Chiral Spiro Phosphoric Acid-Catalyzed Friedel–Crafts Conjugate Addition/Enantioselective Protonation Reactions

Abstract

Asymmetric Friedel–Crafts conjugate addition reactions that generate an α-chiral center are challenging because the configuration-determining step is a proton-transfer reaction of a highly active enol intermediate. Herein, we report a protocol for highly enantioselective Friedel–Crafts conjugate addition of indoles and pyrroles to exocyclic enones catalyzed by chiral spiro phosphoric acids. This protocol provides a straightforward, efficient approach to synthetically important indole-containing cyclic ketones with an α-chiral center and features with high yields (up to 99%) and high enantioselectivities (up to 98% ee) for a broad substrate scope. Density functional theory calculations suggest that the spiro phosphoric acid initially catalyzed the addition reaction by acting as a Brønsted acid and then catalyzed an enantioselective proton-transfer reaction of the enol intermediate by acting as a chiral proton-transfer shuttle. The enantiocontrol strategy described herein may be widely applicable to other addition reactions in which a proton transfer is the configuration-determining step.