Catalytic asymmetric and stereodivergent oligonucleotide synthesis

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. [Related article:]702

Abstract

Chiral Brønsted acid catalysts allow efficient access to oligonucleotide targets through P(III) stereogenic intermediates.

Abstract

We report the catalytic stereocontrolled synthesis of dinucleotides. We have demonstrated, for the first time to our knowledge, that chiral phosphoric acid (CPA) catalysts control the formation of stereogenic phosphorous centers during phosphoramidite transfer. Unprecedented levels of diastereodivergence have also been demonstrated, enabling access to either phosphite diastereomer. Two different CPA scaffolds have proven to be essential for achieving stereodivergence: peptide-embedded phosphothreonine-derived CPAs, which reinforce and amplify the inherent substrate preference, and C2-symmetric BINOL-derived CPAs, which completely overturn this stereochemical preference. The presently reported catalytic method does not require stoichiometric activators or chiral auxiliaries and enables asymmetric catalysis with readily available phosphoramidites. The method was applied to the stereocontrolled synthesis of diastereomeric dinucleotides as well as cyclic dinucleotides, which are of broad interest in immuno-oncology as agonists of the stimulator of interferon genes (STING) pathway.