Total synthesis of variolin B
Degree GrantorUniversity of Canterbury
Degree NameDoctor of Philosophy
This thesis describes the development of methodology which has led to the total synthesis of variolin B, a marine alkaloid with potent antitumour properties. In Chapter One, a brief summary of the association of organic synthesis and marine natural products is provided. This is followed by an account of the variolin family of natural products and synthetic efforts that have been directed towards them. A new strategy is proposed that exploits the hidden symmetry in variolin B. Chapter Two covers investigations into the synthesis of the variolin skeleton using a variety of reagent systems. A rapid entry into the core structure of the variolins was found, with the key step being a deoxygenation/cyclisation protocol, which was mediated by the combination of triethylsilane and trifluoroacetic acid. Evidence was obtained to suggest an unexpected mechanism for this reaction. Straightforward functional group manipulation led to a synthesis of deoxyvariolin B. In Chapter Three, the previously established methodology was applied to an alternative starting material, appropriate for a synthesis of variolin B. However, the process was low-yielding and gave variable results. Some modifications to the methodology led to a reliable and efficient procedure for the synthesis of the variolin skeleton, which was subsequently transformed to variolin B. The synthesis proceeded in a total of eight linear steps, with an overall yield of 13%. The methodology which has been developed lends itself to the production of analogues of the variolins. The synthesis and biological testing of some analogues are presented in Chapter Four, along with a discussion on the structural features which confer biological activity on variolin B. A brief summary of the work described in this thesis and potential future studies is given in Chapter Five.