| Abstract
| - Hydrolytic reactions of 3‘-amino-3‘-deoxyuridylyl-3‘,5‘-uridine (2a), an analogue of uridylyl-3‘,5‘-uridine having the 3‘-bridging oxygen replaced with nitrogen, have been followed by RP HPLC over a widepH range. The only reaction taking place under alkaline conditions (pH > 9) is hydroxide ion-catalyzedhydrolysis (first-order in [OH-]) to a mixture of 3‘-amino-3‘-deoxyuridine 3‘-phosphoramidate (7) and uridine(4). The reaction proceeds without detectable accumulation of any intermediates. At pH 6−8, apH-independent formation of 3‘-amino-3‘-deoxyuridine 2‘-phosphate (3) competes with the base-catalyzedcleavage. Both 3 and in particular 7 are, however, rather rapidly dephosphorylated under these conditionsto 3‘-amino-3‘-deoxyuridine (5). In all likelihood, both 3 and 7 are formed by an intramolecular nucleophilicattack of the 2‘-hydroxy function on the phosphorus atom, giving a phosphorane-like intermediate or transitionstate. Under moderately acidic conditions (pH 2−6), the predominant reaction is acid-catalyzed cleavageof the P−N3‘ bond (first-order in [H+]) that yields an equimolar mixture of 5 and uridine 5‘-phosphate (6).The reaction is proposed to proceed without intramolecular participation of the neighboring 2‘-hydroxylgroup. Under more acidic conditions (pH < 2), hydrolysis to 3 and 4 starts to compete with the cleavageof the P−N bond, and this reaction is even the fastest one at pH < 1. Formation of 2‘-O,3‘-N-cyclicphosphoramidate as an intermediate appears probable, although its appearance cannot be experimentallyverified. The rate constants for various partial reactions have been determined. The reaction mechanismsand the effect that replacing the 3‘-oxygen with nitrogen has on the behavior of the phosphorane intermediateare discussed.
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