(Dearomative) cross-coupling of two (hetero)arenes via single-electron processes without the need for prefunctionalized partners and precious metals represents an attractive strategy for the assembly of (hetero)biaryl or dearomative scaffolds. However, the current known methods predominantly utilize two electron-rich (hetero)arenes as coupling partners. In addition, the inherent obstacle of selectivity issues poses a notable challenge. Here, we report a photocatalytic strategy for site-selective dearomative cross-coupling of electron-deficient indoles and naphthalenes with electron-rich (hetero)arenes. Enabled by an organic photocatalyst-isoazatruxene derivative ITN-2, electron-deficient (hetero)arenes are converted into carbocations through sequential SET reduction, protonation, and SET oxidation. The resulting electrophilic species can then be trapped by a variety of electron-rich (hetero)arenes to furnish the coupling. When electron-deficient indoles serve as the coupling partners, the dearomative cross-coupling takes place at the C3 position with reversed regioselectivity, allowing access to indoline derivatives bearing all-carbon quaternary centers in high yields. In addition, we demonstrate that naphthalene derivatives participate well in an unconventional C4-site-selective dearomative coupling with electron-rich (hetero)arenes. Alternatively, the formal C-H/C-H cross-coupling of electron-deficient and electron-rich (hetero)arenes is accomplished with extraordinary site-selectivity through a one-pot dearomatization/aromatization approach.

Dynamic assembly of the complex I signalosome mediated by three death domain (DD)-containing proteins-TNFR1, TRADD and RIPK1-is key for transmitting extracellular TNF stimuli to intracellular NF-kappa B signalling in controlling 'live or die' cell fate1. This signalling hub features the rapid recruitment of TRADD and RIPK1 after engagement of TNFR1 by TNF for the formation of complex I, followed by timed disassembly for transition into downstream signalling complexes2,3, but the mechanism driving the dynamic reversibility of complex I remains unclear. Here we captured the assembly core of complex I and determined its cryo-electron microscopy structure, showing a pentameric fibre comprising 31 DDs, with a single layer of a TRADD-DD pentamer sandwiched between multiple layers of TNFR1-DD and RIPK1-DD homopentamers. Structural analysis revealed a strong opposing electric dipole moment (EDM) generated by RIPK1-DD oligomerization relative to that of TNFR1-DD and TRADD-DD. Structure-guided mutagenesis in TNFR1-TRADD-RIPK1 pentameric fibres altering the EDM without affecting DD oligomerization demonstrated the role and mechanism of EDM in driving the dynamic reversibility mediating the rapid assembly and disassembly of complex I. Our study demonstrates a role for long-range interactions mediated by protein EDMs in driving the assembly and disassembly of super-signalling complex I for promoting NF-kappa B signalling.

The incorporation of trinitromethyl or dinitromethyl moieties into nitrogen-rich heterocycles represents an effective strategy for the development of high-energy-density materials (HEDMs). In this work, we report the synthesis of a highly oxygen-balanced energetic compound, 2-trinitromethyl-4-(tetrazol-5-yl)-5-nitro-1,2,3-tria-zole (2), characterized by four nitro groups and a high oxygen balance (OBCO2) of-2.4 %. Subsequently, a series of energetic salts based on trinitromethyl-and dinitromethyl-functionalized 1,2,3-triazoles were derived from compound 2. All the newly synthesized energetic compounds were fully characterized via infrared (IR) spectroscopy, multinuclear NMR (1H, and 13C) spectroscopy, and elemental analysis. With the exception of the aminoguanidinium salt 5 (Td =115 degrees C), the salt derivatives exhibit notable thermal stability with decomposition temperatures exceeding 142 degrees C. Furthermore, these compounds display favorable densities (rho = 1.62 g cm-3-1.85 g cm-3) and superior detonation performances (vD = 7880-9256 m s-1, P = 22.8-37.2 GPa). Notably, compound 2 possesses excellent oxygen balance and detonation properties (rho = 1.87 g cm-3, vD = 9256 m s-1, P = 37.2 GPa) that surpass those of RDX. These findings suggest that compound 2 and its energetic salts are promising candidates for application as secondary explosives.

Amipurimycin is a peptidyl nucleoside antibiotic characterized by a C9 high-carbon sugar, with potent activity against the rice blast pathogen Pyricularia oryzae. The biosynthetic machinery of the C-4' methylene group in its deoxy sugar has remained unknown. This study reveals that ApmL, a hypothetical protein in the DUF3500 family, functions as a 4 ',5 '-dehydratase whose activity is strictly dependent on the PKS assembly line. Together with its partner reductase ApmM, they complete a two-step C-4 ' deoxygenation process via dehydration-reduction. We achieve the first in vitro reconstitution of this unique PKS-coupled dehydration process and show direct interaction between ApmL and PKS proteins. Our findings establish ApmL as a new family of dehydratase and uncover a noncanonical deoxygenation strategy in nucleoside antibiotic biosynthesis.

Although FGFR2 is a well-validated oncogenic target, no selective FGFR2 inhibitors have been approved for clinical use. In this study, we report the discovery of 2H-pyrazolo[3,4-d]pyrimidin-4-amine derivative as novel, irreversible FGFR2 inhibitors. The optimal compound, PLW559, potently inhibited FGFR2 with an IC50 value of 13.59 nM and demonstrated exceptional selectivity over FGFR1, FGFR3, and FGFR4. Covalent binding to the target was confirmed by mass spectrometry. In cellular models, PLW559 exhibited potent and selective antiproliferative effects against FGFR2-driven cancer cells, effectively suppressed downstream FGFR2 signalling and induced cancer cell apoptosis. Notably, it showed minimal activity in non-FGFR2-dependent cells. This work presents a new class of selective FGFR2 inhibitors based on a novel scaffold, offering promising lead compounds for the development of FGFR2-target therapies.

Achieving precise stereocontrol when forging two vicinal C(sp & sup3;)-C bonds on unsymmetrical internal alkenes remains a formidable challenge. The comparable reactivity of alkyl radicals often compromises chemo- and regioselectivity, while the concurrent induction of diastereo- and enantioselectivity has proven elusive. Here, we show a unified metallaphotoredox strategy that addresses these challenges through two complementary multicomponent difunctionalization protocols. First, a Ni/terpyridine catalyst system enables anti-selective 1,2-dialkylation of both cyclic and acyclic internal alkenes, delivering vicinal C(sp & sup3;)-C(sp & sup3;) linkages with high levels of chemo-, regio-, and diastereoselectivity. A switch to a chiral biimidazole ligand and replacement of the alkyl halide with a (hetero)aryl bromide unlocks enantioselective 1,2-alkylarylation of cyclic internal alkenes. This transformation affords beta-aryl-alpha-alkylated lactones and related scaffolds bearing two contiguous stereocenters with excellent diastereo- and enantioselective control. This dual strategy offers a rapid and efficient access to drug-like molecular architectures.

Acyclic aminooxycarbene (AAOC) ligands, analogues of N-heterocyclic carbene (NHC), are believed to possess superior sigma-donating and pi-accepting abilities over those of NHCs. Their coordination chemistry, however, remains largely unexplored. In this study, we demonstrate that AAOC ligands can effectively stabilize coordinatively unsaturated cobalt complexes. The equimolar reactions of CoCl2 with the AAOC ligands, N,N-diisopropyl-2,6-dimethylphenoxylmethylidene (L iPrXyl) and N,N-diisopropyl-2,6-diisopropylphenoxylmethylidene (L iPrDipp), in THF afford the tetrahedral cobalt(II) complexes [(AAOC)(THF)CoCl2] (AAOC = L iPrXyl, 1; L iPrDipp, 2) in good yields, whereas the reaction of CoCl2 with N,N-diisopropyl-1-adamantanoxylmethylidene (L iPrAd) yields the dimeric complex devoid of THF coordination [(L iPrAd)Co(Cl)(mu-Cl)2Co(Cl)(L iPrAd)] (3). The solvent affects the reaction outcome as the interaction of CoCl2 with two equiv of L iPrDipp in toluene produces the square planar cobalt(II) complex [trans-(L iPrDipp)2CoCl2] (4). Reduction of 4 with Mg in THF yields the three-coordinate cobalt(I) complex [(L iPrDipp)2CoCl] (5), which further reacts with NaBPh4 to form the two-coordinate cobalt(I) complex [(L iPrDipp)2Co][BPh4] (6). Moreover, the three-coordinate cobalt(0) complexes with AAOC ligation [(AAOC)Co(dvtms)] (dvtms = divinyltetramethyldisiloxane, AAOC = L iPrXyl, 7; L iPrDipp, 8; L iPrAd, 9) proved accessible from the reduction reactions of 1-3 with Mg in the presence of dvtms. Complexes 1-9 have been fully characterized by 1H NMR spectroscopy, magnetic susceptibility measurement, single-crystal X-ray diffraction, and elemental analysis.

Syntheses of low-dimensional macromolecules with increasing size and complexity in solution pose substantial challenges in terms of their precise structural characterization. Electrospray ionization coupled with scanning tunneling microscopy (ESI-STM) has emerged as a promising tool for the characterization of these nonsublimable macromolecules in real space. However, the weak ionization of such macromolecules and the three-dimensional configuration of the attached solubilizing groups severely impede high-resolution STM imaging. In this work, we synthesized a series of graphyne-graphdiyne concentric macrocycles with triphenylamine groups to enhance the ionization efficiency, which in turn ensures the sample cleanliness for STM characterization. To tackle imaging interference from solubilizing groups, single-molecule tip manipulation and large-scale bromine-assisted thermal treatment were developed for alkoxy and/or alkyl chain removal, enabling the acquisition of unprecedented bond-resolving structural images and angstrom-resolution frontier molecular orbital maps. Our methods resolve the long-standing dilemma between the solubility requirements of solution synthesis and the molecular planarization demands of high-resolution STM characterization, pushing the resolution limit of macromolecules to the angstrom level.

A series of nonsymmetric tetranuclear spiro alpha-diol-beta-diimine nickel complexes with a non-coordinating aryl group (Site 1) and a coordinating side-arm tertiary amine group (Site 2) were designed, synthesized, and characterized for studying the roles of Ni(II)s in the cluster in olefin polymerizations. Upon activation with MMAO, these complexes show moderate to high activity in ethylene homo- and co-polymerization with 3-buten-1-ol and 9-decen-1-ol. These nonsymmetric tetranuclear complexes exhibit bimodal catalytic behavior besides great activity, up to 2569 kg/(mol Cat h atm). The Mw distribution of PE from bimodal to monomodal and Mw of the low molecular weight (LMW) fraction from 11 to 66 kg/mol can be efficiently tuned by the introduced coordinating side arm tertiary amine or aryl group at Site 2. Polymer 1H NMR shows vinyl end group exists in PEs with LMW fraction and its absence in PEs without LMW fraction, suggesting the Site 2 Ni center with side-arm tertiary alkyl amine leads to LMW PE and beta-H elimination is the chain termination pathway. DFT studies were carried out supporting the different roles of the Ni sites bearing different steric and electronic environments in the tetranuclear complex on activity, polymer dispersity and Mw of the LMW fraction in ethylene polymerization.