Catalytic asymmetric and stereodivergent oligonucleotide synthesis

Abstract

A P catalyst for stereogenic P(III) Phosphodiesters, the key linkage in DNA, RNA, and bioactive oligonucleotide and cyclic nucleotides, are typically synthesized from phosphoramidite precursors. Phosphorothioate linkages, which are more stable, can also be produced this way but have the complication of chirality at the P center, which is synthetically problematic, especially for multiple linkages. Featherston et al. found that two different chiral phosphoric acid catalysts provide stereodivergent synthesis of a stereogenic phosphite intermediate that can be oxidatively modified to the desired stereopure nucleotide derivative. They used this approach in the synthesis of a phosphorothioate derivative of the cyclic dinucleotide 2′,3′-cyclic guanosine monophosphate adenosine monophosphate, which is an important human immune signaling molecule. Science , this issue p. 702