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.

Automated summary

The regio- and enantioselective (3+3) cycloaddition of nitrones with 2-indolylmethanols was successfully achieved through the cooperative catalysis of hexafluoroisopropanol (HFIP) and chiral phosphoric acid (CPA). This approach resulted in the synthesis of indole-fused six-membered heterocycles with high yields, excellent enantioselectivities, and exclusive regiospecificity. The role of the cocatalyst HFIP in helping CPA control the reactivity and enantioselectivity of the reaction was elucidated through theoretical calculations, demonstrating a new mode of cooperative catalysis.