Nucleoside modifications by palladium catalyzed methods

• US 6,846,918 B2
• Filed: 01/24/2003
• Issued: 01/25/2005
• Est. Priority Date: 09/25/1998
• Status: Expired due to Fees

• Current Assignee: Gilead Sciences Inc.
• Original Assignee: Gilead Sciences Inc.
• Inventors: Tu, Chi, Beckvermit, Jeffrey T.
• Primary Examiner(s): Barts, Samuel
• Assistant Examiner(s): Lewis, Patrick T.
• Application Number:
  US10/351,468
• Publication Number:
  US 20040034212A1
• Time in Patent Office: 732 Days
• Field of Search: 536/22.1, 536/25.3, 536/28.1, 536/28.2, 536/28.4, 536/28.6, 536/28.7
• US Class Current: 536/22.1
• CPC Class Codes: C07H 19/06 Pyrimidine radicals

Abstract

This invention discloses a method for the preparation of 2′-modified nucleosides, using a palladium catalyst and an alkene functionalized with a heteroatom. Included in the invention are the novel pyrimidines and purines that can be prepared according to the method of the invention and oligonucleotides containing said modified pyrimidines and purines.

Claims

1. An oligonucleotide comprising a purine nucleoside modified at the 2-, 6- or 8-position of the purine ring prepared according to a method comprising comprising the steps of:

reacting a purine starting material containing a leaving group attached to the 2-, 6- or 8-position of said purine starting material with a functionalized alkene having the formula;

wherein

Y is selected from the group consisting of —

CHROH, —

C(O)R, —

COOR, —

C(O)NRR′

, —

CN, a substituted or unsubstituted aryl group or heterocylic group, selected from the group consisting of phenyl, 2-,3- or 4-hydroxyphenyl, 2-,3- or 4-pyridyl and 1H-tetrazol-5-yl;

R and R′

are independently selected from the group consisting of H, substituted or unsubstituted alkyl, alkenyl and aryl; and

n is an integer from 0-15

in the presence of a palladium catalyst of the general formula PdL₃ or PdL₄, wherein L is a ligand of palladium; and

isolating said modified nucleoside or nucleotide.

2. The oligonucleotide of claim 1 wherein said oligonucleotide is a ribonucleic acid.

3. The oligonucleotide of claim 1 wherein said oligonucleotide is a deoxyribonucleic acid.

4. An oligonucleotide comprising a pyrimidine nucleoside modified at the 5-or 6-position of the pyrimidine ring prepared according to a method comprising the steps of:

reacting a pyrimidine starting material containing a leaving group attached to the 5- or 6-position of said pyrimidine starting material with a functionalized alkene having the formula;

wherein

Y is selected from the group consisting of —

C(O)R, —

COOR, —

C(O)NRR′

, —

CN, phenyl, 2-, 2- or 4- hydroxyphenyl, 2-,3- or 4-pyridyl and 1H-tetrazol-5-yl;

R and R′

are independently selected from the group consisting of H, alkyl, alkenyl and aryl; and

n is an integer from 1-15 in the presence of a palladium catalyst of the general formula PdL₃ or PdL₄, wherein L is a ligand of palladium to produce a pyrimidine nucleoside having the following formula;

wherein

Z is selected from the group consisting of H, ribose, deoxyribose, dideoxyribose and derivatives thereof; and

isolating said modified nucleoside.

5. The oligonucleotide of claim 4 wherein said oligonucleotide is a ribonucleic acid.

6. The oligonucleotide of claim 4 wherein said oligonucleotide is a deoxyribonucleic acid.

7. An oligonucleotide comprising a pyrimidine nucleoside modified at the 5-or 6-position of the pyrimidine ring prepared according to a method comprising the steps of:

reacting a pyrimidine starting material containing a leaving group attached to the 5- or 6-position of said pyrimidine starting material with a functionalized alkene having the formula;

wherein

Y is CHROH;

R is independently selected from the group consisting of H, alkyl, alkenyl and aryl; and

n is an integer from 0-15 in the presence of a palladium catalyst of the general formula PdL₃ or PdL₄, wherein L is a ligand of palladium to produce a pyrimidine nucleoside having the following formula;

wherein

Z is selected from the group consisting of H, ribose, deoxyribose, dideoxyribose and derivatives thereof; and

isolating said modified nucleoside.

8. The oligonucleotide of claim 7 wherein said oligonucleotide is a ribonucleic acid.

9. The oligonucleotide of claim 7 wherein said oligonucleotide is a deoxyribonucleic acid.