Synthesis of β-triphosphotriester pronucleotides

Abstract

Dinucleoside phosphorochloridite were synthesized from phosphorus trichloride and three nucleoside analogues, 3′-fluoro-2′,3′-dideoxythymidine (FLT), 2′,3′-dideoxy-5-fluoro-3′-thiacytidine (FTC), and 2′,3′-dideoxy-3′-thiacytidine (3TC), in a multistep synthesis. Polymer-bound N-Boc p-acetoxybenzyl 5′-O-2′-deoxythymidine was reacted with dinucleoside phosphorochloridite in the presence of 2,6-lutidine, followed by the reaction with dodecyl alcohol and 5-(ethylthio)-1H-tetrazole, oxidation with tert-butyl hydroperoxide, and acidic cleavage, respectively, to afford the β-triphosphotriester derivatives containing three different nucleosides.

A new approach to phosphorylation of nucleosides using oxyonium phosphobetaines as intermediates

“…Phosphorylation strategies using P(III) agents are classified into two major groups: phosphitylation and phosphonylation, both followed by oxidation. The former uses tervalent phosphorus compounds, e.g., PCl 3 (Beni et al, 2015 ; Brusentsev and Eklund, 2016 ), phosphoro[mono/di]chloridites (Letsinger et al, 1975 ; Mara et al, 2011 ; Stowell et al, 1995 ), phosphoro[mono/di]amidites (Beaucage and Caruthers, 1981 ), and phosphorochloridoamidites (Beni et al, 2015 ). These reactants are usually highly reactive, particularly in the presence of bases (P–Cl compounds) or acids (P–N compounds), and are moisture and air sensitive.…”

Synthesis and Properties of Oligonucleotides Containing LNA-Sulfamate and Sulfamide Backbone Linkages

“…Commercially available compound 1 was converted to protected LNA-T nucleoside 2 following a reported procedure (SI Scheme S1). Next, the benzyl group was removed by catalytic hydrogenation to give 3 , and the 3′–OH group was protected with tert -butyldimethylsilyl to give 4 . The mesyl group was then replaced by azide to give 5 which was reduced to the amine by catalytic hydrogenation, yielding TBS-protected 5′-NH 2 -LNA-T nucleoside 6 (Scheme A).…”

“… 15 Next, the benzyl group was removed by catalytic hydrogenation to give 3 , and the 3′–OH group was protected with tert -butyldimethylsilyl to give 4 . 16 The mesyl group was then replaced by azide to give 5 which was reduced to the amine by catalytic hydrogenation, 12a yielding TBS-protected 5′-NH 2 -LNA-T nucleoside 6 ( Scheme 1 A). Intermediate 7 ( 14 ) for use in dinucleotide synthesis was prepared by reacting 6 with p-nitrophenylsulfurochloridate in the presence of p-nitrophenol and triethylamine ( Scheme 1 B).…”