Ligand-Enabled Palladium-Catalyzed Asymmetric Synthesis of Indole-Fused Chiral Eight-Membered <i>N</i> -Heterocycles via [4 + 4] Cycloaddition

Indole-fused chiral eight-membered <i>N</i>-heterocycles are found in natural products and biologically active molecules. However, their synthesis still remains a great challenge due to the disadvantageous enthalpy and entropy factors as well as the transannular interactions. Therefore, it is highly desirable to develop an efficient and practical approach to indole-fused chiral eight-membered <i>N</i>-heterocycles with high stereoselectivity. In this paper, we have developed a palladium-catalyzed asymmetric [4 + 4] cycloaddition of α,β-unsaturated <i>N</i>-<i>p</i>-tosyl-iminoindoles with γ-methylidene-δ-valerolactones, and diverse and highly functionalized indole-fused chiral eight-membered <i>N</i>-heterocycles were prepared in high yields (60-88%), excellent diastereoselectivity (>20:1 dr), and high to excellent enantioselectivity (80-99% ee), in which our newly developed axially chiral phosphoramidite ligand obviously promoted the reactivity of the substrates and the stereoselectivity of the products. Further derivatization of the obtained products provided other indole-fused chiral eight-membered <i>N</i>-heterocycles.