ChemInform Abstract: Synthesis and Characterization of Oligodeoxyribonucleotides Modified with 2′‐Amino‐α‐L‐LNA Adenine Monomers: High‐Affinity Targeting of Single‐Stranded DNA.

Abstract

The development of conformationally restricted nucleotide building blocks continues to attract considerable interest because of their successful use within antisense, antigene, and other gene-targeting strategies. Locked nucleic acid (LNA) and its diastereomer α-l-LNA are two interesting examples thereof. Oligonucleotides modified with these units display greatly increased affinity toward nucleic acid targets, improved binding specificity, and enhanced enzymatic stability relative to unmodified strands. Here we present the synthesis and biophysical characterization of oligodeoxyribonucleotides (ONs) modified with 2′-amino-α-l-LNA adenine monomers W–Z. The synthesis of the target phosphoramidites 1–4 is initiated from pentafuranose 5, which upon Vorbruggen glycosylation, O2′-deacylation, O2′-activation and C2′-azide introduction yields nucleoside 8. A one-pot tandem Staudinger/intramolecular nucleophilic substitution converts 8 into 2′-amino-α-l-LNA adenine intermediate 9, which after a series of nontrivia...