Method of preparation of known and novel 2'-modified nucleosides by intramolecular nucleophilic displacement

• US 6,090,932 A
• Filed: 10/30/1996
• Issued: 07/18/2000
• Est. Priority Date: 06/22/1994
• Status: Expired due to Fees

• Current Assignee: Sigma-Aldrich Company (Sigma-Aldrich Corporation)
• Original Assignee: Proligo, LLC
• Inventors: Sebesta, David P., Pieken, Wolfgang A., McGee, Danny P., Zhai, Yansheng
• Primary Examiner(s): Wilson, James O
• Application Number:
  US08/732,283
• Time in Patent Office: 1,357 Days
• Field of Search: 536/26.7, 536/26.8, 536/23.1, 536/22.1, 536/25.31, 536/25.32, 536/25.33, 536/25.34, 536/4.1, 544/263
• US Class Current: 536/25.3
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07H 19/06 Pyrimidine radicals
• CPC Class Codes: C07H 19/16 Purine radicals

Abstract

A method for the preparation of 2'"'"'-modified nucleosides is provided. The method comprises a novel intramolecular nucleophilic displacement reaction. Included in the invention are novel 2'"'"'-modified pyrimidines and purines prepared according to the method of the invention, novel pyrimidines and purines bearing a 2'"'"',3'"'"' heterocyclic substituent and oligonucleotides containing said 2'"'"'-modified pyrimidines and purines. The 2'"'"'-modified nucleosides are useful as anti-viral and anti-neoplastic agents.

Claims

1. A method for the synthesis of 2'"'"' modified nucleosides which comprises:

a) performing the intramolecular nucleophilic reaction of an intermediate compound having the formula;

##STR20## wherein B is a nucleobase;

W is independently selected from the group consisting of O and S;

X is selected from the group consisting of O, S, NH, and NR⁴ ;

Y is selected from the group consisting of a metal, C, Si, Se, S, B, and P;

Z is selected from the group consisting of imidazole, Cl, F, H, ² H, ³ H, OH, NHOR¹, NHOR⁵, NHNHR⁵, NHR⁵, ═

NH, CHCN, CHCl₂, SH, SR⁵, CFH₂, CF₂ H, CR²₂ Br, OR⁴ ;

R¹ is selected from the group consisting of H and an alchohol protecting group;

R² is selected from the group consisting of ═

O, ═

S, H, OH, CCl₃, CF₃, halide, optionally substituted C₁ -C₂₀ alkyl, alkenyl, aryl, C₁ -C₂₀ acyl, benzoyl, OR⁴ and esters;

R³ is selected from the group consisting of OH, H, CCl₃, CF₃, halide, C₁ -C₂₀ alkyl, alkenyl, aryl, benzoyl, esters, OR⁴, omitted as a variable when R² is ═

O or ═

S, and cyclopentadiene, cyclooctadiene, CO, trialkylphosphines if Y is metal;

R⁴ is selected from the group consisting of an optionally substituted C₁ -C₂₀ alkyl, C₂ -C₂₀ alkenyl, C₂ -C₂₀ alkynyl, and aryl, and phosphate;

R⁵ is selected from the group consisting of R², R⁴, CN, C(O)NH₂, C(S)NH₂, and SO₂ R⁴, in the presense of a base; and

b) isolating said 2'"'"' modified nucleoside.

2. The method of claim 1 wherein:

B is selected from the group consisting of a pyrimidine connected to X at the 2-position, a pyrimidine connected to X at the 6-position, and a purine connected to X at the 8-position;

W is O;

X is selected from the group consisting of O, S, and NH;

Y is selected from the group consisting of a metal, C, Si, B, and P;

Z is selected from the group consisting of imidazole, H, NHOR¹, NHOR⁵, NHNHR², NHR², ═

NH, SH, and OR⁴ ;

R¹ is selected from the group consisting of H and an alcohol protecting group;

R² is selected from the group consisting of ═

O, ═

S, OH, H, CCl₃, CF₃, halide, C₁ -C₂₀ alkyl, alkenyl, aryl, C₁ -C₂₀ acyl, benzoyl, and ester;

R³ is selected from the group consisting of ═

O, ═

S, H, CCl₃, CF₃, halide, C₁ -C₂₀ alkyl, alkenyl, aryl, benzoyl, esters and omitted as a variable;

R⁴ is selected from the group consisting of optionally substituted C₁ -C₂₀ alkyl, C₂ -C₂₀ alkenyl, C₂ -C₂₀ alkynyl, and aryl; and

R⁵ is selected from the group consisting of R² and R⁴.

3. The method of claim 1 wherein B is a pyrimidine nucleobase.

4. The method of claim 1 wherein B is a purine nucleobase.

5. The method of claim 1 further comprising:

c) preparing the 3'"'"'-phosphoramidite of said 2'"'"' modified nucleoside.

6. The method of claim 1 further comprising:

c) preparing the 5'"'"'-triphosphate of said 2'"'"' modified nucleoside.

7. The method of claim 1 further comprising:

c) preparing the 5'"'"'-diacylglycerophosphate of said 2'"'"' modified nucleoside.

56. The method of claims 1 or 2 wherein said metal is selected from Al of Sn.

8. A compound prepared according to the method comprising:

a) performing the intramolecular nucleophilic reaction of an intermediate compound having the formula;

##STR21## wherein B is a nucleobase;

W within the ring is S;

W at the 3'"'"' and 5'"'"' positions of the ring is independently selected from the group consisting of O, S, CR²₂, and NR² ;

X is selected from the group consisting of O, S, NH, and NR⁴ ;

Y is selected from the group consisting of a metal, C, Si, Se, S, B, and P;

Z is selected from the group consisting of imidazole, Cl, F, H, ² H, ³ H, OH, NHOR¹, NHOR⁵, NHNHR⁵, NHR⁵, ═

NH, CHCN, CHCl₂, SH, SR⁵, CFH₂, CF₂ H, CR² 2Br, OR⁴ ;

R¹ is selected from the group consisting of H and an alcohol protecting group;

R² is selected from the group consisting of ═

O, ═

S, H, OH, CCl₃, CF₃, halide, optionally substituted C₁ -C₂₀ alkyl, alkenyl, aryl, C₁ -C₂₀ acyl, benzoyl, OR⁴ and esters;

R³ is selected from the group consisting of OH, H, CCl₃, CF₃, halide, C₁ -C₂₀ alkyl, alkenyl, aryl, benzoyl, esters, OR⁴, omitted as a variable when R² is ═

O or ═

S, and cyclopentadiene, cyclooctadiene, CO, trialkylphosphines if Y is metal;

R⁴ is selected from the group consisting of an optionally substituted C₁ -C₂₀ alkyl, C₂ -C₂₀ alkenyl, C₂ -C₂₀ alkynyl, aryl and phosphate;

R⁵ is selected from the group consisting of R², R⁴, CN, C(O)NH₂, C(S)NH₂ and SO₂ R⁴ in the presence of a base; and

b) isolating said compound.

9. The compound prepared according to the method of claim 8, wherein said method further comprises:

c) preparing the 3'"'"'-phosphoramidite of said compound.

10. The compound prepared according to the method of claim 8, wherein said method further comprises:

c) preparing the 5'"'"'-triphosphate of said compound.

11. The compound prepared according to the method of claim 8, wherein the method further comprises:

c) preparing the 5'"'"'-diacylglycerophosphate of said compound.

12. A method for the synthesis of 2'"'"' modified pyrimidines which comprises:

a) performing the intramolecular nucleophilic reaction of an intermediate compound having the formula;

##STR22## wherein R¹ is H or an alcohol protecting group, and R² is selected from the group consisting of --C(O)NHOTBDMS, ##STR23## in the presence of a base; and

b) isolating said 2'"'"'-modified pyrimidine.

13. The method of claim 12 further comprising:

c) preparing the 3'"'"'-phosphoramidite of said 2'"'"' modified pyrimidine.

14. The method of claim 13 further comprising:

c) preparing the 5'"'"'-triphosphate of said 2'"'"' modified pyrimidine.

15. The method of claim 13 further comprising:

c) preparing the 5'"'"'-diacyl glycerophosphate of said 2'"'"' modified pyrimidine.

16. The method of claim 12 further comprising:

preparing an oligonucleotide comprising at least one of said 2'"'"' modified pyrimidines.

17. A modified pyrimidine compound having the formula:

##STR24## wherein R¹ is H or an alcohol protecting group, and R² is selected from the group consisting of --C(O)NHOTBDMS, ##STR25##

18. A 2'"'"' modified nucleoside having the formula:

wherein

B is a pyrimidine or a purine, R¹ and R² are independently selected from the group consisting of H, an alcohol protecting group, a phosphoramidite, a triphosphate or a diacyl glycerophosphate, R³ is H, alkyl, alkenyl, aryl, oligoethylene glycol or benzoyl, and R⁴ is H, alkyl, alkenyl, aryl, silyl protecting group, oligoethylene glycol or benzoyl.

19. The 2'"'"' modified nucleoside of claim 18 wherein R⁴ is selected from the group consisting of CH₃, Bn and TBDMS and R³ is CH₃.

20. An oligonucleotide comprised of at least one residue of a compound of the formula:

##STR26## wherein B is a pyrimidine or a purine, R¹ is selected from H, alkyl, alkenyl, aryl, oligoethylene glycol or benzoyl, and R² is selected from H, alkyl, alkenyl, aryl, silyl protecting group, oligoethylene glycol or benzoyl.

21. A 2'"'"' modified nucleoside having the formula:

##STR27## wherein B is a pyrimidine or purine, R¹ and R² are independently selected from the group consisting of H, an alcohol protecting group, a phosphoramidite, a triphosphate or a diacyl glycerophosphate, X is selected from the group consisting of F, Cl, Br and I, R is selected from the group consisting of H and substituted or unsubstituted alkyl, and n is 0-3.

22. A 3'"'"'-phosphoramidite of a 2'"'"' modified nucleoside of claim 21.

23. A 5'"'"'-triphosphate of a 2'"'"' modified nucleoside of claim 21.

24. A 5'"'"'-diacyl glycerophosphate of a 2'"'"' modified nucleoside of claim 21.

25. An oligonucleotide comprised of at least one residue of the 2'"'"' modified nucleoside of claim 21.

26. A compound having the formula:

##STR28## wherein B is a nucleobase;

W is independently selected from the group consisting of O and S;

Y is selected from the group consisting of a metal, C, Si, Se, S, B, and P;

Z is selected from the group consisting of Cl, F, H, ² H, ³ H, OH, NHOR¹, NHOR⁵, NHNHR⁵, NHR⁵, ═

NH, CHCN, CHCl₂, SH, CFH₂, CF₂ H, CR²₂, OR⁴, CHR² ;

R¹ is selected from the group consisting of H and an alcohol protecting group;

R² is selected from the group consisting of ═

O, ═

S, H, OH, CCl₃, CF₃, halide, optionally substituted C₁ -C₂₀ alkyl, alkenyl, aryl, C₁ -C₂₀ carbonyl, C₁ -C₂₀ acyl, benzoyl, OR⁴ and esters;

R³ is selected from the group consisting of OH, H, CCl₃, CF₃, halide, C₁ -C₂₀ alkyl, alkenyl, aryl, benzoyl, esters, OR⁴ and omitted as a variable when R² is ═

O or ═

S;

R⁴ is selected from the group consisting of an optionally substituted C₁ -C₂₀ alkyl, C₂ -C₂₀ alkenyl, C₂ -C₂₀ alkynyl, and aryl, and phosphate; and

R⁵ is selected from the group consisting of R², R⁴, CN, C(O)NH₂, peptide and C(S)NH₂.

27. The compound of claim 26 wherein:

B is selected from the group consisting of a pyrimidine connected to X at the 2-position, a pyrimidine connected to X at the 6-position, and a purine connected to X at the 8-position;

W is O

Y is selected from the group consisting of a metal, C, Si, B, and P;

Z is selected from the group consisting of imidazole, H, NHOR¹, NHOR⁵, NHNHR², NHR², ═

NH, SH, and OR⁴ ;

R¹ is selected from the group consisting of H and an alcohol protecting group;

R² is selected from the group consisting of ═

O, ═

S, OH, H, CCl₃, CF₃, halide, C₁ -C₂₀ alkyl, alkenyl, aryl, C₁ -C₂₀ acyl, benzoyl, and ester;

R³ is selected from the group consisting of H, CCl₃, CF₃, halide, C₁ -C₂₀ alkyl, alkenyl, aryl, benzoyl, esters and omitted as a variable when R² is ═

O or ═

S;

R⁴ is selected from the group consisting of optionally substituted C₁ -C₂₀ alkyl, C₂ -C₂₀ alkenyl, C₂ -C₂₀ alkynyl, and aryl; and

R⁵ is selected from the group consisting of R², R⁴ and peptide.

57. The compound of claims 8, 26, 27, 43 or 47 wherein said metal is selected from Al or Sn.

28. A compound having the formula:

##STR29## wherein B is a pyrimidine or purine;

W is selected from the group consisting of S, O, CH₂, and N; and

R¹ is H or an alcohol protecting group.

29. A method for the stereospecific reduction of the 2'"'"'-position of 2,2'"'"' anhydropyrimidine comprising:

performing the intramolecular introduction of a substituent to the 2'"'"' position of a 2,2'"'"' ambydropyrimidine via an activatable 3+ substituent wherein said activatable 3'"'"' substituent is reducing agent, and isolating said stereospecifically reduced pyrimidine.

30. A process for preparing a compound having the formula:

##STR30## comprising;

a) reacting a compound having the formula ##STR31## with a metal alkoxide, M(OR⁴)_n, wherein R¹ is selected from the group consisting of H and an alcohol protecting group;

W is independently selected from the group consisting of S and O;

X is selected from the group consisting of O, S, NH, and NR⁴ ;

B is a nucleobase;

R² is selected from the group consisting of ═

O, ═

S, H, OH, CCl₃, CF₃, halide, optionally substituted C₁ -C₂₀ alkyl, alkenyl, aryl, C₁ -C₂₀ acyl, benzoyl, OR⁴ and esters;

R⁴ is selected from the group consisting of optionally substituted hydrocarbon (C_1-19) alkyl, alkenyl, alkynyl , aryl, and phosphate;

M is a metal capable of forming a bis or higher alkoxide with OR⁴ selected from the group consisting of Mg, Be, Sr, Ba, Th, Zr, Cr, Fe, Ni, Cu, Zn, Mn, Ca, Ce, Ti, Si, Sn, Pd, and the lanthanide series; and

n is 2-6.

31. The process of claim 30 wherein M is selected from the group consisting of calcium, magnesium or cerium.

32. The process of claim 30 wherein B is selected from the group consisting of uracil, cytosine, guanine, and adenine.

33. The process of claim 30 wherein B is a pyrimidine.

34. The process of claim 30 wherein R¹ is selected from the group consisting of dimethoxytrityl or t-butlydipheny silyl.

35. The process of claim 30 wherein R⁴ is selected from the group consisting of methyl, ethyl, propyl, allyl, butyl, and pentyl.

36. The process of claim 30 wherein W and X are both O.

37. The process of claim 30 wherein X is S.

38. The process of claim 37 which further comprises:

b) desulfurizing the compound with a desulfurizing reagent.

39. The process of claim 37 wherein B is a purine.

40. The process of claim 37 wherein B is an N-protected guanine or adenine.

41. The process of claim 37 wherein B is 2,6-diaminopurine.

42. The process of claim 30 wherein the metal alkoxide used is magnesium methoxide.

43. A compound prepared according to the method comprising:

a) performing the intramolecular nucleophilic reaction of an intermediate compound having the formula;

##STR32## wherein B is a nucleobase;

W is independently selected from the group consisting of S, CR²₂, and NR² ;

X is selected from the group consisting of O, S, NH, and NR⁴ ;

Y is selected from the group consisting of a metal, C, Si, Se, S, B, and P;

Z is selected from the group consisting of imidazole, Cl, F, H, ² H, ³ H, OH, NHOR¹, NHOR⁵, NHNHR⁵, ═

NH, NHR⁵,CHCN, CHCl₂, SH, SR⁵, CFH₂, CF₂ H, CR²₂ Br, OR⁴ ;

R¹ is selected from the group consisting of H and an alcohol protecting group;

R² is selected from the group consisting of ═

O, ═

S, H, OH, CCl₃, CF₃, halide, optionally substituted C₁ -C₂₀ alkyl, alkenyl, aryl, C₁ -C₂₀ acyl, benzoyl, OR⁴ and esters;

R³ is selected from the group consisting of OH, H, CCl₃, CF₃, halide, C₁ -C₂₀ alkyl, alkenyl, aryl, benzoyl, esters, OR⁴, omitted as a variable when R² is ═

O or ═

S, and cyclopentadiene, cyclooctadiene, CO, trialkylphosphines if Y is metal;

R⁴ is selected from the group consisting of an optionally substituted C₁ -C₂₀ alkyl, C₂ -C₂₀ alkenyl, C₂ -C₂₀ alkynyl, and aryl and phosphate;

R⁵ is selected from the group consisting of R², R⁴, CN, C(O)NH₂, C(S)NH₂ and SO₂ R⁴ in the presence of a base; and

b) isolating said compound.

44. The compound of claim 43, wherein said method further comprises:

c) preparing the 3'"'"'-phosphoramidite of said compound.

45. The compound prepared according to the method of claim 43, wherein said method further comprises:

c) preparing the 5'"'"'-triphosphate of said compound.

46. The compound prepared according to the method of claim 43, wherein said method further comprises:

c) preparing the 5'"'"'-diacylglycerophosphate of said compound.

47. A compound prepared according to the method comprising:

a) performing the intramolecular nucleophilic reaction of an intermediate compound having the formula;

##STR33## wherein B is a nucleobase;

W is S;

X is selected from the group consisting of O, S, NH, and NR⁴ ;

Y is selected from the group consisting of a metal, C, Si, Se, S, B, and P;

R¹ is selected from the group consisting of H and an alcohol protecting group;

R² is selected from the group consisting of ═

O, ═

S, H, OH, CCl₃, CF₃, halide, optionally substituted C₁ -C₂₀ alkyl, alkenyl, aryl, C₁ -C₂₀ acyl, benzoyl, OR⁴ and esters;

R³ is selected from the group consisting of OH, H, CCl₃, CF₃, halide, C₁ -C₂₀ alkyl, alkenyl, aryl, benzoyl, esters, OR⁴, omitted as a variable when R² is ═

O or ═

S, and cyclopentadiene, cyclooctadiene, CO, trialkylphosphines if Y is metal;

R⁴ is selected from the group consisting of an optionally substituted C₁ -C₂₀ alkyl, C₂ -C₂₀ alkenyl, C₂ -C₂₀ alkynyl, and aryl, alcohol protecting group and phosphate;

R⁵ is selected from the group consisting of R², R⁴, CN, C(O)NH₂, C(S)NH₂ and SO₂ R⁴

R⁶ is selected from the group consisting of OR⁷, CCl₃, CF₃, optionally substituted (C₁ -C₂₀ alkyl, C₂ -C₂₀ alkenyl, C₂ -C₂₀ alkynyl, and aryl), benzoyl, esters, CN, C(O)NH₂, C(S)NH₂, OR⁴, carbonyl, thiocarbonyl and SO₂ R⁴ ;

R⁷ is selected from the group consisting of CCl₃, CF₃, optionally substituted C₁ -C₂₀ alkyl, C₂ -C₂₀ alkenyl, C₂ -C₂₀ alkynyl, and aryl, benzoyl, esters, C(O)NH₂, C(S)NH₂, and SO₂ R⁴ ;

in the presence of a base; and

b) isolating said compound.

48. A 3'"'"'-phosphoramidite of the compound of claim 47.

49. A 5'"'"'-triphosphate of the compound of claim 47.

50. A 5'"'"'-diacylglycerophosphate of the compound of claim 47.

51. A 2'"'"' modified nucleoside having the formula:

##STR34## wherein B is a pyrimidine or a purine, R¹ and R² are H or an alcohol protecting group, R³ is H and R⁴ is alkyl, alkenyl, aryl, oligoethylene glycol or benzoyl.

52. A 3'"'"'-phosphoramidite of a 2'"'"' modified nucleoside of claim 51.

53. A 5'"'"'-triphosphate of the 2'"'"' modified nucleoside of claim 51.

54. A 5'"'"'-diacyl glycerophosphate of the 2'"'"' modified nucleoside of claim 51.

55. An oligonucleotide comprised of at least one residue of the 2'"'"' modified nucleoside of claim 51.

58. A 2'"'"' modified nucleoside prepared according to the method comprising:

a) performing the intramolecular nucleophilic reaction of an intermediate compound having the formula;

##STR35## wherein B is a nucleobase;

X is selected from the group consisting of S, NH, and NR⁴ ;

Y is selected from the group consisting of a metal, C, Si, Se, S, B, and P;

Z is selected from the group consisting of imidazole, Cl, F, F, H, ² H, ³ H, OH, NHOR¹, NHOR⁵, NHNHR⁵, NHR⁵, ═

NH, CHCN, CHCl₂, SH, SR⁵, CFH₂, CF₂ H, CR²₂ Br, OR⁴ ;

R¹ is selected from the group consisting of H and an alcohol protecting group;

R² is selected from the group consisting of ═

O, ═

S, H, OH, CCl₃, CF₃, halide, optionally substituted C₁ -C₂₀ alkyl, alkenyl, aryl, C₁ -C₂₀ acyl, benzoyl, OR⁴ and esters;

R³ is selected from the group consisting of OH, H, CCl₃, CF₃, halide, C₁ -C₂₀ alkyl, alkenyl, aryl, benzoyl, esters, OR⁴, omitted as a variable when R² is ═

O or ═

S, and cyclopentadiene, cyclooctadiene, CO, trialkylphosphines if Y is metal;

R⁴ is selected from the group consisting of an optionally substituted C₁ -C₂₀ alkyl, C₂ -C₂₀ alkenyl, C₂ -C₂₀ alkynyl, and aryl and phosphate;

R⁵ is selected from the group consisting of R², R⁴, CN, C(O)NH₂, C(S)NH₂ and SO₂ R⁴ in the presence of a base; and

b) isolating said 2'"'"' modified nucleoside.

60. A 2'"'"' modified nucleoside prepared according to the method comprising:

a) performing the intramolecular nucleophilic reaction of an intermediate compound having the formula;

##STR36## wherein B is a nucleobase;

Y is selected from the group consisting of a metal, C, Si, Se, S, B, and P;

Z is selected from the group consisting of imidazole, F, ² H, ³ H, NHNHR⁵, ═

NH, CHCN, CHCl₂, SR⁵, CF₂ H, CR²₂ Br, OR⁴ ;

R¹ is selected from the group consisting of H and an alcohol protecting group;

R² is selected from the group consisting of ═

O, ═

S, H, OH, CCl₃, CF₃, halide, optionally substituted C₁ -C₂₀ alkyl, alkenyl, aryl, C₁ -C₂₀ acyl, benzoyl, OR⁴ and esters;

R³ is selected from the group consisting of OH, H, CCl₃, CF₃, halide, C₁ -₂₀ alkyl, alkenyl, aryl, benzoyl, esters, OR⁴, omitted as a variable when R² is ═

O or ═

S, and cyclopentadiene, cyclooctadiene, CO, trialkylphosphines if Y is metal;

R⁴ is selected from the group consisting of an optionally substituted C₁ -C₂₀ alkyl, C₂ -C₂₀ alkenyl, C₂ -C₂₀ alkynyl, and aryl and phosphate;

R⁵ is selected from the group consisting of R², R⁴, CN, C(O)NH₂, C(S)NH₂ and SO₂ R⁴ in the presence of a base; and

b) isolating said 2'"'"' modified nucleoside.

61. The method of claim 60 wherein said metal is selected from Al or Sn.

62. An oligonucleotide comprising at least one nucleotide prepared according to the method comprising:

a) performing the intramolecular nucleophilic reaction of an intermediate compound having the formula;

##STR37## wherein B is a nucleobase;

X is selected from the group consisting of S, NH, and NR⁴ ;

Y is selected from the group consisting of a metal C, Si, Se, S, B, and P;

Z is selected from the group consisting of imidazole, Cl, F, F, H, ² H, ³ H, OH, NHOR¹, NHOR⁵, NHNHR⁵, NHR⁵, ═

NH, CHCN, CHCl₂, SH, SR⁵, CFH₂, CF₂ H, CR²₂ Br, OR⁴ ;

R¹ is selected from the group consisting of H and an alcohol protecting group;

R² is selected from the group consisting of ═

O, ═

S, H, OH, CCl₃, CF₃, halide, optionally substituted C₁ -C₂₀ alkyl, alkenyl, aryl, C₁ -C₂₀ acyl, benzoyl, OR⁴ and esters;

R³ is selected from the group consisting of OH, H, CCl₃, CF₃, halide, C₁ -C₂₀ alkyl, alkenyl, aryl, benzoyl, esters, OR⁴, omitted as a variable when R² is ═

O or ═

S, and cyclopentadiene, cyclooctadiene, CO, trialkylphosphines if Y is metal;

R⁴ is selected from the group consisting of an optionally substituted C₁ -C₂₀ alkyl, C₂ -C₂₀ alkenyl, C₂ -C₂₀ alkynyl, and aryl and phosphate; and

R⁵ is selected from the group consisting of R², R⁴, CN, C(O)NH₂, C(S)NH₂ and SO₂ R⁴ in the presence of a base.

63. An oligonucleotide comprising at least one nucleotide prepared according to the method comprising:

a) performing the intramolecular nucleophilic reaction of an intermediate compound having the formula;

##STR38## wherein B is a nucleobase;

Y is selected from the group consisting of a metal, C, Si, Se, S, B, and P;

Z is selected from the group consisting of imidazole, F, ² H, ³ H, NHNHR⁵, ═

NH, CHCN, CHCl₂, SR⁵, CF₂ H, CR²₂ Br, OR⁴ ;

R¹ is selected from the group consisting of H and an alcohol protecting group;

R² is selected from the group consisting of ═

O, ═

S, H, OH, CCl₃, CF₃, halide, optionally substituted C₁ -C₂₀ alkyl, alkenyl, aryl, C₁ -C₂₀ acyl, benzoyl, OR⁴ and esters;

R³ is selected from the group consisting of OH, H, CCl₃, CF₃, halide, C₁ -C₂₀ alkyl, alkenyl, aryl, benzoyl, esters, OR⁴, omitted as a variable when R² is ═

O or ═

S, and cyclopentadiene, cyclooctadiene, CO, trialkylphosphines if Y is metal;

R⁴ is selected from the group consisting of an optionally substituted C₁ -C₂₀ alkyl, C₂ -C₂₀ alkenyl, C₂ -C₂₀ alkynyl, and aryl and phosphate; and

R⁵ is selected from the group consisting of R², R⁴, CN, C(O)NH₂, C(S)NH₂ and SO₂ R⁴ in the presence of a base.

64. A method for the synthesis of 2'"'"' modified nucleosides which comprises:

a) performing the intramolecular nucleophilic reaction of an intermediate compound having the formula;

##STR39## wherein B is a nucleobase;

X is selected from the group consisting of O, S, NH, and NR⁴ ;

Y is selected from the group consisting of a metal, C, Si, Se, S, B, and P;

Z is selected from the group consisting of imidazole, Cl, F, H, ² H, ³ H, OH, NHOR¹, NHOR⁵, NHNHR⁵, NHR⁵, ═

NH, CHCN, CHCl₂, SH, SR⁵, CFH₂, CF₂ H, CR²₂ Br, OR⁴ ;

R¹ is selected from the group consisting of H and an alcohol protecting group;

R² is selected from the group consisting of ═

O, ═

S, H, OH, CCl₃, CF₃, halide, optionally substituted C₁ -C₂₀ alkyl, alkenyl, aryl, C₁ -C₂₀ acyl, benzoyl, OR⁴ and esters;

R³ is selected from the group consisting of OH, H, CCl₃, CF₃, halide, C₁ -C₂₀ alkyl, alkenyl, aryl, benzoyl, esters, OR⁴, omitted as a variable when R² is ═

O or ═

S, and cyclopentadiene, cyclooctadiene, CO, trialkylphosphines if Y is metal;

R⁴ is selected from the group consisting of an optionally substituted C₁ -C₂₀ alkyl, C₂ -C₂₀ alkenyl, C₂ -C₂₀ alkynyl, aryl, and phosphate;

R⁵ is selected from the group consisting of R², R⁴, CN, C(O)NH₂, C(S)NH₂, and SO₂ R⁴, in the presence of a base; and

b) isolating said 2'"'"' modified nucleoside.

59. The method of claim 65 wherein said metal is selected from Al or Sn.

65. The method of claim 64 further comprising:

c) preparing an oligonucleotide comprising at least one of said 2'"'"' modified nucleosides.