Expedient Total Syntheses of Pladienolide-Derived Spliceosome Modulators

Atom and step economical total syntheses of spliceosome modulating natural products pladienolides A and B are described. The strategic functionalization of an unsaturated macrolide precursor enabled the most concise syntheses of these natural products to date and provides convenient, flexible access to stereodefined macrolides to streamline medicinal chemistry explorations. Notably, this synthetic route does not depend on protecting group manipulations that traditionally define synthesis planning for polyhydroxylated natural products of polyketide origin. Its utility is further demonstrated by the enantioselective total synthesis of H3B-8800, a hitherto semisynthetic pladienolide-derived spliceosome modulator undergoing clinical trials for hematological malignancies.