Organocatalytic Asymmetric Cycloaddition for the Construction of Chiral Indole‐Fused Medium‐ and Large‐Sized Rings
Bo-Wen Lai, Hao-Hui Zhang, Bo‐Xuan Yao, Rui Li, Shao‐Fei Ni, Kuiyong Dong, Feng Shi
Abstract
Catalytic asymmetric construction of chiral indole-fused medium- and large-sized rings represents an important issue in synthetic chemistry but with significant challenges. To overcome these challenges, herein, we report highly enantioselective synthesis of chiral indole-fused medium- and large-sized rings via organocatalytic asymmetric (4 + 4) and (4 + 4 + m) cycloadditions of 2-indolylacetates with benzofuranyl azadienes, providing an efficient strategy for accessing these enantioenriched frameworks. By designing 2-indolylacetates as a new class of four-carbon platform molecules for higher-order cycloadditions and modulating the nucleophilicity of benzofuranyl azadienes, we achieved the catalytic asymmetric synthesis of chiral indole-fused eight-membered rings and eleven- to fourteen-membered macrocycles in high yields with good enantioselectivity. This work not only demonstrates the first application of 2-indolylacetates as four-carbon platform molecules in cycloaddition reactions, but also represents the first catalytic asymmetric (4 + 4) and (4 + 4 + m) cycloadditions of 2-indolylacetates. Furthermore, biological evaluation revealed that several chiral indole derivatives exhibit some extent of antitumor activity, indicating their potential applications in medicinal chemistry.