Tamiflu is often refered to as a neuraminidase inhibitor. Viral neuraminidase is a protein (actually, the N in H1N1 refers to Neuraminidase) found on the surface of influenza viruses. Its activity is related to proliferation of the viruses and their reproduction inside infected cells. Oseltamivir acts by blocking this protein. The new viruses are prevented from emerging from infected cells, and if the drug is taken early enough, the spreading of the virus to the organism can be efficiently prevented. Current limitations of this type of treatment are that neuraminidase inhibitors are not renewable (they are consumed doing their job) and some resistance can occur – viral neuraminidase can be protected from the drug’s effect.

From a biomedical point of view, oseltamivir is described as a pro-drug: an ester bond has to be cleaved by enzymes in order to generate the efficient inhibitor. Several synthetic pathways are known. The commercial production starts form the biomolecule shikimic acid (see figure), which limited availability makes the large-scale production of Tamiflu complicated.

(-)-Quinic acid (1) and (-)-shikimic acid (2), two widely used starting materials for the synthesis of ostelamivir phosphate (3). They are extracted from the bark of cincona trees, and from the Chinese star anise, respectively.

Knowing that the daily dose is 150 mg per patient, one easily understands that the search for alternative synthetic routes was fueled by the need of more abundant starting materials. So far, the large scale production is still based on the original protocols developed by Gilead Sciences (I actually wonder whether this name comes from Stephen King’s novel The Dark Tower…), which starts from shikimic acid and involves several potentially hazardous steps (including azide chemistry, see here for details regarding this synthetic route). Alternative syntheses were recently developed at Roche, and by various research groups worldwide. One may cite research led by E. J. Corey, M. Shibasaki, T. Fukuyama or Barry M. Trost, which synthesis is the shortest so far (eight steps, starting from commercially available materials). Anyway, it seems industry’s requirements have not (yet?) allowed any different mode of production than the original one, but the increasing need and long production time (ca. 6 months) may well push one of the above mentioned syntheses to industrial production.

Here is a nice animation showing the mode of action of Tamiflu against influenza virus.

Mechanistic investigations have shown the importance of the Cu(I) and of the carboxylate anion for the cross-coupling to work efficiently. These two species are therefore clearly involved in the catalytic mechanism, which is shown below. The thiol ester undergoes complexation to the copper(I) carboxylate, followed by oxydative addition of the bound thiol ester to the Pd(0) catalyst (1). A copper-mediated transmetallation then allows to form the organopalladium compound (2) and eliminates the copper thiolate and boron derivative byproducts. The final ketone (3) is obtained by a reductive elimination that also regenerates the palladium catalyst.

The reaction described above uses a stoechiometric amount of the copper(I) carboxylate. To make it catalytic, it is necessary to regenerate the Cu(I) oxygenate from the eliminated Cu-SR. This was achieved by performing the reaction with an excess of boronic acid, and under air. The Cu-SR bond is broken to form a thioether with the excess boronic acid, and a copper oxygenate is made available to the system. A particular thiol ester was necessary to make the reaction work:

Ref: L. S. Liebeskind, J. Srogl, J. Am. Chem. Soc. 2000, 122, 11260;
J. M. Villalobos, J. Srogl, L. S. Liebeskind, J. Am. Chem. Soc. 2007, 129, 15734.