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Oseltamivir phosphate (Tamiflu) Pt. 2   

4 May 2006 5,324 views 8 Comments

tamiflu.jpg

Shibasaki, Fukuta, Mita, Fukuda, Kanai. JACS, 2006, ASAP, DOI: 10.1021/ja061696k

Part-two of our flu-busting master class brings us to Shibasaki’s synthesis of Tamiflu, published, as I mentioned in the previous post, on the same day as Corey’s. This nitrogen-tastic route employs an enantioselective ring-opening of meso-aziridines with azide (hmm… don’t fancy doing that on scale…!), leading to anti-addition of nitrogen.

tamiflu_3.jpg

Using this impressive methodology, they construct the first intermediate in the scheme below, and convert to a meso diamide in five steps. The C2 symmetry was then lost by SeO2 allylic oxidation, generating the next intermediate. Addition of cyanide and asymmetric reduction generated the final stereocentre, and allowed completion of the synthesis in seven further steps.

tamiflu_4.jpg

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8 Comments

  • [...] So it’s entirely apropos to think about making your own. Totally Synthetic, an organic chemistry blog, reviews the highlights of two Tamiflu total syntheses, published just last week or so. Soak in the retrosynthetic analytical genius of the Corey and Shibasaki groups. Tamiflus is still patented no matter how you make it, but without explosive azide salts and less of similar nasties, Corey’s synthesis seems to have potential for scaling up. (It’s still twelve steps, so it’s not going to be super-fun, but hey.) [...]

  • NoName says:

    even though outshined by virtuoso synthesis of EJ, this is darn pretty good synthesis. especially, the incorporation of major three functionalities is least substrate-dependent; i think they have to sacrifice a few steps for that idea.

  • Jeremiah says:

    Shibasaki just can’t compete with EJ. I mean… EJ came up with the Woodward-Hoffman rules, for God sake!

  • scared_anonym says:

    did he or he did not? Or he just talked with woodward and then woodward kept thinking about it and next morning had “eurika”? Why didn’t he tell that before 1980? To woodward’s face?

  • Tot. Syn. says:

    Hmm… Exactly. But, hey, let’s not get in the way. What do we know? We’re only grad-students (I am at least). However, I’ve spoken to Ian Fleming about this, and he has audio recordings of the Woodward lectures. Amazing. Okay, I’m not jeopardising my career anymore. Time to bail on this subject.

  • scared_anonym says:

    yeah, better have “no comment” on that issue….

  • [...] Update 5/4: Take a look at the good folks at Totally Synthetic. They just did a two part series on the Corey synthesis of Tamiflu if you enjoy the organic synthesis side of things (Part One, Part Two). [...]

  • Tot. Syn. says:

    Because of heavy spamming of this post and the previous one, I’ve closed commenting. If you want to add anything, email me at
    ts at totallysynthetic dot com