The RAvIN Platform: A Noncarbohydrate Platform for Oligonucleotide Synthesis

Oligonucleotide therapeutics (ONTs) are poised to become a third pillar of modern medicine. However, the practical and large-scale synthesis of ONTs and their constituent nucleoside analogue (NA) building blocks remains a major challenge. As each of the NA units must be individually designed and tailored to enhance the desired ADMET properties of the ONT, identifying economic, flexible, and scalable syntheses of these compounds is of critical importance. To date, the field has relied almost exclusively on carbohydrates as starting materials for NA synthesis. While these compounds are enantiopure and share common structural and stereochemical features with NAs, their conversion into NAs often requires challenging, low-yielding, and expensive synthetic campaigns. As a result, a large fraction of the ONT chemical space remains underexplored, and the full impact of chemical modification on the pharmacokinetic properties of the ONTs remains poorly understood. Here, we present a streamlined platform to produce NAs that will improve access to precision-edited ONTs. This approach uses achiral starting materials and relies on a dual organocatalyst, one-pot process to furnish a key class of ONT building blocks: the RAvIN (rapid access to value-added innovative nucleosides) ketones (RKs). Notably, RKs can incorporate appropriately protected natural nucleobases as well as nucleobase analogues, be made on scale in 2-4 steps with carbohydrate-like levels of enantiomeric purity, and are readily diversified to create the next-generation NAs required to improve the pharmacokinetic properties of the ONTs. Finally, we demonstrate the versatility and potential of this methodology in a totally noncarbohydrate synthesis of the all-MOE-modified 18mer ONT Nusinersen.