Unit

UNIT 1.24 Synthesis of 2′,4′-Bridged Nucleosides Using a New Orthogonally Protected Sugar Synthon: 5-O-(tert-Butyldiphenylsilyl)-4-C-Hydroxymethyl-1,2-O-Isopropylidene-3-O-Napthyl-α-d-Allofuranose

  1. Punit P. Seth,
  2. Thazha P. Prakash

Published Online: 1 MAR 2011

DOI: 10.1002/0471142700.nc0124s44

Current Protocols in Nucleic Acid Chemistry

Current Protocols in Nucleic Acid Chemistry

How to Cite

Seth, P. P. and Prakash, T. P. 2011. Synthesis of 2′,4′-Bridged Nucleosides Using a New Orthogonally Protected Sugar Synthon: 5-O-(tert-Butyldiphenylsilyl)-4-C-Hydroxymethyl-1,2-O-Isopropylidene-3-O-Napthyl-α-d-Allofuranose. Current Protocols in Nucleic Acid Chemistry. 44:1.24:1.24.1–1.24.23.

Author Information

  1. Isis Pharmaceuticals, Carlsbad, California

Publication History

  1. Published Online: 1 MAR 2011
  2. Published Print: MAR 2011

Abstract

2′,4′-Bridged nucleic acids (BNA) provide unprecedented increases in the thermal stability of oligonucleotide duplexes. Locked nucleic acids (LNA), a representative member of the BNA class, have shown promise in antisense applications and as a diagnostic tool. While a number of BNA analogs have been reported in the literature, their evaluation in vivo has been stymied by difficulties in securing enough amidite to support extensive animal experiments. A bottleneck has been the ability to prepare a key mono-protected allofuranose synthon that is the common starting material for all BNA analogs. This unit presents the synthesis of a novel orthogonally protected sugar synthon, 5-O-(tert-butyldimethylsilyl)-4-C-hydroxymethyl-1,2-O-isopropylidene-3-O-(2-methylnaphthlene)-α-d-allofuranose, which can be prepared in 100-gram quantities without any chromatographic purification of intermediates or the final product. The utility of this new synthon is exemplified by the synthesis of BNA analogs containing uracil nucleobases, substituted 2′,4′-bridges, and oxyamino functionalities that are otherwise more difficult to prepare using the 3′-O-benzyl protecting group strategy most commonly used in the literature. Curr. Protoc. Nucleic Acid Chem. 44:1.24.1-1.24.23. © 2011 by John Wiley & Sons, Inc.

Keywords:

  • constrained MOE (cMOE);
  • N-OMe-2′-amino BNA;
  • Nap protecting group