Synthesis of (±)-Idarubicinone via Global Functionalization of Tetracene

Anthracyclines are archetypal representatives
of the tetracyclic
type II polyketide natural products that are widely used in cancer
chemotherapy. Although the synthesis of this class of compounds has
been a subject of several investigations, all known approaches are
based on annulations, relying on the union of properly prefunctionalized
building blocks. Herein, we describe a conceptually different approach
using a polynuclear arene as a starting template, ideally requiring
only functional decorations to reach the desired target molecule.
Specifically, tetracene was converted to (±)-idarubicinone, the
aglycone of the FDA approved anthracycline idarubicin, through the
judicious orchestration of Co- and Ru-catalyzed arene oxidation and
arenophile-mediated dearomative hydroboration. Such a global functionalization
strategy, the combination of site-selective arene and dearomative
functionalization, provided the key anthracycline framework in five
operations and enabled rapid and controlled access to (±)-idarubicinone.