Synthesis and anti-HIV activity of 4′-substituted 4′-thiothymidines: A new entry based on nucleophilic substitution of the 4′-acetoxy group

Article abstract of DOI:10.1021/jm070824s

Diacetoxylation of 1-(2,5-dideoxy-β-L-glycero-pent-4-eno-4- thiofuranosyl)thymine (13) with Pb(OAc)₄ allowed introduction of an acetoxy leaving group to the 4′-position. Nucleophilic substitution of the resulting 4′-acetoxy derivative (14) with

Full text of DOI:10.1021/jm070824s

J. Med. Chem. 2008, 51, 1885–1893
1885
Synthesis and Anti-HIV Activity of 4′-Substituted 4′-Thiothymidines: A New Entry Based on
Nucleophilic Substitution of the 4′-Acetoxy Group
Kazuhiro Haraguchi,*,† Hisashi Shimada,† Hiromichi Tanaka,† Takayuki Hamasaki,‡ Masanori Baba,‡ Elizabeth A. Gullen,§
Ginger E. Dutschman,§ and Yung-Chi Cheng§
School of Pharmaceutical Sciences, Showa UniVersity, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan, DiVision of AntiViral
Chemotherapy, Center for Chronic Viral Diseases, Graduate School of Medical and Dental Sciences, Kagoshima UniVersity,
Kagoshima 890-8544, Japan, and Department of Pharmacology, School of Medicine, Yale UniVersity, New HaVen, Connecticut 06520
ReceiVed July 9, 2007
Diacetoxylation of 1-(2,5-dideoxy-ꢀ-L-glycero-pent-4-eno-4-thiofuranosyl)thymine (13) with Pb(OAc)4
allowed introduction of an acetoxy leaving group to the 4′-position. Nucleophilic substitution of the resulting
4′-acetoxy derivative (14) with silicon reagents enabled us to prepare the 4′-phenylthio (17a), 4′-azido (18a),
4′-methoxy (20a), and 4′-allyl (21a) analogues of 4′-thiothymidine. 4′-Cyano (25a) and 4′-ethynyl (31)
nucleosides were also synthesized from 3′,5′-bis-O-TBDMS derivative (24). Among novel 4′-substituted
4′-thiothymidines, the 4′-azido (33), 4′-cyano (36), and 4′-ethynyl (37) derivatives were found to show
potent inhibitory activity against HIV-1 and HIV-2. It is noteworthy that 36 and 37 were also inhibitory
against replication of HIV variant resistant to 3TC (HIV-1M184V), being as potent as against HIV-1IIIB
.
Introduction
Nucleoside analogues are recognized as an important class
of biologically active compounds, especially as antiviral and
antitumor agents.1Among the sugar-modified nucleosides, 4′-
thionucleosides, in which the oxygen atom in the furanose
ring is replaced with sulfur atom, have attracted much
attention since the discovery that 4′-thiothymidine (1) and
4′-thio-2′-deoxycytidine (2) possess potent antiviral and
antitumor activities (Figure 1).2
Although many reports have dealt with the synthesis of 4′-
thionucleoside analogues, the availability of their 4′-substituted
derivatives has been quite limited,3–5 2′-deoxy-4′-methyl-4′-
thiopyrimidine nucleosides (I) being the sole precedent.6 In this
instance, Vorbrüggen-type glycosidation was applied to the
reaction between a 2-deoxy-4-methyl-4-thiofuranosyl derivative
and a pyrimidine base, but the undesired R-anomer was also
formed.
Recently, it has been reported that 4′-substituted nucleoside
such as the 4′-azido (3), 4′-methoxy (4), 4′-cyano (5), and 4′-
ethynyl (6) analogues of thymidine exhibit potent anti-HIV
activity.7 These findings motivated us to synthesize their 4′-
thio counterparts. We describe here a novel method for the
synthesis of 4′-thiothymidines having a variety of 4′-substituents
and their inhibitory activity against HIV.
The present method consists of the following two reactions
shown in Scheme 1: (1) Pb(OAc)4-mediated vicinal diacetoxy-
lation of a 4′,5′-unsaturated 4′-thiothymidine derivative II and
(2) nucleophilic substitution of the resulting 4′-acetoxy analogue
III with silicon reagents to furnish the target molecule IV.
Figure 1. 4′-Thionucleosides 1, 2, I, and 4′-substituted thymidines
3–6.
ine, was prepared from the TIPDS (1,1,3,3-tetraisopropyldisi-
loxane-1,3-diyl)-protected 4-thiofuranoid glycal (7) on the basis
of electrophilic glycosidation. We have already reported that
PhSeCl-mediated glycosidation between 7 and silylated uracil
gave both the ꢀ- and R-anomers in a ratio of ꢀ/R ) 18/1.8 When
the present reaction of 7 with silylated thymine was carried out
using N-iodosuccinimide (NIS) as an electrophile, the ꢀ-anomer
(8) was obtained exclusively in 75% yield (Scheme 2).
Subsequent radical reduction of 8 with Bu3SnH/Et3B/O2 gave
the 4′-thiothymidine derivative (9) in 98% yield.Compound 9
was desilylated with Bu4NF in the presence of Ac2O to give
the 3′,5′-di-O-acetyl derivative (10, 93%). Deacetylation of 10
followed by iodination with I2/PPh3 gave 5′-deoxy-5′-iodo-4′-
thiothymidine (11, 81%). Attempted elimination of HI from 11
by treatment with NaOMe/MeOH resulted in an intractable
mixture of products. Therefore, 11 was converted to its
3′-acetate, and the elimination was effected by reacting it with
DBN in CH3CN at room temperature. This gave the 4′,5′-
Results and Discussion
Preparation of 4′,5′-Unsaturated 4′-Thiothymidine (13),
the Substrate for Vicinal Diacetoxylation. Compound 13,
1-(2,5-dideoxy-ꢀ-L-glycero-pent-4-eno-4-thiofuranosyl)thym-
* Corresponding author. Tel: 81-3-3784-8187. Fax: 81-3-3784-8252.
E-mail: harakazu@pharm.showa-u.ac.jp.
†
Showa University.
Kagoshima University.
Yale University.
‡
§
10.1021/jm070824s CCC: $40.75
2008 American Chemical Society
Published on Web 02/27/2008

1886 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 6
Haraguchi et al.
Scheme 3. Pb(OAc)4-Mediated Diacetoxylation of 13
Scheme 1. Synthetic Scheme for 4′-Substituted
4′-Thiothymidines
Scheme 4. Mechanism of Diacetoxylation of 13
Scheme 2. Synthesis of 4′,5′-Unsaturated 4′-Thiothymidines 12
and 13
experiment (H-6/4′-OCOCH3: 0.3%). The other two products
were the ring-expanded compounds 15 (34%) and 16 (15%),
their thiopyranosyl structures being evident from the observed
HMBC correlations between H-5′ and C-1′.11 A plausible
reaction mechanism for the formation of these products is
depicted in Scheme 4.
Electrophilic addition of the cationic species (AcO)3Pb+ to
the enol thioether structure of 13 leads to the thiocarbenium
intermediate V, which would prefer the depicted 5′-conformation
due to the presence of the 3′-silyloxy group. There could be
two possible origins for an acetoxy group to be introduced to
the 4′-position: a ligand of the 5′-Pb substituent and the
counteranion. By considering the advantage of intramolecular
reaction as well as the fact that 14 was formed exclusively, we
assume ligand transfer from the 5′-Pb substituent would be a
likely pathway.
unsaturated derivative 12 in 83% yield. The corresponding 3′-
O-TBDMS derivative 13 was also prepared in 72% yield
from 12.
Vicinal Diacetoxylation of the 4′,5′-Unsaturated Deriva-
tives (12 and 13). Vicinal diacetoxylation of 12 was first
examined by reaction with Pb(OAc)4 (3 equiv) in benzene at
room temperature.9 However, even after 24 h, most of 12
remained intact. Since the initial step of the diacetoxylation of
olefins is considered to be electrophilic in nature, it is conceiv-
able that the presence of an electronegative acetoxy group at
the 3′-position of 12 decreases its reactivity toward Pb(OAc)4.10
In fact, 13 having a silyloxy group at the 3′-position showed a
much higher reactivity. Thus, when the reaction with Pb(OAc)4
(3 equiv) was carried out under conditions similar to those
discussed above, the complete disappearance of 13 was observed
after 10 h at room temperature. Three products were obtained
from this reaction (Scheme 3). The major product was the 4′-
acetoxy-4′-thionucleoside 14 (42%) with the R-L-configuration
as evidenced by HMBC correlation (H-5′/5′-OCOMe) and NOE
Upon departure of Pb(OAc)2 from the resulting intermediate
VI, there are two competing pathways depending upon the
nucleophile. The attack of acetate anion (path a) forms 14, while
that of the sulfur atom (path b) leads to the formation of
bicylo[3.1.0]sulfonium intermediate VII and then to the thi-
opyranosyl carbenium ion VIII. Finally, nucleophilic attack of
acetate anion would take place either at the 4′-position of VIII
leading to 15 (path c) or at the carbonyl carbon of the 4′-acetoxy
group forming 16 (path d).

Synthesis and Anti-HIV ActiVity of 4′-Substituted 4′-Thiothymidines
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 6 1887
Scheme 6. Reaction of 14 with Me3SiCN
a
Table 1. Reaction of 13 with Pb(OAc)4
yield (%)
entry
solvent
additive (equiv)
14b
42
33
trace
56
15c
16c
13b
1
2
3
4
benzene
THF
CH2Cl2
benzene
–
–
–
34
5
19
28
15
10
58
14
0
37
0
Na2CO3(2.3)
0
a All reactions were carried out with Pb(OAc)4 (3 equiv for entries 1–3
or 2.3 equiv for entry 4) at rt under Ar atmosphere overnight. b Isolated
yield. c The yields of 15 and 16 were calculated by comparison of integration
of H-1′ in 1H NMR spectroscopy.
to introduce a cyano group to the 4′-position. The 4′-phenylthio
derivative (17, a mixture of two 4′-epimers) prepared above was
converted to the 4′-acetoxy-3′,5′-bis-O-TBDMS derivative (24)
over three steps: deacetylation followed by silylation to give
23 (93%), and acetolysis of 23 with Hg(OAc)2/AcOH to yield
24 (98%, 24a/24b ) 4.2/1).
Scheme 5. 4′-Substituted 4′-Thiothymidines 17-21
When 24 was reacted with Me3SiCN/SnCl4 in CH2Cl2 at -30
°C, the desired 4′-cyano derivative 25 was obtained as a mixture
of two 4′-epimers albeit in a low yield (25a/25b ) 4.5/1,
combined yield 29%) (Figure 2). In this reaction, two byproduct
were obtained: the 4′-isonitrile (26b, 11%) with R-L-configu-
ration and the elimination product 27 (27%). In terms of
stereoselectivity, use of BF3 ·OEt2 instead of SnCl4 appeared
to be effective, but the yield of 25 remained much the same
(25a/25b ) 20/1, combined yield 37%). Two 4′-isonitriles were
also formed in this reaction (26a, 23%; 26b, 9%).13 The resulting
product 25 was further converted to its 3′,5′-di-O-acetyl
derivative which could be separated into the R-cyano (28a) and
ꢀ-cyano nucleoside (28b).
An attempted introduction of an ethynyl group by reacting
24 with Me3SiCt CAl(Cl)Et according to our recently published
method9 was unsuccessful, forming a complex mixture of
products. Therefore, the crude 4′-cyano derivative (25a) con-
taining 25b and 26b was transformed to the 4′-formyl derivative
(29) by reacting with Dibal-H followed by acid hydrolysis
(Figure 3). Conversion of the 4′-formyl group of 29 to an ethynyl
group was carried out by reacting with MeC(O)C(N2)P(OMe)2/
K2CO3 in MeOH.14 The resulting product 30 was further
converted to its 3′,5′-di-O-acetyl derivative (31) to provide an
analytically pure sample (30% yield from 29).
In Table 1 are shown several attempts to improve the yield
of 14 with the aforementioned result being listed in entry 1.
When THF was used as a solvent, a considerable amount of 13
was recovered (entry 2). Use of CH2Cl2 encouraged the ring
expansion pathway, and 14 was formed in a trace amount (entry
3). A slight increase in the yield of 14 was observed upon
carrying out the reaction in benzene in the presence of Na2CO3
as shown in entry 4.
Synthesisof4′-Substituted4′-ThiothymidinesbyDisplace-
ment of the 4′-Acetoxy Leaving Group. Displacement of the
4′-acetoxy group of 14 was carried out by using silicon reagents
in combination with SnCl4 in CH2Cl2 (Scheme 5). The reaction
with Me3SiSPh went to completion after 6 h at -30 °C to give
the 4′-phenylthio-ꢀ-D-isomer (17a) in 74% yield as well as its
4′-epimer (17b, 12%). The stereochemistry of these products
was assigned on the basis of NOE experiments: 17a, H-3′/H-
5′a (2.7%); Hꢀ-2′/H-5′b (1.4%); 17b, H-6/SPh (2.1%).12 The
predominant formation of the 4′-substituted ꢀ-D-isomer over its
R-L-counterpart was also seen in the reaction with Me3SiN3 (18a,
69%; 18b, 30%) and with Me3SiCH2CHdCH2 (21a/21b ) 10/
1, combined yield 53%). In contrast to the above stereochemical
trend, the reaction of 14 with Me3SiOMe/SnCl4 resulted in the
sole formation of the R-L-isomer (19b, 58%). The ꢀ-D-isomer
(19a) was formed, as an inseparable mixture with 19b, when
BF3 ·OEt2 was employed as a Lewis acid. Treatment of this
mixture with NH3/MeOH allowed isolation of each isomer, but
the R-L-isomer appeared to be the major product (20a, 23%;
20b, 44%).
anti-HIV and anti-HBV Activity of 4′-Substituted 4′-
Thiothymidines (32–37). The 4′-substituted derivatives thus
prepared were deprotected to yield the corresponding free 4′-
In the case of the reaction between 14 and Me3SiCN/SnCl4,
the spiro nucleosides were formed [22a (less polar product)/
22b (more polar product) ) 3/10, combined yield 92%],
apparently as a result of nucleophilic attack of the carbonyl
oxygen of the 5′-O-acetyl group at the 4′-position (Scheme 6).
The fact that 22a and 22b have the same 4′-configuration
supports conformational preference of the 5′-O-acetyl group of
the thiocarbenium intermediate as depicted as IX, which is
reminiscent of V in Scheme 4. The observed formation of 22
from 14 led us to prepare a 3′,5′-bis-O-silyl-protected substrate
Figure 2. Compounds 23-28.

1888 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 6
Haraguchi et al.
of the 4′,5′-unsaturated 4′-thiothymidine 13 was employed.
During this diacetoxylation reaction, ring-expansion to the
thiopyranosides (15 and 16) was observed. Lewis acid assisted
nucleophilic substitution of 14 furnished the desired compounds
such as the 4′-phenylthio (17a), 4′-azido (18a), 4′-methoxy
(20a), 4′-allyl (21a), and 4′-cyano (28a) analogues of 4′-
thiothymidine. The 4′-ethynyl (31) analogue was also synthe-
sized. Among the six deprotected 4′-substituted 4′-thiothy-
midines (32-37), the 4′-azido (33), 4′-cyano (36), and 4′-ethynyl
(37) analogues showed inhibitory activity against HIV-1 as well
as HIV-2. In particular, the 4′-cyano derivative 36 exhibited a
potent anti-HIV-1 activity with EC50 0.037 µM and did not show
any cytotoxicity to MT-4 cells up to 100 µM. It is noteworthy
that 4′-cyano (36) and 4′-ethynyl (37) analogues of 4′-thiothy-
midine were also inhibitory to replication of HIV-1 variant
resistant to 3TC (HIV-1M184V). By comparison with the reported
SI value 4′-cyanothymidine, it was found that the 4′-thio
counterpart (36) has a 3-fold better value. These facts suggest
that replacement of the furanose oxygen with sulfur atom is a
promising approach for development of new nucleoside antiviral
agents. As have already been published from our laboratory,3b,4,8
the present glycosidation method, electrophilic addition of
nucleobases to 4-thiofuranoid glycals, is applicable to the
preparation of cytosine and adenine 4′-thionucleosides. We are
currently working along this line.
Figure 3. Compounds 29-31.
Figure 4. 4′-Substituted 4′-thiothymidines 32-37.
Table 2. Inhibitory Effects of 4′-Substituted 4′-Thiothymidines (32–37)
on HIV-1 and HIV-2 Replication in Cell Culture
HIV-1
EC50
(µM)a
>100
0.02
>4.0
>100
HIV-2 (EHO)
CC50
EC50
CC50
compd
4′-substituent
(µM)b
(µM)c
(µM)d
32
33
34
35
36
37
SPh
N3
OMe
CH2CHdCH2
>100
40
>100
>100
>100
>100
>100
0.024
1.2
>100
>100
>10
>100
>100
>10
Ct
N
0.037
0.31
0.023
0.13
Experimental Section
Chemistry. Melting points are uncorrected. H and 13C NMR
Ct CH
>10
1
a Inhibitory concentration required to achieve 50% protection of MT-4
cells against the cytopathic effect of HIV-1IIIB
required to reduce the viability of mock-infected MT-4 cells by 50%.
c Inhibitory concentration required to achieve 50% protection of M8166
cells against the cytopathic effect of HIV-2. d Cytotoxic concentration
required to reduce the viability of mock-infected M8166 cells by 50%.
spectra were recorded either at 400 MHz or at 500 MHz. Chemical
shifts are reported relative to Me4Si. Mass spectra (MS) were taken
in FAB mode with m-nitrobenzyl alcohol as a matrix. Column
chromatography was carried out on silica gel. Thin-layer chroma-
tography (TLC) was performed on silica gel. When necessary,
analytical samples were purified by high-performance liquid chro-
matography (HPLC). THF was distilled from benzophenone ketyl.
Diaetoxylation of 13 with Pb(OAc)4: 1-[4-O-Acetoxy-5-O-
acetyl-3-O-(tert-butyldimethylsilyl)-2-deoxy-r-L-threo-4-thio-
pentofuranosyl]thymine (14), 5,5-Bis-acetoxy-(4S)-O-(tert-bu-
tyldimethylsilyl)-(2R)-(thymin-1-yl)thiane (15), and (4S)-O-(tert-
Butyldimethylsilyl)-(2R)-(thymin-1-yl)thian-5-one (16). To a
benzene (50 mL) solution of 13 (1.45 g, 4.09 mmol) were added
Na2CO3 (996.3 mg, 9.4 mmol) and Pb(OAc)4 (4.2 g, 9.4 mmol) at
0 °C under Ar atmosphere, and the mixture was stirred at rt
overnight, quenched with saturated aq NaHCO3, and filtered through
a Celite pad. The filtrate was partitioned between CHCl3/saturated
aq NaHCO3. Column chromatography (hexane/AcOEt ) 2/1–1/1)
of the organic layer gave 14 (1.08 g, 56%, foam) and a mixture of
15 and 16 (749.8 mg) [15: 530.8 mg (28%), 16: 219 mg (14%),
calculated by comparison of integration of H-1′]. Compounds 15
(foam, tR 20.0 min) and 16 (solid, tR 17.7 min) were separated by
HPLC (hexace/EtOAc ) 1/2).
.
b Cytotoxic concentration
thiothymidines (32-37) (Figure 4). Table 2 summarizes the anti-
HIV-1 activity, HIV-2 activity, and cytotoxicity of these
compounds. Except for the 4′-phenylthio (32) and 4′-allyl (35)
analogues, the compounds synthesized in this study showed
inhibitory activity against HIV-1. Especially, the 4′-azido (33),
4′-cyano (36), and 4′-ethynyl (37) analogues exhibited potent
anti-HIV activity, with EC50’s of 0.02, 0.037, and 0.31 µM,
respectively, although 33 showed a significant cytotoxicity to
MT-4 cells. Compounds 33, 36, and 37 also showed inhibitory
activity against HIV-2 as shown in Table 2. With regard to 36
and 37, the activity against HIV-1 variant resistant to 3TC (HIV-
1
M184V) was also tested. It was found that these compounds
suppressed replication of HIV-1M184V with an almost equal
potency to HIV-1IIIB (data not shown). These compounds did
not show any anti-HBV activity up to 10 µM.15
Comparison of the selectivity indices (SI) was made between
4′-substituted 4′-thiothymidines (33, 34, 36, and 37) and the
corresponding thymidine derivatives (3-6) by employing the
reported CC25/EC50 values of 3-51 or CC50/EC50 value of 6.16
In the case of 4′-azido-, 4′-methoxy-, and 4′-ethynyl derivatives,
comparable SI values were obtained: 3 (800) and 33 (670); 4
(>24) and 34 (>11); 6 (>120) and 37 (>322). Interestingly,
4′-cyano-4′-thiothymidine 36 was found to possess an SI value
of 1586, which is three times better than that of 4′-cyanothy-
midine (5) (SI 500).
Physical data of 14: UV (MeOH) λmax 269 nm (ꢀ 10800), λmin
236 nm (ꢀ 2700). 1H NMR (CDCl3) δ 0.12 and 0.16 (6H, each as
s), 0.93 (9H, s), 1.93 (3H, d, J ) 1.2 Hz), 2.07 (3H, s), 2.13 (3H,
s), 2.23 (1H, ddd, J ) 10.0, 12.4, 3.2 Hz), 2.45 (1H, dd, J ) 6.0,
12.4 Hz), 4.41 (1H, d, J ) 12.0 Hz), 5.12 (1H, d, J ) 12.0 Hz),
4.54 (1H, br), 6.62 (1H, dd, J ) 10.0, 6.0 Hz), 7.27 (1H, d, J )
1.2 Hz), 8.95 (1H, br); NOE experiment H-6/CH3CO-4′ (0.3%);
HMBC H-5′/CH3CO-5′; 13C NMR (CDCl3) δ -5.3, -4.7, 12.7,
17.7, 20.6, 21.6, 25.4, 41.7, 61.4, 61.5, 76.5, 100.3, 111.9, 135.6,
150.5, 163.6, 168.7, 169.7; FAB-MS (m/z) 435 and 473 (M+
H). Anal. Calcd for C20H32N2O7SSi: C, 50.83; H, 6.82; N, 5.93.
Found: C, 50.93; H, 6.86; N, 5.87.
+
Conclusion
Physical data of 15: UV (MeOH) λmax 269 nm (ꢀ 11100), λmin
1
In conclusion, we have developed a novel synthetic approach
to 4′-substituted 4′-thiothymidines on the basis of nucleophilic
substitution. For the preparation of the substrate 14 having an
acetoxy leaving group at the 4′-position, vicinal diacetoxylation
235 nm (ꢀ2300); H NMR (CDCl3) δ 0.06 and 0.11 (6H, each as
s), 0.91 (9H, s), 1.95 (3H, d, J ) 1.2 Hz), 2.06 (3H, s), 2.11 (1H,
ddd, J ) 2.9, 13.4, 4.6 Hz), 2.20 (3H, s), 2.47 (1H, ddd, J ) 12.2,
13.4, 2.0 Hz), 3.61 (2H, s), 4.91 (1H, d, J ) 3.2 Hz), 6.21 (1H, dd,

Synthesis and Anti-HIV ActiVity of 4′-Substituted 4′-Thiothymidines
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 6 1889
J ) 2.9, 12.2 Hz), 7.14 (1H, d, J ) 1.2 Hz), 8.86 (1H, br); 13C
NMR (CDCl3) δ -5.2, -4.6, 12.6, 17.8, 21.7, 21.8, 25.6, 29.3,
38.7, 48.5, 68.3, 100.0, 111.8, 135.6, 149.7, 163.2, 168.1, 168.5;
HMBC C-1′/H-5′. Anal. Calcd for C20H32N2O7SSi: C, 50.83; H,
6.82; N, 5.93. Found: C, 50.83; H, 6.88; N, 5.83.
4.40–4.44 (2H, m), 6.66 (1H, dd, J ) 8.5, 6.4 Hz), 7.42 (1H, d, J
) 1.2 Hz), 9.17 (1H, br); NOE experiment H-5′a/H-2′ (1.2%) and
H-5′b/H-6 (0.4%); 13C NMR (CDCl3) δ -5.0, -4.9, 12.6, 18.1,
20.7, 25.7, 42.5, 59.8, 67.3, 77.7, 83.9, 112.2, 135.6, 150.4, 163.4,
170.2; FAB-MS (m/z) 456 (M+ + H); high-resolution FAB-MS
(m/z) calcd for C18H30N5O5SSi 456.1737 (M+ + H), found
456.1764.
Physical data of 16: mp 207–209 °C; UV (MeOH) λmax 269 nm
1
(ꢀ 11300), λmin 236 nm (ꢀ 2700); H NMR (CDCl3) δ 0.06 and
Physical data of 18b: IR (neat) 2120 cm-1 (N3); 1H NMR
(CDCl3) δ 0.12 and 0.14 (6H, each as s), 0.92 (9H, s), 1.98 (3H,
d, J ) 1.2 Hz), 2.13 (3H, s), 2.31 (1H, ddd, J ) 10.1, 3.0, 13.3
Hz), 2.45 (1H, ddd, J ) 6.6, 1.2, 13.3 Hz), 4.18–4.19 (1H, m),
4.42 (1H, d, J ) 11.9 Hz), 4.62 (1H, d, J ) 11.9 Hz), 6.75 (1H,
dd, J ) 10.1, 6.6 Hz), 7.37 (1H, d, J ) 1.2 Hz), 8.88 (1H, br);
NOE experiment H-1′/H-5′b (0.3%); 13C NMR (CDCl3) δ -5.1,
-4.6, 12.8, 17.9, 20.6, 25.5, 42.5, 61.7, 66.2, 78.3, 87.4, 112.6,
135.6, 150.4, 163.2, 169.9; FAB-MS (m/z) 456 (M+ + H); high-
resolution FAB-MS (m/z) calcd for C18H30N5O5SSi 456.1737 (M+
+ H), found 456.1771.
0.12 (6H, each as s), 0.94 (9H, s), 1.93 (3H, d, J ) 1.2 Hz), 2.57
(1H, ddd, J ) 3.2, 13.6, 4.4 Hz), 2.71 (1H, ddd, J ) 11.6, 13.6,
2.0 Hz), 2.86 (1H, d, J ) 12.4 Hz), 4.21 (1H, dd, J ) 4.4, 2.0 Hz),
4.35 (1H, d, J ) 12.4 Hz), 6.56 (1H, dd, J ) 3.2, 11.6 Hz), 7.15
(1H, d, J ) 1.2 Hz), 8.20 (1H, br); 13C NMR (CDCl3) δ -5.1,
-5.07, 12.6, 18.0, 25.6, 32.7, 46.9, 48.8, 76.7, 112.3, 135.4, 149.7,
163.1, 201.8; HMBC C-1′/H-5′a and C-1′/H-5′b; FAB-MS (m/z)
371 (M+ + H). Anal. Calcd for C16H26N2O4SSi: C, 51.86; H, 7.07;
N, 7.56. Found: C, 51.98; H, 7.15; N, 7.49.
Reaction of 14 with Phenylthiotrimethylsilane: 1-[5-O-Acetyl-
3-O-(tert-butyldimethylsilyl)-4-phenylthio-2-deoxy-ꢀ-D-erythro-
4-thiopentofuranosyl]thymine (17a) and 1-[5-O-Acetyl-3-O-
(tert-butyldimethylsilyl)-4-phenylthio-2-deoxy-r-L-threo-4-thio-
pentofuranosyl]thymine (17b). To a CH2Cl2 (12 mL) solution of
14 (497.5 mg, 1.05 mmol) were added phenylthiotrimethylsilane
(0.99 mL, 5.25 mmol) and SnCl4 (1.0 M CH2Cl2 solution) (3.2
mL, 3.2 mmol) at -30 °C under Ar atmosphere, and the mixture
was stirred at -30 °C for 6 h. The reaction mixture was partitioned
between CHCl3/saturated aq NaHCO3, and silica gel column
chromatography (hexane/AcOEt ) 3/1) of the organic layer gave
a mixture of 17a and 17b (540.8 mg, 99%, 17a/17b ) 6.7/1, foam),
which were separated by HPLC (hexane/AcOEt ) 1/1) to give 17a
(tR 12.4 min, 406.2 mg, 74%, foam) and 17b (tR 10.5 min, 65.9
mg, 12%, foam).
Reaction of 14 with Methoxytrimethylsilane: 1-[3-O-(tert-
Butyldimethylsilyl)-4-methoxy-2-deoxy-ꢀ-D-erythro-4-thiopento-
furanosyl]thymine (20a) and 1-[3-O-(tert-Butyldimethylsilyl)-
4-methoxy-2-deoxy-r-L-threo-4-thiopentofuranosyl]thymine (20b).
To a CH2Cl2 (2.0 mL) solution of 14 (35 mg, 0.074 mmol) were
added methoxytrimethylsilane (51 µL, 0.37 mmol) and BF3 ·OEt2
(28 µL, 0.22 mmol) at -30 °C under Ar atmosphere, and the
mixture was stirred at 0 °C for 12 h. The reaction mixture was
partitioned between CHCl3/saturated aq NaHCO3. Silica gel column
chromatography (hexane/AcOEt ) 3/1) of the organic layer gave
a mixture of 19a and 19b (26.8 mg, 81%). The mixture was treated
with methanolic ammonia (6 mL) at rt for 20 h. The reaction
mixture was evaporated to dryness and separated by preparative
TLC (hexane/EtOAc ) 2/1) to give 20a (6.8 mg, 23%, foam) and
20b (13 mg, 44%, foam).
Physical data of 17a: UV (MeOH) λmax 269 nm (ꢀ 13100), λmin
241 nm (ꢀ 5100); 1H NMR (CDCl3) δ 0.11 and 0.12 (6H, each as
s), 0.95 (9H, s), 1.94 (3H, d, J ) 1.0 Hz), 2.12 (3H, s), 2.24 (1H,
ddd, J ) 4.1, 5.1, 16.7 Hz), 2.90 (1H, ddd, J ) 7.7, 8.8, 16.7 Hz),
4.31 (1H, d, J ) 12.2 Hz), 4.38 (1H, d, J ) 12.2 Hz), 4.66 (1H,
dd, J ) 5.1, 8.8 Hz), 6.32 (1H, dd, J ) 4.1, 7.7 Hz), 7.33–7.42
and 7.59–7.61 (6H, each as m), 8.32 (1H, br); NOE experiment
H-5′a/H-3′ (2.7%), H-PhS/H-1′ (2.4%), H-2′/H-5′b (1.4%), and
H-3′/H-5′a (2.7%); 13C NMR (CDCl3) δ -5.1, -4.6, 12.8, 18.1,
20.8, 25.6, 41.8, 58.3, 65.1, 74.8, 75.7, 111.4, 128.7, 129.6, 130.4,
136.1, 136.1, 137.8, 150.6, 163.5, 169.8; FAB-MS (m/z) 523 (M+
+ H). Anal. Calcd for C24H34N2O5S2Si: C, 55.14; H, 6.56; N, 5.36.
Found: C, 54.79; H, 6.54; N, 5.32.
1
Physical data of 20a: H NMR (CDCl3) δ 0.10 and 0.13 (6H,
each as s), 0.91 (9H, s), 1.96 (3H, d, J ) 1.2 Hz), 2.21 (1H, ddd,
J ) 3.4, 5.8, 13.7 Hz), 2.27 (1H, dd, J ) 5.6, 6.7 Hz), 2.65 (1H,
ddd, J ) 7.7, 9.8, 13.7 Hz), 3.50 (3H, s), 3.82 (1H, dd, J ) 5.6,
11.7 Hz), 3.87 (1H, dd, J ) 6.7, 11.7 Hz), 4.60 (1H, dd, J ) 5.8,
9.8 Hz), 6.28 (1H, dd, J ) 3.4, 7.7 Hz), 7.55 (1H, d, J ) 1.2 Hz),
8.47 (1H, br); NOE experiment H-6/H-5′a (0.6%) and H-1′/OMe-
4′ (0.8%); 13C NMR (CDCl3) δ -4.70, -4.66, 12.8, 18.1, 25.7,
42.4, 53.0, 57.8, 64.4, 76.1, 100.5, 111.6, 136.2, 150.3, 163.1; high-
resolution FAB-MS (m/z) calcd for C17H31N2O5SSi 403.1723 (M+
+ H), found 403.1755.
1
Physical data of 17b: H NMR (CDCl3) δ–0.06 and 0.03 (6H,
Physical data of 20b: UV (MeOH) λmax 271 nm (ꢀ 10200), λmin
237 nm (ꢀ 2500); 1H NMR (CDCl3) δ 0.14 and 0.15 (6H, each as
s), 0.93 (9H, s), 1.87 (1H, dd, J ) 3.7, 8.0 Hz), 1.96 (3H, d, J )
1.2 Hz), 2.30 (1H, ddd, J ) 9.6, 3.2, 13.1 Hz), 2.43 (1H, ddd, J )
7.1, 1.3, 13.1 Hz), 3.50 (3H, s), 3.88 (1H, dd, J ) 3.4, 12.2 Hz),
4.39 (1H, dd, J ) 7.8, 12.2 Hz), 4.38 (1H, dd, J ) 1.3, 3.2 Hz),
6.63 (1H, dd, J ) 9.6, 7.1 Hz), 7.32 (1H, d, J ) 1.2 Hz), 8.46 (1H,
br); NOE experiment H-6/OMe-4′ (1.2%); 13C NMR (CDCl3) δ
-5.2, -4.6, 12.9, 17.9, 25.6, 42.5, 50.9, 58.6, 61.3, 78.0, 106.3,
112.1, 136.6, 150.4, 163.2; FAB-MS (m/z) 403 (M+ + H). Anal.
Calcd for C17H30N2O5SSi: C, 50.72; H, 7.51; N, 6.96. Found: C,
50.81; H, 7.60; N, 6.81.
each as s), 0.87 (9H, s), 1.99 (3H, d, J ) 1.2 Hz), 2.11 (3H, s),
2.46 (1H, ddd, J ) 6.6, 2.0, 13.2 Hz), 2.87 (1H, ddd, J ) 9.9, 3.4,
13.2 Hz), 4.21 (1H, d, J ) 11.7 Hz), 4.40 (1H, d, J ) 11.7 Hz),
4.49 (1H, dd, J ) 2.0, 3.4 Hz), 6.72 (1H, dd, J ) 6.6, 9.9 Hz),
7.37–7.49 and 7.52–7.57 (5H, each as m), 7.76 (1H, d, J ) 1.2
Hz), 8.36 (1H, br); NOE experiment H-6/H-PhS-4′ (2.1%); 13C
NMR (CDCl3) δ -5.3, -4.7, 12.8, 17.9, 20.8, 25.6, 42.5, 61.7,
65.8, 75.2, 78.4, 112.2, 129.4, 130.2, 130.9, 136.5, 136.6, 150.4,
163.1, 170.2; high-resolution FAB-MS (m/z) calcd for
C24H35N2O5S2Si 523.1712 (M+ + H), found 523.1762.
Reaction of 14 with Azidotrimethylsilane: 1-[5-O-Acetyl-4-
azido-3-O-(tert-butyldimethylsilyl)-2-deoxy-ꢀ-D-erythro-4-thio-
pentofuranosyl]thymine (18a) and 1-[5-O-Acetyl-4-azido-3-O-
(tert-butyldimethylsilyl)-2-deoxy-r-L-threo-4-thiopentofurano-
syl]thymine (18b). To a CH2Cl2 (6 mL) solution of 14 (104.0 mg,
0.22 mmol) were added azidotrimethylsilane (0.14 mL, 1.1 mmol)
and SnCl4 (1.0 M CH2Cl2 solution) (0.66 mL, 0.66 mmol) at -30
°C under Ar atmosphere, and the mixture was stirred at -30 °C
for 7 h. The reaction mixture was partitioned between CHCl3/
saturated aq NaHCO3, and silica gel column chromatography
(hexane/AcOEt ) 5/1–3/1) of the organic layer gave 18a (68.9 mg,
69%, foam) and 18b (30.3 mg, 30%, foam).
Reaction of 14 with Allyltrimethylsilane: 1-[5-O-Acetyl-4-
allyl-3-O-(tert-butyldimethylsilyl)-2-deoxy-ꢀ-D-erythro-4-thio-
pentofuranosyl]thymine (21a) and 1-[5-O-Acetyl-4-allyl-3-O-
(tert-butyldimethylsilyl)-2-deoxy-r-L-threo-4-thiopentofurano-
syl]thymine (21b). To a CH2Cl2 (3 mL) solution of 14 (73.1 mg,
0.15 mmol) were added allyltrimethylsilane (0.24 mL, 1.50 mmol)
and SnCl4 (1.0 M CH2Cl2 solution) (0.45 mL, 0.45 mmol) at -30
°C under Ar atmosphere, and the mixture was stirred at -30 °C
for 1.5 h. The reaction mixture was partitioned between CHCl3/
saturated aq NaHCO3. Silica gel column chromatography (hexane/
AcOEt ) 5/1) of the organic layer gave a mixture of 21a and 21b
(36.6 mg, 53%, 21a/21b ) 10/1, foam). Compounds 21a (foam, tR
27.5 min) and 21b (syrup, tR 23.6 min) were separated by HPLC
(hexane/EtOAc ) 2/1).
Physical data of 18a: IR (neat) 2115 cm-1 (N3); 1H NMR
(CDCl3) δ 0.15 and 0.19 (6H, each as s), 0.96 (9H, s), 1.98 (3H,
d, J ) 1.2 Hz), 2.16 (3H, s), 2.21 (1H, ddd, J ) 8.5, 3.9, 13.6 Hz),
2.51 (1H, ddd, J ) 6.4, 4.2, 13.6 Hz), 4.18 (1H, d, J ) 11.7 Hz),

1890 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 6
Haraguchi et al.
Physical data of 21a: UV (MeOH) λmax 270 nm (ꢀ 10200), λmin
236 nm (ꢀ 2600); 1H NMR (CDCl3) δ 0.10 and 0.11 (6H, each as
s), 0.94 (9H, s), 1.97 (3H, s), 2.13 (3H, s), 2.23 (1H, m), 2.46 (2H,
m), 2.67 (2H, dd, J ) 5.2, 11.2 Hz), 4.18 (1H, d, J ) 9.2 Hz), 4.22
(1H, d, J ) 9.2 Hz), 4.30 (1H, t, J ) 2.8 Hz), 5.15 (1H, s), 5.18
(1H, d, J ) 8.0 Hz), 5.77 (1H, m), 6.45 (1H, dd, J ) 6.8, 5.2 Hz),
7.57 (1H, s), 8.12 (1H, br); NOE experiment H-5′/H-3′ (3.0%),
H-5′a,b/H-6 (1.6%), and H-6/H-3′ (1.9%); 13C NMR (CDCl3) δ
-5.0, -4.5, 12.7, 18.1, 20.9, 38.1, 42.9, 59.9, 64.8, 66.6, 75.8,
111.5, 119.5, 133.8, 136.0, 150.3, 163.0, 170.4; FAB-MS (m/z) 455
(M+ + H); (+KI) 493 (M+ + K). Anal. Calcd for C21H34N2O5SSi:
C, 55.48; H, 7.54; N, 6.16. Found: C, 55.68; H, 7.75; N, 5.99.
13.7 Hz), 2.93 (1H, ddd, J ) 8.3, 9.9, 13.7 Hz), 3.67 (1H, d, J )
11.2 Hz), 4.00 (1H, d, J ) 11.2 Hz), 4.84 (1H, dd, J ) 5.7, 9.9
Hz), 6.28 (1H, dd, J ) 2.7, 8.3 Hz), 7.29–7.40 and 7.54–7.57 (5H,
each as m), 7.63 (1H, d, J ) 1.2 Hz), 8.29 (1H, br), (selected data
for 23b) δ 2.40 (1H, ddd, J ) 2.2,6.6, 13.2 Hz), 3.51 (1H, d, J )
10.5 Hz), 4.03 (1H, d, J ) 10.5 Hz), 4.38 (1H, dd, J ) 2.2, 2.9
Hz), 6.63 (1H, dd, J ) 6.6, 9.8 Hz), 7.69 (1H, d, J ) 1.2 Hz); 13
C
NMR (CDCl3) δ (for 23a) -5.4, -5.4, -5.0, -4.6, 12.6, 18.1,
18.5, 25.7, 25.9, 41.6, 57.1, 64.5, 74.5, 77.8, 111.5, 129.1, 131.3,
136.3, 137.8, 150.7, 163.6; (selected data for 23b) -5.2, -4.8, 12.7,
17.9, 18.4, 25.5, 42.5, 60.7, 65.2, 78.3, 78.7, 111.9, 128.9, 129.7,
132.3, 136.7, 136.7, 163.7; FAB-MS (m/z) 595 (M+ + H). Anal.
Calcd for C28H46N2O4S2Si2: C, 56.52; H, 7.79; N, 4.71. Found: C,
56.47; H, 7.85; N, 4.66.
1
Physical data of 21b: H NMR (CDCl3) δ 0.09 and 0.10 (6H,
each as s), 0.91 (9H, s), 1.97 (3H, s), 2.09 (3H, s), 2.15–2.21 (1H,
m), 2.45–2.53 (2H, m), 2.64 (1H, dd, J ) 7.5, 14.3 Hz), 4.23 (1H,
d, J ) 10.9 Hz), 4.26–4.31 (2H, m), 5.21 (1H, dd, J ) 1.7, 17.2
Hz), 5.25 (1H, dd, J ) 1.7, 10.3 Hz), 5.87–5.93 (1H, m), 6.40
(1H, t, J ) 7.5 Hz), 7.52 (1H, d, J ) 1.2 Hz), 8.04 (1H, br); NOE
experiment H-6/CH2dCHCH2 (1.9%); 13C NMR (CDCl3) δ -5.0,
-4.5, 12.8, 17.9, 20.9, 25.6, 29.7, 41.4, 43.1, 59.8, 64.0, 65.9, 111.6,
119.9, 132.9, 136.2, 150.2, 162.9, 170.3; FAB-MS (m/z) 455 (M+
+ H); (+KI) 493 (M++ K); high-resolution FAB-MS (m/z) calcd
for C21H35N2O5SSi 455.2036 (M+ + H), found 455.1993.
1-[4-Acetoxy-3,5-bis-O-(tert-butyldimethylsilyl)-2-deoxy-ꢀ-D-
erythro-4-thiopentofuranosyl]thymine (24a) and 1-[4-Acetoxy-
3,5-bis-O-(tert-butyldimethylsilyl)-2-deoxy-r-L-threo-4-thiopento-
furanosyl]thymine (24b). To a AcOH (8.9 mL, 156 mmol) solution
of 23 (596.4 mg, 1.00 mmol) was added Hg(OAc)2 (701.1 mg, 2.2
mmol) ar rt under Ar atmosphere and the mixture was stirred at rt
for 5 h. The reaction mixture was diluted with CHCl3 and the
solution was washed with H2O, saturated aq NaHCO3 and aq. KCN.
Silica gel column chromatography (hexane/AcOEt ) 4/1) of the
organic layer gave a mixture of 24a and 24b (523 mg, 96%, 24a/
(3′S)-O-(tert-Butyldimethylsilyl)-(5′R)-(thymin-1-yl)-tetrahy-
drothiophene-2′-spiro-4-(2-cyano-2-methyl)-1,3-dioxolane (22a
and 22b). To a CH2Cl2 (3 mL) solution of 14 (41 mg, 0.087 mmol)
were added cyanotrimethylsilane (116 µL, 0.87 mmol) and SnCl4
(1.0 M CH2Cl2 solution) (0.26 mL, 0.26 mmol) at -30 °C under
Ar atmosphere, and the mixture was stirred at -30 °C for 3.5 h.
The reaction mixture was partitioned between CHCl3/saturated aq
NaHCO3. Silica gel column chromatography (hexane/AcOEt ) 5/1)
of the organic layer gave 22a (less polar product: 8.5 mg, 22%,
syrup and more polar product: 26 mg, 68%, syrup).
1
24b ) 4.2/1, foam): H NMR (CDCl3)δ(for 24a) 0.09, 0.11, 0.12
and 0.13 (12H, each as s), 0.92 and 0.93 (18H, each as s), 1.95
(3H, d, J ) 1.2 Hz), 2.09 (3H, s), 2.04–2.10 (1H, m), 2.44 (1H,
ddd, J ) 7.1, 4.4, 13.1 Hz), 3.94 (1H, d, J ) 11.0 Hz), 4.13 (1H,
d, J ) 11.0 Hz), 4.69 (1H, t, J ) 4.4 Hz), 6.46 (1H, t, J ) 7.1 Hz),
7.49 (1H, d, J ) 1.2 Hz), 8.74 (1H, br): δ(selected data for 24b)
0.04, 0.05, 0.14, 0.16 (12H, each as s), 0.89 and 0.94 (18H, each
as s), 1.94 (3H, d, J ) 1.2 Hz), 2.13 (3H, s), 4.13 (1H, d, J ) 10.7
Hz), 4.37 (1H, d, J ) 10.7 Hz), 4.55 (1H, br), 6.58 (1H, dd, J )
6.1, 9.9 Hz), 7.29 (1H, d, J ) 1.2 Hz); 13C NMR (CDCl3)δ: (for
24a) -5.4, -4.7, 12.6, 18.1, 18.3, 21.5, 25.6, 25.8, 40.8, 59.5, 64.0,
74.2, 97.3, 111.5, 136.1, 150.5, 163.5, 169.9; (for 24b)δ-5.4, -4.9,
12.9, 17.9, 25.5, 42.0, 59.9, 61.4, 76.0, 103.4, 111.8, 135.9, 150.5,
163.4, 168.7. FAB-MS (m/z) 545 (M++H). Anal. Calcd for
C24H44N2O6SSi2: C, 52.91; H, 8.14; N, 5.14. Found: C, 53.06; H,
8.28; N, 5.14.
Physical data of 22a (less polar product): IR 2231 cm-1 (CN).
1H NMR (CDCl3) δ 0.16 and 0.19 (6H, each as s), 0.92 (9H, s),
1.91 (3H, s), 1.97 (3H, d, J ) 1.2 Hz), 2.17 (1H, ddd, J ) 9.2,
12.8, 2.4 Hz), 2.55 (1H, dd, J ) 6.8, 12.8 Hz), 4.41 (1H, d, J )
10.4 Hz), 4.50 (1H, d, J ) 10.4 Hz), 4.58 (1H, d, J ) 2.4 Hz),
6.71 (1H, dd, J ) 9.2, 6.8 Hz), 7.45 (1H, d, J ) 1.2 Hz), 8.55 (1H,
br); NOE experiment H-5′b/H-3′ (4.1%); HMBC acetal-C/acetal-
CH3; 13C NMR (CDCl3) δ -4.9, -4.3, 12.9, 17.8, 25.2, 25.5, 43.1,
62.2, 72.7, 80.2, 101.3, 104.9, 112.5, 116.9, 136.0, 150.4, 163.1;
high-resolution FAB-MS (m/z) calcd for C19H29N3O5SSi 440.1675
(M+ + H), found 440.1651.
Reaction of 24 with cyanotrimethylsilane in the presence of
SnCl4: Formation of 1-[3,5-Bis-O-(tert-butyldimethylsilyl)-4-
cyano-2-deoxy-ꢀ-D-erythro-4-thiopentofuranosyl]thymine (25a),
1-[3,5-Bis-O-(tert-butyldimethylsilyl)-4-cyano-2-deoxy-r-L-threo-
4-thiopentofuranosyl]thymine (25b), 1-[-3,5-Bis-O-(tert-butyldi-
methylsilyl)-4-isocyano-2-deoxy-r-L-erythro-4-thiopentofurano-
syl]thymine (26b), and 1-[-3,5-Bis-O-(tert-butyldimethylsilyl)
-2-deoxy-4,5-didehydro-ꢀ-D-erythro-4-thiopentofuranosyl]thym-
ine (27). To a CH2Cl2 (3.5 mL) solution of 24 (81.7 mg, 0.15 mmol)
were added cyanotrimethylsilane (0.1 mL, 0.75 mmol) and SnCl4
(1.0 M CH2Cl2 solution) (0.45 mL, 0.45 mmol) at -30 °C under
Ar atmosphere, and the mixture was stirred at -30 °C overnight.
The reaction mixture was partitioned between CHCl3/saturated aq
NaHCO3. Preparative TLC (hexane/AcOEt ) 2/1) of the organic
layer gave a mixture of 25 and 26b (22.3 mg) [25; 14.0 mg (18%,
25a: 25b ) 1: 0.22), 26b; 8.3 mg (11%)], and 27 (19.6 mg, 27%,
foam).
Physical data of 22b (more polar product): IR 2229 cm-1 (CN);
1H NMR (CDCl3) δ 0.13 and 0.14 (6H, each as s), 0.92 (9H, s),
1.85 (3H, s), 2.00 (3H, d, J ) 1.2 Hz), 2.13 (1H, ddd, J ) 9.2,
12.4, 3.2 Hz), 2.49 (1H, dd, J ) 6.8, 12.4 Hz), 4.16 (1H, d, J )
3.2 Hz), 4.23 (1H, d, J ) 10.4 Hz), 4.56 (1H, d, J ) 10.4 Hz),
6.64 (1H, dd, J ) 9.2, 6.8 Hz), 7.55 (1H, d, J ) 1.2 Hz), 8.99 (1H,
br); NOE experiment H-5′b/H-3′ (2.4%); HMBC acetal-C/acetal-
CH3, acetal-C/H-5′b and CN/acetal-CH3; 13C NMR (CDCl3)δ 12.9,
17.9, 25.0, 25.5, 42.7, 61.7, 68.8, 79.6, 100.1, 104.6, 112.4, 116.4,
136.0, 150.3, 163.0; high-resolution FAB-MS (m/z) calcd for
C19H29N3O5SSi 440.1675 (M+ + H), found 440.1668.
1-[3,5-Bis-O-(tert-butyldimethylsilyl)-4-phenylthio-2-deoxy-ꢀ-
D-erythro-4-thiopentofuranosyl]thymine (23a) and 1-[3,5-Bis-
O-(tert-butyldimethylsilyl)-4-phenylthio-2-deoxy-r-L-threo-4-
thiopentofuranosyl]thymine (23b). Compound 17 (561.1 mg, 1.07
mmol) was treated with metanolic ammonia (35 mL), and the
mixture was kept at rt. The reaction mixture was evaporated to
dryness, and the residue was dried in vacuo overnight. To a DMF
(10 mL) solution of the residue were added imidazole (437.1 mg,
6.42 mmol) and tert-butyldimethylsilyl chloride (645 mg, 4.28
mmol) at 0 °C under Ar atmosphere, and the mixture was stirred
at rt overnight. The reaction mixture was partitioned between
AcOEt/H2O. Silica gel column chromatography (hexane/AcOEt )
5/1) of the organic layer gave a mixture of 23a and 23b (589.9
mg, 93%, 23a/23b ) 12.1:1, foam): 1H NMR (CDCl3) δ (for 23a)
0.03, 0.04, 0.11 and 0.12 (12H, each as s), 0.89 and 0.94 (18H,
each as s), 1.93 (3H, d, J ) 1.2 Hz), 2.16 (1H, ddd, J ) 2.7, 5.7,
Physical data of 25 and 26b: IR (neat) 2120 (NdC:) and 2240
1
cm-1 (CN); H NMR (CDCl3) δ (for 25a) 0.11, 0.12, 0.13 and
0.15 (12H, each as s), 0.92 and 0.93 (18H, each as s), 1.96 (3H, d,
J ) 1.2 Hz), 2.24 (1H, ddd, J ) 6.8, 4.4, 13.7 Hz), 2.50 (1H, ddd,
J ) 6.8, 5.4, 13.7 Hz), 3.79 (1H, d, J ) 10.7 Hz), 3.95 (1H, d, J
) 10.7 Hz), 4.63 (1H, dd, J ) 4.6, 5.4 Hz), 6.48 (1H, t, J ) 6.8
Hz), 7.30 (1H, d, J ) 1.2 Hz), 8.89 (1H, br): δ (selected data for
25b) 4.36 (1H, t, J ) 4.1 Hz), 6.55 (1H, dd, J ) 6.4, 8.1 Hz), 7.59
(1H, d, J ) 1.2 Hz), 8.87 (1H, br); δ (selected data for 26b) 0.91
and 0.92 (18H, each as s), 2.36 (1H, ddd, J ) 8.9, 3.5, 13.5 Hz),
2.44 (1H, ddd, J ) 6.9, 1.2, 13.5 Hz), 3.85 (1H, d, J ) 9.8 Hz),
3.96 (1H, d, J ) 9.8 Hz), 4.22 (1H, br), 6.63 (1H, dd, J ) 8.9, 6.9
Hz), 7.67 (1H, d, J ) 1.1 Hz), 8.58 (1H, br); 13C NMR (CDCl3) δ
(for 25a) -5.42, -5.36, -4.9, -4.7, 12.7, 18.0, 18.3, 25.6, 25.7,

Synthesis and Anti-HIV ActiVity of 4′-Substituted 4′-Thiothymidines
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 6 1891
41.4, 60.1, 60.2, 65.4, 74.2, 79.5, 99.7, 112.2, 118.0, 135.6, 150.3,
163.3; (selected data for 26b) δ -5.5, -5.0, -4.4, 17.8, 18.4, 25.8,
25.9, 42.9, 61.4, 67.1, 79.5, 112.0, 137.3, 150.6, 163.6.
1-[3,5-Bis-O-(tert-butyldimethylsilyl)-4-formyl-2-deoxy-ꢀ-D-
erythro-4-thiopentofuranosyl]thymine (29)To a toluene (6.0 mL)
solution of a mixture of 25 and 26b [148.2 mg; 25,115.5 mg (0.23
mmol); 26b, 32.7 mg (0.064 mmol)] was added DIBAL-H (0.99
M toluene solution) (0.88 mL, 0.87 mmol) at -70 °C under Ar
atmosphere, and the mixture was stirred at -70 °C for 4 h. To the
reaction mixture was added 10 M H2SO4 (30 drops), and the mixture
was stirred at rt for 30 min. The reaction mixture was partitioned
between CHCl3/H2O, and the organic layer was washed with
saturated aq NaHCO3. Silica gel column chromatography (hexane/
AcOEt ) 4/1) of the organic layer gave 29 (50.2 mg, 42%, foam):
UV (MeOH) λmax 270 nm (ꢀ 9900), λmin 236 nm (ꢀ 2500); 1H NMR
(CDCl3) δ 0.08, 0.09, 0.13 and 0.14 (12H, each as s), 0.89 and
0.93 (18H, each as s), 1.97 (3H s, J ) 1.2 Hz), 2.34 (1H, ddd, J )
7.0, 5.6, 13.4 Hz), 2.52 (1H, ddd, J ) 7.0, 5.6, 13.4 Hz), 3.86 (1H,
d, J ) 11.2 Hz), 4.09 (1H, d, J ) 11.2 Hz), 4.80 (1H, t, J ) 5.6
Hz), 6.56 (1H, t, J ) 7.0 Hz), 7.58 (1H, d, J ) 1.2 Hz), 8.57 (1H,
br), 9.65 (1H, s); NOE experiment H-6/Ha-5′ (0.6%) and CHO/
H-1′ (0.9%); 13C NMR (CDCl3) δ -5.4, -5.3, -5.2, -4.7, 12.7,
17.9, 18.5, 25.5, 25.9, 43.8, 60.5, 62.9, 71.0, 76.7, 111.9, 135.7,
150.3, 163.0, 195.9; FAB-MS (m/z) 515 (M+ + H). Anal. Calcd
for C23H42N2O5SSi2: C, 53.66; H,8.22; N, 5.44. Found: C, 53.85;
H, 8.37; N, 5.40.
Physical data of 27: UV (MeOH) λmax 267 nm (ꢀ 11900), λmin
1
245 nm (ꢀ 9100); H NMR (CDCl3) δ 0.08, 0.09 and 0.18 (12H,
each as s), 0.89 and 0.95 (18H, each as s), 1.90–1.97 (1H, m),
1.94 (3H, s), 2.40 (1H, ddd, J ) 6.1, 2.7, 12.7 Hz), 4.81–4.83 (1H,
m), 6.63 (1H, s), 6.69 (1H, dd, J ) 8.9, 6.1 Hz), 7.41 (1H, s), 8.51
(1H, br); 13C NMR (CDCl3) δ -5.3, -5.2, -4.64, -4.55, 12.7,
18.0, 18.2, 25.5, 25.7, 45.5, 61.1, 73.4, 111.7, 122.4, 133.7, 136.1,
150.3, 163.1; FAB-MS (m/z) 484 (M+); (+KI) 523 (M+ + K).
Anal. Calcd for C22H40N2O4SSi2: C, 54.50; H, 8.32; N, 5.78. Found:
C, 54.87; H, 8.55; N, 5.84.
Reaction of 24 with cyanotrimethylsilane in the presence of
BF3 ·OEt2: Formation of 25, 1-[-3,5-Bis-O-(tert-butyldimethyl-
silyl)-4-isocyano-2-deoxy-ꢀ-D-erythro-4-thiopentofuranosyl]th-
ymine (26a) and 26b/1-[3,5-Di-O-acetyl-4-cyano-2-deoxy-ꢀ-D-
erythro-4-thiopentofuranosyl]thymine (28a), and 1-[3,5-Di-O-
acetyl-4-cyano-2-deoxy-r-L-threo-4-thiopentofuranosyl]thym-
ine (28b). To a CH2Cl2 (7.0 mL) solution of 24 (206.8 mg, 0.38
mmol) were added cyanotrimethylsilane (0.25 mL, 1.9 mmol) and
BF3 ·OEt2 (0.14 mL, 1.14 mmol) at -30 °C under Ar atmosphere,
and the mixture was stirred at -30 °C for 20 h. The reaction mixture
was partitioned between CHCl3/saturated aq NaHCO3. Silica gel
column chromatography (hexane/AcOEt ) 4/1) of the organic layer
gave a mixture of 25 and 26b (89.7 mg) [25; 72.5 mg (37%, 25a:
25b ) 1: 0.05), 26b; 17.3 mg (9%)] and 26a (44.1 mg, 23%, foam).
To a THF (3.5 mL) solution of a mixture of 25 and 26b was added
Bu4NF (1 M THF solution) (0.36 mL, 0.36 mmol) at 0 °C under
Ar atmosphere, and the mixture was stirred for 3 h. To the reaction
mixture was added Ac2O (35 µL, 0.37 mmol), and the mixture was
stirred for 12 h. The reaction mixture was partitioned between
CHCl3/saturated aq NaHCO3. Preparative TLC (hexane/AcOEt )
1/1) of the organic layer gave 28a (31.4 mg, 61%, crystallized from
benzene/CH2Cl2) and 28b (1.6 mg, 3%, syrup).
1-[3,5-Di-O-acetyl-4-ethynyl-2-deoxy-ꢀ-D-erythro-4-thiopento-
furanosyl]thymine (31). To a MeOH (5.0 mL) solution of 29
(103.5 mg, 0.2 mmol) were added dimethyl 1-diazo-2-oxopropy-
lphosphonate (96.1 mg, 0.5 mmol) and K2CO3 (110.6 mg, 0.8
mmol) at 0 °C under Ar atmosphere, and the mixture was stirred
at rt for 16 h. The reaction mixture was neutralized with AcOH
and evaporated to dryness. The residue was partitioned between
CHCl3/saturated aq NaHCO3. Silica gel column chromatography
(hexane/AcOEt ) 4/1) of the organic layer gave a crude product
of 30 (41.8 mg). To a THF (2.0 mL) solution of the crude product
was added Bu4NF (1 M THF solution) (0.17 mL, 0.17 mmol) at 0
°C under Ar atmosphere, and the mixture was stirred at 0 °C for
1 h. To the reaction mixture was added Ac2O (20 µL, 0.21 mmol)
at 0 °C, and the mixture was stirred at rt for 16 h. The reaction
mixture was partitioned between CHCl3/saturated aq NaHCO3.
Silica gel column chromatography (hexane/AcOEt ) 1/1) of the
organic layer gave 31 (21.8 mg, 30%, foam): IR (neat) 2117 cm-1
(Ct CH); UV (MeOH) λmax 269 nm (ꢀ 10700), λmin 236 nm (ꢀ
Physical data of 26a: IR (neat) 2117 cm-1 (N ) C:); UV
1
(MeOH) λmax 270 nm (ꢀ 10600), λmin 236 nm (ꢀ 2600); H NMR
(CDCl3) δ 0.13, 0.145, 0.149, 0.16 (12H, each as s), 0.93 and 0.94
(18H, each as s), 1.99 (3H, d, J ) 0.7 Hz), 2.45 (1H, ddd, J ) 9.8,
2.7, 13.2 Hz), 2.54 (1H, dd, J ) 6.7, 13.2 Hz), 3.84 (1H, d, J )
10.2 Hz), 4.00 (1H, d, J ) 10.2 Hz), 4.54 (1H, br), 6.72 (1H, dd,
J ) 6.7, 9.8 Hz), 7.52 (1H, d, J ) 0.7 Hz), 8.62 (1H, br); NOE
experiment: H-3′/ H-5′b (1.7%); 13C NMR (CDCl3) δ -5.3, -5.3,
-5.1, -4.6, 12.9, 17.9, 18.4, 25.5, 25.8, 42.6, 61.8, 64.8, 78.3,
82.0, 113.0, 135.9, 150.4, 162.1, 163.1; FAB-MS (m/z) 359 (M+
- NC - B + H), 485 (M+ - NC); (+KI) 550 (M++K). Anal.
Calcd for C23H41N3O4SSi2: C, 53.97; H, 8.07; N, 8.21. Found: C,
54.26; H, 8.30; N, 7.85.
1
3600); H NMR (CDCl3) δ 1.99 (3H, d, J ) 1.2 Hz), 2.17 and
2.18 (6H, each as s), 2.42 (1H, ddd, J ) 7.2, 5.1, 14.2 Hz), 2.60
(1H, s), 2.67 (1H, ddd, J ) 7.2, 5.1, 14.2 Hz), 4.36 (1H, d, J )
11.4 Hz), 4.45 (1H, d, J ) 11.4 Hz), 5.50 (1H, t, J ) 5.1 Hz), 6.59
(1H, t, J ) 7.1 Hz), 7.50 (1H, d, J ) 1.2 Hz), 8.39 (1H, br); 13C
NMR (CDCl3)δ: 12.8, 20.8, 20.9, 39.0, 56.2, 59.9, 67.0, 75.0, 75.9,
79.4, 112.4, 135.3, 150.3, 162.8, 169.8, 170.2; FAB-MS (m/z) 367
(M+ + H) and 307 (M+ - OAc). Anal. Calcd for C16H18N3O6S·1/2-
AcOEt: C, 52.67; H,5.40; N, 6.83. Found: C, 53.02; H, 5.55; N,
6.94.
Physical data of 28a: mp 190–191 °C; IR (neat) 2243 cm-1 (CN);
1
UV (MeOH) λmax 268 nm (ꢀ 10900), λmin 236 nm (ꢀ 2900); H
NMR (CDCl3) δ 1.99 (3H, d, J ) 1.2 Hz), 2.19 and 2.24 (6H,
each as s), 2.56 (1H, ddd, J ) 7.1, 5.0, 14.4 Hz), 2.69 (1H, ddd, J
) 7.1, 5.0, 14.4 Hz), 4.44 (1H, d, J ) 11.7 Hz), 4.50 (1H, d, J )
11.7 Hz), 5.58 (1H, t, J ) 5.0 Hz), 6.53 (1H, t, J ) 7.1 Hz), 7.31
(1H, d, J ) 1.2 Hz), 8.79 (1H, br); NOE experiment H-6/CH2-5′
(1.0%), H-2′a/ H-5′a (0.7%) and H-2′a/ H-5′b (0.4%); 13C NMR
(CDCl3) δ 12.7, 20.5, 20.8, 29.7, 38.2, 54.7, 60.6, 74.5, 113.0, 116.1,
134.8, 150.2, 162.8, 169.5, 169.9; FAB-MS (m/z) 368 (M+ + H).
Anal. Calcd for C15H17N3O6S: C, 49.04; H,4.66; N, 11.44. Found:
C, 49.00; H, 4.53; N, 11.04.
Physical data of 28b: IR (neat) 2235 cm-1 (CN); 1H NMR
(CDCl3) δ 2.01 (3H, d, J ) 1.2 Hz), 2.14 and 2.18 (6H, each as s),
2.56 (1H, ddd, J ) 9.8, 3.7, 14.6 Hz), 2.79 (1H, ddd, J ) 6.8, 1.2,
14.6 Hz), 4.24 (1H, d, J ) 11.2 Hz), 4.51 (1H, d, J ) 11.2 Hz),
5.81 (1H, dd, J ) 3.7, 1.2 Hz), 6.81 (1H, dd, J ) 9.8, 6.8 Hz),
7.48 (1H, d, J ) 1.2 Hz), 8.17 (1H, br); 13C NMR (CDCl3) δ 12.9,
20.4, 20.7, 29.7, 41.2, 54.6, 61.6, 62.5, 113.8, 118.9, 134.8, 150.2,
162.4, 168.9, 169.6; FAB-MS (m/z) 368 (M+ + H); high-resolution
FAB-MS (m/z) calcd for C15H18N3O6S 368.0952 (M+ + H), found
368.0895.
1-[4-Phenylthio-2-deoxy-ꢀ-D-erythro-4-thiopentofuranosyl]th-
ymine (32). To a THF (4 mL) solution of 17a (91.7 mg, 0.18 mmol)
was added Bu4NF·3H2O (70.6 mg, 0.27 mmol) at 0 °C, and the
mixture was stirred at 0 °C for 3 h. Silica gel column chromatog-
raphy (2–4% MeOH in CH2Cl2) of the reaction mixture gave a
1-[5-O-acetyl-4-phenylthio-2-deoxy-ꢀ-D-erythro-4-thiopentofurano-
syl]thymine. The product was treated with methanolic ammonia
(6 mL) at rt for 5 h. The reaction mixture was evaporated to dryness.
Silica gel column chromatography (4% MeOH in CH2Cl2) of the
residue gave 32 (66 mg, 100%) as syrup, which was triturated from
Et2O: mp 100–102 °C; UV (MeOH) λmax 269 nm (ꢀ 12600), λmin
242 nm (ꢀ 5200); 1H NMR (CD3OD) δ 1.86 (3H, d, J ) 1.2 Hz),
2.41 (1H, ddd, J ) 3.6, 5.1, 13.4 Hz), 2.80 (1H, ddd, J ) 7.3, 9.5,
13.4 Hz), 3.70 (1H, d, J ) 12.2 Hz), 3.89 (1H, d, J ) 12.2 Hz),
4.69 (1H, dd, J ) 5.1, 9.5 Hz), 6.18 (1H, dd, J ) 3.6, 7.3 Hz),
7.32–7.41 and 7.62–7.65 (5H, each as m), 8.19 (1H, d, J ) 1.2
Hz); 13C NMR (CD3OD) δ 12.5, 42.8, 59.8, 66.0, 75.4, 78.3, 111.5,
129.7, 130.3, 132.4, 138.8, 139.3, 152.6, 166.2; FAB-MS (m/z) 367
(M+ + H). Anal. Calcd for C16H18N2O4S2: C, 52.44; H, 4.95; N,
7.64. Found: C, 52.71; H, 5.08; N, 7.48.

1892 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 6
Haraguchi et al.
1-[4-Azido-2-deoxy-ꢀ-D-erythro-4-thiopentofuranosyl]thym-
ine (33). To a THF (3 mL) solution of 18a (60.2 mg, 0.13 mmol)
was added Bu4NF·3H2O (52.3 mg, 0.20 mmol) at 0 °C, and the
mixture was stirred for 1 h. Silica gel column chromatography (3%
MeOH in CH2Cl2) of the reaction mixture gave 1-[5-O-acetyl-4-
azido-2-deoxy-ꢀ-D-erythro-4-thiopentofuranosyl]thymine. The prod-
uct was treated with methanolic ammonia (6 mL) at rt for 6 h. The
reaction mixture was evaporated to dryness. Silica gel column
chromatography (3% MeOH in CH2Cl2) of the residue gave 33
(30.9 mg, 79%) as syrup, which was triturated from Et2O: IR (KBr)
2117 cm-1 (N3); mp 100–102 °C; UV (MeOH) λmax 270 nm (ꢀ
mp 229–231 °C; UV (MeOH) λmax 270 nm (ꢀ 10100), λmin 237 nm
(ꢀ 2500); 1H NMR (CD3OD) δ 1.90 (3H, d, J ) 1.2 Hz), 2.40
(1H, ddd, J ) 4.6, 5.1, 13.4 Hz), 2.58 (1H, ddd, J ) 6.8, 7.9, 13.4
Hz), 2.95 (1H, s), 3.79 (1H, d, J ) 11.7 Hz), 3.87 (1H, d, J ) 11.7
Hz), 4.41 (1H, dd, J ) 4.6, 7.9 Hz), 6.31 (1H, dd, J ) 5.1, 6.8
Hz), 8.11 (1H, t, J ) 1.2 Hz); 13C NMR (CD3OD) δ 12.5, 42.7,
60.3, 61.5, 66.8, 75.1, 77.2, 82.8, 111.6, 139.0, 152.6, 166.2; FAB-
MS (m/z) 283 (M+ + H) and 267 (M+ - OH). Anal. Calcd for
C12H14N2O4S2 ·1/4H2O: C, 50.25; H, 5.10; N, 9.77. Found: C, 50.21;
H, 4.96; N, 9.90.
Anti-HIV Assay. MT-4 cells17 were maintained in RPMI 1640
medium supplemented with 10% heat-inactivated fetal bovine serum
(FBS), 100U/mL of penicillin G, and 100 mg/mL of streptomycin.
The IIIB strain of HIV-1 was used throughout the experiment. The
virus was propagated and titrated in MT-4 cells. Virus stocks were
stored at -80 °C until use.
1
12800), λmin 237 nm (ꢀ 4100); H NMR (CD3OD) δ 1.91 (3H, d,
J ) 1.0 Hz), 2.41–2.54 (2H, m), 3.77 (1H, d, J ) 11.7 Hz), 3.82
(1H, d, J ) 11.7 Hz), 4.48 (1H, dd, J ) 5.1, 7.1 Hz), 6.41 (1H, d,
J ) 6.1), 7.88 (1H, d, J ) 1.0 Hz); 13C NMR (CD3OD) δ 13.0,
42.0, 60.4, 67.8, 77.5, 88.1, 112.7, 138.9, 153.0, 166.5; FAB-MS
(m/z) 300 (M+ + H). Anal. Calcd for C10H13N5O4S·1/2AcOMe:
C, 41.07; H, 4.79; N, 20.82. Found: C, 41.00; H, 4.44; N, 21.22.
1-[2-Deoxy-4-methoxy-ꢀ-D-erythro-4-thiopentofuranosyl] thy-
mine (34). To a THF (3.0 mL) solution of 20a (49.5 mg, 0.12
mmol) was added Bu4NF·3H2O (47.1 mg, 0.18 mmol) at 0 °C,
and the mixture was stirred for 1 h. Silica gel column chromatog-
raphy (3% MeOH in CH2Cl2) of the reaction mixture gave 34 (30.7
mg, 89%), which was triturated from Et2O: mp 85–87 °C; UV
The anti-HIV-1 activity of the test compounds was determined
by the inhibition of either virus-induced cytopathogenicity in MT-4
cells.18 Briefly, MT-4 cells (1 × 105cells/mL) were infected with
HIV-1 at a multiplicity of infection (MOI) of 0.02 and were cultured
in the presence of various concentrations of the test compounds.
In the case of HIV-2, M8166 cells (1 × 105) were infected at a
MOI of 0.1. After a 4-day incubation at 37 °C, the number of viable
cells was monitored by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphe-
nyltetrazolium bromide (MTT) method.19 The cytotoxicity of the
compounds was evaluated in parallel with their antiviral activity,
based on the viability of mock-infected cells, as determined by the
MTT method.
1
(MeOH) λmax 271 nm (ꢀ 10200), λmin 238 nm (ꢀ 2480); H NMR
(CD3OD) δ 1.90 (3H, d, J ) 1.0 Hz), 2.33 (1H, ddd, J ) 3.4, 5.6,
10.7 Hz), 2.58 (1H, ddd, J ) 7.3, 10.0, 10.7 Hz), 3.46 (3H, s),
3.84 (1H, d, J ) 10.5 Hz), 3.94 (1H, d, J ) 10.5 Hz), 4.51 (1H,
dd, J ) 5.6, 10.0 Hz), 6.15 (1H, dd, J ) 3.4, 7.3 Hz), 8.00 (1H, d,
J ) 1.0 Hz); 13C NMR (CD3OD) δ 12.6, 42.0, 53.1, 58.8, 63.0,
75.1, 101.9, 111.7, 138.9, 152.6, 166.2; FAB-MS (m/z) 289 (M+
+ H). Anal. Calcd for C11H16N2O5S: C, 45.82; H, 5.59; N, 9.72.
Found: C, 45.95; H, 5.57; N, 9.41.
Acknowledgment. Financial support from the Japan Society
for the Promotion of Science (KAKENHI No. 19590106 to K.H.
and No. 17590094 to H.T.), the Research Foundation of Phar-
maceutical Sciences (to K.H.), and the Japan Health Sciences
Foundation (SA 14804 to H.T.) is gratefully acknowledged. We
are also grateful to Ms. K. Shiohara and Y. Odanaka (Center
for Instrumental Analysis, Showa University) for technical
assistance with NMR, MS, and elemental analyses. Dr. T.
Hamasaki is a Research Resident of the Japanese Foundation
for AIDS Prevention.
1-[4-Allyl-2-deoxy-ꢀ-D-erythro-4-thiopentofuranosyl]thym-
ine (35). To a THF (3.5 mL) solution of 21a (93.4 mg, 0.21 mmol)
was added Bu4NF·3H2O (100.2 mg, 0.38 mmol) at 0 °C, and the
mixture was stirred for 2 h. Silica gel column chromatography (2%
MeOH in CH2Cl2) of the reaction mixture gave 5′-O-acetyl
derivative. The acetate was treated with methanolic ammonia (2.5
mL) at rt for 7 h. The reaction mixture was evaporated to dryness.
Silica gel column chromatography of the crude product gave 35
(38.8 mg, 46%) as syrup, which was triturated from Et2O: mp 86–88
°C; UV (MeOH) λmax 272 nm (ꢀ 9800), λmin 237 nm (ꢀ 2600); 1H
NMR (CD3OD) δ 1.90 (3H, d, J ) 1.0 Hz), 2.40–2.43 (2H, m),
2.54–2.56 (2H, m), 3.68 (2H, s), 4.38 (1H, t, J ) 4.4 Hz), 5.09
(1H, dd, J ) 2.4, 10.0 Hz), 5.15 (1H, dd, J ) 2.4, 16.8 Hz),
5.81–5.91 (1H, m), 6.36 (1H, t, J ) 7.2 Hz), 8.10 (1H, d, J ) 1.2
Hz); 13C NMR (CD3OD) δ 13.0, 39.3, 44.1, 61.5, 67.3, 68.1, 76.4,
112.2, 119.3, 136.5, 139.7, 153.1, 166.7; FAB-MS (m/z) 299 (M+
+ H). Anal. Calcd for C13H19N2O4S: C, 52.33; H, 6.08; N, 9.39.
Found: C, 52.10; H, 5.98; N, 9.05.
Supporting Information Available: Experimental procedures
and full characterization for compounds 8-13. This material is
available free of charge via the Internet at http://pubs.acs.org.
References
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York, 1993.
(2) For a review, see: Yokoyama, M. Synthesis and biological activity of
thionucleosides. Synthesis 2000, 1637–1655.
(3) For examples of 1′-carbon-substituted analogues, see: (a) MacCulloch,
A.; Coe, P.; Walker, R. T. Stereoselective synthesis of novel
1′-substituted 2′-deoxy-4′-thionucleosides. J. Chem. Soc., Perkin Trans.
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furanoid glycal: synthesis of 4′-thioangustmycin C. Tetrahedron Lett.
2002, 43, 5657–5660.
(4) For an example of 2′-ꢀ-carbon-substituted analogues, see: Haraguchi,
K; Shiina, N.; Yoshimura, Y.; Shimada, H.; Hashimoto, K.; Tanaka,
H. Novel stereoselective entry to 2′-ꢀ-carbon-substituted 2′-deoxy-
4′-thionucleosides from 4-thiofuranoid glycals. Org. Lett. 2004, 16,
2645–2648.
(5) For an example of 3′-carbon-substituted analogues, see: Branalt, J.;
Kvarnstrom, I.; Niklasson, S. C. T.; Classon, B.; Samuelson, B.
Synthesis of 2′,3′-dideoxy-3′-C-(hydroxymethyl)-4′-thionucleosides as
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1-[4-Cyano-2-deoxy-ꢀ-D-erythro-4-thiopentofuranosyl]thym-
ine (36). Compound 28a was treated with methanolic ammonia (8
mL) at rt for 9 h. The reaction mixture was evaporated to dryness.
Silica gel column chromatography (3% MeOH in CH2Cl2) of the
residue gave 36 (21.5 mg, 77%) as syrup, which was triturated
from Et2O: IR (KBr) 2223 cm-1 (Ct N); mp 234–237 (dec) °C;
1
UV (MeOH) λmax 270 nm (ꢀ 10500), λmin 236 nm (ꢀ 2500); H
NMR (CD3OD) δ 1.90 (3H, d, J ) 1.2 Hz), 2.46–2.58 (2H, m),
3.91 (1H, d, J ) 11.7 Hz), 3.95 (1H, d, J ) 11.7 Hz), 4.59 (1H,
dd, J ) 4.9, 6.6 Hz), 6.43 (1H, t, J ) 6.6 Hz), 7.82 (1H, d, J ) 1.2
Hz); 13C NMR (CD3OD) δ 12.5, 41.9, 61.16, 61.23, 66.0, 75.0,
112.3, 119.8, 138.3, 152.4, 166.0; FAB-MS (m/z) 284 (M+ + H).
Anal. Calcd for C11H13N3O4S: C, 46.63; H, 4.63; N, 14.83. Found:
C, 46.70; H, 4.60; N, 14.47.
1-[2-Deoxy-4-ethynyl-ꢀ-D-erythro-4-thiopentofuranosyl]thym-
ine (37). Compound 31 (25.5 mg, 0.07 mmol) was treated with
methanolic ammonia (5 mL) at rt for 5 h. The reaction mixture
was evaporated to dryness. Silica gel column chromatography (3%
MeOH in CH2Cl2) of the residue gave 37 (16.7 mg, 84%) as syrup,
which was triturated from Et2O: IR (KBr) 2103 cm-1 (Ct CH);
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Synthesis and Anti-HIV ActiVity of 4′-Substituted 4′-Thiothymidines
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 6 1893
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