beta-fluorocarbanions have garnered considerable attention for their dual reactivity in nucleophilic processes and beta-fluorine elimination. In this study, a thorough computational analysis was conducted to explore the reactions of alpha-(trifluoromethyl)styrenes with 2-pyridones to delineate the factors determining protonation or defluorination pathways for the in situ generated beta-fluorocarbanions under varied basic conditions. Our findings illuminate the critical role of organobase basicity in steering the direction of the competitive protonation and beta-fluorine elimination reactions. We propose the use of pKaH values of organobases as a quantitative indicator for discerning the predominant reaction pathways. This provides an efficient approach to predict and control the reaction outcome, facilitating the deliberate design of reactions to leverage the unique reactivity of beta-fluorocarbanions in the realm of fluorine chemistry.

A palladium-catalyzed divergent synthesis of spiro-cyclohexadienones with a five- or a six-membered ring by a cycloaddition reaction of vinylidenecyclopropane-diesters (VDCP-diesters) with p-quinone methides (p-QMs) was disclosed. This protocol features a switchable process between [3 + 2] and [4 + 2] cycloadditions tuned by subtle choice of the phosphine ligand. The substrate scopes have been investigated and the reaction mechanism has been clarified by mechanistic studies; and DFT calculations also revealed that the coordination modes of the ligands with the substrates and the bite angle of the ligands play critical roles in the product regioselectivity.

By rational modification of electronic and steric properties of pincer ligands, a Co/Fe dual catalyst system is developed for one-pot sequential Markovnikov alkyne hydrosilylation and stereoselective alkene isomerization. The protocol provides an atom-economical and efficient approach to trisubstituted (E)-alkenyl silanes from widely accessible terminal alkynes with high regio- and stereoselectivities under mild conditions. The utility of this reaction was demonstrated by gram-scale synthesis and derivatization of bioactive molecules. The radical clock and trapping experiments indicated that radical pathway might be operative in the alkene isomerization step.

Organic afterglow panels show promising applications in display and information anti-counterfeiting. Like other panels, organic afterglow panels are susceptible to contamination when used, which can affect their aesthetics and clarity. Here, a kind of visible-light-excitable anti-smudge organic afterglow panels based on a dopant-matrix strategy and easily prepared through the UV light-curing method is reported. The phosphorescence lifetime of the panel is up to 9.45 s with an afterglow duration longer than 100 s. Moreover, the transparent panels with low dynamic friction (0.129), large water contact angle (108 degrees) and oleic acid contact angle (77 degrees), display high performance of anti-smudge, water and oil repellency, and removability of fingerprints, avoiding the influence of ink or sewage on its aesthetics and clarity. This study will expand the pathways for practical applications of afterglow materials. An anti-smudge organic afterglow panel is creatively fabricated based on the dopant-matrix strategy and through a UV-curing process under mild conditions. The fluorinated panel not only exhibits an ultralong phosphorescence lifetime of up to 9.45 s, but also shows excellent anti-smudge and anti-fingerprint properties, high transparency, flexibility and good water/oil repellency, showing potential applications in displays. image

Two novel copper-catalyzed cyclization reactions involvinga remote propargylic substitution/cyclization/isomerization cascade aredisclosed. Derivatives of the seldomly studied heterocycles thieno[2,3-c]pyrrole and thieno[2,3-d]pyridazine are conveniently synthesized inmoderate to good yields from primary amines or arylhydrazinesthrough [4+1] and [4+2] reactions, respectively. Preliminary mechanis-tic experiments corroborated the occurrence of the designed cascadereactions

The unprecedented copper-catalyzed asymmetric alkynylallylic monofluoroalkylation reaction is described via the use of 1,3-enynes and fluorinated malonates. A series of 1,4-enynes bearing a monofluoroalkyl unit are achieved in high yields, excellent regio- and enantioselectivity and high E/Z selectivity. The asymmetric propargylic monofluoroalkylation is also developed. The reliability and synthetic value of the work are highlighted by a gram-scale test and a couple of downstream transformations. Preliminary mechanistic studies unveil a negative nonlinear effect for the catalytic process. 1,4-Enyne bearing a monofluoroalkyl unit is achieved in a high yield and stereoselectivity via Cu-catalyzed asymmetric alkynylallylic monofluoroalkylation.

The oxidative dehydrogenation Povarov/tandem reaction between electrochemically oxidized glycine derivatives and olefins was investigated. Specifically, a nitrogen oxide radical 2,2,6,6-tetramethylpiperidoxyl (TEMPO) was used as a redox mediator to reduce the potential of the electrochemical reaction and avoid over-oxidation of electron-rich aromatic amines at higher potentials. The reaction provides a potential pathway for the nitrogen-a functionalization of glycine derivatives. Further, the reaction represents an efficient method for synthesizing quinoline derivatives under mild conditions to achieve high yields through a combination of Shono oxidation and Povarov reactions.

Autophagy is a lysosome-dependent degradation pathway essential for cellular homeostasis, which decreases with age. However, it is unclear how aging induces autophagy decline. Here we show the role of protein S-palmitoylation in autophagy. We identify the palmitoyl acyltransferase DHHC5 as a regulator of autophagy by mediating the palmitoylation of beclin 1, which in turn promotes the formation of ATG14L-containing class III phosphatidylinositol-3-kinase complex I and its lipid kinase activity by promoting the hydrophobic interactions between beclin 1 and adapter proteins ATG14L and VPS15. In aging brains of human and nonhuman primate, the levels of DHHC5 exhibit a marked decrease in expression. We show that DHHC5 deficiency in neurons leads to reduced cellular protein homeostasis in two established murine models of Alzheimer's disease, which exaggerates neurodegeneration in an autophagy-dependent manner. These findings identify reduction of DHHC5-mediated beclin 1 S-palmitoylation as an underlying mechanism by which aging induces autophagy decline.

Phase separation is a vital mechanism that mediates the formation of biomolecular condensates and their functions. Necroptosis is a lytic form of programmed cell death mediated by RIPK1, RIPK3, and MLKL downstream of TNFR1 and has been implicated in mediating many human diseases. However, whether necroptosis is regulated by phase separation is not yet known. Here, we show that upon the induction of necroptosis and recruitment by the adaptor protein TAX1BP1, PARP5A and its binding partner RNF146 form liquid -like condensates by multivalent interactions to perform poly ADP-ribosylation (PARylation) and PARylationdependent ubiquitination (PARdU) of activated RIPK1 in mouse embryonic fibroblasts. We show that PARdU predominantly occurs on the K376 residue of mouse RIPK1, which promotes proteasomal degradation of kinase-activated RIPK1 to restrain necroptosis. Our data demonstrate that PARdU on K376 of mouse RIPK1 provides an alternative cell death checkpoint mediated by phase separation -dependent control of necroptosis by PARP5A and RNF146.

We developed a new strategy to enhance the chiral discrimination capability of F-19-labeled probes by tuning the torsion angle of the probe's backbone, allowing for the resolution of challenging analytes. Its versatility is demonstrated through the superior performance and the wide analyte scope.

Hematopoietic progenitor kinase 1 (HPK1) is a negative regulator of T-cell receptor signaling. While HPK1 is considered as a promising target for cancer immunotherapy, no small-molecule HPK1 inhibitors have been approved for cancer treatment. Herein, we report the discovery of a series of new HPK1 inhibitors with a 5aminopyrido[2,3-d]pyrimidin-7(8H)-one scaffold. The most potent compound 9f inhibited HPK1 kinase activity with an IC50 of 0.32 nM in the time-resolved fluorescence resonance energy transfer (TR-FRET) assays, while displayed reasonable selectivity in a panel of 416 kinases. Cellular engagement of HPK1 by compound 9f was confirmed through the nano-bioluminescence resonance energy transfer (Nano-BRET) experiments. Compound 9f effectively reduced the phosphorylation of the downstream protein SLP-76 in primary peripheral blood mononuclear cells (PBMCs) and human T lymphocytic leukemia Jurkat cells. Compound 9f also enhanced the IL2 and IFN-gamma secretion in PBMCs. Furthermore, the binding mode of compound 9f with HPK1 was confirmed by the resolved cocrystal structure. Taken together, this study provides HPK1 inhibitors with a novel scaffold and clear binding mode for further development of HPK1-targeted therapeutic agents.

Chiral trisubstituted vicinal diols are a type of important organic compounds, serving as both common structure units in bioactive natural products and chiral auxiliaries in asymmetric synthesis. Herein, by using siloxypropadienes as the precursors of allyl copper(I) species, a copper(I)-catalyzed diastereoselective and enantioselective reductive allylation of ketones was achieved, providing both syn-diols and anti-diols in good to excellent enantioselectivity. DFT calculations show that cis-gamma-siloxy-allyl copper species are generated favorably with either 1-TBSO-propadiene or 1-TIPSO-propadiene. Moreover, the steric difference of TBS group and TIPS group distinguishes the face selectivity of acetophenone, leading to syn-selectivity for 1-TBSO-propadiene and anti-selectivity for 1-TIPSO-propadiene. Easy transformations of the products were performed, demonstrating the synthetic utility of the present method. Moreover, one chiral diol prepared in the above transformations was used as a suitable organocatalyst for the catalytic asymmetric reductive self-coupling of aldimines generated in situ with B2(neo)2. An asymmetric synthesis of trisubstituted vicinal diols is accomplished by copper(I)-catalyzed diastereoselective and enantioselective reductive allylation of ketones with siloxypropadienes. The generation of both syn-diols and anti-diols is rationalized by DFT calculations, which show that cis-gamma-siloxy-allyl copper species are generated favorably in the reduction of either 1-TBSO-propadiene or 1-TIPSO-propadiene by copper hydride species.+ image