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Oseltamivir phosphate (Tamiflu) Pt. 3   

13 April 2008 22,855 views 29 Comments

Trost and Zhang, ACIEE, 2008, EarlyView. DOI: 10.1002/anie.200800282. Article PDF Supporting Information Group Website ResearchBlogging.org

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 (−)-Oseltamivir. Angewandte Chemie International Edition DOI: 10.1002/anie.200800282

InChiKey Dump:
VSZGPKBBMSAYNT-RRFJBIMHBB TVEXGJYMHHTVKP-UHFFFAOYAE BTYZRXAPVOYBCT-NWDGAFQWBG
AXMSEDAJMGFTLR-XRSDMRJBBJ AKIOBSLPVWJYQI-GFCCVEGCBL CIEGFMYTKZTTNC-YBJWPOLQBGBGLHCYVZEDLVRT-XBHQNQODAE

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29 Comments

  • earth23 says:

    Pretty sweet Pd-AAA. Always nice to have a paper where an academic group’s research is applicable to real world problem.

  • InfMP says:

    Curious. Why does it say phosphate in the title? I don’t see any phosphorus atoms.

  • Candid says:

    Is compound 14 really, DuBois catalyst? Just wondering, but haven’t these dirhodium catalysts been looked at by MP Doyle, or HMW Davies, or someone else.

  • largo says:

    of course but doyle and davies are at crap schools so nobody pays any attention.

  • Potstirrer says:

    I believe the phosphate refers to the salt form of the free base.

    Certainly Doyle and Davies have extensively used dirhodium tetracetate derivatives in their work, but DuBois was probably the first one to make that actual rhodium complex. Sometimes small changes are all it takes.

  • Tot. Syn. says:

    Yep, sorry for the confusion. The target is actually the phosphate salt, which Corey and Shibasaki both complete, but Trost didn’t bother. Meh…

  • WestCoast85 says:

    A french researcher (Emmanuel Roulland from the ICSN) completed the total synthesis of (+)-Oocydin A in ACIE (http://www3.interscience.wiley.com/cgi-bin/abstract/118002903/ABSTRACT) with excellents yields … Nice and concise synthesis with an original Suzuki-Miyaura cross-coupling

  • Tot. Syn. says:

    WestCoast85: Give me a chance! Trost’s paper was first in line, so I’ll tackle Roulland’s fairly soon… don’t underestimate how long it takes to put these things together!

  • Caustic says:

    What the french research is not dead????

  • WestCoast85 says:

    Thank you Tot. Syn. !

  • sjb says:

    “The target is actually the phosphate salt, which Corey and Shibasaki both complete, but Trost didn’t bother. Meh…”

    Does this only count as a “formal” total synthesis of tamiflu then? :)

    S

  • Caustic says:

    Tot. Syn. you should have entitled Oseltamivir phosphate (Tamiflu) Pt. 4 and not Pt. 3, since Fang has published a paper before Trost.

    http://dx.doi.org/10.1021/ja073992i

    Even if this is the less “sexy” synthesis….

  • lemi says:

    Caustic
    Don’t misunderstand, Paul just mean that this is the third time he post Oseltamivir here, in fact, there are far more than four about Oseltamivir’s synthesis …

  • npsynthesis says:

    Great synthesis! Short, effective, but as the blogger has mentioned…scalable? I see several problems with the synthesis — including their use of chromatography and a thiol reagent — both of which are to be avoided in industry. On the bright side — their avoidance of quinic and shikimic acid as starting materials stands out among older syntheses and yet their sm was commercially available (Corey’s and Shibisaki’s sm was not commercially available!!) I wonder if Trost is keeping the synthesis in the public domain as EJ had done with his brilliant route.

  • Matt says:

    Is this synthesis patented?

  • Caustic says:

    My apologizes, I just wanted to mention that in recent Jacs or Angewandte there was another publication.
    But it’s no big deal.
    And I check on WIPO and no patent….but maybe elsewhere???

  • milkshake says:

    Patenting a synthetic scheme is not a very useful invention protection – it is exceptionally easy to bypass. Anyone can make a simple add-on like changing solvent for recrystallisation and claim “improved, new and unexpected” and get his own version also patented. You would have to patent the absolutely key transformation, the catalyst etc – and still someone can scoop you by changing the protecting groups around. The only thing that such a patent can give you is a peace of mind to your investors that you could probably make it by your own route without being harassed for infringing on someones patent.

    The only secure way to patent in chemistry is to patent a new structure – a “composition of matter” – and its use.

  • Anon says:

    Milkshake and Others:

    Can some body patent the Natural product if they were to isolate for the first time? Do they posess the entire rights on the molecule which infact was made by nature? How do industries get around such patents? Does it mean that somebody else can not patent if they find new use for that compound?

  • milkshake says:

    You cannot patent a natural compound as a structure (but you can make the simplest semisynthetic analog – and if it was never disclosed you can stake your claim on it). With a natural compound you can patent its use, a process of isolation/manufacture, a specific drug formulation, etc but it is obviously a much weaker protection.

  • ChemicalProcrastinator says:

    Milkshake – IIRC the head of AMRI patented a process for the preparation of a marketed drug, and that is why he is so immensely rich. Could be wrong.

  • Jose says:

    Ah yes, Tom D’Ambra. It is amazing anyone trusts AMRI with proprietary info after that little stunt he pulled… while working on Allegra (under contract) he patented an improved synthetic route, and then sold it back. Slick.

  • dione says:

    Roche (the only company that makes Tamiflu) makes it from quinic acid which inturn is obtained solely from nature (a chinese herb)!!

  • Nyabuto says:

    Dione,

    I’m pretty sure they still make it from Shikimic acid (http://www.nature.com/doifinder/10.1038/nrd1917) although this Nature article is a few years old now. In this piece, Novartis are quoted as saying they get a third of their Shik acid by microbial fermantation… I’m sure that’s increased by now!

  • milkshake says:

    In pharma process plant, once you have FDA approved way of making the active ingredient, the last thing you ever want is to swich over to a completely new synthetic scheme. It requires documenting everything all over again, including the impurity profiles (characterizing every identifiable impurity), and carrying out the stress experiments to determine acceptable range of reaction conditions, finding the right equipment to do the chemistry and making the process safe (for example anything that is below -35C, has a strong exotherm or requires evaporationn to dryness is a non-trivial operation). Modifying the first step, the shikimic acid isolation, is enough trouble – and that channels right back into the established route.

    Drug manufacturing cost is only such a tiny fraction of the final price. You see a brand new synthesis mostly once the drug patent expires and generic indian and israeli companies jump in, trying to make it by the cheapest (and proprietary) route.

  • Hadriel says:

    perhaps you’d like to complete the picture by reviewing the first total synthesis of oseltamivir by Karpf / Trussardi in 2001? There’s also one by Fukuyama in 2007. Was looking through wikipedia so thought maybe its worth mentioning.

    btw i’m not even an undergrad yet =P

  • Tot. Syn. says:

    The fact is that there’s been loads of syntheses of oseltamivir – I’ve just focused on those that caught my eye. It’s the same policy I have for other targets – it’s almost impossible to cover ‘em all. And that’s what Natural Product Reports is for…

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