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.