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Ciguatoxin   

10 July 2006 54,663 views 27 Comments

Ciguatoxin1.jpg

Hirama, Inoue, Miyazaki, Ishihara, Tatami, Ohnuma, Kawada, Komano, Yamashita, Lee, and Masahiro . JACS, 2006, ASAP. DOI: 10.1021/ja063041p.

We’re back!! And with a tasty number to start the week with. Or rather not that tasty at all, what with the toxicity of this beast! Originally isolated from four metric tonnes of Moray Eels, at least the eels can breath a sigh of relief that Hirama et al. have finished their total synthesis of Ciguatoxin and its 51-HydroxyCTX3C analogue. Most of the ground work for this synthesis has been published already, including the synthesis of the main fragments, constituting their synthesis of CTX3C.

Ciguatoxin_2.jpg

Starting with the pair of fragments shown above, they formed the S,O acetal directly, and then used that to create the G-ring using an interesting radical cyclisation, which, by using the the correct “protecting group” they were able to derive the correct stereochemistry.

Ciguatoxin_1.jpg

This then set them up for a final RCM to make the 9-member ring-F, and completion of the molecule. Interestingly, they have used the NAP protecting group throughout this project, which seems to be easily removed with DDQ. I’m not sure I’ve seen it used before, but it’s certainly seems useful.

Ciguatoxin_3.jpg

So, a massive effort, and a slightly difficult to read paper (that main scheme is busy); perhaps the eels can sleep easy tonight…

Update: Derek Lowe has a great piece on his blog about the isolation of ciguatoxin.

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27 Comments

  • ochemist says:

    nice synthesis,
    i heard that KCN is trying to sythesize Maitotoxin

  • Tot. Syn. says:

    Bloody hell! I don’t fancy that one at all! A pic of it can be found here:

    http://ja.wikipedia.org/wiki/%E7%94%BB%E5%83%8F:%E6%A7%8B%E9%80%A0%E5%BC%8F_Maitotoxin.PNG

    Is that bigger than Palyotoxin ( http://homepages.gac.edu/~bobrien/OrganicII/palytoxin.gif )? I ain’t redrawing those buggers (again…).

  • ddd says:

    all this stuff is a HUGE waste of money and people’s time

  • secret milkshake says:

    maitotoxin is going to be a piece of cake – there is a good disconnection point right in the middle of the molecule.

    Btw., I heard that even partialy protected fragments of these molecules are pretty potent and that some Kishi students were repeatedly carried out of their lab on a stretcher.

  • Tot. Syn. says:

    I can believe that. My natural product is damn potent – lets just say you’ve got some floating around in you just now – and I’m quite concerned about at what point the ass-kickity activity is going to kick in.
    I’ve got to be honest, though, maitotoxin is a massive waste of time. You all know I think natural products kick-ass, but you’ve got to learn something on the way to making them. I don’t see what’ll be learnt that wasn’t making brevetoxin. But we don’t know the grand plan, so perhaps there’ll be some cool stuff in there. We know two things for certain, though:

    1. It’s gonna be nasty to work with. As Secret Milkshake suggested, a lot of the fragments are gonna be seriously evil.
    2. This one’s going to need the entirity of “Classics In Total Synthesis, 3″

  • ddd says:

    Not classicS…just maytotoxin alone is enough to write a book named “classic in total synthesis” haha

    as of point 1. we shoudl then expect that size of KC’s group will decrease dramatically :)))))

    I agree with the point of brevitoxin vs maytotoxin. Just adding 20 damn additional pyran rings will not make you learn anything

  • Vince says:

    Once Maitotoxin is made and they want to publish, KCN will require 32 different colours for filling each and every ring present in the molecule. If I were epileptic, I would sure have seizures reading that paper.

  • ddd says:

    oh yeah, massively irritating colours as well as his homepage. Same way he does his presentations…Strategy similar to celebrity, how do we know janet Jackson…Yeah she had that case on ABC, after which they broadcast 10 sec late…

  • Klug says:

    Does anyone know how the myriad Japanese groups that do marine polyether total synthesis justify their funding? Is it the standard ‘potent biological tool’-type stuff?

  • ddd says:

    I have no idea, I saw Yoshinori Yamamoto when he came to our school. He said that “here is poisonous compound, trace amount was isolated, “very potent biological activity” we need to make more for biological studies, and we want to do SAR….

    I thnk it is just a regular bull shit

  • TPG says:

    KCN started working on maitotoxin 10+ years ago. Last I heard, they had all of the fragments and just needed to figure a way to put it together, though the grad student who was working on it jumped ship and the project has been in limbo for a couple of years now. KC just needs to convince a first year to take it up again and then give him a team of post docs, though I think its pretty doubtful.

  • Tot. Syn. says:

    I’m just not convinced that is the right way to work – I don’t understand why he would have a 1st year Ph. D student responsible for some of the most complex steps, and some well-trained and experienced post-docs bringing-through material. Is it beacuse the Ph. D student will be there for longer (it’s five years in the US, right?), and will have a better handle on the project towards the end?

  • TPG says:

    The 1st year wouldn’t work on the frontier at first but would ease into that role as they became more skilled in the lab, if they were fresh out of undergrad. A small percentage of new grad students already have a masters or several years of industrial experience before they start and such a person could work at the frontier sooner. The time issue is a major factor, large projects such as that are better assigned to starting or early year grad students since it better preserves the continuity.

  • ciguatera says:

    In response to Klug, there really are several reasons for examining (through synthesis) these compounds: First, there is a need for the development of an assay for ciguatera, the food poisoning event that come from eating fish that have ingested algae that make compounds like ciguatoxin. It’s probably clear why the Japanese are so interested in this area. Second, these compounds bind (often selectively) to ion channels (mostly voltage gated sodium channels but other channels as well) at a different site than other toxins making them another tool to better understand ion channel biology. In response to DDD, the compounds being synthesized are being tested. Third, the algae that make these compounds do not make much of them and obviously can’t make potentially important analogs. Efforts aimed at fermentation have been largely unsuccessful so far. This isn’t to say that fermentation won’t be a viable route to the natural product in the future. Finally, as with most total synthesis efforts, work in this area really pushes the frontier in terms of what synthesis can accomplish. In contrast to some of the comments on this blog, I guess that I don’t think that everything has been accomplished in this area.

  • ddd says:

    to ciguatera:

    what else are you going to learn from maitotoxin synth. OTHER from what you have learnt from brevitoxin synth?

    do not tell me KC will not be using RCM or oxonium ions in his maitotoxin synthesis….

  • ciguatera says:

    DDD:
    I’m sorry for the confusion, I wasn’t referring to maitotoxin but to other simpler members of the family. Although I know that maitotoxin was a target at one time, I am not aware that it is still on KC’s plate. As to what will be learned: I feel fortunate that synthesis (and science in general) is still mostly empirical-it is beyond my humble abilities to accurately predict what will come from any synthetic efforts.

  • fissl says:

    To my knowledge (referring to a talk, I heard some time ago), they use NAP groups, because they had problems in global deprotecting benzyls. So they (just) synthesised everything again with NAP groups.

  • Tot. Syn. says:

    Thats not the first time I’ve heard of that situation… and it won’t be the last! It must be a real b*stard to get to the end of your synthesis and be unable to deprotect… seems to happen pretty often. That’s why we have DMB et c.

  • Tot. Syn. says:

    Ciguatera:

    Can we really say that research in any area is complete? Afterall, in the late 19th century, most physicists believe their work was almost done, just a few loose ends to tie up… and then quantum theory and relativity unraveled the science entirely.
    Sure, some cool stuff will come out of a synthesis of maitotoxin. But do the ends justify the means? We’re talking about serious man-hours here, and a lot of academic funding. Sure, the project will train a load of chemists, and the field will move on, but aren’t there more pressing targets? I realise, however, that this is now a matter of opinion… so I won’t press mine any further.

  • Klug says:

    Ciguatera: I was aware of the 2nd reason, but not the first. Thanks for the new knowledge.

    I asked the question because it seems that the sheer number of papers from Japanese groups towards these molecules point to a non-’fundamental science’ reason.

  • secret milkshake says:

    A funny deprotection story: A guy in Prague was working on a complicated aminotrisacharide for about a year (I think it was a part of some antibiotics, if I remember correctly). He got everything assembled except for an azide reduction and 4 benzyl groups. But 2 of the benzyls liked to stay in his molecule no matter how hard he hydrogenated. He tried dissolved metal reduction, oxidation, what not and nothing worked – until he tried PtO2. Next day he came and started asking: “Say, how do you cleave cyclohexylmethyl group?”

    • fanofkcn says:

      For the question “How do you cleave cyclohexylmethyl group?”
      The answer is simple. Cyclohexylmethyl group will be cleaved by NaH under oxidative condition.

  • Tot. Syn. says:

    And then there’s the times where your protecting groups leap-off the molecule for no apparent reason. I recently lost a TBS group to catechol-borane. Huh? And also the lies perpetrated about deprotections. Ever tried to remove a benzyl/PMB group with BCl3.DMS complex? It’s a nice reaction, very little faff, but the paper would have you believe it’s done in an hour with only a couple of eqs. Me? Four days and 12 eqs (I know that any oxygens in your SM need an extra eq, but still… and that was a hell of a quench!).

  • evgeny says:

    That is a pretty good story milkshake. I’m going to add it to my repertoire… with a bibliography of course.

  • WaltDe says:

    Very good reading. Peace until next time.
    WaltDe

  • Benz says:

    Does anyone know how to brominate the benzyl position of p-tolyldiphenylphosphine (a triarylphosphine)? I have tried this rxn umpteen times and low or no yield with NBS/CCl4, Br2/UV, La(OAc)3,/Br2, etc. Thanks