Thesis (PhD (Chemistry and Polymer Science))—University of Stellenbosch, 2006. / This study describes the exploitation of numerous donor ligand possibilities presented by selected nitrogen-rich heterocyclic ligands towards gold(I). The preparation and structural characterisation of novel gold(I) complexes, apart from conventional gold(I) bonding possibilities, also encompassed a study of bi- and polytopic bonding modes within a range of multifunctional ligands.

Thesis (PhD)--Stellenbosch University, 2001. / ENGLISH ABSTRACT: Please refer to fulltext for abstract / AFRIKAANSE OPSOMMING: Sien asb volteks vir opsomming.

published_or_final_version / abstract / Chemistry / Doctoral / Doctor of Philosophy

<strong>Chapters 1</strong> and <strong>2</strong> of this thesis focus on the application manganese(III) and copper(II)-mediated oxidative radical cyclisation of alkenyl amidomalonates to the formation of pyrrolidinone-lactones and their subsequent use in the total syntheses of highly bioactive natural products. A novel concise total synthesis of (-)-salinosporamide A based on the oxidative cyclisation previously developed in the group is presented in <strong>chapter 1</strong>. The second chapter discusses the work towards the pyrrolidinone core of the oxazolomycin. Each chapter contains its own introduction to set in context the presented results, which discusses the isolation and the biological activity of the two families of natural products. Previous synthetic work toward salinosporamide A and the oxazolomycin family achieved in the group and reported in the literature is also described in the introduction of each chapter. The third chapter of the thesis succinctly presents the extension of the scope of the manganese(III) and copper(II)-mediated oxidative radical cyclisation reaction. The optimisation, development and scope of the rapid access to fused THF-lactones via the cyclisation of alkenyl oxymalonates is described. Preliminary synthetic manipulations of the resultant bicyclic products to study the application possibilities of the new reaction in future complex molecules syntheses are also presented. The final conclusion gives a summary of the results obtained and introduces the proposed future work that may arise from these three areas.

Bohlmann et al. reported the oxidative spirocyclisation of 2-(ω-hydroxyalkyl)furans under Clauson-Kaas conditions to furnish 1,6-dioxaspiro[4.5]dec-3-enes, thereafter termed the “Bohlmann cyclisation.” This thesis describes the development of an analogous aza-Bohlmann cyclisation. Treatment of 2-(ω-aminoalkyl)furans with m-CPBA or singlet oxygen generates hydroxy- or methoxybutenolides, respectively, which undergo spirocyclisation upon treatment with H₂SO₄ to generate [4.4]- and [4.5]-spiroaminoacetals. The axial/equatorial preferences of N-sulfonylspiroaminoacetals featuring a 3-O-isovaleryl or 3-O-benzyl substituent are described. Acid-catalysed equilibration revealed that in acetonitrile the axial isomer is thermodynamically favoured for both substrates. The first total synthesis of the spiroaminoacetal alkaloid pandamarilactone-1 is discussed, via an aza-Bohlmann cyclisation, in 13 steps and 3% overall yield from 4-pentyn-1-ol.

For the purpose of incorporating indoles into organometallic complexes for catalysis, as well as in the generation of new heterocyclic systems, various reactions have been carried out at C2, C6 and C7 of the indole system. In order to achieve this, 3-substituted 4,6-dimethoxyindoles and 6-hydroxy- 4-methoxyindoles were necessary as starting materials. Consequently, a lithium-bromide-templated one-pot procedure for the synthesis of some 3-substituted 4,6-dimethoxyindoles and a selective demethylation procedure for 3-substituted 6-hydroxy-4-methoxyindoles were developed. Various kinds of novel methylene-bridged bi-, tri-, and tetradentate pyridyl-indole ligands were synthesised via Vilsmeier-Haack, Friedel-Crafts or electrophilic addition reactions on the indole heterocycle. However, their metal complexing properties were generally weak and variable. Nevertheless, some of the tridentate pyridylindole ligands showed strong anion binding to halides, whereas a remarkable ligand transformation occurred with a bidentate 2-pyridylindole ligand and zinc(II), giving a substituted indolo[2,3-c]pyrrolo-[3,2,1-ij]quinoline system. Two new types of tetradentate Schiff base ligands were prepared from 2-formyl-indoles and 7-formyl-6-hydroxyindoles, and diamines. These preformed ligands were reacted with first- and second-row transition metals to give neutral metal complexes. Novel heterocyclic systems such as 4H-pyrrolo[3,2,1-ij]quinolines, 3H-pyrrolo-[1,2-a]indoles, and 1H-furo[2,3-g]indoles were synthesised from 2-formyl-, 7-formyl-, and 6-hydroxyindoles, utilising mainly intra-molecular Wittig reactions, Claisen-Schmidt condensations or acid- and base-catalysed cyclisations. A common feature of the prepared 4H-pyrrolo[3,2,1-ij]quinolines and 3H-pyrrolo-[1,2-a]indoles was their intense fluorescent character, which was examined as well.

The development of novel selective 5-HT6 and 5-HT7 receptor antagonists is an ever-growing area of interest among medicinal chemists. The potential of developing a therapeutic agent useful as an antipsychotic or antidepressant, as well as the possibility to develop a drug for Alzheimer’s disease and obesity has led to an increase in synthesis of possible lead compounds. The synthesis of unfused biheteroaryl derivatives is described within. The derivatives have been evaluated for binding affinity at 5-HT2A, 5-HT6 and 5-HT7 receptors. The most potent 5-HT6 receptor antagonists include a benzene ring, a hydrophobic group and a protonated nitrogen atom. The most potent and selective compound synthesized is 1-[3-butyl-5-(thienyl)phenyl]-4-methylpiperazine. The binding site of the 5-HT7 receptor is similar to that of the 5-HT6 receptor and the most selective and potent 5-HT7 receptor antagonist also contains a potonated nitrogen atom and a hydrophobic group. The difference in selectivity between the 5-HT6 and 5-HT7 receptor antagonists is the aromatic ring. The most potent 5-HT7 receptor antagonist synthesized contains a pyridine ring instead of benzene, as in the 5-HT6 receptor antagonist. The most potent and selective 5-HT7 receptor antagonist is 1-[4-(3-furyl)-6-methylpyridin-2-yl]-4-methylpiperazine. The need to increase selectivity for both 5-HT6 and 5-HT7 receptors has led to the synthesis of flexible-chain linked derivatives and the results are described within.

The development of novel selective 5-HT6 and 5-HT7 receptor antagonists is an ever-growing area of interest among medicinal chemists. The potential of developing a therapeutic agent useful as an antipsychotic or antidepressant, as well as the possibility to develop a drug for Alzheimer’s disease and obesity has led to an increase in synthesis of possible lead compounds. The synthesis of unfused biheteroaryl derivatives is described within. The derivatives have been evaluated for binding affinity at 5-HT2A, 5-HT6 and 5-HT7 receptors. The most potent 5-HT6 receptor antagonists include a benzene ring, a hydrophobic group and a protonated nitrogen atom. The most potent and selective compound synthesized is 1-[3-butyl-5-(thienyl)phenyl]-4-methylpiperazine. The binding site of the 5-HT7 receptor is similar to that of the 5-HT6 receptor and the most selective and potent 5-HT7 receptor antagonist also contains a potonated nitrogen atom and a hydrophobic group. The difference in selectivity between the 5-HT6 and 5-HT7 receptor antagonists is the aromatic ring. The most potent 5-HT7 receptor antagonist synthesized contains a pyridine ring instead of benzene, as in the 5-HT6 receptor antagonist. The most potent and selective 5-HT7 receptor antagonist is 1-[4-(3-furyl)-6-methylpyridin-2-yl]-4-methylpiperazine. The need to increase selectivity for both 5-HT6 and 5-HT7 receptors has led to the synthesis of flexible-chain linked derivatives and the results are described within.

Tetrahydrobenzofurans and tetrahydroindoles are two very valuable classes of substances which have wide usage area / either as starting materials for drug substances or many other compounds which have fused heterocyclic rings in their structures and pharmacophore for many complex natural products / syntheses of derivatives of these compounds with different substitution patterns, is an exciting challenge for many scientists. Benzofuran and tetrahydroindole derivatives, which are potent bioactive substances, are synthesized from various cyclohexanone derivatives that are allylated by Stork-enamine or Mn(OAc)3 mediated allylation methods. Allylated ketones are later transformed to benzofuran derivatives upon treatment with base or tetrahydroindole derivatives upon treatment with primary amines.

The work presented in this thesis involves new transformations of azacycles, focusing on the introduction of functionality &alpha;-to N. &alpha;-C-H functionalisation on an azetidine has been a long-standing challenge, with N-protecting/activating groups that work well in the higher and lower azacyclic systems not viable. A recent breakthrough in the Hodgson group showed the rarely used N-thiopivaloyl group was effective for &alpha;-deprotonation– electrophile trapping on azetidines, but was not without limitations concerning harsh removal conditions and scope for further substitutions. This thesis describes efforts to overcome these issues by development of a new protecting/activating group for N, t-butoxythiocarbonyl (Botc).