Comparison of glycosyl donors: a supramer approach

Abstract

The development of new methods for chemical glycosylation commonly includes comparison of various glycosyl donors. An attempted comparison of chemical properties of two sialic acid-based thioglycoside glycosyl donors, differing only in the substituent at O-9 (trifluoroacetyl vs chloroacetyl), at different concentrations (0.05 and 0.15 mol·L^-1) led to mutually excluding conclusions concerning their relative reactivity and selectivity, which prevented us from revealing a possible influence of remote protective groups at O-9 on glycosylation outcome. According to the results of the supramer analysis of the reaction solutions, this issue might be related to the formation of supramers of glycosyl donors differing in structure hence chemical properties. These results seem to imply that comparison of chemical properties of different glycosyl donors may not be as simple and straightforward as it is usually considered.

Keywords: concentration; glycosylation; protecting groups; reactivity; sialic acids; stereoselectivity.

Scheme 1

Model sialylation reaction. TFA = CF₃CO; ClAc = ClCH₂CO.

Scheme 2

Synthesis of sialyl donor 2.

Figure 1

Concentration dependence of the specific optical rotation ([α]_D²⁸ / deg·dm⁻¹·cm³·g⁻¹) of solutions of sialyl donor 1 (a) and sialyl donor 2 (b) in MeCN at 28 °C. Each point represents an average of ten measurements (relative error <1% unless specified otherwise, see the error bars; the error bar is on the order of the symbol size if not visible). The standard deviations were calculated by using the Student’s distribution (95% probability). The grey boxes in the figure are drawn to guide the eye and designate different ranges of concentrations. Vertical arrows designate concentrations (0.05 and 0.15 mol·L⁻¹) chosen for performing sialylation reactions. See also Table 1.

Figure 2

Comparison of the outcome of the sialylation of glycosyl acceptor 3 with sialyl donors 1 or 2 performed at different concentrations: yield of disaccharide 4 [36] (a), stereoselectivity (α/β) (b), and reaction time (c). See Scheme 1 for the structures of the compounds. The reaction was quenched after complete consumption of glycosyl donors (TLC control). The crude product was treated with MeONa in MeOH in order to remove all O-acyl groups and then with Ac₂O in Py to install O-acetyl groups. The disaccharide fraction was isolated by gel permeation chromatography on Bio-Beads S-X3 (toluene) and analyzed by ¹H NMR spectroscopy to give the anomeric ratio (α/β). Individual anomers of disaccharides were then separated by silica gel chromatography to give the yield.