Organic & Biomolecular Chemistry最新文献

Premarineosin A undergoes rapid, chemoselective halogenation at C12 under mild conditions, enabling efficient access to brominated, chlorinated, fluorinated, and iodinated analogs without the need for protecting groups or extensive synthetic manipulation. Reaction conditions were optimized to favor selective functionalization of the electron-rich pyrrole ring while preserving the integrity of the macrocyclic scaffold. The resulting halogenated derivatives were readily isolated and characterized by LC-MS/MS and NMR spectroscopy. Biological evaluation revealed that all halogenated analogs retained potent antiplasmodial activity against both chloroquine-sensitive (3D7) and chloroquine-resistant (Dd2) Plasmodium falciparum strains. Across the series, the halogenated compounds displayed smaller differences in potency between the chloroquine-sensitive and chloroquine-resistant parasite strains than the parent compound, resulting in reduced resistance indices while maintaining low-nanomolar antiplasmodial activity. Although the molecular target of premarineosin A remains unknown, these findings demonstrate that C12 halogenation is potent in both parasite backgrounds. Collectively, these results establish late-stage C12 halogenation as an operationally efficient strategy for diversifying premarineosin A and demonstrate that subtle halogen substitution can modulate the antimalarial profile of this scaffold, providing a foundation for the future development of premarineosin-derived antiplasmodial agents.

A divergent multicomponent reaction of α-aminoketone, ketones and ammonium acetate has been developed for the selective synthesis of 2H-imidazoles and 3-imidazolines. Under mild, non-oxidative conditions, the reaction delivers 3-imidazolines, while aerobic oxidation enables further dehydrogenation to furnish aromatic 2H-imidazoles. This protocol features broad substrate compatibility, tolerating diverse aliphatic, heteroatom-containing and drug-derived ketone substrates. Gram-scale and post-modification experiments demonstrate the practicability of the method. Mechanistic investigations reveal that 3-imidazoline acts as a key intermediate toward 2H-imidazole, and ammonium acetate serves as both ammonia source and mild acid promoter. This divergent strategy offers a convenient route to access two important nitrogen heterocycles from identical starting materials.

Dihydroquinolines are established as important scaffolds in medicinal chemistry owing to their ubiquitous occurrence in bioactive molecules. Utilising water as a solvent in photochemical synthesis provides a synthetic route for chemical transformations under mild conditions. Herein, we report a step-economical and efficient heterogeneous N-doped Bi₂WO₆ catalysis to obtain a diverse array of dihydroquinolines by using ammonium acetate as a cheap nitrogen source. The protocol exhibits excellent functional group tolerance and is amenable to gram-scale synthesis. The post-synthetic transformations open a window to access structurally complex as well as molecularly diverse heterocyclic scaffolds.

While significant efforts have been devoted to understanding the mechanisms that govern electrolysis reactions, relatively little emphasis has been placed on elucidating the electrode/substrate interactions that are often key to reaction success. Toward this goal, the present work specifically examines the selectivity of competition studies using the TEMPO-mediated oxidation of 4-methoxybenzyl alcohol (MBA) and 4-nitrobenzyl alcohol (NBA). The selectivity for the reaction was found to be 1 : 1 when the reactions were confined to the surface of a Pt anode, but 19 : 1 when the reactions were confined to the surface of a reticulated vitreous carbon (RVC) anode. Potential-dependent ab initio molecular dynamics (AIMD) and density functional theory (DFT) simulations were carried out with explicit substrate and solvent molecules to elucidate the mechanistic features that control the observed selectivity differences. Our results indicate that the different selectivity originates from the changes in the substrate adsorption energies on the different electrodes along with the changes in their intrinsic activation barriers for selective oxidation. The Pt electrode strongly binds both benzyl alcohols and induces significant structural changes to the adsorbed aromatic. On the contrary, the positively charged carbon-electrode binds weakly to the two benzyl alcohols via van der Waals and π-π interactions, a situation that preserves the structure of the aromatic rings and allows for the electronic differences between the rings to dictate the selectivity of the reactions. This computational model was experimentally confirmed with studies that illustrated how fundamental insights into substrate/electrode interactions can be translated into new chemical selectivity.

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.

Nitrones are versatile building blocks and their intramolecular cyclizations have served as powerful strategies to construct useful and important N-heterocycles. This review summarizes recent advances in the intramolecular cyclizations of nitrones for the preparation of distinctive N- or N,O-heterocycles over the past fifteen years. Herein, we focus on various cyclizations of N-alkyl, N-aryl, N-alkenyl, and N-allenyl nitrones, including direct cyclization, O-transfer reaction, electrocyclization, skeletal rearrangement, intramolecular cycloaddition, and related cascade reactions, and their applications in the total synthesis of natural products and alkaloids through intramolecular cyclization of nitrones.

Filamentous fungi generate chemical diversity through several evolutionary strategies, including the elaboration of conserved biosynthetic intermediates into structurally distinct secondary metabolites. Emodin and its corresponding anthrone are central intermediates in fungal aromatic polyketide metabolism, yet the enzymatic logic that remodels these precursors into more complex scaffolds remains incompletely understood. To investigate this process, we examined an infection-responsive non-reducing polyketide synthase biosynthetic gene cluster (barc) from the entomopathogenic fungus Metarhizium anisopliae predicted to encode an emodin-derived aromatic polyketide pathway. Heterologous reconstruction of the barc cluster in Aspergillus nidulans led to the production of the previously reported diphenyl ether barceloneic acid A (1) and the xanthene barceloneic acid C2 (2), together with two new compounds derived from 2, barceloneic acids D and E (3 and 4). Compound 3 is a cyclopentanone adduct of the xanthene 2, whereas 4 is a polyketide-indole hybrid, highlighting the chemical reactivity of the xanthene 2 scaffold. Through combinatorial heterologous expression and feeding assays, we identified a predicted glucose-methanol-choline oxidoreductase (BarcL) as the enzyme responsible for converting diphenyl ether 1 to xanthene 2. This defines a previously uncharacterised oxidative scaffold-remodelling step in barceloneic acid biosynthesis, revealing how an emodin-derived pathway can access a xanthene scaffold. Deletion of the backbone gene barcB in M. anisopliae did not significantly alter virulence towards Tenebrio molitor (mealworm) under the conditions tested, suggesting that barceloneic acids are not essential for pathogenicity in this insect model.

Herein, we establish the first synthetic strategy for the direct β-C-H nitration of a free base meso-tetraaryl porphycene using HNO₃ in CHCl₃ in a selective and controlled manner. The reaction affords two regioisomers of the β-nitro porphycene (regioselectivity upto β : β' = 3 : 7) without the formation of any over-nitrated products or compromising the integrity of the macrocycle. Beyond synthetic access, β-functionalization enables precise electronic and steric modulation of the porphycene macrocycle, resulting in distinct optical properties, including enhanced Q-band absorption and red-shifted near-infrared (NIR) fluorescence extending up to 720 nm with good quantum yields. Moreover, comprehensive spectroscopy, X-ray crystallography, and computational studies revealed that the β-selective nitration shows a strong electronic bias on the intrinsically rapid N-H tautomerization, establishing a highly biased equilibrium that majorly favours a single tautomeric state at room temperature within the rectangular cavity of the porphycene. Furthermore, the reduction of the electron-deficient β-nitro porphycene to an electron-rich β-amino porphycene reverses the electronic perturbation and favours the opposite tautomeric form. This simple protocol provides electronically tuned β-functionalized porphycenes that not only serve as promising building blocks to design molecular systems for finely tuned NIR emissive optoelectronics, biological and material applications, but also act as model substrates to study the fundamentally important hydrogen transfer in porphycene macrocycles.

A method for the synthesis of β,N-diphosphoryl-substituted α-aminocinnamates from 2-bromo-2H-azirine-2-carboxylic esters and trimethyl or triethyl phosphite has been developed. The transformation affords the target phosphoramidates in generally high yields across a broad range of 3-aryl-substituted azirines. A reaction mechanism, supported by DFT calculations, includes a five-step domino process involving two phosphite molecules: the first effects the Michaelis-Arbuzov phosphorylation of the azirine via S_N2'-substitution of bromine, whereas the second promotes opening of the azirine ring through attack at the CN bond, ultimately leading to the diphosphorylated α-aminocinnamate. The found transformation represents the first example of N-phosphorylation by a trialkyl phosphite.

Boric acid (B(OH)₃) can significantly improve the chemoselectivity of the transformation of D-glucosamine to 2,5-deoxyfructosazine (2,5-DOF), but the origin of the chemoselective formation of 2,5-DOF over fructosazine (FZ) has long remained unknown. In this work, we systematically investigated the possible mechanisms of boric acid-mediated transformation of D-glucosamine using density functional theory (DFT). The fundamental reaction pathway includes four stages: ring-opening, C-N bond formation, dehydration, and selective generation of 2,5-DOF over FZ. This study shows that boric acid plays a key role in both the dehydration stage and the selective formation stage of 2,5-DOF. Notably, the dehydration stage has been theoretically studied for the first time and identified as the rate-determining step, and the pathway promoted by two molecules of boric acid, 2B(OH)₃, is more energetically favorable than the widely proposed pathway involving the coordination of only one boric acid. Using the projection of orbital coefficient vector (POCV) method, we further analyzed the atomic activity vector and Fukui function vector values at the possible reaction sites in the presence and absence of boric acid to explore the role of boric acid and predict the chemoselectivity. This work clarifies the specific roles of boric acid and advances the application of theoretical calculations to this kind of organocatalytic reaction with high chemoselectivity.