Synthesis of protected 3′-amino nucleoside monomers
Orthogonally protected 3′-amino nucleoside monomers and efficient methods for their synthesis are described. The methods employ selective protection of the 3′-amino group in the presence of the unprotected nucleoside base.
1. A method of preparing an thymidine monomer having a free 5′-hydroxyl group and a protected 3′-amino group comprising:
(a) selectively reacting a 3′-amino group of a 3′-amino-3′-deoxy thymidine monomer in which the 5′-hydroxyl group and 3′-amino group are unprotected with a first protecting group, wherein the first protecting group is (i) a triarylmethy group or (ii) fluorenylmethoxycarbonyl (Fmoc) or a derivative thereof.
2. The method of claim 1 , wherein said triarylmethyl group is triphenylmethyl (trityl), monomethoxytrityl (MMT) or dimethoxytrityl (DMT).
3. The method of claim 1 , wherein the first protecting group is fluorenylmethoxycarbonyl (Fmoc) or a derivative thereof.
4. The method of claim 3 , wherein the first protecting group is removable with DBU or piperidine.
5. The method of claim 1 , wherein the method further comprises phosphitylation of the 5′-hydroxyl group.
6. The method of claim 2 , wherein said triarylmethyl group is triphenylmethyl (trityl) or monomethoxytrityl (MMT).
7. A method of preparing a thymidine monomer having a phosphitylated 5′-hydroxyl group and a protected 3′-amino group comprising:
(a) selectively reacting a 3′-amino group of a 3′-amino-3′-deoxy thymidine monomer in which the 5′-hydroxyl group and the 3′-amino group are unprotected with a triarylmethyl protecting group; and
(b) phosphitylating the 5′-hydroxyl group.
8. The method of claim 7 , wherein said triarylmethyl protecting group is triphenylmethyl (trityl), monomethoxytrityl (MMT) or dimethoxytrityl (DMT).
9. The method of claim 8 , wherein said triarylmethyl protecting group is triphenylmethyl (trityl) or monomethoxytrityl (MMT).
10. A method of preparing a thymidine monomer having a phosphitylated 5′-hydroxyl group and a protected 3′-amino group comprising:
(a) selectively reacting a 3′-amino group of a 3′-amino-3′-deoxy thymidine monomer in which the 5′-hydroxyl group and the 3′-amino group are unprotected with a fluorenylmethoxycarbonyl (Fmoc) protecting group; and
(b) phosphitylating the 5′-hydroxyl group.