Catalytic Asymmetric and Stereodivergent Oligonucleotide Synthesis

Abstract

<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>

Two-Step Transesterification of Phosphates, Phosphorothioates, and Phosphonates with a Binaphthyl Group for the Synthesis of P-Chirogenic Phosphates and Phosphonates

“…2 Recent promising methods for their synthesis involve dynamic kinetic resolution of racemic phosphoric chlorides with optically active organocatalysts, 3 the use of chiral auxiliaries derived from limonenes, 4 and the phosphoric acid-catalyzed coupling reaction of trivalent organophosphorus compounds with alcohols. 5 Besides these oligonucleotides, P -chirogenic phosphonates and phosphates with simple alcohols have also been documented, 6 although methods for their synthesis have not been as fully developed. Oxazolidinones were used as a chiral auxiliary for the synthesis of P -chirogenic phosphates, but the method required separation of the diastereomers.…”

Scalable convergent synthesis of therapeutic oligonucleotides

“…The stereoselectivity of the coupling reaction is determined mainly by the amidites, their coupling partners and the activator. [30][31][32] DCI was used as an activator to maintain similar stereochemistry in both the LPOS and SPOS processes. Solvents were chosen to en able telescoping with high reaction efficiency and work-up simplicity.…”