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A series of <i>N</i>-acylated and –alkyated aminobromopyridines were prepared, and under 2,2’-azobisisobutyronitrile (AIBN) initiation in the presence of <i>n</i>-tributyltin hydride (Bu₃SnH), readily underwent cyclisation to produce 4-aza and 7-azaoxindole derivatives. Upon recrystallisation in polar solvents in the presence of atmospheric oxygen, these compounds were found to undergo quantitative autoxidation.  Inspection of NMR and MS data suggest that the mechanism proceeds by hydrogen abstraction to form a hydroperoxide intermediate. The second part of the study reveals a simple and effective synthesis towards pyrrolo[2,3-<i>d</i>]pyrimidine derivatives as substitutes for purine analogues.  The purine-type nucleus is secured <i>via </i>tributyltin hydride mediated radical cyclisation, which provides a convenient route to access compounds for studies of biological activity and structure activity relationships. The third part describes radical addition of iodopyridines and functionalised pyrimidines to arenes, effected under mild conditions using tris(trimethylsilyl)silane and oxygen to promote the bimolecular radical addition pathway.  Initial reactions yielded intractable pyridine products with tris(trimethylsilyl)silane by-products. This was overcome by initial quaternisation of the heterocycles. The fourth part of the study  concerns the synthesis of the pyrimidine backbone unit of the natural product isolated from the <i>heterostemma brownii.  </i>This was obtained by the regioselective radical addition of halopyrimidine to electron-deficient methyl methacrylate (MMA). The final part describes the radical translocation reaction and the effect of variation in cycloalkane ring sizes and electron-donating ability.  This provided a route towards horsfiline derivatives. Under the high temperatures experienced by the horsfiline precursors this serendipitously yielded macrocyclic pyrimidines.

The novel substituted pyridylboronic acids 2-bromo-5-pyridylboronic acid 92, 3-hromo-5- pyridylboronic acid 97, 2-chloro-5-pyridylboronic acid 103, 2-fluoro-5- pyridylboronic acid 108, 2-methoxy-5-pyridylboronic acid 123, 2-ethoxy-5- pyridylboronic acid 125, 2-medioxy-3-pyridylboronic acid 131, 3-bromo-6-methoxy-4- pyridylboronic acid 134, 3-chloro-6-methoxy-4-pyridylboronic acid 137 and 3-hromo-6- ethoxy-4-pyridylboronic acid 138 have been synthesised and shown to undergo palladium-catalysed Suzuki cross-coupling reactions with a vast variety of heteroaryl bromides to yield novel heteroarylpyridine derivatives.5-Formylfnran-2-boronic acid 170 has been synthesised and isolated and has been shown to undergo palladium-catalysed Suzuki cross-coupling reactions with a variety of heteroaryl bromides to yield novel heteroaryl substituted furyl derivatives. These derivatives have been shown to undergo efficient functionalisation by Wittig chemistry.

Submitted in partial fulfillment for the Degree of Master of Applied Sciences in Biotechnology, Durban University of Technology, Durban, South Africa, 2016. / Pharmacological research is essential for the advancement of treatment therapies to combat diseases that plague mankind. Pyrimidines have been a subject under investigation by medicinal chemists for many years due to their interesting pharmacological properties. In previous studies, pyrimidines and their derivatives have been reported to have antimicrobial, anti-inflammatory, antimalarial, analgesic, and antitumour activities amongst other biological activities. Although there has been a significant amount of research carried out on these heterocycles, there will always be a continuous need for the discovery of novel synthetic drugs which have a higher degree of potency and fewer side effects. Hence, this study was undertaken to determine the pharmacological activities of eight novel 1, 4 dihydropyrimidine analogues (DHPM 1 – 8), that have been synthesized in our laboratory. The dihydropyrimidines were synthesized and characterized and thereafter evaluated for in vitro antimicrobial, antioxidant, anti-inflammatory, cytotoxicity and apoptotic activities. The compounds also underwent a safety study. Antimicrobial activity was evaluated using the disk diffusion assay; compounds displaying superior activity were subjected to further analysis to establish the minimum inhibitory concentration. Overall compounds DHPM 7 and 8 showed the best antibacterial activity against Gram positive bacteria. The minimum inhibitory concentration (MIC) for DHPM 7 against the Gram positive organisms (B.cereus, S.aureus and B.coagulans) was 0.75 µg/mL; however DHPM 7 had a MIC of 0.37 µg/mL against M. luteus. DHPM 8 displayed an MIC of 0.75 µg/mL against B.cereus, S.aureus, M.luteus, S.faecalis and B.coagulans. Antioxidant activity was assessed using the DPPH method. DHPM 2 showed outstanding free radical scavenging capacity of 90.63% at a concentration of 1 mg/mL. The DHPM 1 - 8 were analysed for their lipoxygenase inhibitory activity. Excellent inhibition ranging from 59.37 ± 0.6 to 81.19 ± 0.94% was demonstrated. The inhibitory activity was elucidated by a molecular docking study against the lipoxygenase enzyme (PDB code = 3V99) using the MOE 2013.08 and Leadit 2.1.2 software and high affinities were demonstrated. DHPM 1 - 8 were tested for cytotoxic activity against two human cancer cell lines, MCF-7 and UACC-62 by means of the MTT assay. It was observed for the MCF-7 cell line, DHPM 1, 4, 6, 7 and 8 displayed cytotoxicity above 89% at 50 µg/mL. The DHPMs at 50 µg/mL were noted to be very effective against the Melanoma cell line with DHPM 2 having a cytotoxicity value of 82.62% and DHPM 1, 4, 5, 6, 7 and 8 exhibiting cytotoxicity greater than 96%. Only slight inhibition of the proliferation of PBMC’s was noted. IC50 values of DHPM 1-8 were determined and the best activity overall was displayed by DHPM 8. The IC50 of DHPM 8 was 0.92 ± 0.09 and 1.97 ± 0.08 µM against MCF - 7 and UACC - 62 cell lines, respectively. The compounds that displayed toxicity towards the UACC - 62 cell line were investigated for their apoptotic inducing potential. The apoptotic studies were performed by flow cytometry using the following assays; Annexin V, JC-1 and Caspase -3 assays. The effect of these compounds was compared to a known anti-cancer drug, Camptothecin. On evaluation of the mechanism of action of the compounds, it was found that most compounds are using apoptotic pathways for cell death. Our studies have identified antimicrobial activity (DHPM 1-8) against Gram positive organisms, high antioxidant activity (DHPM 2), anti-inflammatory activity (DHPM 1-8) and anticancer activity (DHPM 1-8) against UACC-62 and MCF-7 cells. DHPM 1-8 were found to have no toxicity at 100 µg/mL in the brine shrimp assay and hence are probably safe as therapeutic agents. Furthermore molecular docking studies confirmed the activity of DHPM 1-8 as potential lipoxygenase inhibitors. DHPM 1-8 are novel compounds with great potential to be developed into chemotherapeutic agents. / M

Thesis (M.Sc.)--University of the Witwatersrand, Faculty of Science, School of Chemistry, 2017. / In this work, commercially relevant palladium catalysed direct arylation reactions, in which the molecule oxazole is coupled to toluene were investigated computationally. These involve the Pd(II)/Pd(0) manifold. Each of the three hydrogen atoms of oxazole can be replaced by a toluene molecule, and as both mono- and di-substitution occurs there are 6 possible products. Experimental results, using the catalyst Pd(OAc)2 in DMA solvent, show that both the presence and quantity of tri-tertiary butyl phosphine (PtBu3) ligand has a significant impact on the observed product distributions. The aims of this study were to discover why and to ascertain the rate determining step (RDS) of the catalytic cycle under various conditions. All geometry optimisation and frequency calculations were conducted using the TPSSh hydrid DFT functional in conjunction with the Def2-SVP basis set. Single point energy benchmarks at the DLPNO-CCSD(T)/Def2-TZVP level of theory revealed that the double hybrid (DH) functional DSDPBEP86 in conjunction with the Def2-TZVP basis set was the best compromise between accuracy and efficiency for the systems at hand. The generally accepted concerted metallation deprotonation(CMD) mechanism was investigated under phosphine free conditions, where a DMA solvent molecule was modelled bound to the palladium centre. The results correctly predicted the experimental product distibutions for both mono- and di-substitution. The CMD mechanism was also investigated under conditions of 1 equivalent of PtBu3 ligand. In this case a PtBu3 molecule was modelled bound to the palladium centre. The results correctly predicted the major mono-substituted experimental product and from the data formation of the major disubstituted product was readily rationalized. Finally, oxidative addition (OA) was investigated under both conditions. It was found that the COSMO solvation model had a dramatic impact on OA reaction Gibbs energies. It was discovered that the presence of PtBu3 ligand significantly reduced the total Gibbs energy required for OA. In the absence of PtBu3, no DMA is coordinated to the palladium centre during OA. Regeneration of the active Pd(II) catalyst via deprotonation was the modelled completing the entire catalytic cycle. The RDS under phosphine free conditions was calculated to the CMD transition state (TS). Under condition of 1 equivalent of PtBu3 ligand the RDS was a mixture of both the CMD TS as well as coordination of oxazole to the active Pd(II) catalyst. / LG2018

半日花烷型二萜天然產物 pallambins A-D 是從中國苔植物Pallavicinia ambigua 中分獲取的，這二萜中的許多化合物都呈現出有趣的生物活性。從分子結構觀點看，pallambins C 和D 由獨特的梯型[6-5-5-5]四環骨架構成，該分子骨架中包含7 個毗的體中心及三烯部分。並且，二環[3.2.1]辛烷酮片段的橋接部分分別由個橋頭甲基以及橋中的乙烯基密集取代。該分子的骨架新穎性及潛在的生物活性激發我們去進相關的全合成探。在此，我們將報導pallambins C 和D 的首次全合成。 / 本文第一章首先概述pallavicinin 系的天然源，結構特點以及生物學效用。此外，重點介紹pallambins C 和D 的分，結構鑒定以及反合成分析。 / 第二章討消旋體pallambins C 和D 的全合成細節。該合成以消旋Wieland-Miescher ketone (WMK)為起始原，經38 步線性步驟得到最終產物。該合成線突出以下個重要的化學轉化：a) 一個由Grob 碎及分子內aldol成環反應組成的多米式程，構建目標分子內關鍵的二環[3.2.1]辛烷酮單元；b) 一個由脲/鈀體系催化的烷氧羰基化增環反應，構建稠環型四氫呋喃/γ 內酯雙環框架。 / 第三章總結本文的相關研究工作。 / 第四章給出相關工作的詳細實驗據。 / Naturally occurring pallambins A-D isolated from the Chinese liverwort Pallavicinia ambigua are classified as modified labdane-type diterpenoids, many of which exhibit interesting biological activities. From a structural perspective, pallambins C and D are consisting of trienes and an unprecedented ladder-shaped [6-5-5-5] tetracyclic skeleton bearing seven contiguous stereogenic centers. Furthermore, the bridge of the bicyclo[3.2.1]octane segment is densely substituted with two methyl groups on the bridge-heads and a vinyl group on the carbon bridge. The skeletal novelty and potential bioactivities of pallambins C and D inspired us to explore their total synthesis. In this thesis, the first total synthesis of (±)-pallambins C and D is described. / In Chapter 1, a general introduction to the natural occurrence, structural features and biological potency of pallavicinin family is presented briefly. In addition, the background of pallambins C and D including isolation, structural elucidation and retrosynthetic analysis is emphasized. / In Chapter 2, detailed synthesis of (±)-pallambins C and D involving a linear 38 steps starting from the known (±)-Wieland-Miescher ketone is discussed. The synthetic approach features the following two key conversions: a) a domino process including Grob fragmentation and intramolecular aldol cyclization to build up the bicyclo[3.2.1]octanone embedded in the target molecules; b) a thiourea/palladium-catalyzed alkoxycarbonylative annulation to assemble the fused tetrahydrofuran/γ-lactone bicyclic framework. / Chaper 3 provides a conclusion of this research work. / Chapter 4 is concerned with the experimental details. / [With images.] / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Xu, Xuesong. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2013. / Includes bibliographical references. / Abstracts also in Chinese. / ACKNOWLEDGEMENTS --- p.I / CONTENTS --- p.II / ABBREVIATIONS --- p.V / PART I: / ABSTRACT --- p.1 / Chapter CHAPTER 1. --- INTRODUCTION / Chapter 1.1 --- General background --- p.4 / Chapter 1.1.1 --- General introduction to liverworts --- p.4 / Chapter 1.1.2 --- General introduction to terpenoids in liverworts --- p.5 / Chapter 1.2 --- Introduction to pallavicinin family --- p.9 / Chapter 1.2.1 --- Isolation and structural elucidation of pallavicinin compounds --- p.9 / Chapter 1.2.2 --- Synthetic advances on pallavicinin family --- p.13 / Chapter 1.3 --- Introduction to the present research --- p.16 / Chapter 1.3.1 --- Structural elucidation and features of pallambins C and D --- p.16 / Chapter 1.3.2 --- Biogenetic hypothesis and retrosynthetic analysis of pallambins C and D --- p..20 / Chapter 1.4 --- Aim of the present work --- p.22 / Chapter CHAPTER 2. --- RESULTS AND DISCUSSION --- p.24 / Chapter 2.1 --- Previous synthetic effort on pallambin D (2) --- p.24 / Chapter 2.2 --- Successful synthetic approach to 1 and 2 --- p.25 / Chapter 2.2.1 --- Synthesis of compound 24 --- p.25 / Chapter 2.2.2 --- Synthesis of compound 14 --- p.30 / Chapter 2.2.3 --- Synthesis of compound 13 --- p.37 / Chapter 2.2.4 --- Synthesis of compound 12 --- p.43 / Chapter 2.2.5 --- Synthesis of 1 and 2 --- p.53 / Chapter CHAPTER 3. --- CONCLUSION --- p.60 / Chapter CHAPTER 4. --- EXPERIMENTAL SECTION --- p.62 / REFERENCES --- p.104 / PART II: / ABSTRACT --- p.110 / Chapter CHAPTER 1. --- INTRODUCTION --- p.113 / Chapter 1.1 --- Introduction to bicyclo[3.2.1]octane skeleton --- p.113 / Chapter 1.1.1 --- Structural features of bicyclo[3.2.1]octane --- p.113 / Chapter 1.1.2 --- Bicyclo[3.2.1]octane-containing bioactive natural products --- p.114 / Chapter 1.1.3 --- Methodologies for synthesis of bicyclo[3.2.1]octane derivatives --- p.116 / Chapter 1.1.4 --- Gold-catalyzed construction of bicyclo[3.2.1]octane unit --- p.117 / Chapter 1.2 --- Background of the present research --- p.119 / Chapter 1.2.1 --- Introduction to dhilirolides A-D --- p.119 / Chapter 1.2.2 --- Retrosynthetic analysis of dhilirolide A (1) --- p.121 / Chapter 1.3 --- Aim of the present work --- p.122 / Chapter CHAPTER 2. --- RESULTS AND DISCUSSION --- p.124 / Chapter 2.1 --- Synthesis of the key acetal allene precursor 6 --- p.124 / Chapter 2.1.1 --- Preparation of the starting dimethoxyl ketone 7 --- p.124 / Chapter 2.1.2 --- Preparation of alkynyl furan 11 --- p.126 / Chapter 2.1.3 --- Preparation of acetal allene 6 --- p.128 / Chapter 2.2 --- Synthesis of bicyclo[3.2.1]octenone derivative 5 --- p.134 / Chapter 2.3 --- Synthesis of mono-tosylate 26 --- p.138 / Chapter CHAPTER 3. --- CONCLUSION --- p.141 / Chapter CHAPTER 4. --- EXPERIMENTAL SECTION --- p.143 / REFERENCES --- p.162 / APPENDIX --- p.167

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