Protection of nucleosides

Lavandera, I., Garda, J., Fernandez, S., Ferrero, M., Gotor, V. and Sanghvi, Y. (2005) Current protocols in nucleic add chemistry, in Protection of Nucleosides for... 

The directed protection of nucleoside functional groups is a fundamental problem in nucleoside and nucleotide chemistry. Although several chemical methods are available for the regioselective acylation of the nucleoside carbohydrates, enzymatic... 

Table 3.29 Transient Silylation and /V-Protection of Nucleoside Derivatives ...

Sulfenic acid esters from alcohols and reverse reaction Protection of nucleoside hydroxyl... 

Protection of nucleoside alcohol groups as silyl ethers s. 30, 61 s. a. J. Carbo-hyd. Nucleos. Nucleot. 3, 197 (1976)... 

In a study of the partial protection of nucleosides, it was shown that acylation of a ribonucleoside with 1.2-1.5 equivalents of an acyl chloride in pyridine gave mostly the 2 -0-acyl isomer. Use of 2.2-3.0 equivalents of acyl chloride gave mostly the 2, 5 -di-0-acyl derivative, which rearranged over silica to the 3, 5 -diacyl... 

Other N-Protection Reactions. The protection of an amide as its N-Chz derivative can be achieved using CbzCl with Et3N/DMAP, or by initial deprotonation of the amide using BuLi or (Me3Si)2NLi. The N-protection of nucleosides is usually ineffective with CbzCl but can be selectively and efficiently accomplished using A-Cbz imidazolium salts generated in situ from the reaction of CbzCl with A -alkylimidazoles (eq... 

DMF dimethyl acetal is an effective methylating reagent. For example, heterocyclic thiols are transformed to 5-methyl heterocycles in high yields (76-86%). DMF dibenzyl acetal is an interesting reagent for selective protection of nucleosides. For example, uridine and guanosine are selectively blocked at the -CONH function (eq 5). ... 

We shall describe a specific synthetic example for each protective group given above. Regiosdective proteaion is generally only possible if there are hydroxyl groups of different sterical hindrance (prim < sec < tert equatorial < axial). Acetylation has usually been effected with acetic anhydride. The acetylation of less reactive hydroxyl groups is catalyzed by DMAP (see p.l44f.). Acetates are stable toward oxidation with chromium trioxide in pyridine and have been used, for example, for protection of steroids (H.J.E. Loewenthal, 1959), carbohydrates (M.L. Wolfrom, 1963 J.M. Williams, 1967), and nucleosides (A.M. Micbelson, 1963). The most common deacetylation procedures are ammonolysis with NH in CH OH and methanolysis with KjCO, or sodium methoxide. 

The protected nucleoside-3-phosphoramidite monomer units such as 671 are used in the solid-phase oligonucleotide synthesis. In the 60mer synthesis, 104 allylic protective groups are removed in almost 100% overall yield by the single Pd-catalyze reaction with formic acid and BuNH2[432], N,(9-protection of uridine derivatives was carried out under pha.se-transfer conditions[433]. 

These were originally prepared by Khorana as selective protective groups for the 5 -OH of nucleosides and nucleotides. They were designed to be more acid-labile than the trityl group because depurination is often a problem in the acid-catalyzed removal of the trityl group. Introduction of p-methoxy groups increases the rate of hydrolysis by about one order of magnitude for each p-methoxy substituent. For 5 -protected uridine derivatives in 80% AcOH, 20°, the time for hydrolysis was... 

This group was developed for protection of the 5 -OH group in nucleosides. The derivative is prepared from the corresponding triaiylmethyl chloride, and is cleaved by reductive cleavage (Zn/AcOH) of the phenacyl ether to the p-hydroxyphenyl-diphenylmethyl ether followed by acidic hydrolysis with formic acid. ... 

The pixyl ether is prepared from the xanthenyl chloride in 68-87% yield. This group has been used extensively in the protection of the 5 -OH of nucleosides it is readily cleaved by acidic hydrolysis (80% AcOH, 20°, 8-15 min, 100% yield, or 3% trichloroacetic acid). It can be cleaved under neutral conditions with ZnBrj, thus reducing the extent of the often troublesome depurination of A -6-benzyloxy-adenine residues during deprotection. Conditions which remove the pixyl group also partially cleave the THP group (t,/2 for THP at 2 -OH of ribonucleoside = 560 s in 3% Cl2CHC02H/CH2Cl2). ... 

The following ortho esters have been prepared to protect the diols of nucleosides. They are readily hydrolyzed with mild acjd to afford monoester derivatives, generally as a mixture of positional isomers. 

Protective group chemistry for these amines has been separated from the simple amines because chemically they behave quite differently with respect to protective group cleavage. The increased acidity of these aromatic amines makes it easier to cleave the various amide, carbamate, and sulfonamide groups that are used to protect this class. A similar situation arises in the deprotection of nucleoside bases (e.g., the isobutanamide is cleaved with methanolic ammonia ), again, because of the increased acidity of the NH group. 

In a quest to develop the perfect nucleoside protection scheme, the Cpeoc group was devised for protection of the 5 -OH. It is introduced through the chloro-formate in 58-83% yield. Cleavage is achieved with 0.1 M DBU with half-lives of 7-14 sec, depending on the nucleoside. ... 

The 2-nitrobenzenesulfenamide has been used for the protection of amino acids and nucleosides. ... 

Product distributions obtained on esterification of nucleosides and nucleotides under basic conditions throw further light on factors affecting selective reactivity. p-Toluenesulfonylation of adenosine 5 -monophosphate in aqueous alkali yielded exclusively (in 54-61% yield) the 2 -p-toluenesulfonate.107 Lack of reaction at HO-3 was attributed either to formation of a phosphoric p-toluenesulfonic anhydride, which sterically protected this hydroxyl group, or to the higher acidity of HO-2. It has been shown that the acidic site (with pKa 12.5) in adenosine is associated with the presence of both HO-2 and HO-3, as replacement of either of these by hydrogen, or of HO-2 by methoxyl, results in loss of this acidity.108 Inductive effects, or the sta-... 

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