Oseltamivir phosphate (Tamiflu) Pt. 4
Zutter, Iding, Spurr and Wirz1. JOC, 2008, ASAP. DOI: 10.1021/jo800264d.
Again, I’m stretching that brief to include Tamiflu, basically because I find it such an interesting target. The more click-happy readers will have noticed that this paper comes to us from The Professionals at Roche, who make this bad-boy their business. And quite a synthesis it is too. Retrosynthetic analysis won’t get us anywhere here, so lets leap in with the forward.
Now that’s what I call a reduction! 5% Ru-Al2O3 with a fair old pressure of hydrogen resulted in an all-cis configuration in a respectable yield. You’ll also note that whilst this reduction wasn’t asymmetric, the product is meso. So next up (after demethylation) was a highly efficient desymmetrisation, using pig-liver-esterase, resulting in the desired product in excellent enantiomeric excess.
So far, so smart, but many a synthesis trips up at this point with a stumbling series of functional group transformations to get to the target. However, the folks at Roche used an interesting and effective strategy. A bit 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 base led to a ‘transcarbonation’ (or something) type process forming a bridged carbonate. This compound is then set perfectly to do an elimination/decarboxylation process, installing the required unsaturation. Completion of the molecule required a more familiar approach of displacement of the hydroxyl group (as it’s triflate analogue) using azide and then reduction, and a few more less interesting steps. However, the synthesis and strategy are compelling, and well described in this paper. Read!
 This dude has an awesome name: Beat Wirz! ‘spec!
Zutter, U., Iding, H., Spurr, P., Wirz, B. (2008). New, Efficient Synthesis of Oseltamivir Phosphate (Tamiflu) via Enzymatic Desymmetrization of a meso-1,3-Cyclohexanedicarboxylic Acid Diester. The Journal of Organic Chemistry DOI: 10.1021/jo800264d