Nucleophilic substitution approach to 4′-substituted thymidines by employing 4′-benzenesulfonyl leaving group

Article abstract of DOI:10.1016/j.tet.2009.05.078

Synthesis of 4′-substituted thymidines was investigated based on nucleophilic substitution using organosilicon and organoaluminum reagents. Two substrates having a benzenesulfonyl leaving group at the 4′-position were prepared for this purpose: 1-[4-benzenesulfonyl-3,5-bis-O-(tert-butyldimethylsilyl)-2-deoxy-α-l-threo-pentofuranosyl]thymine (8α) and the 4′-(benzenesulfonyl)thymidine derivative (8β). The reaction of 8α with organosilicon reagents (Me₃SiCH₂CH{double bond, long}CH₂ and Me₃SiN₃) in combination with SnCl₄ gave preferentially the 4′-substituted β-d-isomer: the 4′-allyl (12β) and 4′-azido (15β) derivatives, respectively. The reaction of 8α with AlMe₃, however, gave the 4′-methyl-α-l-isomer (16α) as the major product, presumably through an ion pair mechanism. By employing the substrate 8β in this reaction, the 4′-methylthymidine derivative (16β) was obtained exclusively in high yield. The 4′-ethyl (20β) and 4′-cyano (24β) derivatives were also synthesized by reacting 8β with the respective organoaluminum reagent.

Full text of DOI:10.1016/j.tet.2009.05.078

Tetrahedron 65 (2009) 6008–6016
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Nucleophilic substitution approach to 40-substituted thymidines by employing
40-benzenesulfonyl leaving group
*
Hisashi Shimada, Satoshi Kikuchi, Saori Okuda, Kazuhiro Haraguchi, Hiromichi Tanaka
School of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan
a r t i c l e i n f o
a b s t r a c t
Synthesis of 40-substituted thymidines was investigated based on nucleophilic substitution using orga-
nosilicon and organoaluminum reagents. Two substrates having a benzenesulfonyl leaving group at the
40-position were prepared for this purpose: 1-[4-benzenesulfonyl-3,5-bis-O-(tert-butyldimethylsilyl)-2-
Article history:
Received 9 April 2009
Received in revised form 26 May 2009
Accepted 27 May 2009
Available online 3 June 2009
deoxy-
The reaction of 8
SnCl4 gave preferentially the 40-substituted
respectively. The reaction of 8
with AlMe3, however, gave the 40-methyl-
product, presumably through an ion pair mechanism. By employing the substrate 8
40-methylthymidine derivative (16 ) was obtained exclusively in high yield. The 40-ethyl (20
) derivatives were also synthesized by reacting 8 with the respective organoaluminum
a-
L
-threo-pentofuranosyl]thymine (8
with organosilicon reagents (Me3SiCH2CH]CH2 and Me3SiN3) in combination with
-isomer: the 40-allyl (12 ) and 40-azido (15
) derivatives,
-isomer (16 ) as the major
in this reaction, the
) and 40-
a b).
) and the 40-(benzenesulfonyl)thymidine derivative (8
a
b
-D
b
b
Keywords:
Thymidine
Nucleophilic substitution
Benzenesulfonyl leaving group
Organosilicon reagent
Organoaluminum reagent
a
a-
L
a
b
b
b
cyano (24
b
b
reagent.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
30,40-epoxysugar nucleosides with organoaluminum or organo-
silicon reagents,4,5 and the other is nucleophilic substitution with
these reagents by employing 40-benzoyloxy nucleosides.6,7 In the
latter approach, the 40-benzoyloxy leaving group was introduced by
using unsaturated-sugar nucleosides. One example is shown in
Scheme 1 for the preparation of the 40-benzoyloxy thymine-nu-
cleoside 2 from the 40,50-unsaturated derivative 1.6
Several analogues of thymidine substituted at the 40-position
(azido, cyano, and ethynyl) have been reported to exhibit potent
anti-HIV activity.1 Synthesis of this class of nucleosides has mostly
been carried out by manipulating the 40-hydroxymethyl de-
rivatives of nucleosides or sugars that can be prepared by the well
O
N
O
N
O
N
O
N
Me
Me
Me
Me
NH
NH
NH
NH
O
O
O
O
BzO
BzO
O
BzO
Me
Pb(OBz)4/i-Pr2NEt
O
O
O
O
AlMe3
Ph
Me
+
O
O
O
O
toluene, rt
CH2Cl2, rt
O
TBS
TBS
TBS
3 (76%)
TBS
4 (15%)
1
2
Scheme 1.
known aldol-Cannizzaro reaction of the corresponding alde-
hyde,2,3 although several other newer synthetic methods are also
available.1
For the synthesis of 40-substituted nucleosides, we have learned
that nucleophilic substitution is certainly an efficient approach
through the studies in Refs. 6 and 7. However, there still remains
much room for its improvement. For example, as shown in
Scheme 1, the reaction of 2 with AlMe3 resulted in the pre-
ponderance formation of the spiro derivative 3, not the desired 4.6
In the present study, we focus on employing substrates having the
30,50-bis-O-silyl protecting group as well as a different 40-leaving
group from the benzoyloxy group.
We have developed two different approaches to the 40-
substituted nucleosides: one is ring-opening reaction of 40,50- or
* Corresponding author.
E-mail address: hirotnk@pharm.showa-u.ac.jp (H. Tanaka).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.05.078

H. Shimada et al. / Tetrahedron 65 (2009) 6008–6016
6009
O
N
O
N
O
Me
Me
Me
O
NH
NH
NH
O
N
O
O
PhO2S
RO
TBSO
7 R = H
H
PhS
HO
TBSO
1) PhS+/Et3N/CH2Cl2
2) NaBH4/MeOH
1) m-CPBA
O
O
O
2) TBSCl
TBSO
5
6
8α R = TBS
Scheme 2.
2. Results and discussion
benzenesulfonyl derivative 7 in quantitative yield, which was
silylated to furnish the substrate 8 (92% yield).
a
2.1. Preparation of the 40-benzenesulfonyl derivatives
The stereochemical outcome observed in the above benzene-
sulfenylation of 5 is assumed to be a reflection of the steric re-
pulsion between the 30-‘down’-O-TBS group and the sulfenylating
reagents. To confirm this assumption, the 50-aldehyde 9 having the
opposite 30-configuration was prepared and subjected to the re-
action with N-(benzenesulfenyl)succinimide followed by NaBH4 as
shown in Scheme 3. This resulted in the sole formation of 10 (82%),
the stereochemistry of which was evident from its NOE experi-
ment: H-50b/H-6 (2.0%).16 Compound 10 was converted to the
40-benzenesulfonyl derivative 11.
Since benzenesulfinic acid is much more acidic (pKa 1.50) than
benzoic acid (pKa 4.20),8 one would expect that a benzenesulfonyl
group serves as a better leaving group than does benzoyloxy group.
In fact, there have been a considerable number of reports for the
nucleophilic substitution of a benzenesulfonyl group, especially
those at the 2-position of cyclic ethers.9 We first examined ben-
zenesulfenylation at the 40-position of thymidine by reacting the 50-
aldehyde (5)10 with several different reagents in the presence of
a base (Scheme 2). Compound 5 was prepared in 83% yield by
oxidizing 30-O-(tert-butyldimethylsilyl)thymidine with 2-iodoxy-
benzoic acid (IBX)11 in CH3CN.
2.2. Reaction of 8
a
or 11 with organosilicon reagents
is actually a suit-
When a mixture of 5 and freshly distilled PhSCl12 (3 equiv) in
CH2Cl2 was treated with dropwise addition of Et3N (6 equiv),
the 40-sulfenylated product was formed. After partial purifica-
tion by column chromatography, this product was dissolved in
MeOH and reacted with NaBH4 to give 6 as the sole product in
69% yield (Scheme 2). The depicted stereochemistry of 6 was
confirmed based on NOE experiments: H-50/H-10 (1.5%) and H-6/
Ph (4.1%). Compound 6 can also be prepared in 60% yield by
To see if the 40-benzenesulfonyl derivative 8
a
able substrate for the introduction of 40-substituents, its reaction
with Me3SiCH2CH]CH2 was investigated in the presence of several
different Lewis acids (Scheme 4). As summarized in Table 1,
BF3$OEt2 and Me3SiOTf did not work at all (entries 1 and 2). In
contrast, as shown by entries 3 and 4, both SnCl4 and MeAlCl2 gave
a high yield of the 40-allylated product 12 with a high selectivity for
the
tion to 8
in entry 3, again the
stereoisomer (entry 5). These results suggested that the 40-allyla-
b
-D
-isomer (12
, was reacted under the same reaction conditions as those
-isomer (13 ) was formed as the major
b
). When 11, having the opposite 30-configura-
13
using PhSCl generated in situ from PhSH/NCS/CH2Cl2 in the
a
presence of Et3N.14 The highest yield of 6 (75%) was obtained
when the stable crystalline N-(benzenesulfenyl)succinimide
(3 equiv) was employed. Although the published method for the
preparation of this reagent involves the use of Bu3SnSPh and
NBS,15 it was prepared in our hands simply by reacting PhSH/
Et3N with NCS in CH2Cl2, as described in the Experimental
section. Conventional oxidation of 6 with m-CPBA led to the
b-D
b
tion of 8
a and 11 would not be a simple Lewis acid-promoted
substitution, but 40-chlorination of the substrate may possibly be
involved as an initial reaction pathway.
Although such a 40-chlorinated intermediate was assumed to be
quite unstable, we were able to isolate the 40-chloro derivative 14
O
N
O
O
N
O
N
Me
O
Me
Me
NH
NH
NH
1)
N
SPh
O
O
O
RO
HO
H
Et3N/CH2Cl2
1) TBSCl
O
O
O
O
O
O
O
2) m-CPBA
2) NaBH4/MeOH
PhS
PhO2S
TBS
TBS
TBS
9
10
11 R = TBS
Scheme 3.
O
N
O
Me
Me
NH
NH
Me3SiCH2CH=CH2
Lewis acid
CH2Cl2, −30 °C, 1 h
O
O
N
TBSO
O
X
O
X
8α or 11
+
TBSO
Y
Y
12β X = H, Y = OTBS
13β X = OTBS, Y = H
12α X = H, Y = OTBS
13α X = OTBS, Y = H
Scheme 4.

6010
H. Shimada et al. / Tetrahedron 65 (2009) 6008–6016
Table 1
two diastereomers (16
b
/16
a
¼1/5.3). However, NOE experiment of
Reaction of 8 or 11 with allyltrimethylsilane by changing Lewis acida
the major isomer showed that it has the wrong 40-stereochemistry:
H-50b/H-10 (1.1%). The use of 11 in this reaction gave the corre-
sponding 40-methyl-
b-D-isomer (17b) as the major product (17b/
b
Ratio of b-D/a-L
Entry
Substrate
Lewis acid
Yield (%) of 12 or 13
c
1
2
3
4
5
8
8
8
8
a
a
a
a
BF3$OEt2
d
0
95
94
62
d
Me3SiOTfd
SnCl4
d
17
a
¼ca. 20/1, combined yield: 95%). Also observed in these re-
9/1
20/1
5/1
actions is the formation of variable amounts of methyl phenyl
sulfoxide, which had presumably been formed through the reaction
of Me2AlOSOPh with AlMe3.18
MeAlCl2
SnCl4
11
a
All reactions were carried out by adding the respective Lewis acid (4 equiv) to
The above fact that both reactions proceeded mostly with re-
tention of configuration at the 40-position suggests an ion pair
mechanism (SNi mechanism) as reported recently from our labo-
a mixture of 8a or 11 and allyltrimethylsilane (10 equiv) in CH2Cl2.
b
The ratio was determined based on 1H NMR spectroscopy.
A complex mixture of products was observed by TLC (hexane/EtOAc¼1/1)
c
ratory.19 In fact, when the above reaction of 8
a
was carried out in
the less polar solvent CCl4, an increase of the ratio of 16 was ob-
served (16 /16
analysis.
d
Compound 8a remained intact as evidenced by TLC analysis.
a
b
a
¼1/7.1, combined yield: 93%).
(Fig. 1) in 73% yield upon reacting 8a with MeAlCl2 alone in CH2Cl2
These results clearly suggest that, for the stereoselective entry to
followed by HPLC purification (hexane/EtOAc¼1/1, tR 8.1 min). The
MS spectrum of 14 thus isolated supported the structure: MþþH m/z
505 (35Cl) and 507 (37Cl); MþꢀCl m/z 465. The 1H and 13C NMR
spectra of 14 measured in CD2Cl2 showed that it was contaminated
with an unknown product (ca. 8%, the 40-epimer?), but allowed us
to assign all the proton and carbon signals corresponding to the
depicted structure.17 Its NOE experiment led to the confirmation of
the a-L
-stereochemistry: H-50a/H-10 (0.4%). It should be mentioned
that, when the above NMR sample in CD2Cl2 was measured again
after 6 h, some additional signals derived from decomposed prod-
uct(s) appeared.
When the above isolated 40-chloro derivative (14) was dissolved
in CH2Cl2 and treated with Me3SiCH2CH]CH2, no reaction took
place. However, addition of MeAlCl2 (3 equiv) to the solution gave
12 in 99% yield with exactly the same diastereomer ratio as that of
entry 4.
40-substituted thymidines through the reaction with organo-
aluminum reagents, the 40-benzenesulfonyl substrate having a
configuration was needed.
b-D-
2.4. Inversion of the 40-benzenesulfenyl group
An attempt to invert the 40-configuration was made first by
reacting the 40-benzenesulfonyl derivative 8
with Me3SiSPh in the
presence of MeAlCl2 in CH2Cl2. However, this reaction gave an equal
a
amount of 18
b
and 18
a
at ꢀ78 ꢁC for 1 h, as evidenced by 1H NMR
spectroscopy. We, therefore, turned to the use of the 40-benzene-
sulfenyl derivative 18a which was prepared by silylation of 6.
Although no inversion took place upon reacting 18
a with
Me3SiSPh in the presence of SnCl4 (CH2Cl2, ꢀ30 ꢁC),20 treatment
with Hg(OAc)2/AcOH in CH2Cl2 at rt for 0.5 h gave the 40-acetoxy
derivative 19 (19
b
/19
a
¼1/0.61) in almost quantitative yield
(Scheme 6). Reaction of 19 with Me3SiSPh in the presence of SnCl4
O
O
Me
Me
at ꢀ30 ꢁC for 1 h gave the 40-sulfenylated
b-D-isomer 18b as the
NH
NH
major product (18
b/18
a
¼20/1, combined yield: 78%) together with
O
O
N
N
the 50-O-desilylated products (6 and its
20% yield). After oxidation of 18 with m-CPBA, the desired 40-sul-
fone having -erythro-configuration (8 ) was isolated by HPLC
b-D
-erythro-isomer,21 ca.
Cl
X
O
O
TBSO
TBSO
Y
b
-D
b
TBSO
separation (Fig. 2).
14
15β X = CH2OTBS, Y = N3
15α X = N3, Y = CH2OTBS
2.5. Reaction of 8b with organoaluminum reagents
Figure 1.
When the above prepared 8
a manner similar to the case of 8
methylated product 16
b
was reacted with AlMe3 in
(in CH2Cl2, 0 ꢁC to rt), the 40-
a
Attempts to introduce a cyano group to the 40-position of 8
a by
reacting with Me3SiCN under the conditions of either entry 3 or 4
failed. In contrast, the use of Me3SiN3 in the presence of SnCl4 gave
the 40-azido derivative 15 (Fig. 1) in 99% yield in favor of the
b-D-
b
was obtained exclusively in 93% yield
(Scheme 7), which was formed as a result of retention of the 40-
configuration. This fact certainly strengthens our recently proposed
ion pair mechanism19 in that, even the 40-leaving group and the
neighboring 30-silyloxy substituent occupy the same face, the alu-
minate [Me3AlOSOPh]ꢀ formed after coordination to the leaving
group remains on the side it departed, from which nucleophilic
transfer of a methyl ligand inevitably takes place from the same
face.
isomer (15
b
/15
a
¼2/1).
2.3. Reaction of 8
a
or 11 with AlMe3
We next examined the reaction of 8
a with AlMe3 (Scheme 5).
When 8
a
was reacted with AlMe3 (8 equiv) in CH2Cl2 for 1 h, the 40-
The high b-D-selectivity observed in the reaction with AlMe3
was also the case for AlEt3 to give the 40-ethyl derivatives 20
b and
methylated product (16) was obtained in 92% yield as a mixture of
O
N
O
Me
Me
NH
NH
O
N
O
Me
TBSO
AlMe3
CH2Cl2, 0 °C to rt
O
X
O
X
8α or 11
+
TBSO
Me
Y
Y
16β X = H, Y = OTBS
17β X = OTBS, Y = H
16α X = H, Y = OTBS
17α X = OTBS, Y = H
Scheme 5.

H. Shimada et al. / Tetrahedron 65 (2009) 6008–6016
6011
O
Me
O
N
O
N
Me
PhS
Me
NH
NH
NH
O
N
O
O
X
X
O
O
O
Hg(OAc)2/AcOH
CH2Cl2
Me3SiSPh/SnCl4
CH2Cl2
TBSO
TBSO
Y
Y
TBSO
TBSO
18α
19β X = CH2OTBS, Y = OAc
19α X = OAc, Y = CH2OTBS
18β X = CH2OTBS, Y = SPh
18α X = SPh, Y = CH2OTBS
Scheme 6.
a clear explanation for this result, but one might assume that this
aluminum reagent formed a complex with THF during its prepa-
ration24 and, therefore, acts simply as a base rather than co-
ordinating to the 40-benzenesulfonyl group.
O
N
Me
NH
O
TBSO
O
Finally, we examined the synthesis of 40-cyanothymidine which
PhO2S
TBSO
was not obtained from 8
previously. Compound 8
a
by reacting with Me3SiCN as mentioned
was reacted with Et2AlCN in refluxing
b
8β
toluene for 4 h.25 Since separation of the resulting mixture of
products failed even by HPLC,26 the mixture was desilylated with
Bu4NF/THF and then acetylated. HPLC separation (CHCl3/
MeOH¼100/2) of the acetylated mixture enabled us to isolate 30,50-
Figure 2.
O
O
N
di-O-acetyl-40-cyanothymidine (24
b) in 45% yield (Fig. 3).
Me
Me
R
NH
NH
O
N
organoaluminum
reagent
O
TBSO
3. Conclusion
O
O
8β
+
CH2Cl2, 0 °C to rt
TBSO
TBSO
20α R = Et
R
TBSO
A nucleophilic substitution approach to the 40-substituted ana-
logues of thymidine was investigated by using the substrates 8
and 8 having a benzenesulfonyl leaving group. In the reaction of
the -threo-isomer 8 with organosilicon reagents, Lewis acids
used such as SnCl4 and MeAlCl2 serve as a chlorinating agent to
generate the 40-chloro intermediate (14). Organosilicon nucleo-
philes then react with 14 presumably through the SN2 mechanism
a
b
16β R = Me
20β R = Et
21β R = H
22α R = C CSiMe3
a
-L
a
22β R = C CSiMe3
Scheme 7.
to give the 40-allyl (12
b
) and 40-azido (15
b
) analogues. In contrast to
this, organoaluminum reagents seem to react with 8 mostly
through an SNi mechanism, which results in retention of configu-
ration at the 40-position to afford the 40-substituted
-nucleo-
sides. Compound having -erythro-configuration was,
therefore, prepared from 18 . Its reaction with organoaluminum
reagents allowed to synthesize the 40-methyl (16 ), 40-ethyl (20
),
and 40-cyano (24
) analogues of thymidine.
a
20
a
in a ratio of 14/1 (combined yield: ca. 79%) together with
(ca. 10%): retention
)¼ca. 84/5. We also examined in-
troduction of an ethynyl group through the reaction between 8
a-L
a small amount of the reduction product 21
b
8
b
b-D
(20 plus 21 )/inversion (20
b
b
a
a
b
b
b
and EtAl(C^CSiMe3)2. The reagent was prepared by reacting
EtAlCl2/toluene with lithium (trimethylsilyl)acetylide (2 equiv)/
hexane. However, this reaction gave the 40-ethynylthymidine de-
b
b
) only in 9% yield.22 Other products were the 40-ethyl
4. Experimental section
4.1. General
rivative (22
(20
, 58%), 30,50-bis-O-TBS-thymidine (21
nyl-
inversion (22
b
b
, 13%), and the 40-ethy-
, 13%): retention (22 plus 20 plus 21 )/
a
-L
-nucleoside (22
a
b
b
b
a
)¼80/13.23
NMR spectrawere recorded either at 400 MHz (JNM-GX 400) orat
500 MHz (JNM-LA 500). Chemical sifts are reported relative to Me4Si.
Mass spectra (MS) were taken in FAB mode with m-nitrobenzyl al-
cohol as a matrix on a JNS-SX 102A. UV spectra were measured on
a JASCO Ubest-55 spectrophotometer. Column chromatography was
carried out on silica gel (Micro Bead Silica Gel PSQ 100B, Fuji Silysia
Chemical Ltd.). Thin-layer chromatography (TLC) was performed on
silica gel (precoated silica gel plate F254, Merck). High performance
liquid chromatography (HPLC) was carried outona ShimadzuLC-6AD
with a Shim-pack PREP-SIL (H) KIT column (2ꢂ25 cm).
In contrast to the above cases, when AlPh3 was employed for
this reaction (in CH2Cl2 at rt for 3 h), 8
denced by TLC analysis (hexane/EtOAc¼1/1). By performing the
reaction under reflux for 4 h, most 8 (Rf 0.5) was converted to one
b remained intact as evi-
b
less polar product (Rf 0.6). However, this product was found to be
23 (93%, stereochemistry not known), which was formed through
an elimination pathway (Fig. 3). At the present time, we do not have
O
N
O
N
Me
Me
NH
NH
O
O
AcO
TBSO
O
O
4.2. 30-O-(tert-Butyldimethylsilyl)thymidine-50-aldehyde (5)
NC
AcO
An CH3CN (17 mL) solution containing IBX (980 mg, 3.5 mmol)
and 30-O-(tert-butyldimethylsilyl)thymidine (1.04 g, 2.92 mmol)
was refluxed with vigorous stirring for 1 h. The reaction mixture
was filtered through a Celite pad. The resulting filtrate was
TBSO
23
24β
Figure 3.

6012
H. Shimada et al. / Tetrahedron 65 (2009) 6008–6016
evaporated and then partitioned between EtOAc and saturated
aqueous NaHCO3. Column chromatography (hexane/EtOAc¼1/2) of
the organic layer gave 5 (859 mg, 83%) as a foam.
(hexane/EtOAc¼5/1) gave 8
a
(2.56 g, 92%) as a foam: UV (MeOH)
3400); 1H NMR (CDCl3)
lmax 266 nm ( 10,400), lmin 237 nm (
3
3
d
ꢀ0.32, ꢀ0.13, 0.18 and 0.20 (12H, each as s), 0.72 and 0.93 (18H,
each as s), 2.05 (3H, d, J¼1.2 Hz), 2.39 (1H, ddd, J¼3.2, 6.8 and
13.4 Hz), 2.61 (1H, ddd, J¼7.3, 7.6 and 13.4 Hz), 3.95 (1H, d,
J¼11.7 Hz), 4.15 (1H, d, J¼11.7 Hz), 5.23 (1H, dd, J¼3.2 and 7.3 Hz),
6.67 (1H, dd, J¼7.6 and 6.8 Hz), 7.48–7.82 (5H, m), 7.86 (1H, d,
4.3. Preparation of N-(benzenesulfenyl)succinimide
To a CH2Cl2 (15 mL) solution of NCS (1.01 g, 7.53 mmol) were
added PhSH (0.77 mL, 7.53 mmol) and then Et3N (1.05 mL,
7.53 mmol) dropwise at 0 ꢁC. The reaction mixture was stirred for
18 h at rt. After the reaction mixture being partitioned between
CH2Cl2 and saturated aqueous NH4Cl, column chromatography
(CHCl3) of the organic layer gave N-(benzenesulfenyl)succinimide
(1.34 g, 86%), which was crystallized from CH2Cl2/Et2O: mp 116 ꢁC
(identical with that reported in Ref. 15).
J¼1.2 Hz), 9.19 (1H, br); 13C NMR (CDCl3)
d
ꢀ5.99, ꢀ5.83, ꢀ5.21,
ꢀ5.00, 12.65, 17.94, 18.33, 25.57, 25.67, 40.73, 62.43, 72.41, 85.51,
103.57, 112.28, 128.64, 129.89, 133.80, 135.60, 137.63, 150.40, 163.70;
FABMS (m/z) 611 (MþþH). Anal. Calcd for C28H46N2O7SSi2: C, 55.05;
H, 7.59; N, 4.59. Found: C, 55.34; H, 7.74; N, 4.54.
4.7. The aldehyde (9) derived from 1-[3-O-(tert-butyl-
dimethylsilyl)-2-deoxy-b-D-threo-pentofuranosyl]thymine
4.4. 1-[4-Benzenesulfenyl-3-O-(tert-butyldimethylsilyl)-
2-deoxy-
a
-
L
-threo-pentofuranosyl]thymine (6)
This compound was prepared as a foam in 94% yield from 1-[3-
O-(tert-butyl-dimethylsilyl)-2-deoxy- -threo-pentofuranosyl]-
thymine by the procedure described for the preparation of 5.
Physical data for 9: 1H NMR (CDCl3)
0.03 and 0.08 (6H, each as s),
b-D
A
mixture of N-(benzenesulfenyl)succinimide (354 mg,
1.71 mmol) and Et3N (0.48 mL, 3.42 mmol) in CH2Cl2 (4 mL) was
stirred for 1 h at rt. To this solution was added a CH2Cl2 (5 mL) so-
lution of 5 (200 mg, 0.57 mmol). After stirring for 24 h, the reaction
mixture was partitioned between CH2Cl2 and saturated aqueous
NH4Cl. Column chromatography (hexane/EtOAc¼6/1) of the organic
layer gave the product (203 mg), which was dissolved in MeOH
(5 mL) and reacted with NaBH4 (33.3 mg, 0.88 mmol) at rt for 0.5 h.
The reaction mixture was evaporated, partitioned between CH2Cl2
and saturated aqueous NH4Cl. Purification of the organic layer by
column chromatography (hexane/EtOAc¼3/1) gave 6 (198 mg, 75%)
d
0.82 (9H, s), 1.94 (3H, d, J¼1.2 Hz), 2.15 (1H, ddd, J¼1.0, 2.2 and
14.6 Hz), 2.62 (1H, ddd, J¼5.1, 7.8 and 14.6 Hz), 4.52 (1H, d,
J¼4.4 Hz), 4.84 (1H, ddd, J¼1.0, 4.4 and 5.1 Hz), 6.32 (1H, dd, J¼2.2
and 7.8 Hz), 7.86 (1H, d, J¼1.2 Hz), 9.58 (1H, br), 9.72 (1H, s); 13C
NMR (CDCl3)
d
ꢀ5.49, ꢀ4.99, 12.59, 17.76, 25.31, 41.88, 72.50, 86.04,
88.74, 110.28, 136.31, 150.58, 164.09, 197.20; FABMS (m/z) 355
(MþþH). FAB-high resolution MS (m/z) calcd for C16H27N2O5Si:
355.1689, found: 355.1668 (MþþH).
as a foam: UV (MeOH) lmax 261 nm (
3
11,800), lmin 237 nm (
3
4800);
4.8. 1-[4-Benzenesulfenyl-3-O-(tert-butyldimethylsilyl)-2-
deoxy-b-D-threo-pentofuranosyl]thymine (10)
1H NMR (CDCl3)
d
0.117 and 0.119 (6H, each as s), 0.91 (9H, s),1.92 (3H,
d, J¼1.2 Hz), 2.42 (1H, ddd, J¼2.7, 6.3 and 13.7 Hz), 2.48–2.55 (2H, m,
J¼5.4, 6.8, 7.8 and 13.7 Hz), 3.72 (2H, d, J¼6.8 Hz), 4.51 (1H, dd, J¼2.7
and 5.4 Hz), 6.63 (1H, dd, J¼6.3 and 7.8 Hz), 7.32–7.57 (5H, m), 7.73
(1H, d, J¼1.2 Hz), 9.23(1H, br); NOE experiment H-50/H-10 (1.5%); 13C
A mixture of 9 (276.5 mg, 0.78 mmol), N-(benzenesulfe-
nyl)succinimide (485 mg, 2.34 mmol), and Et3N (0.65 mL,
4.68 mmol) in CH2Cl2 (7.0 mL) was stirred for 24 h at rt. The
reaction mixture was evaporated and partitioned between
CH2Cl2 and saturated aqueous NaHCO3. Column chromatogra-
phy (hexane/EtOAc¼4/1) of the organic layer gave the 40-sul-
fenylated aldehyde (314.5 mg), which was dissolved in MeOH
(8.0 mL) and treated with portionwise addition of NaBH4
(51.4 mg, 1.36 mmol). The reaction mixture was stirred for
20 min at rt and then partitioned between CH2Cl2 and saturated
aqueous NH4Cl. Column chromatography (hexane/EtOAc¼3/1)
of the organic layer gave 10 (298.1 mg, 82%) as a foam: UV
NMR (CDCl3)
d
ꢀ5.22, ꢀ4.90, 12.58, 17.93, 25.60, 40.46, 62.86, 77.61,
86.69, 99.92, 111.59, 129.19, 129.25, 129. 69, 134.70, 136.04, 150.42,
163.72; FABMS (m/z) 465 (MþþH). Anal. Calcd for C22H32N2O5SSi: C,
56.87; H, 6.94; N, 6.03. Found: C, 57.01; H, 6.99; N, 6.00.
4.5. 1-[4-Benzenesulfonyl-3-O-(tert-butyldimethylsilyl)-
2-deoxy-a-L-threo-pentofuranosyl]thymine (7)
A mixture of 6 (105 mg, 0.23 mmol) and m-CPBA (126 mg,
0.51 mmol) in CH2Cl2 (5 mL) was stirred for 24 h at rt. The reaction
mixture was partitioned between CH2Cl2 and saturated aqueous
NaHCO3. Purification of the organic layer by column chromatog-
raphy (hexane/EtOAc¼3/1) gave 7 (112 mg, 100%) as a foam: UV
(MeOH) lmax 264 nm (
(CDCl3) 0.12 and 0.17 (6H, each as s), 0.92 (9H, s), 1.90 (3H, d,
3 11,900), lmin 238 nm (3
4200); 1H NMR
d
J¼1.0 Hz), 1.95 (1H, ddd, J¼2.2, 4.1 and 14.1 Hz), 2.63 (1H, dd,
J¼3.2 and 10.5 Hz), 3.08 (1H, ddd, J¼6.1, 7.8 and 14.1 Hz), 3.69
(1H, dd, J¼3.2 and 12.0 Hz), 3.80 (1H, dd, J¼10.5 and 12.0 Hz),
4.39 (1H, dd, J¼2.2 and 6.1 Hz), 6.59 (1H, dd, J¼4.1 and 7.8 Hz),
7.33–7.57 (5H, m), 7.64 (1H, d, J¼1.0 Hz), 9.27 (1H, br); NOE
(MeOH) lmax 266 nm (
(CDCl3)
3 10,400), lmin 238 nm (3
4100); 1H NMR
0.22 and 0.24 (6H, each as s), 0.95 (9H, s), 2.05 (3H, d,
d
J¼1.2 Hz), 2.38 (1H, ddd, J¼1.2, 6.1 and 13.7 Hz), 2.67 (1H, ddd,
J¼6.3, 9.5 and 13.7 Hz), 3.64 (1H, d, J¼12.4 Hz), 4.04 (1H, d,
J¼12.4 Hz), 5.33 (1H, dd, J¼1.2 and 6.3 Hz), 6.76 (1H, dd, J¼6.1 and
9.5 Hz), 7.55–7.82 (5H, m), 7.89 (1H, d, J¼1.2 Hz), 8.87 (1H, br); 13C
experiment H-50b/H-6 (2.0%); 13C NMR (CDCl3)
d
ꢀ5.19, ꢀ5.05,
12.52, 17.95, 25.60, 41.56, 62.12, 83.85, 99.98, 111.43, 128.52,
129.12, 129.49, 136.12, 136.21, 150.46, 163.76; FABMS (m/z) 465
(MþþH). Anal. Calcd for C22H32N2O5SSi: C, 56.87; H, 6.94; N,
6.03. Found: C, 57.08; H, 6.97; N, 6.19.
NMR (CDCl3)
d
ꢀ5.24, ꢀ4.96, 12.69, 17.96, 25.62, 40.84, 62.16, 73.80,
86.20, 102.38, 112.50, 129.26, 129.93, 134.70, 135.25, 150.40, 163.34;
FABMS (m/z) 497 (MþþH). Anal. Calcd for C22H32N2O7SSi: C, 53.20;
H, 6.49; N, 5.64. Found: C, 53.28; H, 6.52; N, 5.54.
4.9. 1-[4-Benzenesulfonyl-3,5-bis-O-(tert-butyldimethylsilyl)-
2-deoxy-b-D-threo-pentofuranosyl]thymine (11)
4.6. 1-[4-Benzenesulfonyl-3,5-bis-O-(tert-butyldimethylsilyl)-
2-deoxy-
a
-
L
-threo-pentofuranosyl]thymine (8
a
)
This compound was prepared as a foam in 96% yield from 10 by
the procedure described for the preparation of 8 from 6. Physical
data for 11: UV (MeOH) lmax 266 nm ( 10,400), lmin 237 nm (
3900); 1H NMR (CDCl3)
s), 0.70 and 0.95 (18H, each as s), 1.90 (3H, d, J¼1.0 Hz), 2.01 (1H,
ddd, J¼3.4, 4.9 and 14.1 Hz), 3.25 (1H, ddd, J¼7.1, 7.8 and 14.1 Hz),
a
A mixture of 7 (2.25 g, 4.53 mmol), TBSCl (1.37 g, 9.08 mmol),
and imidazole (1.55 g, 22.7 mmol) in DMF (30 mL) was stirred for
15 h at rt. The reaction mixture was partitioned between EtOAc and
H2O. Purification of the organic layer by column chromatography
3
3
d
ꢀ0.30, ꢀ0.14, 0.20 and 0.23 (12H, each as

H. Shimada et al. / Tetrahedron 65 (2009) 6008–6016
6013
4.16 (2H, s), 5.15 (1H, dd, J¼3.4 and 7.1 Hz), 6.77 (1H, dd, J¼4.9 and
7.8 Hz), 7.50–7.91 (6H, m), 9.48 (1H, br); 13C NMR (CDCl3)
ꢀ5.75, ꢀ5.11, 12.38, 17.94, 18.49, 25.60, 25.68, 41.81, 62.78, 72.72,
85.73, 104.91, 111.81, 128.59, 130.27, 133.78, 135.80, 136.98, 150.44,
163.76; FABMS (m/z) 611 (MþþH). Anal. Calcd for C28H46N2O7S0Si2:
C, 55.05; H, 7.59; N, 4.59. Found: C, 55.27; H, 7.66; N, 4.42.
and 7.3 Hz), 6.15 (1H, dd, J¼3.4 and 7.6 Hz), 7.65 (1H, d, J¼1.2 Hz), 8.83
(1H, br); NOE experiment H-6/H-50 (1.9%); 13C NMR (CDCl3)
ꢀ5.31, ꢀ5.15, ꢀ4.81, 12.57, 17.92, 18.33, 25.60, 26.00, 38.31, 41.69,
63.52, 73.58, 84.20, 90.18, 109.99, 118.95, 132.88, 136.49, 150.37,
163.88; FABMS (m/z) 511 (MþþH). Anal. Calcd for C25H46N2O5Si2: C,
58.78; H, 9.08; N, 5.48. Found: C, 58.75; H, 9.28; N, 5.31.
d
ꢀ5.88,
d
ꢀ5.42,
Physical data for 13
a
: UV (MeOH) lmax 268 nm (
3 9600), lmin
4.10. Reaction between 8
presence of MeAlCl2: preparation of 40-ally-30,50-bis-O-(tert-
butyldimethylsilyl)thymidine (12
) and its 40-epimer (12
as a typical procedure for the reactions listed in Table 1
a
and allyltrimethylsilane in the
234 nm ( d
3
1700); 1H NMR (CDCl3)
0.057, 0.061 and 0.10 (12H, each
as s), 0.89 and 0.91 (18H, each as s), 1.88–1.93 (4H, m, J¼1.2, 1.5, 2.7
and 14.4 Hz), 2.42 (1H, dd, J¼8.3 and 14.6 Hz), 2.64 (1H, dd, J¼6.1
and 14.6 Hz), 2.83 (1H, ddd, J¼5.6, 7.8 and 14.4 Hz), 3.28 (1H, d,
J¼10.2 Hz), 3.53 (1H, d, J¼10.2 Hz), 4.38 (1H, dd, J¼1.5 and 5.6 Hz),
5.13–5.17 (2H, m), 5.83–5.94 (1H, m, J¼6.1 and 8.3 Hz), 6.21 (1H, dd,
J¼2.7 and 7.8 Hz), 7.63 (1H, d, J¼1.2 Hz), 8.95 (1H, br); NOE experi-
b
a)
To a solution of 8a (100.6 mg, 0.16 mmol) in CH2Cl2 (3.0 mL),
were added allyltrimethylsilane (0.25 mL, 1.60 mmol) and then
MeAlCl2 (1.0 M hexane solution, 0.64 mL, 0.64 mmol) at below
ꢀ30 ꢁC under positive pressure of dry Ar. The reaction mixture was
stirred for 1 h at ꢀ30 ꢁC, and quenched by adding saturated aque-
ous NH4Cl. The mixture was filtered through a Celite pad and the
resulting filtrate was extracted with CH2Cl2. Column chromatog-
raphy (hexane/EtOAc¼6/1) of the extract gave 12 (79.3 mg, 94%,
ment H-50a/H-10 (3.3%); 13C NMR (CDCl3)
d
ꢀ5.66, ꢀ5.61, ꢀ5.14, ꢀ4.88,
12.61, 17.97, 18.07, 25.64, 25.75, 35.78, 42.07, 64.77, 73.02, 84.89,
90.64, 110.15, 118.39, 133.58, 136.68, 150.44, 163.95; FABMS (m/z)
511 (MþþH). Anal. Calcd for C25H46N2O5Si2: C, 58.78; H, 9.08;
N, 5.48. Found: C, 58.82; H, 9.28; N, 5.32.
12
the isolation of 12
Physical data for 12
234 nm (
1900); 1H NMR (CDCl3)
b
/12
a
¼20/1). HPLC separation (hexane/EtOAc¼2/1) of 12 led to
(tR 12.2 min) and 12 (tR 13.2 min).
: UV (MeOH) lmax 267 nm ( 9700), lmin
0.087, 0.094 and 0.10 (12H, each
4.12. 1-[3,5-Bis-O-(tert-butyldimethylsilyl)-4-chloro-2-
deoxy-a-L-threo-pentofuranosyl]thymine (14)
b
a
b
3
3
d
To a solution of 8 (200.5 mg, 0.33 mmol) in CH2Cl2 (6.0 mL) was
added MeAlCl2 (1.0 M hexane solution, 2.64 mL, 2.64 mmol) at be-
low ꢀ30 ꢁC under positive pressure of dry Ar. The reaction mixture
was stirred for 1 h at ꢀ30 ꢁC, quenched byadding saturated aqueous
NH4Cl, and filtered through a Celite pad. The filtrate was partitioned
between CH2Cl2 and saturated aqueous NH4Cl. HPLC purification
(hexane/EtOAc¼1/1) of the organic layer gave 14 (tR 8.1 min,
119.6 mg, 73%, containing ca. 8% of unknown product); 1H NMR
as s), 0.91 and 0.93 (18H, each as s), 1.92 (3H, d, J¼1.2 Hz), 2.13–2.20
(2H, m, J¼6.3, 6.8, 7.1,13.4 and 14.4 Hz), 2.30 (1H, ddd, J¼3.7, 6.3 and
13.4 Hz), 2.48–2.54 (1H, m, J¼6.1 and 14.4 Hz), 3.55 (1H, d,
J¼10.7 Hz), 3.69 (1H, d, J¼10.7 Hz), 4.46 (1H, dd, J¼3.7 and 6.3 Hz),
5.08 (1H, s), 5.12 (1H, d, J¼4.9 Hz), 5.82–5.92 (2H, m, J¼4.9, 6.1 and
6.8 Hz), 6.28 (1H, dd, J¼6.3 and 7.1 Hz), 7.49 (1H, d, J¼1.2 Hz), 9.19
(1H, br); NOE experiment H-50b/H-6 (2.3%); 13C NMR (CDCl3)
d
ꢀ5.46, ꢀ5.41, ꢀ5.10, ꢀ4.60, 12.55, 17.98, 18.35, 25.71, 25.90, 36.78,
(CD2Cl2) d 0.126, 0.130 and 0.15 (12H, each as s), 0.92 and 0.93 (18H,
41.57, 66.15, 72.55, 83.60, 88.76,110.68,118.18,133.62,135.51,150.35,
163.96; FABMS (m/z) 511 (MþþH). Anal. Calcd for C25H46N2O5Si2: C,
58.78; H, 9.08; N, 5.48. Found: C, 59.00; H, 9.27; N, 5.40.
each as s),1.92 (3H, d, J¼1.2 Hz), 2.31 (1H, dd, J¼5.9 and 13.4 Hz), 2.57
(1H, ddd, J¼3.7, 9.5 and 13.4 Hz), 3.90 (1H, d, J¼11.2 Hz), 4.10 (1H, d,
J¼11.2 Hz), 4.65 (1H, d, J¼3.7 Hz), 6.64 (1H, dd, J¼5.9 and 9.5 Hz),
7.65 (1H, d, J¼1.2 Hz), 8.91 (1H, br); NOE experiment H-50a/H-10
Physical data for 12a: d 0.077, 0.083 and 0.09
1H NMR (CDCl3)
(12H, each as s), 0.90 and 0.92 (18H, each as s),1.93 (3H, d, J¼1.2 Hz),
2.10 (1H, ddd, J¼5.1, 7.6 and 13.4 Hz), 2.35–2.37 (2H, m), 2.54 (1H,
ddd, J¼6.1, 7.1 and 13.4 Hz), 3.59 (1H, d, J¼10.7 Hz), 3.82 (1H, d,
J¼10.7 Hz), 4.29 (1H, dd, J¼6.1 and 7.6 Hz), 5.14–5.20 (2H, m), 5.80–
5.91 (1H, m), 6.26 (1H, dd, J¼5.1 and 7.1 Hz), 7.22 (1H, d, J¼1.2 Hz),
7.98 (1H, br); NOE experiment H-50b/H-10 (1.4%); 13C NMR (CDCl3)
(0.4%), H-50b/H-10 (0.6%); 13C NMR (CD2Cl2)
d
ꢀ5.84, ꢀ5.81, ꢀ5.68,
ꢀ5.44, 12.04, 17.51, 18.08, 25.09, 25.38, 37.69, 64.53, 78.45, 87.32,
111.33, 113.45, 135.43, 150.31, 163.70; FABMS (m/z) 505 (MþþH) and
505 (MþþH), 496 (MþꢀCl). FAB-high resolution MS (m/z) calcd for
C22H42ClN2O5Si2: 505.2321, found: 505.2289 (MþþH).
d
ꢀ5.54, ꢀ5.49, ꢀ5.03, ꢀ4.49, 12.61, 17.89, 18.25, 25.66, 25.93, 38.98,
4.13. 40-Azido-30,50-bis-O-(tert-butyldimethylsilyl)-
) and its 40-epimer (15
thymidine (15b a)
41.07, 65.17, 73.59, 84.79, 88.16,110.55,119.13,133.08,135.86,149.83,
163.38; FABMS (m/z) 511 (MþþH). FAB-high resolution MS (m/z)
calcd for C25H47N2O5Si2: 511.3024, found: 511.3035 (MþþH).
These compounds were prepared by the procedure described
for the preparation of 12. The following amounts of reagents and 8
a
4.11. 1-[4-Allyl-3,5-bis-O-(tert-butyldimethylsilyl)-2-deoxy-
(107.7 mg, 0.18 mmol), were employed: Me3SiN3 (0.24 mL,
1.80 mmol) and SnCl4 (1.0 M CH2Cl2 solution, 0.72 mL, 0.72 mmol).
Column chromatography (hexane/EtOAc¼5/1) of the CH2Cl2 extract
b-
D-threo-pentofuranosyl]-thymine (13
b
) and its 40-
epimer (13
a
)
gave 15 (88.9 mg, 99%, foam, 15
b/15a
¼2/1). HPLC separation
(tR 11.7 min)
These compounds were prepared by the procedure described
for the preparation of 12. The following amounts of reagents and
11 (100.6 mg, 0.16 mmol) were employed: allyltrimethylsilane
(0.26 mL, 1.65 mmol) and SnCl4 (1.0 M CH2Cl2 solution, 0.66 mL,
0.66 mmol). After workup of the reaction mixture, the CH2Cl2 ex-
tract was purified by column chromatography (hexane/EtOAc¼5/1).
(hexane/EtOAc¼2/1) of 15 led to the isolation of 15
and 15 (tR 14.0 min).
Physical data for 15
265 nm (
b
a
b
: IR (neat) 2116 cmꢀ1 (N3); UV (MeOH) lmax
9800), lmin 234 nm ( 0.13 and
2500); 1H NMR (CDCl3)
3
3
d
0.15 (12H, each as s), 0.93 and 0.94 (18H, each as s), 1.93 (3H, d,
J¼1.2 Hz), 2.23 (1H, ddd, J¼6.3, 6.6 and 13.2 Hz), 2.44 (1H, ddd, J¼4.6,
6.6 and 13.2 Hz), 3.64 (1H, d, J¼11.0 Hz), 3.83 (1H, d, J¼11.0 Hz), 4.54
(1H, dd, J¼4.6 and 6.3 Hz), 6.49 (1H, t, J¼6.6 Hz), 7.39 (1H, d,
J¼1.2 Hz), 8.32 (1H, br); NOE experiment H-50b/H-6 (1.2%); 13C NMR
This gave 13 (50.8 mg, 62%, foam, 13
(hexane/EtOAc¼2/1) of 13 led to the isolation of 13
and 13 (tR 12.6 min).
Physical data for 13
235 nm (
b
/13
a
¼5/1). HPLC separation
b
(tR 14.3 min)
a
b
: UV (MeOH) lmax 268 nm (
3
9500), lmin
(CDCl3)
d
ꢀ5.52, ꢀ5.48, ꢀ5.08, ꢀ5.01,12.53,18.10,18.30, 25.60, 25.78,
3
1700); 1H NMR (CDCl3)
d
0.04, 0.08 and 0.09 (12H, each as
39.99, 64.50, 73.62, 84.60, 99.79, 111.28, 134.99, 150.23, 163.95;
FABMS (m/z) 512 (MþþH). Anal. Calcd for C22H41N5O5Si2: C, 51.63; H,
8.08; N, 13.68. Found: C, 51.53; H, 8.18; N, 13.82.
Physical data for 15
265 nm ( 9400), lmin 234 nm (3 d 0.11, 0.12
s), 0.87 and 0.92 (18H, each as s), 1.92 (3H, d, J¼1.2 Hz), 1.97 (1H, ddd,
J¼2.9, 3.4 and 14.4 Hz), 2.27 (1H, dd, J¼7.3 and 14.1 Hz), 2.36 (1H, dd,
J¼7.1 and 14.1 Hz), 2.77 (1H, ddd, J¼5.6, 7.6 and 14.4 Hz), 3.81 (2H, s),
4.20 (1H, dd, J¼2.9 and 5.6), 5.11–5.16 (2H, m), 5.75–5.85 (1H, m, J¼7.1
a
: IR (neat) 2113 cmꢀ1 (N3); UV (MeOH) lmax
3
2900); 1H NMR (CDCl3)

6014
H. Shimada et al. / Tetrahedron 65 (2009) 6008–6016
and 0.13 (12H, each as s), 0.91 and 0.93 (18H, each as s), 1.97 (3H, d,
J¼1.2 Hz), 2.27–2.30 (2H, m, J¼1.7, 3.2, 6.6 and 8.3 Hz), 3.96 (1H, d,
J¼10.7 Hz), 4.00 (1H, d, J¼10.7 Hz), 4.19 (1H, dd, J¼1.7 and 3.2 Hz),
6.57 (1H, dd, J¼6.6 and 8.3 Hz), 7.34 (1H, d, J¼1.2 Hz), 8.43 (1H, br);
1.93 (4H, m, J¼1.2, 2.0 and 14.0 Hz), 2.88 (1H, ddd, J¼5.6, 8.0 and
14.0 Hz), 3.41 (1H, d, J¼10.2 Hz), 3.42 (1H, d, J¼10.2 Hz), 4.29 (1H,
d, J¼5.6 Hz), 6.24 (1H, dd, J¼2.0 and 8.0 Hz), 7.65 (1H, d, J¼1.2 Hz),
8.35 (1H, br); NOE experiment H-50/H-10 (3.9%), H-6/40-CH3
NOE experiment H-50a/H-10 (0.8%); 13C NMR (CDCl3)
d
ꢀ5.73, ꢀ5.59,
(2.2%); 13C NMR (CDCl3)
d
ꢀ5.66, ꢀ5.56, ꢀ5.15, ꢀ5.01, 12.60, 17.99,
ꢀ5.22, ꢀ4.76, 12.67, 17.85, 18.28, 25.55, 25.78, 39.12, 64.57, 75.49,
86.04, 101.54, 111.99, 134.88, 150.61, 163.84; FABMS (m/z) 512
(MþþH). Anal. Calcd for C22H41N5O5Si2: C, 51.63; H, 8.08; N, 13.68.
Found: C, 51.68; H, 8.14; N, 13.68.
18.12, 18.17, 25.60, 25.78, 42.43, 68.05, 73.05, 84.89, 90.11, 110.18,
136.84, 150.54, 164.04; FABMS (m/z) 485 (MþþH). FAB-high res-
olution MS (m/z) calcd for C23H45N2O5Si2: 485.2867, found:
485.2893 (MþþH).
4.14. 30,50-Bis-O-(tert-butyldimethylsilyl)-40-methyl-
thymidine (16
b
) and its 40-epimer (16
a
)
4.16. 1-[4-Benzenesulfenyl-3,5-bis-O-(tert-butyldi-
methylsilyl)-2-deoxy-a-L-threo-pento-
To a solution of 8
a
(102.0 mg, 0.17 mmol) in CH2Cl2 (3.0 mL)
furanosyl]thymine (18a)
cooled at 0 ꢁC was added AlMe3 (1.08 M hexane solution, 1.26 mL,
1.36 mmol). The reaction mixture was then stirred at rt for 1 h,
quenched by adding saturated aqueous NH4Cl, and filtered through
a Celite pad. The filtrate was partitioned between CH2Cl2 and sat-
urated aqueous NH4Cl. Column chromatography of the organic
This compound (solid, mp 199 ꢁC) was prepared from 6 in 91%
yield by the procedure described for the preparation of 8 . Physical
data for 18 : UV (MeOH) lmax 260 nm ( 11,900), lmin 236 nm (
4300); 1H NMR (CDCl3)
ꢀ0.09, ꢀ0.03, 0.10 and 0.12 (12H, each as
a
a
3
3
d
layer gave 16 (74.3 mg, 92%, 16
(hexane/EtOAc¼3/1) of 16 led to the isolation of 16
and 16 (tR 13.6 min).
Physical data for 16
234 nm (
b
/16
a
¼ca. 1/5.3). HPLC separation
s), 0.87 and 0.92 (18H, each as s), 1.85 (3H, d, J¼1.2 Hz), 2.31 (1H,
ddd, J¼5.1, 6.3 and 13.2 Hz), 2.56 (1H, ddd, J¼6.1, 6.8 and 13.2 Hz),
3.67 (1H, d, J¼10.7 Hz), 3.92 (1H, d, J¼10.7 Hz), 4.37 (1H, dd, J¼6.1
and 6.3 Hz), 6.47 (1H, dd, J¼5.1 and 6.8 Hz), 7.28–7.58 (6H, m,
b
(tR 12.2 min)
a
b
: UV (MeOH) lmax 267 nm (
3
9700), lmin
3
2000); 1H NMR (CDCl3)
d
0.07, 0.08 and 0.11 (12H, each as
J¼1.2 Hz), 9.07 (1H, br); 13C NMR (CDCl3)
d
ꢀ5.76, ꢀ5.50, ꢀ4.86,
s), 0.91 and 0.93 (18H, each as s), 1.14 (3H, s), 1.92 (3H, d, J¼1.2 Hz),
2.16 (1H, ddd, J¼6.3, 6.6 and 13.4 Hz), 2.29 (1H, ddd, J¼3.7, 6.3 and
13.4 Hz), 3.54 (1H, d, J¼11.0 Hz), 3.69 (1H, J¼11.0 Hz), 4.37 (1H, dd,
J¼3.7 and 6.3 Hz), 6.27 (1H, dd, J¼6.3 and 6.6 Hz), 7.53 (1H, d,
J¼1.2 Hz), 9.15 (1H, br); NOE experiment H-50b/H-6 (1.9%); 13C NMR
ꢀ4.68, 12.65, 17.94, 18.21 25.65, 25.87, 40.69, 63.51, 75.65, 86.27,
99.09, 110.99, 128.43, 128.87, 131.07, 134.10, 136.27, 150.28, 163.88;
FABMS (m/z) 579 (MþþH). Anal. Calcd for C28H46N2O5SSi2: C, 58.09;
H, 8.01; N, 4.84. Found: C, 58.35; H, 8.13; N, 4.82.
(CDCl3)
d
ꢀ5.45, ꢀ5.41, ꢀ5.13, ꢀ4.69, 12.55, 18.00, 18.21, 18.39,
25.69, 25.92, 41.61, 67.74, 72.35, 83.45, 87.95, 110.62, 135.57, 150.37,
163.96; FABMS (m/z) 485 (MþþH). Anal. Calcd for C23H44N2O5Si2: C,
56.98; H, 9.15; N, 5.78. Found: C, 57.02; H, 9.36; N, 5.69.
4.17. 40-Acetoxy-30,50-bis-O-(tert-butyldimethylsilyl)-
thymidine (19
b a)
) and its 40-epimer (19
Physical data for 16
a
: UV (MeOH) lmax 268 nm (
3
9900), lmin
A mixture of 18a (500.4 mg, 0.86 mmol), Hg(OAc)2 (602.3 mg,
234 nm (
3
2000); 1H NMR (CDCl3)
d
0.079 and 0.084 (12H, each as
1.89 mmol), and AcOH (0.49 mL, 8.60 mmol) in CH2Cl2 (7.0 mL)
was stirred at rt for 0.5 h. The reaction mixture was partitioned
between CH2Cl2 and saturated aqueous NaHCO3. The organic layer
separated was washed with 5% aqueous NaCN and then purified by
column chromatography (hexane/EtOAc¼3/1). This gave 19
s), 0.90 and 0.92 (18H, each as s), 1.29 (3H, s), 1.94 (3H, d, J¼1.2 Hz),
2.16 (1H, ddd, J¼5.1, 6.8 and 13.2 Hz), 2.56 (1H, ddd, J¼6.3, 6.8 and
13.2 Hz), 3.60 (1H, d, J¼10.5 Hz), 3.77 (1H, d, J¼10.5 Hz), 4.16 (1H,
dd, J¼6.3 and 6.8 Hz), 6.19 (1H, dd, J¼5.1 and 6.8 Hz), 7.19 (1H, d,
J¼1.2 Hz), 9.12 (1H, br); NOE experiment H-50b/H-10 (1.1%); 13C
(448.9 mg, 98%, foam, 19
ane/EtOAc¼2/1) of 19 led to the isolation of 19
19 (tR 11.0 min).
Physical data for 19
233 nm (
1900); 1H NMR (CDCl3)
b
/19
a
¼1.0/0.61). HPLC separation (hex-
NMR (CDCl3)
d
ꢀ5.51, ꢀ5.11, ꢀ4.68, 12.69, 17.91, 18.29 22.09, 25.64,
b
(tR 6.8 min) and
25.92, 41.26, 66.14, 76.35, 85.73, 87.08, 110.42, 135.71, 150.08,
164.04; FABMS (m/z) 485 (MþþH). Anal. Calcd for C23H44N2O5Si2: C,
56.98; H, 9.15; N, 5.78. Found: C, 57.15; H, 9.35; N, 5.72.
a
b
: UV (MeOH) lmax 266 nm (
3 9500), lmin
3
d
0.09, 0.10, 0.128 and 0.129 (12H,
each as s), 0.90 and 0.94 (18H, each as s), 1.92 (3H, d, J¼1.2 Hz), 2.06
(3H, s), 2.26 (1H, ddd, J¼5.4, 8.0 and 13.4 Hz), 2.55 (1H, ddd, J¼5.6,
7.3 and 13.4 Hz), 3.96 (1H, d, J¼10.7 Hz), 4.02 (1H, d, J¼10.7 Hz),
4.74 (1H, dd, J¼5.6 and 8.0 Hz), 6.50 (1H, dd, J¼5.4 and 7.3 Hz), 7.33
(1H, d, J¼1.2 Hz), 9.64 (1H, br); NOE experiment H-50b/H-6 (1.1%);
4.15. 1-[3,5-Bis-O-(tert-butyldimethylsilyl)-2-deoxy-
4-methyl-
b-D-threo-pentofuranosyl]thymine (17b)
and its 40-epimer (17
a)
These compounds were prepared from 11 (101.5 mg, 0.17 mmol)
in 95% yield (17 /17
¼ca. 20/1) by the procedure described for the
preparation of 16 from 8
. HPLC separation (hexane/EtOAc¼2/1) of
17 led to the isolation of 17 (tR 18.0 min) and 17 (tR 14.3 min).
Physical data for 17 : UV (MeOH) lmax 268 nm ( 9400), lmin
235 nm ( 0.05, 0.09 and 0.10 (12H, each as
1900); 1H NMR (CDCl3)
13C NMR (CDCl3)
d
ꢀ5.36, ꢀ5.05, ꢀ4.79, 12.51, 17.79, 18.42, 21.72,
b
a
25.53, 25.87, 40.43, 63.61, 71.34, 86.10, 109.70, 110.95, 135.99,
150.21, 164.06, 168.73; FABMS (m/z) 529 (MþþH). Anal. Calcd for
C24H44N2O7Si2: C, 54.51; H, 8.39; N, 5.30. Found: C, 54.55; H, 8.49;
N, 5.26.
a
b
a
b
3
3
d
Physical data for 19
a
: UV (MeOH) lmax 265 nm (
3 9300), lmin
s), 0.88 and 0.92 (18H, each as s), 1.20 (3H, s), 1.92–1.96 (4H, m,
J¼1.2, 1.7, 2.9 and 14.6 Hz), 2.81 (1H, ddd, J¼5.1, 7.6 and 14.6 Hz),
3.74 (1H, d, J¼10.2 Hz), 3.88 (1H, d, J¼10.2 Hz), 4.09 (1H, dd, J¼1.7
and 5.1 Hz), 6.20 (1H, dd, J¼2.9 and 7.6 Hz), 7.65 (1H, d, J¼1.2 Hz),
9.27 (1H, br); NOE experiment H-50a/H-6 (3.3%); 13C NMR (CDCl3)
232 nm ( d
3
2000); 1H NMR (CDCl3)
0.059, 0.062, 0.13 and 0.14
(12H, each as s), 0.89 and 0.91 (18H, each as s), 1.92 (3H, d,
J¼1.2 Hz), 2.09 (3H, s), 2.14 (1H, ddd, J¼4.1, 8.5 and 13.4 Hz), 2.43
(1H, dd, J¼5.9 and 13.4 Hz), 4.18 (1H, d, J¼11.0 Hz), 4.24 (1H, d,
J¼11.0 Hz), 4.60 (1H, d, J¼4.1 Hz), 6.48 (1H, dd, J¼5.9 and 8.5 Hz),
7.37 (1H, d, J¼1.2 Hz), 9.44 (1H, br); NOE experiment H-50/H-10
d
ꢀ5.40, ꢀ5.28, ꢀ5.20, ꢀ4.93, 12.58, 17.96, 18.42, 21.30, 25.60, 25.98,
41.69, 65.07, 75.18, 83.90, 88.60, 109.96, 136.67, 150.54, 164.08;
FABMS (m/z) 485 (MþþH). Anal. Calcd for C23H44N2O5Si2: C, 56.98;
H, 9.15; N, 5.78. Found: C, 57.13; H, 9.19; N, 5.78.
Physical data for 17
(12H, each as s), 0.90 and 0.91 (18H, each as s), 1.33 (3H, s), 1.88–
(1.3%); 13C NMR (CDCl3)
d
ꢀ5.69, ꢀ5.43, ꢀ5.17, ꢀ4.80, 12.69, 17.85,
18.16, 21.81, 25.57, 25.74, 39.29, 60.14, 74.85, 87.11, 111.08, 113.01,
135.17, 150.34, 163.90, 168.75; FABMS (m/z) 529 (MþþH). Anal.
Calcd for C24H44N2O7Si2: C, 54.51; H, 8.39; N, 5.30. Found: C, 54.24;
H, 8.48; N, 5.21.
a: d 0.06, 0.07 and 0.09
1H NMR (CDCl3)

H. Shimada et al. / Tetrahedron 65 (2009) 6008–6016
6015
4.18. Preparation of a mixture of 18
b
and 18
a
from 19
/19
¼1.0/0.61) in
64.28, 74.37, 85.16, 88.99, 110.50, 135.83, 150.10, 163.95; FABMS
(m/z) 499 (MþþH). Anal. Calcd for C24H46N2O5Si2: C, 57.79; H, 9.30;
N, 5.62. Found: C, 58.00; H, 9.58; N, 5.57.
To a solution of 19 (422.8 mg, 0.80 mmol, 19
b
a
CH2Cl2 (7.0 mL) were added Me3SiSPh (1.51 mL, 8.00 mmol) and then
SnCl4 (1.0 M CH2Cl2 solution, 3.20 mL, 3.20 mmol) at below ꢀ78 ꢁC
under positive pressure of dry Ar. Immediately after addition of these
reagents, the reaction mixture was warmed to ꢀ30 ꢁC and stirred for
1 h. The mixture was partitioned between CH2Cl2 and saturated
aqueous NaHCO3. Column chromatography (hexane/EtOAc¼5/1) of
4.21. Reaction of 8b with EtAl(C^CSiMe3)2: formation
of 22 , 22 , 20 , and 21b
b
a
b
The aluminum reagent was prepared as follows. To a solution of
Me3SiC^CH (1.42 ml, 10.24 mmol) in toluene (5.5 mL) was added
BuLi (1.65 M in hexane, 6.20 mL, 10.24 mmol) at 0 ꢁC under positive
pressure of dry Ar. After the above mixture being stirred for 0.5 h at
0 ꢁC, EtAlCl2 (1.04 M in hexane, 4.92 mL, 5.12 mmol) was added and
the whole mixture was stirred at 0 ꢁC for 0.5 h.
the organic layer gave 18 (356.5 mg, 78%, foam, 18
b/18a¼20/1).
4.19. 40-Benzenesulfonyl-30,50-bis-O-(tert-butyldimethylsilyl)-
thymidine (8 a)
) and its 40-epimer (8
b
To a solution of 8b (99.7 mg, 0.16 mmol) was added the above
To a solution of 18 (354.9 mg, 0.61 mmol, 18
b
/18
a
¼20/1) in
prepared reagent (4.51 mL, containing 1.28 mmol of the aluminum
reagent) at 0 ꢁC under positive pressure of dry Ar. The reaction
mixture was stirred for 1 h at rt, and quenched by adding saturated
aqueous NH4Cl. Filtration of the reaction mixture through a Celite
pad was followed by partition between CH2Cl2 and saturated
NH4Cl. Column chromatography (hexane/EtOAc¼2/1) of the or-
CH2Cl2 (7.0 mL) was added m-CPBA (330.3 mg, 1.34 mmol) at 0 ꢁC.
The reaction mixture was stirred for 5 h at rt, and partitioned be-
tween CH2Cl2 and saturated aqueous NaHCO3. Column chroma-
tography (hexane/EtOAc¼3/1) of the organic layer gave
8
(355.4 mg, 95%, foam, 8 /8
b
a
¼20/1). HPLC separation (hexane/
EtOAc¼1/1) of 8 led to the isolation of 8
b
(tR 10.2 min) and 8
a
(tR
ganic layer gave a mixture of 22
combined yield: 93%, 22 /22 /20
tions of pure 22 and 22 were obtained by repeating HPLC sep-
aration (hexane/EtOAc¼2/1).
Physical data for 22
: 1H NMR (CDCl3)
b
, 22
a
, 20
b, and 21b (78.5 mg,
8.8 min).
b
a
b/21
b¼1/1.4/6.2/1.4). Small por-
Physical data for 8
b
: UV (MeOH) lmax 266 nm (
3
10,500), lmin
b
a
235 nm (
3
3300); 1H NMR (CDCl3)
d
0.02, 0.03, 0.16 and 0.18 (12H, each
as s), 0.85 and 0.98 (18H, each as s), 1.89 (3H, d, J¼1.2 Hz), 2.27 (1H,
ddd,J¼4.1, 8.8and13.4 Hz), 3.02(1H, ddd,J¼8.0,8.3and13.4 Hz), 3.64
(1H, d, J¼11.2 Hz), 4.27 (1H, d, J¼11.2 Hz), 5.14 (1H, dd, J¼8.0 and
8.8 Hz), 6.80 (1H, dd, J¼4.1 and 8.3 Hz), 7.06 (1H, d, J¼1.2 Hz), 7.54–
b
d 0.09, 0.10, 0.12 and 0.13
(12H, each as s), 0.17 (9H, s), 0.92 and 0.94 (18H, each as s), 1.91 (3H,
d, J¼1.2 Hz), 2.10 (1H, ddd, J¼6.6, 6.8 and 12.9 Hz), 2.42 (1H, ddd,
J¼5.4, 6.3 and 12.9 Hz), 3.76 (1H, d, J¼11.2 Hz), 3.91 (1H, d,
J¼11.2 Hz), 4.45 (1H, dd, J¼5.4 and 6.8 Hz), 6.37 (1H, dd, J¼6.3 and
6.6 Hz), 7.41 (1H, d, J¼1.2 Hz), 8.54 (1H, br); NOE experiment H-50b/
7.91 (5H, m), 9.16 (1H, br); 13C NMR (CDCl3)
d
ꢀ5.52, ꢀ5.47, ꢀ5.01,
ꢀ4.69, 12.70, 18.01, 18.38, 25.57, 25.78, 39.46, 60.68, 71.55, 84.90,
101.98, 111.89, 128.85, 129.90, 133.90, 134.91, 137.20, 150.05, 163.52;
FABMS (m/z) 611 (MþþH). Anal. Calcd forC28H46N2O7SSi2: C, 55.05; H,
7.59; N, 4.59. Found: C, 55.13; H, 7.70; N, 4.50.
H-6 (1.4%); 13C NMR (CDCl3)
d
ꢀ5.38, ꢀ5.34, ꢀ4.87, ꢀ4.67, ꢀ0.17,
12.54, 18.07, 18.41, 25.69, 25.91, 40.55, 65.61, 71.15, 83.68, 85.44,
93.51, 100.72, 110.83, 135.47, 150.02, 163.53; FABMS (m/z) 567
(MþþH). FAB-high resolution MS (m/z) calcd for C27H51N2O5Si3:
567.3106, found: 567.3126 (MþþH).
4.20. 30,50-Bis-O-(tert-butyldimethylsilyl)-4-ethylthymidine
(20
b
) and its 40-epimer (20
a
)
Physical data for 22
a
: UV (MeOH) lmax 268 nm (
3 9700), lmin
235 nm (
3
2100); 1H NMR (CDCl3)
d
0.11, 0.128 and 0.131 (12H, each
These compounds and 21
AlEt3 (0.96 M hexane solution) by the procedure for the preparation
of 16 from 8 . After column chromatography of the reaction mix-
ture, a mixture of the three products (74.5 mg, combined yield: 89%,
b
were prepared from 8
b
by using
as s), 0.20 (9H, s), 0.91 and 0.92 (18H, each as s), 1.96 (3H, d,
J¼1.2 Hz), 2.31 (1H, ddd, J¼4.1, 7.8 and 13.2 Hz), 2.44 (1H, ddd,
J¼2.2, 5.6 and 13.2 Hz), 3.76 (1H, d, J¼9.8 Hz), 3.88 (1H, d, J¼9.8 Hz),
4.45 (1H, dd, J¼2.2 and 4.1 Hz), 6.36 (1H, dd, J¼5.6 and 7.8 Hz), 7.67
(1H, d, J¼1.2 Hz), 8.91 (1H, br); NOE experiment H-50b/H-10 (1.0%);
a
20
b
/20
a
/21
b
¼1/0.07/0.13) was obtained. Compounds 20
b
and 20
a
were separated by HPLC (hexane/EtOAc¼2/1): 20
b
tR 11.1 min; 20
a
13C NMR (CDCl3)
d
ꢀ5.25, ꢀ5.20, ꢀ5.06, ꢀ4.82, ꢀ0.18, 12.76, 17.98,
tR 13.1 min.
18.42, 25.64, 25.95, 41.51, 63.89, 76.68, 85.16, 86.48, 93.08, 105.06,
110.65, 135.98, 150.21, 163.88; FABMS (m/z) 567 (MþþH). Anal.
Calcd for C27H50N2O5Si3: C, 57.20; H, 8.89; N, 4.94. Found: C, 57.60;
H, 8.99; N, 4.83.
Physical data for 20
b
: UV (MeOH) lmax 267 nm (
3 9600), lmin
235 nm (
3
1900); 1H NMR (CDCl3)
d
0.07, 0.08 and 0.11 (12H, each as
s), 0.90 (9H, s), 0.92–0.96 (12H, m, J¼7.6 Hz), 1.41–1.50 (1H, m, J¼7.6
and 14.9 Hz), 1.69–1.78 (1H, m, J¼7.6 and 14.9 Hz), 1.93 (3H, d,
J¼1.2 Hz), 2.15 (1H, ddd, J¼6.3, 7.1 and 13.4 Hz), 2.28 (1H, ddd,
J¼3.7, 6.3 and 13.4 Hz), 3.56 (1H, d, J¼10.7 Hz), 3.73 (1H, d,
J¼10.7 Hz), 4.44 (1H, dd, J¼3.7 and 6.3 Hz), 6.25 (1H, dd, J¼6.3 and
7.1 Hz), 7.51 (1H, d, J¼1.2 Hz), 9.41 (1H, br); NOE experiment H-50b/
4.22. Reaction of 8b with AlPh3: formation of 23
To a suspension of AlCl3 (1.00 g, 7.50 mmol) in CH2Cl2 (9.4 mL)
was added a THF solution of PhMgBr (1.09 M, 20.6 mL, 22.5 mmol)
at 0 ꢁC under positive pressure of dry Ar. The resulting yellow so-
H-6 (2.0%); 13C NMR (CDCl3)
d
ꢀ5.49, ꢀ5.42, ꢀ5.16, ꢀ4.64, 8.08,
12.55, 17.95, 18.33, 24.48, 25.68, 25.89, 41.69, 65.74, 72.72, 83.52,
89.40, 110.64, 135.53, 150.45, 164.09; FABMS (m/z) 499 (MþþH).
Anal. Calcd for C24H46N2O5Si2: C, 57.79; H, 9.30; N, 5.62. Found: C,
58.17; H, 9.59; N, 5.62.
lution was stirred at rt for 10 h. A solution of 8b (97.7 mg,
0.16 mmol) in CH2Cl2 (1.0 mL) was reacted with the above prepared
AlPh3 (5.12 mL, 1.28 mmol) at rt for 3 h, and then at refluxing
temperature for 4 h. The reaction mixture was treated with aque-
ous NH4Cl and filtered through a Celite pad. The resulting filtrate
was partitioned between CH2Cl2 and saturated aqueous NH4Cl.
Column chromatography (hexane/EtOAc¼3/1) of the organic layer
gave 23 (69.6 mg, 93%).
Physical data for 20
a
: UV (MeOH) lmax 267 nm (
3 9600), lmin
234 nm (
3
1700); 1H NMR (CDCl3)
d
0.079, 0.082 and 0.085 (12H,
each as s), 0.90 and 0.92 (18H, each as s), 0.97 (3H, t, J¼7.6 Hz),1.57–
1.73 (2H, m, J¼7.6 Hz),1.94 (3H, d, J¼1.2 Hz), 2.13 (1H, ddd, J¼5.1, 7.6
and 12.9 Hz), 2.54 (1H, ddd, J¼6.1, 7.3 and 12.9 Hz), 3.62 (1H, d,
J¼10.7 Hz), 3.81 (1H, d, J¼10.7 Hz), 4.25 (1H, dd, J¼6.1 and 7.6 Hz),
6.23 (1H, dd, J¼5.1 and 7.3 Hz), 7.17 (1H, d, J¼1.2 Hz), 8.98 (1H, br);
Physical data for 23: 1H NMR (CDCl3)
d 0.067, 0.071 and 0.15
(12H, each as s), 0.86 and 0.92 (18H, each as s), 1.90 (3H, d,
J¼1.2 Hz), 2.02 (1H, ddd, J¼5.4, 7.6 and 13.4 Hz), 2.42 (1H, ddd,
J¼2.0, 5.9 and 13.4 Hz), 4.68 (1H, dd, J¼2.0 and 5.4 Hz), 5.78 (1H, s),
6.56 (1H, dd, J¼5.9 and 7.6 Hz), 7.06 (1H, d, J¼1.2 Hz), 9.51 (1H, br);
NOE experiment H-50b/H-10 (1.5%); 13C NMR (CDCl3)
ꢀ5.11, ꢀ4.49, 8.34, 12.71, 17.89, 18.23, 25.67, 25.92, 27.89, 41.33,
d
ꢀ5.55, ꢀ5.52,

6016
H. Shimada et al. / Tetrahedron 65 (2009) 6008–6016
6. Haraguchi, K.; Sumino, M.; Tanaka, H. J. Org. Chem. 2006, 71, 4433.
13C NMR (CDCl3)
d
ꢀ5.43, ꢀ5.22, ꢀ4.72, ꢀ4.64, 12.55, 17.95, 18.43,
7. Kubota, Y.; Kunikata, M.; Ishizaki, N.; Haraguchi, K.; Odanaka, Y.; Tanaka, H.
Tetrahedron 2008, 64, 2391.
8. Data taken from: Lange’s Handbook of Chemistry, 15th ed.; Dean, J. H., Ed.;
McGraw-Hill: New York, NY, 1999.
25.63, 41.81, 69.53, 86.00, 111.37, 119.44, 134.52, 142.43, 150.17,
163.92; FABMS (m/z) 469 (MþþH). FAB-high resolution MS (m/z)
calcd for C22H41N2O5Si2: 469.2554, found: 469.2549 (MþþH).
9. For typical examples, see: (a) Brown, D. S.; Ley, S. V.; Bruno, M. Heterocycles
1989, 28, 773; (b) Lee, S.; Oh, S. Tetrahedron Lett. 2002, 43, 2891.
10. Giese, B.; Erdmann, P.; Giraud, J.; Go¨bel, T.; Peyretta, M.; Scha¨fer, T.; von
Raumer, M. Tetrahedron Lett. 1994, 35, 2683.
4.23. 30,50-Di-O-acetyl-40-cyanothymidine (24
b)
11. Frigerio, M.; Santagostino, M.; Sputore, S. J. Org. Chem. 1999, 64, 4537.
12. Drew, M. G. B.; Ennis, S. C.; Gridley, J. J.; Osborn, H. M. I.; Spackman, D. G.
Tetrahedron 2001, 57, 7919.
13. Bhandari, P.; Crombie, L.; Harper, M. F.; Rossiter, J. T.; Sanders, M.; Whiting, D. A.
J. Chem. Soc., Perkin Trans. 1 1992, 1685.
To a solution of 8 (130.2 mg, 0.21 mmol) in toluene (3.0 mL)
b
was added Et2AlCN (1.0 M in toluene, 1.68 mL, 1.68 mmol). The re-
action mixture was heated at reflux for 4 h, and then treated with
saturated aqueous NH4Cl. Filtration of the reaction mixture through
a Celite pad was followed by partition of the filtrate between CH2Cl2
and saturated aqueous NH4Cl. Column chromatography (hexane/
14. Use of i-Pr2NEt instead of Et3N in this reaction lowered the yield of 6 to 32%.
15. Harpp, D. N.; Aida, T.; DeCesare, J.; Tisnes, O.; Chan, T. H. Synthesis 1984, 1037.
16. Of the two protons at the 50-position, the one that appears at a lower field is
designated as H-50b, and the other as H-50a, throughout the text and the Ex-
perimental section. The same applies to the two protons at the 20-position.
17. The 13C NMR spectrum of the 40-chloro derivative (14) gave the C-40 resonance
at 114.15 ppm (in CD2Cl2), which is reasonable as compared with those of the
EtOAc¼3/1) of the organic layer gave a mixture of products and 8
b,
which was reacted with Bu4NF (1.0 M in THF, 0.42 mL, 0.42 mmol)
in THF (3.0 mL) at rt for 1 h. The resulting solution was then reacted
with Ac2O (0.20 mL, 2.10 mmol) for 17 h at rt. The reaction mixture
was partitioned between CH2Cl2 and saturated aqueous NaHCO3.
Column chromatography (hexane/EtOAc¼1/1) of the organic layer
gave a mixture of products (57.0 mg), HPLC separation (CHCl3/
40-benzenesulfonyl derivative (8
derivative (16 : 87.08 ppm in CDCl3).
18. The 1H and 13C NMR data for the methyl phenyl sulfoxide obtained in these
reactions are as follows: 1H NMR (CDCl3) 2.74 (3H, s), 7.49–7.68 (5H, m); 13C
NMR (CDCl3) 43.95, 123.47, 129.34, 131.01, 145.69. These data are identical
a
: 103.57 ppm in CDCl3) and the 40-methyl
a
d
d
with those of commercially available sample (purchased from Aldrich). Re-
action of benzenesulfonyl chlorides with trialkylaluminums has been reported
to yield alkyl aryl sulfoxide: Jahnke, D.; Reinheckel, H. Organomet. Chem. Syn.
1970/1971, 31.
MeOH¼100/2) of which gave 24
b (33.1 mg, 45%, tR 11.5 min).
Physical data for 24
b
: IR (neat) 2254 cmꢀ1 (CN); 1H NMR (CDCl3)
d
1.94 (3H, d, J¼1.2 Hz), 2.17 and 2.22 (6H, each as s), 2.58 (1H, ddd,
19. Kubota, Y.; Kunikata, M.; Haraguchi, K.; Tanaka, H. J. Org. Chem. 2009, 74, 3402.
J¼4.9, 6.8 and 14.4 Hz), 2.64 (1H, ddd, J¼7.1, 7.3 and 14.4 Hz), 4.50
(1H, d, J¼12.0 Hz), 4.52 (1H, d, J¼12.0 Hz), 5.56 (1H, dd, J¼4.9 and
7.3 Hz), 6.31 (1H, dd, J¼6.8 and 7.1 Hz), 7.08 (1H, d, J¼1.2 Hz), 9.71
(1H, br); NOE experiment H-50/H-30 (10.3%); 13C NMR (CDCl3)
20. Partial 50-O-desilylation of 18
a
to yield 6 was the sole event observed.
-erythro-isomer were separated by HPLC (CHCl3/
MeOH¼100/2). Physical data for the
-erythro-isomer, 40-benzenesulfenyl-30-
O-(tert-butyldimethyl silyl)thymidine, are as follows: UV (MeOH) lmax 263 nm
11,700), lmin 236 nm ( 0.14 and 0.18 (6H, each as s),
3900); 1H NMR (CDCl3)
21. Compound
6 and its b-D
b-D
(
3
3
d
d
12.48, 20.53, 20.70, 35.52, 64.17, 72.79, 81.47, 86.96, 112.13, 114.48,
0.96 (9H, s), 1.82 (3H, d, J¼1.2 Hz), 2.34 (1H, ddd, J¼4.1, 8.3 and 13.4 Hz), 2.69
(1H, ddd, J¼8.0, 8.3 and 13.4 Hz), 2.85 (1H, dd, J¼4.9 and 8.0 Hz), 3.68 (1H, d,
J¼4.9 and 12.4 Hz), 3.75 (1H, dd, J¼8.0 and 12.4 Hz), 4.92 (1H, dd, J¼8.0 and 8.
3 Hz), 6.58 (1H, dd, J¼4.1 and 8.3 Hz), 7.14 (1H, d, J¼1.2 Hz), 7.33–7.59 (5H, m),
135.62, 149.94, 163.60, 169.62, 169.63; FABMS (m/z) 352 (MþþH).
FAB-high resolution MS (m/z) calcd for C15H18N3O7: 352.1145,
found: 352.1163 (MþþH).
8.45 (1H, br); NOE experiment 50-OH/H-6 (1.9%); 13C NMR (CDCl3)
d
ꢀ5.03, ꢀ4.
69, 12.45, 18.01, 25.62, 39.15, 63.14, 71.61, 83.59, 98.90, 111.43, 128.85, 128.89,
130.18, 136.38, 137.12, 149.73, 163.48; FABMS (m/z) 465 (MþþH). Anal. Calcd for
C22H32N2O5SSi: C, 56.87; H, 6.94; N, 6.03. Found: C, 56.97; H, 7.07; N, 5.88.
Acknowledgements
22. The yield was calculated based on 1H NMR measurement of a mixture of 22
b,
Financial support from Showa University Research Grant for
Young Researchers (to H.S.) is gratefully acknowledged. The authors
thank Ms. K. Shiohara, S. Matsubayashi, and Y. Odanaka (Center for
Instrumental Analysis, Showa University) for technical assistance
with NMR, MS, and elemental analyses.
22
23. When 8
study in Ref. 6, the
a
, 20
b
b
, and 21
b by integrating the respective H-6 resonance.
was reacted with Me3SiC^CAl(Et)Cl, the reagent used in our previous
a-L-nucleoside 22a was formed as the sole product in 58%
yield, presumably through chlorination at the 40-position.
24. This reagent was prepared by reacting AlCl3 with a THF solution of PhMgBr as
described in the Experimental section.
25. No reaction took place by reacting 8
26. Based on 1H NMR analysis of this mixture, it was confirmed that, in addition to
and the 40-cyano- -isomer, there were formed 23 and the 40-cyano-
isomer. At this stage, a small portion of the 40-cyano-
-isomer, 1-[3,5-bis-O-
(tert-butyldimethylsilyl)-4-cyano-2-deoxy- -threo-pentofuranosyl]thymine,
was isolated by HPLC (hexane/EtOAc¼2/1). Physical data for this compound are
as follows: IR (neat) 2254 cmꢀ1 (CN); 1H NMR (CDCl3)
0.13, 0.149, 0.153 and 0.
b with Et2AlCN in toluene at rt for 16 h.
References and notes
8
b
b
-D
a-L-
a-L
a-L
1. For an excellent review, see: Hayakawa, H.; Kohgo, S.; Kitano, K.; Ashida, N.;
Kodama, E.; Mitsuya, H.; Ohrui, H. Antiviral Chem. Chemother. 2004, 15, 169.
2. Nomura, M.; Shuto, S.; Tanaka, M.; Sasaki, T.; Mori, S.; Shigeta, S.; Matsuda, A.
J. Med. Chem. 1999, 42, 2901.
3. Ohrui, H.; Kohgo, S.; Kitano, K.; Sakata, S.; Kodama, E.; Yoshimura, K.; Matsuoka,
M.; Shigeta, S.; Mitsuya, H. J. Med. Chem. 2000, 43, 4516.
4. (a) Haraguchi, K.; Takeda, S.; Tanaka, H. Org. Lett. 2003, 5, 1399; (b) Haraguchi,
K.; Takeda, S.; Tanaka, H.; Nitanda, T.; Baba, M.; Dutschman, G. E.; Cheng, Y.-C.
Bioorg. Med. Chem. Lett. 2003, 13, 3775.
5. Kubota, Y.; Haraguchi, K.; Kunikata, M.; Hayashi, M.; Ohkawa, M.; Tanaka, H.
J. Org. Chem. 2006, 71, 1099.
d
16 (12H, each as s), 0.92 and 0.93 (18H, each as s), 1.98 (3H, J¼1.2 Hz), 2.37 (1H,
ddd, J¼3.4, 9.0 and 13.4 Hz), 2.48 (1H, dd, J¼5.6 and 13.4 Hz), 3.84 (1H, d, J¼10.
0 Hz), 3.95 (1H, d, J¼10.0 Hz), 4.70 (1H, d, J¼3.4 Hz), 6.51 (1H, dd, J¼5.6 and 9.
0 Hz), 7.36 (1H, d, J¼1.2 Hz), 8.33 (1H, br); NOE experiment H-10/H-50b (0.3%);
13C NMR (CDCl3)
d
ꢀ5.45, ꢀ5.33, ꢀ5.15, ꢀ4.84, 12.75, 17.97, 18.34, 25.57, 25.82,
40.44, 61.85, 75.39, 84.86, 86.58, 112.34, 119.51, 134.58, 150.04, 163.08; FABMS
(m/z) 496 (MþþH). FAB-high resolution MS (m/z) calcd for C23H42N3O5Si2: 496.
2663, found: 496.2675 (MþþH).