Organic & Biomolecular Chemistry最新文献

Roseobacticides are algicidal tropofuranones produced by the marine roseobacter Phaeobacter inhibens during interactions with the bloom-forming coccolithophore Gephyrocapsa huxleyi. We report a divergent synthesis based on chemoselective annulation of the multifunctional 2-methoxy-6-(methylthio)tropone with aryl- and indolylacetates, followed by subsequent oxidation or substitution at the C-7 sulfur functionality, enabling the first total syntheses of roseobacticides A, B, C and I and the proposed structure of L. Synthetic roseobacticides showed potent algicidal activity against G. huxleyi and Amphidinium carterae.

Formamides are indispensable intermediates in the synthesis of pharmaceuticals, agrochemicals, and functional materials. Yet, their conventional preparation relies on toxic stoichiometric reagents, including acetic formic anhydride, formyl chloride, and chloral, resulting in poor atom economy and substantial waste generation. Transition-metal catalysis has emerged as a sustainable alternative, enabling direct N-formylation of amines using renewable C1 feedstocks under mild conditions. This review summarizes advances reported from 2019 to 2026, covering six major C1 sources: carbon dioxide, methanol, biomass-derived carbonyl compounds (glycolic acid, glycerol derivatives, and oxalic acid), formic acid, paraformaldehyde, and triethyl orthoformate. Recent homogeneous manganese-, iron-, and copper-based systems for CO₂ utilization, together with heterogeneous cobalt-based metal-organic frameworks and Co(II)-embedded covalent organic framework photocatalysts, demonstrate the expanding scope of catalytic N-formylation. This review critically evaluates mechanistic pathways involving carbamate and formamide intermediates, cobalt-formate species, silyl formates, oxidative C-C bond cleavage, and radical processes. By comparing catalyst architectures, C1-source characteristics, reaction conditions, mechanistic features, and sustainability considerations, this review identifies key structure-activity and selectivity trends and highlights emerging opportunities for the rational development of efficient, selective, recyclable, and sustainable N-formylation methodologies.

Phenothiazine (PTZ)-based antipsychotic drugs are extensively metabolised in vivo, with S-oxidation representing a major metabolic pathway. Herein, we report the application of an electrosynthetic (ES) S-oxidation strategy to three distinct classes of PTZ-based drug analogues: amino alkyl, piperidine, and piperazine-containing derivatives. The sulfoxide metabolites of the amino alkyl-containing PTZs, including chlorpromazine sulfoxide (2a, 68%), promazine sulfoxide (3a, 34%), triflupromazine sulfoxide (4a, 36%), and promethazine sulfoxide (5a, 11%), were generated under mild, constant-current conditions. For the piperidine-containing PTZs, electrooxidation of thioridazine (6) selectively afforded mesoridazine (7, 15%), while further S-oxidation of 7 at the PTZ ring system yielded the novel bis-sulfoxide 7a (3%). The piperazine-containing PTZs trifluoperazine (8) and fluphenazine (9) provided sulfoxide metabolites 8a (9%) and 9a (5%), alongside unprecedented ring-opened products 8b (1%) and 9b (2%) arising from electrochemical cleavage of the piperazine ring. Two distinct ring-opening mechanisms via decarboxylation (N-demethylation, Shono-type pathway) and via α-cleavage (neighbouring group participation) are proposed. Cyclic voltammetry confirmed successful S-oxidation through the characteristic disappearance of the first oxidation wave in all metabolite products. The methodology was further extended to thioether-containing active pharmaceutical ingredients (APIs) extracted from commercial dosage forms.

Under open-vessel atmospheric conditions, the one-pot construction of oxadibenzofused thiabicyclo[6.4.1]tridecen dioxides was developed via the K₂CO₃-mediated tandem annulation of 1,3-diaroyl sulfones with 2.2 equivalents of o-bisbromomethylarenes. A plausible mechanism is proposed and discussed. This high-yielding protocol provides C-/O-alkylative ring-closure via the formation of three carbon-carbon single (C-C) bonds and one carbon-oxygen single (C-O) bond.

This work presents a TD-DFT computational study of the visible-light-driven [2 + 2] cycloaddition between alkynes and bromodifluoroacetylsilanes, leading to gem-difluorocyclobutenones. Visible-light irradiation of bromodifluoroacetylsilanes was recently shown by Zhou et al. to generate difluoroketene in situ for [2 + 2] cycloaddition with alkynes; the electronic origin of this photoactivation, however, had not been established. The results show that irradiation at 450 nm is vertically resonant only with the T₁ triplet state of the brominated precursor, consistent with heavy-atom-enhanced spin-orbit coupling, although the specific population mechanism remains unresolved. On the triplet surface, barrierless C-Br homolysis generates an acyl radical and Br˙. We propose a S_H2-type radical fragmentation mechanism in which the bromine radical attacks silicon, releasing difluoroketene through a low-barrier (ΔG^‡ = 5.7 kcal mol^-1) and highly exergonic process (ΔG = -25.0 kcal mol^-1). The resulting difluoroketene subsequently undergoes a concerted, asynchronous, and barrier-moderate [π2_s + π2_s] cycloaddition with several alkynes on the ground-state surface (ΔG^‡ ≈ 15.3-16.5 kcal mol^-1), producing highly stable cyclobutenone products (ΔG ranging from -57.0 to -59.0 kcal mol^-1). ELF analysis indicates a sequential bond-formation process initiated by nucleophilic attack at the electrophilic ketene carbonyl carbon. Overall, this study provides an electronic-structure and mechanistic analysis of photoexcitation, C-Br bond cleavage, silicon-mediated radical fragmentation, and ground-state ketene cycloaddition for this transformation, offering a computational basis to support the design of visible-light-driven fluorinated [2 + 2] cycloadditions.

Protein fibrils are pathological hallmarks of many neurodegenerative diseases, including Parkinson's disease. The preparation of α-synuclein (αSyn) fibrils in vitro is widely used in research relating to these conditions. However, αSyn fibrils exhibit substantial structural polymorphism. How fibril morphology evolves during formation, storage, or in the presence of small molecule ligands is poorly understood. Here, the evolution of αSyn fibril morphology was investigated using fluorescence assays, circular dichroism, transmission electron microscopy, and ligand profiling. Fibril morphology was found to evolve continuously during both aggregation of αSyn and subsequent storage, even at -79 °C. The inclusion of ligands, such as Thioflavin X, during aggregation affected both the reaction kinetics and the fibril morphologies formed. The addition of ligands to pre-formed fibrils also produced changes in fibril morphology. As different fibril morphologies exhibit distinct properties, more careful characterization and controls are required to ensure reproducibility and reliable interpretation of results. Additionally, these findings suggest the potential to use ligands to remodel fibril structure, possibly allowing for pathological morphologies to be converted to less pathological forms.

An efficient base-free approach for the remote C5-H sulfonylation of 8-aminoimidazo[1,2-a]pyridine (8-AIP) derivatives with sulfonyl chloride has been described under Cu^II-catalysis without an external oxidant. This strategy shows high conversion efficiency, a broad substrate scope, and good tolerance towards different functional groups. Furthermore, mechanistic investigations suggest that a single-electron-transfer process is involved in this C-S cross-coupling reaction. Considering that imidazopyridine derivatives and their analogues are known to be pharmacological agents for treating cancers through inhibition of the tankyrase-2 (TNKS-2) enzyme, docking studies were performed to understand the binding potential of our compounds to this protein, and the results revealed that several compounds had higher predicted binding energies than the crystal-bound ligand. Accordingly, our findings offer plausible mechanistic insights into the radical aromatic substitution of remote C-H bonds and open new avenues for the rational design of novel, drug-like molecules as potent TNKS-2 inhibitors.

A palladium-catalyzed synthesis of substituted 1,5-benzodiazocines and 1,5-benzooxazocines from bis-nucleophiles and an allylic dicarbonate was developed. N,N'-Disubstituted 2-aminobenzylamines underwent cyclization in the presence of Pd(PPh₃)₄ to afford the corresponding 1,5-benzodiazocines in 40% to quantitative yields. The reaction was also applicable to N,N'-disubstituted naphthalene-1,8-diamines, providing naphthalene-fused diazocine derivatives. N-Substituted 2-hydroxybenzylamines reacted under Pd(OAc)₂/DPPP catalysis to give the corresponding 1,5-benzooxazocines in 54% to quantitative yields. These cyclizations construct two carbon-heteroatom bonds through sequential allylic substitutions and provide straightforward access to diverse eight-membered N,N- and N,O-heterocycles bearing an exocyclic methylene group.

The synthetic geranylfarnesyl diphosphate analog iso-GFPP I in which one double bond is shifted from C6C7 to C7C24 was incubated with nine sesterterpene synthases from fungi and bacteria, resulting in efficient conversion by five of the tested enzymes. Four new sesterterpenoids were isolated, two of which exhibited novel skeletons, indicating opening of new reaction paths upon minor structural alteration in the substrate.

We report a photocatalyst-free, visible-light-driven three-component synthesis of perfluoroalkylated pyrimido[1,2-b]indazoles. Enabled by an in situ electron donor-acceptor complex between DABCO and perfluoroalkyl iodides, this scalable, transition-metal-free approach provides an efficient pathway to access and modify biologically important nitrogen-fused heterocycles.