A1 Refereed original research article in a scientific journal
Hydrolytic Reactions of the cis-methyl ester of 3 '-deoxy-3 '-thiothymidine 3 ',5 '-cyclic(phosphorothiolate)
Authors: Elzagheid MI, Mattila K, Oivanen M, Jones BCNM, Cosstick R, Lonnberg H
Publisher: WILEY-V C H VERLAG GMBH
Publication year: 2000
Journal:: European Journal of Organic Chemistry
Journal name in source: EUROPEAN JOURNAL OF ORGANIC CHEMISTRY
Journal acronym: EUR J ORG CHEM
Issue: 10
First page : 1987
Last page: 1991
Number of pages: 5
ISSN: 1434-193X
Abstract
Hydrolysis of the cis-methyl ester of 3'-deoxy-3'-thiothymidine 3'-S,5'-O-cyclic(phosphorothiolate) (la) has been followed by HPLC and MS. At pH < 2 hydrolysis of the thiophosphate triester moiety is acid-catalyzed (first order), while between pH = 2 and 5 the reaction is pH-independent and at pH > 5 first order in hydroxide ion. The uncatalyzed and acid-catalyzed reactions yield two thiophosphate diesters, the 3'-S,5'-O-cyclic phosphorothiolate 2 and 3'-S-phosphorothiolate methyl ester 3, in a 9:1 and 1:3 molar ratio, respectively. The hydroxide ion catalyzed reaction gives the endocyclic P-O and P-S bond-cleavage products (3 and 4, respectively) in a 1:2 molar ratio. The pH-independent reaction is suggested to take place by attack of a water molecule on the carbon atom and concomitant C-O bond rupture, whereas the alkaline and acidic reactions involve attack of the nucleophile on the phosphorus atom and formation of a pseudorotating thiophosphorane intermediate. Under acidic conditions, cleavage of the N-glycosidic linkage competes with the phosphoester hydrolysis, corresponding to 20% of the hydrolysis products at pH < 1.
Hydrolysis of the cis-methyl ester of 3'-deoxy-3'-thiothymidine 3'-S,5'-O-cyclic(phosphorothiolate) (la) has been followed by HPLC and MS. At pH < 2 hydrolysis of the thiophosphate triester moiety is acid-catalyzed (first order), while between pH = 2 and 5 the reaction is pH-independent and at pH > 5 first order in hydroxide ion. The uncatalyzed and acid-catalyzed reactions yield two thiophosphate diesters, the 3'-S,5'-O-cyclic phosphorothiolate 2 and 3'-S-phosphorothiolate methyl ester 3, in a 9:1 and 1:3 molar ratio, respectively. The hydroxide ion catalyzed reaction gives the endocyclic P-O and P-S bond-cleavage products (3 and 4, respectively) in a 1:2 molar ratio. The pH-independent reaction is suggested to take place by attack of a water molecule on the carbon atom and concomitant C-O bond rupture, whereas the alkaline and acidic reactions involve attack of the nucleophile on the phosphorus atom and formation of a pseudorotating thiophosphorane intermediate. Under acidic conditions, cleavage of the N-glycosidic linkage competes with the phosphoester hydrolysis, corresponding to 20% of the hydrolysis products at pH < 1.
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