Diastereoselective Indole-Dearomative Cope Rearrangements by Compounding Minor Driving Forces.

Abstract

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.

Diastereoselective Indole-Dearomative Cope Rearrangements by Compounding Minor Driving Forces

“…Thus, compounding individual minor substrate-destabilizing and product-stabilizing effects results in thermodynamically favorable dearomatization. The understanding that minor driving forces built into a substrate can amount to a successful transformation that is normally considered kinetically and thermodynamically unfavorable will allow for much continued study, both fundamental and applied …”

“…The understanding that minor driving forces built into a substrate can amount to a successful transformation that is normally considered kinetically and thermodynamically unfavorable will allow for much continued study, both fundamental and applied. 33 ■ ASSOCIATED CONTENT * sı Supporting Information…”