School of Chemistry - Theses
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ItemTowards Total Synthesis of Icumazole A( 2022)Detailed is work towards the enantioselective synthesis of the NADH oxidase inhibitor icumazole A. Key reactions include an organocatalysed asymmetric self-aldol reaction of propionaldehyde towards the synthesis of the oxazole containing fragment. An enantioselective synthesis of the Diels-Alder precursor of the isochromanone fragment has been performed. Key steps included an enzyme catalysed enantioselective desymmetrisation which was then substituted with epoxide formation and ozonolysis. Further work towards the intramolecular [4+2] cycloaddition/aromatisation sequence to give aryl bromide followed by elaboration of product to the desired isochromanone fragment through borylation and obtaining the aldehyde constituted a formal total synthesis of noricumazole B.
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ItemIt’s hip to be square: a cyclobutene diester approach to alkyl citrate natural products( 2018)This thesis features an enatiospecfic synthesis of a key alkyl citrate retron that was leveraged in the total syntheses of squalene synthase inhibitors (-)-CJ-13,982, (-)-CJ-13,981 and (-)-L-731,120 (featured in Org. Let. 2018, 20, 4255–4258). This key retron was prepared in 7 linear steps, requiring only 4 purification, with a 40% yield from (S)-(+)-γ-hydroxymethy-γ-butyrolactone. The synthesis highlights the application of a formal [2+2] cycloaddition and a remarkable acid-mediated rearrangement sequence to furnish the correct stereochemistry and oxidation level of the citrate moiety. This thesis demonstrates the shortest enantiospecifc total synthesis of (-)-CJ-13,981 to date, via the use of this key citrate retron, affording this natural product in 7.7% total yield over 10 steps. Efforts towards the squalene synthase inhibitor (-)-L-731,120 and the viridiofungins, a family of serine palmitoyl transferase inhibitors that have activity inhibiting hepatitis C replication, are also featured.
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ItemTowards the synthesis of the emestrin family of natural products( 2018)A Cope rearrangement of a vinyl pyrrole epoxide (397) was utilised to form the dihydrooxepino[4,3-b]pyrrole core (398) of the emestrin family of natural products which involved the first examples of the dearomatisation of pyrrole in this type of rearrangement. It was found that an electron withdrawing ester substituent on the C2 position of the epoxide was essential for the [3,3]-rearrangement to occur. The vinyl pyrrole epoxides were synthesised in an efficient manner by a vinylogous Darzens reaction. Density functional calculations showed lower transition state energies for Cope rearrangements of epoxides with C2 esters when compared to the unsubstituted substrates which agreed with the observed experimental results. Silyl substituted vinyl bromide esters also participated in the Darzens reactions to give the desired vinyl pyrrole epoxides in good to excellent yields. Only the triethoxysilyl vinyl epoxide 313c underwent Cope rearrangement to provide the fully substituted emestrin core dihydrooxepine. The anion derived from an aryl bromosulfone did not give the Darzens product but underwent a previously unobserved stereoselective trimerization to afford the cyclohexene 343 as a single diastereoisomer. A mechanistic rationale involving SN2’ additions, [3,3]-Cope rearrangements and a stereoselective intramolecular conjugate addition was proposed and this was supported by density functional theory (DFT) calculations. A four-step total synthesis of biaryl ether natural product violaceic acid (11) is described. The steps include an SNAr reaction to afford the biaryl ether 136, tin chloride-mediated chemoselective reduction of the nitro group to amine 135. A Cu-mediated Sandmeyer reaction of 135 gave violaceic acid methyl ester 374 which is hydrolysed to give pure violaceic acid 11. An improved synthesis of the known biaryl iodide 119 is also described via a Sandmeyer reaction of amine 135.
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ItemStudies toward a divergent synthesis of the ustiloxins( 2015)The total synthesis of natural products is an endeavour with roots dating back at least 200 years. Over the course of this field’s development, its protagonists have sought to justify their work through reference to other domains. With the passing of time, natural products chemistry has evolved to service the requirements of an ever- changing scientific landscape. In the early part of the twenty-first century it has been suggested that the field of natural product chemistry is a ‘mature science’. In order to assess this claim, an analysis of the introduction of Nicolaou’s Classics in Total Synthesis was carried out. Nicolaou’s assertions in support of continuing investment in natural products synthesis were subjected to a close reading. It was found that while some of his claims do not stand up to scrutiny, there remain compelling reasons for the continued practice of total synthesis. A family of cyclic tetrapeptides, the ustiloxins, were identified as a viable target for total synthesis. The ustiloxins have demonstrated low micromolar activity against various cancer cell lines. A divergent synthesis of all members of the ustiloxins was proposed. It was envisaged that this synthesis would serve a number of purposes: Firstly, it would enable further work to be carried out toward the elucidation of the mechanism of action of the ustiloxins. Secondly, it would enable confirmation of the structural assignment of the members of the family that had not yet succumbed to total synthesis. We were able to complete the synthesis of ustiloxin D in a convergent manner. Our strategy incorporated an asymmetric allylic alkylation to construct a tertiary- alkyl–aryl ether linkage between the dopa and isoleucine residues. The elaborated hydroxydopa derivative was then rapidly converted to a linear tripeptide through an ammonia-Ugi reaction. Subsequent cyclisation and global deprotection afforded ustiloxin D in six steps from a known hydroxydopa derivative. We had planned to synthesise ustiloxins A and B using a late stage intermediate from the synthesis of ustiloxin D. This required an iodination at the 6- position of the dopa aromatic-ring. Unfortunately, this transformation proved to be problematic. As a consequence, our synthetic strategy was revised to incorporate an early stage aromatic iodination. Using this strategy we were able to synthesise an iodinated cyclic tetrapeptide. Unfortunately, the planned transition-metal catalysed cross coupling to install the desired sulfinylnorvaline sidechain was unsuccessful.
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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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ItemTotal synthesis of the deshydroxyajudazols A and B( 2013)The asymmetric total synthesis of the proposed structures for the deshydroxyajudazols A (28) and B (29) is described. The C9-C10 stereochemistry was installed using a Brown asymmetric crotylmetallation reaction with (-)-(Ipc)2BOMe and trans-2-butene, whilst the isochromanone ring system was generated by an intramolecular Diels-Alder reaction of bromide 103 followed by DDQ oxidation. Br-OH exchange using a Pd catalysed cross coupling between pinacolborane and bromide 103 followed by oxidation and hydrolysis of the resulting boronate furnished phenol 180. The installation of the oxazole began with a one carbon extension of 229 before dihydroxylation of the resulting alkene to give diol 235. Further functionalisation of 235 provided azide 244. Attempted reduction of 244 did not result in the isolation of amine 245. A new method was investigated to allow for the formation of the oxazole. Esterification of diol 235 with acid (+)-69 was followed by conversion of the secondary alcohol to the corresponding azide. Reduction in the presence of base induced an O,N- acyl shift to give amide 286, which underwent oxidation and cyclodehydration to give the oxazole. The total synthesis of deshydroxyajudazol B (29) was completed after Sonogashira coupling of alkyne 292 and iodide 75 and subsequent P-2 Ni partial hydrogenation. The total synthesis of deshydroxyajudazol A (28) was completed in a similar fashion. Esterification of diol 235 and acid 305 gave ester 306 which was subjected to the oxazole synthetic sequence employed for the synthesis of deshydroxyajudazol B (29). Following oxazole synthesis, mesylation and elimination installed the 1,2-disubstituted alkene. Sonogashira coupling between alkene 311 and iodide 75 followed by a Zn(Cu/Ag) partial reduction completed the synthesis. Synthesis of the isochromanone fragment of the ajudazols was also investigated. An initial attempt utilising a Grignard addition of vinyl magnesium bromide under Felkin-Anh control to provide the desired anti-anti stereochemistry proved lengthy and the selectivity could not be improved from a 3.9:1 ratio of anti:syn diastereomers. In a revised approach, a Brown crotylmetallation of the chiral aldehyde 347 derived from D-mannitol provided the stereotriad with higher selectivity. Manipulation of the protecting groups before elaboration of the fragment provided the dieneyne 363, which underwent a thermal Diels-Alder reaction to give the isochromanone fragment 364.
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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.