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Total Synthesis of Tiacumicin B: Study of the Challenging β-Selective Glycosylations

preprint
revised 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.

Funding

ANR-14-CE16-0019-02

History

Email Address of Submitting Author

stephanie.norsikian@cnrs.fr

Institution

Université Paris-Saclay, CNRS, Institut de Chimie des Substances Naturelles

Country

France

ORCID For Submitting Author

0000-0003-2706-4007

Declaration of Conflict of Interest

The authors declare no conflict of interest.

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