Total Synthesis of (+)-Nankakurines A and B and (±)-5-epi-Nankakurine A

We report the development of the chemistry that allowed the first total syntheses of nankakurine A, -nankakurine B, and the originally proposed structure of nankakurine A to be accomplished, syntheses that confirmed the relative configuration and established the absolute configuration of these rare alkaloids.11

Ryan A. Altman


Scholarcy highlights

  • The first total syntheses of the Lycopodium alkaloids-nankakurine A,-nankakurine B and the originally purported structure 1 of nankakurine A were accomplished
  • The Kobayashi laboratory reported that further purification of this club moss extract provided a less abundant alkaloid,-nankakurine B, for which structure 3 was suggested
  • 1H NMR NOE data were interpreted to support a configuration at the spiro stereocenter opposite to that originally proposed for nankakurine A
  • It was provocative that nankakurines A and B bore no obvious structural relationship to other small molecule neurotrophic agents reported at that time, and, that their structures were devoid of polar functional groups known to negatively affect central nervous system exposure of small-molecule drugs
  • Cis-octahydronaphthalene amine 8 was seen deriving from the Diels–Alder reaction of-5-methyl-2-cyclohexen-1-one and diene 10, a strategy that drew ample precedent from Oppolzer’s pioneering early synthesis of-luciduline
  • The total syntheses of-2 and-3, together with the synthesis of the originally purported structure 1 of nankakurine A, rigorously establish the relative and absolute configuration of these Lycopodium alkaloids. These syntheses were sufficiently concise that substantial quantities of these alkaloids could be prepared for biological evaluation.-Nankakurine A and-nankakurine B showed no effect on neurite outgrowth in rat hippocampus H-19 cells over a concentration range of 0.3–10 μM, which stands in contrast to the report of neurotrophic activity of the former in human astrocytoma cells

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