Synthesis of [;2.2.1];bicyclo nucleosides

• US 6,639,059 B1
• Filed: 03/24/2000
• Issued: 10/28/2003
• Est. Priority Date: 03/24/1999
• Status: Expired due to Term

• Current Assignee: Qiagen GmbH (Qiagen NV)
• Original Assignee: Exiqon A/S (Qiagen NV)
• Inventors: Kochkine, Alexei, Fensholdt, Jef, Pfundheller, Henrik M.
• Primary Examiner(s): Richter, Johann
• Assistant Examiner(s): CRANE, LAWRENCE E
• Application Number:
  US09/534,769
• Time in Patent Office: 1,313 Days
• Field of Search: 536/4.1, 536/18.6, 536/27.11, 536/27.14
• US Class Current: 536/4.1
• CPC Class Codes: C07H 19/06 Pyrimidine radicals
• CPC Class Codes: C07H 19/16 Purine radicals

Abstract

A synthesis of [2.2.1]bicyclo nucleosides which is shorter and provides higher overall yields proceeds via the key intermediate of the general formula III, wherein R₄ and R₅ are, for instance, sulfonates and R₇ is, for instance, a halogen or an acetate. From compounds of the general formula II, such as 3-O-aryl-4-C-hydroxymethyl-1,2-O-isopropylidene-α-D-ribofuranose, intermediates of the general formula III are suitable for coupling with silylated nucleobases. Upon one-pot base-induced ring-closure and desulfonation of the formed [2.2.1]bicyclo nucleoside, a short route to each the LNA (Locked Nucleic Acid) derivatives of adenosine, cytosine, uridine, thymidine and guanidine is demonstrated. The use of the 5′-sulfonated ring-closed intermediate also allows for synthesis of 5′-amino- and thio-LNAs.

Claims

1. A method for the synthesis of a compound of the general formula II:

wherein

R₁ is selected form optionally substituted aryl(C_1-6-alkyl), optionally substituted tetrahydropyran-2-yl, optionally substituted arylcarbonyl and optionally substituted aryl;

each of the substituents R₂ and R₃ is independently selected from hydrogen, optionally substituted C_1-6-alkyl, optionally substituted aryl, and optionally substituted aryl(C_1-6-alkyl), or R₂ and R₃ together designate C_3-7-alkylene, with the proviso that R₂ and R₃ are not both hydrogen; and

each of the substituents R₄ and R₅ independently is R′

SO₂O—

wherein R′

is selected from optionally substituted alkyl and optionally substituted aryl;

said method comprising the following step;

treatment of a compound of the general formula I;

wherein

R₁ is selected form optionally substituted aryl(C_1-6-alkyl), optionally substituted tetrahydropyran-2-yl, optionally substituted arylcarbonyl and optionally substituted aryl;

each of the substituents R₂ and R₃ is independently selected from hydrogen, optionally substituted C_1-6-alkyl, optionally substituted aryl, and optionally substituted aryl(C_1-6-alkyl), or R₂ and R₃ together designate C_3-7-alkylene, with the proviso that R₂ and R₃ are not both hydrogen; and

with R′

SO₂X wherein R′

is selected from optionally substituted C_1-6-alkyl and optionally substituted aryl, and X designates halogen.

2. A method according to claim 1, wherein R₁ is selected from benzyl, ortho-, meta-, and para-methylbenzyl, 2-chlorobenzyl, 4-phenylbenzyl, tetrahydropyran-2-yl, benzoyl and phenyl.

3. A method according to claim 1, wherein each of the substituents R₂ and R₃ independently represent hydrogen, methyl, trifluoromethyl, ethyl, propyl, iso-propyl, butyl, t-butyl, pentyl, cyclopentyl, hexyl, cyclohexyl, phenyl, benzyl, phenylethyl, ortho-, meta-, or para-methylbenzyl, or 2-chlorobenzyl, or R₂ and R₃ together designate 1,5-pentylene.

4. A method according to claim 1, wherein R′

is selected from the group consisting of methyl, trifluoromethyl, ethyl, 2,2,2-trifluoroethyl, propyl, iso-propyl, butyl, nonafluorobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl, benzyl, ortho-, meta-, and para-methylbenzyl, 2-chlorobenzyl, phenyl, ortho-, meta-, and para-bromophenyl, and para-nitrophenyl, and X is a halogen.

5. A method according to claim 4, wherein R′

SO₂X is selected from methanesulfonyl chloride, trifluoromethanesulfonyl chloride, ethanesulfonyl chloride, 2,2,2-trifluoroethanesulfonyl chloride, propanesulfonyl chloride, iso-propanesulfonyl chloride, butanesulfonyl chloride, nonafluorobutanesulfonyl chloride, cyclopentanesulfonyl chloride, hexanesulfonyl chloride, cyclohexanesulfonyl chloride, α

-toluenesulfonyl chloride, p-toluenesulfonyl chloride, p-bromobenzenesulfonyl chloride and p-nitrobenzenesulfonyl chloride.

6. A method according to claim 1, wherein R′

SO₂X is methanesulfonyl chloride.

7. A method according to claim 1, wherein the molar ratio between compound I and R′

SO₂X is in the range of 1;

2 to 1;

10.

8. A method according to claim 7, wherein the molar ratio between compound I and R′

SO₂X is in the range of 1;

2-1;

4.

9. A method according to claim 1, wherein R₁ represents benzyl and R₂ and R₃ both represent methyl.

10. A compound of the general formula II:

wherein

R₁ is selected from optionally substituted aryl(C_1-6-alkyl), optionally substituted tetrahydropyran-2-yl, optionally substituted arylcarbonyl and optionally substituted aryl; and

each of the substituents R₂ and R₃ is independently selected from hydrogen, optionally substituted C_1-6-alkyl, optionally substituted aryl, and optionally substituted aryl(C_1-6-alkyl), or R₂ and R₃ together designate C_3-7-alkylene, with the proviso that R₂ and R₃ are not both hydrogen; and

each of the substituents R₄ and R₅ independently is R′

SO₂O—

wherein R′

is selected from optionally substituted alkyl and optionally substituted aryl.

11. A compound according to claim 10, wherein each of the substituents R₄ and R₅ are selected from methanesulfonyl, trifluoromethanesulfonyl, ethanesulfonyl, 2,2,2-trifluoroethanesulfonyl, propanesulfonyl, iso-propanesulfonyl, butanesulfonyl, nonafluorobutanesulfonyl, pentanesulfonyl, cyclopentanesulfonyl, hexanesulfonyl, cyclohexanesulfonyl, α

-toluenesulfonyl, 2-chloro-α

-toluenesulfonyl, ortho-, meta-, and para-toluenesulfonyl, benzenesulfonyl, ortho-, meta-, and para-bromobenzenesulfonyl, and ortho-, meta-, and para-nitrobenzenesulfonyl.

12. A compound of the general formula III:

wherein

R₁ is selected form optionally substituted aryl(C_1-6-alkyl), optionally substituted tetrahydropyran-2-yl, optionally substituted arylcarbonyl and optionally substituted aryl; and

each of the substituents R₄ and R₅ independently is R′

SO₂O—

wherein R′

is selected from optionally substituted alkyl and optionally substituted aryl; and

R₆ is selected from hydrogen, optionally substituted (C_1-6-alkyl)carbonyl, optionally substituted arylcarbonyl, optionally substituted aryl(C_1-6-alkyl), optionally substituted C_1-6-alkyl, and tri(alkyl/aryl)silyl; and

R₇ is selected from optionally substituted (C_1-6-alkyl)carbonyloxy, optionally substituted C_1-6-alkoxy, halogen, optionally substituted arylthio, optionally substituted C_1-6-alkylthio, and optionally substituted aryloxy.

13. A compound according to claim 12, wherein R₁ is selected from benzyl, ortho-, meta-, and para-methylbenzyl, 2-chlorobenzyl, tetrahydropyran-2-yl, benzoyl and phenyl.

14. A compound according to claim 12, wherein each of the substituents R₄ and R₅ are selected from methanesulfonyl, trifluoromethanesulfonyl, ethanesulfonyl, 2,2,2-trifluoroethanesulfonyl, propanesulfonyl, iso-propanesulfonyl, butanesulfonyl, nonafluorobutanesulfonyl, pentanesulfonyl, cyclopentanesulfonyl, hexanesulfonyl, cyclohexanesulfonyl, α

-toluenesulfonyl, 2-chloro-α

-toluenesulfonyl, ortho-, meta-, and para-toluenesulfonyl, benzenesulfonyl, ortho-, meta-, and para-bromobenzenesulfonyl, and ortho-, meta-, and para-nitrobenzenesulfonyl.

15. A compound according to claim 12, wherein R₆ represents acetyl, benzoyl, m-trifluoromethylbenzoyl or benzyl.

16. A compound according to claim 12, wherein R₇ represents acetyloxy, methoxy, ethoxy, chloride, fluroride, bromide, iodide or —

SC₆H₅.

17. A compound according to claim 12, wherein R₁ represents benzyl, R₄ and R₅ represent methanesulfonyl, R₆ represents acetyl, and R₇ represents acetyloxy.