New phosphoramidates as protecting groups in ribooligonucleotides synthesis

Area of Science:

• Organic Chemistry
• Nucleotide Chemistry
• Biochemistry

Background:

• Phosphoramidates are key intermediates in nucleotide synthesis.
• Stability of phosphoramidate linkages is crucial for efficient oligonucleotide construction.
• Developing more stable phosphoramidate derivatives can improve synthetic yields.

Purpose of the Study:

• To synthesize and characterize novel phosphoramidate derivatives of uridine 5"-phosphate.
• To assess the chemical stability of these derivatives under various conditions.
• To explore the utility of a stabilized phosphoramidate in dinucleotide synthesis.

Main Methods:

• Condensation reactions involving uridine 5"-phosphate with specific amines.
• Stability testing in anhydrous pyridine, aqueous pyridine, and acetic acid.
• Oxidation of a thioether phosphoramidate to a sulfoxide.
• Dinucleotide synthesis via phosphoramidate coupling.

Main Results:

• Several phosphoramidates of uridine 5"-phosphate were successfully synthesized.
• The p-methylthioanilidate derivative was oxidized to the corresponding p-methylsulfoxylanilidate.
• The p-methylsulfoxylanilidate exhibited a 5-fold increase in stability compared to the p-methylthio compound.
• A protected dinucleotide, MMTrU(OBz)-p-U(OBz)-p, was synthesized in 28% yield using the stabilized phosphoramidate.

Conclusions:

• The oxidation of p-methylthioanilidate to p-methylsulfoxylanilidate significantly enhances its stability.
• This enhanced stability facilitates its use in the synthesis of dinucleotides.
• The developed methodology offers a promising route for constructing more complex nucleotide structures.