title: Stereoselective synthesis of the 5'-hydroxy-5'-phosphonate derivatives of cytidine and cytosine arabinoside.
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.
authors.affiliation: Department of Chemistry, University of Iowa, Iowa City, Iowa 52242-1294, USA.
authors.forename: Xuemei
authors.initials: X
authors.lastname: Chen
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Wiemer
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Hohl
authors.forename: David F
authors.initials: DF
authors.lastname: Wiemer
mesh_terms: D003561:Cytarabine / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003562:Cytidine / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D006868:Hydrolysis; D020014:K562 Cells / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D063065:Organophosphonates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D063065:Organophosphonates; D003561:Cytarabine; D003562:Cytidine