published_or_final_version / abstract / Chemistry / Doctoral / Doctor of Philosophy

A thesis submitted to the Faculty of Science University of the Witwatersrand Johannesburg In fulfilment of the requirements for the Degree of Doctor of Philosophy June 2015 / The first two chapters of this thesis deals with the synthesis of 6H-benzo[d]-naphtho[ 1,2- b]pyran-6-one motif found in gilvocarcin as well as related aromatic compounds containing the aromatic pyranone moiety. The synthesis was undertaken by employing the Suzuki- Miyaura cross coupling reaction and a novel N-bromosuccinimide induced ring cyclization reaction to afford the pyranone. It was established that the treatment of both [2-(1,4- dimethoxynaphthalen-2-yl)phenyl]methanol and (2',5'-dimethoxy-[1,1'-biphenyl]-2- yl)methanol separately with N-bromosuccinimide results in the unexpected synthesis of a naphthopyranone ring system in the form of 12-methoxy-6H-dibenzo[c,h]chromen-6-one and 2-methoxy-6H-benzo[c]chromen-6-one respectively. Application of the same methodology for the attempted synthesis of related compounds namely, 1-hydroxy-12-methoxy-6Hdibenzo[ c,h]chromen-6-one and 8-fluoro-12-methoxy-6H-dibenzo[c,h]chromen-6-one unfortunately did not generate the desired results. Attempts were made to elucidate the mechanism of this reaction. The most apparent mechanism indicates that Nbromosuccinimide, in the presence of air, oxidizes the benzylic alcohol to an aldehyde which is then converted to an acid bromide allowing for the ring closure with the adjacent aromatic ether to afford the desired pyranone. In Chapter 3 and 4 of this thesis we dealt with the synthesis of benzo[b]phenanthridine-7,12- dione motif, the backbone of biologically important secondary metabolite jadomycin B. Again, a key step involves employing the Suzuki-Miyaura cross coupling reaction. The synthetic methodology also sheds some light on the dynamics of the ring closure of benzylic amines onto naphthoquinones resulting in the synthesis of benzo[i]phenanthridine-11,12- dione, 12-methoxybenzo[i]phenanthridine and 1-hydroxybenzo[i]phenanthridine-11,12-dione. The synthesis of benzo fused phenanthridines has been undertaken in Chapter 5 and 6 by employing Suzuki-Miyaura cross coupling reaction and a potassium t-butoxide and light mediated cyclization reaction as the key steps. The synthesis of 5- phenylbenzo[i]phenanthridine was undertaken successfully but attempts to execute the same methodology to form a compound library of related benzo-fused phenanthridines was unsuccessful. The same methodology employing a Suzuki-Miyura cross coupling reaction and potassium tbutoxide and light mediated cyclization reaction was applied in Chapter 7 and 8 of the thesis directed towards the synthesis of 13H-indolo[3,2-c]acridine and 3-methoxy-13H-indolo[3,2- c]acridine. The successful synthesis of the 13H-indolo[3,2-c]acridine is reported using this methodology.

A 5-membered INOC cycloadduct 84 was employed to prepare alcohol 91, which was transformed into several cyclopent-2-enone derivatives 94-96. / By using intramolecular nitrile oxide-alkene cycloaddition (INOC) as the kep step to construct hydroxylated carbocycles, gabosine F was synthesized for the first time from L-arabinose. Hence, theoretically, gabosine B, which is the enantiomer of gabosine F, can also be synthesized from D-arabinose by the same synthetic strategy. / In this thesis, the background information on the construction of carbocycles from carbohydrates via intramolecular 1,3-dipolar cycloaddition is presented. A review regarding the syntheses of gabosine B and cocaine are also descibed. / Starting with D-ribose, INAC of nitrones 113, 129, and 140, bearing an alpha/beta-unsaturated ester as the dipolarophile was studied. The INAC endo-cycloadduct 141 (cycloheptane) was converted into natural cocaine sucessfully, together with cocaine analogues 162,169,170,173,175, and 177. / The regioselectivity of intramolecular nitrone-alkene cycloaddition (INAC) was studied. The INAC of hept-6-enose nitrone 98, with a 3,4- trans-pentylidene acetal as the only blocking group, afforded endo-cycloadduct 97 (cycloheptane) exclusively. This result concluded that the regiospecific outcome of this INAC reaction is due to the present of the 3,4-trans-pentylidene acetal blocking group. / To investigate the regioselectivity in INAC of hex-5-enose with a 2,3- trans-pentylidene acetal blocking group, nitrones 178 and 195 were prepared from D-mannitol. endo-Cycloadducts (cyclohexanes) were afforded exclusively. / So, King Ho. / Adviser: Kung Ming Tony Shing. / Source: Dissertation Abstracts International, Volume: 73-06, Section: B, page: . / Thesis (Ph.D.)--Chinese University of Hong Kong, 2011. / Includes bibliographical references (leaves 165-171). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [201-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

Hak-fun Chow. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1981. / Bibliography: leaves 70-73.

by Huichang Zhang. / Thesis (Ph.D.)--Chinese University of Hong Kong, 1996. / Includes bibliographical references (leaves 114-130). / Acknowledgment --- p.i / Abstract --- p.ii / Abbreviations --- p.iii / Table of Contents --- p.iv-v / Chapter Chapter I --- Introduction --- p.1 / Chapter I --- The basis of asymmetric catalysis --- p.6 / Chapter II --- Chiral catalyst --- p.8 / Chapter II-I --- Center metal --- p.9 / Chapter II-II --- Chiral ligand --- p.10 / Chapter III --- Structural analysis of effective chiral ligands --- p.13 / Chapter III-I --- Monodentate ligand --- p.15 / Chapter III-II --- Bidentate Ligand --- p.16 / Chapter 1 --- Bidentate phosphine ligand --- p.16 / Chapter 2 --- Bidentate oxygen ligand --- p.17 / Chapter 3 --- Bidentate nitrogen ligand --- p.19 / Chapter 4 --- "Bidentate ligand with N, 0，P, or S donor atom" --- p.21 / Chapter III-III --- Potentially tridentate ligand --- p.22 / Chapter III-IV --- Potentially tetradentate ligand --- p.23 / Chapter IV --- Tentative conclusions on the effect of structural elements --- p.24 / Chapter Chapter II --- "Design, synthesis and resolution of novel chiral pyridylphenols" --- p.27 / Chapter I --- Design of chiral ligand --- p.27 / Chapter II --- Synthesis of chiral ligands --- p.29 / Chapter II-I --- "Synthesis of the chiral N, O-donor ligands" --- p.29 / Chapter 1 --- Synthesis of the chiral ligands 75a-75c --- p.29 / Chapter 2 --- Synthesis of the chiral ligands 93a and 93b --- p.37 / Chapter 3 --- Synthesis of the chiral ligands 97a-97c --- p.41 / Chapter II-II --- "Synthesis of the chiral N, P-donor ligand 98 and N, S-donor ligand 101" --- p.42 / Chapter III --- Resolution of racemates of chiral ligands --- p.44 / Chapter III-I --- Resolution of of the pyridylphenol 75b --- p.44 / Chapter III-II --- Resolution of of the pyridylphenol 93a --- p.48 / Chapter III-III --- Racemization study of 75b and 93a --- p.52 / Chapter 1 --- Racemization test of 75b --- p.52 / Chapter 2 --- Racemization test of 93a --- p.52 / Chapter Chapter III --- Asymmetric addition of diethylzinc to aromatic aldehydes catalyzed by chiral pyridylphenols / Chapter I --- Backgound --- p.53 / Chapter II --- Asmmetric addition of Et2Zn to aldehydes catalyzed by chiral pyridylphenols --- p.61 / Chapter II-I --- Asmmetric addition of Et2Zn to aldehydes catalyzed by (R)-(+)-75b --- p.61 / Chapter 1 --- The influence of the solvent --- p.61 / Chapter 2 --- The influence of the reaction temperature --- p.64 / Chapter 3 --- The influence of the concentration of catalyst --- p.66 / Chapter 4 --- Electronic effect on the enantioselectivity of asymmetric addition of Et2Zn to aromatic aldehydes --- p.67 / Chapter II-II --- Asmmetric addition of Et2Zn to aldehydes catalyzed by (5)-(+)-75b --- p.73 / Chapter II-III --- Asmmetric addition of Et2Zn to aldehydes catalyzed by (R)-(+)-93a --- p.75 / Chapter III --- Conclusions --- p.78 / Chapter Chapter V --- Experimental Section --- p.79 / References --- p.114 / NMR Spectra --- p.131

Wong, Wing Yan. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2010. / Includes bibliographical references (leaves 76-79). / Abstracts in English and Chinese. / Contents --- p.i / Acknowledgments --- p.iii / Abstract --- p.iv / Abbreviations and Acronyms --- p.vii / Publications Originated from the Work of this Thesis --- p.ix / Chapter Part I: --- "Self-Assemblyy Stability Quantification, Controlled Molecular Switching, and Sensing Properties of an Anthracene-Containing Dynamic [2]Rotaxane" / Chapter Chapter 1 - --- Introduction / Chapter 1.1 --- Definition of Rotaxane --- p.2 / Chapter 1.2 --- Dynamic Covalent Chemistry in Rotaxane Synthesis --- p.5 / Chapter 1.3 --- Thermodynamic Template --- p.6 / Chapter 1.4 --- Molecular Sensing Properties in Rotaxane --- p.10 / Chapter 1.5 --- Examples --- p.13 / Chapter Chapter 2 - --- Anthracene-Containing Dynamic [2]Rotaxane / Chapter 2.1 --- Background --- p.17 / Chapter 2.2 --- Modification and Design of Dynamic [2]Rotaxane --- p.18 / Chapter 2.3 --- Self-Assembly of Rotaxane and Synthesis of Components --- p.19 / Chapter 2.4 --- Characterization / Chapter 2.4.1 --- 1H NMR Spectroscopy --- p.21 / Chapter 2.4.2 --- 13C NMR Spectroscopy --- p.23 / Chapter 2.4.3 --- Mass Spectrometry --- p.24 / Chapter 2.4.4 --- X-Ray Crystallography --- p.25 / Chapter 2.4.5 --- UV/Visible Absorption and Fluorescence Spectroscopies --- p.26 / Chapter 2.5 --- Effect of External Stimuli / Chapter 2.5.1 --- Addition of Water --- p.29 / Chapter 2.5.2 --- Addition of Acid --- p.33 / Chapter 2.5.3 --- Addition of Salts --- p.38 / Chapter 2.5.4 --- Addition of Amines --- p.40 / Chapter 2.6 --- Conclusions --- p.43 / Chapter Part II: --- Substituent Effect in Imine-Containing Molecular Tweezers / Chapter Chapter 3 - --- Molecular Tweezers / Chapter 3.1 --- Introduction --- p.46 / Chapter 3.2 --- Synthesis --- p.48 / Chapter 3.3 --- Characterization of Molecular Tweezers / Chapter 3.3.1 --- 1H NMR Spectroscopy --- p.49 / Chapter 3.3.2 --- Mass Spectrometry --- p.51 / Chapter 3.4 --- Characterization of Molecular Tweezers / Chapter 3.4.1 --- 1H NMR Spectroscopy --- p.51 / Chapter 3.4.2 --- X-Ray Crystallography --- p.59 / Chapter 3.4.3 --- Mass Spectrometry --- p.60 / Chapter 3.4.4 --- UV/Visible Absorption Spectroscopy --- p.61 / Chapter 3.5 --- Conclusions --- p.63 / Chapter Chapter 4 - --- Experimental Procedures / Chapter 4.1 --- General Information --- p.64 / Chapter 4.2 --- General Synthetic Procedures for Molecular Tweezers (34-40) --- p.65 / Chapter 4.3 --- Experimental Procedures --- p.65 / Chapter 4.4 --- Determination of Binding Constant K --- p.73 / References --- p.76 / Appendix / List of Spectra --- p.A-l / List of Crystal Data --- p.A-2

He, Xiao. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2011. / Includes bibliographical references (leaves 75-83). / Abstracts in English and Chinese. / Acknowledgement --- p.I / Abstract --- p.II / 摘要 --- p.III / Abbreviation --- p.IV / List of Compounds --- p.VI / List of Figures --- p.VII / Contents --- p.IX / Chapter Chapter 1 --- Introduction --- p.1 / Chapter 1.1 --- Transition Metal-Carboranyl Complexes --- p.2 / Chapter 1.1.1 --- Late Transition Metal-Carboranyl Complexes --- p.2 / Chapter 1.1.2 --- Early Transition Metal-Carboranyl Complexes --- p.6 / Chapter 1.2 --- Transition Metal-Carboryne Complexes --- p.12 / Chapter 1.3 --- Five-Membered Heterocycles Incorporating Main Group Elements --- p.20 / Chapter 1.3.1 --- Synthesis and Reactivity of Boroles --- p.20 / Chapter 1.3.2 --- Synthesis and Reactivity of Phospholes --- p.24 / Chapter 1.3.3 --- Synthsis and Reactivity of Silole --- p.28 / Chapter 1.4 --- Our Objectives --- p.31 / Chapter Chapter 2 --- Nickelacycles Incorporating a Carboranyl Unit --- p.32 / Chapter 2.1 --- Introduction --- p.32 / Chapter 2.2 --- "Synthesis, Characterization and Reactivity of Nickelacycles Bearing (2-CPh2O-l,2-C2B10H10)2-Ligand" --- p.32 / Chapter 2.2.1 --- Synthesis and Characterization --- p.32 / Chapter 2.2.2 --- Reactivity Study --- p.34 / Chapter 2.2.3 --- X-ray Structure --- p.36 / Chapter 2.3 --- "Synthesis and Characterization of Nickelacycles Bearing [2-C(Ph)=N-l,2-C2B10H10]2- Ligand" --- p.44 / Chapter 2.3.1 --- Synthesis and Characterization --- p.44 / Chapter 2.3.2 --- X-ray Structure --- p.45 / Chapter Chapter 3 --- Five-membered Heterocycles of Main Group Elements Incorporating a Carboranyl Unit --- p.47 / Chapter 3.1 --- Synthesis and Characterization of Heterocycles Bearing Phosphorus Element --- p.47 / Chapter 3.2 --- Synthesis and Characterization of Heterocycles Bearing Silicon Element --- p.53 / Chapter 3.3 --- Synthesis and Characterization Heterocycles Bearing Boron Element --- p.58 / Chapter Chapter 4 --- Conclusion --- p.61 / Chapter Chapter 5 --- Experimental Section --- p.63 / References --- p.75 / Appendix --- p.84 / Chapter I. --- Crystal Data and Summary of Data Collection and Refinement --- p.84 / Chapter II. --- X-ray crystallographic data in CIF (electronic form)

The work presented in this dissertation is a composite of experiments in the growth of gold nanoparticles with specific optical properties of interest. The goal is to synthesize these gold nanoparticles using soybean extract for not only shape control, but for propensity as a biocompatible delivery system. The optical properties of these nanoparticles has found great application in coloring glass during the Roman empire and, over the centuries, has grown into its own research field in applications of nanoparticulate materials. Many of the current functions include use in biological systems as biosensors and therapeutic applications, thus making biocompatibility a necessity. Current use of cetyltrimethylammonium bromide leads to rod-shaped gold nanoparticles, however, the stability of these gold nanoparticles does not endure for extended periods of time in aqueous media. In my research, two important components were found to be necessary for stable, anisotropic growth of gold nanoparticles. In the first experiments, it was found that bromide played a key role in shape control. Bromide exchange on the gold atoms led to specific packing of the growing crystals, allowing for two-dimensional growth of gold nanoparticles. It was also discerned that soybean lecithin contained ligands that blocked specific gold facets leading to prismatic gold nanoparticle growth. These gold nanoprisms give a near infrared plasmon absorption similar to that of rod-shaped gold nanoparticles. These gold nanoprisms are discovered to be extremely stable in aqueous media and remain soluble for extended periods of time, far longer than that of gold nanoparticles grown using cetyltrimethylammonium bromide. Since soy lecithin has a plethora of compounds present, it became necessary to discover which compound was responsible for the shape control of the gold nanoprisms in order to optimize the synthesis and allow for a maximum yield of the gold nanoprisms. Many of these components were identified by high performance liquid chromatography and liquid chromatography-mass spectrometry. However, re-spike of these components into growth solutions did not enhance the growth of gold nanoprisms. Upon separating the shapes of the gold nanoparticles using gel electrophoresis, addition of KCN to the separated gold nanoparticles allowed us to extract the culpable ligands for shape control. Analysis of these ligands by mass spectrometry elucidated the identity of PA and upon re-spike of the PA into a growth solution of PC95, the growth of a near-infrared plasmon absorption was seen. The stability of these gold nanoparticles was tested with and without the addition of decane thiol and it was concluded that addition of the thiol allowed for improved stability of the gold nanoparticles towards cyanide. It was determined that at a concentration of 2 μM decanethiol, spherical gold nanoparticles remained stable to cyanide at the expense of the prismatic gold nanoparticles. However, at 5 μM decanethiol, both spherical and prismatic gold nanoparticles retained stability to cyanide in aqueous conditions.

PART I. Asymmetric syntheses of both natural (+)- and nonnatural (-)- byssochlamic acid via a [2+2] photoaddition-cycloreversion strategy are described. X-ray crystallographic analysis of the cyclohexylamine salt 99 showed that the structure of the monomethyl ester 100 from esterase hydrolysis of 44 was originally misassigned as 56. The enantiomeric relationship of the two diolides 106 and 70 permitted syntheses of nonnatural byssochlamic acid (-)-3 and natural byssochiamic acid (+)-3 from enantiopure alcohol (+)-64 and from its enantiomer (-)-110, respectively. Through the use of (��)-103 to reach both enantiomers of byssochlamic acid (3) and subsequent epimerization of the npropyl chain, it was proved that the cis configuration of the two alkyl substituents is strongly preferred in the natural product. PART II. An asymmetric approach towards the nootropic agent huperzine A is described. Formation of cyclobutane 122 with the desired stereochemistry was accomplished using intramolecular [2+2] photoaddition of the enantiopure enone 121. Attempts to prepare the methoxypyridine system via an azadiene Diels- Alder reaction were unsuccessful. However, intramolecular Michael addition of 181 produced silyl ether 182 which was converted into the pyridone 187 by treatment with hydrogen fluoride followed by selenoxide elimination. Attempts to effect the key sigmatropic rearrangement of ketone 197 into a direct precursor of huperzine A were unsuccessful. / Graduation date: 2001

Graduation date: 1997