Woody plants are the most abundant renewable resources on the earth. From the paper we consume to the house we live in, our daily lives rely heavily on woody plants. Over the past decades, enormous efforts have been expended to improve the utilization of fiber and wood. For example, much research has been conducted to develop environmentally benign, and economically feasible techniques for pulp and papermaking. The economical conversion of wood to useful sugars and alcohol has also been the subject of intensive research. Investigations aimed at the genetic manipulation of wood growth to better meet our needs are also underway. Nonetheless, harsh pulping and bleaching conditions are still required in the pulp and paper industry, and the bioconversion of polysaccharides in biomass to alcohol is still too expensive. An argument could be put forth that a major reason for this is the lack of basic knowledge concerning the structural and biochemical characteristics of the plant cell wall. The three major polymeric components of plant cell walls, cellulose, hemicellulose and lignin, are intimately associated with one another. Cellulose is associated with hemicellulose via non-covalent linkages, whereas lignin is theorized to be associated with cellulose and hemicellulose via both covalent and non-covalent linkages. The nature of associations between wood polymers is still poorly understood. However, it is these intimate associations that make delignification difficult, and make the bioconversion of polysaccharides to alcohol inefficient. It is also believed that the linkages between lignin and polysaccharides are responsible for the reduced digestibility of grasses by ruminants. Besides cellulose, hemicellulose and lignin, there are many secondary metabolites such as lignans, neolignans, tannins and terpenoids. The structures of lignans and neolignans are analogous to the interunits of lignin. Lignin is considered an optically inactive polymer, whereas lignans and neolignans are optically active small molecules. Although it has been proposed that the biosynthesis of lignin, lignans and neolignans are via the same oxidative coupling mechanism, it is still unclear that how the plant cell wall differentiates the formation of lignans, neolignans and lignin. How and why plant cell wall generates so many lignans and neolignans having broad structural variation is also unknown. As a matter of fact, it is still uncertain which enzymes are actually involved in the biosynthesis of lignin. A better understanding of biosynthetic pathways of lignin, lignans and neolignans is a prerequisite for the genetic manipulation of plant growth. Investigations described in this dissertation were an effort to better understand the fundamental aspects of covalent linkages between lignin and hemicellulose in wood. Enantiomeric synthesis of neolignans provides a tool for investigating the optically active nature of neolignans, and may be helpful to study the biosynthetic pathways of neolignans. Chapter | describes chemical structures of wood components and the biosynthesis of lignin, lignans and neolignans. The mechanisms of lignin-carbohydrate bond formation are also discussed, and a concise review of lignin-carbohydrate linkages proposed in the literature concludes Chapter 1. Chapter 2 presents the methods used in investigating covalent linkages in wood, which include methods of isolating lignin-carbohydrate complexes, chemical cleavage methods, DDQ oxidation and model compound/NMR methods. The synthesis of plant cell wall model compounds and neolignans are reviewed in Chapter 3. The experimental work performed for the completion of this thesis is described in Chapters 4-8. A method which provides β-𝘖-4 lignin model dimers with complete threo stereospecificity is described in Chapter 4. This method is complementary to the current method for the preparation of erythro lignin model dimers. Chapter 5 presents a practical synthesis of methyl 4-𝘖-methy] α-D-glucopyranosiduronic acid. Methyl 4-𝘖-methyl-α-D-glucopyranosiduronic acid was prepared from methyl α-D-glucopyranoside in 4 steps (74% overall yield). Previous preparations of this compound were much lengthier, and had very low overall yields. Chapter 6 deals with the synthesis and rearrangement reactions of ester-linked lignin-carbohydrate model compounds. A series of ester-linked lignin-carbohydrate model compounds were synthesized, and migration of the uronosy] group between the primary (γ) and benzyl (α) position of lignin side chain is discussed. Several approaches to synthetic neolignans are described in Chapter 7. Chapter 8 presents a novel approach for the preparation of chiral aryl alkylethers. The successful application of this novel approach to synthesis of several optically active 8-𝘖-4 neolignans and a 1,4- benzodioxane neolignan is described, as is the introduction of an alkyl] aryl ether bond in carbohydrate molecules. Some of the material of this dissertation has been reported in the following papers: 1. Li, K. and Helm, R. F. Approaches to Synthetic Neolignans. J. Chem. Soc. Perkin Trans 1. Accepted. 6. Li, K. and Helm, R. F. Use of Carbohydrates as Building Blocks to Synthesize Neolignans. 211th ACS National ACS Meeting, New Orleans, March 24-28, 1996. CELL-079. 2. Li, K. and Helm, R. F. A Practical Synthesis of Methyl 4-𝘖-Methylα-D-Glucopyranosiduronic Acid. Carbohydr. Res. 273(1995), 249-253. 3. Li, K. and Helm, R. F. Synthesis and Rearrangement Reactions of Ester-Linked Lignin-Carbohydrate Model Compounds. J. Agric. Food Chem. 48(1995), 2098-2103. 4. Helm, R. F. and Li, K. Complete threo Stereospecificity for the Preparation of β-𝘖-4 Lignin Model Dimers. Holzforschung. 49(1995), 533-536. 5. Helm, R. F. and Li, K. Synthesis and Rearrangement Reactions of Lignin-uronic Acid Model Compounds Related to Hardwood Cell Wall Structure. The 8th International Symposium on Wood and Pulping Chemistry. Helsinki, Finland, June 1995, vol. 1, pp107-114. 7. Li, K. and Helm, R. F. Approaches to Synthetic Neolignans, 34th National Organic Symposium, Williamsburg, VA. June 11-15, 1995. Poster 281. / Ph. D.

Parkinson’s disease is an age-related neurodegenerative disorder. The major symptoms of Parkinson’s disease are closely linked to the pathology of the disease. The main pathology of Parkinson’s disease consists of the degeneration of neurons of the substantia nigra pars compacta (SNpc), which leads to reduced amounts of dopamine in the brain. One of the treatment strategies in Parkinson’s disease is to conserve dopamine by inhibiting the enzymes responsible for its catabolism. The monoamine oxidase (MAO) B isoform catalyses the oxidation of dopamine in the central nervous system and is therefore an important target for Parkinson’s disease treatment. Inhibition of MAO-B provides symptomatic relief for Parkinson’s disease patients by increasing endogenous dopamine levels as well as enhancing the levels of dopamine after administration of levodopa (L-dopa), the metabolic precursor of dopamine. Recent studies have shown that phthalide can be used as a scaffold for the design of reversible MAO inhibitors. Although phthalide is a weak MAO-B inhibitor, substitution on the C5 position of phthalide yields highly potent reversible MAO-B inhibitors. In the present study, sesamol and benzodioxane were used as scaffolds for the design of MAO inhibitors. The structures of sesamol and benzodioxane closely resemble that of phthalide, which suggests that these moieties may be useful for the design of MAO inhibitors. This study may be viewed as an exploratory study to discover new scaffolds for MAO inhibition. Since substitution at C5 of phthalide with a benzyloxy side chain yielded particularly potent MAO inhibitors, the sesamol and benzodioxane derivatives possessed the benzyloxy substituent in the analogous positions to C5 of phthalide. These were the C5 and C6 positions of sesamol and benzodioxane, respectively. The sesamol and benzodioxane derivatives were synthesised by reacting sesamol and 6- hydroxy-1,4-benzodioxane, respectively, with an appropriate alkyl bromide in the presence of potassium carbonate (K2CO3) in N,N-dimethylformamide (DMF). 6-Hydroxy-1,4- benzodioxane, in turn, was synthesised from 1,4-benzodioxan-6-carboxaldehyde. The structures of the compounds were verified with nuclear magnetic resonance (NMR) and mass spectrometry (MS) analyses, while the purities were estimated by high-pressure liquid chromatography (HPLC). Sixteen sesamol and benzodioxane derivatives were synthesised. To determine the inhibition potencies of the synthesised compounds the recombinant human MAO-A and MAO-B enzymes were used. The inhibition potencies were expressed as the corresponding IC50 values. The results showed that the sesamol and benzodioxane derivatives are highly potent and selective inhibitors of MAO-B and to a lesser extent MAOA. The most potent MAO-B inhibitor was 6-(3-bromobenzyloxy)-1,4-benzodioxane with an IC50 value of 0.045 μM. All compounds examined displayed selectivity for the MAO-B isoform over MAO-A. Generally the benzodioxane derivatives were found to be more potent inhibitors of human MAO-A and MAO-B than the sesamol derivatives. The reversibility and mode of MAO-B inhibition of a representative derivative, 6-(3- bromobenzyloxy)-1,4-benzodioxane, was examined by measuring the degree to which the enzyme activity recovers after dialysis of enzyme-inhibitor complexes, while Lineweaver- Burk plots were constructed to determine whether the mode of inhibition is competitive. Since MAO-B activity is completely recovered after dialysis of enzyme-inhibitor mixtures, it was concluded that 6-(3-bromobenzyloxy)-1,4-benzodioxane binds reversibly to the MAO-B enzyme. The Lineweaver-Burk plots constructed were linear and intersected on the y-axis. Therefore it may be concluded that 6-(3-bromobenzyloxy)-1,4-benzodioxane is a competitive MAO-B inhibitor. To conclude, the C6-substituted benzodioxane derivatives are potent, selective, reversible and competitive inhibitors of human MAO-B. These compounds are therefore promising leads for the future development of therapy for Parkinson’s disease. / MSc (Pharmaceutical Chemistry), North-West University, Potchefstroom Campus, 2015

Parkinson’s disease is an age-related neurodegenerative disorder. The major symptoms of Parkinson’s disease are closely linked to the pathology of the disease. The main pathology of Parkinson’s disease consists of the degeneration of neurons of the substantia nigra pars compacta (SNpc), which leads to reduced amounts of dopamine in the brain. One of the treatment strategies in Parkinson’s disease is to conserve dopamine by inhibiting the enzymes responsible for its catabolism. The monoamine oxidase (MAO) B isoform catalyses the oxidation of dopamine in the central nervous system and is therefore an important target for Parkinson’s disease treatment. Inhibition of MAO-B provides symptomatic relief for Parkinson’s disease patients by increasing endogenous dopamine levels as well as enhancing the levels of dopamine after administration of levodopa (L-dopa), the metabolic precursor of dopamine. Recent studies have shown that phthalide can be used as a scaffold for the design of reversible MAO inhibitors. Although phthalide is a weak MAO-B inhibitor, substitution on the C5 position of phthalide yields highly potent reversible MAO-B inhibitors. In the present study, sesamol and benzodioxane were used as scaffolds for the design of MAO inhibitors. The structures of sesamol and benzodioxane closely resemble that of phthalide, which suggests that these moieties may be useful for the design of MAO inhibitors. This study may be viewed as an exploratory study to discover new scaffolds for MAO inhibition. Since substitution at C5 of phthalide with a benzyloxy side chain yielded particularly potent MAO inhibitors, the sesamol and benzodioxane derivatives possessed the benzyloxy substituent in the analogous positions to C5 of phthalide. These were the C5 and C6 positions of sesamol and benzodioxane, respectively. The sesamol and benzodioxane derivatives were synthesised by reacting sesamol and 6- hydroxy-1,4-benzodioxane, respectively, with an appropriate alkyl bromide in the presence of potassium carbonate (K2CO3) in N,N-dimethylformamide (DMF). 6-Hydroxy-1,4- benzodioxane, in turn, was synthesised from 1,4-benzodioxan-6-carboxaldehyde. The structures of the compounds were verified with nuclear magnetic resonance (NMR) and mass spectrometry (MS) analyses, while the purities were estimated by high-pressure liquid chromatography (HPLC). Sixteen sesamol and benzodioxane derivatives were synthesised. To determine the inhibition potencies of the synthesised compounds the recombinant human MAO-A and MAO-B enzymes were used. The inhibition potencies were expressed as the corresponding IC50 values. The results showed that the sesamol and benzodioxane derivatives are highly potent and selective inhibitors of MAO-B and to a lesser extent MAOA. The most potent MAO-B inhibitor was 6-(3-bromobenzyloxy)-1,4-benzodioxane with an IC50 value of 0.045 μM. All compounds examined displayed selectivity for the MAO-B isoform over MAO-A. Generally the benzodioxane derivatives were found to be more potent inhibitors of human MAO-A and MAO-B than the sesamol derivatives. The reversibility and mode of MAO-B inhibition of a representative derivative, 6-(3- bromobenzyloxy)-1,4-benzodioxane, was examined by measuring the degree to which the enzyme activity recovers after dialysis of enzyme-inhibitor complexes, while Lineweaver- Burk plots were constructed to determine whether the mode of inhibition is competitive. Since MAO-B activity is completely recovered after dialysis of enzyme-inhibitor mixtures, it was concluded that 6-(3-bromobenzyloxy)-1,4-benzodioxane binds reversibly to the MAO-B enzyme. The Lineweaver-Burk plots constructed were linear and intersected on the y-axis. Therefore it may be concluded that 6-(3-bromobenzyloxy)-1,4-benzodioxane is a competitive MAO-B inhibitor. To conclude, the C6-substituted benzodioxane derivatives are potent, selective, reversible and competitive inhibitors of human MAO-B. These compounds are therefore promising leads for the future development of therapy for Parkinson’s disease. / MSc (Pharmaceutical Chemistry), North-West University, Potchefstroom Campus, 2015