Organocatalytic Asymmetric Cycloaddition for the Construction of Chiral Indole‐Fused Medium‐ and Large‐Sized Rings

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.