Hydrolysis of 2 ',3 '-O-methyleneadenosin-5 '-yl bis-5 '-O-methyluridin-3 '-yl phosphate: The 2 '-hydroxy group stabilizes the phosphorane intermediate, not the departing 3 '-oxyanion, by hydrogen bonding

摘要

Hydrolytic reactions of 2',3'-O-methyleneadenosin-5'-yl bis-5'-O-methyluridin-3'-yl phosphate (11 a) have been followed by RP HPLC over a wide pH range to elucidate the role of the 2'-OH group as an intermolecular hydrogen bond donor facilitating the cleavage of la. At pH < 2, where the decomposition of 1 is first-order in hydronium-ion concentration, the P-O5'and P-O3 bonds are cleaved equally rapidly. Over a relatively wide range from pH 2 to 4, the hydrolysis is pH-independent and the P-O5' bond is cleaved 1.6 times as rapidly as the P-O3' bond. At pH 6, the reaction becomes first-order in hydroxide-ion concentration and cleavage of the P-O3' bond starts to predominate, accounting for 89 % of the overall hydrolysis in 10 mmol L-1 aqueous sodium hydroxide. Under alkaline conditions, the 2'-OH group facilitates the cleavage of 1 by a factor of 27 compared to the 2'-OMe counterpart, the influence on the P-O3' and P-O5' bond cleavage being equal. Accordingly, the 2'-hydroxy group stabilizes the phosphorane intermediate, not the departing 3'-oxyanion, by hydrogen bonding.