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Organic Chemistry Highlights

Total Synthesis

Monday, August 3, 2009
Douglass F. Taber
University of Delaware

The Overman Syntheses of Nankakurines A and B

The tetracyclic alkaloids Nankakurine A and Nankakurine B were isolated from the club moss Lycopodium hamiltonii. A preliminary study of the biological activity of Nankakurine A suggested that it could induce secretion of neurotrophic factors and promote neuronal differentiation. The key step in the first syntheses of Nankakurine A and of Nankakurine B, reported (J. Am. Chem. Soc. 2008, 130, 11297. DOI: 10.1021/ja804624u) by Larry E. Overman of the University of California, Irvine was the intriguing intramolecular aza-Prins cyclization of 1 to 2.

The starting material for the synthesis was 5-methyl cyclohexenone 6, prepared from (R)-pulegone. The diene 5 was prepared from the alkyne 4, following the procedure developed by Diver. There were two issues in developing the Diels-Alder addition of the enone 4 to the diene 6. The first was the relative lack of reactivity of 4 as a dienophile. The other issue was the ready epimerization of the product ketone 9. Both of these problems were solved using the activation method devised by Gassman. Condensation of 4 with 7 in the presence of the bis-silyl ether 7 and the diene 6 at cryogenic temperatures led to the ketal 8. It is thought that the active dienophile was the cation 11.

Gentle hydrolysis of the ketal 8 was effected with minimal epimerization. Reductive amination with the hydrazide 10 proceeded with high diastereocontrol, to give the precursor 1.

The intramolecular aza-Prins cyclization of 1 to 2 proceeded well, though the desired tetracyclic 2 was only observed when base was included in the reaction medium. In the absence of base, tricyclic alkenes dominated.

Reduction of the N-N bond of 2 proceeded smoothly with freshly prepared SmI2. After reductive methylation, hydrogenation removed the benzyl ether, and AlH3 converted the benzamide to the benzyl amine. At low temperature, mesylation of the alcohol was apparently faster than mesylation of the secondary amine, enabling cyclization to 14. Removal of the benzyl protecting group gave Nankakurine A, which was successfully methylated to give Nankakurine B.

The completion of a total synthesis is an anxious moment, as for the first time it is possible to compare spectra of the synthetic material with those reported for the natural product. There is always a concern as to whether or not the spectra are being acquired under precisely the same conditions employed by those who did the initial isolation. This is particularly true for very polar molecules such as these diamines. In fact, the spectra in CD3OD did not initially match, but on the addition of small amounts of CF3CO2H they were brought into congruence.

Although in this synthesis the starting enantiomerically-pure cyclohexenone 4 was derived from natural sources, one could imagine that enantioselective conjugate methylation of cyclohexenone or a derivative could get one into the same manifold.

D. F. Taber, Org. Chem. Highlights 2009, August 3.