M. Wenska et al. / Tetrahedron Letters 42 (2001) 8055–8058
8057
pyridine (9:1, v/v) (10 mL; sometimes gentle heating
was necessary to dissolve 6) was added to 5%-O-(4,4%-
dimethoxytrityl)nucleoside of type 1 (1 mmol; made
anhydrous by repeated evaporation of added anhy-
drous pyridine). The aryl nucleoside cyclic phosphite of
type 7 formed was treated after 5 min with a mixture of
H2S (5 molar equiv., 1 M solution in dioxane) and
trimethylsilyl chloride (15 molar equiv.) and then (after
another 5 min) elemental sulfur (3 molar equiv.) was
added. When the sulfurisation was complete (ca. 5 min,
31P NMR and TLC), the reaction mixture was neu-
tralised with 5% aq. NaHCO3 (5 mL) and the solvents
were removed by evaporation under reduced pressure.
The residue was dissolved in methylene chloride con-
taining triethylamine (1%, v/v; 30–40 mL), washed with
5% aq. NaHCO3 (3×10 mL) and the organic layer
evaporated. The removal of the 5%-O-dimethoxytrityl
group was effected by treatment of the oily residue with
80% aq. acetic acid (10 mL) during 20 min. After
evaporation of acetic acid, the crude product was dis-
solved in a minimum volume of methylene chloride/
methanol (4:1, v/v) and applied on a silica gel column
pre-equilibrated with methylene chloride/triethylamine
(99:1, v/v). Chromatography was performed using a
stepwise gradient (0–10%, v/v) of methanol in methyl-
ene chloride containing triethylamine (1%, v/v). The
fractions containing pure product were collected, evap-
orated and freeze-dried from benzene/methanol (4:1,
v/v). Cyclic phosphorodithioates 5 (triethylammonium
salts) were obtained as white amorphous solids (purity
of the produced cyclic H-phosphonothioate 3 with ele-
mental sulfur. All transformations involved can be car-
ried out as ‘a one-pot reaction’, and are compatible
with nucleosidic substrates bearing unprotected amino
functions. The method is very efficient and experimen-
tally simple.
Acknowledgements
Financial support from the State Committee for Scien-
tific Research, Republic of Poland and the Swedish
Natural Science Research Council is gratefully
acknowledged.
References
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1
>98%, H NMR). Yields: 5a 95%, 5b 85%, 5c 90%, 5d
84%.†
7. Ora, M.; Peltomaki, M.; Oivanen, M.; Lonnberg, H. J.
Org. Chem. 1998, 63, 2939–2947.
In conclusion, we have developed a new, general proto-
col for the preparation of nucleoside 2%,3%-O,O-cyclic
phosphorodithioates of type 5. The method relies on
8. Eckstein, F.; Gish, G. TIBS 1989, 97–100.
9. Jankowska, J.; Wenska, M.; Popenda, M.; Stawinski, J.;
Kraszewski, A. Tetrahedron Lett. 2000, 41, 2227–2229.
10. Eckstein, F. J. Am. Chem. Soc. 1970, 92, 4718–4723.
11. Kers, A.; Kers, I.; Stawinski, J.; Sobkowski, M.;
Kraszewski, A. Tetrahedron 1996, 52, 9931–9944.
12. 4-Nitrophenol (4.2 g, 30 mmol; rendered anhydrous by
repeated addition and evaporation of excess acetonitrile)
and phosphorus trichloride (1.4 g, 10 mmol) were
refluxed in acetonitrile (50 mL) for 3 days under slightly
reduced pressure to evacuate the HCl evolved. After
cooling to rt and concentration to half of the initial
volume, white crystals of product 6 precipitated and were
filtered off and dried. Yield 3.5 g (80%). 31P NMR lP
(DMF) 126.17 ppm; m/z 445.0301, calculated for
C18H12N3O9P 445.0311; mp=174–176°C.
13. Walsh, E. N. J. Am. Chem. Soc. 1959, 81, 3023–3026.
14. In separate experiments we showed that the integrity of
the phospholane ring in 3a remained intact upon pro-
longed (3–4 h) treatment with hydrogen sulfide (31P
NMR).
15. On this occasion we also studied the stability of the
phosphorodithioates moiety in 2%,3%-cyclic phosphates
under acidic conditions [see Ora et al. (Ref. 16) on the
pH-dependent desulfurisation of nucleoside phospho-
rodithioates and their 2%,3%-O,O-phosphorodithioates].
When uridine 2%,3%-O,O-cyclic phosphorodithioate 5a
sulfhydrolysis of 4-nitrophenyl cyclic phosphite
7
[accessible from ribonucleosides using the stable, crys-
talline, and readily available phosphitylating agent,
tris(4-nitrophenyl) phosphite 6], followed by oxidation
† Chemical identity of compounds 5a–d was confirmed by, 1H, 31P
NMR and HRMS. 5a, lH (D2O) 1.32 (9H, t, J=7.5 Hz, CH2CH3),
3.22 (6H, q, J=7.5 Hz, CH2CH3), 3.79 (1H, m, 5%, 5¦-H2), 4.42 (1H,
m, 4%-H), 4.96 (1H, m, 3%-H), 5.07 (1H, m, 2%-H), 5.68 (1H, d, J=7.5
Hz, 5-H), 6.06 (1H, d, J=2.4 Hz, 1%-H), 7.78 (1H, d, J=7.5 Hz,
6-H); lP (D2O) 138.22 (dd, 3JHP=10.1 and 7.3 Hz); m/z 336.9740,
calculated for [C9H10N2O6PS2]− 336.9718. 5b, lH (D2O) 1.09 (9H, t,
J=7.5 Hz, CH2CH3), 2.97 (6H, q, J=7.5 Hz, CH2CH3), 3.74 (2H,
m, 5%, 5¦-H2), 4.44 (1H, m, 4%-H), 5.12 (1H, m, 3%-H), 5.40 (1H, m,
2%-H), 6.29 (1H, d, J=4.2 Hz, 1%-H), 8.06 (1H, s, 2-H), 8.16 (1H, s,
8-H); lP (D2O) 137.65 (dd, 3JHP=11.9 and 5.5 Hz); m/z 359.9992,
calculated for [C10H11N5O4PS2]− 359.9990. 5c, lH (D2O) 1.30 (9H,
t, J=7.5 Hz, CH2CH3), 3.19 (6H, q, J=7.5 Hz, CH2CH3), 3.78
(2H, m, 5%, 5¦-H2), 4.44 (1H, m, 4%-H), 4.98 (1H, m, 3%-H), 5.03 (1H,
m, 2%-H), 5.95 (1H, d, J=7.5 Hz, 5-H), 6.05 (1H, d, J=2.4 Hz,
3
1%-H), 7.81 (1H, d, J=7.5 Hz, 6-H); lP (D2O) 137.10 (dd, JHP
=
11.9 and 6.4 Hz); m/z 335.9852, calculated for [C9H11N3O5PS2]−
335.9878. 5d, lH (D2O) 1.30 (9H, t, J=7.3 Hz, CH2CH3), 3.22 (6H,
q, J=7.3 Hz, CH2CH3), 3.80 (2H, m, 5%, 5¦-H2), 4.49 (1H, m, 4%-H),
5.18 (1H, m, 3%-H), 5.38 (1H, m, 2%-H), 6.24 (1H, d, J=3.9 Hz,
1%-H), 7.93 (1H, s, 8-H); lP (D2O) 136.91 (t, 3JHP=8.7 Hz); m/z
375.9947, calculated for [C10H11N5O5PS2]− 375.9939.