Direct Intermolecular C–H Functionalization Triggered by 1,5-Hydride Shift: Access to <i>N</i>‑Arylprolinamides via Ugi-Type Reaction

A novel Ugi-type reaction triggered by 1,5-hydride shift has been established, giving access to <i>N</i>-arylprolinamides and related compounds in high atom economy and good yields. This is an example of a two starting material–three component reaction. The benzyl alcohol substrate <b>1</b> acts as a dual synthon, which upon treatment with a Brønsted acid affords iminium ion and water. Nucleophilic attack at the iminium ion by the third component isocyanide, followed by hydrolysis with the endogenic water, gives the Ugi-type reaction products. The reaction proceeds under mild conditions and is tolerable to a broad scope of substrates

Visible-Light Induced Isoindoles Formation To Trigger Intermolecular Diels–Alder Reactions in the Presence of Air

Visible-light induced isoindole formation triggered an intermolecular Diels–Alder reaction with dienophiles such as acetylenedicarboxylate and maleimides in the presence of air. The reaction resulted in excellent diastereoselctivity and high yields under mild reaction conditions. This protocol provides an atom-economical, transition-metal-free (TM-free) and straightforward approach to structurally diverse bridged-ring heterocycles from easily accessible molecules

Discovery of Novel Nucleotide Prodrugs with Improved Potency Against HCV Variants Carrying NS5B S282T Mutation

Resistant HCV variants carrying NS5B S282T mutation confer reduced sensitivity to sofosbuvir, the sole marketed NS5B polymerase inhibitor. On the basis of the finding that 2′-α-F-2′-β-<i>C</i>-methylcytidine 5′-triphosphate (<b>8</b>) was more potent than sofosbuvir’s active metabolite on inhibition of both wild-type and S282T mutant polymerase, a dual-prodrug approach has been established. Twenty-nine phosphoramidates with <i>N</i>⁴-modified cytosine were designed, synthesized, and evaluated for anti-HCV activity. The results showed that compounds <b>4c</b>–<b>4e</b> and <b>4m</b> (EC₅₀ = 0.19–0.25 μM) exhibited comparable potency to that of sofosbuvir (EC₅₀ = 0.15 μM) on inhibition of wild-type replicons. Notably, <b>4c</b> (EC₅₀ = 0.366 μM) was 1.5-fold more potent than sofosbuvir (EC₅₀ = 0.589 μM) on inhibition of S282T mutant replicons. In vitro metabolic studies disclosed the possible metabolic pathways of <b>4c</b>. The toxicity study results indicated a good safety profile of <b>4c</b>. Together, <b>4c</b>–<b>4e</b> and <b>4m</b> hold promise for drug development for the treatment of HCV infection, especially the resistant variants with NS5B S282T mutation