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Caribenol A   

15 September 2010 24,688 views 29 Comments

Li, Yang, Liu,Han, Yue. JACS, 2010, AOP. DOI: 10.1021/ja106585n Article PDF Supporting Information Group Website

It’s weird how diseases that seemed to belong to Charles Dickens can come back to haunt the modern world – except this time armed against our battery of treatments.  One such beastie is TB, which is something that’s becoming increasingly prevalent in the UK, about 60 years after it had been banished to historical literature.  Coupled with the fact that many other nations have just had to deal with it, and we’ve got a new grant-winning target – something Caribenol A has taken a fancy to.  (BTW, I caught my own Victorian ailment when I was at Cambridge – I was hospitalised with pleuracy of all things.  It hurt.  A lot.).  This brings us (with validated interest) to Zhen Yang’s synthesis of the target, the first so far – I’m sure other strategies will appear over the next few years.

Yang get’s into the nitty-gritty fast, referring us to literature syntheses for two chiral building blocks – and handily pointing-out that their syntheses are over 5 and 7 steps in the endnote.  After a further eight steps, his group had completed a precursor to the key step in this synthesis, a rather neat intramolecular Diels-Alder.  By using an activated acetylene, coupling with a fairly unadorned diene, Yang hoped to build a pretty busy cyclohexadiene in one step.  However, with no additive, the reaction failed to progress. And even with a variety of Lewis acids (all the usual suspects – MgBr2, ZnCl2, TMSOTf, AlC3, MeAlCl2, and BF3·Et2O were tried), nothing was doing.  Moving into the throwing-everything-we’ve-got-at-it phase (or to quote ‘With continuous effort, we subsequently found…‘), Yang found that BHT, in catalytic quantities, did the job nicely. (BHT is addressed as 2,6-di-tert-butyl-4-methylphenol if we’re still bring all formal about this…).  So what’s going on?  It’s a fairly heavily stabilised phenol, so I guess it’s fairly acidic, but I’m sure they must have tried other Bronsted acids…  It also acts as a singlet oxygen scavenger, but I’m not sure I can see why that helps.

Regardless, the result is pretty neat – one tricyclic ringsystem installed, and plenty of useful functionality to play with.  The next few steps reduced-down the least-substitited alkene and formed the gamma-lactone, with only one more piece of carbon to install – the methyl group on the cyclopentene.  Yang was slightly luck here, in my opinion, as a simple triflation of a cyclopentanone gave him the correct enol isomer such that a Pd-catalysed coupling reaction with dimethyl zinc gave the group the desired methyl-cyclopentene.  But then a lot of my chemical trimuphs came down to a healthy dose of luck!

Yang clearly like to take the odd chance, though, as he left one of the more challanging steps right to the end of the synthesis.  As can be seen in the final intermediate, the group were missing a hydroxyl group (as part of a 5-hydroxyfuran-2(5H)-one), and left it’s installation to last.  He admits that ‘various oxidative methods were screened in anattempt to achieve this goal…‘ (I wonder how many in reality), but the one that worked is one I’d forgotten – the Corey-Ensley oxidation.  Simple treatment of the substrate and triethylphosphite with oxygen (presumably bubbling through the solution) did what some might call a C-H activation (it isn’t really, and Yang doen’t call that either) to deliver the target in cracking yield.

Nice work – setting the bar for this target rather high.

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  • Quality Control says:

    “It also acts as a singlet oxygen scavenger, but I’m not sure I can see why that helps”

    I’m guessing (I don’t have access to the paper) they were seeing a lot of fully automatized aryl methyl ester.

    So they added BHT to stabilize the product once it was formed. I’m guessing again the reaction conditions were really mild. Something like toluene relux under argon with 0.2 equiv of BHT.

  • Dizzy says:

    Looks like this “Corey-Ensley oxidation” is sort of mentioned in passing in the reference given (“Preparation of an optically active prostaglandin intermediate via asymmetric induction”). Kind of a neat, maybe they decided to give it “named reaction” status since it was their savior.

  • Whatever says:

    I think the BHT works in two ways, to aviod the radical ploymerization of the substrate and the aromatization of the product.

  • Henry says:

    Great comment! Maybe all those Chinese characters confused you when you linked the group website, the right one is this : http://www.scbb.szpku.edu.cn/yang/

  • curious chemist says:

    In the SI they mention that 4 is very sensitive to organic base. The problem in the IMDA may be that the triene 4 is subject to double bond migration (under base catalysis, or via radical intermediates). The question is, whether BHT is really catalysing the IMDA or just preventing double bond migration in the s.m. and product.

  • Cascade says:

    I think BHT as a singlet oxygen quenceher avoids the DA reaction of the singlet oxygen (a good dienophile) with the cis-diene.

  • Struggling Chemist says:

    I’ve been struggling to do a similar addition of a propiolate anion to an aldehyde with an adjacent quaternary carbon (like they do in scheme 1 9->10). Yields are always quite low for me and many examples I’ve seen in the literature. Any advice from someone who has tried this? I don’t know how they got managed to get such high yields in this paper :S

    • Whatever says:

      In my experience, this type of addition always give almost quantative yield if there is no alfa hydrogen in the aldehyde, What is you substrate like?

    • curious chemist says:

      Why is Your yield so low (incomplete formation of the acetylide, instability of the acetylide, incomplete conversion of the addition, formation of by-products, degradation of the addition product, degradation during w/u)? I think the solution of Your problem lies in the answer to this question. Besides that, how about running the reaction in a react-IR, so You can monitor the conversion? Or do some kinetic experiments (product profile vs. time).

    • LiqC says:

      I’m tempted to assume that you overheat the mix during metalation, which results in the reaction of unreacted acetylide with itself (and unreacted propiolate). You want to keep it really cold. Try –94 (acetone/liquid nitrogen).

  • ... says:

    Are you using excess propiolate anion? From my experience, addition of acetylides to complex aldehydes typically require at least 2 equiv of the acetylide to get high yields. Note in the SI that they use 2.9 equiv of the propiolate in their procedure.

  • novaChem says:

    If anyone wants a laugh check out Miles et al. Joc article (furan approach to Vit D, 2010 ASAP. He speaks of an ‘nearly unprecedented ene reaction’! (aka a Michael addition!. Also surprised 3-methylene-2,3-dihydrofuran exists.

    • stir_bar says:

      Want a laugh? Athough I wouldn’t say unprecedented, it isn’t Michael addition.

      Ok ok, it is formally a Michael but almost goes through a concerted process. My guess is that under Michael conditions, that is acid or base, one would get the isomerization to the aromatic compound (probably why you didn’t think the compound existed).

      Take a look!

      Tet. Lett. 1993, 34, 5221.

      • novaChem says:

        stir_bar thanks for the reference, still disagree though, ene reactions do not happen at Austalian room temp! Obviously you can draw a stepwise mechanism for an ene reaction, however ene implies concerted, this is not! The reason I was surprised that 3-methylene-2,3-dihydrofuran exists is due to rapid aerial oxidation, not isomerisation in the presence of acid or base.

  • speaking of... says:

    unprecedented. What do the caribenol authors mean by “unprecedented tricarbocyclic ring system?” Isn’t this the same ring system as JOC, 2006, 71, 6892?

    • tonganlhy says:

      No. Guanacastepene actually is a different system. The positions of methyl groups are different. Besides, guanacastepene has a isopropyl group which makes it easier to propose the biosynthesis. You can check the SI of the isolation paper for the proposal of biosynthesis for caribenol A.

  • ch3mical says:

    off topic. can anyone recall example complex natural products that are isolated racemic?

    • hdhao says:

      You can check Pro Dirk Trauner’s JACS,10.1021/ja803498r,he mentioned some natural products that were isolated racemic.

    • taco says:

      Endiandric acids are a classic example.

    • milkshake says:

      Atropine is another famous compound that comes racemic in nature. (but optically pure as hyosciamine from others). Also some simple terpenes come in various ee depending on the source.

  • Maria says:

    Hey Paul,
    are you sure your email works OK? I sent a message a couple weeks ago, but never got an answer back. Would you please check the Trash maybe?

  • chemist_in_the_making says:

    (+/-) – clausenamide occurs naturally as a racemate

    Artochamins are racemic natural products isolated from the roots of Artocarpus chama

  • chemist_in_the_making says:

    and why do I think that this synthesis is just okay at the best?

    P.S – That last step (corey oxidation) has been utilized atleast 20 times in the literature

  • chemist_in_the_making says:

    This is off topic but has anyone seen this paper. Damn good work in Tet Lett!

    Tetrahedron Lett, 2010, 51, 5546 – The first total synthesis of lactonamycin, a hexacyclic antitumor antibiotic

  • InfMP says:

    Anybody remember the corresponding author getting called out by Baran?


    Footnote 3.
    Whatever happened with that??? Nothing?

  • YaSheeMa says:

    How about that perophoramidine synthesis?

  • DMDO says:

    just for learning~

  • IIT-K chemist says:

    In my opinion luck has little to do with triflation of the cyclopentanone. The angular methyl group offers a significant steric hindrance for the base to pick up that ‘proton under the tree’. Yang orchestrated his synthesis bearing this factor in mind…I guess.