A Robust Strategy for Introducing Amino‐Modifiers in Nucleic Acids: Enabling Novel Amino Tandem Oligonucleotide Synthesis in DNA and RNA

Amino-modifiers are pivotal chemical modifications in nucleic acid scaffolds, serving applications ranging from (bio)conjugation to probing the origins of life. We report a simple, efficient, and cost-effective methodology for the introduction of amino-modifiers into DNA and RNA. This approach leverages a commercially available sulfonyl-containing solid support, which is first converted into a mixed N-hydroxysuccinimide carbonate, enabling robust conjugation with primary and secondary amines whether nucleosidic or non-nucleosidic. Oligonucleotides are synthesized via solid-phase synthesis and purified using standard methods, with little to no modification. Building on this framework, we introduce a novel amino-containing tandem oligonucleotide synthesis (aTOS) methodology, which facilitates the introduction of multiple terminal amino (or monophosphate) groups across two oligonucleotide strands. This innovative method broadens the toolkit for the introduction of amino modifications in nucleic acids, for applications in nucleic acid (bio)chemistry and biotechnology.