School of Chemistry - Theses
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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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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.