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10 August 2009 14,354 views 36 Comments


Jamison, Tanuwidjaja, Ng. JACS, 2009, ASAP. DOI: 10.1021/ja9052366. Article PDF Supporting Information Group Website

Capitalising upon his pontifications analyses in Science (2007), Tim Jamison has come-up with the goods; a poly-epoxide cascade to build a poly-ether.  He’s not the only one – Frank McDonald crafted a nice synthesis last year using the same principles.  However, Jamison has upped the epoxide count, controlling formation of three ether rings in one go.

As ever, the initial trial is construction of the linear, poly-epoxy precursor – with few surprises in Jamison’s route.  The starting material is farnesol, providing on three alkenes, one of which is allylic, so was a perfect candidate for Sharpless’ tasty catalysts.  The homo-terminal olefin was deactivated by oxidation of the terminal methyl group to an allylic alcohol and acetylation, allowing selective Shi epoxidaiton of the internal olefin.  It’s role complete, the acetate was removed to restore the isoprene-type terminus, and attention turned to the other end of the chain.  An oxidation of the primary hydroxyl and olfination provided the last site for epoxidation, which was again accomplished via an SAE.


With the boring stuff done (…kidding!), it was time to let the molecular zipper rip – using NBS to provide bait for the cascade.  Microsieves are essential, as Jamison notes in the Science paper, the presence of water can mess with the stereo- and regio-selectivity of the ring formations, whilst hexafluoroisopropanol is an interesting choice.  He mentions that it’s highly polar and non-nucleophilic nature ‘facilitate[s] the presumably cationic cascade and thus maximize the directing influence of the methyl groups‘.  However, I’ve also seen it used in many radical reactions where premature termination (!) is caused when the solvent has abstractable hydrogen atoms.  Remember, that remaining OH is a homolytically strong bond.


I shouldn’t procrastinate about the solvent choice when such a nice result is evident – all three desired ethereal rings form in excellent yield, with the remaining cyclic carbonate acting as a useful synthetic handle.  The only fly in the ointment is that the bromination is unselective, with a pair of equally prevalent epimers in the flask.  I’m sure it would be possible to convert the stereocenter to the desired position, but rather than slow-down, the group pushed on to the end with a rather tasty sp2-sp3 Suzuki coupling to stitch the THF moiety to the larger fragment.  No loading of catalyst is given, and for some reason my computer doesn’t like the SI, so lets just hope it’s under 10%!


A really nice bit of work; setting up those cascade reactions must be quite nerve-racking!

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  • Old Timer says:

    Nice work for sure! How might one go about tetrasubstituted olefin epoxidations I wonder? That would definitely open up the chemistry to some more interesting compounds.

  • Martyn says:

    Not surprised you’re struggling with the SI – it’s 162 pages long. Catalyst loading is indeed 10 %, on a 0.0153 mmol scale to give 9.7 mg of product.

  • 1 says:

    Nice work! Which variant of Wittig is more Z-stereoslective? How do you improve Z-selectivity….i.e given with paratmeters like nature of the solvent, base, temp etc

  • Atticus says:

    I feel sorry for the student who had to say the name of that natural product in group meetings. Quite a mouthful.

    Job well done!

  • ??? says:

    A little disappointing. The route is pretty efficient, but 1:1 dr at the C-Br bond is unfortunate. They really should have shown that the wrong epimer can be converted to the correct one. My guess is they couldn’t get it to work. I’m just a little disappointed when reading this synthesis because there is nothing really new here. These types of cascades have been around for a while (remember Johnson’s synthesis of progesterone JACS 1978, 100, 4272.) I mean even in Jamison’s science paper they already showed they can make 3 rings. I realize they’re trapping “Br+”, but this is not new either (See Jamison’s citation of Holton’s work, or Sakakura et. al. Nature 2007, 445, 900 and references therein.). Don’t get me wrong, this is a very nice synthesis of the target, but its all just too predictable. I think the route to the epoxide precursor is pretty boring, and with the key step only giving 36% of the right compound, the whole thing falls a little flat. I really wish they had been able to recycle the wrong epimer!

  • stephen says:

    Steroids are one thing. Lotsa precedence for that. Trying to make Brevetoxin by a cascade of epoxide opening is a much different beast.

    • milkshake says:

      even steroid cationic or radical cascade is not a piece of cake – once you move past two-ring-forming system. Sure there are many classic papers but when you actually try to use the methodology to make anything more elaborate than plain cycloprenoids you will find it quite non-trivial.

  • optional says:

    To ??????

    Why dont you appreciate the science and learn to see the glass half full!

    Lets stop having “big egos” in the synthetic world, and just appreciate the science…..and who said that science has to be new???

    • The Next Phil McGroin says:


      The journals…if I copied Overman’s Sarain A synthesis, I could not get that into JACS (maybe Baran or Corey could, jk)

      What is the point of doing something if it is not new, then its a sophomore organic lab expt. where you know the outcome.

      full disclosure:
      I am not suggesting that everything published in these top flight journals is new, merely that it should be.

    • ??? says:

      @ optional:

      I knew someone would misunderstand my post. I can see the glass half-full, and I don’t have a big ego. I said that the synthesis was nice, and I do think it should be published in JACS. However, I just wish people would stop publishing just good science, and rather, go the extra step to publish extraordinary science. If Jamison had waited to publish until they had either improved the dr or found a way to recycle the wrong diastereomer this would be a much more elegant synthesis. Jamison already has tenure, so its not like he needs to get publications out ASAP. I think we (chemists) should strive to publsih awesome science and not just good science. I realize that this may not be too practical in this publish or perish world we have today, but I think we should be striving for that nonetheless.

  • The Next Phil Baran says:

    optional: Science is as old as thought, there is no old or new science, it hasn’t changed. Science is the method a scientist uses to approach a problem. This paper is not science, it is application. Yes, it is a good application of cascade technology, but they haven’t provided anything new to the methodology. They should have worked on developing this method instead of accepting the 50/50 ratio of products, that would have been scientific.

  • The Next Phil Baran says:

    As a matter of fact, trying to “fix” a 50/50 ratio of products is my favorite thing to do. Everyone can grant me that this reaction can easily be deduced by an arrow pushing mechanism. They use a chemoselective epoxide equivalent, the bromonium, to switch on the cascade and the rest follows, lots of precedent. They don’t mention how NIS might work (if you get all the wrong product then mix with an excess of bromide and you have the compound, which in comparison to throwing away half of your material on an advance substrate is pretty good). NIS might increase sterics and therefore organization of the structure as a whole, or it might work at lower temperatures, which again may organize the structure in a particular way. If they had some things then it would be a scientific paper. Also, Tok I didn’t know you and everyone else were waiting on my papers! Does that mean I will get a high IMPACT factor?

    • Tok says:

      Now that’s more like the comments I like to see, well some of it anyway. More of the, “I’ll bet they could recycle the undesired diastereomer like this,” and less of the “This is not a good paper (with no deeper investigation or insight).”

  • optional says:

    To TNPB

    The first thing that you need to realize is that JACS communications are 2-3 page. Now, trying to fit all the gritty nitty details in the two or three pages will not be possible.

    I am very certain that the authors tried a variety of halide electrophiles (including NIS) and also played around with the stoichiometry of the epoxide equivalent and of the reaction temperature. I dont think that Jamison is that dumb to not to have suggested these things to the student.

    Regardless, the full paper will tell the story.

    Getting back to the point I made before, I believe that Synthetic Organic Chemists have the biggest ego, and it shouldn;t be as such.

    A simple statement along the lines of “I wonder what would be the result with X in this reaction” sounds much polite and milder than saying “Its a little disappointing” and “I’m just a little disappointed when reading this synthesis because there is nothing really new here”!!

    More often than not, people negatively criticize the work. They need to take their buttocks out of the “big ego” hot-tub!

    • ChemBioPhys says:

      “believe that Synthetic Organic Chemists have the biggest ego, and it shouldn;t be as such”

      If indeed true, why is that? I mean, among the “hard” sciences synthetic organic chemistry wouldn’t rank that high up, correct? Not that I haven’t met some hard-ass physicists or PChemists, but it’s true some hard-core synthetic types have some lofty air about them!

    • Fluorine says:

      well, 2-3 pages + supp

    • The Next Phil Baran says:

      The question then is: if this is a scientific journal, why are non-scientific synthesis papers being published in it? It would be ok to use a highlight journal, but what JACS and Angie need to realize is that they are a scientific journal first, meaning a communication should not be equivalent to a full paper. In front of a committee these are the same, but scientifically they are not equivalent. If they don’t change to a standard like this then another journal will have to be published to acommodate this need, which may eventually supplant them. The only other way would be to stop purchasing this journal. Right now there is no a journal of pure methodology.

  • PC says:

    regardless of the “ego” thing, it is not so exciting to see the same thing being published again and again, though you must say it’s a nice paper…

  • anon says:

    Good paper and nice writeup, but was ‘pontifications’ really the best word to have used there? It’s rather uncomplimentary…

  • z says:

    I feel like they’re trying to hid the steppiness of the synthesis of the cascade precursor. They mention in the text that the C2-C3 alkene has be converted to an allylic acetate to get selectivity in the Shi reaction, but they say nothing in the text about the subsequent 3 step (or 4 depending on how you count) removal of the acetate. The rest of the scheme represents that moiety as R’, without defining R’ anywhere, so it looks like R’ is the allylic acetate, as if they hope that nobody notices what they’re actually doing. At least, they fooled me, and confused me, at first glance.

    But anyway, it is a nice paper.

  • will says:

    Has anyone ever seen an “asymmetric” version of NBS? One derived from a tartrate or other chiral dicarboxylic acid? I wonder if the bromination could be made stereoselective that way…

    • Moody Blue says:

      Interesting thought……. Along the same lines, t-BuNHBr (from t-BuNH2 + Br2) is also used for brominations. I wonder if a chiral amine can be used instead. This might put the asymmetric environment “closer” to the brominating moiety.

    • ??? says:

      An in situ preparation of a chiral NIS reagent has been used for an olefin cascade to give organic iodides as the final products: Sakakura et. al. Nature 2007, 445, 900. Also you’ll recall that Snyder recently used an asymmetric chlorination in a total synthesis that was also blogged by Tot. Synth. (JACS 2009, 131, 5744).

  • Liquidcarbon says:

    If I’m allowed another thread hijack – does anyone have any idea what’s happening to the NaH paper? It was stated in that Chemistry World article that ACS has yet to comment on the episode. JACS most read articles has not been updated for some 2 weeks now. Could it be that they just don’t want to retract this hot article to attract more visits but unwilling to admit it? Could it be the reason why hexacyclinol article has never been retracted?

  • ... says:

    Liquidcarbon, ACS will not retract the article as the chemistry does in fact work if you set the reaction up sloppy enough. My guess is all that will happen is the authors will submit an addition/correction adding the reference they failed to site, and correct some of their bogus mechanistic ideas.

  • Gururaj says:

    I would say, it is just a hybrid project by the combination of Prof. McDonald and Prof. Robert Holton’s strategies.
    Choice of solvent HFIP solvent is Holton’s idea and the right side carbonate part is from McDonald’s work.

    Only novelity here is one pot(?) formation of tricylic ring system.