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A process of manufacturing protected nucleosides comprises reacting a nucleoside with a protecting reagent in the presence of a regioselective activator to produce a regioselectively protected nucleoside. In some embodiments of the inventive method, an optionally substituted trityl or optionally sub

A process of manufacturing protected nucleosides comprises reacting a nucleoside with a protecting reagent in the presence of a regioselective activator to produce a regioselectively protected nucleoside. In some embodiments of the inventive method, an optionally substituted trityl or optionally substituted pixyl group is selectively added to the 5'-O-position of a nucleoside in the presence of lutidine as activator or activator/solvent. The inventive method results in improved selectivity of the 5'-O-position over the 3'-O-position, thereby improving overall product yield and purity, and permitting simplified purification protocols, in some cases obviating the need for chromatography to produce a purified protected nucleoside suitable for automated synthesis of oligonucleotides, such as primers, probes and antisense molecules.

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We claim: 1. A process comprising contacting a nucleoside with a hindered aryl amine activator and a protecting reagent to produce a regioselectively 5' mono-protected nucleoside. 2. The process of claim 1, wherein the hindered aryl amine activator has the formula: wherein each of R1 and R2 is

We claim: 1. A process comprising contacting a nucleoside with a hindered aryl amine activator and a protecting reagent to produce a regioselectively 5' mono-protected nucleoside. 2. The process of claim 1, wherein the hindered aryl amine activator has the formula: wherein each of R1 and R2 is H, alkyl or substituted alkyl, at least one of R1 and R2 being other than H, and each R3 is independently H, alkyl or substituted alkyl, or two adjacent R3 moieties are taken together to form a fused aromatic or aliphatic ring. 3. The process of claim 2, wherein R1 is alkyl and R2 is alkyl. 4. The process of claim 3, wherein R1 is methyl or ethyl. 5. The process of claim 4, wherein R2 is methyl or ethyl. 6. The process of claim 5, wherein R1 is methyl and R2 is methyl. 7. The process of claim 3, wherein each R3 is H. 8. The process of claim 2, wherein R1 is alkyl, R 2 is H, and R3 is alkyl or substituted alkyl. 9. The process of claim 2, wherein R1 is C3-C6 alkyl, R2 is H and R3 is H. 10. The process of claim 2, wherein two adjacent R3 moieties are taken together to form a fused aromatic ring. 11. The process of claim 10, wherein the fused aromatic ring is a pyrido ring. 12. The process of claim 2, wherein two adjacent R3 moieties are taken together to form an aliphatic ring. 13. The process of claim 2, wherein the hindered aryl amine activator is 2,6-dimethylpyridine. 14. The process of claim 1, wherein the nucleoside has the formula: wherein Bx is a nucleobase; R2' is H, OH, reversibly protected OH, a 2'-substitutent, or together with R4' forms a bridge; R3' is H or a substituent; R4' is H, alkyl, substituted alkyl, or together with R2' or R5' forms a bridge; R5' is H or together with R4' forms a bridge; Q' is O, S, NH, N-alkyl or CH2; and q' is 0 or 1. 15. The process of claim 14, wherein the nucleoside has the formula: wherein R2' is H, OH, reversibly protected OH, a 2'-substituent, or together with R4' forms a bridge; R3' is H or a substituent; R4' is H, alkyl, substituted alkyl, or together with R2' forms a bridge. 16. The process of claim 15, wherein R2' is H or a substituent, or together with R4' forms a bridge; R3' is H, R4' is H or together with R2' forms a bridge. 17. The process of claim 16, wherein R2' is H or a substituent and R4' is H. 18. The process of claim 17, wherein R2' is H, methoxy or methoxyethoxy. 19. The process of claim 15, wherein the nucleoside has the formula: wherein R2' is H, OH, protected OH or a 2'-substituent; and Z5 is H or a ring substituent. 20. The process of claim 19, wherein R2' is H, OH, protected OH, OCH3 or OCH2CH2OCH3; and Z5 is alkyl or alkynyl. 21. The process of claim 19, wherein R2' is H, OCH3 or OCH2CH2OCH3. 22. The process of claim 19, wherein Z5 is methyl or propynyl. 23. The process of claim 1, wherein the protected nucleoside has the formula: wherein Bx is a nucleobase; R2' is H, OH, reversibly protected OH, a 2'-substitutent, or together with R4' forms a bridge; R3' is H or a substituent; R4' is H, alkyl, substituted alkyl, or together with R2' or R5' forms a bridge; R5' is H or together with R4' forms a bridge; Q' is O, S, NH, N-alkyl, CH2; q' is 0 or 1, and bg is a protecting group. 24. The process of claim 23, wherein the protected nucleoside has the formula: wherein R2' is H, OH, reversibly protected OH, a 2'-substitutent, or together with R4' forms a bridge; R3' is H or a substituent; R4' is H, alkyl, substituted alkyl, or together with R2' forms a bridge, and bg is a protecting group. 25. The process of claim 24, wherein bg is an optionally substituted trityl group, an optionally substituted pixyl group, or an optionally substituted thiopixyl group. 26. The process of claim 25, wherein bg is a substituted trityl group selected from 4-methoxytrityl and 4,4'-dimethoxytrityl. 27. The process of claim 26, wherein bg is 4,4'-dimethoxytrityl. 28. The process of claim 24, wherein the protected nucleoside is of the formula: wherein bg is a 5'-protecting group; R2' is H, OH, protected OH or a 2'-substituent; and Z5 is H, a ring substituent, or together with Z5 form a ring, which may optionally be fused to one or more additional rings, and which optionally may be further substituted, or a tautomeric equivalent thereof. 29. The process of claim 28, wherein R2' is H, OH, protected OH, OCH3 or OCH2CH2OCH3; and Z5 is alkyl or alkynyl. 30. The process of claim 29, wherein R2' is H, OCH3 or OCH2CH2OCH3. 31. The process of claim 30, wherein Z5 is methyl or propynyl. 32. The process of claim 31, wherein bg is 4,4'-dimethoxytrityl. 33. The process of claim 28, wherein Bx is 5-methyluracil. 34. The process of claim 28, further comprising the steps of: (a) adding to the protected nucleoside a water-immiscible organic solvent to form a first organic phase; (b) contacting the first organic phase with a basic aqueous phase, whereby the protected nucleoside partitions into the basic aqueous phase; (c) acidifying the basic aqueous phase to form an acidic aqueous phase; and (d) extracting the nucleoside into a second organic phase. 35. The process of claim 34, wherein the basic aqueous phase has a pH in the range of about 8 to about 16. 36. The process of claim 34, wherein the acidic aqueous phase has a pH in the range of about 4.5 to about 6.8. 37. The process of claim 34, wherein the first organic phase comprises toluene. 38. The process of claim 28, further comprising reacting the protected nucleoside with a phosphitylating reagent to form a nucleoside phosphoramidite. 39. The process of claim 38, wherein the phosphitylating agent is a phosphorodiamidite. 40. The process of claim 1, wherein the protecting reagent is selected from an optionally substituted triphenylmethyl halide, an optionally substituted pixyl halide or an optionally substituted thiopixyl halide. 41. The process of claim 1, wherein the protecting reagent is 4,4'-dimethoxytrityl halide. 42. The process of claim 41, wherein the protecting reagent is 4,4'-dimethoxytrityl chloride. 43. The process of claim 1, further comprising steps for purifying the protected nucleoside. 44. The process of claim 43, wherein said steps for purifying the protected nucleoside comprise the steps of: providing the protected nucleoside in a first organic phase; contacting the first organic phase with an aqueous solution; extracting the protected nucleoside from the organic phase into a basic aqueous solution; adding acid to the basic aqueous solution to adjust the pH to a range of about 4.5 to about 6.8 to form an acidic aqueous solution; and extracting the protected nucleoside into an organic solvent to form a second organic phase, whereby a purified protected nucleoside is produced in the second organic phase. 45. The process of claim 44, wherein the first organic phase comprises a water-immiscible organic solvent. 46. The process of claim 45, wherein the water-immiscible organic solvent is toluene or ethyl acetate. 47. The process of claim 44, wherein the acid is citric acid. 48. The process of claim 44, further comprising reacting the purified protected nucleoside with a phosphitylating reagent to produce a phosphoramidite. 49. The process of claim 43, wherein said steps for purifying the protected nucleoside comprise: reacting the protected nucleoside with a derivatizing reagent to form a derivatized protected nucleoside; providing the derivatized protected nucleoside in a first organic phase; contacting the first organic phase with a basic aqueous phase, whereby the derivatized protected nucleoside partitions into the basic aqueous phase; acidifying the basic aqueous phase to form an acidic aqueous phase; and extracting the derivatized protected nucleoside into a second organic phase, whereby a purified derivatized protected nucleoside partitions into the second organic phase. 50. The process of claim 49, wherein the derivatizing reagent is represented by the formula: XL-LN-fg, wherein XL is a leaving group, LN is a linking group and fg is a functional group. 51. The process of claim 50, wherein XL is a halide, an alkylcarbonyloxy, or hydroxy, LN is CO-alkylene-, and fg is COOH, or XL and fg together form an anhydride. 52. The process of claim 49, wherein the derivatizing reagent is a member selected from the group consisting of diacids and diacid anhydrides. 53. The process of claim 52, wherein the derivatizing reagent is a diacid. 54. The process of claim 53, wherein the derivatizing reagent is succinic acid. 55. The process of claim 49, wherein the aqueous phase contains about 0.95 to about 1.05 molar equivalents of base per molar equivalent of derivatized protected nucleoside. 56. The process of claim 55, wherein the base is sodium hydroxide or potassium hydroxide. 57. The process of claim 49, further comprising reacting the derivatized protected nucleoside with a nucleophilic base to produce a purified protected nucleoside. 58. The process of claim 57, wherein the nucleophilic base comprises ammonium hydroxide or methylamine. 59. The process of claim 57, further comprising reacting the purified protected nucleoside with a phosphitylating reagent to produce a phosphoramidite. 60. The process of claim 49, further comprising reacting the derivatized protected nucleoside with a nucleoside support to form a primer support. 61. The process of claim 60, wherein the support is controlled pore glass or a polymer support. 62. The process of claim 49, further comprising removing the organic solvent from the protected nucleoside.