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Synlett 2004(12): 2143-2146  
DOI: 10.1055/s-2004-831325
LETTER
© Georg Thieme Verlag Stuttgart · New York

Oxathiaphospholane Approach to the Synthesis of Nucleoside Methane­phosphonothioates

Konrad Misiura, Wojciech J. Stec*
Department of Bioorganic Chemistry, Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Sienkiewicza 112, 90-363 Lodz, Poland
Fax: +48(42)6815483; e-Mail: wjstec@bio.cbmm.lodz.pl;
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Publication History

Received 7 April 2004
Publication Date:
31 August 2004 (online)

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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

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    General Procedure for the Synthesis of 2-Methyl-2-thio-1,3,2-oxathiaphospholane ( 3):
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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.