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9 March 2009 10,161 views 14 Comments


Morimoto, Okita, Kambara. ACIEE, 2009, EarlyView. DOI: 10.1002/anie.200805857. Article PDF Supporting Information Group Website

This isn’t the first poly-THF we’ve examined at Tot. Syn., but it is the most complex (see sylvaticin back in 2006 for the other example).  To the casual eye, the molecule looks deceptively symmetrical, but it isn’t.  In fact, only the two right-most THFs are alike, with the others differing in substitution, making the synthesis considerably more complex.  And to be frank, that’s the only reason we’re looking at it, as there doesn’t appear to be any biological activity.  More about the isolation of the compound and this family of laurencia targets can be seen in this Helvetica Chimica Acta, found bearing some rather familiar authors…


A look in that HCA (in fact you need only go as far as the title) indicates it’s relation to squalene, and a hint towards their synthesis.  However, rather than simply per-epoxidising squalene and letting the compound zip-up (which is probably what nature does), we chemists have to do be a bit more careful.  Morimoto’s retrosynthesis suggests that the three right-most THFs can be formed in a cascade, whilst the left-most could be derived from Hoye’s cyclisation.  This in turn results from more epoxidation, meaning that the tub of titanium isopropoxide and fructose required had better be big un’s.


Events are brought into motion by firstly selectively epoxidising the allylic alchol using Sharpless’s finger-licking good asymmetric epoxidation, then Shi’s fructose-DMDO thing to oxygenate the internal alkene.  The catch was that the Shi catalyst used is derived from L-fructose – the unnatural variety.  However, as pointed out ages ago on this blog, Shi has a rather nice prep of this catalyst from L-sorbose, which is thankfully the naturally available form.  I wonder if the lower d.r. in the Shi epoxidation is a result of a conflict between substrate and reagent control… it’s getting kinda close to the diol. Anyway, the group lobbed in a bit of base and went off to tea, fingers crossed that the cyclisation would go as before (actually, do Japanese groups go for tea?  I feel I should know more about the Japanese chemist’s life – seeing as Japan is the second-biggest audience for this blog).


It performed like a champ, returning the first THF ‘with high stereospecificity‘; actual numbers are somewhat absent.  Oxidation of the primary alcohol and methylenation gave a terminal olefin ready for metathesis to bolt on the other half of the molecule – all-set with three epoxides in place.  This one of those points where it’s worth going back over old territory, and mentioning just how awesome metathesis is – both halves of this reaction are rather sensative, and yet metathesis treats them like a gentleman, returning an 87% yield.  The freshly installed olefin was the reduced with another smart reaction – a diimide reduction.  This bad-boy reduces olefins really selectively – but I’m not entirely sure how the active reductant is formed in this case.  Any ideas?  Surely it’s not just protonation, decarboxylation and formation of actual diimine?

Anyway, banging this stuff in with a bit of acid in methanol results in reduction, but apparently the protons from the acetic acid aren’t good enough for this cylisation.  A bit of CSA did the trick though, causing three consecutive 5-exo-tet cyclisations, and formation of the three remaining THFs in one cascade.  Nice, even if the yield isn’t amazing.


The end of the synthesis seems to contain a momentary stumble, though.  Removal of the acetonide gave a diol, elimination of which would give the prenyl-style sidechain.  However, the paper describes an oxidative cleavage to give a lactol, and then olefination of the lactol.  Perhaps a Corey-Winter olefination was intended, but didn’t work?

One critical point – although the supporting information is pretty full when it comes to text and numbers, there aren’t any spectra.  Surely a first synthesis of any natural product these days need a comparison between synthetic and natural spectra?  Especially when both samples should be in the same fridge?

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  • Madeline says:

    I have done this reaction using hydrazine and 30 eq. of sodium metaperiodate. The hydrazine is oxidized to the species H-N=N-H, which then reacts with the alkene to give nitrogen. Excellent yields under mild conditions but usually must be run twice to assure complete consumption of starting material.

    see: J. Org. Chem., 2008, 73 (23), pp 9482–9485 and references therein

    • Tot. Syn. says:

      Yeah, I’ve seen that variant before – but in this case they’re using different reagents, so I’m not sure how it works…

      • HPCC says:

        Hope your spam-eater will not ignore me this time.

        Works just like you suggested, T.S. ;) Actually, view this dicarboxylate salt as two carbamic acid salts linked by a N=N double bond. Thus, as any carbamic acid, as soon as formed, evolves CO2 and is transformed to the corresponding NH compound, this will evolve 2X CO2 and turn into diimide, the reducing agent.

        Do I have to add ‘synthesis’ to please your spam-machine? :D

        • Tot. Syn. says:

          Thanks for that! I’m sorta surprised, as I didn’t think that N=N bond would last long with all sorts of shit going on next to it, but clearly it lasts long enough.

          Sorry about the spam-eater – I haven’t the faintest clue why it’s taken a disliking to you. Let me know if you loose comments by dropping me an email; I’ll stick my had down it’s throat and recover them manually.

  • milkshake says:

    I don’t wan’t to spoil the excitement for the showcased methodology – but the molecule is almost meso – look at the three middle THF rings. Then the configuration at the rightmost THF, then the configuration of tertiary alcohol at the left. I thing one ought to be able to start with a meso one THF ring material from Diels Alder, and built on it from both ends, and desymmetrise late in the game.

  • bandit says:

    call me negative if u will, but making a poly-thf ionophore by epoxide opening is all a bit dreary, no?

  • UBChem says:

    As for the diimide work. I wouldn’t be surprised if they tried to do metal mediated hydrogenation and got epimerization and/or epoxide opening. The diimide would be the only clear choice.

  • Jose says:

    Diimde is one of those sweet-ass old school Fieser and Fieser reagents that can save your bacon like nothing else. Maybe someone should start a blog for such things.

  • Hau says:

    This is really cool………
    The asymmetric total synthesis of (-)-securinine
    Chem. Commun., 2009, 463 – 465, DOI: 10.1039/b816576a

    d.e of allylation is 4:1, I beleive they might also have allosecurinine. Let’s see what’s next ……..


    [moved to this post by Tot. Syn.]

  • InfMP says:

    Hau: also look at Leduc and Kerr’s synthesis in Angew last year.

    Everyone else: the hydrazide was also used by Shair in the last step of Cortistatin A; I guess he couldn’t repeat Baran’s Ra Ni hydrogenation.

    I couldn’t find the seminal work on this method though to figure out how it works and who pioneered, but that wikipedia link is helpful.

  • Pete says:

    What did you all think of Evans’ Peluroside? I enjoyed it…Any chance we might get a blog of that Tot. Syn.???

    • Tot. Syn. says:

      Possibly not, actually. It’s a nice bit of work with aldol chemistry, but what’s new? Tell me what you liked! I’ve almost finished one on ent-Malbrancheamide B (10.1021/ja900688y), but frankly I’m knackered, so it’ll be up tomorrow. It’s been one of those weekends…

  • UBChem says:

    Wow Pete, total facial.

  • Metalate says:

    Of course the meso route is strategically cool, but the meso route to these things can be quite complicated. It’s awfully hard to make a racemic polyketide, since everything must be set by substrate control, which could be non-trivial on a piece as large as you suggest. I’m having a tough time coming up with a truly symmetrical synthesis of the meso tris-THF piece, and if you have to go to a non-symmetrical route to a symmetrical piece, you lose much of the benefit of building on both ends at the same time. One of those very tempting ideas to be sure…