Regioselection Switch in Nucleophilic Addition to Isoquinolinequinones: Mechanism and Origin of the Regioselectivity in the Total Synthesis of Ellipticine

Ellipticine was synthesized in six
steps and 20% global yield starting
from the readily available 2,5-dimethoxy isoquinoline. Unprecedented
regioselective control of the nucleophilic attack on the isoquinoline-5,8-dione
is first described. Investigation of the possible pathways of this
transformation through density functional theory calculations reveals
unexpected N-oxide assistance in cascade tautomerizations,
which was crucial for directing the nucleophilic attack and hastening
the overall process. Using this strategy, we prepared the aniline-isoquinolinedione
adduct and submitted it to an intramolecular double C–H cross-coupling
activation to furnish ellipticinequinone, which gave ellipticine after
a MeLi addition/BH3 reduction sequence.