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

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.

J. Org. Chem. 2023, 88, 14, 10156–10163

Improved synthesis of nucleotide blockmers using a precipitative soluble

2020 Grant Winner: Pasi Virta, University of Turku, $50,000

Pasi VirtaPasi Virta, Ph.D., professor of bio-organics at the University of Turku, Finland, has been awarded $50,000 for his research titled “Improved synthesis of nucleotide blockmers using a precipitative soluble.” This research addresses the Roundtable’s goal to optimize oligonucleotide technology and address the environmental challenge of current oligonucleotide manufacturing.

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