Codeine
Magnus, Sane, Fauber, Lynch. JACS, 2009, ASAP. DOI: 10.1021/ja9085534. 
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.
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.
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.
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I guess enantioselectivity is not about nitro-aldol. The very first step should be done asymmetrically – which is probably not so easy.
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.
O god, You are totally right, Paul sorry.
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.
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
I agree it’s not that exotic, even in the lab:
this is a neat example:
http://www3.interscience.wiley.com/journal/78002281/abstract
there are more, e.g. Haufes applications. Saw some members of his group giving a talk a year ago…
by the way, why is ASC not present in the journals list, but tetrahedron is?
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.
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!
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?
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.
although, it was the greatest ever galanthamine synthesis… technically speaking.
(probably) the best codeine synthesis too; as far as I can tell.
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!
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.
This a landmark synthesis. It is easily the most concise diastereocontrolled entry to morphine reported to date – the beauty is in the apparent simplicity
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!
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.
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.
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.
brominations in acetone usually end up in tears
Hah nice one. I used NBS in acetone for a cyclisation once, and when a certain fraction came off the column my lab was not a pleasant place to be.
Holy sh$t
http://pubs.acs.org/doi/pdf/10.1021/ja908194b
scripps IP
hell with IP, holy sh$t indeed! I really liked the idea with dibromoformaldoxime.
Vinigrol is published. JACS ASAP
Baran Jacs Vinigrol = Noise
nice paper
How does the reaction from 20 to 21 work?
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.
Does anyone know what happens to the aryl bromide in the LAH reduction step at the end?
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.