Nucleotides Part LXVIII - Acetals as new 2 '-O-protecting functions for the synthesis of oligoribonucleotides: Synthesis of monomeric building units and oligoribonucleotides

For the efficient synthesis of oligoribonucleotides by the 5 ' -O-(4,4 ' -d imethoxytrityl) phosphoramidite approach, the 2 ' -O-[1-(benzyloxy)ethyl]ac etals 56-67 were investigated. Studies with the 2 ' -O-[1-(benzyloxy)ethyl] -5 ' -O-(dimethoxytrityl)ribonucleoside 3 ' -phosphoramidites 56-59 gave, h owever, only reasonable results. The oligoribonucleotides obtained showed s ome impurities since the acid stabilities of the acetal and dimethoxytrityl functions are too close to guarantee a high selectivity. A combination of new acid-labile protected 2 ' -O-protecting groups with the 2-(4-nitropheny l)ethyl/[2-(4-nitrophenyl)ethoxy]carbonyl (npe/ npeoc) strategy for base pr otection was more successful. The synthesis and physical properties of the monomeric building units and their intermediates 8-67 and the conditions fo r the automated generation of homo- and mixed oligoribonucleotides is descr ibed. The new 2 ' -acetal protecting group could be cleaved off in a two st ep procedure and was designed for Levelling their stability with regard to the attached nucleobase as well. Therefore, we used the 1-((3-fluoro-4-(([2 -(4-nitrophenyl)ethoxy]carbonyl)oxy) benzyl)oxy)ethyl (fnebe) moiety for th e protection of 2 ' -OH of uridine. and for that of 2 ' -OH of A. C. and G, the 1-((4-(([2-(4-nitrophenyl)ethoxy]carbonyl)oxy)benzyl)oxy)ethyl (nebe) residue. After selective deprotection by beta -elimination induced by a str ong organic base like DBU. the remaining activated acetal was hydrolyzed un der very mild acidic protic conditions, which reduced 2 ' -3 ' isomerizatio n and chain cleavage. Also storage, handling, and purification of the chemi cally and enzymatically sensitive oligomers was simplified by this approach .