Reported herein is the discovery of a diastereoselective indole-dearomative Cope rearrangement. A suite of minor driving forces promote dearomatization: (i) steric congestion in the starting material, (ii) alkylidene malononitrile and stilbene conjugation events in the product, and (iii) an unexpected intramolecular π–π* stack on the product side of the equilibrium. The key substrates are rapidly assembled from simple starting materials, resulting in many successful examples. The products are structurally complex and bear vicinal stereocenters generated by the dearomative Cope rearrangement. They also contain a variety of functional groups for interconversion to complex architectures.

Reported herein is the discovery of a diastereoselective indole-dearomative Cope rearrangement. A suite of minor driving forces (substrate destabilizing effects; product stabilizing effects) are what promote this otherwise unfavorable dearomatization reaction. These include the following that work in concert to overcome the penalty for dearomatization: (i.) steric congestion in the starting material, (ii.) alkylidene malononitrile and stilbene conjugation events in the product, and (iii.) an unexpected intramolecular p–p* stack on the product side of the equilibrium. The key substrates are rapidly assembled from alkylidenemalononitriles and indole-phenylmethanol derivatives resulting in many successful examples (high yields and diastereoselectivity). The products are structurally complex bearing vicinal stereocenters generated by the dearomative Cope rearrangement. They also contain a variety of functional groups for interconversion to complex architectures. On this line, also described herein are proof-of-concept strategies for achieving enantioselectivity and conversion of the dearomative products to valuable and functionalized small drug-like molecules.