thiocytidine was found to be able to inhibit the proliferation
of human lymphoblastoid cells probably after reduction,
phosphorylation, and inactivation of RDPR.3d However, the
cytotoxicity of this compound in various cancer cell lines
appeared too low for further evaluation in animals.
2′,3′-Unsaturated 2′-thionucleosides (Scheme 1) also could,
after in vivo phosphorylation, inactivate RDPR through free
radical reactions. In this approach, the corresponding disul-
fides could be reduced and lead to the vinylthiol diphosphate
able to react at the active site from the double bond and/or
the thiol function.
borate,6 but this method failed in the preparation of vinyl
disulfides. The reported reaction constitutes the first example
of direct conversion of a vinyl sulfide to the corresponding
disulfide.
The unsaturated silyl uridine derivative 3 and its 5-methyl
analogue 4 were prepared in four steps from the TMSE
sulfides 16b and 2, respectively (Scheme 2, 60 and 64%
yields): (i) 4,4′-dimethoxytritylation of the 5′-hydroxyl
function, (ii) mesylation at the 3′-position in the same pot,
(iii) removal of the trityl group under acidic conditions, and
(iv) elimination with K2CO3.
The unsaturated silyl cytidine derivative 16 was prepared
in six steps from the silyl sulfide 146b (Scheme 3, 29%): (i)
Scheme 1. Structure of the Target Nucleoside Vinyl
Disulfides and Their Possible Bioactive Derivatives
Scheme 3. Preparation of the Cytidine Derivatives
2′,3′-Unsaturated nucleosides have shown interesting
antiviral effects, for example, the anti-HIV drug 2′,3′-
didehydro-2′,3′-dideoxythymidine (d4T).4 A limited number
of vinyl disulfides have been described in the literature, and
their preparation required the formation of the corresponding
unstable intermediate “vinylthiol” (enethiol) or drastic condi-
tions.5
We now report a straightforward preparation of various
nucleoside vinyl disulfides in high yields under mild condi-
tions using a new reaction of vinyl 2-(trimethylsilyl)ethyl
(TMSE) sulfides with commercially available sulfenyl
chlorides (Scheme 2). Previously, 2-TMSE alkyl sulfides
5′-silylation with tert-butyldiphenylsilyl chloride, (ii) protec-
tion of the amino group with benzoic anhydride, (iii) 3′-
mesylation, (iv) deprotection of the amino group with
ammonia, (v) elimination in the presence of K2CO3, and (vi)
removal of the 5′-silyl protecting group with ammonium
fluoride.
Scheme 2. Preparation of the Uridine and 5-Methyluridine
Derivatives
Attempts to convert the unsaturated silyl nucleosides 3
and 4 to the corresponding methyl disulfides by treatment
with dimethyl(methylthio)sulfonium tetrafluoroborate6a,b failed
under different conditions as well as attempts to convert these
sulfides to the corresponding thiols by treatment with fluoride
ions. Previously, we have shown that TMSE sulfides can be
converted selectively and in high yield to the corresponding
thiocyanates through the von Braun reaction with cyanogen
bromide in methanol.7 Different thiocyanato nucleosides have
been prepared using this reaction. For example, treatment
of the sulfide 1 with cyanogen bromide in methanol led to
the corresponding thiocyanate, but surprisingly, the reaction
(4) For review, see: Len, C.; Mackenzie, G. Tetrahedron 2006, 62,
9085-9107.
(5) (a) Wiejers, H. E.; Boelens, H.; Gen, A. V. D.; Brandsma, L. Recl.
TraV. Chim. Pays-Bas 1969, 88, 519-529. (b) Dekant, W.; Urban, G.;
Gorsmann, C.; Anders, M. W. J. Am. Chem. Soc. 1991, 113, 5120-5122.
(6) (a) Anderson, M. B.; Ranasinghe, M. G.; Fuchs, P. L. J. Org. Chem.
1988, 53, 3125-3127. (b) Chambert, S.; Gautier-Luneau, I.; Fontecave,
M.; De´cout, J.-L. J. Org. Chem. 2000, 65, 249-253. (c) For review, see:
Chambert, S.; De´sire´, J.; De´cout, J.-L. Synthesis 2002, 2319-2334.
(7) Chambert, S.; Thomasson, F.; De´cout, J.-L. J. Org. Chem. 2002, 67,
1898-1904.
have been converted to the corresponding methyl disulfides
by treatment with dimethyl(methylthio)sulfonium tetrafluoro-
3022
Org. Lett., Vol. 9, No. 16, 2007