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Solandelactone E   

29 August 2010 24,731 views 33 Comments

Aggarwal, Robinson. ACIEE2010, EarlyView. DOI: 10.1002/anie.201003236 Article PDF Supporting Information Group Website

A question – how long does one spin-out natural products based on one particular method?  I ask this as this is the second synthesis I’ve written about this year by Aggarwal, both using his lithiation–borylation–allylation sequence (the first one was in Chemistry World in June).  Aggarwal’s work is still very fresh – that’s why it’s on it’s second appearance here – but other groups have been stuck in a methodological rut for sometime (not wanting to name names here, but this is certainly true of some macrolide obsessives…).

Putting that question aside for now, Aggarwal’s work with this chemistry continues to impress me, along with the targets he chooses to make with it.  His heritage (working for Stuart Warren at Cambridge) betrays it’s self early in the synthesis, with a really neat enantioselective cyclopropane formation.  Working from an allylic alcohol derivative, an SAE gave them an epoxide, which after treatment with base and acetonitrile, gave them the cyclopropane. Really neat work, leaving some interesting functionality in the product.

A second fragment, required for the lithiation–borylation–allylboration sequence, also required installation of a stereodefined stannyl group – something I’d have thought would be quite tricky, but was actually done with ease.  Using a commercially available starting material, the group formed a carbamate and then did a substrate directed lithiation and capture of the stannyl group.  The yield might not be stunning, but the diastereoselectivity is impressive, so I’m sure they were very happy with this – even though I’m sure the lab stank…

With this fragment set to go, they were ready to try out their new methodology.  However, the chemistry didn’t go quite to plan – as they only achieved a 15% yield.  Analysis of the reaction mixture showed that the lithiated carbamate was attacking the aldehyde directly, and that the reaction with the vinyl borane was incomplete.  However, by reordering the addition of TMEDA, they were able to get past this problem and boost the yield to 73%, and in a very respectable diastereoselectivity.

To complete the molecule, they still had a few steps to go; firstly they did a selective epoxidation of the allyl silane using Ti(OiPr)4/t-BuOOH.  Treatment of this fragile intermediate with a bit of acid promoted a rearrangement and delivery of the target.  Top work – and I’m looking forward to seeing this methodology again!

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  • HPCC says:

    There needs to be at least one comment about this synthesis. It’s actually chock full of interesting transformations.

  • anon says:

    Since it’s so quiet I have a question maybe some could help with? Does any one know any good primary or secondary references for strategies for the optimization of a new reaction? I understand the “change one variable at a time” but wondered if there was some more specific guidance in the lit. All I’ve found are statistical methods which don’t help with the discrete variables. Thanks.

    • Backtoschool says:

      I don’t know if it is helpful, but there is a excellent book:
      “Design and Optimization in Organic Synthesis” by Rolf Carlson.
      The book stresses the DoE but in general, you can grasp the idea
      of optimization.

  • PotStirrer says:

    I’ll throw out another question that has been bugging the heck out of me. I’m trying Li/I exchange of a relatively simple primary iodide (it is homoallylic and also contains an OBenzyl group). Using tBuLi in Et2O or Et2O/pentane mixtures gives me the desired alkyllithium, but also large amounts of the corresponding primary alcohol! WTF?!? tBuLi is titrated and Et2O is distilled from ketyl. Making a Grignard of the corresponding bromide also gave a lot of this alcohol. I’m racking my brain here…anyone have any ideas?

    • Greenhorn says:

      Perhabs the Et2O was stored not properly or for too long time to give ether-peroxide by autoxidation. The ether-peroxide could react with the alkyllithium or grignard to give the corresponding primary alcohol and ether-alkoxide/metal salt.
      This is just a speculation. You could test the Et2O for peroxides with an acetous iodide solution, which should turn its color to brown in positive case, to rule this out.

    • Stewie Griffin says:

      That’s weird. So the benzyl is falling off?
      Maybe you could try to form the alkyl zinc instead. Reike Zinc is awesome stuff.

    • a-non says:

      try with a new bottle of t-BuLi. Sometimes if any oxygen is present butoxide forms and can cause problems in the reaction. If you’re using N2 swap to Ar – that often does the trick.

      Also, make sure to use 2eq of t-BuLi to mop up any excess t-Bu anion.

      Last thing, if things get really desperate, you can actually re-distill ether from LiAlH4 after distillation from ketyl to get the extra-extra dry stuff

    • Fluorine says:

      do you work under N2 or Ar?
      do you actually get the alkyl lithium and the lithium alkoxide? or do you rather react your intermediate lithium organyl with something else and the alcohol is formed during this transformation?

      • sba says:

        Actually, this is a common problem, especially on smaller scales. It is often difficult to completely get rid of oxygen, which reacts quickly with RLi from I-Li exchange eventually forming the alcohol product. This should be minimized on larger scale. Also , the Li-I exchange should not be extended beyond 1 h at -78. Hope this helps…

    • anon says:

      I’ve seen this before as well, could never quite figure out why I was getting the primary alcohol. I found it helped to always use fresh tBuLi and I degassed all of my solvents, just to be on the safe side. Rxns were always run under argon as well. These changes helped get my yields up from 5-10% to upwards of 70%.

      • PotStirrer says:

        Thanks for the comments everyone. The benzyl group is not falling off. It is still there…the iodide has just been converted to the corresponding primary alcohol (the iodide’s direct precursor not surprisingly). I’m working under Ar and used 2 equivalents of tBuLi, but also tried 1 equiv (see Overman Gaunacastepene paper). Alkoxide seems to form simply after adding tBuLi. I will try a fresh bottle of tBuLi, although I think at least one of my reactions was with a fresh bottle. Degassing isn’t a bad idea, but a ketyl still is supposed to take care of that for me anyway. Again, thanks for your comments!

    • total synthesis says:

      I also met this problem a year before, you can try to degas your system with N2 or Ar, it should help.

    • jurel says:

      how are you characterizing this?

  • maitobaran says:

    Anyone else catch this…


    Check out the SI, “The separation was conducted on an Daicel Chiralcel OJ-H chiral HPLC column (20mmØ×25cm)” !!

    100 mg separation on a chiral column is impressive. That had to cost some $$$.

    • Just Another Chemist says:

      We occasionally separate a decent amount of material by chiral HPLC (even using a very similar Daicel 46mm x 25cm column). The key is to use a fraction collector and auto injector. You can get 100mg pure injecting before you leave at night and when you get back in the morning you have both enantiomers (or diastereomers) pure.

      • NP says:

        An alternative approach is to use an isocratic system with repetitive overlapping injections. It is a common trick that will get the material pure in a fraction of that time.

        • PotStirrer says:

          I love the overlapping injections with an isocratic method. If your impurities have a similar retention time to your product, you can get your injections really close to each other. Makes you feel particularly productive that day. :)

    • peter says:

      Looks like Mr. Pschierer’s career is over.

    • GKA says:

      (Disclaimer: I’m going from memory here, as I have no access at the moment of writing – and sorry for continuing off-topic!)

      I don’t like these retraction notices at all . They seem to be made by the corresponding author in an attempt to only admit to the least incriminating offense, and will only serve to fuel further speculation. As they stand at the moment they have an aura of dishonesty surrounding them. I don’t think they should have been accepted by the editor. If an observant reader has spotted something in the NMR data, what did go wrong? Erroneous assignment of a side-product? If original MS data could not be found, what did the lab notebook say? No printout, no electronic file anywhere? No remaining compound sitting in the fridge? If that’s the case, it should be the simplest thing in the world to reproduce the experiments and get enough material for MS. No? Well, then, why not instead write “The manuscript contained fraudulent data and has been retracted”? (presumably written by the editor..) This is bullshit. I expect more details to emerge.

      • GKA says:

        Now when the retractions are up again online, I must correct myself: “Attempts to repeat the synthesis [...] have failed” / “…denen eine Reproduktion der Ergebnisse nicht gelang”. The conclusion seems to be obvious. Not good :-/

  • barans_baldspot says:

    Anybody see Baran, I mean Dawei Ma synthesis? It is good, but Baran should have done it. too many copy him

    • sba says:

      Beautiful synthesis of communesin F by Dawei Ma and co-workers. For your education, oxidative anion (or enolate) coupling was developed long before your idol was born. For an excellent background, see Overman’s actinophyllic acid synthesis, full paper.

      • 2b24u says:

        You can also read baran’s full papers on the topic for the full history of enolate coupling. The cross coupling of an indole anion with a carbonyl anion (Ma’s key step) was done by baran first.

  • Barans goatee says:

    No but barans new silver method is bad ass. This is going to be used a lot. C-H activation people should have done this. Looks like Palauamine people are responsible.

  • poopooplatter says:

    i wonder what lab/school Mr. goatee is from ?………

  • Cagin says:

    I know that it’s still off-topic but I’m sick of these Baran fans, so I need to write something. (I’ve been following this blog for a couple of years and never wrote anything but this Baran thing started to be very annoying.)

    I read his recent jacs paper and it’s just an ordinary methodology paper; there are good aspects of the paper as well as the bad sides (I’m not discussing the jacs-worthiness; jacs publishes anything on C-H activation so no problem). For instance, in Table 1, the regioselectivities for most of the substrates are so bad that nobody will use this procedure. In Table 2, yields are good and it’s selective, but it needs t-But pyridine so again a very narrow substrate scope. The best example is the quinine one since it can be utilized for the derivatization of many catalysts that contain cinchona alkaloids.

    For me, Bergman-Ellman paper is much better; it requires high temperature and 6 eqv of the pyridine, but at least the substrate scope is much wider.

    So what I’m trying to say is there are hundreds of methodology papers around and this is just one of them. But when he publishes something, these guys just start to scream as if it comes from another planet.

  • barans_baldspot says:

    how come recent people not use oxy-coupling until baran? Check overmen acknoledgement. they thank baran for his help! baran is good. don’t be jealos.

  • Info says:

    As cinchona alkaloids are used in the Baran paper, I would like to add that there are simple and preparatively useful alternatives for this transformation (unfortunately not cited in the paper).


    I also do not understand the Baran hype – nevertheless, it still is an interesting paper…

  • Realist says:

    I think the baran procedure is a lot more practical than the 2 step procedure in that paper. Just read it.

  • beaker says:

    I can barely get through that baran paper – those structures make me want to stab my eyes out…

  • TLC is dead says:

    The Baran procedure is a lot more practical and is currently being utilized by many chemists, thus it is a successful method. I think people should focus on the Aggarwal paper as this lab has produced some fantastic work in recent years and is providing new key bond disconnections that people should take notice of, not continuous Baran hating fanboy internet battles.