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Title

STUDIES ON SYNTHETIC APPLICATIONS OF STEREOSELECTIVE AND REGIOSELECTIVE RING OPENING REACTIONS OF AZIRIDINIUM IONS

Creator

Chen, Yunwei

Date

2014, 2014-12

Description

Aziridinium ions are valuable reactive intermediates in organic synthesis. Regioselective and stereoselective ring opening reactions of...
Show moreAziridinium ions are valuable reactive intermediates in organic synthesis. Regioselective and stereoselective ring opening reactions of aziridinium ions can provide various useful building blocks including optically active vincinal amines, amino alcohols and amino esters. Aziridinium ions are also involved in the biological process of anti-cancer agents. However, aziridinium ions are under-utilized in organic synthesis. In this thesis, we utilize stereoselective and regioselective ring opening reactions of aziridinium ions for synthesis of enantiomerically enriched compounds. Ring opening reactions of aziridinium ions were utilized in intramolecular Friedel-Crafts (FC) reactions for stereoselective and regioselective synthesis of 4-substituted tetrahydroisoquinoline. A series of β-haloamine were prepared as precuresors of aziridinium ions. The reaction conditions for ring opening of aziridinium ions for the FC reactions including temperature, catalysts, and solvents were optimized. Further, the reaction mechanism was studied to prove that the aziridinium ions were formed as the key intermediates during the intramolecular FC reaction. Intermolecular nucleophilic ring opening reaction of aziridinium ions was studied as a convenient method of carbon-carbon formation. Regioselective and stereoselective nucleophilic substitution reactions of aziridinium ions with indole analogues were carried out for the synthesis of optically active tryptamine analogues. The reactions proceeded smoothly to provide the tryptamine analogues in high yield in the presence of halo-sequestering agents, while the reaction provided the tryptamine products in significantly low yield in the absence of halo-sequestering agents. Ring opening reactions of aziridinium ions with malonic esters and Grignard reagents were carried out for the respective synthesis of optically active tryptamine analogues, γ-aminobuyric acid (GABA), and α-amine derivatives. The regiospecific ring opening reactions of aziridinium ions was directly applied for the synthesis of bifunctional ligands which have a potential use in targeted therapy and imaging of cancers. The novel bifunctional chelates with a shorter alkyl spacer C-NETA and 2E-C-NETA as well as the chelates with a longer alkyl spacer 5p-C-NETA were prepared. 5p-C-NETA was conjugated to a cyclic peptide c(RGDyK) as a targeting moiety for use in targeted radiation therapy. In addition, 2E-C-NETA was conjugated to a fluorescent dye Cy5.5 for theranostic applications. The experimental results indicated that the new bifunctional ligands have promising applications in the biomedical field. In summary, stereoselective and regioselective ring opening reactions of aziridinium ions have been successfully applied for the synthesis of optically active compounds such as 4-substituted tetrahydroisoquinolines, tryptamines, γ-aminobuyric acid, α-amine derivatives and the bifunctional chelators. We demonstrated that ring opening of versatile aziridinium intermediates is a strightforward and convenient method for the synthesis of various optically active compounds.
Ph.D. in Chemistry, December 2014
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