Abstract
The utility of thiourea catalysis in selective glycosylation strategies has gained significant momentum lately due to its versatility in hydrogen bonding or anionic recognition activation modes. The use of these non-covalent interactions constitute a powerful means to construct glycosidic linkages as it mimics physiologically occurring glycosyltransferases. However, glycosyl donor activation through the currently employed catalysts is moderate such that, in general, catalyst loadings are rather high in these transformations. In addition, thiourea catalysis has not been well explored for the synthesis of furanosides. Herein, we demonstrate an ultra-low loadings stereoselective and stereospecific thiourea catalyzed strain-release furanosylation and pyranosylation strategy. Our ultra-low organocatalyzed furanosylation enables a multicatalytic strategy, which opens up a unique avenue towards rapid diversification of synthetic glycosides. In-situ NMR monitoring unravel insights into unknown reaction intermediates and initial rate kinetic studies reveal a plausible synergistic hydrogen bonding/Brønsted acid activation mode.
Highlights
The utility of thiourea catalysis in selective glycosylation strategies has gained significant momentum lately due to its versatility in hydrogen bonding or anionic recognition activation modes
The first demonstration of a thiourea catalyzed glycosylation was elegantly reported by Galan and McGarrigle et al in 2012, where D-Galactal derivatives functionalized by a wide range of protecting groups were converted to 2-deoxyglycosides selectively (Fig. 1a) by the employment of the Schreiner’s thiourea catalyst 419–21
In 2016, Toshima et al reported a photoinduced glycosylation by the utility of Schreiner’s thiourea catalyst 4 (30 mol%) as an organophotoacid on a Schmidt’s trichloroacetimidate donor (Fig. 1c)[27]. Another significant breakthrough was reported by Ye et al in 2016, where the first Koenigs–Knorr glycosylation catalyzed by a hydrogen-bonding urea catalyst (20 mol%) was demonstrated (Fig. 1d), and a marked α/β selectivity improvement was observed upon addition of a phosphine on glucose derived donors[28]
Summary
The utility of thiourea catalysis in selective glycosylation strategies has gained significant momentum lately due to its versatility in hydrogen bonding or anionic recognition activation modes The use of these non-covalent interactions constitute a powerful means to construct glycosidic linkages as it mimics physiologically occurring glycosyltransferases. The first demonstration of a thiourea catalyzed glycosylation was elegantly reported by Galan and McGarrigle et al in 2012, where D-Galactal derivatives functionalized by a wide range of protecting groups were converted to 2-deoxyglycosides selectively (Fig. 1a) by the employment of the Schreiner’s thiourea catalyst 419–21 The interest in this activation mode was later picked up by Schmidt et al in 2013 (Fig. 1b), where 4 was effective as a cocatalyst in the presence of a phosphoric acid catalyst 8 in glycosylations utilizing Schmidt’s trichloroacetimidate donors[22]. Another unsolved challenge lies in the plausibility of thioureas to catalyze N- and C-glycosylations, an important transformation to access nucleoside analogs
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