Toward the total synthesis of a hybrid natural product that consists a highly functionalized 11-oxatricycloundecane/macrolide and its structure activity relationships

2013 Fiscal Year Final Research Report

• Project/Area Number: 24790022
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Chemical pharmacy
• Research Institution: Kitasato University
• Principal Investigator: SUGAWARA Akihiro 北里大学, その他の研究科, 助教 (50581683)
• Project Period (FY): 2012-04-01 – 2014-03-31
• Keywords: ルミナミシン / 抗嫌気性菌活性 / 全合成 / 11-オキサトリシクロウンデカン / 酸素架橋シスデカリン / マクロライド / 構造活性相関 / 高歪み10員環ラクトン

Research Abstract

Luminamicin (1) was found to exhibit selective antibacterial activity against anaerobic bacteria in 1985. It contains a highly functionalized 11-oxatricycloundecane, associated with a 10-membered lactone moiety which possesses a (E)-trisubstituted olefin and a 14-membered macrolactone, with an enol ether conjugated with a maleic anhydride functionality.
We have been focusing on its total synthesis due to its intriguing structure and interesting biological activity. We synthesized a framework of the key intermediate from the unsaturated aldehyde via intramolecular 1,6-oxa-Michael reaction and stereoselective protonation at C4 position. Study toward the total synthesis of 1 is in progress in our laboratory.

Research Products

• [Journal Article] Observation of the controlled assembly of preclick components in the in situ click Chemistry generation of a chitinase inhibitor (2013)
  • Author(s): Tomoyasu Hirose, Nobuo Maita, Hiroaki Gouda, Jun Koseki, Tsuyoshi Yamamoto, Akihiro Sugawara, Hirofumi Nakano, Shuichi Hirono, Kazuro Shiomi, Takeshi Watanabe, Hisaaki Taniguchi, K. Barry Sharpless, Satoshi Ōmura, and Toshiaki Sunazuka
  • Journal Title: Proc. Natl. Acad. Sci. USA Volume: 110 Pages: 15892-15897
  • DOI: 10.1073/pnas.1315049110
• [Journal Article] Asymmetric total synthesis of Neoxaline (2013)
  • Author(s): Tetsuya Ideguchi, Takeshi Yamada, Tatsuya Shirahata, Tomoyasu Hirose, Akihiro Sugawara, Yoshinori Kobayashi, Satoshi Omura, and Toshiaki Sunazuka
  • Journal Title: J. Am. Chem. Soc. Volume: 135 Pages: 12568-12571
  • DOI: 10.1021/ja406657v
• [Journal Article] Human acidic mammalian chitinase as a novel target for anti-asthma drug design using in silico screening (2013)
  • Author(s): Masaki Wakasugi, Hiroaki Gouda, Tomoyasu Hirose, Akihiro Sugawara, Tsuyoshi Yamamoto, Kazuro Shiomi, Toshiaki Sunazuka, Satoshi Omura, Shuichi Hirono
  • Journal Title: Bioorg. Med. Chem Volume: 21 Pages: 3214-3220
  • DOI: 10.1016/j.bmc.2013.03.047
• [Journal Article] Borrelidin analogues with antimalarial activity : design, synthesis and biological evaluation against Plasmodium falciparum parasites (2013)
  • Author(s): Akihiro Sugawara, Toshiaki Tanaka, Tomoyasu Hirose, Aki Ishiyama, Yoko Takahashi, Kazuhiko Otoguro, Satoshi Omura, Toshiaki Sunazuka
  • Journal Title: Bioorg. Med. Chem. Lett. Volume: 23 Pages: 2302-2305
  • DOI: 10.1016/j.bmcl.2013.02.075
• [Journal Article] Novel 12-membered non-antibiotic macrolides, EM900 series with anti-inflammatory and/or immunomodulatory activity; synthesis, structure?activity relationships and in vivo study (2012)
  • Author(s): Akihiro Sugawara, Akito Sueki, Tomoyasu Hirose, Hideaki Shima, Kiyoko S Akagawa, Satoshi?mura and Toshiaki Sunazuka
  • Journal Title: J. Antibiot. Volume: 65 Pages: 487-490
  • DOI: 10.1038/ja.2012.51
• [Journal Article] Toward the total synthesis of Luminamicin : construction of 14-membered lactone framework possessing versatile enol ether moiety (2012)
  • Author(s): Aoi Kimishima, Tomoyasu Hirose, Akihiro Sugawara, Takanori Matsumaru, Kaoru Nakamura, Ken Katsuyama, Masaki Toda, Hirokazu Takada, Rokuro Masuma, Satoshi?mura, Toshiaki Sunazuka
  • Journal Title: Tetrahedron Lett. Volume: 53 Pages: 2813-2816
  • DOI: 10.1016/j.tetlet.2012.03.098
• [Presentation] Toward the total synthesis of Luminamicin; construction of 14-membered macrolide with enol ether conjugated with a maleic anhydride (2013)
  • Author(s): Hirokazu Takada, Akihiro Sugawara, Tomoyasu Hirose, Aoi Kimishima, Takanori Matsumaru, Masaki Toda, Takeshi Yamada, Satoshi?mura and Toshiaki Sunazuka
  • Organizer: ICCA-13
  • Place of Presentation: 山梨県(富士ビューホテル)
  • Year and Date: 20130924-27
• [Presentation] Toward the total synthesis of Luminamicin; construction of 11?oxatricyclo[5.3.1. ^1,70^3,8]undecane skeleton (2013)
  • Author(s): Aoi Kimishima, Akihiro Sugawara, Tomoyasu Hirose, Hirokazu Takada, Takanori Matsumaru, Satoshi?mura and Toshiaki Sunazuka
  • Organizer: ICCA-13
  • Place of Presentation: 山梨県(富士ビューホテル)
  • Year and Date: 20130924-27
• [Presentation] Toward the total synthesis of Luminamicin, a specific anti-anaerobic bacteriacide (2013)
  • Author(s): Akihiro Sugawara, Aoi Kimishima, Hirokazu Takada, Tomoyasu Hirose, Takanori Matsumaru, Satoshi?mura, Toshiaki Sunazuka
  • Organizer: Annual Meeting of the American Society of Pharmacognosy
  • Place of Presentation: USA (St. Louis)
  • Year and Date: 20130713-18
• [Remarks]
  • URL: http://seibutuyuuki.sakura.ne.jp/