Synthesis of cis- and trans-α-l-[4.3.0]bicyclo-DNA monomers for antisense technology: methods for the diastereoselective formation of bicyclic nucleosides

J Org Chem. 2013 Sep 20;78(18):9051-63. doi: 10.1021/jo401166q. Epub 2013 Sep 4.

Abstract

Two α-L-ribo-configured bicyclic nucleic acid modifications, represented by analogues 12 and 13, which are epimeric at C3' and C5' have been synthesized using a carbohydrate-based approach to build the bicyclic core structure. An intramolecular L-proline-mediated aldol reaction was employed to generate the cis-configured ring junction of analogue 12 and represents a rare application of this venerable organocatalytic reaction to a carbohydrate system. In the case of analogue 13, where a trans-ring junction was desired, an intermolecular diastereoselective Grignard reaction followed by ring-closing metathesis was used. In order to set the desired stereochemistry at the C5' positions of both nucleoside targets, a study of diastereoselective Lewis acid mediated allylation reactions on a common bicyclic aldehyde precursor was carried out. Analogue 12 was incorporated in oligonucleotide sequences, and thermal denaturation experiments indicate that it is destabilizing when paired with complementary DNA and RNA. However, this construct shows a significant improvement in nuclease stability relative to a DNA oligonucleotide.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bridged Bicyclo Compounds / chemistry*
  • DNA / chemistry*
  • Molecular Conformation
  • Nucleic Acid Denaturation
  • Oligonucleotides, Antisense / chemical synthesis*
  • Oligonucleotides, Antisense / chemistry
  • Stereoisomerism
  • Temperature

Substances

  • Bridged Bicyclo Compounds
  • Oligonucleotides, Antisense
  • DNA