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22 October 2009 19,458 views 30 Comments

codeine

Magnus, Sane, Fauber, Lynch. JACS, 2009, ASAP. DOI: 10.1021/ja9085534. Article PDF Supporting Information Group Website

I don’t think we’ve covered many targets I’ve actually ingested; and I’ve done most of the family too.  The morphine was a bit ‘meh’, as I was so out-of-it I couldn’t really appreciate it.  But the dihydrocodine was the good-stuff – really took the edge off my pluracy.  However, the withdrawal symptoms were kinda harsh.  Other members of this historic family of natural products include galanthamine and narwedine, neither of which I’ve encountered before.  Philip Magnus has, though, as all three are targets in this latest paper, looking at a new route to this scaffold.  Working on a well-known target certainly brings props, but the catch is that you’ve gotta bring something pretty interesting to the party.

Phil’s trick is up pretty early – a really nice dearomatising ring formation, using a surprisingly similar approach to the last post.  Dump in a bit of fluoride (quite mild, in this case), and it does it’s thing with the silyl ether, providing a nucleophilic center.  This shuts-down onto the nearby alkyl bromide, providing an intermediate acetal.  Magnus demonstrated this approach with several examples, but the neatest was followed by a cascade-type ring formation, in which nitromethane was introduced in an Henry-aldol, completing a further ring.

codeine_1

Those readers more familiary with codine and it’s rather more-ish family members will recognise that our E-ring is somewhat malformed, as it should be a dihydrofuran.  Well, a little acid opened up the acetal, providing an aldehyde for a subsequent reductive amination.  More importantly, the phenol revealed in the acidification closed onto the allylic alcohol, dehydrating under the acidic conditions.  No advanced reagents or conditions here; just a damn-smart pair of ring formations.

codeine_2

We’re very close to finishing codine, but for a functionalisation of the C-ring.  This alkene looks perfectly set for a substrate controlled epoxidation, but unfortunately, this and similar substrates are approached from the wrong face.  As Magnus points-out, it’s incredible that after the decades of research in this area, no one has successfully functionalised this alkene from the correct face.  Using a slightly exotic brominating agent, Magnus was able to form a bromohydrin with the desired stereochemistry, such that a tickle with base provided the sought-after epoxide.  However, this reactive little dobromo-imidazolidinedione also brominated the aryl ring, requiring a reductive dehalogenation a few steps later.  Importantly, though, the epoxide could be opened regioselectively, and the nucleophile eliminated to give codine in 13 steps total.  Neat work – which may become enantioselective if Magnus can get that nitro-aldol to go asymmetrically.

codeine_3

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30 Comments

  • krest17 says:

    I guess enantioselectivity is not about nitro-aldol. The very first step should be done asymmetrically – which is probably not so easy.

  • The Next Phil McGroin says:

    the product of the first step, “6 is a single compound since the stereochemical relationship between epimers at the C16 lactol is that they are mirror images (axial symmetry of the dienone).” – pg 1. So enantioselectivity is impossible to achieve here.

    • krest17 says:

      O god, You are totally right, Paul sorry.

    • alkaloid says:

      Enantioselectivity will depend on the asymmetric conjugate addition step after the initially formed b-nitroalcohol (which of the two enones is attacked by the nitronate with the help of a chiral catalyst) . Once the conjugate addition occurs the quaternary center is formed in each of the enantiomers of the precursor. Subsequent steps will remove that center, thus 2 isomers will be reduced down to one. Now whether they can achieve the same stereochemistry at the quat.center for each of the dienone enantiomers …we’ll have to wait and watch.

  • milkshake says:

    dibromohydantoin is not exotic reagent, it is cheap and common, and it is often a preferred alternative to NBS in process scale-ups. Very classical but pretty chemistry scheme here

  • gyges says:

    milkshake bet me to it.

    a slightly exotic brominating agent,

    It was funny to read, I don’t mean to skit you, but the comment betrays an academic rather than industrial background.

    Of course, excellent blog; I’m sure a large part of your readership doesn’t have an Athens account (or similar) and so would not have an opportunity to have an access to this work otherwise.

  • Will says:

    Nice synthesis, especially the three steps from the biphenyl to pentacycle – definitely amenable to library preparations.

    I will quibble only slightly that galanthamine and codiene/morphine et al are not really members of the same family. They have different mechs of action, and are isolated from different natural sources

    Nice post though – hopefully none of us will ever need galanthamine!

  • The Next Phil McGroin says:

    I always wonder when its so quiet on here, if that is indifference or silent agreement in the quality of the work? IMO, Nice work. If only they could have found a way to use NaH as an oxidant in one of the steps, ya know cutting edge chemistry?

    • The Next Phil Baran says:

      I think you are right. There is a lot of good in this synthesis. I guess the bloggers are in tacit agreement. Plus, it wasn’t Baran or someone popular so there is no: “greatest ever” homage, or the equivalent trashing. I liked the formation of the two heterocyclic ring systems in one step. That was very nice.

      • stop says:

        although, it was the greatest ever galanthamine synthesis… technically speaking.

        (probably) the best codeine synthesis too; as far as I can tell.

      • Jetset says:

        After doing my stint in Phils lab for 2 years I’m willing to be there are a lot people who’ve had the please of his mentorship and friendship who was love to add the homage, equal number the trashing as well no doubt, for once it’s nice to see a really good organic chemist using his brains to solve a complex problem, not a ton of funding and postdoc hours to bash your way through a synthesis – and yes I’m referring to palau’amine – prep HPLC purification at the end of a tricky synthesis fine, we do it all the time in the pharma industry, but half way though! Sheesh!

  • Anonymous says:

    The intramolecular alkylation and subsequent nitro-aldol set up the morphine ring framework in astonishingly short order.

    What the blog entry fails to mention is the exquisitely short synthesis of galanthamine, which is also disclosed in the same paper.

    Very impressive all around.

  • jack says:

    This a landmark synthesis. It is easily the most concise diastereocontrolled entry to morphine reported to date – the beauty is in the apparent simplicity

  • a-non says:

    I would have been very curious to see whether the authors tried any of the asymmetric epoxidising conditions? Any thoughts on whether that would work.

    Also why not try hydroboration? If conditions could be found to install the alcohol regioselectively then oxidise to the ketone and some IBX or Sageusa would give the desired enone.

    But really interesting synthesis!

    • Anonymous says:

      Interesting ideas, but I presume the steric congestion that denies epoxidation from the desired face would also lead to the undesired epoxide product/epimer under asymmetric (Shi, etc.) conditions. The same goes for hydroboration — it will add on the wrong face. That would force oxidation of the alcohol intermediate, as you suggest, which would require use of the codeinone intermediate and its subsequent reduction to codeine.

      This synthesis is unique in that they generate the correct epoxide epimer, and forego the additional steps required in other approaches.

      The beauty of Magnus’ route resides in the details.

      • milkshake says:

        The step that you want to make asymmetric in this case is the Henry reaction and cyclization with nitromethane. There is a number of promising precedents, both metal catalysis and organocatalysis have a chance to work.

  • Tok says:

    I wanted to try the conditions for bromo-hydrin formation from this paper, but while scheme 4 says the solvent was dioxane-water, the SI says acetone-water. I wonder which it is? I guess I’ll just try both.

  • konrad says:

    Vinigrol is published. JACS ASAP

  • spottospot says:

    Baran Jacs Vinigrol = Noise

  • PC says:

    nice paper

  • cotboy says:

    How does the reaction from 20 to 21 work?

    • Martyn says:

      Look up the Cope elimination: http://en.wikipedia.org/wiki/Cope_reaction

      This is basically the same mechanism but with sulfur instead of nitrogen, and PhSOH (phenylsulfenic acid) as the side-product instead of a hydroxylamine. Selenium usually does the same reaction under much milder conditions. I have no idea if there is a separate name for the sulfur/selenium version, but it’s much more commonly used than the Cope elimination.

      Because there is a proton syn to the sulfoxide on the carbons to either side, it can go either way – if the reaction goes to the right, you get product 22, and if it goes left you get an enol, which quickly tautomerises to the ketone 21.

  • Sean says:

    Does anyone know what happens to the aryl bromide in the LAH reduction step at the end?

    • anon says:

      Do you read German?
      EP 0983215

      If not, here’s the English version:
      WO 1998/052885

      Oxygen also promotes the readuction (yes, it’s true), so there’s more to it than a straight-up SNAr.