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Totally Synthetic by Paul H. Docherty, 4 January 2009

Total Synthesis of Oseltamivir (Tamiflu)


H. Ishikawa, T. Suzuki, Y. Hayashi, Angew. Chem. Int. Ed. 2009, 48, 1304-1307.

DOI: 10.1002/anie.200804883

Tamiflu is back! To quote Hayashi, this is a ” three one-pot operations” synthesis, so over very quick; in fact, there’s only one synthesis scheme in the paper. However, to explain more of the chemistry going on, I’ve dismembered the scheme to show more of the intermediates, and give a better idea of what’s going on.

The synthesis of Tamiflu starts with an organocatalytic Michael reaction, using the groups own methodology (here and applications here). This installed the first two stereocenteres, and allowed the group to perform a further, diastereocontrolled Michael addition into a vinylphosphonate. The intermediate produced is then perfectly set for a HWE reaction completing the cyclohexene. This approach is particularly interesting, as most previous routes used Diels-Alder chemistry to install the ring, and then up to ten steps to functionalise the ring. As we see later, Hayashi has most of the functional groups already imparted. However, a mixture of diastereoisomers was produced a the C-5 center bearing the nitro group. Neither acid nor base epimerisation was entirely successful, but heating with toluene thiol and a potassium carbonate did the job. This also ‘protected’ the alkene by Michael addition of toluene thiol, completing the first of the ‘one pot’ operations.

Following is selective acidic deprotection of the t-butyl ester, formation of the acid chloride, displacement with azide and finally Curtius rearrangement and amide formation. Neatly done in one pot, but the use of azides is perhaps a drawback. Completion of the synthesis then only required reduction of the nitro group using in situ generated HCl with zinc, then elimination of the thiol to finish the target. This involved passing ammonia gas through the reaction mixture, generating a Zn(II)-ammonia complex, then retro-Michael.

A very nice total synthesis!