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

Cédric Tresse (1) , Marc François-Heude (1) , Vincent Servajean (1) , Rubal Ravinder (1) , Clémence Lesieur (1) , Lucie Geiben (1) , Louis Jeanne-Julien (2) , Vincent Steinmetz (1) , Pascal Retailleau (1) , Emmanuel Roulland (2) , Jean-Marie Beau (1, 3) , Stéphanie Norsikian (1)

1 ICSN - Institut de Chimie des Substances Naturelles
2 CiTCoM - UMR 8038 - Cibles Thérapeutiques et conception de médicaments
3 ICMMO - Institut de Chimie Moléculaire et des Matériaux d'Orsay

We give 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. We used sulfoxide anomeric leaving-groups in combination with a remote 3-O-picoloyl group on the donors that allowed highly β-selective rhamnosylation and noviosylation that rely on H-bond-mediated aglycone delivery. 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 semiglycosylated aglycone that was engaged directly in the noviolysation step with a virtually total β-selectivity. Finally, a novel deprotection method was devised for the removal of a 2-naphthylmethyl ether on a phenol, and efficient removal of all the protecting groups provided synthetic tiacumicin B.

Domaines: Chimie thérapeutique

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. Chemistry - A European Journal, 2021, 27 (16), pp.5230-5239. ⟨10.1002/chem.202005102⟩. ⟨hal-03299743⟩