Regio‐ and Enantioselective (3+3) Cycloaddition of Nitrones with 2‐Indolylmethanols Enabled by Cooperative Organocatalysis

The regio‐ and enantioselective (3+3) cycloaddition of nitrones with 2‐indolylmethanols was accomplished by the cooperative catalysis of hexafluoroisopropanol (HFIP) and chiral phosphoric acid (CPA). Using this approach, a series of indole‐fused six‐membered heterocycles were synthesized in high yields (up to 98 %), with excellent enantioselectivities (up to 96 % ee ) and exclusive regiospecificity. This approach enabled not only the first organocatalytic asymmetric (3+3) cycloaddition of nitrones but also the first C3‐nucleophilic asymmetric (3+3) cycloaddition of 2‐indolylmethanols. More importantly, theoretical calculations elucidated the role of the cocatalyst HFIP in helping CPA control the reactivity and enantioselectivity of the reaction, demonstrating a new mode of cooperative catalysis.