TY - JOUR
T1 - Total Synthesis and Biological Evaluation of Irciniastatin A (a.k.a. Psymberin) and Irciniastatin B
AU - Uesugi, Shun Ichiro
AU - Watanabe, Tsubasa
AU - Imaizumi, Takamichi
AU - Ota, Yu
AU - Yoshida, Keisuke
AU - Ebisu, Haruna
AU - Chinen, Takumi
AU - Nagumo, Yoko
AU - Shibuya, Masatoshi
AU - Kanoh, Naoki
AU - Usui, Takeo
AU - Iwabuchi, Yoshiharu
N1 - Funding Information:
This research is partially supported by the Platform Project for Supporting in Drug Discovery and Life Science Research Platform for Drug Discovery, Informatics, and Structural Life Science from Japan Agency for Medical Research and Development, and Grant-in-Aid for Scientific Research on Innovative Areas Advanced Molecular Transformations by Organocatalysts (No. 23105011) from MEXT, Japan, by a Grant-in-Aid for Scientific Research (B)(No. 24390001), and by a Grant-in-Aid for Young Scientists (A)(No. 23689001) from JSPS.
Publisher Copyright:
© 2015 American Chemical Society.
PY - 2015/11/6
Y1 - 2015/11/6
N2 - 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.
AB - 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.
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U2 - 10.1021/acs.joc.5b02256
DO - 10.1021/acs.joc.5b02256
M3 - Article
C2 - 26544018
AN - SCOPUS:84952778531
VL - 80
SP - 12333
EP - 12350
JO - Journal of Organic Chemistry
JF - Journal of Organic Chemistry
SN - 0022-3263
IS - 24
ER -