Total synthesis of hydroxystrobilurin A
Degree GrantorUniversity of Canterbury
Degree NameDoctor of Philosophy
This thesis describes the first three total syntheses of hydroxystrobilurin A, a member of the strobilurin family of fungicidal natural products which are produced by a variety of fungal species worldwide. Chapter 1 provides an account of the discovery, structure, and biological activity of the strobilurins, describes the total syntheses of strobilurins reported to date, and covers the synthetic and spectroscopic work that has been conducted on the strobilurins by other workers in this department. An overview of the use of palladium-catalysed carbon-carbon bond forming methodologies in syntheses of several natural products and strobilurin analogues is given, followed by a retro synthetic analysis of hydroxystrobilurin A which delineates two possible strategies for the synthesis of this compound based on the utilisation of such palladium-based chemistry. Chapter 2 details investigations of these two strategies, with the diene-based route proving more successful than the enyne-based approach. Efficient diene synthesis was achieved via Stille coupling, but direct access to hydroxystrobilurin A via Stille coupling between a diene alcohol and a β-methoxyacrylate unfortunately proved impossible. The use of hydroxyl-group protection enabled the formation of two triene analogues of hydroxystrobilurin A via Stille coupling, and although one of these was found to have isomerised into a non-natural strobilurin triene system, the other possessed the correct stereochemistry and was able to be deprotected to afford a low yield of the natural product. An efficient synthesis of the triene ester analogue of hydroxystrobilurin A was developed, and this compound was reduced to give a low yield of the natural product. Access to the corresponding triene aldehyde was also established, and its reduction to hydroxystrobilurin A was slightly higher yielding, although efforts to improve the efficiency of this process were not successful. A summary of the above results is given in Chapter 3, followed by a description of several pathways by which future workers may be able to achieve a more efficient synthesis of hydroxystrobilurin A. Chapter 4 describes preliminary results from the application of the palladium-catalysed carbon-carbon bond-forming techniques described in Chapter 2 to synthetic approaches towards 9-methoxystrobilurins A and K & phomoidrides A and B.