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.