Use of methylphosphonic dichloride for the synthesis of oligonucleoside methylphosphonates

• Published in: Nucleic acids research Vol. 11; no. 15; pp. 5189 - 5204
• Main Authors: Miller, Paul S., Agris, Cheryl H., Blandin, Michel, Murakami, Akira, Reddy, Parameswara M., Spitz, Sharon A., Ts'o, Paul O.P.
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 11.08.1983
• Subjects: Indicators and Reagents; Methods; Oligonucleotides - chemical synthesis; Organophosphorus Compounds; Structure-Activity Relationship
• ISSN: 0305-1048; 1362-4962
• DOI: 10.1093/nar/11.15.5189

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.