A practical synthesis of 4′-thioribonucleosides

Article abstract of DOI:10.1016/j.tetlet.2005.11.049

A practical synthesis of 4′-thioribonucleosides starting from inexpensive l-arabinose is described. 1,4-Anhydro-2,3-O-isopropylidene-4- thioribitol, which was prepared by using a novel reductive ring-contraction reaction, was converted to the 5-O-silylated sulfoxides. The Pummerer-type thioglycosylation of the sulfoxides gave the 4′-thioribonucleosides stereoselectively.

Full text of DOI:10.1016/j.tetlet.2005.11.049

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 591–594
A practical synthesis of 40-thioribonucleosides
Yuichi Yoshimura,a,* Tetsuya Kuze,b Mari Ueno,b Fumiko Komiya,b
Kazuhiro Haraguchi,b Hiromichi Tanaka,b Fumitaka Kano,c Kohei Yamada,c
Kazuhiro Asami,a Nobuaki Kanekoa and Hiroki Takahataa,*
aTohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan
bSchool of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan
cBiochemicals Division, Yamasa Corporation, 2-10-1 Araoicho, Choshi, Chiba 288-0056, Japan
Received 6 October 2005; revised 4 November 2005; accepted 10 November 2005
Available online 28 November 2005
Abstract—A practical synthesis of 40-thioribonucleosides starting from inexpensive L-arabinose is described. 1,4-Anhydro-2,3-O-iso-
propylidene-4-thioribitol, which was prepared by using a novel reductive ring-contraction reaction, was converted to the 5-O-silyl-
ated sulfoxides. The Pummerer-type thioglycosylation of the sulfoxides gave the 40-thioribonucleosides stereoselectively.
Ó 2005 Elsevier Ltd. All rights reserved.
The replacement of the lactol oxygen of nucleosides with
a sulfur atom proved to be an effective modification that
permits the preparation of novel nucleoside antimetabo-
lites. 40-Thionucleosides are attractive candidates for use
as both antiviral and antineoplastic agents1 and, to date,
a number of 40-thionucleosides have been reported.1,2
We focused on the design and synthesis of 20-modified
40-thionucleosides and found that 40-thioDMDC1g,h
(1) and 40-thioFAC1h,3 (2, X = F, B = Cyt) had potent
antineoplastic activities (Fig. 1).
tions of structure–activity relationships. Thus, for the
production of new 40-thionucleoside analogues, the
development of a suitable synthetic method would be
highly desirable. This was the case for the synthesis of
40-thioDMDC. To synthesize this compound, we
explored two new methods: (1) a novel method for
constructing the 4-thiosugar portion1g,h and (2) a new
coupling reaction of a sulfoxide of the 4-thiosugar por-
tion with persilylated N4-acetylcytosine.1g,h The latter
thioglycosylation reaction was based on the sila-Pum-
merer-type reaction originally developed by Kita6 and
would be applicable to the synthesis of a wide variety
of 40-thionucleoside derivatives including 40-thioribo-
nucleosides.7 This reaction was applied to the synthesis
of 40-thioribonucleosides (3). We also planned to synthe-
size the 4-thioribose moiety via a novel and practical
method because the synthesis of the 4-thiosugar portion
has often been met with various difficulties. Here, we
report on a novel synthesis of the 4-thioribose moiety
and the Pummerer-type thioglycosylation of the corre-
sponding sulfoxide with persilylated nucleobases.
In addition, we have shown that both 40-thioarabino-
nucleosides4 (2, X = OH) and 20-deoxy-20-fluoro-40-thio-
arabinonucleosides5 (2, X = F) have potent antiherpes
virus activities. Despite the unique biological activities
of 40-thionucleosides, the difficulties associated with
the synthesis of these analogues have impeded investiga-
B
Cyt
B
HO
HO
HO
S
S
S
X
HO OH
To construct the 4-thioribose portion, a novel reductive
ring-contraction reaction was developed, in which 1,4-
anhydro-4-thio-D-ribitol was synthesized from a 5-thio-
arabinose derivative: since the synthesis of the D-isomer
of 5-thioarabinose 9 was reported by Hughes et al.8 We
synthesized L-9 by modifying this method.9 Commer-
cially available L-arabinose was treated with acidic
methanol to give the 1-methyl arabinoside 4, and was
HO
HO
2 : X = F or OH
1
3a: B = Cyt
3b: B = Ura
Figure 1.
*
Corresponding authors. Tel.: +81 22 234 4181x2503; fax: +81 22 275
2013; e-mail: yoshimura@tohoku-pharm.ac.jp
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.11.049

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Y. Yoshimura et al. / Tetrahedron Letters 47 (2006) 591–594
then tosylated at the primary hydroxyl group. The
resulting 5-tosylate 5 was acetylated to give 6 in 56%
yield from L-arabinose. Nucleophilic substitution of
the 5-tosyloxy group of 6 with potassium thioacetate
afforded the 5-thioacetate 7, which was deacetylated by
treatment with sodium methoxide and then with hydro-
chloric acid to give 5-thio-L-arabinose 8. The cis-diol of
5-thio-L-arabinoside 8 was protected by an isopropylid-
ene group to give 9 in good yield (Scheme 1).
MsCl, Et3N
THF, then
NaBH4,
+
EtOH, H2O
MeO
RO
S
MeO
S
0 oC
O
O
O
O
A
9 : R = H
10 : R = Ms
To our knowledge, several ring-contraction reactions of
5-thiopyranose to 4-thiofuranose have been reported.8,10
Hughes et al. reported that the 2-mesylate of the L-enan-
tiomer of 9 was transformed to the dimethyl acetal of
4-thiofurose 5-aldehyde under basic methanolysis condi-
tions.8 This encouraged us to examine the direct conver-
sion of the mesylate 10 to the desired 4-thioribose under
reductive conditions. Compound 9 was converted to 2-
mesylate 10, which was used for the next reductive
ring-contraction reaction without any purification,
because of its instability. The reaction mixture containing
10 was treated with NaBH4 in aqueous EtOH to give the
ring contracted product 11 in 86% yield, as expected.11
As shown in Scheme 2, the reaction proceeded via the
following three steps: (1) the intramolecular nucleophilic
attack of sulfur at the 5-position and the formation of
an episulfonium ion A, (2) ring contraction and the gen-
eration of 5-aldehyde C, and (3) the hydride reduction of
the resulting aldehyde C.
H
O
H
+
HO
MeO
H2O
S
-
S
S
BH4
(86%)
O
O
O
O
O
O
C
B
11
Scheme 2.
The 5-O-silylated sulfoxides 12, prepared from 11 by
5-O-silylation and the subsequent MCPBA oxidation,
was subjected to a Pummerer-type thioglycosylation.
The reaction of 12 with persilylated N4-acetylcytosine
in the presence of TMSOTf and triethylamine gave the
desired 40-thiocytidine derivatives 13 with the predomi-
nant formation of b-anomers (40%; a:b = 1:5). The
yield of the reaction was improved slightly (61%) when
the persilylated N4-acetylcytosine was premixed with
TMSOTf (3 equiv) and triethylamine (3 equiv) prior to
the addition of 12.13 The reason as to why the premixing
of the reagents improves the reaction yield is not clear.
The deprotection of 13 was achieved by the treatment
with aq NH4OH/MeOH followed by an acidic resin
(Dowex 50W H+ form) in MeOH. The resulting mixture
was then purified by ODS column chromatography to
give pure b-40-thiocytidine 3a in 56% yield (Scheme 3).
Although the synthesis of 1,4-anhydro-4-thio-D-ribitol
was reported by Minakawa et al.,12 it was necessary to
remove undesired L-isomer by crystallization. Our meth-
od to access 11 is facile since some of the reaction steps
can be done in one-flask and is highly stereospecific.
1) TsCl
Pyridine
2) Ac2O
HCl
MeOH
O
MeO
OH
L-Arabinose
The reaction of 12 with the persilylated uracil gave the
corresponding 40-thiouridine derivative in poor yield
(<33%). We attempted to optimize the conditions used
in the Pummerer-type thioglycosylation for the 40-thio-
uridine derivative using a model reaction. The reaction
of persilylated uracil 14 or uracil 15 with tetramethylene
sulfoxide 16 was investigated under various conditions.
As a result, the reaction of persilylated uracil 14 with
an excess of diisopropylethyamine at 0 °C gave 17 in
70% yield (Method A). In the proposed reaction mech-
anism, the sulfenium ion is formed from the reaction
of the sulfoxide with TMSOTf. Our results suggest that
the excess amine should facilitate abstraction of the
a-proton of the O-silylated tetramethylene sulfoxide to
generate the corresponding sulfenium ion. Indeed, the
reaction of uracil 15 and 16 with an excess of TMSOTf
(7 equiv) and diisopropylethylamine (14 equiv) also gave
17 in 86% yield (Method B) (Scheme 4).
OH
HO
4
KSAc
DMF
O
MeO
O
MeO
OR1
OR2
SAc
OAc
(56%, 4 steps)
R2O
AcO
5 : R1 = Ts, R2 = H
6 : R1 = Ts, R2 = Ac
7
1) NaOMe
MeOH
pTsOH
2) HCl
2,2-DMP
acetone
MeOH
reflux
MeO
HO
S
MeO
HO
S
(92%)
(71%)
O
OH
O
OH
Using the conditions mentioned above, the Pummerer-
type thioglycosylation of uracil with 12 was investigated.
Even though the model reaction using uracil afforded
the corresponding thioglycosylated product in excellent
8
9
Scheme 1.

Y. Yoshimura et al. / Tetrahedron Letters 47 (2006) 591–594
593
1) TBSCl
O
N
-Ac-bis(TMS)cytosine
Imidazole
DMAP
TBSO
TMSOTf, Et3N
CH2Cl2, PhCH3
S
DMF (86%)
11
(61%, α: β= 1:5)
2) m-CPBA
CH2Cl2
O
O
–50oC (74%)
12
NHAc
NH2
1) concNH4OH
MeOH
N
N
2) Dowex 50W (H+ form)
MeOH
N
O
O
TBSO
N
O
S
HO
S
H
(56%, 2 steps)
O
HO
O
OH
3a
13
Scheme 3.
OR
O
NH
Method A or B
N
S
N
O
+
S
N
OR
14: R = SiMe3
15: R = H (uracil)
17
16
Method A: 14, TMSOTf (3.0),
Method B: 15, TMSOTf (7.0),
i
i
-Pr2NEt (7.0)/ CH2Cl2, 0 oC, (70%)
-Pr2NEt (14)/ CH2Cl2, PhCH3, 0 oC, (86%)
Scheme 4.
yield, the reaction of uracil 15 with 12, under the same
conditions as in Method B, gave a 40-thiouridine deriv-
ative 18 only in 29% yield. Meanwhile, the reaction of
persilylated uracil 14 with 12 as in Method A gave the
40-thiouridine derivative 18 in 89% yield.14 The ratio
of a- and b-anomers obtained, as determined by 1H
NMR, was 1:6 to a-18:b-18.15 Finally, the deprotection
of 18 by the acid treatment furnished 40-thiouridine 3b in
good yield (Scheme 5). However, separation of the
a- and b-anomers of 3b was unsuccessful.
Acknowledgments
This work was supported, in part, by a grant from The
Foundation for Japan Chemical Research (Y.Y.) and by
a Grant-in-Aid for Scientific Research, Encouragement
of Scientists (No. 12771439) (Y.Y.).
References and notes
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The application of this reaction to the synthesis of pur-
ine 40-thioribonucleosides is currently underway and will
be reported in a future report.
O
1) bis(TMS)uracil
TMSOTf,i Pr2NEt
NH
CH2Cl2, PhCH3
(89%,α:β = 1:6)
N
O
R1O
S
12
2) Dowex 50W (H+ form)
MeOH (95%)
H
R2O
OR2
18: R1 = TBS, R2 = C(CH3)2
3b: R1 = R2 = H
2. (a) Malsen, H. J.; Hughes, D.; Hursthouse, M.; De Clercq,
E.; Balzarini, J.; Simons, C. J. Med. Chem. 2004, 47, 5482–
5491; (b) Haraguchi, K.; Shiina, N.; Yoshimura, Y.;
Scheme 5.

594
Y. Yoshimura et al. / Tetrahedron Letters 47 (2006) 591–594
Shimada, H.; Hashimoto, K.; Tanaka, H. Org. Lett. 2004,
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Z.; Kim, H. O.; Shin, D. H.; Moon, H. R.; Hyung, R.;
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8643.
eluates were evaporated to leave crystalline 11 (743 mg,
86%): mp 56–60 °C. [a]D +109 (c 1.4, CHCl3). H NMR
1
(CDCl3) d ppm 4.85 (1H, dt, J = 1.4, 1.7, 4.8 Hz), 4.63
(1H, dd, J = 1.4, 6.4 Hz), 3.59 (1H, dd, J = 6.4, 12.0 Hz),
3.49 (1H, dd, J = 6.4, 12.0 Hz), 3.38 (1H, t, J = 6.4 Hz),
3.03 (1H, dd, J = 1.7, 12.9 Hz), 2.85 (1H, dd, J = 4.8,
12.9 Hz), 2.01 (1H, br, OH), 1.46, 1.26 (each 3H, s); FAB-
MS m/z 191 (M+H+). Anal. Calcd for C8H14O3S: C,
50.50; H, 7.42. Found: C, 50.20; H, 7.20.
12. Minakawa, N.; Kato, Y.; Uetake, K.; Kaga, D.; Matsuda,
A. Tetrahedron 2003, 59, 1699–1702.
13. Experimental procedure and characterization data: To a
suspension of N4-acetylcytosine (76 mg, 0.50 mmol) in
CH2Cl2 (1.5 mL) was added BSA (272 lL, 1.10 mmol).
The mixture was stirred at room temperature for 2 h. The
resulting clear solution was diluted with PhCH3 (1 mL),
then, TMSOTf (90 lL, 0.50 mmol) and Et3N (70 lL,
0.50 mmol) were added. After being stirred for 15 min, a
solution of 13 (50 mg, 0.143 mmol) in PhCH3 (0.6 mL)
was added. The mixture was stirred at room temperature
overnight. The reaction was quenched with satd NaHCO3,
and the resulting insoluble materials were removed by
passing through a pad of Celite. The filtrate was extracted
with CHCl3 and the separated organic layer was washed
with brine, then dried (Na2SO4). After the filtrate was
concentrated under reduced pressure, the residue was
purified by silica gel column chromatography (66% AcOEt
3. (a) Yoshimura, Y.; Endo, M.; Sakata, S. Tetrahedron Lett.
1999, 40, 1937–1940; (b) Yoshimura, Y.; Endo, M.;
Miura, S.; Sakata, S. J. Org. Chem. 1999, 64, 7912–7920.
4. Yoshimura, Y.; Watanabe, M.; Satoh, H.; Ashida, N.;
Ijichi, K.; Sakata, S.; Machida, H.; Matsuda, A. J. Med.
Chem. 1997, 40, 2177–2183.
5. Yoshimura, Y.; Kitano, K.; Yamada, K.; Sakata, S.;
Miura, S.; Ashida, N.; Machida, H. Bioorg. Med. Chem.
2000, 8, 1545–1558.
6. (a) Kita, Y.; Yasuda, H.; Tamura, O.; Itoh, F.; Tamura,
Y. Tetrahedron Lett. 1984, 25, 4681–4682; (b) Kita, Y.;
Tamura, O.; Yasuda, H.; Itoh, F.; Tamura, Y. Chem.
Pharm. Bull. 1985, 33, 4235–4241.
7. Naka, T.; Minakawa, N.; Abe, H.; Kaga, D.; Matsuda, A.
J. Am. Chem. Soc. 2000, 122, 7233–7243.
1
8. Hughes, N. A.; Kuhajda, K.-M.; Miljkovic, D. A.
Carbohydr. Res. 1994, 257, 299–304.
in hexane) to give 13 (39.5 mg, 61%, a:b = 1:5): b-13: H
NMR (400 MHz, CDCl3) d ppm 8.51 (1H, br), 8.35 (1H,
d, J = 7.6 Hz), 7.32 (1H, d, J = 7.6 Hz), 6.02 (1H, d, J =
1.7 Hz), 4.74 (1H, dd, J = 1.7, 6.9 Hz), 4.71 (1H, dd,
J = 2.0, 6.9 Hz), 3.84 (2H, d, J = 4.8 Hz), 3.68 (1H, dt,
J = 2.0, 4.8 Hz), 2.16 (3H, s), 1.54, 1.23 (each 3H, s), 0.85
(9H, s), 0.03, 0.00 (each 3H, s). FAB-MS m/z 456
(M+H+). Anal. Calcd for C20H33N3O5SSiÆEtOH: C,
52.72; H, 7.30; N, 9.22. Found: C, 52.50; H, 6.98; N, 9.42.
14. Compound b-18: 1H NMR (600 MHz, CDCl3) d ppm
8.27 (1H, br), 7.99 (1H, d, J = 8.1 Hz), 6.13 (1H, d, J =
2.8 Hz), 5.75 (1H, dd, J = 2.1, 8.1 Hz), 4.73 (1H, dd,
J = 2.6, 5.5 Hz), 4.70 (1H, dd, J = 2.9, 5.5 Hz), 3.93 (1H,
dd, J = 4.9, 10.8 Hz), 3.87 (1H, dd, J = 3.9, 10.8 Hz), 3.74
(1H, dt, J = 2.6, 4.4 Hz), 1.59 (3H, s), 1.33 (3H, s), 0.92
(9H, s), 0.12 (3H, s), 0.10 (3H, s). HR-EI-MS m/z calcd for
C18H30N2O5SSi 414.1645, found 414.1595.
9. In this work, we investigated the direct tosylation of the
primary hydroxyl group of methyl arabinoside to avoid
using a dithioacetal derivative reported in Ref. 8.
10. Altenbach, H.-J.; Merhof, G. F. Tetrahedron: Asymmetry
1996, 7, 3087–3090.
11. Experimental procedure and characterization data: To a
solution of
9 (1.00 g, 4.54 mmol) and triethylamine
(1.27 mL, 9.08 mmol) in THF (10 mL) was dropwise
added methanesulfonyl chloride (0.71 mL, 9.08 mmol) at
0 °C. The mixture was stirred at 0 °C for 15 min. To a
solution of sodium borohydride (1.72 g, 45.2 mmol) in
THF (20 mL) and water (20 mL) was slowly added the
above mixture at 0 °C. The resulting mixture was stirred at
0 °C for 20 min. After neutralized with AcOH, whole was
extracted with CHCl3. The organic phase was washed with
saturated sodium bicarbonate solution and brine, then
dried over Na2SO4. After the filtrate was concentrated
under reduced pressure, the residue was purified by silica
15. The stereochemistry of the anomeric position of the
thioglycosylated products was determined by NOE
experiments.