Marine natural products are a known source of novel bioactive compounds. However, in many cases, low isolation yields and lack of full structural information necessitate total synthesis to achieve their structural elucidation, and produce sufficient material for biological studies. This thesis outlines the synthesis and stereochemical assignment of the C29-C46 region of hemicalide (1), a complex, highly bioactive polyketide marine natural product. Chapter one introduces the complex polyketide hemicalide and summarises previous work on this natural product. Hemicalide displays impressive bioactivity, registering picomolar IC50 values against numerous cancer cell lines. Preliminary biological evaluation indicated a novel antimitotic mechanism of action, involving microtubule destabilisation. While 1D- and 2D-NMR experiments established the planar 46-carbon structure, the low isolation yield precluded full stereochemical assignment and further biological studies. Previous synthetic and computational studies have determined the relative configuration within the C1-C24 and C34-C42 stereoclusters. However, the configuration of five stereocentres and the interrelationships between isolated stereoclusters remained unassigned.

Chapter two describes the synthesis of the δ-lactone-containing C34-C46 (2) region of hemicalide. A highly diastereoselective route was developed, based on boron-aldol methodology, with flexible installation of (R)- or (S)-configuration at C45. This versatile approach facilitated the configurational assignment of C45, completing the assignment for the C34-C46 region of hemicalide. Chapter three describes the synthesis of the largely unexplored C29-C35 fragment (3) of hemicalide. Literature analysis of previous reports led to the synthesis of two syn-diastereomers believed to contain the most likely configuration for this region. Chapter four outlines the controlled union of the C29-C35 and C34-C46 fragments, by olefin cross metathesis, to produce three diastereomers of the fully elaborated C29-C46 region. This work allowed the relative stereochemistry of C31 and C32 to be assigned and established the relationship between the C27-C32 and C36-C45 stereoclusters. Production of a late-stage aldehyde intermediate positions the synthetic campaign four steps from the final target molecule. Chapter five draws conclusions and outlines future work on the project.