Asymmetric Synthesis of Pochonin E and F, Revision of Their Proposed Structure, and Their Conversion to Potent Hsp90 Inhibitors

A concise and modular synthesis of pochonin E and F, and their epimers at C‐6 established the correct stereochemistry of these two natural products. Several members of the pochonin family have been shown to bind the heat shock protein 90 (Hsp90), which has been the focus of intense drug discovery efforts. Pochonin E and F as well as their epimers were derivatized into the corresponding pochoximes and further modified at the C‐6 position. Molecular dynamics simulations, docking studies, and Hsp90 affinity measurements were performed to evaluate the impact of these modifications. Cooling down the heat shock: Rapid access to pochonin E and F as well as their epimers at the allylic hydroxyl group established the correct stereochemistry of the natural product (see figure). The unnatural epimer afforded a more potent heat shock protein 90 (Hsp90) ligand, which stands as the most potent reported.