Synthesis of cycloSal‐(Glycopyranosyl‐6)‐phosphates as Activated Sugar Phosphates

Abstract

The synthesis of cycloSal‐masked glycopyranosyl phosphates demands suitably protected precursors. A highly regioselective strategy for the preparation of cycloSal‐(1,2,3,4‐tetra‐O‐acetylglycopyranosyl‐6)‐phosphates was developed. Intermediate introduction of the Fmoc‐group allowed the isolation of the 1,2,3,4‐tetra‐O‐acetyl glycopyranoses to be skipped, thus, no isomerization occurred. Glycopyranoses were first converted into the 6‐O‐TBDMS‐1,2,3,4‐tetra‐O‐acetyl derivatives then, in a one‐pot reaction, the silyl ether was cleaved and the resulting 1,2,3,4‐tetra‐O‐acetyl glycopyranoses were trapped with Fmoc‐chloride. In this exchange of protecting groups no acetyl group migration occurred. The 6‐O‐Fmoc‐protected intermediates were selectively converted into the cycloSal‐masked glycopyranosyl phosphates in a one‐pot reaction. Finally, the reactivity of these activated glycopyranosyl‐6‐phosphates was demonstrated in the synthesis of 1,6‐diglycopyranosyl‐phosphates.

Prodrugs of Phosphonates and Phosphates: Crossing the Membrane Barrier

“…The biochemical and/or physiological basis for such significant differences in activity is/are not yet clear, but they clearly validate the effort devoted to diastereoselective syntheses and justify additional research into the cycloSal prodrugs. Applications of the cycloSal group as a leaving group in synthesis of 1,6-diglycopyranosyl-phosphates only further enhances the value of this group [75,76]. …”

Synthesis of Pyranonucleoside‐6′‐triphosphates through the cycloSal‐Method

“…[14] The synthetic strategy involved a regioselective protection of the 6-position of glycopyranoses with a tert-butyldimethylsilyl (TBDMS) group and its selective exchange with a fluorenylmethyloxycarbonyl (Fmoc) group, which was then replaced by the cycloSal-phosphite in a base-driven reaction. [14] The synthetic strategy involved a regioselective protection of the 6-position of glycopyranoses with a tert-butyldimethylsilyl (TBDMS) group and its selective exchange with a fluorenylmethyloxycarbonyl (Fmoc) group, which was then replaced by the cycloSal-phosphite in a base-driven reaction.…”

“…This was again achieved by the Vorbrüggen one-pot method. In the case of gluco-configuration the same protocol as described previously for the glycopyranoses was em-ployed [14,17] and compound 6 was obtained in a yield of 63 % (Scheme 2). The lower yield for the galacto-configuration is a result of lower anomeric selectivity; the product was formed as an anomeric mixture in a ratio of α/β = 0.1:1.…”

“…[14] The same procedure was applied to the pyranonucleoside derivatives (Scheme 7). As our studies with the glycopyranoses showed, the Fmoc-protected derivatives could very efficiently and selectively be converted into the corresponding cycloSal-phosphate triesters.…”

“…[14,17] Compound 4 (1.44 g, 3.16 mmol) was suspended in MeOH (14 mL) and triethylamine (4 mL) was added. [14,17] Compound 4 (1.44 g, 3.16 mmol) was suspended in MeOH (14 mL) and triethylamine (4 mL) was added.…”