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

Xuemei Chen; Andrew J Wiemer; Raymond J Hohl; David F Wiemer

doi:10.1021/jo020483k

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

Journal article

Peer reviewed

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

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

Journal of organic chemistry, Vol.67(26), pp.9331-9339

12/27/2002

DOI: 10.1021/jo020483k

PMID: 12492335

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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, TiCl(4)-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 alpha-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.

Cytarabine - chemical synthesis

Cytarabine - pharmacology

Cytidine - chemistry

Magnetic Resonance Spectroscopy

Stereoisomerism

Humans

Tumor Cells, Cultured - drug effects

Cytidine - pharmacology

Structure-Activity Relationship

K562 Cells - drug effects

Cytidine - chemical synthesis

Hydrolysis

Organophosphonates - chemical synthesis

Organophosphonates - pharmacology

Cytarabine - chemistry

Organophosphonates - chemistry

Molecular Structure

Drug Screening Assays, Antitumor

Details

Title: Subtitle: Stereoselective synthesis of the 5'-hydroxy-5'-phosphonate derivatives of cytidine and cytosine arabinoside
Creators: Xuemei Chen - Department of Chemistry, University of Iowa, Iowa City, Iowa 52242-1294, USA
Andrew J Wiemer
Raymond J Hohl
David F Wiemer
Resource Type: Journal article
Publication Details: Journal of organic chemistry, Vol.67(26), pp.9331-9339
DOI: 10.1021/jo020483k
PMID: 12492335
NLM abbreviation: J Org Chem
ISSN: 0022-3263
eISSN: 1520-6904
Publisher: United States
Language: English
Date published: 12/27/2002
Academic Unit: Neuroscience and Pharmacology; Chemistry; Internal Medicine
Record Identifier: 9983985884102771

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