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22 March 2009 18,739 views 55 Comments


Isobe, Hamajima. ACIEE, 2009, EarlyView. DOI: 10.1002/anie.200805996. Article PDF Supporting Information Group Website

Also: 10.1055/s-2004-817769 , 10.1021/jo980088n , 10.1021/jo034021y, 10.1021/ol0600741 , 10.1016/j.tet.2007.03.012 , 10.1016/S0040-4020(03)00873-1, 10.1016/S0040-4020(02)00044-3… and many more.

As you can perhaps tell by the doi listings, this synthesis has been ongoing for quite some time.  And figuring out what was done, when, and how they did it has taken the best part of five hours now – the literature trail is like a tape worm, and as transparent as London tap water…  This seems to be a common theme for syntheses of marine polyethers, as Crimmin’s synthesis of brevetoxin earlier this year also demonstrates.  However, I’ve done my best to figure this one out, and here’s what I reckon is a full retrosynthesis.


Right, so the key disconnection is down the middle of the F-ring, splitting it into two similar sized fragments.  This is done about the F-G junction, so the G ring goes in at the same time, using an alkynylation to link them.  Then the F ring was installed by Co-complex displacement of an alcohol, then the dissubstituted acetylene was oxidised by removal of a cobalt complex formed earlier.  The G ring was then closed onto the resulting ketone, and the initial hemiketal reduced with BF3.OEt2 / Et3SiH.

There’s a bit of an actual disconnect here, as I’ve no idea how the E ring was installed.  One of the papers describes the synthesis of an E’FGH system, but the E’ ring described is the 6-membered analogue.  And they buy it in.  Moving on a bit, the D ring was created using the same approach mentioned earlier – alkynylation, Co-complex formation, followed by displacement of a propargyl alcohol.  This brings the fragment back to a fused bis-pyran, and to more familiar strategies.  (An oxidative cyclisation formed the C ring as a hemiketal, with BF3.OEt2 / Et3SiH used to reduce again).  Eventually, this brings us back to the SM, methyl-alpha-D-glucoside.


The other large fragment is a more lengthy synthesis, as befits it’s more complex nature (more medium rings…).  Formation of the H ring is done late-stage, through a particularly neat 1,4-addition.  Prior to that, an asymmetric delivery of hydrogen to an exocyclic methylene on the I ring imparts the methyl stereocenter, with formation of the ring done using Co complexes as before.  Union of the two (quite unequally sized) pieces was done using a Sonogashira coupling.


I’m not sure how they get from the starting material (a DHP) to the material show – they reference a previous paper, but I can’t find the actual steps used for this anywhere.  Any ideas where it’s detailed?


The other piece is far better documented, with a typical spiroketalisaiton used to put in the L, M system in, using a SAD to install a glycol on the medium ring.  That ring was build using the now over-familiar Co complex approach, again unifying similar sized chunks with acetylene chemistry.  Taking the synthesis right-back to the starting material, however, unearths a flaw, in that elaboration of the sugar derivatives is far from efficient.  Take the left-handside, a pyran evolved from a methyl alpha-D-glucopyranoside derivative – twenty one steps are required to get to it’s retrosynthetic parent.  Urgh.  However, as they start 1.2 kg, I guess they get the material through…


I want to write more about this synthesis – afterall, even though it’s enormously inefficient, it’s an epic feat.  I’ll put on a bit of mechanistic action about the Co chemistry, and perhaps some of the couplings, but I’d like to have readers input on this one, as it’s quite a task.  What do you like /dislike about this synthesis?

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  • The Dutchess says:

    The drawings look like a millipede… Although that doesn’t answer your question…

  • OZ says:

    Fantastic post Paul. I appreciate the effort.

  • UBChem says:

    I’m sorry to do this, but WHY? In the times of impossible funding lines and departments being closed, why attempt these molecules anymore? Yes they are freaking sweet and I give all the credit to the researchers for their time and effort, but really what is gained from this and many syntheses like it?

  • ,,, says:

    Retrosynthetic.com :)

  • InfMP says:

    thanks so much for going back and piecing it together.

    I saw one author and was freaking out thinking he did the whole thing. however, seeing as he starts with 76mg and manages to use that amount of material to finish sucessfully, its super impressive. who knows how much time it would take to remake that 76mg if he had run out…..

    I wish they had just waited and published it all in one.

  • milkshake says:

    working on a synthesis like this one, the first ten years are the most difficult but then one get used to it.

  • Interested says:

    Whoa! I can’t believe you spent the time putting this post together! Impressive bit of chemistry, but not my cup of tea. Thanks for the effort (both the ciguatoxin researchers, and Paul)!

  • optional says:

    0.4 mg of the final compound. Wow! Thats the last digit of our balance. But you have to have the dexterity to manipulate such amounts of a solid compound. Only people who use chopsticks to pick up rice grains will have that kind of hand eye coordination :)

  • Giagan says:

    Who is Crimmin?

  • UBChem says:

    Glagan… I hope you’re being facetious.

  • Azo says:

    This is a pretty amazing feat of human ingenuity, but what I want to know is how a) you can manage to do NMR on 0.4 mg of compound (according to optional that’s how much they made, although SI says 0.1 mg) and b) be so confident on their assignment with no 2D NMR to help out. The synthetic work I do is organometallic, usually making several 10s or 100s mg so I don’t have this problem, how do you do it on something so complex, is it just comparison to the natural NMR and if so what about the intermediates?

    Also is that really a Sonogashira halfway through?


    • Alex says:

      For small amounts of material, a Shigemi NMR tube is the way to go. The NMR tube has the same magnetic susceptibility as the NMR solvent and there is a glass plunger that is inserted into the NMR tube so that the solvent does not extend above and below the receiver coil in the NMR machine. This minimizes the solvent volume and maximized concentration. As for the final structure, that is indeed done through NMR comparison with an authentic sample. For certain compounds this can be tedious as shifts can be dependent on concentration and trace acid/base for certain classes of compounds. In my own experience, the structures of advanced intermediates are often assigned by analogy to model systems/ earlier intermediates in the expectation that you have not had an unexpected epimierization. Proof by synthesis of the natural product is generally taken as proof of the intermediate structures ( though there are undoubtedely cases out there where undetected epimerizations that lateer re-epimerized occured, or silyl groups migrated that were rendered inconsequential in the final global deprotection.

    • Tot. Syn. says:

      Alex is right that a Shigemi NMR tube, or other similar apparatus can help with NMR, but these days the NMR machine can actually do a lot of the work. A lot of departments (and companies) now have CryoProbe NMR machines, which are capable of decent spectra with fewer scans (and therefore less time). They do this by chilling the probe with liquid helium, which reduces the amount of thermal noise, and increases the signal-to-noise ratio. In my hands, this meant that a 15-20mg sample was able to give a spanking carbon-13 in five minutes, so I guess it would be quite easy to get a proton of half-a-mg.


      Even before CryoProbe machines, it was possible to get NMRs on vanishing quantities – I remember my PhD supervisor working on 1mg for several steps… In some respects, it’s a good amount to work on – easy to vac down, no point in using a balance to weigh the product (just use the signal gain on the NMR machine to estimate yield), good excuse not to run elemental analyses. However, if some thieving bastard steals the NMR tube from the carousel…

      • Azo says:

        Thanks Tot. Syn. I’ve had tubes taken off our carousels too – now if it’s important I use our hands-on machine and shim it myself, might have to wait a while to get on but at least you know where the sample is! I think I’m too clumsy to trust myself to work on such small scales. 13-C in 5 minutes is nice too :D I would guess we probably do have CryoProbes, or the Varian equivalent, on our higher field service machines, but I tend to stick to the 400 MHz as it’s good enough for what I need, so maybe I need to investigate those if I need it when I start my PhD. Cheers for the info.

  • ... says:


    Crimmins is a pretty big fish in organic synthesis. He’s completed a lot of ladder polyethers similar to ciguatoxin. He also invented a chiral auxiliary similar to Evans but with the oxygens swapped out for sulfur. He’s at the University of North Carolina.

    • Seen it before says:

      Crimmins did not ‘invent’ oxazolidine-2-thiones and thiazolidine-2-thiones. They were first reported as an alternative to the Evans’ oxazolidinones by Nagao in the 1980s. It’s ancient history for those born then I guess!

  • Azo says:

    OK so I actually looked at the paper, I see how the Sonogashira is working, sorry ignore the stupid inorg chemist needing every step :)

  • BOB says:

    @ Tot Syn – The thing I like about this synthesis is that they developed a fresh approach to the molecule (the cobalt induced cyclizations). If you do another post about this molecule talk more about that.

  • The Next Phil Baran says:


  • John Wood says:

    @ Baran

    I enjoy alkaloids much more, atleast for now, maybe ill turn on them someday :/, so i kinda sorta am not interested either.

  • ,,, says:

    It doesn’t seem like 20 mg of sample needs a cryoprobe – takes me about 50-100 scans (5-10 minutes or so) for a very nice carbon NMR on a 250-450 g/mol cmpnd…

  • Martyn says:

    So, what are people’s first impressions of Nature Chemistry? Can anyone explain the point of the ‘wired universe’ paper?

  • Giagan says:

    UBChem, …,

    I know very well who *Crimmins* is. His silphinene synthesis is one of my all-time favorites.

    I just can’t seem to pin down this Crimmin fellow.

  • InfMP says:

    I’m surprised no one mentioned this when discussing 0.1 mg. how do you get a 1H? 6144 scans!!! wow!
    When you write the next one, can you cover the protection of alkynes with cobalt? This is something I heard about 3 years ago, but I never came across it…what are the seminal references?

    • Tok says:

      As well as the examples in the replies above, you can use a microprobe. You dissolve your sample in ~50ul rather than 700ul and can get very high s/n on vanishingly small samples. I’m not sure if a microcryoprobe exists, but I can imagine that would be even better.

    • antiaromatic says:

      For even more info on this topic, check out this paper:


  • Gilgerto says:


    You can look at the Nicholas reaction, it might be a good start.

  • InfMP says:

    awesome. named reactions book. thanks

  • Pete says:

    I am surprised to see that UBChem among others are lost when it comes to the educational value/impact of a synthesis of this magnitude. Surely the various routes attempted and/or in depth chemistry discussions throughout the ten year synthetic period are worth something!

  • bill says:


  • InfMP says:

    i agree. the reason i was drawn to total synthesis is the amazment. what a struggle. years of work by many people to make an almost invisible quantity of material as the ultimate prize. I am all about the biggest molecules. Knowing how challenging things are a few steps in when things start going wrong and known reactions don’t work, it’s insane that this can be done.
    I know people hate maitotoxin, but i hope that it gets finished during my lifetime!

  • LW says:

    yeah you have to give plaudits to these steady handed guys and girls…. i personally wouldn’t be able to do it with my patience, or lack of. its just too tedious!

    There has been a massive debate about whether syntheses like these are worthy or not. Perhaps not in the sense that in making these molecules we are just showcasing, just like woodward and robinson were doing years back, that man can make anything with the tools we have. it’s been done, we know we can make anything now, woodward eschenmoser proved that with vit b12. however, i guess the training the phd students get on these projects allows them , i hope, to give something back to society. ok, i guess its still not fully justified ( it is quarter past one and i have 2 meetings from 9 tmrw to prepare for). now that we have the tools do nearly do anything we want, how about we really make a massive effort to actually do something feasible that will help society eh? one thing that really is getting a bit worrying is that with the credit crunch and all that, the research councils are seeming to only want to fund projects with ‘guaranteed’ research……is a project that is full-proof worth funding if you know whats going to happen? should we not be giving funding to ambitious projects where if a referee looks at it and thinks ‘bloody hell, is this guy insane? this sounds impossible!’ – do you see what im saying, or have i lost you all now? im halfway through my phd and i told myself that i will only stay in academia if i trully thought to myself i can come up with an idea that would be extremely ground breaking and where my peers would look at the work and say ‘yeah, this is amazing.’ i dont think i could handle knowing im just run of the mill, doing it for the sake of it. total synthesis is a no no. i think id have a guilt trip taking a multithousand pound grant to make milligram quantities of a natural product because it has an interesting architecture or some lame thing like that. id say just as bad as a city banker. haha. sorry rant over

    going off the topic. gaunt paper in science on Cu meta SEAr? surely this is merely jacs/aciee worthy is it not? im suprised to be frank!

  • HPCC says:

    I am barely into my thirties. Yet, when I see people write the way the previous two commentators did, that is, without capitalis(z)ation, I get a headache trying to read the seemingly fuse paragraph. Seriously, call me outdated, but there are reasons for capital letters and punctuation. For one, they help the reader pace her/himself through the paragraph. And call me a nitpicker, but, with the use of proper capitalis(z)ation, someone who is not 100% familiar with the English language would not have to look up the dictionary to figure out the ‘gaunt’ paper is written by author Matt Gaunt, ‘gaunt’ not being some obscure adjective or whatever.

    Again, call me outdated, and what not. I will take it all. Cheers guys!

    • LW says:

      i totally agree with you. i even write emails to my supervisor like this, which i must confess is really, really, really bad. my capitalis(z)ation, punctuation and grammer has a lot to be desired of. i can assure you that when i write up my thesis i’ll familiarise myself with the shift+F7 button on MS word and the dictionary. let me assure you it’s usually when i’m lying in my bed with my awful laptop or when i’m drunk.

      However, I guess I could stop being lazy from this sentence onwards. You, my friend, may have just changed my life.

      Anyways, off the topic (if I may), reading this paper again and looking at that cobalt octacarbonyl complex got me thinking about the Pauson-Khand reaction. Does anyone know any decent references that might be good to look at with respect to the catalytic variant? I still haven’t got my head around the Co chemistry in this paper though….help

  • ch3mical says:

    but, but, truly…

  • Ian says:

    Agree with HPCC.

    Text speak/poor grammar is the spawn of Satan.

    Re: Gaunt’s paper, flipping the ortho/para selectivity is superb…how often does a paper come along that gives the middle finger to what we all learnt in undergrad?

    • HPCC says:

      Ian: it might definitely belong to MSN chats, since you typically only type one sentence. But on this blog, it makes me dizzier than Kingfisher strong beer! :)

  • Ian says:

    HPCC: It belongs nowhere, young or old. It is worrying that a blog aimed at doctoral level crganic chemists struggles with such fundamental spelling and grammar.

  • Pete says:

    After sifting through LW’s comment, I must add that I fundamentally disagree with the notion that we, as organic chemists, have the tools to make any molecule or that synthesizing any molecule has simply been reduced to engineering, patience and/or hard working/time. See ‘The Way of Synthesis’ chapter(s) 1-2 for a further discussion on this.

  • Jose says:

    I’d put forth Kishi’s palytoxin for the prize of the most scattered, convoluted, published-yet-not-really synthesis.

    • Hap says:

      I have no idea where any coherent version of that thing exists. Hudlicky has the best description of it I’ve seen, but I don’t know where he got his data from. I think I found the Chemica Scripta reference, and it was…incomplete. JACS papers with forty-carbon fragments don’t help much, either.

      I appreciate the work in describing this thing though. Do the authors realize or care that the syntheses of massive fragments should not be considered “an exercise for the reader”?

    • paul says:

      @Jose : Can you explain your thought please ?

      • Hap says:

        The references for the synthesis that I know of (the JACS paper where thallium hydroxide is used as a Suzuki coupling promoter, and the Chemica Scripta paper that Corey’s Logic of Chemical Synthesis uses as its reference for the synthesis are incomplete – they couple large fragments whose origin is not clear. If someone reports a coupling of two forty-carbon fragments in a total synthesis, you would really like to know where they came from, and in palytoxin’s case, I don’t know anywhere that actually explains.

        It’s like replaying a game of Civilization where all you see is a civilization with battleships, tanks, and nukes conquer the world – hat’s great, but how did you get them? A research paper (particularly for a landmark synthesis such as palytoxin) should tell the complete story (at least that part of it that led to its synthesis) and not just the ending.

        • Tot. Syn. says:

          Agreed, and +2 respect for the civilisation reference! I’m not sure how all-encompassing Civ is in terms of popular culture, but damn, I’ve spent more time playing Civ 4 than even this blog! Pulling advanced fragments out of nowhere defeats the purpose of the literature, and reduces it to a bragging ‘cock measurement’ exercise (chickens, obviously…). Playing ‘find the key reference’ isn’t a fun game.

          Oh, and I’m working on another post; should have it done tomorrow. It’s been a busy week(end)… New F1 season getting in the way!

  • kasperl says:

    Maybe I am missing a lot here, but just judging from the date that the final NMR was recorded (07/10/2000) what took them 8 years to publish it? Or was there just a little date error on the NMR machine?
    Otherwise good post and thanks for your effort!

  • Jose says:

    The two bigger papers out there on palytoxin, JACS, 111, 7530 (1989) and JACS 116, 11205 (1994) are total clusterF****, and reference fragments from a long series of TetLets, JACS notes, and a million other scattered pubs. Trying to piece it all together is insane. Although it is in one of the KCN books, right?

    • paul says:

      @Jose : yeah maybe but it doesn’t mean Kishi did not finish the target… This has nothing in common with hexacyclinol for example… We should give more respect to our elders in Chemistry, and enjoy their chemistry instead of throwing them some thiophenol…

  • The Next Phil Baran says:

    I guess the problem with synthesis is the assumption that it is a sum of its parts, it is not. When applying reactions to these large molecules the chemist is learning about the effect of topography and long distance “NGP”, or chemoselectivity. There has been less focus on collecting similar accounts of “strange” reactivity when simple reactions, which work in simple systems, do not work, or do not give the expected products in larger systems. We do need to study reactions int he context of larger systems but we tend to assume that these are one-shot examples and have no context. The problem is most of these reactions could be studied on systems without as much baggage (such as reduction of 3,3-dimethyl cyclopentanone, which does not occur readily). I guess sometimes the rest of the molecule does affect a particular reaction center but most times they are just too far from the action. And big molecules such as Ciguatoxin are not very good starting points for studying this considering the time constraints on a ph.d student. The only interesting part of any synthesis is the methodology (the only general aspect of these publications) used to make it, however this is brushed over too often by our community. These molecules are a one-shot deal most times and rarely does anyone ponder the generality of the reactions they use. This is pointless and not helpful to anyone. We need more context in our studies and our delivery of information, otherwise it is just random facts about one particular that may or may not be applied elsewhere. We are supposed to be interested in all reactivity of carbon not particular aspects of it. An astronomer would not get very far just studying the sun!

  • Jose says:

    In no way was I questioning Kishi’s science or integrity! I just believe a landmark synthesis deserves a full and complete paper to serve as a record for such staggering research. A trail of scattered letters just doesn’t cut it.

    • paul says:

      I agree with you on this, Jose ! I may misunderstand (not speaking about Jose, but a general feeling) but I am tired of seeing people shooting at sight on elders : that’s again Corey or Kishi blahblah… Chemistry is such a jalous world… :-(

      We should be capable of saying : “Wow ! That is a cool synthesis” without back thoughts ! /-)