Organometallic methodologies for nucleic acid synthesis

Abstract

A new, general preparation of 2'-5' ‘-linked oligoadenylates has been developed, which relies on: (1) chemoselective O-phosphorylation of N-unblocked nucleosides via hydroxyl activation by Grignard reagents, (2) one-pot construction of internucleotide linkage using bifunctional phosphorylating agents, and (3) selective production of a 3',5' ‘-di-0-protected adenosine. This solution-phase synthesis allows large-scale preparation of a wide range of related oligomers. Palladium chemistry coupled with allylic protection of functional groups leads to the development of an efficient solid-phase synthesis of DNA oligomers via a phosphoramidite approach. Allyl groups on intemucleotide linkages and allyloxycarbonyl groups on amino moieties of nucleobases are removable all at once on the solid supports by exposure to a palladium(O) complex and nucleophiles. This procedure has been utilized for synthesis of a DNA 60mer of unprecedented high purity. In addition, this marks the realization of the first efficient preparation of solid-anchored DNA oligomers. © 1990, IUPAC.