Intramolecular Participation of Amino Groups in the Cleavage and Isomerization of Ribonucleoside 3′-Phosphodiesters: The Role in Stabilization of the Phosphorane Intermediate

A dinucleoside-3,5-phosphodiester model, 5-amino-4-aminomethyl-5-deoxyuridylyl-3,5-thymidine, incorporating two aminomethyl functions in the 4-position of the 3-linked nucleoside has been prepared and its hydrolytic reactions studied over a wide pH range. The amino functions were found to accelerate the cleavage and isomerization of the phosphodiester linkage in both protonated and neutral form. When present in protonated form, the cleavage of the 3,5-phosphodiester linkage and its isomerization to a 2,5-linkage are pH-independent and 50-80 times as fast as the corresponding reactions of uridylyl-3,5-uridine (3,5-UpU). The cleavage of the resulting 2,5-isomer is also accelerated, albeit less than with the 3,5-isomer, whereas isomerization back to the 3,5-diester is not enhanced. When the amino groups are deprotonated, the cleavage reactions of both isomers are again pH-independent and up to 1000-fold faster than the pH-independent cleavage of UpU. Interestingly, the 2- to 3-isomerization is now much faster than its reverse reaction. The mechanisms of these reactions are discussed. The rate accelerations are largely accounted for by electrostatic and hydrogen-bonding interactions of the protonated amino groups with the phosphorane intermediate.