In Search of Effective Approaches towards the Synthesis ofioactive Aporphine Derivatives
Date Issued
2009
Date
2009
Author(s)
Huang, Jen-Shian
Abstract
The aporphine alkaloids, a family of isoquinoline alkaloids, is characterized by a tetracyclic motif and is oxidized on aromatic rings in different levels. Thaliporphine is an aporphine alkaloid that is separated from Lauraceae and has high affinity to the 5-HT7 receptor in human bodies. The goal of our research is to work out a practical route for the synthesis of different substituted-group aporphinoid alkaloids, using thaliporphine as a lead compound. In addition, the biological activities of our aporphine alkaloids as it binds to the 5-HT7 receptor are studied. Our synthetic strategy is to separate the tetracyclic motif into two parts. Starting from carbamate and phenylvinyl ether derivatives, Pictet-Spengler cyclization would give rise to a tricyclic structure. With the presence of a bromine handle, we successfully applied palladium-catalyzed direct arylation of aryl bromides to form the carbon-carbon linkage and construct the tetracyclic structure. In addition, we try to utilize Nef reaction to modify our synthetic strategy and improve the disadvantages of synthesizing the coupling precursors through Wittig reaction. Starting from benzyl aldehyde 73 and homoveratrylamine 81, we successfully synthesize the aporphine alkaloids via four steps and the total yield is9%. In our synthetic strategies, there are many reactions that do not need to go through purification steps and are able to obtain high-yield products with high purity.Therefore this synthetic strategy is suitable for great amount of aporphine derivatives production. As for the aspect of the biological activities, the ctivities of three compounds for the inhibitor constant to 5-HT7 receptor are examined.
Subjects
aporphine alkaloids
isoquinoline
5-HT7
Type
thesis
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