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Totally Synthetic by Paul H. Docherty, 9 June 2008

Total Synthesis of Oseltamivir phosphate (Tamiflu)


U. Zutter, H. Iding, P. Spurr, B. Wirz, J. Org. Chem. 2008, 73, 4895-4902.

DOI: 10.1021/jo800264d

The current paper comes to us from professionals at Roche, who make this drug compound, which is not a natural product, their business. They present the following interesting synthesis:

Now that’s what I call a reduction! 5% Ru-Al2O3 and a high pressure of hydrogen resulted in an meso product with all-cis configuration in a respectable yield. A demethylation was followed by a highly efficient desymmetrisation using pig liver esterase, which resulted in the desired product in excellent enantiomeric excess.

The folks at Roche used an interesting and effective strategy that reduced the amount of functional group transformations normally required to get to such a target. The use of diphenylphosphoryl azide and base resulted in a Curtius rearrangement in which the isocyanate was trapped by the neighbouring hydroxyl group to give an oxazolidinone.

Boc protection followed by the use of base formed a bridged carbonate. A subsequent elimination/decarboxylation process installed the required unsaturation. The displacement of the hydroxyl group (as its triflate analogue) using azide, reduction, and a few more steps finished this synthesis. The strategy is compelling and well described in this paper!