Organocatalytic Asymmetric (4 + 3) Cycloaddition toward Optically Active Cyclohepta Fused Diindoles.

A novel asymmetric (4 + 3) cycloaddition of indole-2,3-quinodimethanes in situ generated from 3-methyl-2-indolylmethanols with 3-indolylmethanols via chiral phosphoric acid catalysis has been established. The cycloaddition reaction exhibits a broad substrate scope affording the diverse enantioenriched cyclohepta fused diindoles in high yields with good enantioselectivities. Significantly, this work represents the first application of 3-methyl-2-indolylmethanols as 4C synthons instead of the commonly reported three-atom synthons in cycloaddition reactions.

Organocatalytic enantioselective (4+3) cyclization for the synthesis of spiro-fused heterocyclic compounds containing isoindolinone, oxepine and indole moieties.

A refined strategy has been developed to control the regioselective asymmetric (4+3) cyclization of α-(3-isoindolinonyl) propargylic alcohols with 2-indolylmethanols, utilizing chiral phosphoric acid catalysis. This innovative organocatalytic cyclization yields spiro isoindolinone-oxepine-fused indoles featuring a spiro-quaternary stereocenter in high yields and enantioselectivities, facilitated by the solvent of 1,1-dichloro-1-fluoroethane and the additive of hexafluoroisopropanol. Additionally, the photophysical properties of product 3k are examined, revealing bright fluorescence both in the solution and the solid state.

3D-QSAR and Molecular Dynamics Study of Isoxazole Derivatives to Identify the Structural Requirements for Farnesoid X Receptor (FXR) Agonists.

The farnesoid X receptor (FXR) has been recognized as a potential drug target for the treatment of non-alcoholic fatty liver disease (NAFLD). FXR agonists benefit NAFLD by modulating bile acid synthesis and transport, lipid metabolism, inflammation, and fibrosis pathways. However, there are still great challenges involved in developing safe and effective FXR agonists. To investigate the critical factors contributing to their activity on the FXR, 3D-QSAR molecular modeling was applied to a series of isoxazole derivatives, using comparative molecular field analysis (CoMFA (q2 = 0.664, r2 = 0.960, r2pred = 0.872)) and comparative molecular similarity indices analysis (CoMSIA (q2 = 0.706, r2 = 0.969, r2pred = 0.866)) models, which demonstrated strong predictive ability in our study. The contour maps generated from molecular modeling showed that the presence of hydrophobicity at the R2 group and electronegativity group at the R3 group in these compounds is crucial to their agonistic activity. A molecular dynamics (MD) simulation was carried out to further understand the binding modes and interactions between the FXR and its agonists in preclinical or clinical studies. The conformational motions of loops L: H1/H2 and L: H5/H6 in FXR-ligand binding domain (LBD) were crucial to the protein stability and agonistic activity of ligands. Hydrophobic interactions were formed between residues (such as LEU287, MET290, ALA291, HIS294, and VAL297) in helix H3 and ligands. In particular, our study found that residue ARG331 participated in salt bridges, and HIS447 participated in salt bridges and hydrogen bonds with ligands; these interactions were significant to protein-ligand binding. Eight new potent FXR agonists were designed according to our results, and their activities were predicted to be better than that of the first synthetic FXR agonist, GW4064.

Principle on Selecting the Coordination Ligands of Palladium Precursors Encapsulated by Zeolite for an Efficient Purification of Formaldehyde at Ambient Temperature.

High-performance zeolite-supported noble metal catalysts with low loading and high dispersion of active components are the most promising materials for achieving the complete oxidation of formaldehyde (HCHO) at room temperature. In this work, palladium nanoparticles (Pd NPs) with different sizes were successfully encapsulated inside the silicalite-1 (S-1) zeolite framework by using diverse stabling ligands via the one-pot method. Thereafter, the rule on selecting the coordinative ligands for palladium was clarified: more N atoms, a short carbon chain, a smaller branch chain, and bidentate coordination are characteristics of an ideal ligand. Accordingly, the best-performing 0.2Pd@S-1(Ethylenediamine) catalyst exhibited outstanding performance for HCHO oxidation, achieving 100% conversion even at room temperature. High-resolution high-angle annular dark-field scanning transmission electron microscopy (HR HAADF-STEM) and density functional theory (DFT) calculations indicate that the chelate is formed by complexation of Pd2+ ions with ethylenediamine, displaying the smallest spatial site resistance simultaneously with the zeolite synthesis, resulting in Pd located mostly within the 5-membered ring (5-MR) channels of S-1 after calcination, thus limiting the growth of Pd clusters and promoting their dispersion.