Total Synthesis and Biological Evaluation of Irciniastatin A (a.k.a. Psymberin) and Irciniastatin B

Shun Ichiro Uesugi, Tsubasa Watanabe, Takamichi Imaizumi, Yu Ota, Keisuke Yoshida, Haruna Ebisu, Takumi Chinen, Yoko Nagumo, Masatoshi Shibuya, Naoki Kanoh, Takeo Usui, Yoshiharu Iwabuchi

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17 Citations (Scopus)

Abstract

Irciniastatin A (a.k.a. psymberin) and irciniastatin B are members of the pederin natural product family, which have potent antitumor activity and structural complexity. Herein, we describe a full account of our total synthesis of (+)-irciniastatin A and (-)-irciniastatin B. Our synthesis features the highly regioselective Eu(OTf)3-catalyzed, DTBMP-assisted epoxide ring opening reaction with MeOH, which enabled a concise synthesis of the C1-C6 fragment, extensive use of AZADO (2-azaadamantane N-oxyl) and its related nitroxyl radical/oxoammonium salt-catalyzed alcohol oxidation throughout the synthesis, and a late-stage assembly of C1-C6, C8-C16, and C17-C25 fragments. In addition, for the synthesis of (-)-irciniastatin B, we achieved the C11-selective control of the oxidation stage via regioselective deprotection and AZADO-catalyzed alcohol oxidation. The synthetic irciniastatins showed high levels of cytotoxic activity against mammalian cells. Furthermore, chemical footprinting experiments using synthetic compounds revealed that the binding site of irciniastatins is the E-site of the ribosome.

Original languageEnglish
Pages (from-to)12333-12350
Number of pages18
JournalJournal of Organic Chemistry
Volume80
Issue number24
DOIs
Publication statusPublished - 2015 Nov 6

ASJC Scopus subject areas

  • Organic Chemistry

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    Uesugi, S. I., Watanabe, T., Imaizumi, T., Ota, Y., Yoshida, K., Ebisu, H., Chinen, T., Nagumo, Y., Shibuya, M., Kanoh, N., Usui, T., & Iwabuchi, Y. (2015). Total Synthesis and Biological Evaluation of Irciniastatin A (a.k.a. Psymberin) and Irciniastatin B. Journal of Organic Chemistry, 80(24), 12333-12350. https://doi.org/10.1021/acs.joc.5b02256