An expanded framework toward improving the detritylation reaction in solid-phase oligonucleotide syntheses – filling the gap

Abstract

A few interactions should be considered during the detritylation reaction of solid-phase oligonucleotide synthesis (SPOS): (i) interaction of solvent with acid; (ii) interaction (or reaction) of solvent with trityl cation, and (iii) interaction of scavenger with acid, with the last one as the focus of this work. Using a stopped-flow setup, commonly used trityl cation scavengers (methanol, thioanisole, 1-dodecanethiol, triisopropylsilane, triethylsilane, and trihexylsilane) were evaluated for their reactivity toward tritylium hexafluorophosphate. Among the scavengers screened, methanol and thioanisole were found to be the most and least reactive, respectively; however, methanol does interact and react with trichloroacetic acid, thus it should not be pre-mixed and stored with acid as deblock solutions. Overall, all aspects of interactions must be taken into consideration while optimizing the detritylation reaction, especially for large scale SPOS.

Keywords:

• Detritylation
• solid-phase oligonucleotide synthesis
• acid
• solvent
• DMTr cation scavenger

Disclosure statement

No potential conflict of interest was reported by the author(s)

Additional information

Funding

This work was supported by the Natural Sciences and Engineering Research Council of Canada.