Catalytic asymmetric and stereodivergent oligonucleotide synthesis

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.

Innovative developments and emerging technologies in RNA therapeutics

“…The PS stereochemistry is not controlled in standard solid-phase synthesis, which results in the production of stochastic, 2 n diasteroisomeric mixtures, where n is the number of chiral phosphorus atoms in the ASO sequence. Recent synthetic developments [ 12 , 13 ] have facilitated the access to stereo-defined oligonucleotides and to their biological evaluation, but the emerging literature is not unanimous. In some reports stereodefined ASOs improved biological activity [ 14 ], but others are less encouraging [ 15 ].…”

The biomimetic engineering of metal–organic frameworks with single-chiral-site precision for asymmetric hydrogenation

“…Asymmetric catalysis, 1 which is famous as the most economic and efficient tactic for the production of enantiopure substrates, has triggered a research fever in chiral pharmaceuticals, 2,3 pesticides, 4-6 perfumes, 7 imaging materials 8 and other elds. 9,10 As one of the masterpieces, asymmetric hydrogenation 11 has achieved unprecedented successes in both the academic and industrial communities, and was hence awarded the rst Nobel Prize in chemistry of the 21 st century. To date, heterogeneous asymmetric hydrogenation based on metal nanoparticles (NPs) [12][13][14][15] is more promising for implementation in industrial applications than conventional homogeneous metal-chiral ligand complexes owing to its convenience in product separation, catalyst regeneration, and continuous ow operation.…”

Enantioselective Synthesis of Versatile Stereogenic-at-P(V) Building Blocks via Hydrogen-Bond-Donor Catalysis

“…Merck developed a chiral bisimidazole catalyzed synthesis of phosphoramidate prodrugs through the diastereoselective addition of nucleosides to chlorophosphoramidates, proceeding via a cooperative mechanism of covalent activation of P(V) and general-base activation of the alcohol nucleophile (23). An alternative approach was demonstrated by Miller and co-workers in the catalytic, stereodivergent synthesis of P-stereogenic oligonucleotides from phosphoramidites via chiral phosphoric acid catalysis (24). Finally, in work that appeared as this study was being completed, Dixon and co-workers reported a catalytic, enantioselective desymmetrization of diaryl phosphonate esters by substitution with orthosubstituted phenols (25).…”