Rapid Synthesis and Diversification of Thymine-Containing Bridged Nucleic Acids Through Cascade Cyclization Reactions

Bridged nucleic acids (BNAs) are nucleoside analogues (NAs) in which the 2′-alcohol is linked to the C4′-position on ribose. In oligonucleotide therapeutics (ONTs), BNAs can impart beneficial properties, including enhanced stability, duplex melting temperatures, and tissue half-lives. However, their lengthy syntheses challenge medicinal chemistry efforts and larger-scale production. Here we demonstrate that a wide range of BNAs can be produced with various locking ring sizes and substitution patterns from a common thymine-containing aldol product through cascade cyclization processes. Critically, several clinically relevant BNAs are now made available in as little as 3–5 steps. We expect these strategies will inspire and support medicinal and process chemistry efforts in this critical area for ONTs.