Practical synthesis of 2′-deoxy-4′-thioribonucleosides: Substrates for the synthesis of 4′-thioDNA

Article abstract of DOI:10.1021/jo051248f

We report herein a practical synthesis of 4′-thiothymidine (15) and appropriately protected 2′-deoxy-4′-thiocytidine (16), -thioadenosine (27), and -thioguanosine (29) derivatives, substrates for the synthesis of 4′-thioDNA, from the corresponding 4′- thi

Full text of DOI:10.1021/jo051248f

Unlike the 4′-thioRNAs, the properties of oligodeoxy-
ribonucleotides containing 2′-deoxy-4′-thioribonucleosides
(4′-thioDNA) have not been well elucidated. Walker and
co-workers reported the synthesis of 4′-thioDNAs consist-
ing of 2′-deoxy-4′-thiopyrimidine nucleoside units, and
their preliminary properties, including nuclease resis-
tance and hybridization ability.4 However since then,
nothing has been published on the use of 4′-thioDNA as
a functional DNA molecule despite the favorable proper-
ties of 4′-thioDNA. This is probably due in large part to
the difficulty of synthesizing 2′-deoxy-4′-thioribonucleo-
sides.5,6 Haraguchi et al. have recently reported the
stereoselective synthesis of 2′-deoxy-4′-thioribonucleo-
sides based on electrophilic glycosidation of 4-thiofura-
noid glycals.7 Although this method involves interesting
chemistry, the reactions were all carried out on a very
small scale.
Practical Synthesis of
2′-Deoxy-4′-thioribonucleosides: Substrates
for the Synthesis of 4′-ThioDNA
Naonori Inoue, Daisuke Kaga, Noriaki Minakawa,* and
Akira Matsuda*
Graduate School of Pharmaceutical Sciences,
Hokkaido University, Kita-12, Nishi-6, Kita-ku,
Sapporo 060-0812, Japan
matuda@pharm.hokudai.ac.jp;
noriaki@pharm.hokudai.ac.jp
Received June 17, 2005
In view of the above background information, we
decided to develop a practical synthesis of 2′-deoxy-4′-
thioribonucleoside derivatives, which are substrates for
the synthesis of 4′-thioDNA. Since our synthetic method
using the Pummerer reaction can now be carried out on
a large scale,1a,8 deoxygenation of the 2′-hydroxyl groups
of the resulting 4′-thioribonucleoside derivatives seemed
to be the most straightforward and promising method for
our purpose.
Two groups have independently reported the synthesis
of 2′-deoxy-4′-thioribonucleosides from the corresponding
4′-thioribonucleosides using the radical deoxygenation.
Jeong et al. reported the synthesis of the 2′-deoxy-4′-
thiouridine derivative in a brief communication.9 In their
paper, the 2′-deoxy derivative was obtained in 79% yield
by treatment of the corresponding 4′-thioribo derivative
with phenyl chlorothionoformate [PhOC(S)Cl], followed
by tributyltin hydride (Bu3SnH) and triethylborane
(Et3B).10 In contrast, the reaction with the 2-chloro-4′-
thioadenosine derivative under the following conditions
[N,N′-thiocarbonyldiimidazole, and then Bu3SnH, 2,2′-
azobisisobutyronitrile (AIBN), toluene, reflux] afforded
the 2′-deoxy congener in poor yield.11 With these results
in mind, we first examined the radical deoxygenation of
We report herein a practical synthesis of 4′-thiothymidine
(15) and appropriately protected 2′-deoxy-4′-thiocytidine
(16), -thioadenosine (27), and -thioguanosine (29) deriva-
tives, substrates for the synthesis of 4′-thioDNA, from the
corresponding 4′-thioribonucleosides. 2′-Deoxy-4′-thiopyri-
midine nucleosides were synthesized using a radical reaction
of the corresponding 2′-R-bromo derivatives, which were
prepared via 2,2′-O-anhydro derivatives. 2′-Deoxy-4′-thiopu-
rine nucleosides were synthesized using the same radical
reaction of the corresponding 2′-â-bromo derivatives.
We have recently been studying the synthesis of a
series of 4′-thioribonucleosides with the aim of developing
a nucleoside antimetabolite as well as a functional RNA
molecule.1,2 In our preceding papers, we reported the
stereoselective synthesis, via the Pummerer reaction,3 of
4′-thioribonucleosides, which we have since incorporated
into oligoribonucleotides by chemical and enzymatic
approaches to give 4′-thioRNA.2 Because the 4′-thioRNA
showed high nuclease resistance and hybridization
properties,2a we thought that the RNA molecule would
be a promising candidate for functional RNAs such as
antisense, ribozyme, RNA aptamer,2b and short interfer-
ing RNA.2c
(4) (a) Hancox, E. L.; Connolly, B. A.; Walker, R. T. Nucleic Acids
Res. 1993, 21, 3485-3491. (b) Jones, G. D.; Lesnik, E. A.; Owens, S.
R.; Risen, L. M.; Walker, R. T. Nucleic Acids Res. 1996, 24, 4117-
4122. (c) Jones, G. D.; Altmann, K.-H.; Hu¨sken, D.; Walker, R. T.
Bioorg. Med. Chem. Lett. 1997, 7, 1275-1278.
(5) A preferable â-anomer synthesis of the 2′-deoxy-4′-thioribo-
nucleoside derivative has been achieved by glycosidation of 3-O-
carbamoyl-2-deoxythiosugar and 5-ethyluracil with assistance of the
3-O-carbamoyl group; see: Shaw-Ponter, S.; Mills, G.; Robertson, M.;
Bostwick, R. D.; Hardy, G. W.; Young, R. J. Tetrahedron Lett. 1996,
37, 1867-1870.
* To whom correspondence should be addressed. (A.M.) Phone: +81-
11-706-3228. Fax: +81-11-706-4980. (N.M.) Phone: +81-11-706-3230.
Fax: +81-11-706-4980.
(1) (a) Minakawa, N.; Kaga, D.; Kato, Y.; Endo, K.; Tanaka, M.;
Sasaki, T.; Matsuda, A. J. Chem. Soc., Perkin Trans. 1 2002, 2182-
2189. (b) Kaga, D.; Minakawa, N.; Matsuda, A. Nucleosides Nucleotides
Nucleic Acids 2005 in press.
(2) (a) Hoshika, S.; Minakawa, N.; Matsuda, A. Nucleic Acids Res.
2004, 32, 3815-3825. (b) Kato, Y.; Minakawa, N.; Komatsu, Y. Kamiya,
H.; Ogawa, N.; Harashima, H.; Matsuda, A. Nucleic Acids Res. 2005
33, 2942-2951. (c) Hoshika, S.; Minakawa, N.; Kamiya, H.; Harashima,
H.; Matsuda, A. FEBS Lett. 2005, 579, 3115-3118.
(3) (a) Naka, T.; Nishizono, N.; Minakawa, N.; Matsuda, A. Tetra-
hedron Lett. 1999, 40, 6297-6300. (b) Naka, T.; Minakawa, N.; Abe,
H.; Kaga, D.; Matsuda, A. J. Am. Chem. Soc. 2000, 122, 7233-7243.
(6) For examples: (a) Secrist, J. A.; Tiwari, K. N.; Riordan, J. M.;
Montgomery, J. A. J. Med. Chem. 1991, 34, 2361-2366. (b) Dyson, M.
R.; Coe, P. L.; Walker, R. T. J. Med. Chem. 1991, 34, 2782-2786.
(7) (a) Haraguchi, K.; Nishikawa, A.; Sasakura, E.; Tanaka, H.;
Nakamura, K. T.; Miyasaka, T. Tetrahedron Lett. 1998, 39, 3713-
3716. (b) Haraguchi, K.; Takahashi, H.; Shiina, N.; Horii, C.; Yoshimu-
ra, Y.; Nishikawa, A.; Sasakura, E.; Nakamura, K. T.; Tanaka, H. J.
Org. Chem. 2002, 67, 5919-5927.
(8) Minakawa, N.; Kato, Y.; Uetake, K.; Kaga, D.; Matsuda, A.
Tetrahedron 2003, 59, 1699-1702.
(9) Joeng, L. S.; Nicklaus, M. C.; George, C.; Marquez, V. E.
Tetrahedron Lett. 1994, 35, 7573-7576.
(10) The radical reaction was presumably conducted at room tem-
perature because Et3B was used as a radical initiator.
10.1021/jo051248f CCC: $30.25 © 2005 American Chemical Society
Published on Web 09/21/2005
J. Org. Chem. 2005, 70, 8597-8600
8597

SCHEME 1a
SCHEME 2a
a Key: (a) thymine, TMSOTf, Et3N, CH2Cl2-toluene; (b) MeNH2
in MeOH; (c) PhOC(S)Cl, DMAP, CH3CN; (d) Bu3SnH, AIBN,
toluene, 80 °C.
the 2′-hydroxyl group of 1-[3,5-O-(1,1,3,3-tetraisopropyl-
disiloxane-1,3-diyl)-4-thio-â-D-ribofuranosyl]thymine (3)
(Scheme 1).
When the Pummerer reaction of the sulfoxide 1 with
silylated thymine was carried out, the desired 4′-thiori-
bosylthymine derivative 2 was stereoselectively obtained
in 81% yield. Treatment of 2 with methylamine gave 3,
a substrate for the radical deoxygenation. After conver-
sion of 3 into the thionocarbonate [PhOC(S)Cl, (dimethyl-
amino)pyridine (DMAP), CH3CN, rt], the resulting 4,
after a water workup, was subjected to the standard
radical deoxygenation conditions (Bu3SnH, AIBN, tolu-
ene, 80 °C) to furnish the 4′-thiothymidine derivative 5
in 48% yield along with 35% of the unexpected compound
6. In previous papers,9,11 compounds such as 6 were not
obtained.12,13 Treatment of 3 with N,N′-thiocarbonyldi-
imidazole, followed by the radical deoxygenation under
heating conditions also afforded the same results. In
contrast, when the radical deoxygenation of 4 was
conducted at room temperature using Et3B as a radical
initiator, 5 was obtained in only 10% yield after 24 h in
our hands.9,10 In the above reaction, approximately 40%
of 4 was recovered, while the ring opening product 6 was
not observed. From these results, it might be postulated
that formation of the radical intermediate 7 from the
thionocarbonate 4 through homolytic cleavage of the C-O
bond required higher temperature; however, this reaction
is accompanied by homolytic cleavage of the C-S bond
a Key: (a) Tf2O, DMAP, CH2Cl2; (b) LiBr, BF3‚Et2O, 1,4-dioxane,
50 °C; (c) Bu3SnH, V70-L, CH2Cl2; (d) TBAF, THF; (e) MeNH2 in
MeOH.
to give the radical intermediate 8. Consequently, the
radical deoxygenation of 4 afforded 6 along with the
desired 5.
As an alternative method to prepare 2′-deoxy-4′-thiori-
bonucleosides, we next envisioned the strategy of bromi-
nation at the 2′-position of 4′-thioribonucleoside deriva-
tives, followed by radical reduction of the bromo group.
As shown in Scheme 2, compound 3 was first converted
into the 2,2′-O-anhydro derivative 10 by treatment with
trifluoromethanesulfonic anhydride (Tf2O) in CH2Cl2 in
the presence of DMAP. The resulting 10 was then
subjected to bromination conditions (LiBr, BF3‚Et2O in
dioxane)14 to give 12 in 75% yield over two steps. When
12 was treated with Bu3SnH in CH2Cl2 at room temper-
ature in the presence of racemic 2,2′-azobis(2,4-dimethyl-
4-methoxyvaleronitrile) (V70-L), the desired 5 was ob-
tained in 94% yield without formation of 6. Deprotection
of the silyl group of 5 by tetrabutylammonium fluoride
(TBAF) gave 4′-thiothymidine (15) in good yield. Like-
wise, compound 91a was converted into 2′-deoxy-4′-
thiocytidine derivative 1615 via the bromide 13. All
reactions were conducted on a gram scale, and compound
15 and the N-benzoyl derivative 16 were finally obtained
in more than 1 g. Analytical data of 15 and 17 prepared
(11) Tiwari, K. N.; Secrist, J. A.; Montgomery, J. A. Nucleosides
Nucleotides 1994, 13, 1819-1828.
(12) After the report of ref 11, Secrist et al. presented the structure
of the byproduct obtained in the reaction described in ref 11. However,
this type of byproduct was not observed in our substrate; see: Secrist,
J. A.; Parker, W. B.; Tiwari, K. N.; Messini, L.; Shaddix, S. C.; Rose,
L. M.; Bennett, L. L.; Montgomery, J. A. Nucleosides Nucleotides 1995,
14, 675-686.
(14) Aoyama, Y.; Sekine, T.; Iwamoto, Y.; Kawashima, E.; Ishido,
Y. Nucleosides Nucleotides 1996, 15, 733-738.
(15) Kumar, S.; Horton, J. R.; Jones, G. D.; Walker, R. T.; Roberts,
R. J.; Cheng, X. Nucleic Acids Res. 1997, 25, 2773-2783.
(13) Quite recently, Dong and Paquette reported a similar reaction,
Dong, S.; Paquette, L. A. J. Org. Chem. 2005, 70, 1580-1596.
8598 J. Org. Chem., Vol. 70, No. 21, 2005

SCHEME 3a
FIGURE 1. Structures of 12 and 23 confirmed by NOE
experiments.
The configurations of the bromo groups of the pyrimi-
dine (12 and 13) and purine (23 and 24) derivatives were
confirmed by NOE experiments of 12 and 23 (Figure 1).
Thus, NOEs were observed at H-6 (1.2%) and H-3′ (5.9%)
upon irradiation of H-2′ of 12. Therefore, it was deter-
mined that 12 had an R-bromo group at the 2′-position.
In contrast, NOEs were observed at H-1′ (20.2%) and H-4′
(9.7%) upon irradiation of H-2′ of 23, which indicated that
there is a â-bromo group at the 2′-position. Conversion
of 3 into the 2′-bromo derivative 12 proceeded with
overall retention of configuration which can be explained
by the formation of 2,2′-anhydro derivative 10. In the
reaction with 18, the substitution proceeded via an SN2-
type reaction to give 23 with inversion of configuration.
Thus far, a number of reactions have been reported
for 4′-thionucleosides derivatives, and unexpected results
arising from the participation of the sulfur atom were
observed in some cases.13,17 In our reactions reported
here, unexpected cleavage of the C-S bond in the sugar
moiety to give 6 was observed during the radical deoxy-
genation on heating. This unfavorable C-S bond cleavage
was avoided, however, when the radical reaction was
carried out at room temperature. In contrast, participa-
tion of the sulfur atom would be negligible in the
nucleophilic substitution at the C2′-position of 4′-thiori-
bonucleoside derivative. These results agreed with those
of the reactions of the O-congeners.
a Key: (a) BzCl, pyridine, then NaOMe in MeOH; (b) Tf2O,
DMAP, CH2Cl2; (c) TIPDSCl2, pyridine; (d) Bu4NBr, benzene; (e)
Bu3SnH, V70-L, CH2Cl2; (f) TBAF, THF; (g) MeNH2 in MeOH; (h)
NH3 in EtOH, 80 °C.
from 16 were identical with those for the authentic
samples.6
For the synthesis of the 4′-thiopurine derivatives, the
synthetic route is illustrated in Scheme 3. Starting with
18,2a 19 was prepared by treatment with an excess
amount of benzoyl chloride, followed by brief treatment
with sodium methoxide. After introduction of a trifluo-
romethanesulfonyl group on the 2′-hydroxyl group of 19,
bromination of 20 was examined. Among our attempts,
treatment of 20 with Bu4NBr in benzene at room tem-
perature gave the best result, and 23 was obtained in
66% yield in two steps. Reduction of the bromo group
proceeded smoothly under the radical conditions, and the
2′-deoxy-4′-thioadenosine derivative 27 was finally ob-
tained in good yield. The 4′-thioguanosine derivative 29
was also prepared from 21 via protection, bromination,
reduction, and deprotection steps. In these cases, all
reactions were also conducted on gram scale to give 27
and 29 in sufficient quantities. The amino protective
groups of 27 and 29 were deprotected to give 2′-deoxy-
4′-thioadenosine (28) and 2′-deoxy-4′-thioguanosine (30),
respectively. The analytical data of 28 and 30 were
identical with the authentic data.16
In conclusion, we have investigated the practical
synthesis of the 2′-deoxy-4′-thioribonucleosides deriva-
tives 15, 16, 27, and 29 which would be easily converted
into the corresponding phosphoramidite units for 4′-
thioDNA synthesis. The desired compounds were syn-
thesized from 4′-thioribonucleoside derivatives via bro-
mination, followed by radical reduction at room temper-
ature. Since four kinds of 2′-deoxy derivatives are now
available on a gram scale, investigations of the synthesis
and properties of 4′-thioDNA are in progress.
Experimental Section
1-[2-R-Bromo-2-deoxy-3,5-O-(1,1,3,3-tetraisopropyldisi-
loxane-1,3-diyl)-4-thio-â-D-ribofuranosyl]thymine (12). To
a solution of 3 (1.4 g, 2.6 mmol) in dry CH2Cl2 (26 mL) containing
DMAP (1.3 g, 11 mmol) was added Tf2O (0.88 mL, 5.2 mmol) at
0 °C, and the mixture was stirred at room temperature for 2 h.
The reaction was quenched by addition of saturated aqueous
NaHCO3. The reaction mixture was partitioned between AcOEt
(17) For examples: (a) Hancox, E. L.; Walker, R. T. Nucleosides
Nucleotides 1996, 15, 135-148. (b) Otter, G. P.; Elzagheid, M. I.; Jones,
G. D.; MacCulloch, A. C.; Walker, R. T.; Oivanen, M.; Klika, K. D. J.
Chem. Soc., Perkin Trans. 2 1998, 2343-2349. (c) Miller, J. A.; Pugh,
A. W.; Ullah, G. M. Nucleosides Nucleotides Nucleic Acids 2000, 19,
1475-1486.
(16) (a) Montgomery, J. A.; Secrist, J. A. 1991 PCT/US90/05252. (b)
Draanen, N. A. V.; Freeman, G. A.; Short, S. A.; Harvey, R.; Jansen,
R.; Szczech, G.; Koszalka, G. W. J. Med. Chem. 1996, 39, 538-542.
J. Org. Chem, Vol. 70, No. 21, 2005 8599

and H2O. The separated organic layer was washed with satu-
rated aqueous NaHCO3 (three times), followed by brine. The
organic layer was dried (Na2SO4) and concentrated in vacuo to
give crude 10. The resulting 10 was dissolved in dry 1,4-dioxane
(26 mL), then BF3‚Et2O (47%, an Et2O solution, 0.49 mL, 3.9
mmol) and LiBr (340 mg, 3.9 mmol) were added to the solution.
The mixture was heated at 50 °C for 30 min. The reaction was
quenched by addition of H2O. The reaction mixture was parti-
tioned between AcOEt and H2O. The separated organic layer
was washed with saturated aqueous NaHCO3, followed by brine.
The organic layer was dried (Na2SO4) and concentrated in vacuo.
The residue was purified by a silica gel column, eluted with
hexane/AcOEt (9:1-5:1), to give 12 (1.1 g, 75%, as a white
solid): 1H NMR (CDCl3) δ 9.11 (s, 1 H), 8.09 (s, 1 H), 6.04 (s, 1
H), 4.37 (d, 1 H, J ) 4.8 Hz), 4.13 (m, 2 H), 4.03 (d, 1 H, J )
12.9 Hz), 3.72 (d, 1 H, J ) 9.1 Hz), 1.93 (s, 3 H), 0.96-1.12 (m,
28 H); 13C NMR (CDCl3) δ 163.6, 150.6, 136.3, 110.6, 71.2, 65.9,
58.9, 58.0, 51.7, 17.5, 17.4, 17.3, 17.1, 16.9, 16.8, 13.3, 13.1,
12.6, 12.5; FAB-LRMS m/z 581 (MH+); FAB-HRMS calcd for
temperature for 1 h. The reaction was quenched by addition of
H2O. The reaction mixture was partitioned between AcOEt and
H2O. The separated organic layer was washed with saturated
NaHCO3, followed by brine. The organic layer was dried (Na2-
SO4) and concentrated in vacuo. The residue was purified by
silica gel column, eluted with hexane/AcOEt (3:1-1:1), to give
23 (1.0 g, 66%, as a yellow form): 1H NMR (CDCl3) δ 9.02 (s, 1
H), 8.84 (s, 1 H), 8.46 (s, 1 H), 8.03 (m, 1 H), 7.63 (m, 1 H), 7.55
(m, 2 H), 6.24 (d, 1 H, J ) 6.6 Hz), 4.82 (dd, 1 H, J ) 10.7 and
9.4 Hz), 4.41 (dd, 1 H, J ) 6.6 and 10.7 Hz), 4.25 (dd, 1 H, J )
2.9 and 11.1 Hz), 4.17 (dd, 1 H, J ) 2.8 and 11.1 Hz), 3.48 (ddd,
1 H, J ) 9.4, 2.9 and 2.8 Hz), 1.05-1.22 (m, 28 H); 13C NMR
(CDCl3) δ 164.4, 152.7, 152.6, 152.3, 149.6, 142.4, 133.7, 132.7,
128.8, 127.7, 122.6, 60.0, 57.2, 55.4, 50.4, 17.5, 17.4, 17.3, 17.2,
17.1, 13.8, 13.2, 12.6; FAB-LRMS m/z 694 (MH+); FAB-HRMS
calcd for C29H4279BrN5O4SSi2 (MH+) 692.1758, found 692.1761.
N6-Benzoyl-9-[2-deoxy-3,5-O-(1,1,3,3-tetraisopropyldisi-
loxane-1,3-diyl)-4-thio-â-D-ribofuranosyl]adenine (25). In
the similar manner as described for 5, 23 (2.6 g, 3.8 mmol) in
dry CH2Cl2 (20 mL) containing 2,2′-azobis(2,4-dimethyl-4-meth-
oxyvaleronitrile) (racemic form) (0.23 g, 0.76 mmol) was treated
with tributyltin hydride (1.5 mL, 5.6 mmol) to give 25 (2.0 g,
84%, as a white form): 1H NMR (CDCl3) δ 9.01 (s, 1 H), 8.81 (s,
1 H), 8.54 (s, 1 H), 8.02 (m, 1 H), 7.62 (m, 1 H), 7.53 (m, 2 H),
6.12 (d, 1 H, J ) 6.5 Hz), 4.71 (m, 1 H), 4.17 (dd, 1 H, J ) 2.9
and 12.6 Hz), 4.02 (dd, 1 H, J ) 2.6 and 12.6 Hz), 3.47 (ddd, 1
H, J ) 8.8, 2.6 and 2.9 Hz), 2.57-2.69 (m, 2 H), 0.91-1.15 (m,
28 H); 13C NMR (CDCl3) δ 164.4, 152.5, 151.3, 149.4, 142.1,
133.6, 132.7, 128.8, 127.7, 123.4, 72.0, 58.9, 55.2, 54.6, 43.6, 17.5,
17.4, 17.3, 17.2, 17.1, 17.0, 13.4, 13.0, 12.6, 12.5; FAB-LRMS
m/z 614 (MH+); FAB-HRMS calcd for C29H43N5O4SSi2 (MH+)
614.2653, found 614.2682.
C
22H4079BrN2O5SSi2 (MH+) 579.1380, found 579.1387.
1-[2-Deoxy-3,5-O-(1,1,3,3-tetraisopropyldisiloxane-1,3-
diyl)-4-thio-â-D-riofuranosyl]thymine (5). To a solution of 12
(1.1 g, 1.9 mmol) in dry CH2Cl2 (9.5 mL) containing 2,2′-azobis-
(2,4-dimethyl-4-methoxyvaleronitrile) (racemic form) (120 mg,
0.39 mmol) was added tributyltin hydride (0.80 mL, 2.5 mmol),
and the mixture was stirred at room temperature for 15 min.
The mixture was concentrated in vacuo, and the residue was
purified by silica gel column, eluted with hexane/AcOEt (9:1-
1:1), to give 5 (1.0 g, 94%, as a yellow form): 1H NMR (CDCl3)
δ 9.78 (s, 1 H), 7.89 (s, 1 H), 6.07 (d, 1 H, J ) 7.6 Hz), 4.45 (m,
1 H), 4.13 (dd, 1 H, J ) 3.1 and 12.9 Hz), 3.95 (d, 1 H, J ) 12.9
Hz), 3.32 (m, 1 H), 2.48 (m, 1 H), 2.25 (m, 1 H), 1.92 (s, 3 H),
0.88-1.15 (m, 28 H); 13C NMR (CDCl3) δ 163.8, 150.8, 136.5,
110.7, 70.9, 58.0, 57.1, 54.8, 43.0, 17.5, 17.3, 17.1, 17.0, 16.9,
13.4, 13.2, 12.9, 12.6, 12.4; FAB-LRMS m/z 501 (MH+); FAB-
HRMS calcd for C22H41N2O5SSi2 (MH+) 501.2275, found 501.2265.
N6-Benzoyl-9-[2-â-bromo-2-deoxy-3,5-O-(1,1,3,3-tetraiso-
propyldisiloxane-1,3-diyl)-4-thio-â-D-ribofuranosyl]ade-
nine (23). To a solution of 19 (1.4 g, 2.2 mmol) in dry CH2Cl2
(22 mL) containing DMAP (1.1 g, 8.8 mmol) was added Tf2O (0.73
mL, 4.3 mmol) at 0 °C, and the mixture was stirred at room
temperature for 30 min. The reaction was quenched by addition
of saturated aqueous NaHCO3. The reaction mixture was
partitioned between AcOEt and H2O. The separated organic
layer was washed with saturated aqueous NaHCO3 (three
times), followed by brine. The organic layer was dried (Na2SO4)
and concentrated in vacuo. The resulting crude 20 was coevapo-
rated with toluene and then dissolved in dry benzene (37 mL).
To this solution, tetrabutylammonium bromide (1.4 g, 4.3 mmol)
was added, and the reaction mixture was stirred at room
Acknowledgment. This work was supported in part
by a Grant-in-Aid for Scientific Research from the Japan
Society for Promotion of Science (No. 15209003 to A.M.).
We thank Ms. H. Matsumoto and Ms. A. Maeda (Center
for Instrumental Analysis, Hokkaido University) for
elemental analysis and Ms. S. Oka (Center for Instru-
mental Analysis, Hokkaido University) for measure-
ment of mass spectra. This paper constitutes part 237
of Nucleosides and Nucleotides (for part 236 in this
series, see ref 2c).
Supporting Information Available: Experimental pro-
cedures and spectral data for new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
JO051248F
8600 J. Org. Chem., Vol. 70, No. 21, 2005