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Hydrolytic Reactions of the cis ‐Methyl Ester of 3′‐Deoxy‐3′‐thiothymidine 3′,5′‐Cyclic(phosphorothiolate)
Author(s) -
Elzagheid Mohamed I.,
Mattila Kati,
Oivanen Mikko,
Jones Bryan C. N. M.,
Cosstick Richard,
Lönnberg Harri
Publication year - 2000
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/(sici)1099-0690(200005)2000:10<1987::aid-ejoc1987>3.0.co;2-x
Subject(s) - chemistry , hydrolysis , bond cleavage , hydroxide , medicinal chemistry , nucleophile , thiophosphate , moiety , catalysis , organic chemistry
Hydrolysis of the cis ‐methyl ester of 3′‐deoxy‐3′‐thiothymidine 3′‐ S ,5′‐ O ‐cyclic(phosphorothiolate) ( 1a ) 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.