Despite the synthetic versatility of difluorocarbene, its high reactivity severely regulates widespread applications of difluorocarbene in organic synthesis. Here, we report a copper difluorocarbene-involved catalytic coupling, representing a new mode of the difluoromethylation reaction. This method allows difluoromethylation of a wide range of readily available allyl/propargyl electrophiles with NaBH3CN and low-cost difluorocarbene precursor BrCF2CO2K, featuring high cost-efficiency, high stereo- and regioselectivities, and high functional group tolerance, even with complex drug-like molecules. Applying the method led to the efficient synthesis of deuterated difluoromethylated compounds of medicinal interest. The resulting difluoromethylated allyl and allenyl products can serve as versatile synthons for diverse transformations, rendering the approach attractive for synthesizing complex fluorinated structures. Experimental mechanistic studies and computational calculations reveal that the formation of a difluoromethylcopper(I) intermediate through the nucleophilic attack of boron hydride on the copper(I) difluorocarbene is the key step in the reaction.

We report an unprecedented Ni-catalyzed direct monofluoromethylthiolation of acyl chlorides, in situ generated from carboxylic acids, with elemental sulfur (S-8) as the S source and fluoroiodomethane (ICH2F) as the CH2F radical source to produce a series of monofluoromethylthioesters in moderate to good yields. This approach features excellent functional group tolerance and broad substrate scope. Additionally, the late-stage monofluoromethylthiolation of complex bioactive molecules can also be accomplished using this method.

A palladium(II)-catalyzed Markovnikov hydroboration of aryl alkenes with readily available bis(pinacolato)diboron (B(2)pin(2)) is reported. The reaction proceeded with low catalyst loading (0.5 mol %) in the absence of N- or P-containing ligands, affording the products in up to 90% yield. Trifluoracetic acid serves as the hydrogen source, enabling the synthesis of benzylic boronic esters under mild ambient conditions.

The N,N '-bis(thiophen-2-ylmethyl)oxalamide (BTMO) was found to be an effective ligand for Cu-catalyzed ipso-nitration of (hetero)aryl halides (Br, I), making the coupling reaction with sodium nitrite proceed smoothly at 100-120 degrees C with 1-5 mol % CuI and BTMO. Electron-rich substrates were the best coupling partners to give the desired coupling products in good to excellent yields at 100 degrees C. Electron-neutral substrates required heating at 120 degrees C to get complete conversion, while rather low conversions were observed in the case of electron-poor (hetero)aryl bromides.

Nutritional status and pyroptosis are important for host defence against infections. However, the molecular link that integrates nutrient sensing into pyroptosis during microbial infection is unclear. Here, using metabolic profiling, we found that Yersinia pseudotuberculosis infection results in a significant decrease in intracellular glucose levels in macrophages. This leads to activation of the glucose and energy sensor AMPK, which phosphorylates the essential kinase RIPK1 at S321 during caspase-8-mediated pyroptosis. This phosphorylation inhibits RIPK1 activation and thereby restrains pyroptosis. Boosting the AMPK-RIPK1 cascade by glucose deprivation, AMPK agonists, or RIPK1-S321E knockin suppresses pyroptosis, leading to increased susceptibility to Y. pseudotuberculosis infection in mice. Ablation of AMPK in macrophages or glucose supplementation in mice is protective against infection. Thus, we reveal a molecular link between glucose sensing and pyroptosis, and unveil a mechanism by which Y. pseudotuberculosis reduces glucose levels to impact host AMPK activation and limit host pyroptosis to facilitate infection.

Depression is a chronic, severe, and often life-threatening neurological disorder. It not only causes depression in patients and affects daily life but, in severe cases, may lead to suicidal behavior and have adverse effects on families and society. In recent years, it has been found that sub-anesthetic doses of ketamine have a rapid antidepressant effect on patients with treatment-resistant depression and can significantly reduce the suicidal tendencies of patients with major depressive disorder. Current studies suggest that ketamine may exert antidepressant effects by blocking NMDAR ion channels, but its anesthetic and psychotomimetic side effects limit its application. Here, we report efforts to design and synthesize a novel series of ketamine derivatives of NMDAR antagonists, among which compounds 23 and 24 have improved activity compared with ketamine, introducing a new direction for the development of rapid-acting antidepressant drugs.

The strength of inhibitory neurotransmission depends on intracellular neuronal chloride concentration, primarily regulated by the activity of cation-chloride cotransporters NKCC1 (Sodium-Potassium-Chloride Cotransporter 1) and KCC2 (Potassium-Chloride Cotransporter 2). Brain-derived neurotrophic factor (BDNF) influences the functioning of these co-transporters. BDNF is synthesized from precursor proteins (proBDNF), which undergo proteolytic cleavage to yield mature BDNF (mBDNF). While previous studies have indicated the involvement of BDNF signaling in the activity of KCC2, its specific mechanisms are unclear. We investigated the interplay between both forms of BDNF and chloride homeostasis in rat hippocampal neurons and in utero electroporated cortices of rat pups, spanning the behavioral, cellular, and molecular levels. We found that both pro- and mBDNF play a comparable role in immature neurons by inhibiting the capacity of neurons to extrude chloride. Additionally, proBDNF increases the endocytosis of KCC2 while maintaining a depolarizing shift of EGABA in maturing neurons. Behaviorally, proBDNF-electroporated rat pups in the somatosensory cortex exhibit sensory deficits, delayed huddling, and cliff avoidance. These findings emphasize the role of BDNF signaling in regulating chloride transport through the modulation of KCC2. In summary, this study provides valuable insights into the intricate interplay between BDNF, chloride homeostasis, and inhibitory synaptic transmission, shedding light on the underlying cellular mechanisms involved.

Hsp90 alpha, a pivotal canonical chaperone, is renowned for its broad interaction with numerous protein clients to maintain protein homeostasis, chromatin remodeling, and cell growth. Recent studies indicate its role in modifying various components of membraneless organelles (MLOs) such as stress granules and processing bodies, suggesting its participation in the regulation of protein condensates. In this study, we found that Hsp90 alpha possesses an inherent ability to form dynamic condensates in vitro. Utilizing LC-MS/MS, we further pinpointed proteins in cell lysates that preferentially integrate into Hsp90 alpha condensates. Significantly, we observed a prevalence of RG motif repeats in client proteins of Hsp90 alpha condensates, many of which are linked to various MLOs. Moreover, each of the three domains of Hsp90 alpha was found to undergo phase separation, with numerous solvent-exposed negatively charged residues on these domains being crucial for driving Hsp90 alpha condensation through multivalent weak electrostatic interactions. Additionally, various clients like TDP-43 and hnRNPA1, along with poly-GR and PR dipeptide repeats, exhibit varied impacts on the dynamic behavior of Hsp90 alpha condensates. Our study spotlights various client proteins associated with Hsp90 alpha condensates, illustrating its intricate adaptive nature in interacting with diverse clients and its functional adaptability across multiple MLOs. This study reveals that Hsp90 alpha can undergo condensation, and its client proteins feature a high frequency of RG motif repeats. Client proteins with varying RG motif patterns exhibit different impacts on the dynamics of Hsp90 alpha condensates.

gem-Difluorinated alkenes represent versatile building blocks to divergently access functional molecules containing gem-difluorinated methyl groups; however, little advances have been made on the transformations of gem-difluoro-1,3-dienes, particularly for the enantioselective versions. In this paper, we introduced an enantioselective [4 + 2] cycloaddition of gem-difluoro-1,3-butadienes with azodicarbonates catalyzed by AgSF6 and (S)-MOP at a low catalyst loading that enables the generation of enantioenriched hydropyridazine derivatives in high yields and enantioselectivities (up to 98% yield, 98% ee). Control experiments and DFT analysis revealed that the cycloaddition reactions probably undergo a cascade reaction pathway, and azodicarbonates are activated by the chiral silver-(S)-MOP complex to control the enantioselectivities of the reactions.

Despite the significant achievements in dearomatization and C-H functionalization of arenes, the arene ring-opening remains a largely unmet challenge and is underdeveloped due to the high bond dissociation energy and strong resonance stabilization energy inherent in aromatic compounds. Herein, we demonstrate a novel carbene assisted strategy for arene ring-opening. The understanding of the mechanism by our DFT calculations will stimulate wide application of bulk arene chemicals for the synthesis of value-added polyconjugated chain molecules. Various aryl azide derivatives now can be directly converted into valuable polyconjugated enynes, avoiding traditional synthesis including multistep unsaturated precursors, poor selectivity control, and subsequent transition-metal catalyzed cross-coupling reactions. The simple conditions required were demonstrated in the late-stage modification of complex molecules and fused ring compounds. This chemistry expands the horizons of carbene chemistry and provides a novel pathway for arene ring-opening.