Diastereoselective Synthesis of Indoline- and Pyrrole-Embedded Tetracycles via an Unprecedented Dearomative Indole-C3-Alkylation/Aza-Friedel–Crafts Cascade Reaction

Abstract

Dearomative indole C3-alkylation─intramolecular iminium trapping cascade reaction of indole-C3-tethered nucleophiles is a well-known blueprint for accessing 2,3-fused indolines. In exploring this strategy, synthetic chemists have utilized diverse classes of electrophilic reagents. However, the tethered nucleophiles have mainly been limited to heteronucleophiles and enolates; exploitation of tethered arenes/heteroarenes remains unknown. We herein describe the first examples of pyrrole-intercepted dearomative indole C3-allylation and benzylation of indole-tethered pyrroles toward the synthesis of 2,3-cis-fused tetracyclic indolines featuring a C3 all-carbon quaternary stereocentre. Our methodology capitalizes on the capability of NaOtBu/Et3B combination to direct the intermolecular alkylation to take place regioselectively at the indole C3 position over the other reactive sites (indole N and C2 and pyrrole C2 positions) and leverages the high nucleophilicity of the pyrrole template for the concomitant aza-Friedel–Crafts ring closure that traditionally would require an additional acid-catalyzed synthetic step. This cascade reaction is accomplished with broad substrate scope and excellent yields and chemo-, regio-, and diastereoselectivities.