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Title: The total synthesis of the bicyclic acetal core of zaragozic acid C
Author: Finlay, M. R. V.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 1997
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Zaragozic acid C 33 is a member of a family of naturally occurring, structurally complex fungal metabolites. These natural products are potent inhibitors of the enzyme squalene synthetase. All the zaragozic acids show a common, highly oxygenated 2,8-dioxobicyclo[3.2.1]octane "core" unit and differ only at the Cl alkyl and C6 acyl side chains. The first part of this thesis describes the synthesis of the model zaragozic acid bicyclic acetal core systems 171 and 172 (Scheme A) via acid catalysed cyclisation of the highly functionalised epoxides 158 and 148. The synthesis of the model cores was achieved in nine steps and good overall yield. Key steps include: (i) a highly diastereoselective anti, anti-aldol reaction between the ketone 112 and dienals 155 and 138; (ii) diastereo- and regioselective oxidation of the diene portion of 156-AA and 139-AA to provide the cyclisation precursors 158 and 148 and (iii) acid catalysed rearrangement of epoxides 158 and 148 under extremely mild conditions to provide the model zaragozic acid cores 171 and 172 in good yield. The second part of the dissertation describes synthetic studies directed towards the more highly functionalised model zaragozic acid bicyclic acetal core 187 (Scheme B). By exploiting the aldol chemistry of ketone 175, the correct oxygen functionally at C7 was established, and potential methods of introducing the C1 side chain were also explored. By use of the asymmetric diene oxidation methodology developed in the first part of the dissertation, the cyclisation precursor 211 was prepared. Upon treatment with catalytic acid, however, in contrast to the simpler cyclisation precursors 158 and 148, the epoxide 211 gave the kinetic acetal 213. Equilibration under acidic conditions did not deliver the desired model zaragozic acid bicyclic acetal core 187, but rather the isomeric acetal system 218. The final part of this thesis describes the synthesis of the C6 acyl side chain and the bicyclic acetal core of zaragozic acid C. The C1 side chain fragment 261 (Scheme C) was coupled to the bicyclic acetal core precursor 198 to provide the key diene fragment 276. Subsequent asymmetric stepwise oxidation of the diene portion of 276 provided the highly functionalised bicyclic acetal core precursors 279 and 282 which upon treatment with acid provided the zaragozic acid C bicyclic acetal core 249 with pendant C1 side chain.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available