A convergent approach toward fidaxomicin: Syntheses of the fully glycosylated northern and southern fragments

Ryan Hollibaugh, Xueliang Yu, Jef K. De Brabander

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Efficient approaches that enable the synthesis of analogs of natural product antibiotics are needed to keep up with the emergence of multiply-resistant strains of pathogenic organisms. One promising candidate in this area is fidaxomicin, which boasts impressive in vitro anti-tubercular activity but has poor systemic bioavailability. We designed a flexible synthetic route to this target to enable the exploration of new chemical space and the future development of analogs with superior pharmacokinetics. We developed a robust approach to each of the key macrocyclic and sugar fragments, their union via stereoselective glycosylation, and a convergent late-stage macrolide formation with fully glycosylated fragments. Although we were able to demonstrate that the final Suzuki cross-coupling and ring-closing metathesis steps enabled macrocycle formation in the presence of the northern resorcylic rhamnoside and southern novioside sugars, these final steps were hampered by poor yields and the formation of the unwanted Z-macrocycle as the major stereoisomer.

Original languageEnglish (US)
Article number131673
JournalTetrahedron
Volume76
Issue number49
DOIs
StatePublished - Dec 4 2020

Keywords

  • Lipiarmycin
  • Macrolide antibiotics
  • Ring closing metathesis
  • Tiacumicin

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

Fingerprint

Dive into the research topics of 'A convergent approach toward fidaxomicin: Syntheses of the fully glycosylated northern and southern fragments'. Together they form a unique fingerprint.

Cite this