Stepwise Mechanism of Hydroxide Ion Catalyzed Cyclization of Uridine 3′‐Thiophosphates

Abstract

AbstractDiastereoisomeric isopropyl‐, 2‐ethoxyethyl‐, 2,2‐dichloroethyl‐ and 2,2,2‐trichloroethyl uridine 3′‐thiomonophosphates, 1a–1d, respectively, have been synthesized, and their hydrolyses in aqueous alkali at 25° have been followed by HPLC. According to the time‐dependent product distributions obtained, the alkyl phosphorothioates 1a–1d undergo cleavage to uridine 2′‐ and 3′‐thiophosphates, 7a and 7b, respectively, via a uridine 2′,3′‐cyclic thiophosphate (6). The rate of the hydroxide ion‐catalyzed cyclization of both (RP)‐ and (SP)‐diastereoisomer is highly dependent on the polar nature of the leaving group, the βlg values being −1.23±0.03 and −1.24±0.03, respectively. Brønsted dependence of the second‐order rate constants (kOH [dm3 mol−1 s−1]) on the pKa values of the leaving alcohols shows a convex breakpoint on going from alkyl esters 1a–1d to aryl esters studied earlier. This may be considered as a strong evidence for a stepwise mechanism, where the formation and breakdown of the phosphorane intermediate is the rate‐limiting step with aryl and alkyl esters, respectively.