Tetrahydrofuran (THF) and tetrahydropyran (THP) rings are commonly found in a wide range of natural products and biologically active compounds. In total synthesis, the formation of THF/THP motifs is often the key step but existing methods often involve numerous steps and low overall efficiencies. Part one of this thesis details the development of a practical method for the synthesis of THF rings by the controlled mono-addition/cyclisation of organolithium species to C2-symmetric diepoxides (Scheme A-1). This method can also be applied to the synthesis of bis-THF rings from triepoxides and has potential applications in more complex cascade reactions. A similar cyclisation process providing THF rings from epoxyaldehydes is also described. Part two of this thesis details our efforts towards the synthesis of the marine macrolide neopeltolide. Wright and co-workers reported the isolation of neopeltolide 211 from a deep-water sponge of the family neopeltidae off the north coast of Jamaica. The structure, which was assigned by NMR and HRMS studies and reassigned by total synthesis, contains a 14-membered macrolactone, a 2,6-cis THP ring and an unsaturated oxazole side-chain. Chapter four describes the synthesis of the C2-C8 and C9-C16 fragments (Scheme A-2). Chapter five details our initial attempts in the coupling of subunits 268 and 320, as well as a revised synthetic strategy that allowed us to successfully couple C2-C9 alkyne 347 with C10-C16 aldehyde 348 and the preparation of an advanced intermediate 364 (Scheme A-3).

Spiro-γ-lactones are widely distributed among natural products, several of them being well known by their interesting biological activities. We describe herein the synthesis of 1-oxaspiro[4.4]nonan derivatives and (+-)-andirolactone starting from easily available Diels-Alder adducts of 5-methylene-2(5H)-furanome 1 and classical dianes / La química de les espiro-γ-lactones ha despertat un considerable interès principalment degut a què moltes molècules que posseeixen aquesta estructura presenten diverses i significatives activitats biològiques. En aquesta tesi doctoral, prenent com a precursors els adductes de Diels-Alder, s’han investigat noves rutes sintètiques cap a 2(3H)-dihidrofuanones 5.5-disubstituïdes i oxaspiro[4.4]nonans polifuncionalitzats. Es presenten dues noves síntesis de (+-)-andirolactona 2, sesquiterpenoid amb estructura d’espiro-γ-butirolactona, recentment aïllat del Cedrus Libanotica i interessant per les seves propietats medicinals i biològiques potencials

Department of Chemistry / MSc (Chemistry) / See the attached abstract below

MSc (Chemistry) / Department of Chemistry / Chromones are well known naturally occurring heterocyclic compounds with oxygen as a heteroatom. Chromones are also one of the major classes of naturally occurring compounds, and the interest in their chemistry is due to their wide range of their biological activity. In this study, three classes of target compounds were synthesized through three different pathways. The first pathway, chromone-3-carbaldehyde analogues were afforded in good to excellent yield followed by the oxidation thereof to 4-oxo-4H-chromene-3-carboxylic acids. A series of chromone-3-carboxamides was obtained from corresponding 4-oxo-4H-chromene-3-carboxylic acid via the in situ generation of the corresponding acid chloride in good yield. The second class of compounds were achieved by reacting corresponding chromone-3-carbaldehyde analogues with thiazolidine-2,4-dione to afford 5-((4-oxo-4H-chromen-3-yl)methylene)thiazolidine-2,4-dione analogues. The third class of compounds followed the same reaction pathway as the second class of compounds from corresponding 8-allyl-chromone-3-carbaldehyde analogues to afford 5-((8-allyl-4-oxo-4H-chromen-3-yl)methylene)thiazolidine-2,4-dione analogues in good yield. Compounds were characterized by 1D NMR (1H, 13C and DEPT), 2D NMR (COSY, HSQC and HMBC), IR and elemental analysis (CHN analysis). Selected synthesized chromone derivatives were evaluated in vitro for two biological assays; namely trypanocidal activity and cytotoxicity. Among all tested compounds, 41A, 55B and 63D displayed promising trypanocidal activity by reducing the percentage parasite viability to 0.61, 0.15 and 0.21 respectively. These results were further substantiated by their IC50 values 4.3, 1.3 and 1.9 μg/mL respectively. Compounds 41B and 59A also showed significant trypanocidal activity, however it was below the positive control. Compounds 41A and 55B displayed cytotoxicity against the HeLa cells whilst compound 63D displayed no toxicity against the HeLa cells. / NRF