Chemoselective Activation of Nucleoside 3‘-O-Methylphosphonothioates with 1,3,5-Triazinyl Morpholinium Salts

Abstract

Chemoselective and stereospecific O-activation of 2'-deoxynucleoside 3'-O-methylphosphonothioates 5 with N-methyl-N-4,6-dimethoxy-1,3,5-triazin-2-yl morpholinium salts results in formation with retention of configuration of 5'-O-DMT-2'-deoxynucleoside 3'-O-(4,6 dimethoxy-1,3,5-triazin-2-yl methylphosphonothioates (7). Active esters 7 are convenient intermediates for hydrolytic interconversion of RP-5 into SP-5 and can be used as monomers for stereoselective synthesis of dinucleoside (3',5')-methyl phosphonothioates.

Modified internucleoside linkages for nuclease-resistant oligonucleotides

“…The MPS linkage achieved a superior resistance to SVPDE but better results were expected when combining both PS and MP modifications. Although further work on the synthesis of MPS-ODN has been reported, [288][289][290] no biological applications have been published to date, presumably because of their surprising low resistance to nucleases.…”

Synthesis of 2-(4,6-Dimethoxy-1,3,5-triazin-2-yloxyimino) Derivatives: Application in Solution Peptide Synthesis

“…The related triazine, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMTMM, 11 ), formed by a simple reaction of CDMT ( 9 ) with N -methylmorpholine (NMM), has been found applications in amidation [38,39,40,41,42], esterification [42], glycosidation [43,44] and phosphonylation [45] methodology. The present work presents the synthesis and application of a new family of 1,3,5-triazine derivatives and their comparison with CDMT ( 9 ) as well as the uronium based type coupling reagents [46].…”

The Medicinal Chemistry of Artificial Nucleic Acids and Therapeutic Oligonucleotides

“…However, their affinity to natural nucleic acids is low, and they cannot activate RNAse H [ 122 ]. The incorporation of methylphosphonothioate units (MPS) into oligonucleotides slightly decreases the stability of duplexes, while significantly increasing the half-life of the oligomer [ 130 , 131 , 132 , 133 , 134 ]. Phosphotriester (PT) oligos such as methylphosphotriester (MPT) derivatives have better cellular uptake due to their neutral backbone.…”