There's been a lot of press coverage the last week or so about two new routes to Tamiflu (oseltamavir). Roche famously starts from shikimic acid, most of which they get from Chinese star anise, and the new syntheses are attempts to get around that bottleneck.
E. J. Corey's getting more attention than Masakatsu Shibasaki, partly because he's a Nobel winner and partly because he's made a point of placing his synthesis in the public domain. (Shibasaki's applied for a patent). It's nice to see organic synthesis make the headlines, but unfortunately, a lot of the coverage has been of the "Nobel Prize Winner Solves Tamiflu Problem" sort. I've also seen several stories that suggest that Corey's route opens the door (at last, right?) to mass production.
Not so fast. Roche has already been producing rather large amounts of oseltamavir, although they'd be glad to find a better route. And it's not like they haven't been trying themselves, as this PDF will make clear. And it's far from clear that Corey's route will be of commercial value, even though his overall yield, as given, is about 27%, which news articles are saying is roughly twice the yield from shikimic acid. (Note, though, that that Roche PDF claims a higher yield than Corey's - I'm not sure who's right).
Let's get technical and take a look at the chemistry. First off, the repeated claim that Corey's route starts from two of the cheapest feedstocks available - butadiene and acrylic acid - is only partly true. The key Diels-Alder reaction actually uses trifluoroethyl acrylate, which is substantially more expensive than acrylic acid, although admittedly ten times cheaper than the same amount of shikimic acid from the same source. Moving on, there are eleven steps, and according to the supplementary material for the paper (where the full experimentals are), steps 1, 3, 4, 5, 6, and 8 have chromatography in their workup. The others are run through a plug of silica or are taken on crude, which tells me that Corey's students probably tried to do the same with the remaining steps but took a hit on the yields. Every chromatographic purification adds a great deal to the cost of a process route, needless to say.
There are other wrinkles. Steps 1 and 2 start at -78 degrees before coming up to more process-friendly temperatures. Step 8 is a slow addition at -40, and step 9 is an inverse addition at -20. Low-temperature reactions are certainly doable on scale, but again, they'll add to the cost and complexity. Those last two steps involve an acylaziridine intermediate, whose thermal stability would need to be checked out, and could partially negate the advantage of not using azide in the route.
The scale of the reactions in this paper is in the ten-gram range, which is fine, until you get to steps 8 and 9. Those low-temperature reactions are shown on 300 and 160 milligrams, respectively. That tenfold drop in scale indicates another area that would need to be checked out; there can be a huge difference between something that works on a couple of hundred mgs and a useful process, especially in the cold.
All this isn't to say that Corey's route doesn't work, or that it can't work on scale. But it's important to keep in mind that the kind of chemistry done in his lab is about as far from industrial scale as you can get. It may be that the more interesting features of his route (the catalyzed Diels-Alder, for example) could be combined with some of Roche's own process ideas and turned into something feasible. But for now, this is an interesting route that's a long way from solving anyone's Tamiflu shortage.
To be fair, Corey himself isn't responsible for some of the hype, except I wish he wouldn't let himself be quoted as saying that the thinks that the Tamiflu production problems are "solved". Headline writers know nothing about organic chemistry or drug development, and they run with what's in the press releases. Of course, there's the larger question hanging over all of this: will Tamiflu even do anyone any good if there is a human outbreak of avian flu? And that, nobody knows.