Stereoselective skeletal modification of tryptanthrins to install chiral piperidine-2-ones enabled by Br?nsted acid catalysis

The stereoselective skeletal modification of natural product scaffolds, such as tryptanthrin-based frameworks, remains a challenging task in organic synthesis. Herein, we describe an asymmetric formal [4 + 2] cyclisation between azlactones and aza-dienes derived from simple tryptanthrins, enabled by the catalysis of a chiral phosphoric acid. With this established protocol, a series of novel piperidine-2-one-fused tryptanthrins can be smoothly obtained in good yields with excellent enantio-selectivities (up to >99 : 1 er) under mild conditions. Experimental mechanistic investigations support a step-wise reaction pathway involving an asymmetric aza-Michael addition and intramolecular aminolysis of lactone.