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.