These are preliminary reports that have not been peer-reviewed. They should not be regarded as conclusive, guide clinical practice/health-related behavior, or be reported in news media as established information. For more information, please see our FAQs.
Total Synthesis of Tiacumicin B: Study of the Challenging β-Selective Glycosylations
preprintrevised on 06.11.2020, 12:51 and posted on 09.11.2020, 07:28 by cedric Tresse, Marc François-Heude, Vincent Servajean, Rubal Ravinder, Clemence Lesieur, Lucie Geiben, Louis Jeanne-Julien, Vincent Steinmetz, Pascal Retailleau, Emmanuel Roulland, Jean-Marie Beau, Stephanie Norsikian
We report here a full account of the total synthesis of tiacumicin B (Tcn-B), a natural glycosylated macrolide with remarkable antibiotic properties. Our strategy is based on our experience with the synthesis of the tiacumicin B aglycone and on unique 1,2-cis-glycosylation steps. It features the conclusive use of sulfoxide anomeric leaving-groups in combination with a remote 3-O-picoloyl group on the donors allowing highly beta-selective rhamnosylation and noviosylation that rely on H-bond-mediated Aglycone Delivery (HAD). The rhamnosylated C1-C3 fragment was anchored to the C4-C19 aglycone fragment by a Suzuki-Miyaura cross-coupling. Ring-size selective Shiina macrolactonization provided a semi-glycosylated aglycone that was engaged directly in the noviosylation step with a virtually total beta-selectivity. Finally, a novel deprotection method was devised for the removal of a 2-naphthylmethylidene (Nap) ether on a phenol and efficient removal of all the protecting groups provided synthetic tiacumicin B.