Organocatalytic Enantioselective Synthesis of Axially Chiral N,N′‐Bisindoles

• Published in: Angewandte Chemie International Edition 2023-04, Vol.62 (15), p.e202300419-n/a
• Main Authors: Chen, Zhi‐Han, Li, Tian‐Zhen, Wang, Ning‐Yi, Ma, Xiao‐Fang, Ni, Shao‐Fei, Zhang, Yu‐Chen, Shi, Feng
• Format: Article
• Language: English
• Subjects: Asymmetric Synthesis; Asymmetry; Atropisomers; Catalysis; Catalytic activity; Chiral Phosphoric Acid; Cytotoxicity; Enantiomers; N,N′-Bisindoles; Organocatalysis; Phosphine; Phosphines; Phosphoric acid; Synthesis; Toxicity
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.202300419

This study establishes the first organocatalytic enantioselective synthesis of axially chiral N,N′‐bisindoles via chiral phosphoric acid‐catalyzed formal (3+2) cycloadditions of indole‐based enaminones as novel platform molecules with 2,3‐diketoesters, where de novo indole‐ring formation is involved. Using this new strategy, various axially chiral N,N′‐bisindoles were synthesized in good yields and with excellent enantioselectivities (up to 87 % yield and 96 % ee). More importantly, this class of axially chiral N,N′‐bisindoles exhibited some degree of cytotoxicity toward cancer cells and was derived into axially chiral phosphine ligands with high catalytic activity. This study provides a new strategy for enantioselective synthesis of axially chiral N,N′‐bisindoles using asymmetric organocatalysis and is the first to realize the applications of such scaffolds in medicinal chemistry and asymmetric catalysis. An organocatalytic enantioselective synthesis of axially chiral N,N′‐bisindoles has been established via chiral phosphoric acid‐catalyzed formal (3+2) cycloaddition of indole‐based enaminones with 2,3‐diketoesters. This study provides a new strategy for the highly selective synthesis of axially chiral N,N′‐bisindoles and shows the successful application of such skeletons in medicinal and synthetic chemistry.