Total Syntheses of Lepadiformine Marine Alkaloids with Enantiodivergency, Utilizing Hg(OTf)2-Catalyzed Cycloisomerization Reaction and their Cytotoxic Activities

Keisuke Nishikawa, Kengo Yamauchi, Seiho Kikuchi, Shinnosuke Ezaki, Tomoyuki Koyama, Haruka Nokubo, Kunihiro Matsumura, Takeshi Kodama, Momochika Kumagai, Yoshiki Morimoto*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

The enantioselective total syntheses of lepadiformine marine alkaloids, azatricyclic natural products isolated from marine tunicates, were completed. These alkaloids have a unique chemical structure characterized by the trans-1-azadecalin (AB ring system) fused with the spirocyclic ring (AC ring system). Here we found that a cycloisomerization reaction from functionalized linear substrates to a 1-azaspiro[4.5]decane framework corresponding to the AC ring in lepadiformines is promoted by a catalytic amount of mercury(II) triflate (Hg(OTf)2). The total syntheses of (−)-lepadiformines A and B were achieved in 28 % and 21 % overall yields, respectively, through the novel cycloisomerization reaction. The syntheses of (+)- and (−)-lepadiformine C hydrochloride salts also enabled us to determine the absolute configuration of natural lepadiformine C. It has been found that a phenomenon of enantiodivergence occurs in lepadiformine alkaloids from a single species of marine tunicate, Clavelina moluccensis. The cytotoxic activities of synthesized lepadiformine hydrochloride salts and their synthetic intermediates were evaluated.

Original languageEnglish
Pages (from-to)9535-9545
Number of pages11
JournalChemistry - A European Journal
Volume23
Issue number40
DOIs
StatePublished - 2017/07/18

Keywords

  • alkaloids
  • cytotoxicity
  • natural products
  • spiro compound
  • total synthesis

ASJC Scopus subject areas

  • Catalysis
  • General Chemistry
  • Organic Chemistry

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