Palladium(II)-Catalyzed Enantioselective Functionalization of C(sp³)-H Bonds

Chiral molecules are ubiquitous in nature and play an important role in natural products, pharmaceuticals, agriculture, advanced materials, as well as living organisms. Therefore, the development of efficient strategies to enable the facile construction of enantiopure chiral compounds in an atom- and step-economical manner is of great importance. The enantioselective functionalization of C-H bonds without multi-steps transformation is arguably one of the most powerful and straightforward strategies to fulfill this goal. This emerging research field has been rapidly developed with the innovation of various chiral catalysts and/or ligands in recent years. In particular, significant advances have been achieved in palladium-catalyzed enantioselective functionalization of C(sp(3))-H bonds, streamlining the efficient and concise construction of chiral molecules from readily available hydrocarbon feedstocks. The stereoselective functionalization of C(sp(3))-H bonds with the assistance of chiral ligand to form a chiral palladacycle intermediate, which could be transformed into various chemical bonds to form functionalized chiral compounds, has attracted tremendous attention. Thus, this perspective summarizes the advances on palladium(II)-catalyzed enantioselective functionalization of C( sp(3))-H bonds via asymmetric C-H palladation. According to the type of C-H bonds, this perspective is classified into several sections, including methyl C(sp(3))-H bonds, methylene C(sp(3))-H bonds in constrained cycloalkanes, functionalization of methylene C(sp(3))-H bonds adjacent to alpha-heteroatom, benzylic methylene C(sp(3))-H bonds, and unbiased methylene C(sp(3))-H bonds. The emphasis of this perspective focuses on the discussion of the philosophy of developing novel chiral ligands and the mode of stereocontrol. The remaining limitations and challenges regarding to chemo- and enantioselective control in this field is also discussed. Further development of new chiral ligands and catalytic systems is expected to address these issues and expands the scope of this powerful synthetic strategy. We anticipate that this perspective might inspire more efforts to this emerging research field and the strategy might find wide applications in the synthesis of complicated chiral molecules, such as natural products and drugs.