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Norhalichondrin B Pt. I   

16 February 2009 12,065 views 17 Comments


Phillips, Jackson, Henderson, Motoyoshi. ACIEE, 2009, EarlyView. DOI: 10.1002/anie.200806111. Article PDF Supporting Information Group Website

As I said in the last post, it was a rather quiet fortnight for total synthesis, at least as the big journals go.  However, I think Andy Phillips can feel justified in his absence when he’s been cooking molecules like this ‘un up.  Norhalichondrin B is part of the halichondrin family, isolated about twenty years ago – plenty of time for a bit of synthetic action, kicked off by Kishi back in ’92.  Impressively, the synthesis hasn’t been entirely academic, with the peeps at Eisai Pharma also working on analogues.  So how to start (lots of grant-application forms…)?   Retro time:


The bulk of the fragment couplings are shown above, but there’s a hell of a lot of work before we get there.  Phillips’ route to even the smallest fragments is remarkably interesting, starting with that of the left-hand-side pyranopyran.  Beginning with a diazobutenoate and a chiral auxiliary, a bit of rhodium caused insertion into furan, resulting in the rather interesting bicycle.  This chemistry was developed by Huw Davies back in ’96, and is apparently better suited to this synthesis than Phillip’s own ideas.  A few functional-group beating steps (methanolysis, Curtius rearrangement, reduction and acetal formation) left them set to do a bit of RORCAM (ring-opening-ring-closing-alkene-metathesis).


Next up is a bit more diazo chemistry, using a chiral ?-hydroxy ketone (asymmetry installed using a Noyori hydrogenation).  Treatment with copper ack-ack lead to a 2,3-sigmatropic rearrangement, building the THF in a cracking yield.  This works (unsurprising) by extrusion of nitrogen and then addition of the resulting carbene to the allylic ether.  This leaves an intermediate  oxonium ylide which rearranges to give the THF – more about this here.


A few steps further on (Wittig methylenation, hydroboration, oxidation), and the group were ready for a rather nice asymmetric NHK coupling, developed of course by the man himself.  The catch, of course, is the high loading of catalyst – half an equiv.  However, I’m sure the aniline / dihydrooxazole moiety is recoverable, so it’s probably not a disaster.  And the result is pretty sweet, allowing the two new stereocenters to be installed quickly, if only in moderate yield.  One thing I’ve been pondering, though, is the stereochemical control issues; the ‘catalyst’ imparts reagent control, whilst both substrates themselves apply induction.  The THF is probably the weaker factor, whilst the iodide is more complex with that ?-methyl.  Any thoughts?


Moving on to another fragment, we’re still dealing with furans, though in their more oxidised state.  Stereochemistry in this fragment was installed using addition of (-)-Ipc2-(E)-crotylborane into a furfural precursor; a Brown crotylation.  I think a lot of readers will know that particular named reaction, but the next was one I’d almost forgotten – an Achmatowicz oxidation.  This chemistry takes an ?-hydroxy furan and performs a stereoselective ring expanion by incorproating the hydroxyl stereocenter; however, the reagents used by Phillips seem slightly rarefied, so I’m not sure where these particular conditions originate from.  He does explain, though, that the immediate product is a pyranone
hemiacetal – this is then reduced in-situ using TFA-mediated ionic hydrogenation.  Nice yield, too…


Time to start unifying fragements, and a bit more from the top row of the periodic table (please Carol… btw, do undergrads at many universities still have to memorise the periodic table like I had to?  Top row was SCottish Television Cannot Make Films COncerning NIce CUte Zebras.  Not exactly poetic genius, but it sat in the mind rather well… thanks Jim).  In this case, a fairly-well prescedented domino reaction was used to perform the key NHK and mesylate displacement, building the pyran ring in exactly the same way Kishi did almost two decades ago.  If it works… and all that.


I’m going to pause here… and add a second post to finish the synthesis later this week.  Bloody awesome stuff, highlighting some superb modern chemistry.

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  • TH says:

    Mow that’s a nice piece of synthesis!

  • optional says:

    Does the final spiroacetalization give a thermodynamic control product?

  • Ondrugs says:

    “building the pyran ring in exactly the same way Kishi did almost two decades ago. If it works… and all that.” Why bother with new things then, if thats the strategy ;)

  • optional says:

    when can I see you again? when can my heart beat again? When does my sunday begin? cause all these things are not making sense!!!!
    so when can I see you (again)?

  • odum says:

    this is the next generation of synthesis?


  • Mike C says:

    Ondrugs: If you’ve ever seen Andy Phillips talk I think he explains their thinking on this sort of thing pretty well. They do lots of new things, but sometimes new isn’t better, and unlike lots of academic chemists he can admit that sometimes taking a page from someone else is the best approach.

  • Ondrugs says:

    It’s a grey zone, I agree in this synthesis, there are plenty of new contributions to the field of total synthesis, and it doesn’t stick out as much, but suddenly you could find yourself in a position in a project were more and more are just copy/paste. And how much new chemistry makes it OK to use another groups published key step. I am just putting it out there.

  • LW says:

    does jacs get stupidheads to referee its papers? spot the mistake


    • HPCC says:

      Easy, LOL, it’s highlighted in RED! *rolls on the floor in convulsing laugh*.

      Soon to be followed: the erratum. ;)

      • LW says:

        does the erratum count as another jacs paper? if so, its a nice way of bumping up the number of publications!

        • Mike says:

          What’s more, the erratum will cite the original paper… so you increase your citation count nicely as well.

  • LW says:

    oh another mistake. this time in nature-


    the picture of the ‘ribosome’ is actually a tRNA. what the hells going on?!

    refereeing is getting a bit sloppy. but the jacs one is unforgivable!

  • TWYI says:

    It says a lot about synthesis that this post can get 2000-odd views and only 12 posts, half of which are about a typo in an unrelated paper?

    Nothing jumps out whilst reading this in what was hundreds of thousands of dollars in chemicals/students..

    I hope to God they are getting this tested

  • chem says:

    TWYI – I think your comment indicates that you haven’t read the paper nor understood the contents of it. Eisai Pharma are putting halichondrin analogs on the market, so I think the testing part is pretty well covered, and this synthesis is significantly shorter than Kishi’s. I am sure the majority of readers haven’t commented as there is nothing in the paper to criticize – it is a beautifully executed piece of work.

  • bandit says:

    Well said Chem, a fantastic piece of work from Phillips and co. The sanctimonious paper-bashing on this website has become so relentless these days…

  • LW says:

    yep sorry for going off the topic earlier on. i agree, when i first saw this beast i thought is there in any point in making this for future manufacturing. but after reading the first part of the article pointing out that truncated analogues of this are being made by a pharma, then i think this total synthesis is very worthy. indeed, the molecule was (if i remember correctly) put together from four different fragments, so i guess they could play around more and make many more analogues merely by chopping off one of the four fragments etc. i think this paper is a rather refreshing total synthesis compared to some of the unnecessary bulls*it that gets churned out. im not a total synthesis chemist, but i do appreciate this badboy.

  • SK says:

    anyone knows which group is doing the total synthesis of BIELSCHOWSKYSIN