Efficient process technologies for the preparation of oligonucleotides.

Abstract

Efficient process technologies for the preparation of 2'-substituted nucleoside monomers, as well as for oligonucleotide preparation, are introduced. A novel method for efficient preparation of 2'-substituted uridines is presented. This method employs the 3'-hydroxyl group of 2,2'-anhydrouridine as a tether for the facile intramolecular introduction of nucleophiles to the 2'-position. It allows access to 2'-alkoxy substituents from their alcohol precursors and to substituted 2'-amino substituents, such as the novel O-substituted 2'-hydroxylaminouridines. A novel process for large-scale oligonucleotide synthesis is discussed, which allows solution phase coupling of the monomer to the growing oligonucleotide chain. This is followed by selective isolation of productive coupling product by anchoring to a resin. Release from this resin completes a coupling cycle.