Compounds and methods for synthesis of bicyclic nucleic acid analogs
View Patent ↗The present invention provides compounds and methods of using them for preparing bicyclic nucleosides. The bicyclic nucleosides are useful for preparing chemically modified oligomeric compounds. Oligomeric compounds comprising these bicyclic nucleosides have enhanced properties such as increased nuclease resistance.
1. A compound having formula I:
wherein:
R 1 is H or a hydroxyl protecting group;
R 2 is H or a hydroxyl protecting group;
R 3 and R 4 are each independently C 1 -C 6 alkyl or substituted C 1 -C 6 alkyl; and
Q is an optionally substituted polycyclylic aromatic or heteroaromatic radical.
2. The compound of claim 1 wherein said optionally substituted polycyclylic aromatic or heteroaromatic radical comprises from 2 to about 5 fused rings.
3. The compound of claim 2 wherein Q comprises two fused rings.
4. The compound of claim 2 wherein Q comprises at least one heteroaromatic ring.
5. The compound of claim 3 wherein Q includes only carbon and hydrogen atoms.
6. The compound of claim 5 wherein Q is 2-naphthalenyl.
7. The compound of claim 1 wherein Q is pyrenyl, purinyl, acridinyl, xanthenyl, fluorenyl, phenanthrenyl, anthracenyl, quinolinyl, isoquinolinyl, naphthalenyl, perylenyl, phenanthridinyl, phenazinyl, anthraquinonyl, azulenyl or dibenzofuranyl.
8. The compound of claim 1 wherein R 1 and R 2 are each H.
9. The compound of claim 1 wherein R 1 and R 2 are each, independently, a hydroxyl protecting group.
10. The compound of claim 1 wherein one of R 1 and R 2 is H and the other of R 1 and R 2 is a hydroxyl protecting group.
11. The compound of claim 1 wherein R 3 and R 4 are each, independently, C 1 -C 6 alkyl.
12. The compound of claim 11 wherein R 3 and R 4 are each methyl.
13. The compound of claim 1 wherein:
R 1 is a hydroxyl protecting group;
R 2 is H; and
R 3 and R 4 are each methyl.
14. The compound of claim 13 wherein Q is 2-napthalenyl.
15. The compound of claim 1 having the configuration:
16. The compound of claim 15 having the formula:
17. The compound of claim 1 having the configuration:
18. The compound of claim 17 having the formula:
19. A method of preparing a bicyclic nucleoside comprising a bridge between the 4′ and 2′ ring carbons using the compound of claim 1 .
20. The method of claim 19 wherein said bridge comprises from 2 to 3 bivalent subunits.
21. The method of claim 20 wherein said bivalent subunits are each, independently, selected from —CR 5 R 6 —, —C(═O)—, —NR 5 , and —O—, wherein each R 5 and R 6 is, independently, H, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, a substituted heteroatom (O, S or N) or a protecting group.
22. The method of claim 21 wherein said bivalent subunits form a bridge having the formula:
—CH 2 —O—, —(CH 2 ) 2 —O—, —CH 2 —O—N(R 5 )—, —CH 2 —N(R 5 )—O—, CH 2 —N(R 5 )—CH 2 —, —CH(R 5 )—O—, —CH 2 —N(R 5 )—N(R 5 )— or —C(═O)—N(R 5 )—CH 2 —.
23. The method of claim 19 wherein said compound has the configuration:
24. The method of claim 23 wherein said compound has the formula:
25. The method of claim 19 wherein said compound has the configuration:
26. The method of claim 25 wherein said compound has the formula: