Electrooxidative glycosylation through C-S bond cleavage of 1-arylthio-2,3-dideoxyglycosides. Synthesis of 2′,3′- dideoxynucleosides

Article abstract of DOI:10.1021/ol051776d

(Chemical Equation Presented) The electrooxidative glycosylation of newly designed 1-arylthio-substituted 2,3-dideoxyglycosides is described. The halide salt-mediated electrooxidation utilizing either of the α- or β-thiodideoxyglycosides proceeded smoothl

Full text of DOI:10.1021/ol051776d

ORGANIC
LETTERS
2005
Vol. 7, No. 21
4649-4652
Electrooxidative Glycosylation through
S Bond Cleavage of
1-Arylthio-2,3-dideoxyglycosides.
Synthesis of 2 ,3 -Dideoxynucleosides
C−
′
′
Koichi Mitsudo, Takashi Kawaguchi, Seiji Miyahara, Wataru Matsuda,
Manabu Kuroboshi, and Hideo Tanaka*
Department of Applied Chemistry, The Graduate School of Natural Science and
Technology, Okayama UniVersity, 3-1-1 Tsushima-Naka, Okayama 700-8530, Japan
tanaka95@cc.okayama-u.ac.jp
Received July 27, 2005
ABSTRACT
The electrooxidative glycosylation of newly designed 1-arylthio-substituted 2,3-dideoxyglycosides is described. The halide salt-mediated
electrooxidation utilizing either of the - or -thiodideoxyglycosides proceeded smoothly at 78 C to give dideoxynucleosides in a -selective
r
â
−
°
â
manner, presumably through a 1-halo-substituted glycosyl donor.
2′,3′-Dideoxynucleosides are of considerable interest because
several of these derivatives exhibit potent antiviral activity
against HIV (Figure 1).1 In the synthesis of 2′,3′-dideoxy-
nucleosides, selective formation of the â-glycosidic linkage
is critical since only the â-anomers show significant biologi-
cal activity. The glycosylation of nucleobases using thiogly-
(1) (a) Herdewijn, P.; Balzarini, J.; De Clercq, E. 2′,3′-Dideoxynucleoside
Analogues as Antiviral Agents. In AdVances in AntiViral Drug Design; De
Clerck, E., Ed.; JAI Press: Greenwich, CT, 1993; Vol. 1. (b) De Clercq,
E. Trends Pharmacol. Sci. 1990, 11, 198. (c) Mitsuya, H.; Weinhold, K.
J.; Furman, P. A.; St. Clair, M. H.; Lehrman, S. N.; Gallo, R. C.; Bolognesi,
D. B.; Barry, D. W.; Broder, S. Proc. Natl. Acad. Sci. U.S.A. 1985, 82,
7096. (d) Barre-Sinoussi, F.; Chermann, J. C.; Rey, F.; Nugeyre, M. T.;
Chamaret, S.; Gruest, J.; Daugeuet, C.; Axler-Blin, C.; Vezinet-Brun, F.;
Rozenbaum, W.; Montagnier, L. Science 1983, 220, 868. (e) Gallo, R. C.;
Salahuddin, S. Z.; Popovic, M.; Shearer, G. M.; Kaplan, M.; Haynes, B.
F.; Palker, T. J.; Redfield, R.; Oleske, J.; Safai, B.; White, G.; Foster, P.;
Markham, P. D. Science 1984, 224, 500.
Figure 1. Potent anti-HIV reagents.
cosides is one of the most effective methods for preparing
nucleosides and has been investigated intensively.2 The
stereochemical outcome at the anomeric position is mainly
determined by neighboring group effects from the group at
10.1021/ol051776d CCC: $30.25
© 2005 American Chemical Society
Published on Web 09/16/2005

C2 in the glycosyl donors. However, anchimeric assistance
cannot be used in the synthesis of 2′-deoxynucleosides
because of the lack of a participatory group at C2′. Therefore,
the development of efficient methods for the synthesis of
â-anomers of 2′,3′-dideoxynucleosides (in a stereoselective
manner) is still an important issue.
electricity was passed through a CH2Cl2 solution of the
glycosyl donors 1aR-1cR and the silylated uracil 2 (4 equiv)
in the presence of tetrabutylammonium tetrafluoroborate
(Bu4NBF4) as a supporting electrolyte (Scheme 2). However,
Divalent sulfur compounds have received much attention
as targets for electrooxidation.3 Various transformations have
been reported, including glycosylations by electrooxidation
of thio-substituted glycosyl donors.4,5 However, to our
knowledge, there have been no reports of the electrooxidative
synthesis of 2′,3′-dideoxynucleosides, which as a conse-
quence led us to investigate such an approach. Herein, we
report on the electrooxidative glycosylation of 2,3-dideoxy-
thioglycosides to obtain 2′,3′-dideoxynucleosides in a â-se-
lective manner.
Scheme 2. Direct Electrooxidative Glycosylation
Since the glycosyl donors for glycosylation reactions
should be stable yet highly reactive after activation, we
designed a series of thioglycosides 1a-c that had readily
oxidizable electron-rich arylthio moieties at the anomeric
position (Scheme 1).6
the coupling products 3 were obtained in only 27%, 25%,
and 9% yields, respectively, and the â/R ratios were in the
range of 1.1-1.7.
These disappointing results prompted us to investigate the
indirect electrooxidative glycosylation. To our delight, we
found that the reaction efficiency and stereoselectivity of
glycosylation reaction was highly improved by the halide
salt-mediated electrooxidation ([X-]/[X+]-mediated elec-
trooxidation). Electrolysis of the glycosyl donor 1aR with
TMS-uracil 2 was performed in CH2Cl2 containing Bu4NCl
(1.5 equiv) as the halide salt to afford nucleoside 3â in low
yield (19%), but the â/R ratio was significantly improved to
4.8 (Table 1, entry 1). Addition of Bu4NBr improved the
Scheme 1. Glycosyl Donors 1a-c
Table 1. [X-]/[X+]-Mediated Electrooxidative Glycosylation
We first investigated the direct electrooxidative glycosy-
lation of R-anomers 1aR-1cR. A 2 F/mol7 amount of
(2) Glycosylation using thioglycosides: (a) Motawia, S. M.; Pedersen,
B. E. Liebigs Ann. Chem. 1990, 599. (b) Okabe, M.; Sun, C. R.; Tam, K.
Y.; Torado, J. L.; Coffen, L. D. J. Org. Chem. 1988, 53, 4780. (c)
Kawakami, H.; Ebata, T.; Koseki, K.; Matsumoto, K.; Itoh, K. Heterocycles
1990, 31, 2041. (d) Farina, V.; Benigni, A. D. Tetrahedron Lett. 1988, 29,
1239. (e) Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin Trans.
1 1975, 1574. (f) Chu, K. C.; Babu, R. J.; Lee, J. S. J. Org. Chem. 1990,
55, 1418. (g) Kim, U. C.; Misco, F. P. Tetrahedron Lett. 1992, 39, 5733.
(h) Sujino, K.; Sugimura, H. Synlett 1992, 553. (i) Young, R. J.; Shaw-
Ponter, S.; Hardy, G. W.; Mills, G. Tetrahedron Lett. 1994, 35, 8687. (j)
Sujino, K. Sugimura, H. Tetrahedron Lett. 1994, 12, 1883.
(3) Review: (a) Torii, S. Electrooxidation of Sulfur Compounds.
Monographs in Modern Chemistry, Vol. 15: Electro-Organic Syntheses.
Methods and Applications, Part 1: Oxidation; VCH Publishers: Deerfield
Beach, FL, 1985. Our previous work: (b) Torii, S.; Tanaka, H.; Kasaoka,
M.; Saito, N.; Shiroi, T.; Nokami, J.; Tada, N. Denki Kagaku 1983, 51,
139.
(4) Electrochemical O-glycosylation: (a) Noyori, Y.; Kurimoto, I. J. Org.
Chem. 1986, 51, 4320. (b) Amatore, C.; Jutand, A.; Mallet, J.-M.; Meyer,
G.; Sinay, P. J. Chem. Soc., Chem. Commun. 1990, 718. (c) Balavoin, G.;
Gref, A.; Fischer, J.-C.; Lubineau, A. Tetrahedron Lett. 1990, 31, 5761.
(d) Balavoine, G.; Berteina, S.; Gref, A.; Fischer, J.-C.; Lubineau, A. J.
Carbohydr. Chem. 1995, 14, 1217. (e) Balavoine, G.; Berteina, S.; Gref,
A.; Fischer, J.-C.; Lubineau, A. J. Carbohydr. Chem. 1995, 14, 1237. (f)
Yamago, S.; Kokubo, K.; Yoshida, J. Chem. Lett. 1997, 111. (g) Suzuki,
S.; Matsumoto, K.; Kawamura, K.; Suga, S.; Yoshida, J. Org. Lett. 2004,
6, 3755.
entry
1a
additive yielda (%) â/Rb recovered 1aa (%)
1
2
3
4
1aR Bu4NCl
1aR Bu4NBr
1aâ Bu4NBr
1aR Bu4NI
19
79
72
18
4.8
3.6
4.1
1.7
33
9
trace
44
a Isolated yield. b Determined by H NMR.
1
reaction efficiently to afford nucleoside 3â in 79% yield with
moderate â-selectivity (â/R ) 3.6, entry 2). By way of
contrast, with Bu4NI, the reaction proceeded to give nucleo-
side 3â in low yield with poor â-selectivity (entry 4).
Noteworthy is that the isomer 3â was obtained predominantly
from the electrooxidative glycosylation of each stereoisomer
1aR or 1aâ (entries 2 and 3), suggesting that the reactions
proceeded through the same intermediate from each stereo-
isomer.
(5) Electrochemical N-glycosylation: Nokami, J.; Osafune, M.; Ito, Y.;
Miyake, F.; Sumida, S.; Torii, S. Chem. Lett. 1999, 1053.
(6) The stereoisomers of 1a-c could be separated easily by silica gel
column chromatography, and the pure isomers were used for the following
reactions.
(7) F (Faraday constant) is the amount of electric charge of one mol of
electrons (1 F ) 9.64853415 × 104 C/mol).
4650
Org. Lett., Vol. 7, No. 21, 2005

[X-]/[X+]-mediated electrooxidative glycosylation of gly-
cosyl donors 1b and 1c was carried out in a similar manner
(Table 2). Bu4NBr was used as the halide salt. The glycos-
Table 3. [X-]/[X+]-Mediated Stepwise Electrooxidative
Glycosylation
Table 2. [X-]/[X+]-Mediated Electrooxidative Glycosylation
of 1bR and 1cR
entry
thioglycoside 1
yielda (%)
â/Rb
recovered 1a (%)
1
2
3
1aR
1bR
1cR
81
c
45
5.1
7
24
4.1
yielda (%)
â/Rb
1
a Isolated yield. b Determined by H NMR. c Complex mixture.
entry
thioglycoside 1
1
2
1bR
1cR
c
86
3.6
Aâ, respectively. The C-S bond of A is then cleaved to
form the same intermediate, oxonium cation B. Halide ion
X- probably reacts with B reversibly, generating the second
intermediate CR and Câ. The intermediate CR is probably
generated predominantly due to steric hindrance. As a result,
the subsequent SN2 reaction with a nucleophile affords 2â
as the major product. To support this hypothesis, the
electrooxidation of 1aR without nucleoside 2 was conducted
a Isolated yield. b Determined by 1H NMR. c Complex mixture containing
3.
ylation of 1cR proceeded smoothly to form the nucleoside 3
in 86% yield (â/R ) 3.6, entry 2), while only a complex
mixture was obtained from 1bR (entry 1).8
The electrooxidative glycosylation of both 1aR and 1aâ
afforded nucleoside 3 with a similar level of reactivity and
stereoselectivity. This result indicates that the reaction
probably does not proceed via an SN2 mechanism. A
plausible mechanism is illustrated in Scheme 3. The EG [X+]
1
in the presence of Bu4NCl, and H NMR was recorded at
-50 °C. The anomeric proton of the chlorinated dideox-
ysugar CR was observed at 6.42 ppm (doublet, J ) 3.3 Hz).9
In this reaction, the oxonium cation B reacts with the
nucleophile competitively to give a mixture of the nucleo-
sides 3R and 3â in poorly selective manner. One way to
suppress the undesired process would be to effect the
preoxidation of 1 without nucleobase 2. Therefore, we
conducted the electrooxidation of 1R without nucleophile
and then nucleophile was added to the electrolysis solution.
Scheme 3. A Plausible Mechanism
Table 4. Electrooxidative Glycosylation with Several
Nucleophiles
(X ) Cl, Br), generated by electrooxidation of X-, attacks
the sulfur atom of 1R and 1â to give sulfenium ion AR and
1
a Isolated yield. b Determined by H NMR. c Mixture of N9-R + N7-R
+ N9-â + N7-â. d Ratio of (N9-â + N7-â)/(N9-R + N7-R).
1
(8) Brominated anthracenyl groups were observed by H NMR.
Org. Lett., Vol. 7, No. 21, 2005
4651

The results of the two-step sequence involving the halide
salt-mediated electrooxidation of glycosyl donors 1aR-1cR
and subsequent reaction with TMS-uracil 2 are summarized
in Table 3. Electrolysis of glycosyl donor 1aR in CH2Cl2
was performed under a constant current condition (10 mA,
24 min, 1.5 F/mol) at -78 °C in an undivided cell. Then, to
this reaction mixture was added TMS-uracil 2 in CH2Cl2.
The reaction proceeded smoothly to afford the corresponding
nucleoside 3 in 81% yield with a â/R ratio of 5.1 (entry 1).
The glycosyl donor 1cR also gave nucleoside 3 in 45% yield
and the â/R ratio was 4.1 (entry 3). On the other hand, only
a complex mixture was obtained from glycosyl donor 1bR
(entry 2).
4, entries 1 and 2). When TMS-adenine was employed as a
nucleobase, the reaction proceeded similarly to afford the
corresponding nucleoside 6 in a 68% yield with moderate
â-selectivity (â/R ) 4.4, entry 3). Unfortunately, nucleoside
6 was produced as a mixture of regioisomers (N9 and N7
isomers).
In summary, the halide salt-mediated electrooxidative
glycosylation using 2,3-dideoxyglycosides was found to
proceed smoothly to afford 2′,3′-dideoxynucleosides with
moderate to high â-selectivity. Further investigation of this
strategy is currently in progress in our laboratory.
Acknowledgment. We thank the SC-NMR Laboratory
1
of Okayama University for H and 13C NMR analysis.
Finally, we carried out the electrooxidative glycosylation
in the presence of other nucleobases. The reaction with TMS-
thymine and TMS-cytosine gave the corresponding nucleo-
sides 4 and 5 with high â-selectivity (â/R ) 13.8, 12.4, Table
Supporting Information Available: Experimental pro-
cedures and characterization data for new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(9) The anomeric proton of Câ was also observed at 6.35 ppm (doublet,
J ) 3.9 Hz)
OL051776D
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Org. Lett., Vol. 7, No. 21, 2005