Development of a new synthetic method for oligodeoxynucleotides using 3′-H-phosphonamidate derivatives

Abstract

In this study, we developed a new approach for the solution-phase synthesis of oligodeoxynucleotides (ODNs) using nucleoside 3ʹ-H-phosphonamidate derivatives as monomers. The H-phosphonamidate monomers having a heterocyclic amino group as...

Internucleotidic bond formation using H-phosphonamidate derivatives and acidic activators

“…H -Phosphonamidate 1 was synthesized following our previously reported procedure. 9 Next, we activated the thiomorpholino group of H -phosphonamidate monomer using various acidic activators. The 1.2 equivalents of H -phosphonamidate 1 were condensed with 2 bearing the 5′-OH group using acidic activators.…”

“…Our previous study revealed that this sulfurization reaction proceeded instantly to yield the stable phosphorothioate diester 8 and phosphorothioamidate monoester derivative 9 from H -phosphonate diester 3 and H -phosphonamidate monomer 1, respectively. 9 Therefore, the condensation efficacy can be determined via the 31 P NMR analysis of the reaction mixture after sulfurization. The results are shown in Table 5 and Fig.…”

“…The excess amount of 1 was removed completely via simple extraction because H -phosphonamidate monomer 1 was converted into a water-soluble derivative by a detritylation reaction. 9 The sulfurization reaction was accelerated by the addition of BSA as a silylating reagent; BSA promoted the conversion of H -phosphonamidate monomer 1 to phosphorothioamidate monoester derivative 9, which was not removed by extraction after detritylation. 9 It has been shown that an H -phosphonate diester linkage shows a higher reactivity to electrophiles than an H -phosphonamidate linkage.…”

“…H- Phosphonamidate monomers 4 and 5, which possess piperidino and morpholino group as leaving groups, respectively, were synthesized following literature procedures. 3,9 H-Phosphonamidate monomers 4 and 5 were isolated via silica-gel column chromatography. TET was used as an acidic activator to condense 1.2 equivalents of H-phosphonamidate monomers 1, 4, and 5 with 2 bearing the 5 ′ -OH group.…”

“…Recently, we have reported a novel synthesis method for ODNs using H -phosphonamidate derivatives as monomers. 9 In this method, H -phosphonamidate monomers having heterocyclic amino groups, such as thiomorpholino, morpholino, and N -methylpiperadino groups, reacted with an alcohol to form an internucleotidic H -phosphonate diester under mild basic conditions without the use of additives ( Scheme 1 ). In the reaction, the heterocyclic amino groups of H -phosphonamidate monomers worked as leaving groups, and one-step formation of the H -phosphonate diester linkage from H -phosphonamidate derivatives was achieved.…”