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.

Key words

antisense agents - antiviral agents - nucleoside - oxathiaphospholane - methanephosphonothioate

References

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• 14a

  General Procedure for the Synthesis of 2-Methyl-2-thio-1,3,2-oxathiaphospholane ( 3):
  Into a solution of methanephosphonodichloridothioate (7.45 g, 50 mmol) in dry toluene (75 mL), a solution of 2-mercap-toethanol (3.5 mL, 50 mmol) and dry Et₃N (15.5 mL, 60 mmol) in dry toluene (50 mL) was added dropwise under stirring. The reaction mixture was cooled in a water bath and then left for 2 h. The resulting suspension was filtered and the filtrate was concentrated. The oily residue (7.62 g) was distilled under reduced pressure to provide the product in 59% yield (4.54 g); bp 115-118 °C/1 mmHg, (lit. [14b] 114-116 °C/1 mmHg)], TLC: R_f = 0.65 (CHCl₃). ³¹P NMR (CDCl₃): δ = 115.0.

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15

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.

18

Reaction conditions were the same as described for synthesis 1a-e. Desired compounds were purified by means of column chromatography on silica gel using a mixture of CHCl₃ and EtOH 9:1 (v/v) containing 5% of Et₃N as eluent. For obtained products the correct ¹H NMR spectra and FAB-MS data were obtained. ¹H NMR and ³¹P NMR spectra were run in CDCl₃.