{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T11:31:09Z","timestamp":1789644669618,"version":"4.0.0"},"reference-count":62,"publisher":"Wiley","issue":"30","license":[{"start":{"date-parts":[[2007,7,25]],"date-time":"2007-07-25T00:00:00Z","timestamp":1185321600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Chemistry A European J"],"published-print":{"date-parts":[[2007,10,15]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>To obtain detailed data on the kinetics of hydrolytic reactions of triester\u2010like nucleoside 5\u2032\u2010<jats:italic>O<\/jats:italic>\u2010aryl\u2010<jats:italic>N<\/jats:italic>\u2010alkylphosphoramidates, potential prodrugs of antiviral nucleoside monophosphates, the hydrolysis of diastereomeric (<jats:italic>R<\/jats:italic><jats:sub>P<\/jats:sub>\/<jats:italic>S<\/jats:italic><jats:sub>P<\/jats:sub>) thymidine 5\u2032\u2010{<jats:italic>O<\/jats:italic>\u2010phenyl\u2010<jats:italic>N<\/jats:italic>\u2010[(1<jats:italic>S<\/jats:italic>)\u20102\u2010oxo\u20102\u2010methoxy\u20101\u2010methylethyl]phosphoramidate} (<jats:bold>3<\/jats:bold>), a phosphoramidate derived from the methyl ester of <jats:sc>L<\/jats:sc>\u2010alanine, has been followed by reversed\u2010phase HPLC over the range from <jats:italic>H<\/jats:italic><jats:sub>0<\/jats:sub>=0 to pH\u20058 at 90\u2009\u00b0C. According to the time\u2010dependent product distributions, the hydrolysis of <jats:bold>3<\/jats:bold> proceeds at pH&lt;4 by two parallel routes, namely by nucleophilic displacement of the alaninyl ester moiety by a water molecule and by hydrolysis of the carboxylic ester linkage that allows intramolecular attack of the carboxy group on the phosphorus atom, thereby resulting in the departure of either thymidine or phenol without marked accumulation of any intermediates. Both routes represent about half of the overall disappearance of <jats:bold>3<\/jats:bold>. The departure of phenol eventually leads to the formation of thymidine 5\u2032\u2010phosphate. At pH&gt;5, the predominant reaction is hydrolysis of the carboxylic ester linkage followed by intramolecular displacement of a phenoxide ion by the carboxylate ion and hydrolysis of the resulting cyclic mixed anhydride into an acyclic diester\u2010like thymidine 5\u2032\u2010phosphoramidate. The latter product accumulated quantitatively without any indication of further decomposition. Hydroxide\u2010ion\u2010catalyzed P\uf8ffOPh bond cleavage of the starting material <jats:bold>3<\/jats:bold> occurred as a side reaction. Comparative measurements with thymidine 5\u2032\u2010{<jats:italic>N<\/jats:italic>\u2010[(1<jats:italic>S<\/jats:italic>)\u20102\u2010oxo\u20102\u2010methoxy\u20101\u2010methylethyl]phosphoramidate} (<jats:bold>4<\/jats:bold>) revealed that, under acidic conditions, this diester\u2010like compound is hydrolyzed by P\uf8ffN bond cleavage three orders of magnitude more rapidly than the triester\u2010like <jats:bold>3<\/jats:bold>. At pH&gt;5, the stability order is reversed, with <jats:bold>3<\/jats:bold> being hydrolyzed six times as rapidly as <jats:bold>4<\/jats:bold>. Mechanisms of the partial reactions are discussed.<\/jats:p>","DOI":"10.1002\/chem.200700623","type":"journal-article","created":{"date-parts":[[2007,7,25]],"date-time":"2007-07-25T05:23:21Z","timestamp":1185341001000},"page":"8591-8599","source":"Crossref","is-referenced-by-count":12,"title":["Hydrolytic Reactions of Thymidine 5\u2032\u2010<i>O<\/i>\u2010Phenyl\u2010<i>N<\/i>\u2010Alkylphosphoramidates, Models of Nucleoside 5\u2032\u2010Monophosphate Prodrugs"],"prefix":"10.1002","volume":"13","author":[{"given":"Mikko","family":"Ora","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jarno","family":"Ojanper\u00e4","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harri","family":"L\u00f6nnberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2007,10,2]]},"reference":[{"key":"e_1_2_6_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrd1877"},{"key":"e_1_2_6_2_2","doi-asserted-by":"publisher","DOI":"10.2174\/1389557043403936"},{"key":"e_1_2_6_3_2","doi-asserted-by":"publisher","DOI":"10.2174\/092986706779010270"},{"key":"e_1_2_6_4_2","first-page":"19","volume":"5","author":"McGuigan C.","year":"1997","journal-title":"Int. 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