improved synthesis of purine locked nucleic acid analogues

摘要

The present invention relates to a new method for the synthesis of purine LNA (Locked Nucleic Acid) analogues which provides a higher overall yield. The method comprising a regioselective 9-N purine glycosylation reaction followed by a one-pot nucleophilic aromatic substitution reaction of the 6-substituent in the purine ring and simultaneous nucleophile-induced intramolecular ring closure of the C-branched carbohydrate to form novel purine LNA analogues. The novel strategy is illustrated by the synthesis of the novel compound (1S,3R,4R,7S)-7-benzyloxy-1-methanesulfonylmethyl-3-(guanin-9-yl)-2,5-dioxabicyclo[2.2.1]heptane which is easily converted into (1S,3R,4R,7S)-7-hydroxy-1-hydroxymethyl-3-((2-N-isobutyrylguanin-9-yl)-2,5-dioxabicyclo[2.2.1]heptane after isobutyryl protection of the 2-amino purine group and subsequent substitution of 1-methanesulfonyl with benzoate, debenzoylation and debenzylation.