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18 April 2010 17,165 views 24 Comments

Bradshaw, Bonjoch, Etxebarria-Jard?´. JACS, 2010, ASAP. DOI: 10.1021/ja101994q. Article PDF Supporting Information Group Website

It’s been a while since I wrote about a synthesis from Spain, so it’s nice to return with a rather sweet synthesis from the labs of Josep Bonjoch and his compatriot, Ben Bradshaw. Their efforts have been focused towards a sub-set of diterpenoids produced by Aspergillus, in which the decalin ring junction contains a pair of quaternary carbons.  That’s a pretty significant challenge by itself, but the rest of the decalin in subsituted in an all cis- arrangement, making for a pretty tricky system.  Perhaps this is why there have been no reported syntheses!

The Spanish team’s approach hinges on a rather tasty piece of methodology executed in the first few steps of the campaign.  Using a rather complex-looking proline/BINOL derivative, they were able to perform an asymmetric Robinson annulation, requiring only 1 mol% base catalyst.  This produced the Wieland-Miescher ketone product in an excellent yield and enantiomeric excess, allowing them to proceed directly to a conjugate addition.  Using the usual cuperate conditions, they completed quaternarisation of the decalin in only three steps and in impressive yield.

A selective ketone protection / methylenation / deprotection sequence later, they were ready to functionalise the decalin.  A key synthetic handle was enone-functionality, installed using Nicolaou’s hypervalent-iodine prep.  This might not be a stunning yield, but in terms of route-efficiency, you can’t beat it.  However, IBX at 70C is somewhat of a concern…

A futher methyl group was appended using an interesting approach of enolisation followed by Eschenmoser’s salt.  Reduction then provided the desired methyl group in the correct orientation.  Rather neatly, they then moved the oxygenation around the ring by reducing the ketone and displacing with an aryl-selenide.  Treatment of this with mCPBA allowed the usual sigmatropic rearrangement to occur, where the conformation of the ring allowed for a nicely diastereoselective reaction.  Interestingly, this reaction only performed well when the solvent was wet…

Even-more selenium chemistry was used to install a further enone (I feel sorry for the other workers in this lab – I hope the fume-hoods were up to the task!!), leaving them perfectly set for addition of the indole moiety.  The group admit that they did a screen of Lewis-acids in the lab, and that for no-reason-in-particular, zirconium tetrachloride was the winner.  This lead to the all-cis arrangement required in the target – with an interesting deprotection of the pendant acetate using KF in ethanol.  Anyone done that chemistry before?

Getting to the target took a futher four steps – oxidation of the primary alcohol and methylenation provided a handle for metathesis to complete the prenyl group, followed by deprotection of the remaining TES group.

All things considered, this is a really neat synthesis and a cracking implementation of some powerful methodology.  The best thing is that their methodology fits pretty much perfectly – it isn’t shoe-horned into the synthesis like we see in many other papers.  The only catch is that the route is entirely linear – something that I think is unavoidable with this target, so of no real consequence.

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  • Diels-Alder says:

    Oh I admire so much these people… what beautiful synthesis… I’m medicinal chemistry student and now start my work in synthesis and just love your blog… Compliment for your wonderful blog!!!!

    I share in my blogroll

    good bye and excuse me for my imperfect english

  • milkshake says:

    Sorry for being argumentative but

    1) the asym organocatalyst is a derivative of 2,2′-binaphtyldiamine, not of BINOL, and it is probably made easily in two steps if you have the diamine (Aldrich sells it but it is dear). My guess is that they made their own binaphtyldiamine in one step by heating beta naphtol and hydrazine (a disgusting but scalable procedure) and resolved it with CSA.

    2)Why is IBX at 70C a concern? Explosivity of IBX has been vastly exaggerated, I think the problem was a shock sensitivity, especially in large quantities, especially with an impure product that was made by the old bromate oxidation method. IBX is quite dense so 40 g of it will easily fit the Buchner funnel, and when you made a large batch of it it is easier to have some iodoso impurity present, and as you scrape the hardened cake of IBX with steel spatula bad things can happen. But in DMSO, the IBX slurry will be tame no matter how much you heat it. My only possible concern would be that IBX is acidic – but they have no sensitive functionalities in the molecule.

    3) The indole addition to enone is nifty but not that new, I remember seeing analogous addition of indole to beta-nitrostyrenes. I think the problem was how to control the reactivity because lots of other condensation reactions could continue with the product, and they needed the kinetic product and to prevent the epimerization at a ceenter alpha to C=O. Supressing epimerization was probably reason for using EtOH-KF for transesterification (a normal protocol that carbohydrate people use for deacetylations is a catalytic NaOMe in anhydrous MeOH).

  • forbital says:

    seems like a simple asymmetric diels alder could have installed the bicycle very quickly.

    • stir_bar says:

      forbital I was thinking the same thing. By using Danishefsky’s, Rawal’s, etc diene one could (maybe not so easily) form that bicyclic enone. Just an idea.

  • a-non says:

    Are you suggesting a Diels-Alder to form the two quat centres? If so I would have to say that it will look allot nicer on paper than in the real world.

    • milkshake says:

      I have seen people doing Diels-Alder with 3-methyl-2-cyclohexenone but with such a lousy dienophile one needs to use a very strong Lewis acid activator like AlCl3, and that puts constrains on what can be used as a diene partner. With extra 2-alkyl I think it is pretty hopeless, you would have to have EWG group like carboxyester in the 2-position for the DA to work, then you would have to elaborate the ester into an equivalent of allyl so any step-saving advantage of DA would be defeated. And then we would have to worry about asymmetric version… The Robinson anulation route is not bad at all.

    • forbital says:

      I definitely agree, but then again I’ve seen some very inspiring DA’s. No, I was suggesting that with a thorough lit search one would eventually come across the appropriate substrate that would give the bicycle using DA chemistry, either through asymmetric catalysis or substrate control, inter or intra-molecularly, leaving desirable functionality to quickly modify it to product. I don’t think there is anything wrong with their approach, I just think they looked a bit too much at the WMK-derivate as a starting point, and then had to work around the shortcomings of such a route. Still, great chemistry!

  • chemist_in_the_making says:

    I agree with you Milkshake on many comments of yours.
    Being a synthetic organic chemist, I am fascinated by synthesis of ideas from methodology as applied to the total synthesis of natural products. Congratulations to the Spanish group for their synthesis. I liked this total synthesis, hoever, I did feel the paper lacked in novelty and creative designing.
    First up, a myriad of catalyst exist for doing the asymmetric roboinson annulation. The choice of 2,2?-binaphtyldiamine derivative maybe due to the scale up ease as these are synthesized from 2,2?-binaphtyldiamine (C-2 symmetric).
    Incidentally, I have observed the yield of IBX mediated oxidations to be around 60-75% in my studies for completely different substates(>10). Later, I found out that if the proper procedure for the synthesis of IBX (from 2-Iodobenzoic acid using oxone, temperature = 70 C!)is not followed then it would result in a low purity of IBX. The purity of IBX directly affects the yield of oxidation step. With a pure IBX, I have been able to increase the yield upto 90% for most of them. Also, IBX/DMSO is definitely stable till 150 C.
    I dont think that the group had to worry about the epimerization of the center alpha to C=0 (I disagree Milkshake) as the observed diastereoselectivity is the resultant of thermodynamic equilibrium, a case helped by subjecting the Michael adduct to the refluxing KF-EtOH solution.

  • The Next Phil McGroin says:

    is it me, or do they make the wrong enantiomer of the natural product. The stereochemistry is ultimately determined by the inital annulation with MVK, so the opposite chirality generating catalyst (which likely is non-trivial due to it being from L-proline) should give the oppposite enantiomer of the natural product ultimately.

    I do not think that this is a small point as if it were, the group should have made the correct optically pure natural product.

    • milkshake says:

      You could buy Boc-D-proline – it is not cheap but since they are using just few mol% of the organocatalyst it does not seem like the cost-limiting factor

      • CanChem says:

        I don’t mind at all that they made the ent- product; they explicitly state they didn’t know the absolute config going in, and the Robinson and subsequent chemistry ought be similar with the opposite enantiomer. If the group doesn’t say they were out to make kg’s of the pure natural stuff for biological testing, SAR etc, then make whatever rotation of it you want.

  • WestCoast85 says:

    A boring synthesis for a JACS paper…. It’s just an addition of well known methods. A perfect OL for example !

  • asian chemist says:

    I was wondering if anyone can explain the cis-selectivity of the cuprate addition to the Wieland-Miescher ketone? Pardon me, I was expecting a trans-decalin formation from the pendant allyl group. Thanks! Tot syn – you have a really cool blog.

    • connor says:

      This paper should be helpful:

      Marshal, J. A.; Fanta, W. I.; Roebke, H. J. Org. Chem. 1966, 31, 1016.

  • John Wood says:

    at asian: Its the concave face, i believe.

  • asian chemist says:

    John Wood: Thanks! I was thinking of that too initially and represented it on Chem3D…looks quite flat though (to me), while the allyl group looks dominating on the top face.

  • antiaromatic says:

    John Wood: I agree with asian chemist. This system doesn’t have a “concave” face to speak of because the SM has an sp2 center at the bridgehead.

  • chemist_in_the_making says:

    I agree that the molecule has an sp2 center at bridgehead carbon but, I still believe that the molecule adopts the conformation which facilitates the attack from the top face. The rationale for this (its a hypothesis) is that in the transition state the two carbonyls are chelated to a lithium cation. For this to happen the two ring system in decalin ring system has to adopt a twisted partial chair like conformation where the respective carbonyls are facing down (the allyl group disfavors the chelation from top face), thus directing the addition from the top face.

  • asian chemist says:

    Will one lithium cation be enough to chelate to the 2 rather far apart carbonyls? Besides, Li+ is better with single coordination than chelation. Furthermore, with the Gilman’s reagent, Me2CuLi exists as an aggregrate in the reaction which also mean (at least to me) Me- should be delievered onto the same face as the coordination face. Thats what I thought?

    • LUMO says:

      According to the article at the bottom a dimer of Gilman reagent is chelated by the carbonyl and the double bond. This makes the molecule adopt a curved geommetry thus delivering the methyl from the convex face.

      Wolfram Henze, Tobias Gartner and Ruth M. Gschwind, J. Am. Chem. Soc. 2008, 130, 13718–13726

  • asian chemist says:

    That helps! Thanks LUMO.

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