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In 2006, Baker reported the isolation of palmerolide A, a polyketide derived marine macrolide, from the Antarctic tunicate Synoicum adareanum collected in the shallow waters surrounding Anvers Island. This unique macrolide displayed potent levels of cytotoxic activity in the human melanoma cell lines (UACC-62, LC₅₀ = 18 nM and M14 LC₅₀ = 76 nM), while also inhibiting V ATPase with an IC₅₀ of 2 nM. There have been eight further palmerolides isolated from Synoicum adareanum, which have been shown to possess cytotoxicity activity. The synthetic route devised for palmerolide A, utilised a convergent approach relying on the initial synthesis of three subunits. These subunits were to be coupled via a Horner-Wadsworth Emmons reaction, a Julia-Kocienski olefination, then followed by formation of the macrolcycle. This approach offers both flexibility and convergence, as alterations to the subunits would give access to other members of the palmerolide family and their analogues such as palmerolide E.

In continuation of the Kingston group's work to identify new compounds from natural products as a part of the International Cooperative Biodiversity Group (ICBG) program and in collaboration with the Institute for Hepatitis and Virus Research (IHVR), the two plants Neoharmsia baronii and Lopholaena cneorifolia were studied to identify their chemical components. Structural elucidation and characterization of the compounds were done using mass spectrometry, 1D and 2D NMR spectroscopy techniques. A systematic study of the ethanol extract of the plant Neoharmsia baronii Drake from the Madagascar forest led to the isolation of seven compounds, characterized as isoflavones and pterocarpans. The structures of the compounds were characterized by using 1D NMR and 2D NMR spectra, mass spectroscopy and in one case, x-ray crystallography. The HSQC and HMBC data along with comparison of these data with reported literature values confirmed the structures. The aforementioned isoflavones and pterocarpans showed varying cytotoxicity to ovarian cancer cell lines, with the isoflavone vogelin E being the most active compound. The extract of Lopholaena cneorifolia was studied as a part of a cooperative project with the IHVR to identify its chemical composition. Fractionation of this extract led to the isolation of three compounds which were characterized as stilbenes. Their structures were elucidated by using 1D NMR and 2D NMR spectra and mass spectroscopic data. / Master of Science

This thesis describes the total synthesis of the thiopeptide antibiotic micrococcin P1. It unambiguously elucidates its structure, which has been subject to controversy for over thirty years. The centerpiece of the route to the target molecule is a facile one-pot construction of the central thiazole/pyridine cluster developed in our laboratory. This highlyconvergent route entails a delicate Michael addition to yield a Hantzsch dihydropyridine intermediate, which undergoes further oxidation to the fully aromatised heterocycle. The synthesis was completed by the coupling of this core with a highly-modified sensitive peptide chain. The modular nature of the synthesis can also accommodate modifications for SAR studies, contributing thereby to the fields of medicinal chemistry, pharmacology, and microbiology. At a purely chemical level, we remain confident that this work will serve as a valuable guide in the elaboration of other members of the thiopeptide family.

The chemical constituents of EtOH extracts of the soft coral Sinularia sp. have led to the isolation of nature compounds¡]1-12¡^,sinularioperoxides A-D¡]1-4¡^, sinulariolins A-D¡]5-8¡^, 1a,3b-Dihydroxy-24-methylencholesta-5,9-diene¡]9¡^,¡]3S¡^-3,7-Dimethyl-nona- 6,8-dienoicacid¡]10¡^, ¡]2¢S¡^-Ethyl¡]5¢E¡^-5-(2¢,6¢-dimethylocta-5¢,7¢-dienyl)furan-3-carboxylate¡]11¡^, and one know metabolite, 3'R,4'-((2R, 4S)-2-hydroxy-4-acetoxy-2,6,6-trimethyl-cyclohexylidene)but-3'-en-2'-one¡]12¡^, respectively. Compounds 1-11 are new and 12 is a know metabolite, which had been isolated from the brown alga and the plant. The structures of 1-12 were elucidated by the interpretation of spectroscopic data¡]UV, MS, IR, 1D and 2D NMR¡^.

A synthetic plan for the dimeric diazobenzofluorene natural product lomaiviticin A and lomaiviticin B is presented. The route features a late-stage oxidative enolate dimerization of a monomeric oxanorbornanone, as well as a cyanophthalide-based anionic annulation. In chapter 2, a synthetic route to enone 2.42 is described. Starting from the readily prepared intermediate 1.101, enone 2.42 was prepared in seven steps. A key cyanophthalide annulation utilizing enone 2.42, where the C1 and C5 ketones are differentiated, was successfully applied. Chapter 3 describes an optimization study of the oxanorbornanone enolate dimerization. By using simple ketone 3.3 as a model, reaction conditions minimizing undesired side reactions were identified. These conditions were effectively applied to the dimerization of the fully elaborated tetracyclic precursor. A synthesis of the full carbon skeleton of the lomaiviticin aglycone is illustrated in chapter 4. A tetracyclic intermediate 4.13, prepared from enone 2.42, underwent stereoselective dimerization under the optimized conditions to provide \(C_2\)-symmetric dimer 4.12. During the dimerization study, a critical remote steric effect of C11 substituent was observed. A crystal structure of a dimeric intermediate helps lend support to our hypothesis regarding the remote steric effect. Finally, synthetic efforts to accomplish a synthesis of the lomaiviticin aglycone ent-1.3 is described in chapter 5. Although the C4 sulfone of dimer 4.12 was efficiently substituted with an oxygen atom, the key \(C11_b-O\) bond cleavage was not realized under a variety of strategies. / Chemistry and Chemical Biology

This thesis describes the total synthesis of the thiopeptide antibiotic micrococcin P1. It unambiguously elucidates its structure, which has been subject to controversy for over thirty years. The centerpiece of the route to the target molecule is a facile one-pot construction of the central thiazole/pyridine cluster developed in our laboratory. This highlyconvergent route entails a delicate Michael addition to yield a Hantzsch dihydropyridine intermediate, which undergoes further oxidation to the fully aromatised heterocycle. The synthesis was completed by the coupling of this core with a highly-modified sensitive peptide chain. The modular nature of the synthesis can also accommodate modifications for SAR studies, contributing thereby to the fields of medicinal chemistry, pharmacology, and microbiology. At a purely chemical level, we remain confident that this work will serve as a valuable guide in the elaboration of other members of the thiopeptide family.

This thesis describes the total synthesis of the thiopeptide antibiotic micrococcin P1. It unambiguously elucidates its structure, which has been subject to controversy for over thirty years. The centerpiece of the route to the target molecule is a facile one-pot construction of the central thiazole/pyridine cluster developed in our laboratory. This highlyconvergent route entails a delicate Michael addition to yield a Hantzsch dihydropyridine intermediate, which undergoes further oxidation to the fully aromatised heterocycle. The synthesis was completed by the coupling of this core with a highly-modified sensitive peptide chain. The modular nature of the synthesis can also accommodate modifications for SAR studies, contributing thereby to the fields of medicinal chemistry, pharmacology, and microbiology. At a purely chemical level, we remain confident that this work will serve as a valuable guide in the elaboration of other members of the thiopeptide family. / Science, Faculty of / Chemistry, Department of / Graduate

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