In oligoribonucleotide synthesi

In 1968 Miller and Stirling showed that the 2-tosylethyl ester function (abbreviated TSE) underwent easy base-catalysed elimination in the presence of 1 M sodium hydroxide or sodium carbonate (but not sodium hydrogen carbonate) in aqueous dioxane at room temperature to give p-toluenesulfinate anion, ethylene. and a carboxylate 215 Thus, this ester function complements the methylsul-fonylmethyl function (see section 6.4) derived from methylthiomethyl esters in its base-sensitivity. Electron withdrawing groups (e.g., p-nitro) on the aryl ring increase base lability — a feature that has been exploited for the protection of the 2f hydroxyl function in oligoribonucleotide synthesis.216... 

Capaldi DC, Reese CB. Use of the l-(2-fluorophenyl)-4-methoxypiperidin-4-yl (Fpmp) and related protecting groups in oligoribonucleotide synthesis Stability of intemucleotide linkages to aqueous acid. Nucleic Acids Res 22 2209-2216, 1994. 

Wincott F, Usman N. 2 -(Trimethylsilyl)ethoxymethyl protection of the 2 -hydroxyl group in oligoribonucleotide synthesis. Tetrahedron Lett 35 6827-6830, 1994. 

Stawinski J, Stromberg R, Thelin M, Westman E. Studies on the t-butyldi-methylsilyl group as 2 -(9-protection in oligoribonucleotide synthesis via the i7-phosphonate approach. Nucleic Acids Res 16 9285-9298, 1988. 

Chaix C, Molko D, Teoule R. The use of labile base protecting groups in oligoribonucleotide synthesis. Tetrahedron Lett 30 71-74, 1989. 

The synthesis of 2 -0-tetrahydropyranyladenosine (28) as an intermediate in oligoribonucleotide synthesis led to a mixture of two diastereoiso-mers, differing at C(20, but readily separable and with different properties e.g. [a] -8°, m.p. 171—172.5 °C [ ] -130°, m.p. 199—200 C). Similar results had previously been obseved for the 2 -0-tetrahydropyranyl ethers of uridine and AT(4)-benzoylcytidine. An analysis of the more laevorotatory isomer of (28) proves that it has the absolute stereochemistry (2T-S), and by analogy defines the absolute stereochemistries of the uridine and cytidine derivatives also as (2"-S). 

A synthesis of 2 -0-methyluridine has been carried out by a procedure in which the 3, 5 -0-TIPDS derivative of uridine was protected at N-3 by the p-methoxybenzyl group,208 and the "wobble position" nucleoside 2 -0-methyl-5-(methoxycarboxylmethyl)uridine has also been prepared by similar means.209 The 2 -0-allyl derivative (141) of uridine is accessible by a palladium-catalysed decarboxylation of (142), and a similar reaction is possible on an adenosine derivative.210 2 -0-Propargyl uridine can be prepared via the 2, 3 -0-dibutylstannylene derivative the triple bond of this derivative could then be converted into an unusual carboranyl group, the resultant structure being of potential use in the neutron capture therapy of cancer.211 A conference report has discussed the use of 2-(methylthio)-phenylthiomethyl (MPTM) ethers for protection of the 2 -hydroxyl group in oligoribonucleotide synthesis.212... 

Substituted Trityl Ethers. Khorana and his co-workers found that the conditions of acidic hydrolysis required to remove the trityl group were too drastic for it to be useful in oligoribonucleotide synthesis [37] or in the protection of purine deoxyribonucleosides and their derivatives [38]. These workers overcame this difficulty by using modified trityl groups which had one or more p-methoxy substituents. Thus ribo-nucleoside [37] and deoxyribonudeoside [38] derivatives reacted at their 5 -hydroxyl functions with p-anisyldiphenyl-, di-p-anisylphenyl- and tri-p-anisyl-methyl chlorides (13a, 13b and 13c, respectively) [37] in pyridine solution to give the corresponding substituted trityl ethers (14a, 14b and 14c). It is convenient to refer to the three latter derivatives as mono-, di-and tri-methoxytrityl ethers, respectively. 

The pivaloyl (trimethylacetyl) protecting group has been used in nucleoside chemistry [52, 109]. Presumably due to its bulky size, pivaloyl chloride showed appreciable selectivity in its reaction with thymidine in pyridine solution and crystalline 5 -0-pivaloylthymidine could be isolated from the products in 82% yield [109]. In the same way, 2 -0-tetrahydropyranyl-5 -0-pivaloyluridine (52 R = H), a useful intermediate in oligoribonucleotide synthesis, was prepared from 2 -0-tetra-hydropyranyluridine in satisfactory yield [52]. As pivalate esters are comparatively stable to NHs/MeOH [52], deacetylation is possible in the presence of pivaloyl groups thus (52 ... 

Stawinski, J, Stromberg, R, Thelin, M., and Westman, E (1988) Studies on the /-butyldimethylsilyl group as 2 -C -protection in oligoribonucleotide synthesis via the H-phosphonate approach. Nucl. Acids Res. 16,9285-9298. 

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