Method of making oligonucleotides and oligonucleotide analogs using phospholanes and enantiomerically resolved phospholane analogues
First Claim
1. A method of synthesizing a P-chiral oligonucleotide phosphorothioate of a predetermined length, the P-chiral oligonucleotide comprising a sequence of nucleosides or nucleoside analogs and phosphorothioate or phosphodiester linkages, the phosphorothioate linkages being Rp chiral or Sp chiral, the method comprising the steps of:
- (a) providing a first nucleoside or nucleoside analog attached to a solid phase support, the first nucleoside or nucleoside analog having a protected hydroxyl;
(b) deprotecting the protected hydroxyl to form a free hydroxyl;
(c) reacting with the free hydroxyl a synthon selected from the group defined by the formula;
##STR9## wherein;
RI is a hydroxyl protecting group;
B is a purine or a pyrimidine;
D is hydrogen, halogen, hydroxyl, or --OR'"'"', wherein R'"'"' is alkyl having from 1 to 3 carbon atoms or a 2'"'"'-hydroxyl protecting group;
D'"'"' is hydrogen, hydroxyl, or --OR" such that R" is a 3'"'"'-hydroxyl protecting group;
X is sulfur, Y is oxygen, and Z is sulfur; and
R3, R4, R5, and R6 are separately hydrogen or alkyl having from 1 to 4 carbon atoms or are separately or together with the carbon atoms to which they are attached aryl or alkyl-substituted aryl having from 6 to 12 carbon atoms; and
(d) repeating steps (b) and (c) until the predetermined length of the P-chiral oligonucleotide phosphorothioate is achieved.
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Abstract
Methods and compounds are provided for solid phase synthesis of oligonucleotides and related polymers by condensing protected monomer-O-[1,3,2-dichalcogen-substituted-phospholane] synthons in the presence of a catalytic base. Compounds of the invention include 2-N-substituted-1,3,2-dichalcogen-substituted-phospholane precursors of the above synthons, the protected monomer-O-[1,3,2-dichalcogen-substituted-phospholane] synthons, and P-chiral oligonucleotides and related P-chiral polymers.
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Citations
7 Claims
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1. A method of synthesizing a P-chiral oligonucleotide phosphorothioate of a predetermined length, the P-chiral oligonucleotide comprising a sequence of nucleosides or nucleoside analogs and phosphorothioate or phosphodiester linkages, the phosphorothioate linkages being Rp chiral or Sp chiral, the method comprising the steps of:
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(a) providing a first nucleoside or nucleoside analog attached to a solid phase support, the first nucleoside or nucleoside analog having a protected hydroxyl; (b) deprotecting the protected hydroxyl to form a free hydroxyl; (c) reacting with the free hydroxyl a synthon selected from the group defined by the formula;
##STR9## wherein;
RI is a hydroxyl protecting group;B is a purine or a pyrimidine; D is hydrogen, halogen, hydroxyl, or --OR'"'"', wherein R'"'"' is alkyl having from 1 to 3 carbon atoms or a 2'"'"'-hydroxyl protecting group; D'"'"' is hydrogen, hydroxyl, or --OR" such that R" is a 3'"'"'-hydroxyl protecting group; X is sulfur, Y is oxygen, and Z is sulfur; and R3, R4, R5, and R6 are separately hydrogen or alkyl having from 1 to 4 carbon atoms or are separately or together with the carbon atoms to which they are attached aryl or alkyl-substituted aryl having from 6 to 12 carbon atoms; and (d) repeating steps (b) and (c) until the predetermined length of the P-chiral oligonucleotide phosphorothioate is achieved. - View Dependent Claims (2, 3, 4, 5, 6, 7)
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Specification