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

Cédric Tresse , Marc François-Heude , Vincent Servajean , Rubal Ravinder , Clémence Lesieur , Lucie Geiben , Louis Jeanne- Julien , Vincent Steinmetz , Pascal Retailleau , Emmanuel Roulland , Jean-Marie Beau , Stéphanie Norsikian (1)

1 ICSN - Institut de Chimie des Substances Naturelles

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-cisglycosylation 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 b-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 noviolysation step with a virtually total b-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.

Mots clés: 1; 2-Cis-Glycosylation; Glycochemistry; Catalysis; Palladium Chemistry; Antibiotics; Natural Products; Total Synthesis

Domaines: Chimie organique

Cédric Tresse, Marc François-Heude, Vincent Servajean, Rubal Ravinder, Clémence Lesieur, et al.. Total Synthesis of Tiacumicin B: Study of the Challenging b-Selective Glycosylations. 2020. ⟨hal-03025084⟩