title: Total Synthesis and Biological Evaluation of Irciniastatin A (a.k.a. Psymberin) and Irciniastatin B.
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.
authors.affiliation: Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University , Aobayama, Sendai 980-8578, Japan.
authors.forename: Shun-ichiro
authors.initials: S
authors.lastname: Uesugi
authors.affiliation: Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University , Aobayama, Sendai 980-8578, Japan.
authors.forename: Tsubasa
authors.initials: T
authors.lastname: Watanabe
authors.affiliation: Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University , Aobayama, Sendai 980-8578, Japan.
authors.forename: Takamichi
authors.initials: T
authors.lastname: Imaizumi
authors.affiliation: Graduate School of Life and Environmental Sciences, University of Tsukuba , Tennodai, Tsukuba, Ibaraki 305-8572, Japan.
authors.forename: Yu
authors.initials: Y
authors.lastname: Ota
authors.affiliation: Graduate School of Life and Environmental Sciences, University of Tsukuba , Tennodai, Tsukuba, Ibaraki 305-8572, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Yoshida
authors.affiliation: Graduate School of Life and Environmental Sciences, University of Tsukuba , Tennodai, Tsukuba, Ibaraki 305-8572, Japan.
authors.forename: Haruna
authors.initials: H
authors.lastname: Ebisu
authors.affiliation: Graduate School of Life and Environmental Sciences, University of Tsukuba , Tennodai, Tsukuba, Ibaraki 305-8572, Japan.
authors.forename: Takumi
authors.initials: T
authors.lastname: Chinen
authors.affiliation: Graduate School of Life and Environmental Sciences, University of Tsukuba , Tennodai, Tsukuba, Ibaraki 305-8572, Japan.|Faculty of Life and Environmental Sciences, University of Tsukuba , Tennodai, Tsukuba, Ibaraki 305-8572, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Nagumo
authors.affiliation: Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University , Aobayama, Sendai 980-8578, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Shibuya
authors.affiliation: Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University , Aobayama, Sendai 980-8578, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Kanoh
authors.affiliation: Graduate School of Life and Environmental Sciences, University of Tsukuba , Tennodai, Tsukuba, Ibaraki 305-8572, Japan.|Faculty of Life and Environmental Sciences, University of Tsukuba , Tennodai, Tsukuba, Ibaraki 305-8572, Japan.
authors.forename: Takeo
authors.initials: T
authors.lastname: Usui
authors.affiliation: Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University , Aobayama, Sendai 980-8578, Japan.
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Iwabuchi
mesh_terms: D000818:Animals; D005075:Biological Evolution; D002384:Catalysis; D002460:Cell Line; D003374:Coumarins / Q000138:chemical synthesis* / Q000737:chemistry*; D015394:Molecular Structure; D010084:Oxidation-Reduction; D011485:Protein Binding; D012270:Ribosomes / Q000737:chemistry* / Q000378:metabolism; D013237:Stereoisomerism
chemical_list: D003374:Coumarins; C483487:irciniastatin B; C498383:psymberin