Regiodivergent Glycosylations of 6‑Deoxy-erythronolide B and Oleandomycin-Derived Macrolactones Enabled by Chiral Acid Catalysis

This work describes the first example of using chiral catalysts to control site-selectivity for the glycosyl­ations of complex polyols such as 6-deoxy­erythro­nolide B and oleando­mycin-derived macrolactones. The regio­divergent introduction of sugars at the C3, C5, and C11 positions of macrolactones was achieved by selecting appropriate chiral acids as catalysts or through introduction of stoichio­metric boronic acid-based additives. BINOL-based chiral phosphoric acids (CPAs) were used to catalyze highly selective glycosyl­ations at the C5 positions of macrolactones (up to 99:1 rr), whereas the use of SPINOL-based CPAs resulted in selectivity switch and glycosyl­ation of the C3 alcohol (up to 91:9 rr). Additionally, the C11 position of macrolactones was selectively function­alized through traceless protection of the C3/C5 diol with boronic acids prior to glycosyl­ation. Investigation of the reaction mechanism for the CPA-controlled glycosyl­ations revealed the involvement of covalently linked anomeric phosphates rather than oxo­carbenium ion pairs as the reactive intermediates.