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 (pK(a) 7.1-10) as well as on the basicity of the catalyst (pK(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 degrees C, 0.25 M ionic strength) obey Bronsted linear free energy relationships and the obtained beta(leaving group) (beta(ig)) values are -0.55 and -0.63, respectively. General-base-catalyzed release of 4-nitrophenoxide from the corresponding phosphorothioate also obeys a Bronsted relationship with respect to the basicity of the catalyst (beta = 0.59). Rates of reactions of the phosphorothioates are somewhat lower than for the corresponding phosphates (k((UpAr))/k((Sp-Up(S)Ar)) approximate to 1.7-3.6 and k((UpAr))/k((Rp-Up(S)Ar)) approximate to 1.2-2.6 (the spatial arrangement of phosphorus ligands in the Sp isomer of Up(S)Ar are the same as in the Rp isomer of a dinucleotide). Leffler alpha 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 alpha = 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.