<p>We report the catalytic stereocontrolled synthesis of dinucleotides. Chiral phosphoric acid (CPA) catalysts are demonstrated to control the formation of stereogenic phosphorous centers during phosphoramidite transfer for the first time. Unprecedented levels of diastereodivergence are also demonstrated, enabling access to either phosphite diastereomer. Notably, two different CPA scaffolds prove 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 (CDNs) which are of broad interest in immono-oncology as agonists of the STING pathway.</p>
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