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Lupeol   

20 September 2009 16,477 views 40 Comments

lupeol

Corey, Surendra. JACS, 2009, ASAP. DOI: 10.1021/ja906335u. Article PDF Supporting Information Group Website

Steroid chemistry, anyone?  They seem to back to the fore again – probably due to a bit of cortistatin – but looking to Corey is probably a good move, as he’s been working in this area for years.  And lupeol has been a pretty popular target too – look to Stork for his classic 1971 synthesis, with countless others working past lupeol en route to other steroids.  But more on that later –  we gotta make lupeol first.

A draw back to all the work in this area over the last forty years is that syntheses of relevant fragments abound.  This means that that literature trail back to commercial starting materials is a pest, and I must admit I gave up.  However, examination of Corey’s starting point reveals a cuperate addition to a farnesyl acetate derivative, with the other fragment – a tetra-substituted benzyl Grignard – kinda ignored.  This leaves us with a plenty-conspicuous looking epoxy diene, which is loaded for cyclisation.  A bit of aluminium chlorides (why the mixture?) zips this up like a charm (measure ‘per ring‘, and it’s a 80% yield), completing three rings, installing five stereocenters and dearomatising the catechol.

lupeol_1

Some pretty drastic reductions brought the former catechol to complete saturation, and provided a further trio of stereocenters, the final installed by alkylation to provide the handle for another cyclisation.  This grabbed me a being a bit different – under standard mesylation conditions, the pendant olefin displaced the mesylate to give the final steroid ring, and the final stereocenter – classic steroid chemistry.  However, I’m not sure of the mechanism; I’m thinking attack of chloride (from the mesylation) into the alkene, and from there into the mesylate.  Elimination of the chloride again restores the alkene.  Whad’ya think?

lupeol_2

Removal of the TBS ether completes the initial target, lupeol – a mechanism I can at least handle.  But making this was only a means to an end, as the next thing Corey did was turn that lovely single-spot TLC into what my former advisor called a tartan TLC. Y’see, a spot of acid lets all sorts of shit break loose, giving the group a mixture of six different steroids.  Now, the yields might be kinda useless – but it is damn cool!  The amount of acid used was small, but the potency high, in the form of triflic acid.  The group measured the rate of rearrangement to the six product by comparison of crude material to authentic samples of each of the steroids (but how did they identify these particular products as being part of the brew?  Did they suspect these six in the first place?), and found that that five formed at roughly the same rate, with germanicol the runt of the litter.

lupeol_3

The important consequence of this is that this chemical result is quite different to that found in vivo.  Indeed, the triterpene synthase enzymes can target one steroid only, which Corey attributes to a combination of protein and substrate conformation.  He also concludes that this mechanism must be mostly aprotic, as an acid catalysed biosynthesis should result in the same mess diverse mixture found in the RBF.

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40 Comments

  • WestCoast85 says:

    I am not sur for the the mechanism of the formation of the cyclopentane ring but I think that the mesylation is followed by an elimination and an ene-reaction. My problem is to know if it possible to do this reaction at 0°C… Normaly, to the best of my knowledge, this is under thermic conditions…

  • No Scifinder says:

    Is scifinder down for anyone else? I havent been able to log on for two days.

  • Medchem says:

    impressive work.I found working on steroids (estradiol derivatives) little messy!

  • TA says:

    I guess the final cyclisation (mesylate displacement) is initiated by the solvolysis (though the DCM might be not a very good solvent for this) of the mesylate with the generation of a secondary carbocation (tight ion pair?) which is attacked by the double bond which results in tertiary carbocation followed by proton elimination.
    The support for this pathway comes from the isolation of another by-product which is shown in the SI and is formed by Wagner-Meerwein shift/elimination pathway.

  • WestCoast85 says:

    I am totally agree with you. I saw the by product in the SI and I had a lots of trouble in my mind to support my mechanism proposition :)

  • UBChem says:

    Yawn

  • H.C. Brown says:

    Anyone else see this nice application of some unconventional boron chemistry to the synthesis of palmerolide A (Dennis Hall, JACS ASAP)? Very creative! [I don't know why its not showing up on the JACS ASAP page, but you can find it by searching for the author.]

  • Atticus says:

    That Stork communication is a terrific read. I love how back then a single-sentence introduction was sufficient for a total synthesis paper. The formation of the cyclopropane followed by reductive alkylation of the cyclopropane to give the two angular methyl groups is a slick sequence even by today’s standards.

  • sls says:

    Would someone tell me what’s difference of this work from the late W.S. Johnson’s steroid chemistry (at Stanford) ??
    I think Corey used epoxide instead of olefin from Johnson’s work.
    And cyclisation is almost same but Corey didn’t refer it.
    Totally I can’t understand why Corey didn’t do that.

    • stop says:

      wwejd?

    • Rockin' Ray says:

      sls,

      WS Johnson didn’t use epoxides as cyclization initiators because they rearranged to ketones, etc., in his early studies. He looked for better initiators and found two good ones, acetals and certain allylic alcohols. See Tetrahedron 1991, 47, xi–1. Van Tamelen stayed with the epoxides and they were always troublesome, although some promising results were had eventually. I believe EJ was the first to report good yields and good ee’s from epoxide-initated cyclizations, using Me2AlCl.

      I was a Johnson PD ’84 to ’85 and the energy and focus of that group, even that late in the game, were something else!

  • ZZZZZ says:

    zzzzz

    …yeah, i’m not sure why bill johnson and e.e. van tamelen don’t get referenced – they seem like major (and recurring) omissions from all these corey papers…

    zzzzz

  • SB says:

    This is Org Lett at best………

    • The Next Phil Baran says:

      Agreed. By any other name, would a rose not smell as sweet? Its the name, not the quality. Strong Org. Lett though.

      • TA says:

        Hmmm…so can you suggest a better approach then? I mean, an approach that would be “JACS worthy?”
        Why do you think that no other synthesis of Lupeol hadn’t been reported during the time after Storks 1st synthesis?

  • Knut Jacksworthy says:

    This is beautiful work.

    • sls says:

      ye..
      But this is a 30 year old and Bill johnson’s chemistry.

      • Knut Jacksworthy says:

        Corey’s been trying to figure out for a long time exactly how the huge diversity of steroids and pentacyclic triterpenes is generated from a few important precursors, like JACS 2008 p. 9031. That’s an extremely important and interesting research problem IMO, although it is the prerogative of others to disagree.

  • unlikely says:

    Building multiple stereocenters that quickly will always impress me….However, I would like to see the steroid skeleton built from an oxidative dearomatization, reversing the direction of the cascade.

  • Jose says:

    30 year old chemistry? Hell, this goes back way earlier than that. The heyday was ca. ’55 to ’65.
    JACS? Really. Ah well. WS is probably laughing in his grave.

    Isn’t it “cuprate” and not “cuperate,” or do you Brits have a funny spelling rule for that too?

  • EUChem says:

    Is anybody really surprised that Corey’s paper didn’t get rejected from JACS, or that he decided to send it to JACS instead of OL?

  • UBChem says:

    EUChem…Neither. I’m surprised that 2-page communications stressing the synthesis of these well known frameworks keep getting accepted to JACS. If Corey published full papers demonstrating the biological utility of this route to congeners then hell yeah that would be awesome. But alas, we can only dream.

  • John Wood says:

    What was Corey’s last full Paper?

    • UBChem says:

      JACS this year DOI: 10.1021/ja902601e regarding cortistatin analogs. This is exactly the type of work I would like to see more of.

  • Jose says:

    JW- along those lines, why did brilliant work like Gin’s Ect-743 get relegated to a puny letter, with no full paper?

  • jasdou says:

    Out of topic, really, but has anyone ever purified tributyl(vinyl)tin?

  • Jose says:

    Your going to let an undergrad distill a stannane? *Shudder*

  • Tot. Syn. says:

    A former lab I worked in was in a bay adjacent to an inorganic group. Three undergrads, with virtually no supervision. And all their ligands were thiols and phosphines. I’m getting another headache just thinking about it!

  • stork naked says:

    UBChem – i agree that this isn’t the most exciting work that corey has done, but like the majority of his work it’s concise and scholarly.

    by the way – write anything on the back of your hood lately?

  • cowboychemist says:

    Corey and van Tamelen are contemporaries and at the start of their careers they crossed swords more than once. One example involved who first showed that squalene oxide was the biogenetic precursor for steroids. Corey has also used epoxides for synthetic cyclizations prior to this publication.

    E. J. Corey, William E. Russey, Paul R. Ortiz de Montellano
    J. Am. Chem. Soc., 1966, 88 (20), pp 4750–4751

    E. E. van Tamelen, J. D. Willett, R. B. Clayton, Kathryn E. Lord
    J. Am. Chem. Soc., 1966, 88 (20), pp 4752–4754