Direct C-H functionalization can quickly increase useful structural and functional molecular complexity
. Site selectivity can sometimes be achieved through appropriate directing groups or ...substitution patterns
-in the absence of such functionality, most aromatic C-H functionalization reactions provide more than one product isomer for most substrates
. Development of a C-H functionalization reaction that proceeds with high positional selectivity and installs a functional group that can serve as a synthetic linchpin for further functionalization would provide access to a large variety of well-defined arene derivatives. Here we report a highly selective aromatic C-H functionalization reaction that does not require a particular directing group or substitution pattern to achieve selectivity, and provides functionalized arenes that can participate in various transformations. We introduce a persistent sulfur-based radical to functionalize complex arenes with high selectivity and obtain thianthrenium salts that are ready to engage in different transformations, via both transition-metal and photoredox catalysis. This transformation differs fundamentally from all previous aromatic C-H functionalization reactions in that it provides direct access to a large number of derivatives of complex small molecules, quickly generating functional diversity with selectivity that is not achievable by other methods.
Incorporation of the CF3 group into arenes has found increasing importance in drug discovery. Herein, we report the first photoredox‐catalyzed cross‐coupling of aryl thianthrenium salts with a ...copper‐based trifluoromethyl reagent, which enables a site‐selective late‐stage trifluoromethylation of arenes. The reaction proceeds with broad functional group tolerance, even for complex small molecules on gram scale. The method was further extended to produce pentafluoroethylated derivatives.
Save the best for last: A site‐selective late‐stage trifluoromethylation of arenes proceeds via aryl sulfonium salts. The reaction features broad functional group tolerance and also enables the generation of C2F5 derivatives of drug‐like compounds.
Herein, we report a two‐step process forming arene C−O bonds in excellent site‐selectivity at a late‐stage. The C−O bond formation is achieved by selective introduction of a thianthrenium group, ...which is then converted into C−O bonds using photoredox chemistry. Electron‐rich, ‐poor and ‐neutral arenes as well as complex drug‐like small molecules are successfully transformed into both phenols and various ethers. The sequence differs conceptually from all previous arene oxygenation reactions in that oxygen functionality can be incorporated into complex small molecules at a late stage site‐selectively, which has not been shown via aryl halides.
Efficient diversification: The first site‐selective late‐stage aromatic C−O bond formation from arene C−H bonds proceeds in two steps via arylthianthrenium intermediates. Electron‐rich, ‐poor and ‐neutral arenes as well as complex drug‐like small molecules are successfully transformed into both phenols and various ethers.
Herein, we report a regioselective alkenyl electrophile synthesis from unactivated olefins that is based on a direct and regioselective C−H thianthrenation reaction. The selectivity is proposed to ...arise from an unusual inverse‐electron‐demand hetero‐Diels–Alder reaction. The alkenyl sulfonium salts can serve as electrophiles in palladium‐ and ruthenium‐catalyzed cross‐coupling reactions to make alkenyl C−C, C−Cl, C−Br, and C−SCF3 bonds with stereoretention.
The regioselective synthesis of sulfonium‐based alkenyl electrophiles was achieved directly through C−H functionalization of simple olefins. The alkenyl sulfonium salts participate in palladium‐catalyzed cross‐coupling and ruthenium‐catalyzed (pseudo)halogenation reactions.
We report diverse C–N cross-coupling reactions of aryl thianthrenium salts that are formed site-selectively by direct C–H functionalization. The scope of N-nucleophiles ranges from primary and ...secondary alkyl and aryl amines to various N-containing heterocycles, and the overall transformation is applicable to late-stage functionalization of complex, drug-like small molecules.
Site‐selective functionalization of C−H bonds in small complex molecules is a long‐standing challenge in organic chemistry. Herein, we report a broadly applicable and site‐selective aromatic C−H ...dibenzothiophenylation reaction. The conceptual advantage of this transformation is further demonstrated through the two‐step C−H 18Ffluorination of a series of marketed small‐molecule drugs.
A broadly applicable and site‐selective late‐stage aromatic 18Ffluorination reaction is reported. A collection of three electronically different dibenzothiophenes enables 18F labeling of a series of small complex molecules.
OBJECTIVE:The aim of the current study is to assess the effect of tenofovir alafenamide (TAF) and tenofovir disoproxil fumarate (TDF) on lipids in patients switching from TDF to TAF and back.
...METHODS:Retrospective data collection on patients who were initially switched from TDF to TAF and switched back to TDF after generics of TDF became available.
RESULTS:In total, 385 patients were included. Median duration of TDF exposure before switch was 317 weeks (interquartile range 172–494). After switching from TDF to TAF, mean total cholesterol (TC) increased from 186 ± 37 mg/dl at baseline to 206 ± 43 and 204 ± 43 mg/dl at weeks 12 and 24 (P < 0.001). The increase in TC was mainly due to an increase in LDL cholesterol. However, ratio of TC/HDL remained unchanged, indicating a simultaneous rise of LDL and HDL cholesterol. Baseline triglycerides increased from mean 153 ± 96 to 176 ± 120 and 176 ± 124 mg/dl at weeks, 12 and 24 (P < 0.001). From 385 patients 168 were switched back from TAF to TDF after median duration on TAF of 96 weeks (interquartile range 89–104). At switching back from TAF to TDF, mean TC was 202 ± 40 mg/dl and decreased at weeks 12 and 24 to 183 ± 41 and 185 ± 35 mg/dl (P < 0.001). Mean triglycerides were 163 ± 119 mg/dl and decreased to 145 ± 108 and 157 ± 112 mg/dl, respectively (P < 0.05). Patients with higher increases in TC after switching from TDF to TAF also showed more pronounced decreases after switching back.
CONCLUSION:The results demonstrate a reversible effect on lipids by switching from TDF to TAF and back.
Organelles, proteins, and mRNA are transported bidirectionally along microtubules by plus‐end directed kinesin and minus‐end directed dynein motors. Microtubules are decorated by ...microtubule‐associated proteins (MAPs) that organize the cytoskeleton, regulate microtubule dynamics and modulate the interaction between motor proteins and microtubules to direct intracellular transport. Tau is a neuronal MAP that stabilizes axonal microtubules and crosslinks them into bundles. Dysregulation of tau leads to a range of neurodegenerative diseases known as tauopathies including Alzheimer's disease (AD). Tau reduces the processivity of kinesin and dynein by acting as an obstacle on the microtubule. Single‐molecule assays indicate that kinesin‐1 is more strongly inhibited than kinesin‐2 or dynein, suggesting tau might act to spatially modulate the activity of specific motors. To investigate the role of tau in regulating bidirectional transport, we isolated phagosomes driven by kinesin‐1, kinesin‐2, and dynein and reconstituted their motility along microtubules. We find that tau biases bidirectional motility towards the microtubule minus‐end in a dose‐dependent manner. Optical trapping measurements show that tau increases the magnitude and frequency of forces exerted by dynein through inhibiting opposing kinesin motors. Mathematical modeling indicates that tau controls the directional bias of intracellular cargoes through differentially tuning the processivity of kinesin‐1, kinesin‐2, and dynein. Taken together, these results demonstrate that tau modulates motility in a motor‐specific manner to direct intracellular transport, and suggests that dysregulation of tau might contribute to neurodegeneration by disrupting the balance of plus‐ and minus‐end directed transport.
We isolated endogenous cargoes, along with a complement of kinesin‐1, kinesin‐2, and dynein motors, and reconstituted their bidirectional motility in vitro. We find that tau, a microtubule‐associated protein that stabilizes microtubules in neuronal axons, directs bidirectional cargoes towards the microtubule minus end by tuning the balance of forces exerted by kinesin and dynein teams. These results suggest a general mechanism for regulating the transport of intracellular cargoes through modulating the relative activity of opposing motor teams.
Cytoplasmic dynein is the most complex cytoskeletal motor protein and is responsible for numerous biological functions. Essential to dynein's function is its capacity to respond anisotropically to ...tension, so that its microtubule-binding domains bind microtubules more strongly when under backward load than forward load. The structural mechanisms by which dynein senses directional tension, however, are unknown. Using a combination of optical tweezers, mutagenesis, and chemical cross-linking, we show that three structural elements protruding from the motor domain-the linker, buttress, and stalk-together regulate directional tension-sensing. We demonstrate that dynein's anisotropic response to directional tension is mediated by sliding of the coiled-coils of the stalk, and that coordinated conformational changes of dynein's linker and buttress control this process. We also demonstrate that the stalk coiled-coils assume a previously undescribed registry during dynein's stepping cycle. We propose a revised model of dynein's mechanochemical cycle which accounts for our findings.
The introduction of thianthrene as a linchpin has proven to be a versatile strategy for the C–H functionalization of aromatic compounds, featuring a broad scope and fast diversification. The ...synthesis of aryl thianthrenium salts has displayed an unusually high para regioselectivity, notably superior to those observed in halogenation or borylation reactions for various substrates. We report an experimental and computational study on the mechanism of aromatic C–H thianthrenation reactions, with an emphasis on the elucidation of the reactive species and the nature of the exquisite site selectivity. Mechanisms involving a direct attack of arene to the isolated O-trifluoracetylthianthrene S-oxide (TT+-TFA) or to the thianthrene dication (TT2+ ) via electron transfer under acidic conditions are identified. A reversible interconversion of the different Wheland-type intermediates before a subsequent, irreversible deprotonation is proposed to be responsible for the exceptional para selectivity of the reaction.
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