School of Chemistry - Theses
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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.