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9-Isocyanopupukeanane   

2 December 2009 14,989 views 26 Comments

9-isocyanopupukeanane

Corey, Brown. Org. Lett., 2009ASAP. DOI: 10.1021/ol9025793Article PDF Supporting InformationCorey, Behforouz, Ishiguro. JACS., 1979, 101, 1608–1609. DOI: 10.1021/ja00500a048Article PDF Supporting Information Group Website

Again, it’s been a while since I blogged, and this time the excuses are two-fold.  First of all, I moved home recently to the leafy London suburb of Surbiton (saaf-wess, for natives…), and have been without my computer, interweb access and beer, all three of which are required for blogging.  However, more critically, there’s been a real dearth of total synthesis in the ASAPs, so much so that this paper isn’t even a formal synthesis (not in the title at least).

What we have here is a Corey Org. Lett. examining an interesting array of asymmetric catalysis.  Primarily, the paper discusses ‘highly enantioselective Diels-Alder reaction with an acetylene equivalent to produce chiral-bridged dienes‘.  However, it turns-out that these bridged dienes are also active ligands in a second asymmetric process, ‘enantioselective addition of vinyl or aryl groups to unsaturated ketones‘.  It’s this second reaction that is the centre-piece of this post, as it leads to an intermediate found towards the back of the Corey filling cabinet room, early in a 1979 synthesis of the title compound.  So this is really just an excuse to look at that paper, but it’s always good to read prime-time Corey.

9-isocyanopupukeanane_1

So first up is this new-fangled asymmetric addition chemistry, using a ligand (12) produced earlier in the paper.  This bad-boy coordinates to the rhodium catalyst, allowing delivery of the aryl (or vinyl) boronic acid as a net reduction.  Interesting points are the vanishingly low catalyst (and ligand) loading, as well as the opportunity to produce the ligand in-situ, developing a rather special cascade-type reaction.

9-isocyanopupukeanane_2

Moving to the total synthesis, a reaction I’d virtually forgotten was used to transform the methyl ketone into the corresponding carboxylic acid.  It’s rather mild, requiring only room-temperature and six hours, and produces a product several steps faster than than might otherwise be construed.  The free acid was then chlorinated to the acid chloride, and a bit of Lewis-acid allowed ring-closure onto the proximal aryl position.  A bit of alkylation with TOSMIC (hydrolysing the nitrile and methylating) and methyl iodide provided enough carbon to get on with things.  A key reaction was de-methylation of the phenol, as this promted gamma-lactone formation. Exhaustive hydrogenation using Nishimura’s catalyst did for the benzene ring, establishing three stereocenters with control presumably arising from the lactone bridge.

9-isocyanopupukeanane_31

Job done, the lactone was opened, reduced and tosylated, providing a nice leaving group.  Treatment of the cyclohexanone with base can then, of course, deliver two enolates, with thermodynamically more stable preferred, as internal alkylation with this gives the carbon skeleton of the target.  However, using LDA over-turns this preference, and results in cyclobutane formation.

9-isocyanopupukeanane_4

A few more steps were required to install the isonitrile, but with no problems.  Neat work from a prof at the top of his game.

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26 Comments

  • Organic says:

    I believe there are 2 spelling mistakes in the term Freidel-Krafts.
    Friedel-Crafts looks better to me.

  • Will says:

    I’m having a hard time seeing the lactone formation after the BBr3 demethylation, can it really form when the aromatic ring is still present?

    • The Next Phil McGroin says:

      it is during the hydrogenation…presumably the saturate alcohol attacks the ester forming the lactone

      • Will says:

        Fair enough, but if the alcohol can’t condense with ester until the ring fusion hydrogens are installed, the stereocontrol is from the isopropyl group

  • Gui says:

    IMO, the aromatic ring is hydrogenated first and the resulting cis fused biycicle ows its stereochemistry thanks to the isopropyl groups. Because the rings are cis fused, the alcohol and ester groups are closer in space and their reaction is favourable.

  • Moody Blue says:

    Very important and extremely useful work indeed. I was wondering if the Rh-catalysed conjugate addition of boronic acids works only on alpha, beta-unsaturated ketones, but not on esters? I’d guess not – they would have used that and gotten the acid by simple hydrolysis of the product. Still 60% with the bromine/KOH is not bad.

  • Atticus says:

    Paul,

    Not sure how you can make that ligand in situ. It inolves multiple steps, the last of which is an organometallic addition. Wouldn’t that mess with your ruthenium-catalyzed business?

  • Eraser says:

    The diene ligands and the rhodium chemistry of same is simply an extension of the work by Hayashi and Carreira who came up with this chemistry a 3-4 years back.

    With their ligands the conjugate addition works for unsaturated esters and even unsaturated aldehydes.

    See e.g.
    J.-F. Paquin, C. Defieber, C.R.J. Stephenson, E.M. Carreira, J. Am. Chem. Soc. 2005, 127, 10850.
    Asymmetric Synthesis of 3,3-Diarylpropanals with Chiral Diene-Rhodium Catalysts.
    http://dx.doi.org/10.1021/ja053270w

    Hayashi, T.; Ueyama, K.; Tokunaga, N.; Yoshida, K. J. Am. Chem. Soc.2003, 125, 11508.

    • Moody Blue says:

      Thank you for the references. That would explain why this work ended up in Org Letters (with all due respect), I suppose.

      • milkshake says:

        The Rh(I) asym C=C boronic acid addition method is older than that, it was originally developed with BINAP-Rh and the ees were pretty decent for this class of sunstrates.

        I think a pharma process chemist would not use this route. They would make a beta-subst cinnamic acid by Knoevagenel or by Witting from acetophenone, or by Heck. Then they would look for asym Rh or Ru hydrogenation catalyst that can deliver above 85% ee on hydrogenating free cinnamic acid and would do final enrichment by re-crystallization with some cheap chiral amine

  • The Dutchess says:

    It’s not leafy, it’s arbo…

  • Ed says:

    is there a reason they didn’t start with a benzyl protected aromatic and do an O-debenzylation-aromatic hydrogenation-lactone formation in one step?

    • milkshake says:

      the catalysts that do O-debenzylation (Pd and sometimes Ni) are excruciatingly lazy for hydrogenating benzene rings, so one would have to use drastic conditions to bring this about with the same catalyst. But a good alternative would be to start with Pd, like Pearlman and when all is debenzylated throw in some Nishimura cat and keep hydrogenating.

      • The Next Phil McGroin says:

        but, is that anymore desirable than a easy BBr3 demethylation, over in ten min?

        • milkshake says:

          Process chemists hate BBr3 because it is such an evil smoke, the quench has a huge exotherm and HBr corrodes stainless steel. They would much rather do py.HCl melting at 150C even in cases when BBr3 demethylation finishes cleanly in 10 min at 0C

  • InfMP says:

    Milkshake or anyone:
    speaking of hydrogenation of aromatics, I`m having trouble hydrogenating a 1,1-disub-double bond (methyl and 2-pyrrolo). I think my pyrrole is being reduced by the PdC H2 because the TLC becomes non-UV active mixtures. There is an ester at the C5 position too.

    What catalyst, homo or hetero should I try ?

    • Gui says:

      What have you been using that hasn´t worked? So as to rule out ;)

      • milkshake says:

        It coul be, I accidentally once hydrogenated amide of 5-(TMS-ethynyl)-2-furoic acid all the way down to TMS-ethyl-tetrahydrofuroic piece on Pd-C.
        Although I have seen porphyrine people doing hydrogenolysis of benzyl ester of pyrrole-2-carboxylic acid (with three alkyls on 3,4,5-positions) without a problem.

        I suppose you could try triethyl silane and TFA in DCM because the ester in the 5-position should make pyrrole slightly less el rich and hence less likely to crap up in acidic conditions. I used TFA in similar system.

        Then there is borane-DMS which should leave your ester unharmed if you dont push too much.

        Whats in the 2-position of your C=C that you are trying to hydrogenate?

        • Gui says:

          That is a good suggestion. You can check it out here

          Angew.Chem,.Int.Ed.Engl, 1999, 2934-2936
          or
          Tetthedron Lett.,1991, 32, 2083-2086
          Hope it helps!

        • Gui says:

          One last thing, shouldn´t pyrrole polimerize in acidic conditions???

          • milkshake says:

            no but one has to be gentle. Straight TFA up to 40C is tolerated even with 2,3,4-trialkyl pyrroles. I am not so sure what TESH would do – indoles can be reduced to indolines under similar conditions, thats why peptide chemists use iPr3SiH as a scavanger because it would not reduce tryphtophanes.

            One can easily end up with assortment of funny bright-colored oligomers when the pyrrole has no electron-withdrawing substituents and if one pushes too much

  • Oz says:

    Great post Paul,

    It was great to have a look back at Corey 30 years ago. The route is brilliant. I’m loving your blog.

  • Sergio says:

    Imho there are some ambiguity describing scheme3. TosMic should have been used for homologation of the acid before chlorination and friedel crafts, otherwise one would end up with 4 membered ring? It should be like: acid–homologation with tosmic–methylation–chlorination–friedel crafts. You write: “The free acid was then chlorinated to the acid chloride, and a bit of Lewis-acid allowed ring-closure onto the proximal aryl position”. And only after that you say: A bit of alkylation with TOSMIC (hydrolysing the nitrile and methylating) and methyl iodide provided enough carbon to get on with things”. One can not notice your latter remark:)

  • jayashree says:

    I would like to know whether activating Pd- catalysts with ACids during Hydrogenation and especially -debenzyltion would result in increasing the activity of the catalyst & also the raactionrate and speed of the reaction???Could you cite some references to that effect??