The construction of C(sp3)-C(sp3) bonds remains a fundamental challenge in synthetic chemistry. Herein, we interrogate a photoelectrochemical strategy for the cross-coupling of aliphatic carboxylic acids with alkyl halides. This dual catalytic system synergistically integrates anodic photoinduced ligand-to-metal charge transfer (LMCT) with cathodic nickel-mediated electroreduction. Exploiting the photolysis of a carboxylate-metal complex, our approach enables the mild generation of alkyl radicals at the anode, bypassing the necessity for high-energy irradiation or harsh oxidative conditions. Concurrently, the cathode facilitates the selective reduction of Ni(II) to Ni(I), which engages the alkyl halide and mediates the subsequent radical cross-coupling. This protocol provides an alternative method for assembling complex molecular architectures under exceptionally mild conditions, representing a distinct advance in synthetic photoelectrochemistry.

S-acylation is well known for regulating protein stability and trafficking. In a recent issue of Molecular Cell, Xu et al.(1) reveal a distinct, aggregation-suppressing function of this posttranslational lipid modification: S-acylation of the RNA-binding protein TDP-43 antagonizes poly(ADP-ribos e)-driven condensation. Moreover, reduced S-acylation levels are linked to ALS pathogenesis.

S-Trifluoromethyl sulfonium salt Ph2S+CF3 TfO- has emerged as a powerful reagent for trifluoromethylation. However, a scalable synthesis of this salt has not been reported to date, and its preparation traditionally relies on highly toxic benzene, which raises significant safety and environmental concerns. In this work, we first achieved a practical tens-of-gram-scale synthesis of Ph2S+CF3 TfO-, and then, we realized a >100 g-scale preparation of an analogue, S-trifluoromethyl bis(4-fluorophenyl)sulfonium triflate (F-Sul). The synthesis of this salt avoids the use of benzene and streamlines the purification (no chromatography required). Comprehensive evaluation revealed that F-Sul exhibits nearly identical reactivity to Ph2S+CF3 TfO- in diverse trifluoromethylation reactions. Furthermore, we demonstrated the scalability and synthetic utility of F-Sul by achieving the hundred-gram-scale synthesis of nonafluorobutyl trifluoromethyl sulfonate ((C4F9SO3CF3)-C-n, TFNf), a valuable trifluoromethoxylation reagent and an electrolyte additive for lithium-ion batteries

Copper-catalyzed azide-alkyne cycloaddition (CuAAC) is a cornerstone reaction in modern chemistry. Although binuclear catalytic mechanisms have been widely proposed and certain binuclear complexes exhibit good activity, asymmetric CuAAC still relies on the in situ assembly of copper salts with chiral ligands. Herein, guided by the postulated reaction mechanism, we employ a preassembled chiral binuclear copper catalyst with a well-defined chiral pocket to achieve efficient kinetic resolution of alkyne-functionalized azlactones with azides. This catalyst contains two copper(I) ions within a single chiral ligand framework, providing a rigid planar scaffold, stable coordination geometry, and a semicircular chiral cavity. Both triazole products and recovered azlactones are obtained in high enantiopurity and can be rapidly converted into chiral alpha-quaternary amino acid derivatives. This study establishes chiral binuclear copper complexes as an effective platform for enantioselective CuAAC.

Scholarisine A (1) represents a structurally distinct and synthetically intriguing subfamily of the echitamine/akuammiline-type alkaloids. Inspired by its postulated biogenetic logic, we developed a radical cyclization strategy that retains the key bond-forming site while replacing the aldol reaction. This reaction-altering biomimetic strategy, combined with expeditious preparation of a tetracyclic precursor, enabled a 13-step, scalable synthesis of 1. Moreover, facile access to its congeners, scholarisines I, T, and W (2-4), was achieved. Compound 2 impairs lysosomal degradative capacity and thus inhibits late-stage autophagy in cancer cells.

Transthyretin (TTR) amyloidosis is a protein misfolding disease characterized by amyloid fibril deposition in vital organs, leading to cardiomyopathy (ATTR-CM). Early diagnosis of ATTR-CM remains challenging due to lack of sensitive, rapid screening methods. Here, we report cryo-EM structures of TTR amyloid fibrils extracted from minimally invasive abdominal fat-pad biopsies of three living Ala97Ser ATTR-CM patients. The adipose-derived fibril structures closely mirror those from diseased post-mortem cardiac tissues, validating the use of fat-pad biopsies to investigate the atomic structure of TTR fibrils in living patients. Furthermore, we determined cryo-EM structures of TTR fibrils in complex with two amyloid-binding dyes, Congo Red (CR) and Thioflavin S (ThS), which are widely used in the clinical diagnosis of ATTR-CM. Both CR and ThS predominantly bind to a specific surface arginine site on the TTR fibril via electrostatic interactions. These findings provide structural insights into how small-molecule dyes bind TTR fibrils, offering a molecular foundation for the rational design of TTR-specific tracers to enable early and accurate diagnosis of TTR amyloidosis.

Transition-metal-catalyzed dicarbofunctionalization of alkenes represents a powerful strategy for building molecular complexity in a single step. Here we report an unprecedented nickel-catalyzed 1,2-arylalkenylation of unactivated alkenyl alcohols using alkenyl boronates and aryl iodides. This method uniquely leverages the native hydroxyl group as an intrinsic directing handle, eliminating the need for pre-installed auxiliaries and streamlining the synthesis of structurally diverse alkenol derivatives. The reaction proceeds under mild conditions with broad functional group tolerance and excellent regioselectivity, enabling efficient construction of valuable building blocks. Mechanistic studies, supported by DFT calculations, reveal a Ni(0)/Ni(I)/Ni(II) catalytic cycle probably involving aryl radical intermediates. By exploiting alcohols as directing groups, this work expands the scope of alkene dicarbofunctionalization and provides a versatile platform for late-stage functionalization relevant to pharmaceuticals, agrochemicals, and materials development.

Radical-mediated coupling reactions serve as powerful tools for chemical bond formation, leveraging the high reactivity of radical intermediates to achieve reactions inaccessible through traditional ionic pathways. However, achieving radical-mediated multisite coupling remains a significant challenge. Here, we report an on-surface synthesis strategy of delocalized pi-radical-mediated multisite cooperative coupling for the highly selective synthesis of oxygen-doped nanographene. Initially, dehydrogenation of the hydroxyl group on the molecule generates a sigma-radical, which simultaneously transforms into a delocalized pi-radical due to orbital rehybridization. Subsequently, electron delocalization induced by the pi-radical gives rise to the spin-density distribution along the entire periphery of the molecule, enabling multisite C-O and C-C coupling between two monomer units. Owing to the high regioselectivity imposed by steric hindrance between the carbonyl groups, high-yield (>95.6%) pi-conjugated oxygen-doped nanographene is synthesized. Our work establishes a novel paradigm of cooperative multibond formation mediated by delocalized pi-radicals, opening a promising avenue for the precise bottom-up synthesis of extended pi-conjugated systems.

Precise control over the presence and position of knots in polymers remains a long-standing synthetic challenge, with theory indicating broad implications for properties and function. Here we report on a topological synthon approach-extension and macrocyclization of an overhand knot-that enables the high yielding synthesis of closed-loop trefoiled polymers with narrow polydispersity and tunable topological parameters. From the same set of building blocks we prepared linear, cyclic and trefoiled topoisomers of matched chemical composition, allowing topology-property relationships to be examined directly. Low-temperature ultrahigh-vacuum scanning tunnelling microscopy resolved three conformers of trefoiled polystyrene, with high-, medium- and low-symmetry forms whose populations depend on chain length, local flexibility and solvation. Coarse-grained Langevin dynamics reproduce these distributions and indicate that bending energy and conformational entropy govern conformer stability. Metal binding localizes the knotted region, reminiscent of protein/DNA knot translocation. The synthon also affords trefoiled poly(ethylene glycol) and trefoiled polystyrene-poly(ethylene glycol) diblock copolymers, demonstrating the generality of the approach across polymer backbones.