A1 Refereed original research article in a scientific journal
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
Authors: Lonnberg T, Korhonen J
Publisher: AMER CHEMICAL SOC
Publication year: 2005
Journal:: Journal of the American Chemical Society
Journal name in source: JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Journal acronym: J AM CHEM SOC
Volume: 127
Issue: 21
First page : 7752
Last page: 7758
Number of pages: 7
ISSN: 0002-7863
DOI: https://doi.org/10.1021/ja050325l
Abstract
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.
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.
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