Concise Syntheses of (−)-Galanthamine and (±)-Codeine via Intramolecular Alkylation of a Phenol Derivative

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• 作者：Philip Magnus ; Neeraj Sane ; Benjamin P. Fauber ; Vince Lynch
• 刊名：Journal of the American Chemical Society
• 出版年：2009
• 出版时间：November 11, 2009
• 年：2009
• 卷：131
• 期：44
• 页码：16045-16047
• 全文大小：272K
• 年卷期：v.131,no.44(November 11, 2009)
• ISSN：1520-5126

文摘

Suzuki coupling of 7 to 8 gave the biphenyl derivative 9. Reaction of 9 with ethyl vinyl ether/bromine/base gave 10, which on treatment with CsF/DMF at 130 °C resulted in the cross-conjugated 2,5-cyclohexadienone 6. Acid hydrolysis of 6 gave 11, which was reductively aminated to give (±)-narwedine 2. Since 2 has been converted into (−)-galanthamine 1 in two steps, this synthesis proceeds in eight steps with an overall yield of 63%. Also treatment of the cross-conjugated cyclohexadienone 6 with nitromethane/base gave 12, which was reduced to provide 13. Reduction of the nitro group in 13 to an amine, followed by reductive amination under acidic conditions, arrives at the codeine skeleton 15. Elaboration of 15 into (±)-codeine proceeds via the previously unknown α-epoxide derivative 18. This is the shortest synthesis of codeine (13 steps, 20% overall yield) and, for the first time, allows access to codeine without having to reduce codeinone.