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Totally Synthetic by Paul H. Docherty, 22 October 2009

Total Synthesis of Codeine


P. Magnus, N. Sane, B. P. Fauber, V. Lynch, J. Am. Chem. Soc. 2009, 131, 16045-16047.

DOI: 10.1021/ja9085534

Philip Magnus has covered the construction of codeine, galanthamine and narwedine in his latest paper, looking at a new and very innovative route to this well-known scaffold.

Phil’s key step shows up early - a really nice dearomatising ring formation. Use of a mild fluoride removes the silyl ether and provides a nucleophilic center which reacts with the nearby alkyl bromide, providing an intermediate acetal. Magnus demonstrated this approach with several examples, including one that was followed by a cascade-type ring formation, in which nitromethane was introduced in a Henry reaction, completing a further ring.

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 very smart pair of ring formations.

We’re very close to finishing codine, but some functionalisation of the alkene is still required. Unfortunately, in substrate controlled epoxidation 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, providing the desired epoxide after treatment with a base. However, 1,3-dibromo-5,5-dimethylhydantoin 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 codeine in 13 steps total. A very nice total synthesis, which may has potential to become asymmetric if the team's investigations continue to plan.