The Synthesis-Enabled Stereochemical Elucidation of the Marine Natural Products Hemicalide and Phormidolide A

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Lam, Nelson Yuen Sum  ORCID logo

The structural complexity and biological activity of marine natural products have made them attractive targets for synthetic chemists. In cases where their relative and/or absolute configuration is unknown, total synthesis becomes a powerful method to enable their structural elucidation, as highlighted in Part I. This thesis discusses synthetic efforts towards two marine natural products, hemicalide (1) and phormidolide A (2), with the end goal of establishing and/or confirming the compound’s full stereochemistry.

Hemicalide’s low isolation yield from its marine sponge source meant that none of the 21 stereocenters were assigned in the original patent literature. Previous computational and synthetic work by Ardisson and Cossy, as well as the Paterson and Goodman groups, have narrowed down the possibilities for the C1-C15, C16-C25 and C35-C46 fragments to a single diastereomer with reasonable confidence. However, the relative configuration between fragments and the absolute stereochemistry remains unknown. Part II describes the synthesis of the C16-C28 dihydroxylactone fragment, which was used to successfully assemble a diastereomer of the C1-C28 truncate. Comparisons with the alternative configuration synthesised by Han enabled the definitive assignment of the relative configuration between the C1-C15 and the C16-C25 region of hemicalide. These studies also illuminated the nature of the C1 carboxyl group in the natural product.

Phormidolide A possesses several fascinating structural motifs. Its terminal bromomethoxydiene (BMD) motif in particular, is unprecedented among natural products. Furthermore, inconclusive stereochemical evidence presented in the literature meant that a synthesis-guided stereochemical evaluation is required. Part III discusses synthetic efforts to the natural product, involving the expedient synthesis of the C18-C23 vinyl iodide and the C25-C33 side chain bearing the unique BMD motif. Towards the end goal of a total synthesis, this chapter also illustrates the evolution of the fragment coupling strategy, which led to the reassignment of seven of the 11 stereocentres present in phormidolide A.

Paterson, Ian
Organic Chemistry, Stereocontrolled Synthesis, Total Synthesis, Structural Elucidation, Natural Products, Stereochemical Reassignment, polyketide, NMR, hemicalide, phormidolide A, anticancer
Doctor of Philosophy (PhD)
Awarding Institution
University of Cambridge
I thank the Woolf Fisher Trust and the Krishnan-Ang Scholarship for their generous financial support.