An investigation by 1H NMR spectroscopy into the factors determining te β: α ratio of the product in 2′-deoxynucleoside synthesis

Abstract

By following the course of the reaction between a suitably-protected base and a chlorosugar in an NMR tube at 250 MHz, it has been shown that the products are consistent with those expected from an SN2 mechanism with inversion of configuration at the an carbon of chlorosugar. In order to achieve high yields of β-2′-deoxynucleoside, the crystalline α-chlorosugar used must react swiftly so that anomerization of the sugar moiety is kept to a minimum. If the base is sufficiently reactive (e.g. 5-methyluracil, uracil), then no catalyst is required and chloroform is the preferred solvent. Using equimolar quantities of the reactants, almost quantitative yields of nucleoside can be obtained in one hour with a β:α ratio >4. With an excess of base, the β:α ratio can be increased even further. With less reactive bases (e.g. 5-nitrouracil, 5-acetyluracil), addition of catalyst can increase the rate of condensation more than the rate of anomerization or decomposition of the sugar. ZnCl2 (0.1 equivalents) has been found to give satisfactory results, although the lower the reaction, inevitably the more α-2′-deoxynucleoside is formed. Essentially pure α-2′-deoxynucleoside can be isolated in high yield by allowing chlorosugar to anomerize by letting it stand in a polar solvent (acetonitrile) before addition of the base. © 1984 IRL Press Limited.