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submitted on 16.12.2019, 16:40 and posted on 20.12.2019, 09:21by Stephanie Norsikian, cedric Tresse, Marc François-Eude, Louis Jeanne-Julien, Guillaume Masson, Vincent Servajean, Grégory Genta-Jouve, Jean-Marie Beau, Emmanuel Roulland
We report a total synthesis of tiacumicin B, one of
the most structurally complex natural antibiotic macrolides. Endowed with
remarkable biological properties, it is used to treat very severe intestinal
infections. The strategy is in part based on our experience of the synthesis of
the tiacumicin B aglycone, and on the decisive implementation of an H-bond-mediated
Aglycone Delivery (HAD) using sulfoxides
as anomeric leaving-groups. This new
HAD variant permitted highly beta-selective
rhamnosylation and noviosylation. To increase the convergence, the rhamnosylated
C1-C3 fragment thus obtained was anchored to the C4-C19 aglycone fragment by adapting
the reliable Suzuki-Miyaura cross-coupling conditions used for the aglycone
synthesis. The ring-size selective macrolactonization provided a compound engaged
directly in the noviolysation step with a virtually total beta-selectivity. The final and efficient removal of all
the protective groups (PGs) provided synthetic tiacumicin B.