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Amphidinolide X   

10 May 2009 12,379 views 31 Comments

amphidinolide_x

Lee, Jung. ACIEE, 2009, EarlyView. DOI: 10.1002/anie.200900865. Article PDF Supporting Information Group Website

Another month, another amphidinolide – but we’re getting pretty close to the end of the alphabet now.  Actually, I’m (as ever) being rather over-the-top – we’ve not actually covered that many, but X & Y (as well as being an affront to my ears) were blogged in 2006, where the focus was on the THF synthesis.  This is the case again with Eun Lee’s synthesis, which almost disregards the polyketide-style sections.

The key to his synthesis of the THF is a bit of new methodology, capable of creating two new stereocenters in the process.  The key elements are the two existing stereocenters, and the olefin – which combine to impart asymmetric control.  The actual degree of control stemming from these elements is considered thoroughly in the paper, with a large array of possible substrate chucked into the radical pot.  The 5-exo radical cyclisation seems to be stereospecific, and to quote Lee, ‘the structures of the major products may be predicted on the basis of the double-bond stereochemistry and the sulfoxide configuration.’  As there are two control elements, there are a pair of matched and unmatched possibilities, with the distereomeric ration ranging from 15:1 to 3:1 depending on the case.  Interestingly, the reactions of the less-substituted secondary alcohol starting materials is stereochemically unrelated…

amphidinolide_x_1

After an interesting protection (using a p-nitro benzyl group), it was time to remove the ‘auxilliary’, and this is perhaps where the methodology wins it’s ‘keeper’ status.  A simple treatment with TFAA and a bit of base resulted in a Pummerer rearrangement, and generation of the aldehyde in cracking yield – a nice result.  Going back to the chiral sulfoxide used in this chemistry, it should actually be fairly easy to make using Kagan’s approach.  This uses almost identical conditions to the Sharpless asymmetric epoxidation to allow asymmetric oxidation of a sulfide, and normally works really well if the two sides of the prochiral sulfide are sufficiently differentiated (as in the CBS reduction).

amphidinolide_x_2

As I said in the intro, Lee doesn’t exactly wax lyrical about the rest of the synthesis, aware that the fragments required for the rest of the macrocycle are well documented.  That leaves us with the strategy for coupling, which works well for them, starting with a pair of olefinations to homologate the aldehyde, and then metathesis to bolt-on the rest of the top.  A pair of esterifications (using acid-chloride chemistry) builds up the bottom-half, with RCM to complete the ring.

amphidinolide_x_3

This paper isn’t really about the total-synthesis, but the methodology, and it’s pretty neat; the succinctness of the rest of the synthesis is testament to Lee’s retrosynthetic skill.

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31 Comments

  • big fish says:

    Simple but efficient. A good one from Lee.

  • ryan says:

    good job,but how about its indrustrial uselessness???

  • Leo says:

    Agree this is more a methodology paper, anyway it is a cool methodology.

    And just wondered how the Z-double bond was convert to E-double bond by iodine. Someone can help explain?

    • milkshake says:

      I suppose the Z/E isomerization takes place by addition-elimination mechanism. 1,2-di-iodo compound are not very stable, they like to eliminate I2.

      • European Chemist says:

        Exactly. Same result could be expected using PhSSPh and a bit of heat (50-60°C should be enough), but then it’s by radical addition, statistic bond rotation and elimination of PhS(dot). You can’t exactly rule a radical mechanism with iodine either, but the ionic one appears to predominate.

  • ZZZZZ says:

    zzzzz

    …interesting use of the chiral auxiliary. My bet, Tot Syn, is that they access their auxiliary from the p-tolylsulfinate of menthol rather than through the Kagan asymmetric epoxidation of the sulfide…

    zzzzz

    • European Chemist says:

      It is still a chiral auxiliary in the 21st century (sigh) but I guess that a “methodology paper” which actually makes Amphidinolide X as a demonstration of the method is remarkable by anybody’s standards.

  • nuuuuube says:

    Not to get off the subject here, but am I the only one who saw Snyder’s Napyradiomycin paper? I would’ve thought for sure it would end up here eventually. That stuff was mad impressive. Read the SI and you get a feel for the insane amount of work that had to go into that project.

    10.1021/ja9014716

    • ,,, says:

      Agree, I had the same question a couple of weeks ago…

    • reply says:

      Well, it was in fact a long synthesis that showcased one reaction…if that’s the standard, then practically every synthesis is mad impressive.

    • Tot. Syn. says:

      Dunno how I missed that one. I swear I read it, and started ChemDrawing it, but… meh. One day I’ll drag myself out of this mad, ether-fuel malaise. Should have summat later this week.

    • Liquidcarbon says:

      Milkshake’s nitrite melt bath at work :)

      • milkshake says:

        KNO3+LiNO3 2:1 by weight is actually better. Also there is HiTec commercially available eutectic (53% KNO3 + 40% NaNO2 + 7% NaNO3).

        Both of these mixes melt at around 140C. But the melts ignite organic stuff like wood or paper. A ruptured reaction flask would be a major mishap.

  • OC says:

    succinct synthesis, symmetric asembly~

  • LW says:

    What’s the deal with Samarium Diiodide in scale ups with respect to industry? I heard that it’s a bit of a pain.

    • milkshake says:

      SmI2 is expensive to make – for a stoechiometric one-electron reductant. More seriously, the reactions are run in rather diluted solution, it produces considerable “heavy metal” iodide waste and the solutions of SmI2 are very sensitive to oxygen. HMPA additive used in many SmI2 reactions is verboten in process.

      I still think that a pharma process group could run a SmI2 reduction step on a pilot plant scale if there is no better alternative, especially if the final compound is super-active so they would need to make only kilos (rather than tonns) of the product.

      Process groups could do all these things – column chromatography, Mitsunobu alkylations, diazomethane step, even Bu3SnH radical reductions (catalytical in tin, with NaBH4 as terminal reductant) – it just makes their life miserable and it hugely drives up their costs.

  • hanpisa says:

    I kind of agree with the difficulty of scaling up SmI2 reagent.

    You will be surprised to see how much of smI2 solution you will have to use for considerably small scale. SmI2 solution is usually prepared in 0.1M in THF as far as I know.

    It is a fascinating reducing agent but its dilution can be painful.

  • chinstrap says:

    Preparation of the SmI2 reagent is a pain! Whether one uses 1,2-diodo ethane or I2 the competing disproportion reaction to form SmI3 is still a headache. I finally gave up and ordered it from aldrich.

    Although it may come to a surprise, the aldrich commercial reagent worked ok. However, the bottle was dead 4 h after the septum was initially pierced.

  • Chembotitron says:

    I would not suggest buying the commercial reagent, it NEVER lasts.
    I’ve used the Sm and diiodoethane prep and the sonication method with Sm and CHI3, but I always go back to preparing the reagent fresh from Sm and I2 (most reliable in my hands).

    SmI2 is a strange reagent, lots of interesting reactivity.

  • Fluorine says:

    natural Samarium is radioactive ;-)

  • Dazed and Confused says:

    I’ve never had a problem with SmI2 disproportionating to SmI3 when using Kagan’s prep. using Sm and ICH2CH2I. The ICH2CH2I must be a white solid when setting it up, if its not, it is easily purified by washing an etheral solution with sat’d Na2S2O3. Unfortunately however, 2 equiv of Sm is used (the excess Sm stabilizes the SmI2). Not the most convenient for industrial applications, but Kagan claims the excess Sm can be recovered and reused. I agree that SmI2 should always be prepared fresh when you want to use it.

  • LW says:

    I used to work in the David Procter labs when I was an undergraduate, and their SmI2 seemed to be pretty good. But I guess it depends on the person that prepares it. I agree it is intriguing, I’ve personally never done a reaction with it. I find it quite amusing because I’d never think to put water anywhere near the stuff…….I always assumed it would react violently with water to give dihydrogen.

  • HPCC says:

    I just clicked the link for “X&Y” and must have laughed for 2 minutes straight, re, “an affront to my ears”!!!! :D

    Btw, quick suggestion, is it possible to write the code so that the links one clicks end up in a new tab? I’m so not a web designer!…

  • LW says:

    I thought the blacklisting proposal by the EPSRC has been repealed now?

    On top of Baran’s Nature paper, there is also another chemistry paper in Nature from our research group (JDS at Manchester), albeit Prebiotic chemistry, but it has caused a little bit of a buzz and it is a really nice piece of organic chemistry. Do have a gander if you are bored.

    http://www.nature.com/nature/journal/v459/n7244/full/459171a.html

    http://www.nature.com/nature/journal/v459/n7244/full/nature08013.html