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

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. [Display omitted] •Efficient stereoselective synthesis of the key polyketide fragments of Fidaxomicin.•Efficient stereoselective synthesis of Fidaxomicin’s resorcylic rhamnoside and novioside sugar fragments.•Efficient and selective glycosylation of the polyketide fragments with the sugar fragments.•Krische hydrogenative C–C coupling towards Fidaxomicin’s branched dienoic acid fragment.•[2,3]-Wittig rearrangement tactic to the polyketide stereodiad embedded within Fidaxomicin’s southern polyketide fragment.