sinus‐lined meningeal lymphatic vessels and olfactory/cervical lymphatic routes. The lymphatic drainage system could provide a route or approach for drug targeting of glioma and various other neurological conditions.
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