An Efficient Synthesis of Enantiomeric Ribonucleic Acids from D-Glucose

Abstract

Enantiomeric oligoribonucleotides ( = ent-RNA) up to a sequence length of thirty-five and consisting of the (L-configurated) nucleosides ent-adenosine, ent-guanosine, ent-cytidine, ent-uridine, and 1-(β-L-ribofuranosyl)thymine were prepared by automated synthesis from appropriate building blocks, carrying a known photolabile 2′-O-protecting group. A simple large-scale synthesis of the new, prefunctionalized L-ribose derivative 5 from D-glucose (Scheme 1) and its straightforward conversion into the five phosphoramidites 28-32 and five solid supports 38-42, respectively, were elaborated (Scheme 4). Within this project, a novel, superior strategy for the synthesis of the 2′-O-{[(2-nitrobenzyl)oxy]methyl}-substituted key intermediates 18-22 by regioselective alkylation of their 5′-O-dimethoxytritylated precursors 13-17 was developed. Furthermore, an improved set-up for the final light-induced cleavage of the 2′-O-protecting groups from the oligonucleotide sequences was designed (Scheme 5 and Fig. 1). The correct composition of all ent-oligoribonucleotides prepared was established by their MALDI-TOF mass spectra. The 1H-NMR-spectroscopic data of a dodecameric ent-RNA sequence was in excellent agreement with the published data of its natural counterpart, synthesized by conventional methods. The known specific cleavage of a tetradecamer sequence by a 35mer ribozyme structure could be reproduced by ent-oligoribonucleotides, synthesized by the presented methods (Fig. 4).