Synthesis of Chiral β-Lactams by Pd-Catalyzed Enantioselective Amidation of Methylene C(sp3)-H Bonds Enabled by a 2-Pyridylisopropyl Auxiliary

In recent years,enantioselective C-H functionalization reactions have emerged as an efficient means to construct complicated chiral molecules.Compared to many precedents on the asymmetric functionalization of aryl C-H bonds,enantioselective functionalization of unbiased methylene C(sp3)-H bonds of linear systems via metal insertion is still very challenging for two main reasons(Scheme 1a).[1]First,it is more difficult to differentiate two enantiotopic protons residing on a single carbon center.Second,unbiased methylene C(sp3)-H bonds are less reactive than those of primary methyl and activated by specific electronic or inductive effects,such as C-H bonds adjacent to N-heteroatom,benzylic position or on conformationally rigid cyclic systems.The major breakthrough was first achieved by the Yu group in 2016(Scheme 1b).They developed a Pd(Ⅱ)-catalyzed arylation of unbiased methylene C(sp3)-H bonds in high enantioselectivity by taking advantage of weakly coordinating monodentate DG with a bidentate acetyl-protected aminoethyl quinolone ligand(up to 96%ee).

Synthesis of Chiral β‐Lactams by Pd‐Catalyzed Enantioselective Amidation of Methylene C(sp3)–H Bonds Enabled by a 2‐Pyridylisopropyl Auxiliary†

Qiang Yue, Xu Yang, Meng‐Xue Jiang, Bing‐Feng Shi, Tao Zhou, Yi Ding and Ye‐Qiang Han (from left to right). Mr. Tao Zhou is currently a postdoctoral fellow in the group of Prof. Bing‐Feng Shi in Zhejiang University. Mr. Ye‐Qiang Han is currently a fourth‐year PhD student in the group of Prof. Bing‐Feng Shi in Zhejiang University.