Competent Route to Unsymmetric Dimer Architectures: Total Syntheses of (−)-Lycodine and (−)-Complanadines A and B, and Evaluation of Their Neurite Outgrowth Activities

Le Zhao, Chihiro Tsukano, Eunsang Kwon, Hisashi Shirakawa, Shuji Kaneko, Yoshiji Takemoto, Masahiro Hirama

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Valuable synthetic routes to the Lycopodium alkaloid lycodine (1) and its unsymmetric dimers, complanadines A (4) and B (5), have been developed. Regioselective construction of the bicyclo[3.3.1]nonane core structure of lycodine was achieved by a remote functionality-controlled Diels–Alder reaction and subsequent intramolecular Mizoroki–Heck reaction. A key coupling reaction of the lycodine units, pyridine N-oxide (66) and aryl bromide (65), through C−H arylation at the C1 position of 66 provided the unsymmetric dimer structure at a late stage of the synthesis. This strategy greatly simplified the construction of the dimeric architecture and functionalization. Complanadines A (4) and B (5) were synthesized by adjusting the oxidation level of the bipyridine mono-N-oxide (67). The diverse utility of this common intermediate (67) suggests a possible biosynthetic pathway of complanadines in Nature. Both enantiomers of lycodine (1) and complanadines A (4) and B (5) were prepared in sufficient quantities for biological evaluation. The effect on neuron differentiation of PC-12 cells upon treatment with culture medium, in which human astrocytoma cells had been cultured in the presence of 1, 4, or 5 was evaluated.

Original languageEnglish
Pages (from-to)802-812
Number of pages11
JournalChemistry - A European Journal
Volume23
Issue number4
DOIs
Publication statusPublished - 2017 Jan 1

Keywords

  • C−H arylation
  • complanadine
  • lycodine
  • palladium
  • total synthesis

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Organic Chemistry

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