The discovery of a novel marine natural product hemicalide (1), with promising anticancer activity, has sparked interest in elucidating its full three-dimensional structure. Studies into the total synthesis and stereochemical assignment of the complex polyketide structure of hemicalide are described in this dissertation. Overall, this synthesis-enabled stereochemical assignment has established the relative configuration of 11 stereocentres out of a total of 21. All the requisite stereocentres have been configured with excellent diastereoselectivity and this work establishes a solid foundation for ongoing efforts towards the total synthesis of hemicalide.

In the first chapter, previous synthetic efforts by the Ardisson-Cossy team are outlined, including their initial proposed assignment for the C1-C28 region of hemicalide. This is followed by a discussion of the computational studies undertaken in our group which casts doubt on the suggested 3D structure. Chapter two describes the synthesis of three key hemicalide fragments corresponding to the C1-C6 (A), C7-C15 (B) and C16-C28 (C) regions. Modifications from previous work have been made where appropriate to enable an expedient gram-scale synthesis of these fragments. The experimental results in this chapter support earlier computational DP4 NMR predictions about the most probable C18-19 relative stereochemistry.

The next chapter investigates fragment coupling strategies to furnish two possible diastereomeric candidates for a C1-C28 truncate (D) in conjunction with work carried out in parallel by Lam. Further elaboration enabled detailed NMR chemical shift comparisons to conclude the relative stereochemistry between the C7-C15 and the C16-C28 regions. These experiments also gave further insight on the nature of the C1 carboxyl group. Unlike the earlier fragments, the C26-C35 region has no assigned stereochemistry. The flexible conformational nature of this section has frustrated computational studies so synthetic studies have been undertaken. In the final chapter of this dissertation, a library of fragments (E) was synthesised to help assign the configuration of this section.