Herein is described our work towards the total synthesis of the marine natural product (±)-chartelline C and the potent antibiotic (-)-platensimycin. Part 1 relates the (±)-chartelline C project. The first chapter reviews (±)-chartelline C’s isolation, biogeneity, and previously reported studies relevant to the area. Chapter 2 tells of our contributions including the development of a convergent, regioselective assembly of an indole-imidazole compound en route to the natural product. Chapter 3 includes the experimental details of this work and the characterization of previously unreported compounds. Part 2 recounts the (-)-platensimycin research project. Chapter 4 discusses the importance of the natural product and the relevant previous research reported. Chapter 5 describes our efforts in this area, culminating in the stereoselective synthesis of an intermediate closely related to a known compound, which was converted to the natural product. Chapter 6 includes the experimental details of this work and the characterization of previously unreported compounds. / text

Pyrrolizidine alkaloids (PAs) produce a variety adverse hepatic effects, including acute toxicity, carcinogenicity and potent, persistent antimitotic effects. Additionally several have been evaluated as antineoplastic agents. PAs constitute significant health hazards to man and domestic animals. The mechanism(s) by which PAs induce these effects are not known. These studies were designed to test the hypothesis that some or all of the adverse hepatic effects and possibly the antineoplastic activity of PAs associate with or are mediated by a genotoxic interaction with cellular DNA. The first objective of the studies was to verify the in vivo gentoxicity of the PAs, in the process characterizing the type(s) of DNA damage induced. Hepatic DNA damage induced by the model PA monocrotaline (MCT) was assessed following i.p. administration to adult male Sprague-Dawley rats. DNA damage was characterized by the alkaline elution technique. MCT was found to induce both DNA-DNA interstrand and DNA-protein cross-links. No evidence was seen for the induction of DNA single-strand breaks, although the presence of small numbers of DNA single-strand breaks could have been masked by the overwhelming predominance of DNA cross-links. DNA-DNA interstrand cross-linking reached a maximum within 12 hr and thereafter decreased over a protracted period. By 96 hr post administration, the calculated cross-linking factor was no longer statistically different from zero (control). Further studies were performed to test the effects of agents known to modulate the formation/disposition of the proposed reactive intermediate and the toxic effects of the PAs. Consistent with its involvement in the mechanism of the toxicity of the PAs, genotoxicity was shown to modulate in the same direction and to similar degree as does the toxicity. Other PAs, or derivatives thereof, were evaluated in addition to MCT. Structural requirements for DNA cross-linking potential were shown to be similar to those required for the induction of toxic and antimitotic effects, again consistent with the involvement of DNA cross-linking in the mechanism of these effects. Indicine N-oxide however, an experimental antineoplastic agent, was shown not to mediate its cytotoxic effects via this mechanism.

(Uncorrected OCR) �Abstract of thesis entitled "Structures of Indole Alkaloids from Strychnos angustiflora" submitted by ~ AU Tak-yan, Francis for the degree of Master of Science at the University of Hong Kong in March 1973. - i - ABSTRACT From the leaves of Strychnos angustiflora Benth,three orange-coloured alkaloids angustoline, angus tine and angustidine have been isolated in low yield. / Molecular formulae and electronic spectra indicate that all three alkaloids have the same highly I conjugated polycyclic skeleton. Structure~ shown below \ are proposed� H Alkaloid Formula Rl R2 Angustoline C2'OH1702N3 CH(OH)CH3 H Angustine C20'H1SON3 CH=CH2 ! Angustidine Cl9H1SON3 H CH3 The major alkaloid, angustoline, is monoacidic and the hydrochloride-and the picr~te sa~ts have been prepared. - ii - The presence of a l-hydroxyethyl side chain shown by n.m.r. has been confir.med by acetylation to g~ve an / acetate. Chemical correlation between angustoline and angustine has been achieved in two ways. Firstly, the former was converted to the latter 'by acidic catalysed dehydration � Secondly, an~ustoline or its acetate on heating with collidine yielded dihydroangustine, also obtained from angustine by hydrogenation. Arguments are presented for the structures of the three alkaloids, based substantially on n.m.r. data (including long-range coupling and N.O.E. data) and biogenetic considerations. I i The three alkaloids are postulated to be derived biogenetically from vincoside, the fused pyridine ring being formed via opening of the iridoid glycoside ring by ammonia (or equivalent). / abstract / toc / Chemistry / Master / Master of Science

(Uncorrected OCR) Abstract of thesis entitled SYNTHETIC STUDIES TOWARDS ISAINDIGOTIDIONE Submitted by Poon Ch Yan for the degree of Doctor of Philosophy at The University of Hong Kong in October 2004 Banlangen (WlWMi), more commonly known in the West as baphicacanthus, is a well-reputed traditional Chinese medicinal herbal drug commonly used to treat ailments such as influenza. It was even prescribed recently in Hong Kong for bolstering immunity against the Severe Acute Respiratory Syndrome (SARS) virus. It is the root of Isatis indigotica Fort. (Cruciferae), a biennial plant found along the valley of the Yangtze River (Changjiang) in central China. Isaindigotidione (I) is an alkaloid isolated from the root of I. indigotica. The organic extracts of this root were found to be active in antiendotoxic tests, indicating that isaindigotidione, like other alkaloids from the root, may possess interesting biological activity. As isaindigotidione is found naturally only in small quantities in I. indigotica, further investigation will only be possible when sufficient quantities are synthesized. Chemically, the structure of isaindigotidione is a novel derivative of indolizino[7,6- cjquinoline (II) found in natural and synthetic products for the first time. To our knowledge, no synthetic studies of this compound or its derivatives have yet been reported, and this thesis describes our efforts to synthesize isaindigotidione and its analogues. The main building blocks of the tetracyclic framework II were L-proline (V) and isatin (VI). The acylation of L-proline derivative VII by BOC-protected isatin was achieved under basic conditions to give phenylglyoxylic amide VIII. It was found that, in the presence of base under reflux, VIII underwent bis-cyclization to afford II. It was noted that four transformations (aldol cyclization, dehydration, acylation, and BOC-deprotection) occurred in a one-pot operation very efficiently to produce excellent yields of II. The isaindigotidione analogues III and IV were also synthesized by the same strategy. Substituents at C-7 were introduced by cuprate addition and a Heck reaction to intermediate IX. Epimerization at the C-7 centre was found to occur under the bis-cyclization conditions, and analogues III and IV were obtained as epimeric mixtures. Unfortunately, it was discovered upon extensive investigation that these organometallic conjugate addition reactions did not lend themselves to the addition of the 2,6-dimethoxy-l-phenol moiety to IX and its derivatives, which this retroanalysis indicates is required for the synthesis of isaindigotidione. Several factors were found to deter the addition of the desired substituent, including the steric demands of IX, and the low reactivity of phenyl and aryl organometallic reagents. O. ^N�''/ i H ^O OMe OH OMe II ,NL !""'H ^CH3 i H ^O III IV COOH "N H O^N H VI H .0 OMe OMe � ^ BOC f OMe VII VIII IX / abstract / toc / Chemistry / Doctoral / Doctor of Philosophy

published_or_final_version / Chemistry / Master / Master of Philosophy

published_or_final_version / Chemistry / Doctoral / Doctor of Philosophy

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