Total synthesis of (+)-nankakurines A and B and (±)-5-epi-nankakurine A.
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.
Altman
Ryan A
RA
Department of Chemistry, 1102 Natural Sciences II, University of California, Irvine, California 92697-2025, United States.
Nilsson
Bradley L
BL
Overman
Larry E
LE
Read de Alaniz
Javier
J
Rohde
Jason M
JM
Taupin
Veronique
V
D000470:Alkaloids / Q000138:chemical synthesis* / Q000737:chemistry; D000818:Animals; D061565:Cycloaddition Reaction; D006572:Heterocyclic Compounds, Bridged-Ring / Q000138:chemical synthesis* / Q000737:chemistry; D032502:Lycopodium / Q000737:chemistry*; D015394:Molecular Structure; D051381:Rats; D013237:Stereoisomerism
D000470:Alkaloids; D006572:Heterocyclic Compounds, Bridged-Ring; C504053:nankakurine A; C547491:nankakurine B