用二氯甲基膦酸酯合成寡核苷酸甲基膦酸酯。

Use of methylphosphonic dichloride for the synthesis of oligonucleoside methylphosphonates.

作者信息

Miller P S, Agris C H, Blandin M, Murakami A, Reddy P M, Spitz S A, Ts'o P O

出版信息

Nucleic Acids Res. 1983 Aug 11;11(15):5189-204. doi: 10.1093/nar/11.15.5189.

DOI:10.1093/nar/11.15.5189

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC326248/

Abstract

Methylphosphonic dichloride was used to prepare protected deoxyribonucleoside 3'-methylphosphonate beta-cyanoethyl esters, d-[(MeO)2Tr]NpCNEt, and protected oligonucleoside methylphosphonates in solution. Reaction of d-[(MeO)2Tr]N with methylphosphonic 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.

摘要

二氯甲基膦酸酯用于在溶液中制备受保护的脱氧核糖核苷3'-甲基膦酸酯β-氰基乙酯、d-[(MeO)2Tr]NpCNEt和受保护的寡核苷甲基膦酸酯。d-[(MeO)2Tr]N与二氯甲基膦酸酯反应生成d-[(MeO)2Tr]NpCl。膦酰化以及随后的酯化或缩合反应在60分钟内均能完成。产物可通过硅胶柱上的“快速柱色谱法”轻松纯化。d-[(MeO)2Tr]NpCl或其四唑衍生物d-[(MeO)2Tr]Nptet作为在硅胶聚合物载体上合成寡胸苷甲基膦酸酯的中间体进行了测试。每个偶联步骤的平均产率为76%，且不会随着添加更多的d-[(MeO)2Tr]TpCl而增加。(5'-5')连接的胸苷二聚体的形成表明胸苷单体在载体上紧密聚集在一起。当N为ibuG时，载体上偶联步骤的产率非常低。这可能是由于N-2异丁酰基保护基团对3'-膦酸酯基团的空间位阻作用。

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