Phosphinoamidite carboxylates and analogs thereof in the synthesis of oligonucleotide having reduced internucleotide charge

摘要

Nucleoside phosphinoamidite carboxylates and analogs are provided that have the structure of formula (III);
wherein A is hydrogen, hydroxyl, lower alkoxy, lower alkoxy-substituted lower alkoxy, halogen, SH, NH2, azide or DL wherein D is O, S or NH and L is a heteroatom-protecting group, unsubstituted hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, or substituted heteroatom-containing hydrocarbyl; B is a nucleobase; and one of R11 and R12 is a blocking group and the other is (IV) or (VI)
;
in which W, X, Y, Z, R1 and n are as defined herein.

主权项

1. A compound having the structural formula (I), wherein R1 is a protecting group removable by an elimination reaction; R2 and R3 are independently selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl and substituted heteroatom-containing hydrocarbyl, or R2 and R3 are linked to form a substituted or unsubstituted, five- or six-membered nitrogen-containing heterocycle; R4 is NR5R6, halogen or DL, wherein R5 and R6 are independently selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl and substituted heteroatom-containing hydrocarbyl, or R5 and R6 are linked to form a substituted or unsubstituted, five- or six-membered nitrogen-containing heterocycle, D is O, S or NH, and L is a heteroatom-protecting group, unsubstituted hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, or substituted heteroatom containing hydrocarbyl; X is O, S, NH, or NR7 wherein R7 is hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl or substituted heteroatom-containing hydrocarbyl; n is zero or 1; Y is —(Y′)m-(CR8R9)— wherein m is zero or 1, Y′ is hydrocarbylene, substituted hydrocarbylene, heteroatom-containing hydrocarbylene, or substituted heteroatom-containing hydrocarbylene, wherein R8 and R9 are independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl and substituted heteroatom-containing hydrocarbyl; and Z is O, S, NH or NR10 wherein R10 is as defined for R7 wherein in any substituted moiety at least one hydrogen atom bound to a carbon atom is replaced by at least one of the following: alkoxy, thio, thioester, halo, amino, nitrile, nitro, sulfonyl, phosphoro, carboxyl, carbonyl, silyl and thienyl.