School of Chemistry - Theses
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ItemSynthesis of alkyl citrate natural products( 2014)An asymmetric total synthesis of squalene synthase (SSase) inhibitor ent-CJ-13,982 (ent-4) is presented along with work torwards SSase inhibitors L-731,120 (6), CJ-13,982 (5) the natural isomer of CJ-13,981 (5) and the viridiofungins. The common citrate moieties 286 and 289 were prepared from commercially available 2-deoxyribose. The key step utilised an Ireland-Claisen rearrangement of allyl ester 170 to install a new asymmetric centre. Another key step was a 1,4-addition to the α, β-unsaturated lactone 274 to introduce the C4 asymmetric centre with both diene isomers 279 and 280 being produced. Both isomers were elaborated to the triesters ent-175 and 283, before reduction and Wittig olefination to the citrate cross metathesis partners 286 and 289. Cross metathesis of 286 and 1-undecene followed by hydrogenation and deprotection afforded ent-CJ-13,982 (ent-4). The 3R, 3S diastereomer 295 was produced from 289 in the same manner. Both enantiomers of the L-731,120 side chain cross metathesis partner 227 were synthesised from a single chiral auxiliary 234. The key steps were a Grignard addition to give secondary alcohol 230 followed by a Johnson-Claisen rearrangement to give ester 229. Ester 229 was carried through to 227 using a Wittig olefination. Cross metathesis with both citrate isomers 286 and 289 and both enantiomers of the diene 227 produced the four cross metathesis products 306, 307, 308 and 309. The 3R, 4S, 12R isomer 308 underwent selective reductive hydrogenation to 311 using a NaBH4/RuCl3 procedure. Work towards the natural isomers was investigated with an Ireland-Claisen rearrangement of the extended esters 325 and 329. Ireland-Claisen rearrangement of 325 or 329 produced two new asymmetric centres with two diastereomers 327 and 328 being produced.
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ItemSynthesis and biological evaluation of episilvestrol analogues( 2014)This thesis details the study of the mode-of-action of episilvestrol (2) and related compounds. Improvements were made to the total synthesis of episilvestrol (2) that allowed for sufficient production of this low-abundance natural product for additional manipulation and testing. Various analogues of episilvestrol (2) were synthesized via total synthesis, building on established methods. Biological testing was performed to identify the protein target(s) of silvestrol (1) and episilvestrol (2) for translation inhibition and elucidate the mode-of-action of these anticancer metabolites. Additionally, the total synthesis of the recently isolated natural product 2’’’,5’’’- diepisilvestrol (263) was achieved. Attempts to elaborate the C4’ position of episilvestrol (2) were not successful. Modification of the C2 methyl ester was pursued after it was found that silvestric acid 238 and episilvestric acid 241 retained comparable in vitro translation inhibition activity to the parent natural products. Biotinylated episilvestrol 250 was synthesized from a Huisgen 1,3-dipolar cycloaddition between propargyl amide 244 and biotin azide 249 and found to have satisfactory activity for further testing. Two fluorescent episilvestrol derivatives, 251 and 252, were made in a similar manner and demonstrated analogous activity to 250. Further analogues of episilvestrol (2) were synthesized to study the structure-activity relationship of this compound. It was found that, while 1,2,3,3a,8b-epi episilvestrol 254 had reduced activity as compared to episilvestrol (2), 1’’’, 5’’’-diepisilvestrol 258, 2’’’,5’’’-diepisilvestrol (263), and 1’’’,2’’’,5’’’- triepisilvestrol (268) were all essentially inactive. This demonstrated that the C1’’’ and C2’’’ stereochemistry has a greater effect on translation inhibition. C2 analogues of methyl rocaglate (4) were achieved using the same methodology as the C2 episilvestrol analogues. Propargyl rocaglamide 269 was only ~4 times less active than episilvestrol (2) while biotinylated rocaglamide 270 was almost as active to the parent compound. Simplified analogues of episilvestrol (2) ̶ glycoside 274 and 275, dioxane 281, and the flavone derivative 285 ̶ were found to have far inferior activity. The biotinylated analogues 250, 261, and 270 were used in streptavidin pulldown assays to determine the protein target(s) of these compounds. A direct and exclusive interaction of silvestrol (1) and biotinylated episilvestrol 250 with eIF4AI/II, was identified by Western blot, silver stain, and GC-MS analysis. Crystallography studies to find the binding site of 1 and 2 with eIF4AI were attempted. Investigations into how silvestrol (1) and episilvestrol (2) cause cell death have shown that reduction in the level of anti-apoptosis protein Mc1-1 was not the primary cause of death in a variety of cells. Cell death was also not always controlled by the Bax/Bak pathway. Furthermore, neither proliferation nor differentiation of cells correlated with silvestrol (1) induced cell death. These results suggest that while silvestrol (1) and episilvestrol (2) appear to have only one cellular protein target, eIF4AI/II, they cause cell death via multiple pathways.
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ItemStudies towards the biomimetic total synthesis of dihydrooxepin-containing epipolythiodiketopiperazine natural products( 2009)SCH-64874 (5) is a fungal metabolite that inhibits the epidermal growth factor receptor (EGFR), a high-profile oncology target, with an IC50 of 1.0µg/mL. It is of particular interest because it is unlikely to inhibit the protein’s intramolecular kinase domain (as typical chemical EGFR inhibitors do), and may act instead by obstructing the receptor’s ligand binding and/or dimerisation processes. In this work, the epipolythiodiketopiperazine family of natural products is reviewed, leading to a discussion of the probable biosynthetic pathways by which these complex molecules are produced in nature. A laboratory synthesis based on this proposed biosynthesis was subsequently proposed and undertaken. The oxidation of aromatic systems was investigated, which led to the synthesis, for the first time, of complex functionalised arene oxides such as 178. The regioselective epoxidation of 178 was accessed by derivatisation as the Diels-Alder adduct 180. Subsequent epoxidation and manipulation led to the amino alcohol 195b, possessing the exo-epoxide endo-alcohol stereochemistry shown. This stereochemical assignment was based on detailed NMR analysis of the product, and also on AM1 semi-empirical molecular modelling and Ab initio molecular orbital calculations, which were used to evaluate the relative stabilities of the cyclisation products.