Difluorocarbene, a versatile bipolar intermediate, has been widely exploited in ionic-type coupling reactions. Its direct transformation into a fluorinated carbon-radical species, however, has remained a formidable challenge because of the large singlet-triplet energy gap. Here we report an unprecedented strategy that unlocks difluorocarbene as a precursor for both fluorinated carbanions and carbon radicals through the thermolytic homolysis of an aryldifluoromethylpalladium intermediate. This palladium-catalyzed sequential process enables a modular three-component coupling of aryl iodides, alkenes, and ClCF2H, delivering a broad spectrum of difluoroalkylated arenes in high efficiency. The method features inexpensive and readily available reagents, excellent functional-group tolerance, and opens a new avenue for the precise installation of the difluoromethylene motif.

We report a highly enantio- and diastereoselective reductive coupling of unactivated alkenes with aldehydes catalyzed by an N-heterocyclic carbene (NHC)/nickel complex, which provides efficient access to optically active indanol derivatives. Under mild conditions, a broad range of substrates bearing diverse functional groups & horbar;including electron-donating, electron-withdrawing, and heteroaromatic substituents & horbar;underwent smooth coupling to afford the corresponding products with excellent stereocontrol (all >99:1 dr, up to 97% ee). The method was also successfully extended to ketone substrates, delivering chiral tertiary alcohol derivatives with good enantioselectivity, further demonstrating its synthetic versatility. The use of a bulky chiral NHC ligand proved to be essential for achieving high stereoselectivity in the nickel-catalyzed process.

Alkynylallylic substitution has emerged as a new and reliable model for the construction of 1,4-enyne skeletons. However, this method is limited to regiospecific SN2 ' coupling due to favorable stereocontrol in a small reaction pocket. Here, we demonstrate that the regioselectivity for the transformation can be dictated to occur at the in situ position, and thus achieve the unprecedented remote alkynylallylic substitution. BOX ligands instead of commonly used PyBOX are adopted for Cu metal to guarantee the high remote regioselectivity, and the protocol is suitable for diverse N-, O-, and C-based nucleophiles. More challenging, the asymmetric protocol for in situ remote substitution is established through precise regio- and enantiocontrol via Cu/FOXAP catalysis. Mechanistic studies suggest that a monocopper ligated with multiple ligands might be involved in the enantio-determining step and the cleavage of the remote leaving group works as the rate-determining step.

The development of asymmetric variants of Group 9 Cp*M(III)-catalyzed C-H functionalization is fundamentally challenged by the coordinative saturation of the catalyst. While established strategies employ chiral CpX ligands or chiral anions, a general approach using external L-type chiral ligands has remained elusive. Herein, we introduce a chiral cation strategy that enables an achiral Cp*tBuIr(III) catalyst to achieve high enantioselectivity, orchestrated by a designed bifunctional neutral nitrile-phosphine oxide ligand. This system provides direct and efficient access to pyrazole-containing diaza[6]helicenes-a class of N-doped heteroaromatics with low enantiomerization barriers that have been difficult to access. The synthesized helicenes exhibit promising chiroptical properties, including circularly polarized luminescence. Combined mechanistic and computational studies unveil that enantiocontrol is determined during the C-H activation step, facilitated by the formation of a chiral cationic Cp*tBuIr(III) complex where the bifunctional neutral nitrile-phosphine oxide ligand is integral to the stereodefining transition state. This work establishes a distinct ligand platform for asymmetric C-H functionalization using simple, achiral Cp*M(III) complexes.

Natural products bearing a bicyclo[3.2.2]nonane motif pose a considerable challenge to chemical synthesis. We developed a europium-promoted inverse-electron-demand Diels-Alder reaction of benzo[2,3]tropone derivatives with electron-rich olefins, which offers an expeditious approach to densely substituted bicyclo[3.2.2]nonanes. This method enabled the concise synthesis of a tetracyclic amine, subsequently identified as a downstream suppressor of autophagy. (c) 2026 Published by Elsevier B.V. on behalf of Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.

A general cobalt-catalyzed oxidative cyclization strategy for the stereoselective synthesis of tri- and tetrasubstituted alkenes from readily available 1,3-enynes is presented. This method employs an earth-abundant cobalt catalyst and exhibits broad functional group tolerance, delivering the multisubstituted olefins with high regioselectivity and excellent Z/E control.

Genome-wide association studies strongly implicate neuroinflammation in late-onset Alzheimer's disease (LOAD). Genetic risk loci for LOAD are enriched for genes expressed in microglia, but the relationship among microglial LOAD risk genes has been unclear. We found that the N-terminal SH2 domain of INPP5D, an important LOAD risk gene, directly interacted with the cell death regulator RIPK1 at p-Y383 to suppress RIPK1 kinase activation. Microglial INPP5D deficiency cell-autonomously promoted RIPK1-mediated transcriptional induction of diverse LOAD risk genes, proinflammatory cytokines, complements, and ROS mediators, as well as proinflammatory signaling mediators such as Toll-like receptors (TLRs), MyD88, Nlrp3, gasdermin D, and Zbp1. RIPK1-regulated microglial transcriptomic signatures were found in microglial subtypes implicated in human Alzheimer's disease (AD) pathogenesis. Furthermore, microglial INPP5D deficiency promoted aging-dependent RIPK1-mediated development of neuronal TDP-43 pathology, neuronal loss, and motor dysfunction in a non-cell-autonomous manner. Our data suggest that INPP5D functions as an intracellular rheostat in regulating RIPK1-mediated neuroinflammation for promoting aging-related neurodegenerative diseases, including LOAD and AD-amyotrophic lateral sclerosis comorbidity.