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
M. Oivanen et al., 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, Journal of organic chemistry, 60(17), 1995, pp. 5620-5627
Hydrolytic reactions of the R(P) and S-P diastereomers of the phosphor
omonothioate analog of uridylyl-(3',5')uridine (3',5'-UpU), having a n
onbridging oxygen replaced with sulfur, have been followed by HPLC ove
r a wide pH range at 363.2 K. Under neutral and acidic conditions thre
e reactions compete: (i) desulfurization to an equilibrium mixture of
3',5'- and 2',5'-UpU, (ii) hydrolysis to uridine 2'- and 3'-monophosph
ates with release of uridine (either via a 2',3'-cyclic phosphoromonot
hioate, 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 st
arting material. At pH 3-6, the proportion of this reaction is less th
an 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. Th
e 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 hy
drolysis to uridine 2'- and 3'-thiophosphates with release of uridine
takes place. At pH < 1, the thioate analogs are more than 1 order of m
agnitude more stable than UpU, while at higher pH the reactivities are
comparable.