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 depe ndence on the acidity of the conjugate acid of the leaving aryloxy gro up (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 accomp lished 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. G eneral-base-catalyzed release of 4-nitrophenoxide from the correspondi ng 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 phosp hates (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 pho sphorus 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 abs traction and 0.36 for bond breaking to the leaving group in the transi tion state do not balance (imbalance in alpha = 0.23), indicating some negative charge buildup on the central group of atoms in the transiti on state. The intramolecular transesterification in uridine 3'-(aryl p hosphorothioate)s is considered to be a concerted associative process with a mechanism that is similar to that in the corresponding phosphat e esters, the difference being that the transition state appears to ha ve a slightly more dissociative character for the phosphorothioates.