Total Synthesis and Bioactivity Mapping of Geodiamolide H

The first total synthesis of the actin‐stabilizing marine natural product geodiamolide H was achieved. Solid‐phase based peptide assembly paired with scalable stereoselective syntheses of polyketide building blocks and an optimized esterification set the stage for investigating the key ring‐closing metathesis. Geodiamolide H and synthetic analogues were characterized for their toxicity and for antiproliferative effects in cellulo, by characterising actin polymerization induction in vitro, and by docking on the F‐actin target and property computation in silico, for a better understanding of structure‐activity relationships (SAR). A non‐natural analogue of geodiamolide H was discovered to be most potent in the series, suggesting significant potential for tool compound design.