Uesugi Shun-ichiro, Watanabe Tsubasa, Imaizumi Takamichi, Ota Yu, Yoshida Keisuke, Ebisu Haruna, Chinen Takumi, Nagumo Yoko, Shibuya Masatoshi, Kanoh Naoki, Usui Takeo, Iwabuchi Yoshiharu
Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University , Aobayama, Sendai 980-8578, Japan.
Graduate School of Life and Environmental Sciences, University of Tsukuba , Tennodai, Tsukuba, Ibaraki 305-8572, Japan.
J Org Chem. 2015 Dec 18;80(24):12333-50. doi: 10.1021/acs.joc.5b02256. Epub 2015 Nov 16.
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.
刺尾鱼毒素A（又名苔藓虫素）和刺尾鱼毒素B是海鲷毒素天然产物家族的成员，它们具有强大的抗肿瘤活性和结构复杂性。在此，我们全面描述了（+）-刺尾鱼毒素A和（-）-刺尾鱼毒素B的全合成过程。我们的合成方法具有以下特点：高度区域选择性的三氟甲磺酸铕（Eu(OTf)3）催化、二异丙基叔丁基膦（DTBMP）辅助的环氧乙烷与甲醇的开环反应，这使得能够简洁地合成C1-C6片段；在整个合成过程中广泛使用了2-氮杂金刚烷N-氧基（AZADO）及其相关的硝酰自由基/氧鎓盐催化的醇氧化反应；以及C1-C6、C8-C16和C17-C25片段的后期组装。此外，对于（-）-刺尾鱼毒素B的合成，我们通过区域选择性脱保护和AZADO催化的醇氧化反应实现了氧化阶段的C11选择性控制。合成的刺尾鱼毒素对哺乳动物细胞显示出高水平的细胞毒性活性。此外，使用合成化合物进行的化学足迹实验表明，刺尾鱼毒素的结合位点是核糖体的E位点。
