The study of a codeine bromohydrin rearrangement and investigation of a phenolic alkylation strategy

dc.contributor.advisorMagnus, Philip D.
dc.creatorHodges, Timothy Roberten 2013en
dc.description.abstract(-) Codeine, (-) morphine, and their semi-synthetic derivatives play an integral role in medicinal analgesia. Due to a complex list of undesirable side effects, their effective use is often complicated and troublesome giving cause for the investigation of novel semi-synthetic analogs for efficacy and side-effect profile. It was envisioned that new and interesting codeine analogs could be synthesized via an opening of a hindered 7,8-[alpha]-epoxide. Classically, hindered epoxides are formed via halohydrin formation and subsequent closure. Interestingly, the 7,8-epoxide formed via bromohydrin closure was resistant to reaction with small nucleophiles, such as oxygen and hydride, but reactive towards large and nucleophilic atoms, such as sulfur and bromide. It was discovered that the epoxide was in fact the less hindered 7,8-[Beta] epoxide via x-ray analysis of various compounds. This hinted at an unexpected rearrangement which most likely occurred during the bromohydrin formation due to the severe steric interactions present in the core structure of codeine. Due to the reversibility of bromonium ion formation, a highly hindered double bond can produce the opposite configuration of what is expected when subjected to aqueous brominating conditions. Many popular alkaloids, including codeine and galanthamine, are biosynthetically formed via a spirocyclic dienone intermediate. In nature these intermediates are formed via an enzymatically driven phenolic oxidation; however in the lab this reaction has proven difficult to reproduce. In a previous Magnus publication, (±) codeine and (-) galanthamine, were synthesized via a common spirocyclic cross-conjugated dienone intermediate similar to the intermediate found in nature. Most importantly, this intermediate was formed without a phenolic oxidation. Instead, a para-alkylation of an appropriately substituted phenol efficiently created the key intermediate. Expanding on this phenolic alkylation strategy, various biaryl systems were built in order to investigate the scope and limitations of this reaction. Multiple para- alkylations proved successful while ortho- alkylations unveiled an interesting rearrangement which occurs during the reaction. Lastly, it was determined that a 7-membered ring could not be set using a phenolic alkylation strategy.en
dc.subjectPhenolic alkylationen
dc.subjectBromonium rearrangementen
dc.titleThe study of a codeine bromohydrin rearrangement and investigation of a phenolic alkylation strategyen
dc.typeThesisen University of Texas at Austinen of Artsen

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