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. / text
| Identifer | oai:union.ndltd.org:UTEXAS/oai:repositories.lib.utexas.edu:2152/ETD-UT-2009-12-602 |
| Date | 20 August 2010 |
| Creators | Sane, Neeraj Prakash |
| Contributors | Magnus, Philip D. |
| Source Sets | University of Texas |
| Language | English |
| Detected Language | English |
| Type | thesis |
| Format | application/pdf |
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