Studies on asymmetric total synthesis of (−)-β-hydrastine via a chiral epoxide ring-opening cascade cyclization strategy

Herein, facile and enantioselective approaches to synthesize the core phthalide tetrahydroisoquinoline scaffold of (−)-β-hydrastine via both a CF(3)COOH-catalyzed (86% ee) and KHMDS-catalyzed (78% ee) epoxide ring-opening/transesterification cascade cyclization from chiral epoxide under very mild conditions are described. The key elements include a highly enantioselective epoxidation using the Shi ketone catalyst and an intramolecular CF(3)COOH-catalyzed cascade cyclization in one pot, and a late-stage C-3′ epimerization under MeOK/MeOH conditions as the key steps to achieve the first total synthesis of (−)-β-hydrastine (up to 81% ee).