The Overman Syntheses of Nankakurines A and

The tetracyclic alkaloids Nankakurine A and Nankakurine B were isolated from the club moss Lycopodium hamiltonii. A preliminary study of the biological activity ofNankakurme 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) by Larry E. Overman of the University of California, Irvine was the intriguing intramolecular aza-Prins cyclization of 1 to 2. 

Gentle hydrolysis of the ketal 8 was effected with minimal epimerization. Reductive animation 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 Sml. After reductive methylation, hydrogenation removed the benzyl ether, and AIH3 converted the benzamide to the benzyl amine. At low temperature, mesylation of the alcohol was apparently faster than mesylation of the secondary amine, enabling cycUzation 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 CD OD did not initially match, but on the addition of small amounts of CFjCOjH they were brought into congruence. 

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