We report the first example of Pd(II)-catalyzed γ-C(sp)-H activation of ketones directed by a practical 2,2-dimethyl aminooxyacetic acid auxiliary. 2-Pyridone ligands are identified to enable C(sp)-H activation for the first time. A rare six-membered palladacycle intermediate is isolated and characterized to elucidate the reaction mechanism. Both (hetero)arylation and vinylation of γ-C(sp)-H bonds are demonstrated. Sequential β- and γ-C(sp)-H (hetero)arylation of muscone showcases the utility of this method for late-stage diversification. A convenient Mn(II)-catalyzed auxiliary removal is also developed to further underscore the practicality of this transformation.

We herein report a Pd(II)-catalyzed β-C(sp3)–H (hetero)arylation of a variety of ketones using a commercially available 2,2-dimethyl aminooxyacetic acid auxiliary. Facile installation and removal of the auxiliary as well as its superior scope for both ketones and (hetero)aryl iodides overcome the significant limitations of the previously reported β-C(sp3)–H arylation of ketones. The ready availability of ketones renders this reaction a broadly useful method for alkyl-(hetero)aryl coupling involving both primary and secondary alkyls.

Reported herein is the distal γ‐C(sp3)−H olefination of ketone derivatives and free carboxylic acids. Fine tuning of a previously reported imino‐acid directing group and using the ligand combination of a mono‐N‐protected amino acid (MPAA) and an electron‐deficient 2‐pyridone were critical for the γ‐C(sp3)−H olefination of ketone substrates. In addition, MPAAs enabled the γ‐C(sp3)−H olefination of free carboxylic acids to form diverse six‐membered lactones. Besides alkyl carboxylic acids, benzylic C(sp3)−H bonds also could be functionalized to form 3,4‐dihydroisocoumarin structures in a single step from 2‐methyl benzoic acid derivatives. The utility of these protocols was demonstrated in large scale reactions and diversification of the γ‐C(sp3)−H olefinated products.

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Hepatitis C virus (HCV) alters mitochondrial dynamics associated with persistent viral infection and suppression of innate immunity. Mitochondrial dysfunction is also a pathologic feature of direct-acting antiviral (DAA) treatment. Despite the high efficacy of DAAs, their treatment of patients with chronic hepatitis C in interferon-sparing regimens occasionally produces undesirable side effects such as fatigue, migraine and other conditions, which may be linked to mitochondrial dysfunction. Here we show that clinically prescribed DAAs, including Sofosbuvir, affect mitochondrial dynamics. To counter these adverse effects, we examined HCV- and DAA-induced aberrant mitochondrial dynamics modulated by ginsenoside, which is known to support healthy mitochondrial physiology and the innate immune system. We screened several ginsenoside compounds showing antiviral activity using a robust HCV cell culture system. We investigated the role of ginsenosides in antiviral efficacy, alteration of the mitochondrial transmembrane potential, abnormal mitochondrial fission, its upstream signaling, and mitophagic process caused by HCV infection or DAA treatment. Only One of the compounds, ginsenoside Rg3 (G-Rg3), exhibited the notable and promising anti-HCV potential. Treatment of HCV-infected cells with G-Rg3 increased HCV core protein-mediated reduction in the expression level of cytosolic p21 required for increasing the cyclin-dependent kinase 1 (CDK1) activity, which catalyzes Ser616 phosphorylation of dynamin-related protein 1 (Drp1). The HCV-induced mitophagy, which follows mitochondrial fission, was also rescued by G-Rg3 treatment. CONCLUSIONS G-Rg3 inhibits HCV propagation. Its antiviral mechanism involves restoring the HCV-induced Drp1-mediated aberrant mitochondrial fission process, thereby resulting in suppression of persistent HCV infection.