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Total Synthesis of Tiacumicin B: Study of the Challenging β‐Selective Glycosylations **
Author(s) -
Tresse Cédric,
FrançoisHeude Marc,
Servajean Vincent,
Ravinder Rubal,
Lesieur Clémence,
Geiben Lucie,
JeanneJulien Louis,
Steinmetz Vincent,
Retailleau Pascal,
Roulland Emmanuel,
Beau JeanMarie,
Norsikian Stéphanie
Publication year - 2021
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.202005102
Subject(s) - aglycone , chemistry , anomer , total synthesis , glycosylation , stereochemistry , protecting group , ether , combinatorial chemistry , organic chemistry , glycoside , biochemistry , alkyl
Abstract 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.