Contents 1. Introduction 961 2. Specific Acid/Base Catalyzed Cleavage and Isomerization of the 3′,5′-Phosphodiester Bonds 963 3. General Acid/Base Catalyzed Cleavage and Isomerization of the 3′,5′-Phosphodiester Bonds 969 4. Structural Effects 974 5. Reactions of 2′,3′-Cyclic Phosphates 977 6. The Cleavage and Isomerization of the Phosphodiester Bonds of Polyribonucleotides 980 7. Cleaving Agents. Toward Artificial Nucleases by Proton-Transfer Catalysis 980 8. The Effect of Thia and Aza Substitutions on the Transesterification of Ribonucleoside 3′-Phosphodiesters 985 9. References 988

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Hydrolytic reactions of the R? and Sp 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 (Hq < 0.2, i.e., [HC1] > 0.5 mol Lr1), 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 Ho < 0.2 desulfurization becomes slower than the competing reactions. The R? diastereomer is at pH < 7 up to three times as reactive as the Sp 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.

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