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.
All Science Journal Classification (ASJC) codes
- Organic Chemistry