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(iso)Bongkrekic Acid   

20 December 2009 15,076 views 27 Comments


Ley, Francais, Leyva, Etxebarria-Jardi. Org. Lett., 2009, ASAP. DOI: 10.1021/ol902676t. Article PDF Supporting Information Group Website

For those UKian readers out there, there’s a fittingness to my posting a Cambridge paper following an Oxford last week.  Having spent a bit of time at both, it’s hard for me to pick a particular allegience, but I guess I have to go light blue, and congratulate the boys for their dug-in performance at Twickenham a few weeks back.  But I am particularly lucky to have been at both, as their approach to organic chemistry was so markedly different.  Both universities might be perpetually mentioned in the same breath (or word, the horriffic OxBridge, cause of many a confused tourist in Uxbridge), but the departments couldn’t be more different.  Simply consider the staffing rosters: Ox Cam.  And that difference will only get more dramatic in the near future, as Steve Ley heads for the retiral office (something I’m still uncertain of…).  However, he’s a long way from done, as this new Org. Lett. points out.


Bongkrekic acid is a scene of much synthetic action, with an early triumph by Corey, and a less satisfying effort by Ley last year.  In this paper, Ley admits that their previous effort was somewhat crippled by an ill-fitting methodology, and that this most recent synthesis is an attempt to right this.  And quite success it is too, focusing on using the best methods available for each coupling.  The retro outlines that this paper is indeed coupling-tastic, using quite a few pots from Strem.  But what was often more interesting is how the group made the coupling precursors, with a particular emphasis on installing vinyl iodides.  First up is actually a vinyl-stannane, installed using a stereoselective Piers hydrostannylation, nabbed from this JOC paper.  But what was of more interest to me is a simple piece of convergence I haven’t read before – concommitant deprotection of a TBS ether and oxidation directly to the acid using Jones reagent.  Neat.


And we’re into our first vinyl iodide synthesis, and it’s a prep I’ve used before.  You take your acetylene in hexane, bang in some DiBAL-H, and vac-off the solvent.  The DiBAL-H, meanwhile, has added across your triple-bond in a hydro-alumination, and you isolate this vinyl-alane – not a particularly nice species.  This is then quenched by addition of iodine in THF (better hope it’s dry), giving a pretty decent yield of vinyl iodide, stereoselectively.  This was all well-and-good when I was doing this on a small scale in the lab at Cambridge, but when I moved for my industrial placement at AstraZeneca, the lab-saftey people went nuts, so I ended-out getting a custom synthesis done at their expense…

One iodine isn’t enough here, though – a gem-diiodide (looks real-stable, right?) was formed by oxidising the alcohol to the aldehyde, and then adding hydrazine and iodine.  The details are apparently in this 1970 J. Aust. Chem. paper, but I don’t have access – anyone like to elaborate?


Okay, time to couple something – and using what Ley refers to as the Stille-Migita coupling.  Using CuTC in Stille type couplings is something I’ve written quite a bit about, but I’d always attributed the reaction name to Liebeskind.  A difference is that in most of the Liebeskind work, copper is the sole metal, whereas Ley uses a spot of palladum too.  He also uses a phosphonate base, and explains it’s role as that of tin scavenger.  I wonder if it a) makes the reaction smell less evil and b) allows for a less-streaky column.  One can only hope…


Time to make another vinyl iodide, and this time the chemistry is old school.  Using diethyl methyl malonate (which smells so nice it’s really difficult not to eat it…), a little base and some iodoform, a displacement of one iodine seems to be order of the day.  Following this with a bit more base, and we get a decarboxylation, saponification (of the remaining ester) and elimination, binning the penultimate iodine and generating the vinyl iodide.


This little fragment was coupled up in a Suzuki coupling, quickly generating a diene and finally getting the group ready for a bit of non-flatland chemistry.  Their intention was to do an asymmetry propargylation, and they opted for an Indium mediate reaction using Singaram’s chemistry, which uses an ephedrine-like ligand to provide asymmetry.  The resulted in a cracking yield, but also a disappointing enantiomeric ratio.  The group managed to boost this with some of Greg Fu’s work, using a planar-chiral DMAP-ferrocene catalyst (commercially available) to do a non-enzymatic resolution.  More about that in this Chem. Comm.


And now we get to the final coupling, a Sonogashira using a vinyl-iodide.  Typical conditions using a bog-standard palladium source and similarly common copper salt resulted in a rather neat yield of the enyne.  However, what they desired was of course the E,Z-diene, so a bit of reduction was in order.  The most obvious choice, Lindlar catalyst, failed, giving the group a bit of a headache.  I’ll presume that a few sets of conditions were examined for this reduction, as their success with copper/silver activated zinc seems a little obsure.  I’d have tried diimide, but they didn’t ask me…


It did work, though, giving them a very respectable yield of the desired product (the tri-methyl ester of the natural product), along with some of the undesired Bongkrekic Acid.  Separation at this stage, followed by saponification (without any isomerisation) gave the group a portion of each natural product, rounding-off a cracking read and an interesting synthesis.

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  • Gui says:

    I think you might have an obsession with eating malonates jajajajaja
    About the gem di-iodo, the iodine oxidizes the hydrazone to a diazo compound(the is addition of I2 to double bond and elimination followed by another). The diazo attacks iodine and then nitrogen is eliminated leaving a carbocation. Iodide attacks it forming the di-iodo.

    • Tot. Syn. says:

      I know I have an obsession with malonates – I worked with them for my PhD… I used some today, but managed to resist the urge. I did spend some time smelling it though.
      Thanks for the explanation!

      • tenderbutton says:

        For goodness sake please just indulge yourself with the dimethyl malonate, once, and get it out of your system. 1uL on the tongue, what’s the worst that could happen? At least promise me on your deathbed you’ll cozy up with a warm mug of the sauce.

        I assume you’ve seen the impressively-long list of certified kosher chemicals that Aldrich sells. You can buy kosher 6-methyl-5-hepten-2-one! What a world we live in.

        • claud says:

          One of the largest uses (1000s of tonnes/annum) for methylheptenone is for the manufacture of vitamin A and phytol.

  • MSG says:

    Elaborating the Aust J Chem paper:

    Pross and Sternhell (U of Sydney) conducted a systematic study on the oxidation of hydrazones with iodine in the presence of base, a reaction that was first discovered by Barton (J. Chem. Soc., 1962, 470, doi 10.1039/JR9620000470), but not systematically characterised.

    The reaction (hydrazone, Et3N, I2, Et2O, rt) typically gives the desired gem diiodides in 30-40%, with the major byproduct being the corresponding vinyl iodide (that is, through a ‘formal’ elimination of HI, although the authors do not believe the elimination route explains its formation).

    The mechanism of the reaction was proposed by Barton (and I’m assuming it’s described in the J Chem Soc paper… to which I don’t have electronic access ie couldn’t be bothered going to the library), and it’s a mechanism that the Australian study further confirms. In short, the reaction is believed to go through a diazo intermediate, electrophilic addition of I2, expulsion of N2 to form a cation intermediate. SN1 addition of I- gives the gem diiodide, or E1 gives the vinyl iodide.

  • Sergio says:

    I bet at least half of those reactions could be done without transition metals just involving classical chemistry. I do not want to say that transition metal catalisys is bad. It is great and indispensable in some cases. I done my Ph.D. with that. But now people dump palladium or other TM in almost all the reactions. Why??? I would not be surprised if in 10 years making acetophenone in undergraduate lab in instead of acylatyng benzene would involve reaction of bromobenzene, palladium complex, carbon monoxide and some boron or stannic stuff to put in methyl. Well do not take it all to seriously, it was just my personal point of view, nothing else.

  • Old Timer says:

    FYI: I think you meant to disconnect the adjacent bond for the Stille-Migita in your main graphic :)

  • No Way says:

    I guess I was wrong, and the 5,5-is not invincible.


  • TLC is dead says:

    Put your hands up for Palau’amine, I love that molecule!

  • Santa says:

    Ho. Ho. Ho.

    Palau’amine in yer stockings.

    Ho. Ho. Ho.

  • wow! says:

    Woo hoo, Palau’amine! So famous!

  • GYA says:

    i was about to post a comment that total synthesis is really stalling lately (with a few exceptions) especially if we’re left to discussing polyenes, BUT then Phil goes and toples yet another elusive structure! can’t wait to see it. Happy Holidays from the Baran lab!

  • UBChem says:

    The infamous Sodium Hydride paper has been withdrawn from JACS. Hmmmm.

    • stork naked says:

      i noticed that retraction as well… a bit overdue but the wheels of science grind away…

  • InfMP says:

    The mechanism proposed by Barton in the 1962 JCS is unlikely. Most people would not proposed the C=I+ intermediate.

    The iodide adds to the diazonium and then base eliminates N2, securing the vinyl iodide.

  • BS alert says:

    More BS from chinese: http://pubs.acs.org/doi/abs/10.1021/ja909038t

    who wants to bet this is yet another case of oxygen doing an oxidation?

  • GYA says:

    palau’amine is out!

  • marino says:

    Thank you baran lab – first time wet my pants while reading a paper.

    synthesis of the decade…

  • aaaa says:

    Actually this Stille-Migita coupling using CuTC, Pd, and P-reagent comes from Furstner’s lab.:
    A Versatile Protocol for Stille-Migita Cross Coupling Reactions.
    Chem. Commun. (Cambridge) 2008, 2873-2875.
    And since I was in the group at that time, I know it was developed for the little bastard Amphidinolide H (for the bloody-difficult diene unit).

  • aaaa says:

    Another comment about the Si-protected oxidations. Not very surprising, I have personally used a simple Swern on primary OTES-protected material and it works just fine – simply longer reaction times, and you get the aldehyde in high yield.