Total synthesis of (+)-nankakurines A and B and (±)-5-epi-nankakurine A.

Methods Development

Abstract

The first total syntheses of the Lycopodium alkaloids (+)-nankakurine A (2), (+)-nankakurine B (3), and the originally purported structure 1 of nankakurine A were accomplished. The syntheses of 2 and 3 feature a demanding intramolecular azomethine imine cycloaddition as the key step for generating the octahydro-3,5-ethanoquinoline moiety and installing the correct relative configuration at the spiropiperidine ring juncture. The cyclization precursor was prepared from octahydronaphthalene ketone 50, which was assembled from enone (+)-9 and diene 48 by a cationic Diels-Alder reaction. The Diels-Alder reactants were synthesized from 5-hexyn-1-ol (16) and (+)-pulegone (49), respectively. The tetracyclic ring system of 1 was generated using an unprecedented nitrogen-terminated aza-Prins cyclization cascade. The enantioselective total syntheses of (+)-nankakurine A (2) and (+)-nankakurine B (3) establish the relative and absolute configuration of these alkaloids and are sufficiently concise that substantial quantities of 2 and 3 were prepared for biological studies. (+)-Nankakurine A and (+)-nankakurine B showed no effect on neurite outgrowth in rat hippocampal H-19 cells over a concentration range of 0.3-10 μM.

Authors

Altman, Ryan A; Nilsson, Bradley L; Overman, Larry E; Read de Alaniz, Javier; Rohde, Jason M; Taupin, Veronique;

Keywords

  • Alkaloids/ chemical synthesis
  • Alkaloids/ chemistry
  • Animals
  • Cycloaddition Reaction
  • Heterocyclic Compounds, Bridged-Ring/ chemical synthesis
  • Heterocyclic Compounds, Bridged-Ring/ chemistry
  • Lycopodium/ chemistry
  • Molecular Structure
  • Rats
  • Stereoisomerism

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