HYDROLYTIC REACTIONS OF THE DIASTEREOMERIC PHOSPHOROMONOTHIOATE ANALOGS OF URIDYLYL(3',5') URIDINE - KINETICS AND MECHANISMS FOR DESULFURIZATION, PHOSPHOESTER HYDROLYSIS, AND TRANSESTERIFICATION TO THE 2',5'-ISOMERS

: OIVANEN M, ORA M, ALMER H, STROMBERG R, LONNBERG H

Publisher: AMER CHEMICAL SOC

: 1995

Journal of Organic Chemistry

JOURNAL OF ORGANIC CHEMISTRY

: J ORG CHEM

: 60

: 17

: 5620

: 5627

: 8

: 0022-3263

DOI: https://doi.org/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 pH 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 (H-0 < 0.2, i.e., [HCl] > 0.5 mol L(-1)), representing 20-30% of the total disappearance of the starting material. At pH 3-6, the proportion of this reaction is less than 10%. In the latter pH range, all the reactions are pH-independent. At lower pH, first-order dependence on acidity is observed, but at H-0 < 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.

Chemical sciences