Stereoselective synthesis of the 5′-hydroxy-5′-phosphonate derivatives of cytidine and cytosine arabinoside

Xuemei Chen, Andrew J. Wiemer, Raymond Hohl, David F. Wiemer

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

Both the (R)- and (S)-5′-hydroxy 5′-phosphonate derivatives of cytidine and cytosine arabinoside (ara-C) have been prepared via phosphite addition or a Lewis acid mediated hydrophosphonylation of appropriately protected 5′-nucleoside aldehydes. Phosphite addition to a cytosine aldehyde protected as the 2′,3′-acetonide gave predominately the 5′R isomer, while phosphite addition to the corresponding 2′,3′-bis TBS derivative favored the 5′S stereochemistry. In contrast, phosphite addition to the 2′,3′-bis TBS protected aldehyde derived from ara-C gave only the 5′R adduct. However, TiC4-mediated hydrophosphonylation of the same ara-C aldehyde favored the 5′S stereoisomer by a 2:1 ratio. Once all four of the diastereomers were in hand, the stereochemistry of these compounds could be assigned based on their spectral data or that obtained from their O-methyl mandelate derivatives. After hydrolysis of the phosphonate esters and various protecting groups, the four α-hydroxy phosphonic acids were tested for their ability to serve as substrates for the enzyme nucleoside monophosphate kinase and for their toxicity to K562 cells.

Original languageEnglish (US)
Pages (from-to)9331-9339
Number of pages9
JournalJournal of Organic Chemistry
Volume67
Issue number26
DOIs
StatePublished - Dec 27 2002

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Phosphites
Cytidine
Organophosphonates
Cytarabine
Aldehydes
Derivatives
Stereochemistry
Nucleoside-Phosphate Kinase
Phosphorous Acids
Lewis Acids
Stereoisomerism
Cytosine
Nucleosides
Isomers
Toxicity
Hydrolysis
Esters
Substrates
Enzymes

All Science Journal Classification (ASJC) codes

  • Organic Chemistry

Cite this

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abstract = "Both the (R)- and (S)-5′-hydroxy 5′-phosphonate derivatives of cytidine and cytosine arabinoside (ara-C) have been prepared via phosphite addition or a Lewis acid mediated hydrophosphonylation of appropriately protected 5′-nucleoside aldehydes. Phosphite addition to a cytosine aldehyde protected as the 2′,3′-acetonide gave predominately the 5′R isomer, while phosphite addition to the corresponding 2′,3′-bis TBS derivative favored the 5′S stereochemistry. In contrast, phosphite addition to the 2′,3′-bis TBS protected aldehyde derived from ara-C gave only the 5′R adduct. However, TiC4-mediated hydrophosphonylation of the same ara-C aldehyde favored the 5′S stereoisomer by a 2:1 ratio. Once all four of the diastereomers were in hand, the stereochemistry of these compounds could be assigned based on their spectral data or that obtained from their O-methyl mandelate derivatives. After hydrolysis of the phosphonate esters and various protecting groups, the four α-hydroxy phosphonic acids were tested for their ability to serve as substrates for the enzyme nucleoside monophosphate kinase and for their toxicity to K562 cells.",
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Stereoselective synthesis of the 5′-hydroxy-5′-phosphonate derivatives of cytidine and cytosine arabinoside. / Chen, Xuemei; Wiemer, Andrew J.; Hohl, Raymond; Wiemer, David F.

In: Journal of Organic Chemistry, Vol. 67, No. 26, 27.12.2002, p. 9331-9339.

Research output: Contribution to journalArticle

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