Herein, we report a convergent and practical synthesis of the nonsteroidal mineralocorticoid receptor antagonist (S)-finerenone. The present approach incorporates a scalable, chromatography-free method to attain a racemic precursor with an impressive overall yield of 88%. Leveraging this versatile intermediate, we have developed two complementary approaches, including a robust resolution utilizing (+)-benzoyl tartaric acid and an efficient asymmetric transfer hydrogenation facilitated by chiral phosphoric acid-catalyzed dynamic kinetic resolution (DKR), to avoid cumbersome purification procedures, thereby offering a flexible, high-yielding, and highly enantioselective platform for the industrial-scale production of (S)-finerenone.

Sulfur-containing natural products are widely distributed in nature. Yatakemycin (YTM) is a complex antitumor and antifungal antibiotic featuring a typical cyclopropane moiety as the pharmacophore and containing an S-methyl thioester moiety. In this study, functional characterization of three genes (ytkG/F/W) within the biosynthetic gene cluster (BGC) revealed their roles in sulfur transfer and subsequent S-methylation to form the S-methyl thioester moiety. Identification of the sulfur source further suggests that the S-methyl thioester formation is an intersection between primary and secondary metabolic pathways. Additionally, we demonstrate that a key O-methylation step, catalyzed by a catechol-O-methyltransferase (MT)-like MT encoded by a gene outside the BGC, is the prerequisite of the S-methyl thioester formation. Notably, the catalytic mechanism of YtkW, an unprecedented thiocarboxylic acid S-MT, was elucidated via crystal structure determination, molecular docking, and relevant mutagenesis-based analyses. Based on these findings, a plausible early-stage biosynthetic pathway for YTM involving S-methyl thioester formation is proposed, which not only advances the biosynthetic understanding of YTM but also provides promising tools for exploring structural diversification of this antibiotic.

Self-assembly provides the structural basis for natural photosynthesis, coordinating light-harvesting, energy transfer, and catalysis. However, achieving precise control over assemblies in artificial systems to realize efficient and stable metal-free photocatalysis remains a formidable challenge. Herein, we report the first biomimetic system inspired by the chlorosome, constructed via one-step hierarchical self-assembly of a fluorinated BODIPY amphiphile into well-defined nanoribbons. The integration of perfluoroalkyl chains drives tight molecular packing through fluorous interactions, which crucially enhances the light-harvesting array effect and structural stability. This system achieves exceptional metal-free photocatalytic hydrogen evolution with a rate of 162.5 mu mol & centerdot;g(-1)& centerdot;h(-1)-10 and 30 times higher than that of its nonfluorinated analog PBAH nanoribbons and the molecular control PB, respectively. Under optimized conditions, the system delivers a photocatalytic hydrogen production rate of 1150 mu mol & centerdot;g(-1)& centerdot;h(-1) with a quantum yield of 0.42% at 550 nm. Mechanistic studies reveal an array-enhanced mechanism in which fluorine-induced close packing promotes exciton delocalization and charge separation, stabilizes a key pyridinyl radical intermediate (>5 ns), collectively establishing a new paradigm for efficient metal-free artificial photosynthesis.

INTRODUCTION Sleep-wake disturbances frequently occur at early stages of Alzheimer's disease (AD) and accelerate disease progression, but the underlying neural mechanisms are not fully understood.METHODS We examined sleep-wake behavior and locus coeruleus (LC) activity in young 5xFAD mice using electrophysiology and pharmacological approaches targeting adrenergic signaling and potassium channels.RESULTS 5xFAD mice displayed dark phase-specific hyperarousal and impaired brain state transitions by 2 months of age. LC neurons exhibited increased tonic firing due to impaired Kv4 and Kv7 potassium channel conductance, resulting from soluble amyloid beta (A beta)-induced disruption of alpha 2A adrenergic receptor regulation. Pharmacological activation of alpha 2A adrenergic receptors restored Kv4/7 function and normalized LC excitability. Local administration of guanfacine (alpha 2A agonist) or retigabine (Kv7 modulator) significantly rescued sleep-wake disturbances.DISCUSSION These findings identify LC hyperexcitability as a mechanistic driver of early sleep disruption in AD and implicate alpha 2A receptors and Kv7 channels as promising therapeutic targets for early intervention.

The ability of organic nitrating reagents to release nitro radicals underpins both classical and emerging radical-based nitration strategies. Herein, we report a comprehensive computational study of 55 representative nitrating reagents to quantify their intrinsic nitro-radical donating ability. Homolytic R & horbar;NO2 bond dissociation enthalpies (BDEs) were computed to establish a thermodynamic scale for nitro-radical release, providing quantitative insight into reagent stability and isolability. In parallel, single-electron reduction potentials were computed to evaluate the propensity of these reagents to undergo single-electron transfer (SET)-triggered radical formation. Our results reveal that low BDE values are associated with facile nitro-radical release and poor isolability, whereas relatively high reduction potentials identify reagents capable of SET activation even when direct homolysis is energetically disfavored. By integrating these metrics, we uncover latent radical potential in several classical electrophilic nitrating reagents and identify promising candidates for future SET-enabled nitro-radical chemistry.

The alpha-trifluoromethyl-substituted alpha-hydroxy-hydrazides function as highly efficient ligands for copper-catalyzed coupling reactions between (hetero)aryl halides (Cl, Br) and amines. With (hetero)aryl chlorides, only 1 mol% of the catalyst is required to achieve complete conversion at 130 degrees C. For (hetero)aryl bromides, the reaction proceeds efficiently at room temperature with just 0.5 mol% catalyst loading and can reach nearly 10,000 turnovers when heated to 90 degrees C. These turnover numbers represent the highest reported to date for copper-catalyzed amination of (hetero)aryl halides (Cl, Br). The method is applicable to both primary and secondary amines, as well as a wide range of (hetero)aryl halides, delivering diverse (hetero)aryl amines in good to excellent yields.

We report a nickel-catalyzed electroreductive Giese hydroalkylation of unactivated tertiary alkyl bromides with electron-deficient alkenes. The transformation proceeds under mild, constant-current conditions in a simple undivided cell, employing an iron sacrificial anode and an accessible nickel/bipyridine catalyst system. This protocol features broad substrate scope, excellent functional-group tolerance, and high efficiency, enabling the late-stage modification of structurally complex molecules and pharmaceuticals. Mechanistic investigations-including cyclic voltammetry and deuterium-labeling experiments-indicate that the reaction operates through a Ni(I)/Ni(II) redox cycle that mediates single-electron activation of tertiary alkyl bromides. The resulting alkyl radicals undergo conjugate addition to electron-deficient alkenes, followed by cathodic reduction and protonation to furnish the hydroalkylation products.

Achieving highly regioselective C-H bond functionalization at the bridgehead carbon of a single molecule is a fascinating, yet formidable challenge. BcmD, a P450 enzyme, catalyzes the regioselective hydroxylation at the sp 3-hybridized bridgehead carbon of the bicyclo[4.2.2]piperazinedione ring scaffold during bicyclomycin biosynthesis. Herein, we provide mechanistic details of BcmD to understand its substrate binding and the origin of its regioselectivity. The high-resolution structure of SoBcmD from Streptomyces ossamyceticus in complex with its natural substrate, together with site-directed mutagenesis and computational simulations, reveals that the precise substrate positioning, enabled by specific hydrogen-bonding and hydrophobic interactions with crucial residues, determines the regioselectivity. Intriguingly, we identify SoBcmD as a peroxygenase that could utilize H2O2 as an oxidant to catalyze regioselective hydroxylation. Mechanistic analysis indicates that H2O2 activation in SoBcmD involves a homolytic cleavage process, mediated by a hydrogen-bonding network comprising residues T277, A273, and the substrate. Furthermore, structure-based channel analysis and mutagenesis demonstrate that the I157V mutant exhibits significantly enhanced peroxygenase activity. These findings advance our understanding of regioselectivity control in BcmD and provide valuable guidance for engineering P450 peroxygenases for the C-H bond activation at the chemically challenging bridgehead carbon sites.

Rationale Many perfluoroalkyl and polyfluoroalkyl sulfonic/sulfinic acids and their derivatives are classified as perfluoroalkyl and polyfluoroalkyl substances (PFASs). The use of mass spectrometry techniques to analyze these compounds has attracted considerable research attention. Methods In this article, we employed high-resolution electrospray ionization tandem mass spectrometry (HR-ESI-MS/MS) and all-ion fragmentation (AIF) in negative ion mode to investigate gas-phase F-atom migration reactions of various perfluoroalkyl and polyfluoroalkyl sulfonic/sulfinic anions, particularly those yielding FSO3- or FSO2-. Results HR-ESI-MS/MS of CF3SO3- yielded an unexpected product ion FSO3-, representing a distinct pathway of gas-phase F-atom migration from C-atom to S-atom accompanied by the loss of CF2. Similarly, HR-ESI-MS/MS of CF3SO2- produced a dominant product ion FSO2- also via CF2 elimination. Complementary ESI-MS/MS and AIF experiments on these anions confirmed that FSO2- and/or FSO3- are their characteristic fragmentation ions. Conclusion Theoretical calculations of gas-phase reactions CF3SO3- -> FSO3- + CF2 and CF3SO2- -> FSO2- + CF2 were performed to investigate the possible F-atom migration mechanisms. These results show that FSO3- at m/z 99 and/or FSO2- at m/z 83 could serve as diagnostic ions for structural elucidation of perfluoroalkyl and polyfluoroalkyl sulfonic/sulfinic acids and their derivatives in non-target PFASs analyses by using mass spectrometry.

Based on (S)-azetidine-2-carboxylic acid-derived amides, a class of effective ligands has been developed for the Cu-catalyzed enantioselective coupling of vinyl iodides with alpha-cyano carbonyl compounds, including alpha-alkyl-substituted cyanoacetates, alpha-cyano lactams, and alpha-cyano lactones. This asymmetric transformation affords alpha-vinyl-alpha-alkyl cyanoacetates, alpha-vinyl-alpha-cyano lactams, and alpha-vinyl-alpha-cyano lactones in good to excellent enantioselectivities (up to 99% ee). A wide range of functionalized vinyl groups can be introduced at the quaternary center across these three types of substrates. Furthermore, the reaction accommodates both simple and functionalized alkyl substituents in the alpha-alkyl-substituted cyanoacetates. These advantages make the current coupling strategy highly valuable for constructing enantioenriched molecules featuring an all-carbon quaternary center bearing versatile and easily modifiable functional groups.

Persubstituted alkenyl fluorides represent pivotal motifs in drug discovery, agrochemical development, and biological science. The (E)-isomeric persubstituted alkenyl fluoride, widely recognized as a conformationally stable mimic of the amide bond, frequently exhibits significantly higher bioactivity than the (Z)-counterpart. Despite their potential, the synthesis of this scaffold remains challenging, due to the severe steric encumbrance. Herein, we reported a highly stereoselective carbonyl gem-fluoro(chloro)olefination with an unprecedented sulfoximine reagent, affording an array of (Z)-persubstituted gem-fluoro(chloro)alkenes. Subsequent cross-couplings enabled them rapidly into a wide array of challenging stereodefined (E)- or (Z)-alkenyl fluorides. The experimental and computational data demonstrated that the key mechanistic feature involved a predominant 1,5-attack pathway, which operated as the rate-determining step with kinetic stereocontrol and prevailed over both the 1,3- and 1,4-attack pathways. The synthetic utility was demonstrated through microfluid synthesis, late-stage modifications, and a streamlined stereoselective synthesis of factor Xa inhibitor and RXR regulator.