A Novel Method for the Synthesis of Dinucleoside Boranophosphates by a Boranophosphotriester Method

Abstract

2'-Deoxyribonucleoside-3'-boranophosphates (nucleotide monomers), including four kinds of nucleobases, were synthesized in good yields by the use of new boranophosphorylating reagents. We have explored various kinds of condensing reagents as well as nucleophilic catalysts for the boranophosphorylation reaction with nucleosides. In the synthesis of dinucleoside boranophosphates, undesirable side reactions occurred at the O-4 of thymine and the O-6 of N2-phenylacetylguanine bases. To avoid these side reactions, additional protecting groups, benzoyl (Bz) and diphenylcarbamoyl (Dpc) groups, were introduced to thymine and guanine bases, respectively. As a result, the condensation reactions proceeded smoothly without any side reactions, and the dimers including four kinds of nucleobases were obtained in excellent yields. In the deprotection of the 5'-DMTr group, Et3SiH was found to be effective as a scavenger for the DMTr cation which caused a P-B bond cleavage. After removal of the other protecting groups by the conventional procedure, four kinds of dinucleoside boranophosphates were obtained in good yields.

1,3-Dimethyl-2-(3-nitro-1,2,4-triazol-1-yl)-2-pyrrolidin-1-yl-1,3,2-diazaphospholidinium hexafluorophosphate (MNTP): a powerful condensing reagent for phosphate and phosphonate esters

“…This side reaction was rather unexpected, because the nucleophilic attack of alcohols to a positively charged phosphorus atom assisted by a weak base, such as 2,6-lutidine, is known to be slow. 17,19,25 In fact, this side reaction was not observed when 2 or 3 was used. 34 The ratio of 16 increased upon using a …”

“…[17][18][19] The advantages are: 1) condensation reactions can be carried out without strictly anhydrous conditions; 2) the phosphorylating and phosphonylating reagents can be stored for a long period of time without being oxidized or hydrolyzed; 3) an additional step, such as oxidation, is eliminated. These characteristics would enable one to synthesize some functionalized molecules, which are difficult to be synthesized by the phosphoramidite method.…”

“…These characteristics would enable one to synthesize some functionalized molecules, which are difficult to be synthesized by the phosphoramidite method. As such a successful result, we have developed a new boranophosphorylation reaction of nucleosides mediated by a condensing reagent and could synthesize dinucleoside boranophosphates containing four nucleobases, 18,19 which were difficult to be synthesized by the phosphoramidite method due to serious side reactions on the nucleobases caused by a boronating reagent during the boronation of the phosphite intermediates. [13][14][15][16] Phosphonium-type condensing reagents, which were originally developed for the peptide synthesis, [20][21][22][23] have also proven to be effective for the synthesis of phosphate and phosphonate derivatives.…”

“…[13][14][15][16] Phosphonium-type condensing reagents, which were originally developed for the peptide synthesis, [20][21][22][23] have also proven to be effective for the synthesis of phosphate and phosphonate derivatives. 17,19,[24][25][26][27] For example,…”

Recent Progress in the Synthesis of Glycosyl Phosphate Derivatives

“…As shown in Fig. 10, we first carried out the synthesis by condensation of reducing sugars 36 with triethylammonium dimethyl boranophosphate 37 (55,56). The desired glycosyl boranophosphate triesters were obtained in good yields, although mixtures of α-and β-diastereomers were obtained (57).…”