Metal-Free Access to (Spirocyclic)Tetrahydro-β-carbolines in Water Using an Ion-Pair as a Superacidic Precatalyst

The unprecedented triarylcarbonium ion-pair-catalyzed Pictet-Spengler reaction of tryptamines with aromatic aldehydes and cyclic ketones in water was disclosed. Under metal-free conditions, diverse tetrahydro-beta-carbolines and spirocyclic tetrahydro-beta-carbolines were obtained in good yields with excellent functional group tolerance, including late-stage modification of natural products and small molecular drugs. The practicability of this protocol is also characterized in the gram-scale synthesis of Komavine and several other functional compounds. Preliminary mechanistic studies indicated that in aqueous media the in situ-generated superacidic species from the carbonium ion pair with water was crucial to promote the Pictet-Spengler reaction.

Automated summary

This study reveals the synthesis of diverse tetrahydro-beta-carbolines and spirocyclic tetrahydro-beta-carbolines through the unprecedented triarylcarbonium ion-pair-catalyzed reaction in water under metal-free conditions. The reaction shows good yields and excellent functional group tolerance, allowing for late-stage modification of natural products and small molecular drugs.