A Ni-catalyzed enantioselective hydroamination of vinylarenes has been developed, affording a wide variety of alpha-branched chiral alkylamines in good yields with exclusive Markovnikov regioselectivity and excellent enantioselectivity. The SKP ligand was found to be crucial to both the reactivity enhancement and enantiocontrol of the reaction. The synthetic utility of the protocol was exemplified in a gram-scale reaction and late-stage modification of medicinally relevant molecules. The deuterium-labeling experiment revealed that the irreversible hydronickelation of vinylarenes is most likely the enantioselectivity-determining step.

Pyrroindomycins (PYRs) represent the only spirotetramate natural products discovered in nature, and possess potent activities against methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium. Their unique structure and impressive biological activities make them attractive targets for synthesis and biosynthesis; however, the discovery and generation of new PYRs remains challenging. To date, only the initial components A and B have been reported. Herein, we report a mutasynthesis approach for the generation of nine new PYRs with varying acyl modifications on their deoxy-trisaccharide moieties. This was achieved by blocking the formation of the acyl group 1,8-dihydropyrrolo[2,3-b]indole (DHPI) via gene pyrK1 inactivation and supplying chemical acyl precursors. The gene pyrK1 encodes a DUF1864 family protein that probably catalyzes the oxidative transformation of l-tryptophan to DHPI, and its deletion results in the abolishment of DHPI-containing PYRs and the accumulation of three new PYRs either without acyl modification or with DHPI replaced by benzoic acid and pyrrole-2-carboxylic acid. Capitalizing on the capacity of the Delta pyrK1 mutant to produce new PYRs, we have successfully developed a mutasynthesis strategy for the generation of six novel PYR analogs with various aromatic acid modifications on their deoxy-trisaccharide moieties, showcasing the potential for generating structurally diverse PYRs. Overall, this research contributes significantly to understanding the biosynthesis of PYRs and offers valuable perspectives on their structural diversity. Nine new pyrroindomycins with diverse acyl modification on their deoxy-trisaccharide moieties were created via a mutasynthesis approach. The key feature lies in blocking DHPI formation by gene pyrK1 inactivation and supplying chemical acyl precursors.

Thermal catalytic dehydrogenation of congested alkanes, such as the 1,1-disubstituted ethane (1,1-DSE) motif, is still a largely unsolved challenge. Herein, we report the investigation of biaryl-based atropisomeric diphosphines with various electronic and steric properties and their corresponding chloroiridium complexes for catalytic transfer dehydrogenation (CTD) of 1,1-DSEs using tert-butylethene as H-acceptor. The use of diphosphines of the biaryl backbone with a narrow dihedral angle was found to be essential to forming an effective catalytic species, cis-P2ClIr. A systematic investigation of three atropisomeric diphosphine classes, Segphos, MeO-Biphep, and Binap, revealed that the sterically hindered and electron-rich ligands are more efficient than the less hindered and electron-deficient ones. With an understanding of the structure-activity relationships, we developed two highly encumbered ligands 3,5-TMS,4-MeOMeO-Biphep (M12) and 3-TIPS,5-TMSMeO-Biphep (M13), which afforded >1400 turnovers at 150 degrees C in the cumene/TBE CTD reaction, representing the most efficient catalyst for thermal catalytic dehydrogenation of 1,1-DSEs. Moreover, these two ligands produced similar to 420 turnovers in the CTD of 2-(1-adamantyl)propane, demonstrating their ability in dehydrogenation of unactivated hindered dialkyl-substituted ethanes.

Gasdermin D (GSDMD) is the executor of pyroptosis, which is important for host defence against pathogen infection. Following activation, caspase-mediated cleavage of GSDMD releases an amino-terminal fragment (GSDMD-NT), which oligomerizes and forms pores in the plasma membrane, leading to cell death and release of proinflammatory cytokines. The spatial and temporal regulation of this process in cells remains unclear. Here we identify GSDMD as a substrate for reversible S-palmitoylation on C192 during pyroptosis. The palmitoyl acyltransferase DHHC7 palmitoylates GSDMD to direct its cleavage by caspases. Subsequently, palmitoylation of GSDMD-NT promotes its translocation to the plasma membrane, where APT2 depalmitoylates GSDMD-NT to unmask the C192 residue and promote GSDMD-NT oligomerization. Perturbation of either palmitoylation or depalmitoylation suppresses pyroptosis, leading to increased survival of mice with lipopolysaccharide-induced lethal septic shock and increased sensitivity to bacterial infection. Our findings reveal a model through which a palmitoylation-depalmitoylation relay spatiotemporally controls GSDMD activation during pyroptosis. Xu and colleagues identify a sequential palmitoylation-depalmitoylation mechanism that controls GSDMD cleavage by caspases, plasma membrane trafficking and oligomerization, thereby triggering pyroptosis in a spatial and temporal manner.

The relationship among chemical structure, physicochemical property and aggregation behavior of organic functional material is an important research topic. Here, we designed and synthesized three bis(squaraine) dyes BSQ1, BSQ2 and BSQ3 through the combination of two kinds of unsymmetrical azulenyl squaraine monomers. Their physicochemical properties were investigated in both molecular and aggregate states. Generally, BSQ1 displayed different assembly behaviors from BSQ2 and BSQ3. Upon fabrication into nanoparticles, BSQ1 tend to form J-aggregates while BSQ2 and BSQ3 tend to form H-aggregates in aqueous medium. When in the form of thin films, three bis(squaraine) dyes all adopted J-aggregation packing modes while only BSQ1 presented the most significant rearrangement of aggregate structures as well as the improvement in the carrier mobilities upon thermal annealing. Our research highlights the discrepancy of aggregation behaviors originating from the molecular structure and surrounding circumstances, providing guidance for the molecular design and functional applications of squaraines. Three azulene-containing bis(squaraine) dyes were synthesized, among which BSQ1 showed distinct aggregation behaviors from the other two dimers and demonstrated excellent photothermal conversion efficiency. In nanoparticles, BSQ1 formed J-aggregates while BSQ2 and BSQ3 displayed H-aggregates. In films, BSQ1 presented the most significant rearrangement of aggregate structures upon thermal annealing with improved charge transport capabilities.+ image

The construction of silicon-stereogenic silanols via Pd-catalyzed intermolecular C-H alkenylation with the assistance of a commercially available L-pyroglutamic acid has been realized for the first time. Employing oxime ether as the directing group, silicon-stereogenic silanol derivatives could be readily prepared with excellent enantioselectivities, featuring a broad substrate scope and good functional group tolerance. Moreover, parallel kinetic resolution with unsymmetric substrates further highlighted the generality of this protocol. Mechanistic studies indicate that L-pyroglutamic acid could stabilize the Pd catalyst and provide excellent chiral induction. Preliminary computational studies unveil the origin of the enantioselectivity in the C-H bond activation step. With the assistance of a commercially available L-pyroglutamic acid ligand, the construction of silicon-stereogenic silanols via the Pd-catalyzed intermolecular C-H alkenylation has been realized. Employing the oxime ether as the directing group, the silicon-stereogenic silanol derivatives could be readily prepared with excellent enantioselectivities via desymmetrization and parallel kinetic resolution, featuring a broad substrate scope and good functional group tolerance.+ image

Defects in the prelamin A processing enzyme caused by loss-of-function mutations in the ZMPSTE24 gene are responsible for a spectrum of progeroid disorders characterized by the accumulation of farnesylated prelamin A. Here we report that defective prelamin A processing triggers nuclear RIPK1-dependent signalling that leads to necroptosis and inflammation. We show that accumulated prelamin A recruits RIPK1 to the nucleus to facilitate its activation upon tumour necrosis factor stimulation in ZMPSTE24-deficient cells. Kinase-activated RIPK1 then promotes RIPK3-mediated MLKL activation in the nucleus, leading to nuclear envelope disruption and necroptosis. This signalling relies on prelamin A farnesylation, which anchors prelamin A to nuclear envelope to serve as a nucleation platform for necroptosis. Genetic inactivation of necroptosis ameliorates the progeroid phenotypes in Zmpste24-/- mice. Our findings identify an unconventional nuclear necroptosis pathway resulting from ZMPSTE24 deficiency with pathogenic consequences in progeroid disorder and suggest RIPK1 as a feasible target for prelamin A-associated progeroid disorders. Yang, Zhang et al. identify a non-canonical form of necroptosis driven by nuclear RIPK1-mediated nuclear membrane rupture as a result of ZMPSTE24 deficiency and defective prelamin A processing commonly observed in progeroid disorders.