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 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.

FIGURE 1

Nankakurines A and B and two structurally related Lycopodium alkaloids.

FIGURE 2

Molecular models of low-energy conformations of the most stable disalts of nankakurine B (2); ΔE = E(conf B) – E(conf A) in kcal/mol; energies marked with an asterisk refer to DFT calculations using the COSMO model for methanol solvent.

FIGURE 3

¹H NMR Spectra of the Titration of Synthetic (+)-2 and (+)-3 with TFA. ^a Matches ¹H NMR of 2 reported in 2004. ^b Matches ¹H NMR of 3 reported in 2006.

FIGURE 4

Absence of neurotrophic properties of (+)-nankakurine A (2) and (+)-nankakurine B (3) in rat hippocampus cells; data are expressed as the mean of two separate experiments; control = DMSO; reference = positive reference compound.

SCHEME 1

Retrosynthetic Analysis of 5-epi-Nankakurine (1)

SCHEME 2

Synthesis of cis-Octahydronaphthalene Amine 22.

SCHEME 3

Attempted Nitrogen-Terminated Aza-Prins Reaction of Cyanomethyl Amine 23.

SCHEME 4

Attempted Hydroamination of Tricyclic Unsaturated Sulfonamides 24, 25, and 28.

SCHEME 5

Potential Nitrogen Participation in the Aza-Prins Cyclization to form Octahydro-3,5-ethanoquinoline 24.

SCHEME 6

Attempted Sulfonamide-Terminated Aza-Prins Reaction of Carbamates 37 and 39.

SCHEME 7

Sufonamide-terminated Aza-Prins Cyclization to Form Spirotetracyclic Product 27.

SCHEME 8

Elaboration of 27 to (±)-5-epi-Nankakurine A (1).

SCHEME 9

Retrosynthetic Analysis of (+)-Nankakurines A (2) and B (3)

SCHEME 10

Synthesis of cis-Octahydronaphthalene Hydrazine Derivatives 51–53.

SCHEME 11

Competition Between Intramolecular Azomethine Imine Dipolar Cycloaddition and Aza-Prins Cyclization.

SCHEME 12

Completion of the Enantioselective Total Syntheses of (+)-Nankakurine A (2) and (+)-Nankakurine B (3)