Expedient Total Syntheses of Pladienolide-Derived Spliceosome Modulators

J Am Chem Soc. 2021 Apr 7;143(13):4915-4920. doi: 10.1021/jacs.1c01135. Epub 2021 Mar 23.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biological Products / chemistry
  • Epoxy Compounds / chemical synthesis*
  • Epoxy Compounds / pharmacology
  • Macrolides / chemical synthesis*
  • Macrolides / pharmacology
  • Spliceosomes / drug effects*
  • Stereoisomerism

Substances

  • Biological Products
  • Epoxy Compounds
  • Macrolides