Transient protection in nucleoside synthesis using trityl groups: is it necessary to block hydroxyl groups?

Abstract

The method of Vorbrtiggen’ is now being used extensively in the synthesis of ribonucleosides and their analogs. The method involves glycosylation of trimethylsilyl derivatives of nucleic bases with completely acylated sugars in the presence of Lewis acids, preferentially tin(IV) chloride or trimethylsilyl trifluoromethanesulfonate (triflate). The presence of a 2-O-acyl group in a carbohydrate residue is believed to be crucial for the stereospecificity of this reaction, since it stabilizes the C1 carbonium ion generated via an intermediate 1 ,Zacyloxonium ion2*3 and yields 1,2-truns-derivatives. As a rule, an up-mixture of anomeric nucleoside derivatives is produced in the absence of a 2-O-acyl group4. However, aand j?-nucleosides can be synthesized stereoselectively starting from monosaccharide derivatives with such non-participating groups at C-2 as chlorine’, O-tert-butyldimethylsily16, 2,3-0-isopropylidene’,‘, and 0-tosyl’. Steric factors seem to be responsible for the stereospecificity of these glycosylation reactions. Therefore, a knowledge of how the protecting groups of a ribofuranose residue influence the regio-lo and stereo-selectivity of condensation reactions will help to develop suitable methods for the synthesis of selectively protected nucleoside analogs. We now illustrate the use of the monomethoxytrityl group to protect the primary hydroxyl group of a ribofuranose residue in nucleoside synthesis and its elimination during the reaction. It is known that trityl groups can be removed by the action of Lewis acids”,‘*. The D-ribofuranose derivatives 1 and 2 were synthesized in high yields by monomethoxytritylation of D-ribose followed by acylation. A similar tritylation and acetylation sequence has been reported I3314 Glycosylation of bis(trimethylsilyl)uracil . with 1 in the presence of triflate (2.3 equiv.) in 1 ,Zdichloroethane for 16 h at 20” gave 70% of the p-nucleoside derivative 3. Likewise, glycosylation of the trimethylsilyl derivatives of N4-benzoylcytosine (16 h, 20”) and N6-benzoyladenine (boiling for 2 h, 1,2-dichloroethane) with 2 yielded the p-nucleoside derivatives 4 (70%) and 5 (66%), respectively. The structures of 3 5 were confirmed by ‘H-n.m.r. data and independent