Discovery of a New Sulfonamide Hepatitis B Capsid Assembly Modulator.

Hepatitis B virus (HBV) remains a major health concern with 260 million people having been infected globally, and approximately 680,000 deaths have occurred annually from cirrhosis and liver cancer. The modulation of HBV capsid assembly has emerged as a promising therapeutic approach for curing chronic HBV infection. Small-molecule capsid assembly modulators (CAMs) can broadly be classified as heteroaryldihydropyrimidines and sulfamoylbenzamides (SBAs). SBAs are capsid activators that inhibit viral replication by achieving capsid assembly before polymerase encapsulation. Herein, we report a novel series of HBV CAMs based on NVR 3-778, a potent CAM belonging to the SBA class. The lead compound (KR-26556) exhibited improved pharmacological activity and was examined through molecular docking studies.

Multicomponent Oxidative Trifluoromethylation of Alkynes with Photoredox Catalysis: Synthesis of α-Trifluoromethyl Ketones.

The direct oxidative addition of CF3 and H2O to alkynes was achieved with photoredox catalysis to obtain α-trifluoromethyl ketones via rapid enol-keto tautomerization. The reaction exhibits high functional group tolerance and regioselectivity. Heterocycles of various sizes containing CF3 were synthesized from the α-CF3-substituted diketones obtained through the protocol, thereby demonstrating the versatile applicability of the method. Mechanistic studies of the reaction with isotopes provided insight into the reaction pathway.

Photoredox-Catalyzed Trifluoromethylative Intramolecular Cyclization: Synthesis of CF3-Containing Heterocyclic Compounds.

A general photoredox-catalyzed intramolecular cyclization was developed for the synthesis of trifluoromethylated heterocyclic compounds. The reaction proceeded smoothly under mild photocatalytic conditions with high functional group tolerance, allowing the preparation of oxygen-, sulfur-, or nitrogen-containing heterocycles of different sizes. The broad substrate scope demonstrated the complexity-building potential of the strategy.

Stereoselective Photoredox-Catalyzed Chlorotrifluoromethylation of Alkynes: Synthesis of Tetrasubstituted Alkenes.

A new photoredox-catalyzed chlorotrifluoromethylation reaction of internal arylalkynes under mild conditions using visible light has been developed. The reactions proceed with high levels of regio- and stereoselectivity and utilize commercially available CF3SO2Cl as both the CF3 and Cl source. In the mechanistic pathway for this process, generation of the CF3 radical and chloride ion occurs by Ir(ppy)3-photocatalyzed reductive decomposition of CF3SO2Cl. The synthetically important trifluoromethyl-substituted vinyl chlorides produced in this process can be readily transformed to 1,1-bis-arylalkenes by using Suzuki coupling.

Multicomponent [5 + 2] cycloaddition reaction for the synthesis of 1,4-diazepines: isolation and reactivity of azomethine ylides.

Air-stable azomethine ylides with an unusual pattern of charge distribution were efficiently prepared via the rhodium-catalyzed reaction between pyridines and 1-sulfonyl-1,2,3-triazoles. This reaction allowed for the first example of the catalytic multicomponent [5 + 2] cycloaddition reactions, thus resulting in the formation of biologically active 1,4-diazepine compounds.