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Echinopine A   

3 March 2010 23,170 views 67 Comments

Nicolaou, Chen, Ding, Richard. JACS, 2010, ASAP. DOI: 10.1021/ja9093988. Article PDF Supporting Information Group Website

As I twittered the earlier today, redrawing KC’s crayonisation of Echinopine A took quite a while – but I think one needs to see both representations to get a feeling for the complexity here.  The unique [3.5.5.7] carbon skeleton is pretty special – apparently enough that no biological rationale is given for this work.  Perhaps I spend too much time looking a biological assay results these days…

So with nothing else for me to witter-on about, I’ll get into the synthesis.  The first few steps are actually kinda neat – KC does a CBS reduction (second step in the synthesis…) of a cyclohexenone to get an enatiomerically enriched cychexenol.  This was then ozonolysed to get a di-aldehyde, which was treated with base to get the aldol product – a cyclopentene.  The remaining aldehyde was reduced to the primary alcohol, perfectly set for one of my favourite reactions – a Johnson-Claisen.

This neat little rearrangement provided a moderate level of diastereoselectivity in the creation of a tertiary center, and left a pair of useful functional handles.  Clearly dissatisfied with this result, the group tried an alternative sequence from the same alcohol, appending a conspicuous looking stannane.  When treated with base, this did a 2,3-Wittig rearrangement to give a similar product as before, but in a far reduced yield.  Importantly, though, was the increase in diastereoselectivity, boosted to a more useful 7:1.

It has to said that elaboration to the diazo compound shown in my next scheme was kinda steppy, requiring six steps from the alcohol.  Howeverl the JC product only needed two steps, so it’s tough to say which I’d go with.  I guess it’d come-down to the ease of chromtography.  Anyway, any step I show with a diazo-group is inevitably followed by a pinch of rhodium, and KC doesn’t dissaapoint.  Carbene formation and insertion into the exo-cyclic alkene results in a neat formation of both a cyclopentene and a cyclopropane, and as a single diastereoisomer. Quite a neat route to the desired 5,5,3-system.

A few functional group transformations brought the group to a homoallylic alcohol, which when reduced presents a system recognisably similar to that of the target. Selectivity again went in their favour, with new stereocenter generated entirely in the desired configuration.  As close as this product seems to the natural product, there was actually quite a lot of work to do, as they needed to add quite a lot of carbon to finish the medium ring.

This started with a olefination to extend the C-7 sidehain. Reduction of an ester and the new olefin was done simultaneously using LiEt3BH, providing a terminal alcohol.  A pair of oxidations then gave the group a C-1 ketone, along with an aldehyde – perfectly set for a samarium-mediated coupling.  This rather powerful reaction provided the carbon-carbon bond in a rather reasonable yield (given the complexity of the system), and generated a pair of stereocenters.  As it happens, both hydroxyl groups were removed shortly after this reaction, but that only describes the wealth of hydroxyl chemistry at our disposal.  Unfortunately, the group had to use that ever-so-nasty HMPA, but that seems awfully common when working with samarium diiodide.

As I said, the group had to loose reduce-off the C1 hydroxyl, oxidise and then methylenate the other, and finally one-carbon homologate the sidechain – all accomplished with some efficiency in terms of yield, but again rather steppy.  And that concludes this synthesis rather aptly, as there are simply too many steps for me to be stunned.  Coupled with the alternative routes in this paper, you can tell that this was a battle, and one in which the ultimately succeed.  However, I expect we’ll see a second generation synthesis in the future, as I can’t imagine KC’s done with this target.

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67 Comments

  • Twist Boat says:

    Quite an interesting molecule and impressive accomplishment; however, I am frequently disappointed by KCN’s syntheses due to their lack of innovation.

  • QualityControl says:

    Dude the PI is Chen not KC. KC has the final say but doesn’t drive the intellectual underpinnings of the synthesis in Singapore.

  • andrew says:

    far too many steps for that molecule. many PGs, correction of oxidation states. even the first total synthesis is less than half the steps (published in Org. Lett.)

  • milkshake says:

    its a completely beautiful molecule (the kind that EJC would like) but there must be a more elegant way of making it.

    • Atom Recession says:

      DOI: 10.1021/ol902263k

      Is that the most elegant way to make the molecule? Maybe not. Moreso than the KCN way? I’d say so. And in fewer steps and published first. And in Org lett for some reason.

  • Chemistry with purpose says:

    So why JACS if the 2nd synthesis? More steps than the first in Org. Lett? I guess becos KC was the first author!

    • QualityControl says:

      Wrong. Because it was done first. It is far harder to create a first generation synthesis than a third or fourth.

  • tommy says:

    The whole reviewing process is getting more and more corrupt in my opinion. big name = jacs, no big name = org lett and so on. This has nothing to do with science. It is getting more and more unprofessional.
    I would never accept a paper like Nicolau’s in JACS. I mean, it takes them about 38 steps (!!!) to complete the total synthesis and innovation is missing. There is no reason why Nicolaou’s paper is published in JACS and Mulzer’s in Org. Lett, accept the name of the PI.
    Sad but true.

  • Catalyst says:

    still classic!!……needs more novel and efficient routes……

  • GYA says:

    note–KC’s is a full paper and not a communication. likely what got it in there.

  • tommy says:

    Nevertheless if you take a closer look at JACS papers (especially total syntheses) published over the last months/years I sometimes wonder myself. I frequently come across with papers, which are, in my opinion, no suitable for JACS. Interestingly, these relevant publications (for instance mersicapine-Fukuyama, vindoline-boger,..) always show a famous PI. I don’t want to say that these publications aren’t worth reading, but they do not fulfill the intrinsic inofficial “requirements” for JACS. In earlier days JACS insisted on new methodology or innovative chemistry. Nowadays the politics seem to have changed.
    However, there are still numerous beautiful total syntheses and new methodology published every day!

    • Will says:

      These comments as to whether a particular paper is worthy of whatever journal it appears are so tiresome…paul should just delete them

  • Dennis says:

    “Anyway, any step I show with a diazo-group is inevitably followed by a pinch of rhodium”

    Ahhhh, that’s the reason you haven’t highlighted any of the work done on diazofluorenes.

  • GHB says:

    Ellman moving to Yale…poor Berkeley (lol…how will they now keep Toste). Yale moving on up.

  • ZZZZZ says:

    zzz

    …go Yale! I love Scott Miller…

    zzz

  • saxaphony says:

    can anyone confirm Ellman moving to Yale? These rumors have been circulating for a long time………

    • The Next Phil McGroin says:

      a little while back (2-3 yrs) a similar thing happened with Mike Krische (Texas) moving to Yale…he had a page on Yale’s site and everything. He is still in TX last I checked though.

      • know people at texas and yale says:

        He was definitely going to move. supposedly signed papers and everything, and i heard his group didn’t know about it until they saw him on yale’s site. then he had those following him cancel their apt leases to leave that summer. but he stayed. no doubt texas increased their counter offer.

  • nick says:

    Looks like the Ellman move is on then. On a similar topic, wasn’t Jacobsen all set to move to MIT ~2 years ago? I remember that they more or less announced this, but it never happened. Anyone know why?

  • ... says:

    Jacobsen backed out because Harvard improved their counter offer.

    KCN’s paper is kind of short for a JACS article (3.5pages). It probably was packaged this way to get it into JACS, but not sure why he didn’t just send it to ACIE.

  • tommy says:

    I can imagine that he sent it to ACIE first but finally was rejected.

  • GHB says:

    Given the state California’s in, I can’t see Berkeley keeping Ellman. Besides, Yale is a better place for his type of chemistry than Berkeley.

  • TLC is dead says:

    I love Yale and Ellman equally so this news made me jump for joy.

    • Tot. Syn. says:

      TLC Lives!!! I have *two* very nice LCMS machines and an NMR machine right next to my lab, but I still do TLC. I made up some very lovely vanillin dip last week too. Nothing tells you about impurities like TLC…

      • European Chemist says:

        And not many things smell better than a freshly baked vanillin-dipped TLC ;-)

        • TLC is dead says:

          It is a name only, I run a ton of TLC’s, but sometimes the LCMS gives you a nice non-existant mass which usually drives the chemistry forward…

      • LiqC says:

        I made the vanillin stain, used it once, and was sneezing for hours after…

        Permanganate + aqueous wash and magic stain win.

  • John Wood says:

    Anyone got the down-low on Njardson? What’s he gonna do?

  • GHB says:

    @John Wood. Maybe Colorado State.

  • batterK says:

    Njardson is moving?

  • ,,, says:

    JACS ASAP: chaetocin – it should’ve been Movassaghi…

  • synth says:

    I like the cyclopropanation step, but there’s got to be a faster way of getting to that substrate. Besides that- it’s not bad. I like the series of disconnections that were made, but I think that too many of the steps attached too few carbons at a time.

    Very nice work with the drawings of the molecules, as well.

    And a few dropped words/phrases:

    “It has to said that elaboration” -> I think you’re missing a ‘be’ in here?
    “extend the C-7 sidehain” sidechain?
    “which the ultimately succeed” ? which they ultimately succeeded? Not sure about this one

    I wish that the comments for this molecule focused more on the chemistry displayed than on the politics, there are plenty of other places to discuss politics, and one reason I like reading this blog is the focus on the chemistry.

  • MM says:

    Why HMPA is “ever-so-nasty”?

  • poly says:

    offtopic : has anyone experienced a problem of chloride ion replacing TosO when tosylating primary alcohols with TosCl in pyridine?

    • ac says:

      use silver :D

    • GYA says:

      of course, common problem. more common with mesylates.

    • milkshake says:

      inadvertent Cl displacement happens all the time with allylic and benzylic tosylates – they just love to spit out the cation. You can use tosyl anhydride – easy to make and much cleaner reagent. The same goes for mesyl anhydride. Or you can work with TsCl in toluene at -20 to 0C, with NEt3 1.1 equiv as a base and catalytic DMAP (fem mol%), triethylamine hydrochloride precipitates out in this system so you won’t have muchchloride ion around.

      • stop says:

        On that note, I had triethylamine displace an allylic mesylate once, and I ended up with the allylic triethylamine salt.

        Really confused why it stuck to the baseline until someone pointed out that my “residual” NEt3 kept integrating the same by NMR.

        • milkshake says:

          I used THF once for a displacement where I tried to generate a triflate in situ. I isolated lots of low-melting white solid product from that reaction – it turned out to be THF polymer, product of ring-opening polymerization promoted by oxonium from O-alkylation of THF by the triflate… The polymer had a pretty stunning NMR spectra.

          • Tot. Syn. says:

            I once (accidentally) used BCl3-SMe2 complex in THF, and the reaction went nuts, heating to reflux in seconds. I thought I’d rescued the reaction until I isolated vast amounts of 4-chlorobutan-1-ol…

          • antiaromatic says:

            definitely made the mistake of BCl3 with THF….

    • fungus says:

      Chloride is a BAD ACTOR!

      • krest17 says:

        had the same problem once with TMSI

      • milkshake says:

        this reminds me, old Rappaport totally hated saturated ammonium chloride for working out reaction mixtures. He would always say “There are just two problems with ammonium chloride – ammonium and chloride”

        • antiaromatic says:

          And what’s so bad about ammonium and chloride??

        • European Chemist says:

          Trost always said the same thing. “That Chloride in HCl always does more than it is supposed to”.

  • poly says:

    silver will make my rxn messy, and I have ArCl moiety on my alcohol. Does anyone know any other “cure”? I can try shortening the rxn time, but conversion will suffer.

  • ... says:

    Check out the section on tosylate formation in Greene’s Protective Groups in Organic Synthesis. Several procedures in there. For example, Ts2O/Yb(OTf)3 is supposed to be good to avoid that problem: Synthesis 2004, 885.

    • poly says:

      thank you, I will.

      • antiaromatic says:

        There’s another pretty easy way. I think it involves using triethylamine and N,N,N’,N’ tetramethylhexanediamine with TsCl in acetonitrile. I believe it was Fukuyama that developed this protocol, and the idea is that this amine can effectively coordinate the chloride without the use of any silver salts. Definitely give this a try if those above things don’t work.

  • ymu says:

    Could you help me with the function of a reagent (whose CAS is 13557-42-1) that shows up in every reaction in the sciefinder schemes of the ” Total synthesis of a chlorosulpholipid cytotoxin associated with seafood poisoning.Full Text Available By: Nilewski, Christian; Geisser, Roger W.; Carreira, Erick M.. Nature, 1/29/2009, Vol. 457 Issue 7229, p573-576″? Is it scifinder mistake (typo)?

  • ymu says:

    Thanks.

    How come this Tetraethylammonium trichloride does the stereoselective chlorination on sorbate? Does it mean diastereoselective?

  • jing li says:

    I have done the core structure of semiaquilegin A firstly,which was commented by editors of organic letters as an inelegant way to solve a synthetic chanllenge,and finally was published on Tetrahedron letters, of course I gave up the JOC because of dissatisfaction.Is it why?But I still admire profssor KC mostly,he is the No.1,he is worth of the nobel prize,and I dream to his lab ha ha.