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Synlett 2007(17): 2748-2752  
DOI: 10.1055/s-2007-991072
LETTER
© Georg Thieme Verlag Stuttgart · New York

Nucleoside H-Phosphonates, XXII: Synthesis and Properties of New Nucleotide Analogues - H-Phosphonothiolate Diesters

Renata Hiresovaa, Jacek Stawinski*a,b
a Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, 106 91 Stockholm, Sweden
e-Mail: js@organ.su.se;
b Institute of Bioorganic Chemistry, Polish Academy of Sciences, Noskowskiego 12/14, 61-704 Poznan, Poland
Further Information

Publication History

Received 10 August 2007
Publication Date:
25 September 2007 (online)

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Abstract

Condensation of nucleoside 3′-H-phosphonate mono­esters with various thiols, promoted by condensing agents, provides a convenient access to a new class of H-phosphonate analogues, H-phosphonothiolate diesters. Chemical properties, relevant to possible applications of these compounds as a new type of synthetic ­intermediates in the preparation of nucleotide analogues bearing a sulfur atom at the bridging position of a phosphate group, were ­investigated.

Key words

H-phosphonates - H-phosphonothiolates - phosphate analogues - nucleotide analogues

22

Compound 3 was obtained on independent way by reacting H-phosphonothiolate 2a with pivaloyl chloride in MeCN-pyridine (4:1). The signals of two P-diastereomers were not resolved in the 31P NMR spectrum.

23

Ethyl H-phosphonate reacted with ethanethiol analogously to that of 1, producing compound of type 4 (R = Et) that resonated at δ P = 157.8 ppm (3 J PH = 9.4 Hz, hept). This compound was prepared independently by reacting ethyl phosphorodichloridite with 2 equiv of ethanethiol in MeCN-pyridine (4:1).

25

Comparison with original sample obtained by condensation of 1 with ethanol in the presence of pivaloyl chloride. The P-diastereomers were not resolved.

28

General Procedure for Synthesis and Oxidative Transformations of H-Phosphonothiolates 2a-d Nucleoside H-phosphonate monoester 1 (0.15 mmol) was rendered anhydrous by evaporation of added pyridine, and the residue was dissolved in MeCN-pyridine (4:1; 2 mL) or in CH2Cl2-pyridine (4:1; 2 mL, for thiols c and d). To this solution, the appropriate thiol a-d (2 equiv) and a condensing agent (diphenyl phosphorochloridate; 1 equiv) were added. The reactions were complete within 5 min (31P NMR analysis) producing the expected nucleoside H-phosphonothiolates 2.
³¹ P NMR Data for Compounds 2
Compound 2a: δ = 33.75 and 34.08 ppm (1 J PH = 658.2 Hz, 3 J PH = 11.1 Hz, dq); 2b: δ = 33.96 and 34.23 ppm (1 J PH = 659.9 Hz, 3 J PH = 10.7 Hz, dq); 2c: δ = 32.66 and 32.79 ppm (1 J PH = 672.2 Hz, 3 J PH = 10.7 Hz, dq); 2d: δ = 33.01 and 33.37 ppm (1 J PH = 652.0 Hz, 3 J PH = 11.4 Hz, dt).
To the solution containing 2a-d, a mixture of CCl4 (10 equiv), H2O (50 equiv), and Et3N (2 equiv) was added. The reactions were complete within 5 min (31P NMR analyses), producing quantitatively the corresponding phosphorothiolates 7a-d, that were isolated by silica gel column chromatography (purity >98%, 1H NMR).
³¹ P NMR Data for Compounds 7 Compound 7a (82%): δ = 18.76 ppm (3 J PH = 11.1 Hz, q); 7b (72%): δ = 18.99 ppm (3 J PH = 11.1 Hz, q); 7c (64%): δ = 16.64 ppm (3 J PH = 10.2 Hz, q); 7d (56%): δ = 19.86 ppm (3 J PH = 10.1 Hz, t).
Sulfurization of the in situ generated H-phosphonothiolates 2a-d was performed by the addition of elemental sulfur (3 equiv) and Et3N (2 equiv) to the corresponding reaction mixtures. The reactions were complete within 5 min (31P NMR analyses), affording quantitatively the corresponding phosphorodithioates 8a-d, that were isolated by silica gel column chromatography (purity >98%, 1H NMR).


³¹ P NMR Data for Compounds 8 Compound 8a (67%): δ = 74.22 and 75.26 ppm (3 J PH = 12.6 Hz, q); 8b (61%): δ = 74.39 and 75.26 ppm (3 J PH = 12.7 Hz, q); 8c (65%): δ = 73.85 and 74.17 ppm (3 J PH = 12.6 Hz, q); 8d (59%): δ = 74.54 and 76.35 ppm (3 J PH = 12.9 Hz, t).