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

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.