Dearomative Access to (-)-Thebaine and Derivatives

A synthesis of the natural product thebaine is reported in eight steps from commercially available starting materials, hinging on the dearomatization and coupling of simple aromatic starting materials. This provides divergent access to two unnatural opioid derivatives and is aimed at the long-term development of synthetic opioid analogs of the wonderdrug Naloxone. Additionally, a formal enantioselective synthesis of all reported targets is disclosed that leverages a catalytic asymmetric dearomatization via anion-pairing catalysis.

Automated summary

A synthesis of the natural product thebaine from commercially available starting materials is described, which involves dearomatization and coupling reactions of simple aromatic compounds. This method allows for the production of two unnatural opioid derivatives, with the goal of developing synthetic opioid analogs of Naloxone. Furthermore, a catalytic asymmetric dearomatization using anion-pairing catalysis is proposed for the enantioselective synthesis of all reported targets.