2′-silyl containing thiocarbonate protecting groups for RNA synthesis

• US 7,999,087 B2
• Filed: 11/15/2007
• Issued: 08/16/2011
• Est. Priority Date: 11/15/2006
• Status: Active Grant

• Current Assignee: Agilent Technologies, Inc., The Board of Regents of the University of Colorado (University of Colorado System)
• Original Assignee: Agilent Technologies, Inc.
• Inventors: Caruthers, Marvin H., Dellinger, Geraldine F., Dellinger, Douglas J., Sierzchala, Agnieska
• Primary Examiner(s): McIntosh, III; Traviss C
• Application Number:
  US11/985,598
• Publication Number:
  US 20080227964A1
• Time in Patent Office: 1,370 Days
• Field of Search: None
• US Class Current: 536/22.1
• CPC Class Codes: C07H 19/00 Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
• CPC Class Codes: Y02P 20/55 Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

Nucleoside monomers, nucleic acids, e.g., oligonucleotides and polynucleotides, methods of making each, methods of deprotecting each, and the like are disclosed herein. Aspects of the invention include 2′ silyl containing thiocarbonate protecting groups. Corresponding compositions and methods are provided.

Claims

1. A nucleoside monomer comprising a 2′

silyl containing thiocarbonate protecting group.

2. The nucleoside monomer according to claim 1, wherein said nucleoside monomer has the structure:

3. The nucleoside monomer according to claim 2, wherein Z has the structure:

4. The nucleoside monomer according to claim 3, wherein said nucleoside monomer has the structure of Formula (IIIa);

5. The nucleoside monomer according to claim 3, wherein said nucleoside monomer has the structure of Formula (IIIb);

6. The nucleoside monomer according to claim 3, wherein B^P is protected by a silyl containing thiocarbonate protecting group.

7. A method of synthesizing a 2′

protected nucleoside monomer, said method comprising;

contacting

a nucleoside monomer having the structure;

8. The method according to claim 7, wherein Z has the structure:

9. The method according to claim 8, wherein R¹ and R² are linked to form a Markewicz protecting group.

10. The method according to claim 9, wherein said Markewicz protecting group is a 1,3-tetraisopropyldisiloxane (TIPS) group.

11. The method according to claim 10, wherein said method further comprises removing said Markewicz protecting group.

12. A nucleic acid comprising the structure:

13. The nucleic acid according to claim 12, wherein Z has the structure:

14. A method of synthesizing a nucleic acid, comprising:

(a) providing a nucleoside residue having an unprotected hydroxyl group and a 2′

protected nucleoside monomer, wherein said 2′

protected nucleoside monomer comprises a 2′

silyl containing thiocarbonate protecting group; and

(b) contacting said nucleoside residue and said 2′

protected nucleoside monomer under conditions sufficient to covalently bond said 2′

protected nucleoside monomer to said nucleoside residue to produce said nucleic acid.

15. The method according to claim 14, wherein said method further comprises exposing said nucleic acid to an oxidizing and deprotecting agent.

16. The method according to claim 15, wherein said method further comprises reiterating said contacting step at least once.

17. The method according to claim 16, further comprising removing said 2′

silyl containing thiocarbonate protecting group.

18. The method according to claim 14, wherein said nucleoside residue is covalently bonded to a solid support.

19. The method according to claim 18, wherein said method further comprises cleaving said nucleic acid from said solid support to produce a free nucleic acid.

20. The method according to claim 19, wherein said method further comprises combining said free nucleic acid with a pharmaceutically acceptable vehicle.

21. The method according to claim 14, wherein said method further comprises chemically modifying said nucleic acid to produce a modified nucleic acid.

22. The method according to claim 21, wherein said method further comprises combining said modified nucleic acid with a pharmaceutically acceptable vehicle.