Organic & Biomolecular Chemistry最新文献

We report an efficient synthetic route to the metal-free hydroboration and cyanosilylation of a wide range of alkynyl trifluoromethyl ketones using pinacolborane (4,4,5,5-tetramethyl-1,3,2-dioxaborolane) and trimethylsilyl cyanide under mild reaction conditions at ambient temperature. These highly effective hydroboration and cyanosilylation reactions lead to the corresponding alkynyl trifluoromethyl propargyl alcohols after hydrolysis. In addition, trifluoromethyl (CF₃) group-based pharmaceutically active enflicoxib analogs were synthesized from propargyl alcohol.

A new type of ferrocenyl P,P,N,N,O-ligand has been developed through a one-step transformation. This represents a rare example of a ligand containing both chiral bisphosphine and diamine groups suitable for ruthenium-catalyzed asymmetric hydrogenation. Its ruthenium complex can be directly prepared by stirring the ligand and [Ru(benzene)Cl₂]₂ at 90 °C in DMF for 4 hours. The catalyst showed high reactivity and enantioselectivity in the hydrogenation (AH) of simple ketones and α,β-unsaturated ketones, providing the corresponding chiral aryl alkyl alcohols and chiral allyl alcohols with up to 99% yield and 96% ee.

The palladium-catalyzed [3 + 2] decarboxylative cycloaddition of 4-vinyl-4-butyrolactones with sulfamate-derived cyclic imines has been developed, providing the sulfamate-fused pyrrolidine derivatives in high yields with good diastereoselectivities. The scale-up reaction and further derivation of the product worked well, demonstrating the potential application of the current reaction in organic synthesis. A plausible reaction mechanism was also proposed.

β-Enaminone transformation strategies are widely employed in the synthesis of numerous biologically active drugs and natural products, highlighting their significance in medicinal chemistry. In recent years, various strategies have been developed for synthesizing several five- and six-membered heterocycles, as well as substituted polyaromatic scaffolds, which serve as crucial synthons in drug development, from β-enaminones. Among these approaches, site-selective transformations of β-enaminones via C-H activation and annulation have been particularly well explored. This review summarizes the most recent literature (over the past eight years) on β-enaminone transformations for developing bioactive scaffolds through site-selective C-H bond functionalization and annulation.

Human Immunodeficiency Virus (HIV) has continued to endanger human health for decades and has a substantial impact on global health defence. Peptide-based fusion inhibitors, as an integral part of Highly Active Anti-Retroviral Therapy (HAART), are effective in preventing and controlling the AIDS epidemic. Nevertheless, the current market leader, Enfuvirtide, is facing numerous challenges in clinical application. We herein devised a cutting-edge development strategy leveraging SWISS-MODEL and HDOCK, enabling the design of artificial N-peptides. The most active compound, IZNP02QE, surpassed the positive control by demonstrating remarkable nanomolar-level inhibitory activity against HIV-1. Mechanistic investigations unveiled IZNP02QE's ability to disrupt the crucial endogenous 6-helix bundle (6-HB) by forming heteropolymers, underscoring its potential as a novel anti-HIV-1 agent. This work not only pioneers a novel design methodology for N-peptides but also opens up the possibility of a CADD strategy for designing peptide-based fusion inhibitors.

In the present study, the mechanism, origin of chemoselectivity, and substituent effects of the phosphine-catalyzed ring-opening reaction of cyclopropyl ketone have been investigated using the DFT method. Multiple pathways, including the formation of hydrofluorenone, the Cloke-Wilson product, and cyclopenta-fused product, were studied and compared. The computational results show that the pathway for the formation of hydrofluorenone is the most favorable one, which involves four processes: nucleophilic substitution to open the three-membered ring, an intramolecular Michael addition for the formation of an enolate intermediate, an intramolecular [1,5]-proton transfer to give ylide, and an intramolecular Wittig reaction to deliver the final product. For disclosing the origin of chemoselectivity, structural analysis and local reactivity index analysis were performed. Moreover, substituent effects were also considered using QTAIM analysis. The current study would provide useful insights for understanding phosphine-catalyzed chemoselective reactions.

A sodium trifluoromethanesulfinate-mediated photocatalytic strategy for the aerobic oxidative esterification of aromatic aldehydes and alcohols has been developed, in which the in situ formed pentacoordinate sulfide derived from readily available and inexpensive sodium trifluoromethanesulfinate and oxygen acts as the photocatalyst, and the corresponding aromatic esters were provided in moderate to good yields. The present method is an economical and environmentally friendly protocol.

The NLRP3 inflammasome is implicated in the pathogenesis of a wide array of inflammatory diseases including cancer, type II diabetes, atherosclerosis, gout, and neurodegenerative disease. Research has shown that Bruton's tyrosine kinase (BTK) is a critical regulator of the NLRP3 inflammasome and that the pharmacological inhibition of BTK using the FDA-approved inhibitor ibrutinib diminishes NLRP3-dependent inflammatory response. Herein, we describe our pursuit towards novel anti-inflammatory compounds using a scaffold-hopping approach. In our drug discovery efforts, we identified 5,6,7,8-tetrahydropteridines as underutilized scaffolds in medicinal chemistry. We report the synthesis of 5,6,7,8-tetrahydropteridines with potential as anti-inflammatory compounds.

Solanum undatum is a medicinal plant used for the treatment of oedema, rheumatoid arthritis and toothache, from which seven highly oxygenated steroids (1-7), including three new ones (1-3), have been characterized. Compound 1 is a new steroidal carboxylic acid featuring a cyclohexa-2,5-dien-1-one moiety and compounds 2 and 3 are new withanolide analogs with a 1,6-dimethyl-3,7-dioxabicyclo[4.1.0]heptan-2-ol terminus. Their structures and absolute configurations were determined by a combination of spectroscopic data, quantum chemical calculations, single-crystal X-ray diffraction, and the NMR-based phenylglycine methyl ester (PGME) method. An immunosuppressive activity assay revealed that compounds 2-7 exhibited substantial activities against the proliferation of T and B lymphocytes in vitro, with IC₅₀ values ranging from 1.60 to 7.89 μM and 0.90 to 6.90 μM, respectively. Notably, compound 6 showed selective inhibitory effect toward B cells with the highest selective index (SI = 40.5). Preliminary structure-activity relationships of compounds 1-7 suggest that the terminal 1,6-dimethyl-3,7-dioxabicyclo[4.1.0]heptan-2-ol or 5,5-spiroacetal moiety is critical for immunosuppressive activity. Our study indicated that they could be promising lead compounds for immunosuppressive agents.

Since the early 21st century, organocatalytic reactions have undergone significant advancements. Notably, numerous asymmetric reactions utilizing chiral secondary amine catalysts have been developed and applied in the total synthesis of natural products. In this review, we provide an overview of alkaloid syntheses reported since 2017, categorized by scaffold, with a focus on key steps involving asymmetric reactions catalyzed by secondary amine organocatalysts.