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published_or_final_version / abstract / Chemistry / Doctoral / Doctor of Philosophy

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Several tetrahydroisoquinoline (TIQ) diamine derivatives were prepared for use as ligands in asymmetric transfer hydrogenation (ATH) of acetophenone of which 17 intermediates and the eight target ligands were novel compounds. The initial design followed that of Noyori, who presented the efficiency of his monotosylated diamine in ATH. A series of eight novel secondary amine derivatives (78a-g and 88) were prepared with substituents that influenced the electronics and the sterics of and around the nitrogen donor. Ligand 71 was shown to have no activity for the ATH of acetophenone. It was apparent from experimental observations that a balance between the electronic and steric characteristics of the substituent was necessary to facilitate activity. It was found that ligand 78d possessing a benzyl group, had the greatest activity (81 % conv.). The greatest selectivity was obtained with ligand 78f (77 % ee) having a chiral phenylmethyl substituent. It was discovered in the case of the active diamine ligands that an optimised 1500 equivalents of water was required in order to demonstrate any enantioselectivity. The exact role of the water has never been ascertained, although there are many publications in which the effect of water has been examined. The most active metal precursor was also investigated and [RhCl2(Cp*)]2 was found to be the best for these TIQ diamine ligands in the specified model reactions. This work has recently been accepted for publication and has established criteria for further rational design on this system. / Thesis (M.Sc.)-University of KwaZulu-Natal, Westville, 2010.

The versatility of N-heterocyclic carbenes (NHCs) is demonstrated by numerous practical applications in homogeneous transition metal catalysis, organocatalysis and materials science. There remains a paucity of electropositive metal NHC complexes and so this chemistry is poorly developed with respect to that of the late transition metal and main group elements. This thesis describes the synthesis of new alkoxy-tethered NHC proligands, their use in the synthesis of reactive metal amide and metal alkyl complexes, and finally small molecule activation using these complexes. Chapter One introduces NHCs and discusses their use as supporting ligands for early transition metal and f-block complexes. Small molecule activation using organometallic complexes is examined alongside the use of electropositive metal NHC complexes in catalysis. Chapter Two contains the synthesis and characterisation of new alkoxy-tethered NHC proligands and a variety of electropositive MII (M = Mg and Zn), MIII (M = Y, Sc, Ce and U) and MIV (M = Ce and U) amide complexes. X-ray diffraction studies and a DFT study are used to probe the extent of covalency in the bonding of the MIV complexes. Chapter Three investigates the reactivity of the amide complexes prepared in Chapter Two. The MII complexes are shown to be initiators for the polymerisation of raclactide into biodegradable polymers. The MIII complexes are used to demonstrate additionelimination reactivity of polar substrates across the M-Ccarbene bond which allows the formation of new N-E (E = Si, Sn, P or B) bonds. Treatment of the UIII silylamide complex U(N{SiMe3}2)3 with CO results in the reductive coupling and homologation of CO to form an ynediolate core -OC≡CO- and the first example of subsequent reactivity of the ynediolate group. The MIV complexes are used to examine the potential for forming MIV cationic species and alkyl complexes. Chapter Four examines the synthesis of MIII (M = Ce and Sc) aminobenzyl complexes and MIII (M = Y, Sc and U) neosilyl and neopentyl alkyl complexes. The addition-elimination reactivity discussed in Chapter Three is extended to include C-E bond formation (E = Si, Sn, P, B, I or C). Chapter Five provides overall conclusions to the work presented within this thesis. Chapter Six gives experimental and characterising data for all complexes and reactions in this work.

Submitted in partial fulfillment for the Degree of Master of Applied Sciences in Biotechnology, Durban University of Technology, Durban, South Africa, 2016. / Coumarins are naturally occurring α-benzopyrone derivatives known for their pharmacological properties such as anticoagulant, antimicrobial, anticancer, antioxidant, anti-inflammatory and antiviral properties. The pharmacological, biochemical, and curative applications of coumarins depend on the substitution around the coumarin core structure. In the present study, seven halogenated coumarins CMRN1 - CMRN7 were synthesized and evaluated for mosquito larvicidal, repellancy , and insecticidal activity against Anopheles arabiensis. Furthermore, the antimicrobial properties of compounds CMRN1 - CMRN7 were evaluated by assessing the bacterial and fungicidal activities using the disc diffusion method. The anti-inflammatory properties were evaluated using the 5-lipoxygenase kit assay. The evaluation of the safe use of the compounds was determined using the Brine shrimp lethal test. The potential carcinogenic properties of the studied compounds was done using the Salmonella mutagenicity test. The anti-cancer property of the studied compounds was evaluated against UACC62 (Melanoma), MCF-7 (Breast cancer), and PBMC (Peripheral blood mononuclear) cell lines using of MTT assay. The apoptotic potential of the synthesized coumarin was evaluated against UACC62 (Melanoma) cell by assessing their morphological changes, membrane change, mitochondria membrane potential, and caspase-3 activity using the Annexin V-PI staining, JC-1, caspase-3 enzyme kits, respectively, on flow cytometer. The results were compared to a known anti-cancer drug, doxorubicin. The results showed that compounds CMRN1, CMRN2, CMRN4, CMRN5 and CMRN7 exerted 100% larval mortality within 24 h of exposure. All halogenated coumarins reversibly knocked down adult mosquitoes but did not kill them after 24 h of exposure. Furthermore, the adulticidal activity of the compounds was considered only mild to moderate. The antimicrobial activity of the synthetized coumarins CMRN1 - CMRN7 were assessed against E. coli, K. pneumoniae, S. marcescens, S. faecalis, B. cereus, B. coagulans, B. stearothermophilus, C. freundii, S. aureus and M. luteus bacteria and three yeast cultures, C. albicans, C. utilis, S. cerevisiae as well as two fungal species, A. flavus and A. niger. Compounds CMRN1 and CMRN2 showed bacterial growth inhibition for all the tested species except K. pneumonia and B. stearothermophilus. Compounds CMRN4 and CMRN7 showed moderate bacterial inhibition against B. cereus, M. luteus and S. aureus. The anti-inflammatory activity of the coumarins analogues showed that 1 mg/mL of the compounds CMRN1, CMRN2, CMRN4 and CMRN5 displayed moderate anti-inflammatory activity when compared to the positive control, 15-lapoxygenase. The cytotoxicity results of the studied synthetized coumarins displayed selective activity towards the cancer cell lines used in this study. Our studies showed that CMRN1, CMRN2, CMRN4, and CMRN5 had significant cytotoxity effect against UACC-62 (Melanoma) and MCF-7 ( Breast) cancer cells with an inhibitory concentration (IC50) which displayed significant cytotoxicity effect, in particular CMRN4 and CMRN5. These compounds CMRN1- CMRN7 showed no toxicity effect against PBMCs cell line. The mechanism of cell death, that is, necrosis or apoptosis induced by the coumarins was investigated against UACC-62 (Melanoma). We found that CMRN1, CMRN2, CMRN4, CMRN5 induced morphological changes, characteristic of apoptosis . Annexin V kit showed that CMRN1, CMRN2 and CMRN5 showed early apopotosis and late apoptosis was particularly higher for compound CMRN4. The disruption of the mitochondria membrane was noticed to be greater in CMRN1 and CMRN5 when compared to the positive control doxorubicin. Compound CMRN4 produced high levels of caspase-3 positive compared to the control. The coumarin compounds showed no mutagenicity and were also found to be non-toxic to brine shrimps. In conclusion, compounds CMRN1, CMRN2, CMRN4, CMRN5 and CMRN7 are potential larvicidal agents because they exhibited close to 100% activity within 24 h. Furthermore, the anti-cancer efficiency of compounds CMRN1, CMRN2, CMRN4, and CMRN5, is enough qualification for them to be optimized for increase anticancer potency. / M

Submitted in complete fulfillment for the Degree of Master of Applied Sciences in Biotechnology, Durban University of Technology, Durban, South Africa, 2016. / Piperidine derivatives are essential heterocyclic compounds that have beneficial roles in the medical and commercial sector. They can be isolated from plant material and can be chemically synthesised using simple cost efficient methods. Piperidines and their derivatives are clinically used to prevent postoperative vomiting, facilitate radiological evaluation, correct gastrointestinal function as well as speed up gastric emptying before anaesthesia. Piperidine derivatives also demonstrate a wide spectrum of biological activities which include; antimicrobial, anticancer, anti- TB, anti-HIV, anti-inflammatory, analgesic, anti-influenza, anti-inflammatory and antitumor activity. The properties of piperidine derivatives depend on the nature of the side chains and their orientation. Based on the promising data that demonstrated the synergistic effects of biological agents with piperidine derivatives, the aim of our research is to determine the pharmacological activities, i.e. (i) antimicrobial activity, (ii) anti-inflammatory, (iii) anti-oxidant activity, (iv) cytotoxicity, and (v) biosafety of six piperidine derivatives, PM1 to PM6. All six piperidine derivatives (PM1-PM6) screened for antimicrobial activity exhibit characteristics of varying degrees of microbial inhibition against some Gram-positive and Gram-negative bacteria (B. cereus, B. subtilis, E. coli, S. aureus, Kl. Pneumonia, M. liuteus and P. aurenginosa) with the exception of B. polymixa, S. marcescens and S. faecalis. Certain piperidine derivatives did not demonstrate high inhibition activity towards the fungal strains, with inhibition only shown against four fungal species; A. niger, A. flavus, C. albicans and S. cerevisiae. Thus it is proposed that minor changes could be made to the structure of the compounds so that they can alter the effect that the compounds have on the specific fungi strains. With regard to antioxidant activity it is noted that the concentrations of the test compounds are directly proportional to the percentage of scavenging capacity. In comparison of the piperidine derivatives (PM1-PM6) to Rutin (reference standard), it was illustrated that Rutin displayed the best antioxidant activity. All six piperidine derivatives (PM1-PM6) showed greater than 50% anti-inflammatory activity, whilst the anti-inflammatory reference standard NCGA displayed the greatest activity in comparison to the piperidine derivatives tested. The safety of the piperidine derivatives was tested by assaying cytotoxicity, against melanoma, MCF7 cancer cells and normal fibroblasts as well as Brine shrimp lethality assay. All piperidine derivatives demonstrated high cytotoxicity activity against both cancer cell lines (melanoma and MCF7) and around 50 – 52% cytotoxicity against healthy cells. Chloro substitution of the phenyl ring increases cytotoxicity of compounds (Aerluri et al., 2012). This compound can be used in the treatment of cancer cells while inhibiting 50% of normal cells. All six piperidine derivatives (PM1-PM6) were also tested for toxicity against Artemia salina in a brine shrimp lethality assay. Piperidine derivatives exhibited varying degree of toxic activity towards the shrimp, with all derivatives displaying ± 50% toxic activity at 1000 µg/mL. These results reveal a directly proportional relationship between concentration of drug and toxicity. It remains a future research objective to modify these piperidine compounds (PM1-PM6) chemically to produce more derivatives for further biological evaluation. All the studied piperidine compounds have possible leads for optimization to carry out pre-clinical trials. We can conclude that the substitution of different side chains on the piperidine nucleus results in varying degree of pharmacological activity. Also, compounds containing the substitution of a chloro group at position 4 and a fluoro group at position 2 on the phenyl ring attached to carbon 2 and 6 on the piperidine nucleus resulted in high pharmacological activity. This good pharmacological activity was also exhibited by compounds containing substitutions of a methoxy group at position 3 on the phenyl ring attached to carbon 1 and 6 on the piperidine nucleus. Compounds containing a methoxy group positioned at carbon 4 on the phenyl ring which is attached to carbon 1 and 4 on the piperidine nuleus presented low pharmacological activity. Low activity was also exhibited by compounds containing substitution of a cyano group at position 4 on the phenyl ring which is attached to carbon 2 and 6 on the piperidine ring and a methyl group at position 4 on the phenyl group attached to a nitrogen at position 1 on the piperidine nucleus. / M

This thesis details investigations into organocatalytic reactions promoted by N Heterocyclic Carbenes (NHCs) that proceed via an assumed azolium enolate intermediate. Initial research focused on the catalytic asymmetric synthesis of β-lactones via an NHC-catalysed formal [2+2] cycloaddition of alkylarylketenes and chloral. This process operated in good yield (typically >70%) and moderate diastereoselectivity (typically ~75:25 dr, anti:syn) for a range of alkylarylketenes. The enantioselectivity was consistently high for the major anti diastereomer (typically >80% ee) and minor syn diastereomer (typically >70% ee). Interestingly, when a ketene bearing a 2 substituent on the aryl ring, or one that included an α-branched alkyl group was used, an exclusive asymmetric chlorination pathway was accessed. This is, to the best of our knowledge, the first use of chloral as an electrophilic chlorination agent. This methodology was found to be applicable to a range of 2-arylsubstituted alkylarylketenes in good yield and enantioselectivity (typically >70% yield and up to 92% ee). The scope of this reaction with respect to the aldehyde moiety was then analysed with 2-nitrobenzaldehyde providing β-lactone products in excellent dr (up to 94:6 syn:anti) and with good yield and enantioselectivity (typically >60% yield and >80% ee). Importantly these β-lactone products were amenable to further derivatisation with transformation to β-amino- and β-hydroxy acids. Following the identification of an NHC-catalysed chlorination reaction using chloral, the development of a general procedure was undertaken. Following a wide screen of electrophilic chlorination sources, 2,3,4,5,6,6 hexachlorocyclohexa 2,4 dienone was identified as optimal, operating in excellent yield (up to 97%) but in moderate to poor levels of enantioselectivity (21−61% ee). Efforts to expand the practicality of azolium enolate processes focused on the use of α-aroyloxyaldehydes as bench stable mono-substituted ketene surrogates. A range of differentially substituted α-aroyloxyaldehydes allowed access to δ-lactones via the NHC-catalysed [4+2] cycloaddition between azolium enolates and β,γ unsaturated α ketoesters. Following initial optimisation the reaction proceeded in exquisite diastereo- and enantiocontrol (typically >95:5 dr and >99% ee).

A number of oxygenated heterocycles have been described in nature as having a myriad of biological activities. Owing to these biological activities and their complex structure, these compounds are of interest to us and the preparation of selected oxygenated heterocycles is described in this thesis. Three main sections form this thesis, with each representing a class of oxygenated heterocycle. The first part of the thesis deals with pyranonaphthoquinone analogues where a model study was performed to construct the skeleton of the isochromane kalafungin. The synthesis of isochromane 6,9-dimethoxy-3,3a,5,9b-tetrahydro-2H-furo[3,2-c]isochromen-2-one was successfully achieved from commercially available 2,5-dihydroxybenzoic acid in an overall yield of 9.5%. The key steps employed in the synthesis of the isochromane were a cross metathesis reaction between (2-allyl-3,6-dimethoxyphenyl)methanol and ethyl acrylate to afford the α,β-unsaturated ester (E)-ethyl-4-(2-(hydroxymethyl)-3,6-dimethoxyphenyl)but-2-enoate which, after several synthetic steps, was converted to the isochromane via a radical induced lactonization using a hypervalent iodine reagent. The success of this route led us to the preparation of iscochromane (3aR, 5R, 9bR)-6,9-dimethoxy-5-methyl-3,3a,5,9b-tetrahydro-2Hfuro[ 3,2-c]isochromen-2-one. Our initial aim was to enzymatically resolve intermediate racemic alcohol 1-(2-allyl-3,6-dimethoxyphenyl)ethanol, however, the use of Candida antarctica lipase B (CALB) to facilitate the kinetic resolution was not as successful as we hoped. Therefore, using racemic alcohol 1-(2-allyl-3,6-dimethoxyphenyl)ethanol and the key reaction conditions developed in the model study of 6,9-dimethoxy-3,3a,5,9b-tetrahydro-2H-furo[3,2-c]isochromen-2-one, we successfully prepared isochromane (3aR, 5R, 9bR)-6,9-dimethoxy-5-methyl-3,3a,5,9btetrahydro 2H-furo[3,2-c]isochromen-2-one in an overall yield of 0.4%, albeit racemically. The second part of this thesis involved the use of nitroalkanes as precursors to spiroketals. In this section, we managed to successfully elucidate the mechanism of a novel Nef reaction previously described in our laboratories using three different substrates. The key steps involved during the elucidation of the mechanism were a Henry condensation reaction and a key modified Nef reaction. The preparation of the spiroketal skeleton of the griseusins was also attempted. The last part of this PhD thesis focused on the formation of angucycline analogues, specifically analogues related to the landomycins. We have successfully managed to prepare landomycin analogues tetraphene-7,12-dione, 3-methoxytetraphene-7,12-dione and 3,8-dimethoxytetraphene-7,12-dione. A Suzuki reaction followed by a Wittig reaction, isomerisation and final ring closing metathesis allowed for the smooth preparation of these analogues. The preparation of related analogues bearing seven-membered rings has also been achieved and is described.

Kathleen Shuk Man Poon. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1994. / Includes bibliographical references (leaves 93-94). / Abbreviations --- p.v / Lists of Figures --- p.vi / Lists of Schemes --- p.vii / Lists of Tables --- p.viii / Part I / Chapter Chapter 1 --- Introduction --- p.2 / Chapter 1.1 --- Thermal stability of metallacycles --- p.2 / Chapter 1.2 --- General Synthetic methods of Metallacycle --- p.5 / Chapter 1.3 --- Objective of this work --- p.6 / Chapter 1.4 --- Features of Ligands --- p.6 / Chapter 1.5 --- References --- p.10 / Chapter Chapter 2 --- Synthesis of Transfer Reagents --- p.11 / Chapter 2.1 --- Brief Survey of various Transfer Reagents --- p.11 / Chapter 2.2 --- Introduction to metallation reaction --- p.13 / Chapter 2.3 --- Result and Discussion --- p.16 / Chapter 2.3.1 --- Lithiation and Derivatization of Ligand --- p.16 / Chapter 2.3.2 --- Charge Migration --- p.18 / Chapter 2.3.3 --- Characterization of compounds --- p.23 / Chapter 2.4 --- Experimental --- p.27 / Chapter 2.5 --- References --- p.33 / Chapter Chapter 3 --- Synthesis of Metallacycles --- p.35 / Section I --- p.35 / Chapter 3.1 --- Introduction --- p.35 / Chapter 3.2 --- Results and Discussion --- p.36 / Chapter 3.2.1 --- Synthesis of Metallacycles of Group 14 elements --- p.36 / Chapter 3.2.2 --- Characterization of Group 14 metallacycles --- p.42 / Chapter 3.2.3 --- Experimental --- p.57 / Section II --- p.64 / Chapter 3.3 --- Introduction --- p.64 / Chapter 3.4 --- Result and Discussion --- p.65 / Chapter 3.4.1 --- Synthesis of Metallacycles of Group 4 elements --- p.65 / Chapter 3.4.2 --- Experimental --- p.68 / Chapter 3.5 --- Attempted synthesis of Group 12 Metallacycles --- p.70 / Chapter 3.5.1 --- Results and Discussion --- p.70 / Chapter 3.5.2 --- Experimental --- p.71 / Chapter 3.6 --- References --- p.73 / Part II --- p.75 / Chapter Chapter 4 --- Synthesis of Bimetallic Complex --- p.76 / Chapter 4.1 --- Brief Review on Bimetallic Complexes --- p.76 / Chapter 4.2 --- Results and Discussion --- p.80 / Chapter 4.2.1 --- Synthesis of bimetallic complexes --- p.80 / Chapter 4.2.2 --- Characterization of bimetallic complexes --- p.87 / Chapter 4.2.3 --- Experimental --- p.90 / Chapter 4.3 --- References --- p.93 / Appendix I General Experimental Procedure --- p.95