Published on Oct. 28, 2005 in HELVETICA CHIMICA ACTA volume Volume 88, Issue 10, pages 26.

DOI: 10.1002/hlca.200590209

Abstract:

The first results of a study aiming at an efficient preparation of a large variety of 2′-O-[(triisopropylsilyl)oxy]methyl(=  tom)-protected ribonucleoside phosphoramidite building blocks containing modified nucleobases are reported. All of the here presented nucleosides have already been incorporated into RNA sequences by several other groups, employing 2′-O-tbdms- or 2′-O-tom-protected phosphoramidite building blocks (tbdms = (tert-butyl)dimethylsilyl). We now optimized existing reactions, developed some new and shorter synthetic strategies, and sometimes introduced other nucleobase-protecting groups. The 2′-O-tom, 5′-O-(dimethoxytrityl)-protected ribonucleosides N2-acetylisocytidine 5, O2-(diphenylcarbamoyl)-N6-isobutyrylisoguanosine 8, N6-isobutyryl-N2-(methoxyacetyl)purine-2,6-diamine ribonucleoside (= N8-isobutyryl-2-[(methoxyacetyl)amino]adenosine) 11, 5-methyluridine 13, and 5,6-dihydrouridine 15 were prepared by first introducing the nucleobase protecting groups and the dimethoxytrityl group, respectively, followed by the 2′-O-tom group (Scheme 1). The other presented 2′-O-tom, 5′-O-(dimethoxytrityl)-protected ribonucleosides inosine 17, 1-methylinosine 18, N6-isopent-2-enyladenosine 21, N6-methyladenosine 22, N6,N6-dimethyladenosine 23, 1-methylguanosine 25, N2-methylguanosine 27, N2,N2-dimethylguanosine 29, N6-(chloroacetyl)-1-methyladenosine 32, N6-{{{(1S,2R)-2-{[(tert-butyl)dimethylsilyl]oxy}-1-{[2-(4-nitrophenyl)ethoxy]carbonyl}propyl}amino}carbonyl}}adenosine 34 (derived from L-threonine) and N4-acetyl-5-methylcytidine 36 were prepared by nucleobase transformation reactions from standard, already 2′-O-tom-protected ribonucleosides (Schemes 2–4). Finally, all these nucleosides were transformed into the corresponding phosphoramidites 37–52 (Scheme 5), which are fully compatible with the assembly and deprotection conditions for standard RNA synthesis based on 2′-O-tom-protected monomeric building blocks.