An investigation by 1H NMR spectroscopy into the factors determining the beta:alpha ratio of the product in 2'-deoxynucleoside synthesis.
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 anomeric carbon of chlorosugar. In order to achieve high yields of beta-2'-deoxynucleoside, the crystalline alpha-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 beta:alpha ratio greater than 4. With an excess of base, the beta:alpha 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 slower the reaction, inevitably the more alpha-2'-deoxynucleoside is formed. Essentially pure alpha-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.
D055598:Chemical Phenomena; D002621:Chemistry; D003853:Deoxyribonucleosides / Q000138:chemical synthesis*; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D009690:Nucleic Acid Conformation; D012997:Solvents; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D003853:Deoxyribonucleosides; D007202:Indicators and Reagents; D012997:Solvents