Oligonucleotides having chiral phosphorus linkages
First Claim
1. A method for preparing an oligonucleotide comprising a predetermined sequence of nucleoside units, comprising the steps of:
- (a) selecting a first synthon having structure;
(b) selecting a second synthon having structure;
(c) contacting the second synthon with the first synthon in the presence of a base to effect nucleophilic attack of a 5′
-phosphate of the first synthon at a 3′
-position of the second synthon to yield a new first synthon via a stereospecific inversion of configuration at the 3′
position of the second synthon; and
(d) treating the new first synthon with a reagent to remove the blocking group RF;
wherein;
Q is O or CH2;
RD is O, S, methyl, alkoxy, thioalkoxy, amino or substituted amino;
RE is O or S;
RF is H or a labile blocking group;
RX is H, OH, or a sugar derivatizing group;
BX is a naturally occurring or synthetic nucleoside base or blocked nucleoside base;
L is a leaving group or together L and Bx are a 2-3′
or 6-3′
pyrimidine or 8-3′
purine cyclo-nucleoside; and
Y is a stable blocking group, a solid state support, a nucleotide on a solid state support, or an oligonucleotide on a solid state support.
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Abstract
Sequence-specific oligonucleotides are provided having substantially pure chiral Sp phosphorothioate, chiral Rp phosphorothioate, chiral Sp alkylphosphonate, chiral Rp alkylphosphonate, chiral Sp phosphoamidate, chiral Rp phosphoamidate, chiral Sp phosphotriester, and chiral Rp phosphotriester linkages. The novel oligonucleotides are prepared via a stereospecific SN2 nucleophilic attack of a phosphodiester, phosphorothioate, phosphoramidate, phosphotriester or alkylphosphonate anion on the 3′ position of a xylonucleotide. The reaction proceeds via inversion at the 3′ position of the xylo reactant species, resulting in the incorporation of phosphodiester, phosphorothioate, phosphoramidate, phosphotriester or alkylphosphonate linked ribofuranosyl sugar moieties into the oligonucleotide.
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Citations
39 Claims
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1. A method for preparing an oligonucleotide comprising a predetermined sequence of nucleoside units, comprising the steps of:
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(a) selecting a first synthon having structure;
(b) selecting a second synthon having structure;
(c) contacting the second synthon with the first synthon in the presence of a base to effect nucleophilic attack of a 5′
-phosphate of the first synthon at a 3′
-position of the second synthon to yield a new first synthon via a stereospecific inversion of configuration at the 3′
position of the second synthon; and
(d) treating the new first synthon with a reagent to remove the blocking group RF;
wherein;
Q is O or CH2;
RD is O, S, methyl, alkoxy, thioalkoxy, amino or substituted amino;
RE is O or S;
RF is H or a labile blocking group;
RX is H, OH, or a sugar derivatizing group;
BX is a naturally occurring or synthetic nucleoside base or blocked nucleoside base;
L is a leaving group or together L and Bx are a 2-3′
or 6-3′
pyrimidine or 8-3′
purine cyclo-nucleoside; and
Y is a stable blocking group, a solid state support, a nucleotide on a solid state support, or an oligonucleotide on a solid state support. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 15, 16, 17, 18, 19, 20, 21, 22, 24, 26, 28, 29)
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14. An oligonucleotide comprising a plurality of nucleoside units linked together via phosphate linkages, wherein:
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at least one of the nucleoside units is a non-naturally occurring nucleoside unit; and
at least two of the nucleoside units are linked via chiral phosphate linkages.
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23. An oligonucleotide comprising a plurality of nucleoside units linked together by all SP phosphotriester linkages or by all RP phosphotriester linkages.
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25. An oligonucleotide comprising a plurality of linked of nucleoside units linked together by all SP phosphoramidate linkages or by all RP phosphoamidate linkages.
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27. An oligonucleotide comprising at least 10 nucleoside units linked together by all SP alkylphosphonate linkages or by all RP alkylphosphonate linkages.
- 30. A composition of matter having the structure:
Specification