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Oseltamivir (Tamiflu) Pt. 6   

4 January 2009 16,479 views 27 Comments

Hayashi, Ishikawa and Suzuki. ACIEE, 2009, EarlyView. DOI: 10.1002/anie.200804883. Article PDF Supporting Information Group Website

It’s back! Not just Tot. Syn., reanimated refreshed after a decent winter break, but Tamiflu too (thanks to all those who flagged this one up for me. In this case, in a (marginally) different guise, as what we’ve got here is Oseltamivir-free base, not the phosphate salt normally isolated. Not an important fact, but the salt formation probably makes quite a difference in-vivo

However, that doesn’t matter a damn when the synthesis is a sweet at this. To quote Hayashi, this is a ” three one-pot operations” synthesis, so over pretty damn quick; in fact, there’s only one synthesis scheme in the paper. However, to explain more of the chemistry going on, I’ve dismembered the scheme to show more of the intermediates, and give a better idea of what’s going on.

First up is an organocatalytic Michael reaction, using the groups own methodology… here and applications here. This installed the first two stereocenteres, and allows the group to to a futher, diastereocontrolled Michael addition into a vinylphosphonate. The intermediate produced is then perfectly set to do a ring-closing HWE, completing the cyclohexene. This approach is particularly neat, as most previous routes used Diels-Alder chemistry to install the ring, and then upwards of ten steps to functionalise the ring; as we see later, Hayashi is already imparted most of it. However, a flaw is evident; a mixture of diastereoisomers was produced a the C-5 center, bearing the nitro group. Neither acid nor base epimerisation was entirely succsessful, but heating the with toluene thiol and a spot of pot-carb (still present) did the job. This also ‘protected’ the alkene by Michael addition of toluene thiol, completing the first of the ‘one pot’ operations.

Next up is selective acidic deprotection of the t-butyl ester, formation of the acid chloride, displacement with azide and finally Curtius rearrangement and amide formation. Neatly done in one pot, but the use of azides is perhaps a drawback. Completion of the synthesis then only required reduction of the nitro group (using in-situ generated HCl with zinc), then elimination of the thiol to finish the target. This involved passing ammonia gas through the reaction mixture, generating a Zn(II)-ammonia complex (is that just to remove the zinc, or is it providing an active metal complex?), then retro-Michael.

Damn nice work; I’ve been picking though the experimental, and there’s really not much in the way of an industrial scale up of this synthesis that isn’t present in the main text (like the azide, and possibly the use of toluene thiol). Whether we need another synthesis that can be scaled is another story… resistance to Tamiflu is yet another… but lets just start 2009 with a cracking bit of synthesis.

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27 Comments

  • earth23 says:

    Concise, innovative, straight-forward. Fantastic paper, good thing Angewandte picked it up.

  • Cat Herder says:

    Have there been reports of Tamiflu resistance? This synthesis is fantastic, and I don’t think the azide problem is necessarily that big of a deal. However, I wouldn’t want to be anywhere near a plant running the thiol part of the scheme…

  • clm says:

    The thiol part might not be that stinky, as tolyl thiol is not very volatile (bp = 195 oC).

  • anon says:

    It would have been best route had it not involved that stinking thiol protection, and then deprotection……it would not have saved 2 steps, but also headache.

  • Cat Herder says:

    The problem with thiols is usually that they have extremely low odor thresholds (in some cases ppb levels can be detected by the human nose). So even if they aren’t very volatile, you still notice their presence.

  • LW says:

    This is a really, really good paper- better than Shibasaki’s route with that Diels Alder with his FUJICAPO business on the same ASAP’s page. I too am glad that ACIEE got this one as opposed to JACS. Let’s see how much further they can drag themselves into crappiness this year.

  • LW says:

    Does it matter it’s isolated as the free base? Can’t you just titrate it with phosphoric acid?

  • BOB says:

    This was a nice paper, puts many a previous synthesis to shame. My only criticism is that the starting aldehyde and nitro olefin are not commercially available, so it’s not quite a three pot synthesis.

    It also made me wonder about what the actual definition of a synthetic step is. I usually use the term synonymously with a one-pot prep followed by purification (so I would have referred to this as a three step synthesis). I would never refer to an aldol reaction as two steps, even if you preform a lithium enolate and then add an aldehyde. This paper takes this to the extreme (and I would argue its much more efficient as a result (most of the solvents and waste in doing chemistry is often in the workup/purification phase so fewer w/o = more efficient).

    I would be curious if most people out there agree or disagree with my definition. If not where do you draw the line?

  • mevans says:

    BOB–can’t blame Hayashi for being conservative with his definition of “synthetic step” in this paper. I have a feeling he would’ve been a little bit looser with the definition had the synthesis been longer. :-)

    For me personally, I think it’s easier to organize things mentally to think of “synthetic step” as synonymous with “chemical reaction,” even if multiple reactions are done in one pot.

  • Liquidcarbon says:

    Sweet!

    Aromatic thiols are not as bad as aliphatic, although I don’t mind mercaptoethanol. As long as this biodude down the hall won’t spill it all over himself and start wandering around.

  • Tot. Syn. says:

    Awesome – love the definition ‘Biodude’!! I gotta use that with our entire biology section here.

    As for definitions of reactions vs. steps, I’ve always gone with ‘step’ as the broader definition, i.e. an aldol as one step. If reaction and step are synomynous, then we need another term to describe the bit between ‘sticking stuff in a flask’ and ‘adding water a bit too fast and wondering if it’ll all stay in the pot’.

    Then one needs to define the terminal process in ‘step’. I reckon evapourating (or concentrating) is probably okay, but and extraction, filtration or chromatography are concluding points. I’m not mentioning names, but I know several professors whose definitions are a lot looser than mine…

  • LW says:

    A lot of the organocatalytic boys do quite well to sell their work. It’s almost like a commercial business now. What looks like a ‘one pot synthesis’ indeed involves ‘pronucleophiles’ or electrophiles in their reactions that are, to be frank, are quite a bitch to make. Obviously, you won’t know how much of a nightmare it must be to make them until you read their supplementary information. Nevertheless, this is STILL a good synthesis.

  • BOB says:

    @ Tot. Syn. – I always think of a step ending whenever you do a purification (aqueous w/o, chromatography, filtration). I wouldn’t count a solvent switch.

    For a reaction with multiple steps in the same pot I would go with operations or stages. So the final step for Tamiflu contained 6 synthetic operations. The problem with using ’6 steps’ to describe this is that it gives me a very different perception. 6 steps (like I count them) might be a week of work, but 6 stages in one step might be done before lunch.

    @ LW – I have read though the SI pretty carefully: there is the issue of the starting materials (which is a bit arbitrary – you can buy plenty of more complicated things just because there is demand for them or because they are a side product from some larger process). But otherwise, I was happy to see that nothing funny went on in the main steps. I was worried there would be a plug of silica or aqueous workup that somehow didn’t count, but there wasn’t any salesmanship here, at least not that I found. The synthesis is so damn short that I am tempted to reproduce it myself.

  • The Next Phil Baran says:

    I guess the only way to ameliorate this situation is to not describe the number of steps, or reactions, but to describe the number of isolations performed by the researcher. These are not only the most time consuming aspects of synthetic chemistry, but also one of the most expensive aspects when it is extrapolated to an industrial scale. The problem with this idea is that not all isolations are equivalent, i.e. simple solvent evaporation vs. extraction vs. flash chromatography. The definition of a step by dictionary.com is: a move, act, or proceeding, as toward some end or in the general course of some action; stage, measure, or period, which to me is equivalent to a reaction, therefore, every reaction should be considered a step, even if it is one-pot. This would emphasis the importance of an isolation of product as the limiting factor in a synthesis. Industry is lucky in that it does have a grading system for efficiency, i.e. money, which synthesis as a theoretical/academic pursuit does not.

  • just another chemist says:

    There is a paper that describes the “intricacy” of an organic synthesis by Fuchs in Tetrahedron 2001.

    doi: 10.1016/S0040-4020(01)00474-4

    It’s explanation is a bit more complicated but takes into account starting material, synthetic steps, purifications and more.

    ed: I’ve fixed the link

  • just another chemist says:

    Sorry I linked the paper wrong

    doi:10.1016/S0040-4020(01)00474-4

    Here is the reference too

    Tetrahedron Volume 57, Issue 32, 6 August 2001, Pages 6855-6875

  • LW says:

    Well thank god people are (sort of) in agreement here. Been looking at a bit of Hayashi work…he’s pretty good. Shame he got beaten in the race for a nature paper by List.

    It’s nice to see people in some sort of unison here….new to all this here, but it seems you all love a catfight!

  • milkshake says:

    I think they can do even more steps one-pot: once you form acyl chloride you can just add 1 equiv of TMSN3 to it without any base, acylazide and Curtius take place under very mild and anhydrous conditions. TMS azide is non-explosive but it is quite easy to poison yourself with it.

  • Andrew says:

    The first step of scheme 2 – I am not a very synthetic chemist, so could anyone explain: is that so simple to hydrolize tBu-ester with TFA/DCM leaving other esters (like ethyl in this case or maybe methyl in some other) intact?

  • BOB says:

    I like milkshake’s idea, the sodium azide would probably be the biggest concern of a process chemist who needed to scale this up. I don’t know if TMSN3 is safer? At the least you would want to switch from DCM to toluene for the first two stages of the second step. DCM and azide is a very bad combination, see below…

    Org. Process Res. Dev., 2008, 12 (6), pp 1285–1286
    DOI: 10.1021/op8000977

  • HPCC says:

    Andrew: tert-butyl esters will be selectively converted to the acid, because in the presence of TFA, it “magically” generates a t-butyl cation, something an ethyl or methyl ester is much less capable of doing.

  • Pilky01 says:

    This is a pretty awesome syntheisis in my opinion. I love to see efficiency and I hope to see more papers like this in the future. I think that getting everything going in one pot and just timing the various operations is excellent.

    Do you think they tried it on a 5-10g scale and failed or do you think they didnt bother?

  • LW says:

    tbutyl cations are stable species because of the electron push from the 3 methyl groups to stabilise the delta positive charge. innit

  • LW says:

    scheister- sorry hpcc didnt see that post

  • stork naked says:

    Getting caught up in the number isolations or having a pseudo-scientific debate as to how many steps this synthesis took detracts from the quality of the work. This is a very creative synthesis and people who concoct detractions to it are only being petty.

  • Qitao Tan says:

    I like it. Concise, effective and creactive.