The chemical stability of S-(2-acylthioethyl) and S-acyloxymethyl protected thymidylyl-3 ',5 '-thymidine phosphoromonothiolates and their deacylationeproducts in aqueous solution

The hydrolytic stability of the S-(2-acetylthioethyl) (1a,b), S-(2-pivaloyl thioethyl) (2a,b), and S-acetyloxymethyl (3a,b) protected Rp and Sp phospho romonothiolates of 3',5'-TpT has been studied. Rather unexpectedly, an intr amolecular hydroxide ion catalyzed acetyl migration from the protecting gro up to the nucleoside 3'- and 5'-hydroxy functions was found to compete with the intermolecular displacement of the AcSCH2CH2S- or AcOCH2S-ligand from the phosphorus atom of la,b and 3a,b, respectively. With the S-pivaloylthio ethyl derivative 2a,b no such reaction took place. Additionally, the kineti cs of the cleavage of the S-(2-mercaptoethyl) group from 4a,b, the products of enzymatic deacylation of 1a,b and 2a,b, were studied as a function of p H.