Oseltamivir phosphate (Tamiflu) Pt. 3
Trost and Zhang, ACIEE, 2008, EarlyView. DOI: 10.1002/anie.200800282.
We’ve looked at two previous syntheses of tamiflu before, those of Corey and Shibasaki, so you’re probably used to me stretching the definition of “natural-product total synthesis” to include it. Stretching the definition to breaking point, actually, but never mind, it’s got a very natural-product look to it (which must lend a little to it’s popularity). The other reason for it’s popularity is that apparently chickens and turkeys are still getting a spot of the sniffles occasionally, so the demand for flu-busters is ever present. Retro:
Some interesting reactions in there, but once again we’ve got aziridines in play. Also, it’s no real surprise to see the Trost-developed palladium-catalysed asymmetric allylic alkylation rear it’s head again, but the implementation in this case is particularly nice:
Taking a racemic mixture of the allylic lactone wit a spot of palladium catalyst and a familiar C2 symmetric ligand lead to a cracking yield of the product, setting two stereocentrers. Initial work on this reaction was a bit disappointing for the group, as more “friendly” NHBoc2, NHCbz2, NH(CHO)2 type nucleophiles were ineffective. They also found that they’d have to quickly trap the opened lactone to prevent relactonisation (something that’s scuppered me in the past…). But they got it to work in the end, with a second step (reflux in acidic ethanol) to cleave the TMS-carboxylate initially formed to give the desired ethyl ester.
A few steps later it was time for the aziridination, which was again a little troublesome. Copper, usually the friend of the aspiring aziridinator (I might have made up a new word!) failed in it’s efforts as it was unselective for the desired olefin. Gold and silver also failed, so I bet they were chuffed when DuBois’ Rhodium catalyst did the business in great yield, after the tuning the conditions to fit their need.
Completion of the synthesis from here was relatively straight-forward, commencing with regioselective opening of the aziridine and deprotections (requiring ethanolic hydrazine for the phthalamide…). A really nice piece of work (which they point out to be the shortest synthesis so far) – but scalable?
Trost, B.M., Zhang, T. (2008). A Concise Synthesis of (Ã¢Ë†â€™)-Oseltamivir. Angewandte Chemie International Edition DOI: 10.1002/anie.200800282
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