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Totally Synthetic by Paul H. Docherty, 29 November 2008

Total Synthesis of Oseltamivir phosphate (Tamiflu)


K. Yamatsugu, L. Yin, S. Kamijo, Y. Kimura, M. Kanai, M. Shibasaki, Angew. Chem. Int. Ed. 2009, 48, 1070-1076.

DOI: 10.1002/anie.200804777

Although Tamiflu isn't a natural product, it is of course based on a natural product, shikimic acid - the starting point for the original synthesis. However, shikimic acid is very pricey and other routes used involved chemistry that was perhaps problematic on a larger scale via azides and aziridines. A few years back, Corey announced that the problem was solved with his interesting synthesis that I still love from a chemist’s point of view. However, from a practical perspective, there were still a few problems, including reactions at low temperatures (-78C) which are problematic on a plant scale.

On the same day his former student Masakatsu Shibasaki published his work on Tamiflu, which was also a very nice synthesis, although azides and aziridines occured as intermediates. It appears that he doesn’t think of them as a problem, as even this synthesis features these functional groups.

The total synthesis starts with a very interesting asymmetric Diels Alder reaction (DA), in which the top row of the periodic table was used as additive along with a very complex ligand to induce the asymmetry. It’s indeed a five step synthesis, using some pretty nice chemistry in itself! The result of the DA is very nice, building that asymmetry into the cyclcohexene with apparent ease.

A few steps later the first azides appear. A Curtius rearrangement was used to impressively construct a cyclic carbamate and the Boc-protected amine in one pot. Nice work, as the reaction also differentiates the two amines. However, they were aware of the problems of working with such a problematic functional group, so they optimised the reaction conditions without isolation of the azide-containing intermediate.

After acetylation, they used a C1 acyl anion equivalent for the construction of the carbon skeleton - in this case, a protected hydroxy malononitrile. A Tsuji-Trost allylation was accompanied by opening and decarboxylation of the carbamate and installed the new stereocenter in complete control.

Completion of the synthesis was problematic: a substrate controlled epoxidation went well, as did opening of the epoxide. However, the planned displacement of the newly installed hydroxyl group to install the 3-pentyl ether was very difficult. They finally surmounted this problem by displacing the group with the neighbouring amine in a double Mitsunobu reaction forming an azidiridine. Opening of this aziridine with Lewis acid and 3-pentanol finally finished the total synthesis. A Nice work, that uses some impressive chemistry - read the paper for a full discussion of that Diels-Alder reaction!