Browsing by Subject "Codeine"
Now showing 1 - 2 of 2
Results Per Page
Sort Options
Item The study of a codeine bromohydrin rearrangement and investigation of a phenolic alkylation strategy(2013-12) Hodges, Timothy Robert; Magnus, Philip D.(-) 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.Item The total synthesis of (±)-morphine and (-)-galanthamine(2009-12) Sane, Neeraj Prakash; Magnus, Philip D.; Martin, Stephen F.; Siegel, Dionicio R.; Jones, Richard A.; Kerwin, Sean M.The opiate alkaloid (-)-morphine and the Amaryllidaceae alkaloid (-)-galanthamine are well known for their analgesic and anticholinergic properties, respectively. The chemical feature that connects these two molecules is that they are both biosynthesized from an ortho-para phenolic oxidative coupling. Attempts to mimic this aesthetic chemistry in the laboratory for the practical production of these alkaloids have not resulted in good yields of these compounds and there is a lot of scope for improvement. Despite the enormous amount of work devoted to this area, the simple para-alkylation of an appropriately substituted phenol derivative to generate a cross conjugated 2, 5-cyclohexadienone has not been reported. This strategy would avoid the low-yielding phenolic oxidation reaction and the product would merely require a double reductive amination of the aromatic aldehyde and the latent aldehyde (in the acetal) to produce narwedine, the synthetic precursor to (-)-galanthamine. On the other hand, the same intermediate can be elaborated to (±)-morphine via a Henry reaction, followed by reduction and reductive amination. Following the aforementioned methodology, we have successfully completed the synthesis of both these alkaloids via the common intermediate, a 2, 5-cross-conjugated cyclohexadienone. A demonstration of the use of this methodology towards achieving an enantioselective synthesis of these compounds has also been made. The overall yield of the 8 step procedure for galanthamine proceeds in 65% yield, which is approximately five times the yield of the current manufacturing process for this molecule. The synthesis of (±)-morphine, for the first time, allows access to codeine without having to reduce codeinone and, with an overall yield of 20% for the 14 step process, makes this the shortest synthesis of morphine.