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

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.