Synthesis of Deoxy Glycosides Under Neutral Conditions in LiClO4/Solvent Mixtures

Abstract

2-Deoxy-and 2,6-dideoxyglycosyl trichloroacetimidates, phosphites and fluorides are efficiently activated in 0.1M metal perchlorate/solvent mixtures, i. e. without the need for an additional promoter like a strong Lewis acid or a heavy metal salt. Under these neutral conditions they react with different glycosyl acceptors to give oligosaccharides, amino acid glycosides and cholesteryl glycosides in high yields and with pronounced stereoselectivity. For 3,4,6-tri-O-benzyl protected 2-deoxy glucose the highest yields were observed with the a-imidate, however, the anomer ratio was highest if the corresponding glycosyl fluoride was used. The stereoselectivity was not significantly influenced by the solvent and the metal ion, the yield was highest in 0.1M solutions of LiClO 4 in diethyl ether. Under these gentle conditions also 2-deoxy-L-fucosyl fluoride and D-digitoxosyl fluoride react with different O-silylated glycosyl acceptors to give sensitive 2,6-dideoxyglycosides with preparatively useful results.

Metal-free glycosylation with glycosyl fluorides in liquid SO2

“…The Lewis acidic medium of liquid SO 2 was also facilitating for the synthesis of 2-deoxy glucoside 20 from corresponding fluoride α-19 in 91% yield and good α-selectivity at −10 °C (Scheme 5). Due to the absence of a neighboring group at C2 position, the stereoselective synthesis of 2-deoxy glycosides is challenging [72][73][74]. We hypothesize that the stabilization of the oxocarbenium ion intermediate in a form of a dioxolenium ion by the remote protecting group in C3 or C6 position could be the reason for such a good α-selectivity in liquid SO 2 [75].…”

Methods for 2-Deoxyglycoside Synthesis

“…To this end, activation of the diethyl phosphite glycoside 157 by catalytic TMSOTf in the presence of the pinacol phosphite glycoside 158 led to the formation of a single disaccharide ( 159 ), which was not isolated but rather reacted further with acceptor 160 to afford the corresponding trisaccharide 161 in 50% overall yield in one pot. Several other methods are available for activating deoxysugar phosphites, such as LiClO 4 /Et 2 O and montmorillonite K-10, , although these approaches have not been widely adopted.…”

Catalytic Glycosylations in Oligosaccharide Synthesis

“…Solutions of a range of other metal perchlorate salts were later shown to be good activators of glycosyl phosphites by Schene and Waldmann; however, the stoichiometry of these glycosylations was not reported, but the perchlorate salts were very likely added in excess. 649,650 The Toshima group has conducted a thorough investigation on the use of a heterogeneous solid acid, montmorillonite K-10, as a catalyst in glycosylations with glycosyl phosphites. 651−654 Typically, between 20 and 100 wt % of the solid acid was added to the reaction mixture to facilitate β-selective glycosylations of 2-deoxysugars, 651 glucopyranosyl donors, 652 and mannopyranosyl donors 653 in high yields.…”

“…Dimethyl phosphite glycosyl donors were introduced by the Watanabe group in 1993 and were shortly after shown to be catalytically activated by a 1:2 ratio of ZnCl 2 and AgClO 4 in the presence of a 4-OH sugar acceptor to yield a disaccharide in 86% yield. , ZnCl 2 had previously been used as a stoichiometric activator on the same system. , The Watanabe showed that for reactive donors such as sialyl phosphites, a catalytic amount of ZnCl 2 /AgClO 4 was sufficient, although a stoichiometric amount of the promoter was necessary in some glycosylations, depending on the reactivity of the donors. Solutions of a range of other metal perchlorate salts were later shown to be good activators of glycosyl phosphites by Schene and Waldmann; however, the stoichiometry of these glycosylations was not reported, but the perchlorate salts were very likely added in excess. , …”