This thesis has two parts. The first deals with the conformational behaviour of Nsubstituted and N-unsubstituted bis-tetrahydroisoquinoline derivatives under neutral and acidic conditions and the second describes the design, synthesis and structural characterization of a new class of N-ureidyl bis-tetrahydroisoquinoline derivatives, potential catch and release agents. Four N-alkyl derivatives, two of which were new, were studied in detail for their conformational behaviour and their spectroscopic properties compared extensively with N-unsubstituted compounds. NMR chemical shift changes and vicinal spin couplings were measured and related to conformational change within the heterocyclic rings and about the central C1-C1' axis. The basicity of the amines were determined through pKa measurements, and differences between the behaviour of secondary and tertiary amine examples discussed. Analysis of titration results revealed the formation of discrete 1:1 and 1:2 complexes between the secondary examples and added carboxylic acids, but only 1:1 complexes in the case of tertiary amine complexes. Monitoring of changes in conformation with incremental addition of acid provided new understanding about modes of binding. A new class of nine ureidyl bis-tetrahydroisoquinoline derivatives has been prepared. These contain N'-aryl and N'-adamantyl urea groups attached to the bisisoquinoline core through alkyl linker groups with varying length. The conformation of these derivatives were heavily dependent upon the linker length while the nature of the urea group (in one case a thiourea) played a small role in the preferred conformation of the bis-tetrahydroisoquinoline. Three non-isoquinoline derived model ureidyl amine systems were also synthesized for comparative studies. Four partner ureidyl acids were prepared and their pKa values in DMSO were measured. Studies of the interaction of the ureidyl acids with the ureidyl amines revealed that the chain length of the ureidyl bistetrahydroisoquinoline linker played a small role while the remote aryl and adamantyl groups of both acids and amines played a more important role. DMSO was found to interfere with the normal conformations of the ureidyl bis-tetrahydroisoquinolines and with the interaction of the ureidyl bis-tetrahydroisoquinolines with their partner ureidyl acids in deuterochloroform. The latter studies will provide the basis for future design of catch-and-release agents derived from bis-tetrahydroisoquinolines.

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This thesis has two parts. The first deals with the conformational behaviour of Nsubstituted and N-unsubstituted bis-tetrahydroisoquinoline derivatives under neutral and acidic conditions and the second describes the design, synthesis and structural characterization of a new class of N-ureidyl bis-tetrahydroisoquinoline derivatives, potential catch and release agents. Four N-alkyl derivatives, two of which were new, were studied in detail for their conformational behaviour and their spectroscopic properties compared extensively with N-unsubstituted compounds. NMR chemical shift changes and vicinal spin couplings were measured and related to conformational change within the heterocyclic rings and about the central C1-C1' axis. The basicity of the amines were determined through pKa measurements, and differences between the behaviour of secondary and tertiary amine examples discussed. Analysis of titration results revealed the formation of discrete 1:1 and 1:2 complexes between the secondary examples and added carboxylic acids, but only 1:1 complexes in the case of tertiary amine complexes. Monitoring of changes in conformation with incremental addition of acid provided new understanding about modes of binding. A new class of nine ureidyl bis-tetrahydroisoquinoline derivatives has been prepared. These contain N'-aryl and N'-adamantyl urea groups attached to the bisisoquinoline core through alkyl linker groups with varying length. The conformation of these derivatives were heavily dependent upon the linker length while the nature of the urea group (in one case a thiourea) played a small role in the preferred conformation of the bis-tetrahydroisoquinoline. Three non-isoquinoline derived model ureidyl amine systems were also synthesized for comparative studies. Four partner ureidyl acids were prepared and their pKa values in DMSO were measured. Studies of the interaction of the ureidyl acids with the ureidyl amines revealed that the chain length of the ureidyl bistetrahydroisoquinoline linker played a small role while the remote aryl and adamantyl groups of both acids and amines played a more important role. DMSO was found to interfere with the normal conformations of the ureidyl bis-tetrahydroisoquinolines and with the interaction of the ureidyl bis-tetrahydroisoquinolines with their partner ureidyl acids in deuterochloroform. The latter studies will provide the basis for future design of catch-and-release agents derived from bis-tetrahydroisoquinolines.

Thesis (Ph. D.)--Virginia Polytechnic Institute and State University, 1992. / Vita. Abstract. Includes bibliographical references (leaves 226-236). Also available via the Internet.

Thesis (Ph. D.)--University of Texas at Austin, 2005. / Supervisor: Philip Douglas Magnus. Vita. Includes bibliographical references.

Thesis (M.Sc.)--Memorial University of Newfoundland, 2005. / Bibliography: leaves 106-111.

Many organic compounds are chiral and they are useful because of the biological activities associated with them. The biological activities of chiral compounds are often linked to absolute configuration, i.e. a compound and its mirror image can have different biological activities. For example, one enantiomer can be toxic whereas the other enantiomer is non-toxic. Enantioselective synthesis plays a significant role in the synthesis of biologically active compounds. The activity of tetrahydroisoquinolines prompted us to investigate the stereoselective synthesis of selected 1-substituted tetrahydroisoquinolines. The objectives of this project were to investigate stereoselective synthesis of some 1- substituted tetrahydroisoquinolines and compare different chiral auxiliaries used in the Bischler-Napieralski and Pictet-Spengler reactions and finally to optimize the number of steps needed to prepare the target compounds. The main challenge encountered in the Pictet-Spengler method was the decomposition of the phenylacetaldehyde. The successfully used method was the Bischler-Napieralski reaction because it does not involve the use of a phenylacetaldehyde. Using the Bischler-Napieralski method, non-stereoselective and stereoselective syntheses of tetrahydroisoquinolines have been achieved. The racemic tetrahydroisoquinolines have been synthesized in a three-step procedure starting from 3,4-dimethoxyphenylethylamine whereas the chiral tetrahydroisoquinolines were synthesized from vanillin in a seven-step reaction procedure. The R and S enantiomers of α-methylbenzylamine were successfully employed in the synthesis of 1-benzyltetrahydroisoquinolines. However, the Renantiomer of 1,2,3,4-tetrahydro-1-naphthylamine could be used to form a chiral phenylethylamine, while ring closure in a Biscler-Napieralski reaction was not successful under similar reaction conditions. The diastereoselectivity of the reactions to form the chiral tetrahydroisoquinolines was determined using NMR spectroscopy and was found to be 96% and 90% de for the (R)- and (S)-1-benzyl-6,7-dimethoxy-N-(1-phenylethyl)-1,2,3,4-tetrahydroisoquinoline, respectively. The stereochemistry of the final products was found to be similar to that of the chiral auxiliary starting material for each of the synthesized chiral tetrahydroisoquinolines. Yields for the precursors were good to moderate, especially on the final stages of the synthesis. / Thesis (M.Sc.)-University of KwaZulu-Natal, Pietermaritzburg, 2014.

Thesis (M.Sc.)--Memorial University of Newfoundland, 2004. / Bibliography: leaves 84-88.

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