Oxathiaphospholane Approach to the Synthesis of Nucleoside Methane­phosphonothioates

Abstract

A new and efficient method for preparation of the diastereomers of 5′-O-DMT-nucleoside 3′-O-methanephosphonothioates has been elaborated based on an oxathiaphospholane approach, developed earlier in this laboratory. Appropriately protected 3′-OH nucleosides react in the presence of DBU with 2-methyl-2-thio-1,3,2-oxathiaphospholane providing an equimolar mixture of dia­stereomers of nucleoside 3′-O-methanephosphonothioates which were separated by silica gel column chromatography.

antisense agents - antiviral agents - nucleoside - oxathiaphospholane - methanephosphonothioate

References

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14a

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General Procedure for the Synthesis of Diastereomers of ( R _P )- and ( S _P )-5′- O -DMT-nucleoside 3′- O -methanephos-phonothioate ( R _P -1a-e and S _P -1a-e).
The appropriately protected nucleoside 2a-e (2 mmol) was suspended in dry MeCN (20 mL). 2-Methyl-2-thio-1,3,2-oxathiaphospholane (3, 0.46 g, 3 mmol) and dry DBU (0.60 mL, 4 mmol) were added subsequently under stirring. The reaction mixture was stirred for 30 min and then was concentrated. The residue was purified and separated by short-pad silica gel (40 g) column chromatography using a mixture of CHCl₃ and EtOH as eluent (19:1, v/v; CHCl₃-EtOH 9:1 for 1b), containing 1% of Et₃N. The products 1a-e were obtained as foams consisting of a mixture of diastereomers in ca. 1:1 ratio, which were separated by column chromatography on fine silica gel (50 g) using a mixture of CHCl₃ and EtOH as eluent (39:1, v/v; CHCl₃-EtOH 19:1 for 1b and CHCl₃-acetone 19:1 for 1e), containing 5% of Et₃N. Fast-migrating diastereomers S _P- 1a-e and slow-migrating diastereomers R _P-1a-e were obtained as foams.

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