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Coralloidolides A, B, C, and E   

16 March 2010 14,440 views 13 Comments

Trauner, Kimbrough, Roethle, Mayer. ACIEE, 2010, EarlyView. DOI: 10.1002/anie.200906126. Article PDF Supporting Information Group Website

It’s not often I get to summarise an entire paper in one scheme, so I’m not.  Erm, what I mean to say is that I could, but I think for decencies-sake, I’m going to pad this out a bit!  Back in 2006, Dirk Trauner (still at Berkeley back then) completed a rather neat synthesis of Bipinnatin, completing the target in a rather neat nine steps (including a very nice Alder-ene reaction…).  This synthesis was actually a means to an entire series, as Bipinnatin can be converted into a whole-load of natural products in a biosynthetic fashion.  This was also published in 2006, and resulted in Intricarene (using a 1,3-dipolar cycloaddition), as well as Rubifolide and Isoepilophodione.

This most recent work in Angewantde takes this further, turning Rubifolide into the Coralloidolide family, again using biosynthetic principles.  I’m not going into the Bipinnatin J synthesis – that actually goes pre-TotSyn (PTS), but I’ll mention that reduction of that into Rubifolide needs only a little triethylsilane, selectively nuking that pesky hydroxyl in almost quantitative ease.  Again, that was published earlier, so to the new stuff – starting with an oxidation.  Using that primitive formula of basic peroxide, a nucleophilic epoxiation selectively oxygenates the furanone, entirely diastereoselectively, and yielding the first Coralloidolide, A.  Switching to mCPBA, the oxidation action moves to the furan, ring-opening to a 1,4-diketone and generating a rather suspicious-looking ‘dienedione‘ (???).  This, amazingly, is a further Coralloidolide – E this time.  I’m utterly amazed that this beastie is stable enough to isolate…

Unstable it was – finding reliable conditions for transformation of Coralloidolide E was an effort, with Trauner describing loss of much of their material to ‘a large number of intractable products’, or as I tend to term it, black guff in a flask. Instability is the key, though, as treatment of this with a little scandium triflate (probably quite a long way along the likely-reagents-shelf) resulted in a double trans-annular ring closure, producing a dihydrofuran and a tetrahydro pyran oxepine, along with a pair of stereocenters.  Bizarrely, only dioxane (or dioxan as my lab-mates insist on naming it…) is good enough for this reaction – other polar-aprotic solvents such as DMF don’t do the trick.  Trauner believes the mechanism is distinctly stepwise, with a hydration of the dienedione first, and then closure onto the epoxide, and that the scandium triflate is required for both steps. Trauner also manages to effect a synthesis of Coralloidolide C, using DBU to perform a transannular aldol reaction on Coralloidolide E, rounding off a rather neat bit of work.

Don’t feel too short-changed by this micro-post; I’m working my way through Overman’s epic Actinophyllic Acid paper this week, and might have it out tomorrow.

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  • ,,, says:

    dihydropyran, not tetra…

  • milkshake says:

    maybe the diketone from furan oxidation is isolable because the carbonyls are not in the plane of the C=C because of the macrocycle ring so the conjugation is not as efficient, plus there is methyl group. So this C=C is not as activated as a Michael acceptor

  • gippgig says:

    It isn’t a pyran either – there are 7 atoms in that ring.

  • anon says:

    Nice paper, nice writeup. A minor criticism: I believe you mean ‘biomimetic’ rather than ‘biosynthetic’ throughout…

  • The Next Phil McGroin says:

    have not read the paper yet, though this writeup indicates its a nice piece of work so i will…

    I cannot imagine how many different sets of conditions those students must have tried before landing on Sc(OTf)3. I mean the first two transformations are pretty straightforward, probably one of the first things they tried…KUDOS.

    • chemist_in_the_making says:

      I don’t think it needs an extensive effort to zero in on Sc(OTf)3. Although its a rare earth metal triflate, the lewis acidity is very comparable to TiCl4 (although coordination no can go upto 12). Some other rare earth metal triflates worth a try is Cu and Yb. Overman has employed Sc(OTf)3 for so many lewis acid catalyzed transformations in his recent work.
      Very nice piece of work by Trauner.

      • European Chemist says:

        Uh… I think Cu is not really a “rare earth metal”…
        But indeed Sc, Yb and La triflates are very common Lewis Acids for mild transformations like this one.

  • Gui says:

    Maybe the ketone dienone is stable due to the fact that if it reacted it would produce an sp3 centre and that might bring about transannular strain? I know the ring is too large but its just a thought :)
    Maybe they needed the strong lewis acid Sc(tfo)3 so the hydroxil would attack the rather unreactive conjugated ketone,and in a 1,2 addition fashion. And i agree they probably tried many reagents before using Sc.

    • chemist_in_the_making says:

      Gui, Sc(OTf)3 doesnot activate the ketone group. The cascade reaction starts with the activation of epoxide followed by the subsequent ring formations. After the last ring closure, the resulting carbonium (allylic tertiary carbocation) picks up a molecule of water from reagent to provide the given product. The carbonium doesnot undergo isomerization to allylic secondary carbocation as it is less stable then allylic tertiary carbocation.
      I am sure that other lewis acid will carry out this transformation just fine but, they all need anhydrous conditions to be effective. In the absence of a trapping agent (H20), the hot oxonium (carbonium) undergoes fragmentation pathway = decomposition. Scandium triflate is relative stable to water. You can actually perform these reaction with scandium triflate in water (enantioselctive variant also reported in literature).

      • Gui says:

        Thanks for your imput on the reaction! It makes a lot more sense now!
        I would have imagines that ScOTF would have to be used under anhydrous conditions!

  • fhp says:

    This is a nice body of work by Trauner. I’ve enjoyed reading his papers in the past, but recently I’ve been concerned about his apparent lack of productivity (i.e. publishing). It’s nice to see him back on the ASAP/Early View pages.

  • wozj says:

    it’s a beautiful work