A Facile and General Tandem Oligonucleotide Synthesis Methodology for DNA and RNA

Abstract

Tandem oligonucleotide synthesis (TOS) is an attractive strategy to increase automated oligonucleotide synthesis efficiency. TOS is accomplished via the introduction of an immolative linker within a single sequence composed of multiple oligonucleotide fragments. Here, we report the use of a commercially available building block, typically utilized for the chemical phosphorylation of DNA/RNA oligomers, to perform TOS. We show that the 2,2′‐sulfonyldiethylene linker is efficiently self‐immolated during the standard deprotection of DNA and RNA and presents itself as a generalizable methodology for nucleic acid TOS. Furthermore, we show the utility of this methodology by assembling a model siRNA construct, and showcase a template‐directed ligation pathway to incorporate phosphoramidate or pyrophosphate linkages within DNA oligomers.