Synthesis of Amphibian Alkaloids and Development of Acetaminophen Analogues

The focus of these studies has been toward the development of new synthetic methods and procedures for the synthesis of novel compounds with unique biological properties. This research has led to the development of two new synthetic strategies for the construction of two novel amphibian alkaloids. In addition, the efforts have led to the large-scale process for the preparation of a novel analgesic compound. The regioselective ring opening of lactones (δ-valerolactone and γ-butyrolactone) with aryllithium reagents is reported for the construction of a series of δ-hydroxyarylketones and γ-hydroxyarylketones. Both the R and S enantiomers of the amphibian alkaloid noranabasamine were prepared in >30% overall yield with 80% ee and 86% ee, respectively. An enantioselective iridium-catalyzed N-heterocyclization reaction with either (R)- or (S)-1-phenylethylamine and 1-(5-methoxypyridin-3-yl)-1, 5-pentanediol was employed to generate the 2-(pyridin-3-yl)-piperidine ring system in 69-72% yield. A cis-2, 5-disubstitued pyrrolidine building block derived from (-)-Cocaine•HCl was prepared. We utilized this compound as a chiral building block for the formal synthesis of (+)-gephyrotoxin. Using this pyrrolidine building block, Kishi's intermediate was obtained enantiospecifically in 15 steps and 9.4% overall yield. A large-scale process for the preparation of the analgesic compounds SCP-123 and its sodium salt, SCP-123ss•monohydrate has been developed. The process for the preparation of SCP-123 required three synthetic steps with no chromatography, while the process for the preparation of SCP-123ss required four synthetic steps and no chromatography. The overall yields for both SCP-123 and SCP-123ss were 47% and 46%, respectively, and both compounds were obtained in exceptionally high purity (>99%).

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Chemistry

Year

2009

Author dc:creator

• Miao, Lei

Contributors dc:contributor

• Trudell, Mark
• Gibb, Bruce C.
• Jursic, Branko S.

• ketones
• lactones
• nucleophilic addition
• ring-opening
• enantioselective
• noranabasamine
• N-heterocyclization
• gephyrotoxin
• pyrrolidine
• Kishi's intermediate
• analgesic
• acetaminophen
• propacetamol
• saccharin
• hydrolysis
• parenteral administration

Repository record dc:identifier

https://scholarworks.uno.edu/td/985

OAI identifier oai:identifier

oai:scholarworks.uno.edu:td-1966