Structure Elucidation and Synthesis of Natural Products
Degree GrantorUniversity of Canterbury
Degree NameDoctor of Philosophy
In this thesis, synthetic chemistry was used as a tool in the exploration of various aspects of natural products discovered by the natural products research group at the University of Canterbury. Work on the constituent amino acids and connectivity of the pteratides, a potently cytotoxic series of cyclodepsipeptides, had been completed before the beginning of this work (carried out by Miss C. Chen). The elucidation of the stereochemistry of the constituent amino acids was undertaken in this present work. The synthesis of all stereochemical entities of a number of unusual amino acids, which were either not available commercially or were expensive, was carried out, providing reference materials for comparison to the natural products. The synthesis of the diastereoisomers of one of these amino acids, 4-methylproline, was carried out by modification of literature procedures, which led to the development of an improved, concise and stereoselective synthesis. The hydrolysis of the natural products, derivatisation of the resultant hydrolysates, synthetic and commercial reference amino acids and HPLC analysis allowed the full stereochemical assignment of the pteratide series. The total synthesis of spiro-mamakone A, a cytotoxic polyketide isolated by Dr S. van der Sar, was undertaken. The synthesis was not successfully completed due to difficulties in the late-stage formation of a crucial enedione motif. However, very advanced intermediates were successfully synthesised. These synthetic analogues of the natural product were analysed for biological activity, allowing valuable insight into the structure-activity relationship, for example, demonstrating the importance of the enedione moiety to biological activity.