Total Synthesis of Actinophyllic Acid

• Published in: Angewandte Chemie International Edition Vol. 56; no. 40; pp. 12277 - 12281
• Main Authors: Yoshii, Yu, Tokuyama, Hidetoshi, Chen, David Y.‐K.
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 25.09.2017; Wiley Subscription Services, Inc
• Edition: International ed. in English
• Subjects: Acids; alkaloids; Alkenes; Alkylation; Catalysis; Chemical synthesis; Chemistry; Chemistry, Multidisciplinary; Cycloaddition; desymmetrization; natural products; Palladium; Physical Sciences; Science & Technology; total synthesis; natural products; PACTAMYCIN; cycloaddition; desymmetrization; alkaloids; (+/-)-ACTINOPHYLLIC ACID; total synthesis; INHIBITOR; SILYLATION; (-)-ACTINOPHYLLIC ACID
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.201706312

Herein we report a total synthesis of the indolohydroazocine natural product actinophyllic acid. The target molecule was retrosynthetically deconvoluted to render a greatly simplified and symmetrical [4.4.1] bicyclic trienone, the desymmetrization of which was carefully examined under a variety of conditions, including oxidative, reductive, and transition‐metal‐catalyzed transformations. Ultimately, the successful synthetic strategy featured chemoselective catalytic dihydroxylation, desymmetrizing nitrile oxide dipolar cycloaddition, and palladium‐catalyzed aminoarylation to sequentially modify the three olefins within the trienone, followed by a late‐stage reductive cascade indolization and alkylation to complete the target molecule. Find a mirror to break: The indolohydroazocine natural product actinophyllic acid was synthesized by an expedient route based on the desymmetrization of a trienone precursor. The developed synthesis features chemoselective catalytic dihydroxylation of the trienone, desymmetrizing dipolar cycloaddition with a nitrile oxide, and palladium‐catalyzed aminoarylation as key steps.