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

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 spiro piperidine 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.

Neurotrophic Natural Products: Chemistry and Biology

“…In a recent study, Overman and co-workers reported that 92 and 93 showed no effect on neurite outgrowth in rat hippocampus H-19 cells, [148b] which stands in contrast to the previously reported results. [116b] Certainly, further biological investigation of these intricate Lycodium alkaloids would be necessary to unveil their biological potential.…”

“…[116b] The Overman research group reported the first synthesis of (+)-nankakurine A ( 92 ) and B ( 93 ), thereby establishing their absolute configurations (Scheme 22). [148] Critical to the synthetic strategy was an intramolecular azomethine imine [3+2] cycloaddition of 133 that installed the two nitrogen atoms at C5 and C13 in a stereoselective manner. Reductive cleavage of the N–N bond in 134 released the free amine at C13, which was reductively methylated to form 135 .…”

Synthesis of Natural Products with Polycyclic Systems

“…40) In addition to these bioactivities, the complicated polycyclic structure has attracted much attention in synthetic organic chemistry, and prior to our synthesis, two research groups reported the total synthesis of lyconadin A. [41][42][43][44] Our synthesis commenced with a Diels-Alder reaction between 36 45) and isoprene according to Overman's conditions 46,47) (Chart 3). The Diels-Alder reaction proceeded selectively on the opposite side of the methyl group to give the product.…”

Cycloadditions with Stereoselective C  N Bond Formation in Total Syntheses

“…24,25 The reactive azomethine imine intermediate 51 was generated by condensation of cis-decalin benzoylhydrazide 50 with excess paraformaldehyde in toluene at 115 C with N,Ndiisopropylethylamine. The expected pyrazolidine 52 was therefore obtained regioselectively in 82% yield.…”