Stereo-Controlled Liquid Phase Synthesis of Phosphorothioate Oligonucleotides on a Soluble Support

J Org Chem. 2023 Jul 21;88(14):10156-10163. doi: 10.1021/acs.joc.3c01006. Epub 2023 Jul 10.

Abstract

5'-O-(2-Methoxyisopropyl) (MIP)-protected 2'-deoxynucleosides as chiral P(V)-building blocks, based on the limonene-derived oxathiaphospholane sulfide, were synthesized and used for the assembly of di-, tri-, and tetranucleotide phosphorothioates on a tetrapodal pentaerythritol-derived soluble support. The synthesis cycle consisted of two reactions and two precipitations: (1) the coupling under basic conditions, followed by neutralization and precipitation and (2) an acid catalyzed 5'-O-deacetalization, followed by neutralization and precipitation. The simple P(V) chemistry together with the facile 5'-O-MIP deprotection proved efficient in the liquid phase oligonucleotide synthesis (LPOS). Ammonolysis released nearly homogeneous Rp or Sp phosphorothioate diastereomers in ca. 80% yield/synthesis cycle.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Phosphorothioate Oligonucleotides* / chemistry
  • Stereoisomerism

Substances

  • Phosphorothioate Oligonucleotides
  • thiophosphoric acid