Use of methylphosphonic dichloride for the synthesis of oligonucleoside methylphosphonates

Paul S. Miller, Cheryl H. Agris, Michel Blandin, Akira Murakami, Parameswara M. Reddy, Sharon A. Spitz, Paul O p Ts'o

Research output: Contribution to journalArticle

Abstract

Methylphosphonic dichloride was used to prepare protected deoxyribo-nucleoside 3'-methylphosphonate β-cyanoethyl esters, d-[(MeO)2Tr]NpCNEt, and protected oligonucleoside methylphosphonates in solution. Reaction of d-[(MeO)2Tr]N with methyl phosphonic dichloride gives d-[(MeO)2Tr]NpCl. The phosphonylation and subsequent esterification or condensation reactions are each complete within 60 min. The products are readily purified by "flash chromatography" on silica gel columns. d-[(MeO)2Tr]NpCl, or Its tetrazole derivative, d-[(MeO)2Tr]Nptet, were tested as intermediates for the synthesis of oligothymidine methylphosphonates on a silica gel polymer support. The average yield per coupling step was 76% and did not Increase with addition of more d-[(MeO)2Tr]TpCl . The formation of (5'-5') linked thymidine dimers Indicated that the thymidine monomers are clustered closely together on the support. When N is ibuG, the yield for the coupling step on the support is very low. This may be due to steric hindrance of the 3'-phosphonate group by the N-2 isobutryl protecting group.

Original languageEnglish (US)
Pages (from-to)5189-5204
Number of pages16
JournalNucleic Acids Research
Volume11
Issue number15
DOIs
StatePublished - Aug 11 1983

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ASJC Scopus subject areas

  • Statistics, Probability and Uncertainty
  • Applied Mathematics
  • Health, Toxicology and Mutagenesis
  • Toxicology
  • Genetics(clinical)
  • Genetics

Cite this

Miller, P. S., Agris, C. H., Blandin, M., Murakami, A., Reddy, P. M., Spitz, S. A., & Ts'o, P. O. P. (1983). Use of methylphosphonic dichloride for the synthesis of oligonucleoside methylphosphonates. Nucleic Acids Research, 11(15), 5189-5204. https://doi.org/10.1093/nar/11.15.5189