jo0515879_si_001.pdf (4.17 MB)
Monomers for Preparation of Amide-Linked RNA: Asymmetric Synthesis of All Four Nucleoside 5‘-Azido 3‘-Carboxylic Acids
journal contribution
posted on 2005-11-25, 00:00 authored by Eriks Rozners, Yang LiuRecent discovery of RNA interference as an efficient and naturally occurring mechanism of gene
regulation has reinvigorated the interest in chemically modified RNA. For potential in-vivo
applications small interfering RNAs require chemical modifications to fine-tune the thermal stability
and increase the cellular delivery and potency and in vivo half-life of the RNA duplexes. From this
perspective, amides as neutral and hydrophobic internucleoside linkages in RNA are highly
interesting modifications for RNA interference. Amides are remarkably good mimics of the
phosphodiester backbone of RNA and can be prepared using a relatively straightforward peptide
coupling chemistry. However, the progress in the field has been hampered by the shortage of efficient
methods to synthesize the monomeric building blocks for such couplings, the nucleoside amino
acid equivalents. Herein, we report enantioselective synthesis of 5‘-azido 3‘-carboxylic acid
derivatives of all four natural ribonucleosides. The key transformations in our synthesis are a double
asymmetric ene reaction and a stereoselective iodolactonization that form the basic carbon skeleton
of the modified ribose. Standard nucleoside synthesis is followed by a short and highly efficient
protecting group manipulation to give the enantiomerically pure (>98%) title compounds in 9−10
steps and 15−19% overall yields starting from small achiral molecules. The present results are a
significant improvement over our first-generation racemic synthesis and compare favorably with
the previously reported synthesis from nucleoside and carbohydrate precursors.