Catalytic asymmetric and stereodivergent oligonucleotide synthesis.

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.

Regioselective and enantiospecific rhodium-catalyzed allylic alkylation reactions using copper(I) enolates: synthesis of (-)-sugiresinol dimethyl ether.

The transition metal-catalyzed allylic alkylation represents a fundamentally important cross-coupling reaction for the construction of ternary carbon stereogenic centers. We have developed a regioselective and enantiospecific rhodium-catalyzed allylic alkylation of acyclic unsymmetrical allylic alcohol derivatives using copper(I) enolates to prepare beta-substituted ketones. This protocol represents a convenient asymmetric Claisen rearrangement surrogate in which alpha-substituted enolates permit the introduction of an additional stereogenic center. The synthetic utility of this transformation was highlighted in the construction of a trans-1,2-disubstituted cyclohexene and the total synthesis of (-)-sugiresinol dimethyl ether. Finally, we anticipate that copper(I) enolates may prove useful nucleophiles in related metal-catalyzed reactions.