Base Catalysis and Leaving Group Dependence in Intramolecular Alcoholysis of Uridine 3‘-(Aryl phosphorothioate)s

Base-catalyzed intramolecular transesterification in uridine 3‘-(aryl phosphorothioate)s (Up(S)Ar) has been studied with respect to the dependence on the acidity of the conjugate acid of the leaving aryloxy group (p K a 7.1−10) as well as on the basicity of the catalyst (p K a (BH) = 7−10.2). The synthesis of the studied phosphorothioates was accomplished by using a method based on condensation of a protected uridine 3‘-H-phosphonate with the appropriate phenols. The rate constants for hydroxide and imidazole catalysis (25 °C, 0.25 M ionic strength) obey Brønsted linear free energy relationships and the obtained β leaving group (β lg ) values are −0.55 and −0.63, respectively. General-base-catalyzed release of 4-nitrophenoxide from the corresponding phosphorothioate also obeys a Brønsted relationship with respect to the basicity of the catalyst (β = 0.59). Rates of reactions of the phosphorothioates are somewhat lower than for the corresponding phosphates ( k (UpAr) / k ( S P -Up(S)Ar) ≈ 1.7−3.6 and k (UpAr) / k ( R P -Up(S)Ar) ≈ 1.2−2.6 (the spatial arrangement of phosphorus ligands in the S P isomer of Up(S)Ar are the same as in the R P isomer of a dinucleotide). Leffler α values of 0.59 for proton abstraction and 0.36 for bond breaking to the leaving group in the transition state do not balance (imbalance in α = 0.23), indicating some negative charge buildup on the central group of atoms in the transition state. The intramolecular transesterification in uridine 3‘-(aryl phosphorothioate)s is considered to be a concerted associative process with a mechanism that is similar to that in the corresponding phosphate esters, the difference being that the transition state appears to have a slightly more dissociative character for the phosphorothioates.