Hydrolytic Reactions of the Diastereomeric Phosphoromonothioate Analogs of Uridyl(3',5')uridine: Kinetics and Mechanisms for Desulfurization, Phosphoester Hydrolysis, and Transesterification to the 2',5'-Isomers

Article abstract of DOI:10.1021/jo00122a050

Hydrolytic reactions of the R_P and S_P diastereomers of the phosphoromonothioate analog of uridylyl(3',5')uridine (3',5'-UpU), having a nonbridging oxygen replaced with sulfur, have been followed by HPLC over a wide range at 363.2 K.Under neutral and acidic conditions three reactions compete: (i) desulfurization to an equilibrium mixture of 3',5'- and 2',5'-UpU, (ii) hydrolysis to uridine 2'- and 3'-monophosphates with release of uridine (either via a 2',3'-cyclic phosphoromonothioate, or a desulfurized cyclic triester), and (iii) isomerization to the 2',5'-dinucleoside phosphoromonothioate.With both diastereomers, desulfurization predominates over hydrolysis and migration at pH 1-8.Migration proceeds by retention of configuration at phosphorus and is most pronounced in very acidic solutions (H₀ < 0.2, i.e., > 0.5 mol L^-1), representing 20-30percent of the total disappearance of the starting material.At pH 3-6, the proportion of this reaction is less than 10percent.In the latter pH range, all the reactions are pH-independent.At lower pH, first-order dependence on acidity is observed, but at H₀ < 0.2 desulfurization becomes slower than the competing reactions.The R_P diastereomer is at pH < 7 up to three times as reactive as the S_P isomer.Under alkaline conditions (pH > 9), only base-catalyzed hydrolysis to uridine 2'- and 3'-thiophosphates with release of uridine takes place.At pH < 1, the thioate analogs are more than 1 order of magnitude more stable than UpU, while at higher pH the reactivities are comparable.