To further understand the directing effect, it was found that mixing (CH 3 CN) 4 RuCl 2 with the phosphinite substrate b26 afforded an 18-electron η 6 -coordinated Ru dichloride complex (b26-RuCl 2 ), which was characterized by Xray crystallography (Fig. ). In addition, both (CH 3 CN) 4 RuCl 2 and b26-RuCl 2 were catalytically effective for the directed arene hydrogenation. Interestingly, the p-cymene ligand on [Ru(p-cymene)Cl 2 ] 2 is likely not involved in the catalysis, as it was almost fully released at the early stage of the reaction and no reduced p-cymene was detected (see Supplementary Materials, Section 9). These results suggest that the phosphinite ligand plays a critical role in replacing the p-cymene ligand on the Ru catalyst to form the sandwich complex and also in promoting the following dearomative hydrogenation process. The utility of this directed arene hydrogenation was first explored in the synthesis of cis-Atovaquone analogue (Fig. ). Atovaquone is an approved antimicrobial drug , which exists as a trans isomer. The corresponding cis analogue of Atovaquone was also synthesized, albeit in low yields and long sequences . Capitalizing on the directed arene hydrogenation approach, cis-Atovaquone can be prepared rapidly from an unconventional precursor, triphenylene d, which was accessed in one step from commercially available starting materials. In addition, the reaction is scalable using normal Parr reactors, and good yields on three examples were obtained on gram scale (Fig. ). Finally, owing to the high chemoselectivity of this directed arene hydrogenation method, it has been successfully applied to the late-stage modification of two bioactive compounds: thyroid hormone receptor inhibitor (g1) and leukotriene B4 receptor 1 antagonist/phospholipase A2 inhibitor (g2) 18 (Fig. ). In both cases, the phenyl group adjacent to the phenol OH was selectively converted to the corresponding cyclohexyl group, leading to interesting more sp 3 -rich analogues. In summary, we have developed an unusual site-selective arene saturation strategy taking advantage of the directing effect and homogeneous catalysis, which is conceptually distinct from other arene hydrogenation approaches. The enhanced reactivity and chemoselectivity offered by the DGs allow a wide range of functional groups and various arene substitution patterns to be compatible, thus providing an attractive tool for late-stage modification of complex bioactive compounds. While further expansion of the substrate scope and deeper mechanistic studies are still ongoing, the unique directing mode uncovered in this study could have broad implications for realizing other catalytic, site-selective, and synthetically valuable dearomative transformations.