Assembly-line synthesis of polyhydroxy macrolides by iterative boronic ester homologation: Stereocontrolled total synthesis of antimalarial Bastimolides

Polyketides form a large class of bacterial natural products that present rich structural diversity and broad biological function with longstanding application in human medicine. Nature assembles polyketides starting from simple building blocks in a recursive manner thanks to bacterial polyketide synthase (PKS), an enzymatic machinery able to iteratively assemble acetate or propionate units into polyoxygenated alkyl chains. The development of biomimetic iterative strategies inspired by the PKS machinery is highly sought after in the field of natural product synthesis. They would streamline access to natural polyketides, avoiding multi-step lengthy sequences based on redox-level adjustment and protecting-group tactics. Bastimolides A and B are polyhydroxy macrolides isolated from tropical marine cyanobacteria. Their structural elucidation revealed respectively a 40- and 24-membered macrocyclic lactone and a dense array of hydroxylated stereogenic centers, both in 1,3- and 1,5-relative arrangements. Preliminary biological studies on Bastimolides revealed a potent antimalarial activity against multidrug-resistant strains of Plasmodium falciparium, with IC50 from mM to nM, thus holding promises for antimalarial drug discovery. The current action aims to offer a new strategy to stereocontrolled assembly-line synthesis of these polyhydroxy macrolides. This approach will provide a novel tool for 1,5-polyol stereoselective preparation, a long-standing challenge in acyclic stereocontrol. Moreover, the rapid assemble of recursive boronic ester units into the Bastimolide’s polyacetate skeleton will resemble the chain-growth phase of the polyketide synthase, thus affording a novel biomimetic strategy for sustainable natural product synthesis.

Project details

Drug-based Strategies
Product Development

Oct 2020 — Mar 2022

$94,744

United Kingdom