Stereo-Controlled Liquid Phase Synthesis of Phosphorothioate Oligonucleotides on a Soluble Support
Petja Rosenqvist, Verneri Saari, Ella Pajuniemi, Alejandro Gimenez Molina, Mikko Ora, András Horváth, Pasi Virta
Abstract
High Resolution Image Download MS PowerPoint Slide 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.