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

• Published in: Journal of the American Chemical Society Vol. 141; no. 26; pp. 10193 - 10198
• Main Authors: Dennis, David G, Okumura, Mikiko, Sarlah, David
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 03.07.2019; Amer Chemical Soc
• Subjects: catalytic activity; Chemistry; Chemistry, Multidisciplinary; drug therapy; idarubicin; neoplasms; oxidation; Physical Sciences; polyketides; Science & Technology; GLYCOSIDIC CLEAVAGE; DAUNOMYCIN; QUINONE METHIDE; HYDRONAPHTHACENIC ANTIBIOTICS; C-H OXYGENATION; REDOX CHEMISTRY; STEREOSELECTIVE-SYNTHESIS; N-METHYLTRIAZOLINEDIONE; ANTHRACYCLINES; MOLECULAR-OXYGEN
• ISSN: 0002-7863; 1520-5126; 1520-5126
• DOI: 10.1021/jacs.9b05370

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.