Synthesis of novel nucleosides and stereoselectivity of N-glycosidation

Article abstract of DOI:10.1016/j.tet.2012.11.017

An efficient synthetic route for novel nucleosides has been realized. We report the formation of a-isomers in spite of neighboring group participation by the benzoyl group at the 2-position in N-glycosidation as well as discuss the stereoselectivity obser

Full text of DOI:10.1016/j.tet.2012.11.017

Tetrahedron 69 (2013) 595e599
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of novel nucleosides and stereoselectivity of N-glycosidation
*
Kyosuke Michigami, Satoshi Uchida, Miho Adachi, Masahiko Hayashi
Department of Chemistry, Graduate School of Science, Kobe University, Nada, Kobe 657-8501, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthetic route for novel nucleosides has been realized. We report the formation of a-iso-
Received 18 September 2012
Received in revised form 1 November 2012
Accepted 2 November 2012
Available online 9 November 2012
mers in spite of neighboring group participation by the benzoyl group at the 2-position in N-glyco-
sidation as well as discuss the stereoselectivity observed. We also found that non-silylated pyrimidin-
2(1H)-ones and pyrimidin-2(1H)-thiones having aromatic structures reacted with 1-fluororibose in the
presence of a Lewis acid to give the corresponding nucleosides in good to high yield.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
N-Glycosidation
Pyrimidin-2(1H)-one
Pyrimidin-2(1H)-thione
Neighboring group participation
1. Introduction
route for novel nucleosides and discuss the stereoselectivity ob-
served in N-glycosidation.
Natural occurring or artificial nucleosides are fundamental
bioactive compounds.1 Their biological activities include antitumor,
anticancer, antibacterial, antiviral etc. Some nucleosides have been
reported and used in the medical and pharmaceutical fields.2,3
Consequently, development of their synthetic method and appli-
cation in the medical field is in high demand. So far, many synthetic
methods of nucleosides4,5 and the methods not requiring heavy
2. Results and discussion
Dihydropyrimidin-2(1H)-ones (1aec) were prepared according
to previously reported method,8 followed by treatment with acti-
vated carbon in O2 atmosphere to afford pyrimidin-2(1H)-ones
(2aec)9 (Scheme 2).
Further reactions with Lawesson’s reagent gave pyrimidin-
2(1H)-thiones (3aec) in good to moderate yield. The detailed
metals have been proposed.6 The Vorbruggen reaction, a repre-
€
sentative example of glycosidation reaction, uses a silyl group to
increase nucleophilicity (Scheme 1).6c,7
€
Scheme 1. Vorbruggen reaction.
The neighboring group participation by a carbonyl group, such
as the acetyl and benzoyl moieties at the 2-position is known to
€
control the stereochemistry of the Vorbruggen reaction with ribo-
furanoside, giving the b-isomer. Herein, we will report an efficient
Scheme 2. Synthesis of pyrimidin-2(1H)-ones and corresponding thiones.
* Corresponding author. E-mail address: mhayashi@kobe-u.ac.jp (M. Hayashi).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.11.017

596
K. Michigami et al. / Tetrahedron 69 (2013) 595e599
Table 2
synthetic method of pyrimidin-2(1H)-ones and pyrimidin-2(1H)-
thiones is given in the supplementary data. We first examined the
nature of the Lewis acids (Me3SiOTf, SnCl4, and BF3$OEt2) and
Effect of temperature on the a:b isomer ratio
leaving groups (Table 1). 2,3,5-Tri-O-benzoyl-D-ribo-furanosyl
Table 1
Optimization of the leaving group and Lewis acid
Entrya
Temp/ꢀC
Time/h
Yield/%b
a:
bc
1
2
3
4
5
6
7
8
ꢁ30
ꢁ30
0
3
24
1
24
1
12
1
6
51
58
93
88
94
60
85
39
3:97
0:100
16:84
0:100
15:85
<2:98d
24:76
<5:95d
0
24
26
50
50
Entrya
X
Lewis acid
Yield/%b
Isomerc
1
2
3
4
5
6
Me3SiOTf
SnCl4
BF3$OEt2
Me3SiOTf
SnCl4
11 (57)
49 (15)
31 (50)
31 (24)
73 (0)
b
b
b
b
b
b
b
-OAc
a
BSA (1.9 equiv) was added to a mixture of 4b and 2a (1.3 equiv) in MeCN and
stirred for 1 h at 50 ꢀC, followed by the addition of BF3$OEt2 (3.7 equiv) at 0 ꢀC and
stirred under indicated conditions.
F (
a
:b
¼50:50)
b
Isolated yield after silica gel column chromatography.
BF3$OEt2
53 (0)
c
a
a:b
:
b
ratio was determined after isolation of each isomer.
a
The Lewis acid (3.7 equiv) was added to a mixture of substrate (4a or 4b) and 2a
d
ratio was determined by 1H NMR analysis.
(1.3 equiv) in MeCN was added and stirred for 2 h at 0 ꢀC.
b
Isolated yield after silica gel column chromatography. The values in the pa-
rentheses indicate the yield of the recovered starting material.
Products were obtained in moderate to excellent yield (51e94%).
Interestingly, -isomer was isolated despite the benzoyl moiety at
c
a
-Isomer was not obtained.
a
the 2-position, which was expected to function as the neighboring
participation group (entries 1, 3, 5, and 7). Formation and isolation
fluoride10 (4b) was prepared by fluorination of commercially
available 1-O-acetyl-2,3,5-tri-O-benzoyl- -ribofuranose (4a). 1-O-
Acetyl-2,3,5-tri-O-benzoyl- -ribofuranose as the substrate gave the
products in low to moderate yield (11e49%) (entries 1e3 in Table 1).
On the other hand, fluoro saccharides disappeared completely
(entries 5 and 6) and the corresponding nucleosides were obtained
D
of the minor
a-isomer in the presence of acyl group at 2-position is
D
rare.12
The reaction at a low temperature (ꢁ30 ꢀC) resulted in moderate
yield, however, it was controlled well by the kinetic effect (entry 1).
Stirring for 24 h at ꢁ30 ꢀC gave high
b
-selectivity (
a:
b¼0:100) of the
in moderate yield as the
proceed well using SnCl4 or BF3$OEt2 as the Lewis acid. In all re-
actions, the -isomer was not isolated. For easier manipulation,
b-isomers. Defluorination seemed to
product (entry 2). We also examined the reaction at 0 ꢀC, room
temperature (24 ꢀC), and 50 ꢀC (entries 3, 5, and 7, respectively). In
a
particular, glycosidation at 50 ꢀC gave the highest
a
-ratio
¼24:76) (entry 7). We examined the effect of the reaction time
at each temperature and found that the -ratio decreased (entries
4, 6, and 8). Although the -ratio increased with the increasing
temperature, long time stirring gave the product with high -se-
lectivity compared with short reaction time (1e3 h). Stirring at
70 ꢀC for 30 min gave the product in 60% yield (
¼31:69). We also
examined the amount of Lewis acid under fixed conditions (0 ꢀC,
1 h) and found that the -ratio decreased as the amount of Lewis
acid (BF3$OEt2) was increased to 3.7 and 10.0 equiv (
¼16:84
(93%),
¼0:100 (84%), respectively). An attempt to reduce the
amount of Lewis acid to 1.8 equiv failed, resulting in 60% yield
¼19:81). These results suggested that conversion of the -iso-
mer into the -isomer was promoted by the Lewis acid. Accord-
ingly, we exposed the isolated -isomer to BF3$OEt2 in the presence
of silylpyrimidinone in CD3CN at 50 ꢀC and observed gradual for-
mation of the
-isomer by 1H NMR. Thus, we assume that the
BF3$OEt2 was selected to further optimize the reaction. Reducing
the amount of BF3$OEt2 to less than 3.7 equiv resulted in low yield.
It should be noted that coordination of BF3$OEt2 to pyimidin-2(1H)-
one was detected by 1H NMR, suggesting trapping of the Lewis acid
by pyrimidin-2(1H)-one. The amount of Lewis acid as the active
catalyst is reduced by the coordination. The trap might reduce both
the nucleophilicity and the reactivity of pyrimidin-2(1H)-ones.
However, the reducing nucleophilicity has smaller effect on the
yield of the product than reducing amount of active Lewis acid
because excess amount of BF3$OEt2 (3.7 equiv) increased the yield
of the product.
(a:b
a
a
b
a:b
a
a:b
a:b
It should be mentioned that the glycosidation reaction did not
(a:
b
a
proceed
diphenylpyrimidin-2(1H)-one-carboxylate (1a) was used as the
nucleophile. This indicates that a lone pair in the orbital on a ni-
when
non-aromatic
ethyl
3,4-dihydro-4,6-
b
a
s
trogen in aromatic pyrimidin-2(1H)-ones (2aec) is essential to
promote nucleophilic attack.
b
anomerization of the nucleoside proceeded via the oxocarbenium
ion catalyzed by the Lewis acid.13 Conversion of each isomer via the
SN2 mechanism would be unlikely because of the bulky structures
of pyrimidin-2(1H)-ones and nucleosides. Other pyrimidin-2(1H)-
ones (2bec) were introduced (Table 3) for comparison of nucleo-
phile size.
The a:b ratio of product 5b was 30:70 using ethyl 4,6-dimethyl
pyrimidin-2(1H)-one-5-carboxylate (2b) as the nucleophile (entry
2), and introducing 4,6-diphenylpyrimidin-2(1H)-one (2c) afforded
Next, we examined the glycosidation condition using N,O-bis-
trimethysilylacetamide (BSA)11 as the silylation reagent to promote
the reaction (Table 2). Silylation reagent was added to the corre-
sponding substrate and pyrimidinone in MeCN and stirred at 50 ꢀC
for 1 h. After silylation had completed, the reaction mixture was
cooled to 0 ꢀC, followed by slow addition of BF3$OEt2. After stirring
under the indicated conditions, the reaction was quenched with
aqueous NaHCO3 at 0 ꢀC, followed by work-up and purification.

K. Michigami et al. / Tetrahedron 69 (2013) 595e599
597
Table 3
Table 4
Synthesis of glycosides with various pyrimidin-2(1H)-ones
Synthesis of novel nucleosides having a pyrimidin-2-thione moiety
Entrya
R1
R2
Product
Yield/%b
a
:
bc
Entrya
X
Time/h R1
Ph
R2
Product Yield/%b
a:
bc
1
2
3
Ph
Me
Ph
CO2Et
CO2Et
H
6a
6b
6c
78
66
47
b
b
b
1
2
3
4
5
6
CO2Et 5a
84 (0)
90 (0)
12:88
30:70
10:90
0:100
0:100
0:100
F (
a
:b
¼50:50)
2
Me CO2Et 5b
Ph
Ph
H
5c
93 (0)
a
CO2Et 5a
62 (26)
34 (16)
46 (52)
BF3$OEt2 (3.0 equiv) was added to a mixture of 4b and 3aec (1.2 equiv) in MeCN
and stirred for 1 h at 0 ꢀC.
b-OAc
3
Me CO2Et 5b
Ph 5c
b
H
Isolated yield after silica gel column chromatography. The values in the pa-
rentheses indicate the yield of the recovered starting material.
a
To a mixture of substrate (4a or 4b) and 2aec (1.2 equiv) in MeCN was added
BSA (2.0 equiv) and stirred for 1 h at 50 ꢀC, followed addition of BF3$OEt2 (3.5 equiv)
at 0 ꢀC and stirred for indicated time at 0 ꢀC.
c
a
-Isomer was not obtained.
b
Isolated yield after silica gel column chromatography. Values in the parentheses
nucleophilic than pyrimidin-2(1H)-ones. Formation of S-glycoside
and inversion of the tagging point between nitrogen and sulfur are
unlikely to occur based on the additional experiment (Scheme 3)
indicate the yield of recovered starting material.
c
a:b ratio was determined after isolation of each isomer.
and other references.4b,c In all entries, the
a-isomer was not ob-
product 5c in 93% yield (
to the case of using ethyl 4,6-dimphenylpyrimidin-2(1H)-one-car-
boxylate (2a). Stirring with pyrimidin-2(1H)-one (2bec) for 24 h at
a
:
b
¼10:90), which is, as expected, similar
served. Using other pyrimidin-2(1H)-thiones, such as 3b and 3c
provided the nucleosides in moderate yield. It is noteworthy that a-
€
0
ꢀC provided product 5bec (
a
:b
¼0:100 (22%),
respectively). The ratio of the products might be affected by the
nucleophile size in the reaction with 2,3,5-tri-O-benzoyl- -ribo-
furanosyl fluoride. However, the -isomer was not obtained in all
cases using 1-O-acetyl-2,3,5-tri-O-benzoyl- -ribofuranose (4a) as
a
:b
¼6:94 (67%),
isomer was not observed under the above mentioned Vorbruggen
conditions using ethyl 4,6-diphenylpyrimidin-2(1H)-thione-5-
carboxylate (3a) as the nucleobase.
D
a
D
the substrate (entries 4e6). In the case of fluoro saccharide (4b),
defluorination proceeded so fast that the nucleophile attacked the
oxocarbenium ion before coordination of the benzoyl group at the
2-position. The reaction was controlled mainly by steric hindrance
of the oxocarbenium ion and nucleophile. On the other hand, in
case of acetyl saccharide (4a), elimination of the leaving group was
so slow that formation of oxocarbenium ion and coordination of the
benzoyl group at the 2-position to the anomeric position occurred
at the same time, leading to complete b-selectivity supported by
the neighboring participation effect. Silylated pyrimidinone has
higher reactivity than pyrimidinone itself, so the silylated pyr-
imidinone can only react with the oxocarbenium ion before co-
ordination of the benzoyl group, affording the mixture of a- and b-
isomer. On the other hand, the reaction with pyrimidinone itself is
too slow and thus the coordination of the benzoyl moiety occurred
prior to the oxocarbenium ion attack, affording only the b-isomer.
We conclude that neighboring group participation by the benzoyl
moiety at the 2-position does not always occur in the glycosidation
reaction with fluoro saccharide. After the glycosidation, anomeri-
zation occurred, resulting in isolation of
Thus, the reaction itself provided more
b
a
-isomer predominantly.
-isomer than the final
yield. At least for the nucleoside having a possible leaving moiety at
the anomeric center, we could assume that the final a:b ratio does
not indicate the reaction selectivity.
Scheme 3. Determination of the nucleophilic atom in glycosidation.
Now, we will report the synthesis of novel nucleosides having
a pyrimidin-2-thione moiety (Table 4). The present method is very
simple compared with the silyl method described above.
The change between pyrimidin-2(1H)-ones and pyrimidin-
2(1H)-thiones brought a significant effect to the nucleophilicity. In
the case of pyrimidin-2(1H)-thiones, a silylation reagent is not es-
sential for achieving good yield. Pyrimidin-2(1H)-thiones are more
In conclusion, we developed a non-metallic method for syn-
thesizing novel nucleosides having a pyrimidin-2(1H)-one or pyr-
imidin-2(1H)-thione moiety. The silylated-method under
€
Vorbruggen conditions was not always required for the glyco-
sidation with aromatic pyrimidin-2(1H)-ones and, especially,

598
K. Michigami et al. / Tetrahedron 69 (2013) 595e599
thiones. We also showed and discussed the stereoselectivity in N-
glycosidation due to the kinetics of ‘neighboring group participa-
tion’ and thermodynamics of ‘anomerization’.
133.5, 137.3, 153.8, 158.6, 165.0, 165.5, 165.5, 166.3, 172.2; MS [ESIþ]
m/z 787.1 [MþNa]þ. Anal. calcd for C45H36N2O10: C, 70.67; H, 4.74;
N, 3.66. Found: C, 70.33; H, 4.75; N, 3.68.
3. Experimental
3.1. General
3.2.3. 1-(20,30,50-Tri-O-benzoyl-
ycarbonyl)-4,6-dimethylpyrimidin-2-one (
a
-
D
-ribo-pentofuranosyl)-5-(ethox-
-5b). 52 mg (27%), col-
ꢁ1.05 (c 0.5, CHCl3); IR (KBr):
a
28
orless solid; mp 80e81 ꢀC; [
(cmꢁ1) 1720, 1451, 1315, 1262, 1177, 1091, 1067, 1025, 705; 1H NMR
(400 MHz, CDCl3):
a
]
y
D
All reactions were carried out in oven-dried glassware with
magnetic stirring under an argon atmosphere unless otherwise
mentioned. All starting materials were obtained from commercial
sources and used without further purification unless otherwise
stated. MS spectra were recorded using Thermo Quest LCQ DECA
XPplus. High resolution mass spectra (HRMS) were measured by
JEOL JMS-T100LP AccuTOF LC-Plus (ESI). Melting points, which
were uncorrected were recorded using Yanaco MP-500D. 1H and
13C NMR spectra (JEOL JNM-LA, 400 and 100.6 MHz, respectively)
were recorded on a JEOL JNM-LA 400 using Me4Si as the internal
standard (0 ppm). The following abbreviations are used: s¼singlet,
d¼doublet, t¼triplet, q¼quartet, m¼multiplet. Optical rotations
were measured on a HORIBA SEPA-300 Polarimeter for solution in
a 1 dm cell. IR spectra were measured with a Thermo SCIENTIFIC
NICOLET iS 5. Elemental analyses were performed with a Yanaco
CHN Corder MT-5.
d
1.31 (t, J¼6.4 Hz, 3H, OCH2CH3), 2.44 (s, 3H, Me),
2.31 (s, 3H, Me), 4.37 (q, J¼6.8 Hz, 2H, OCH2CH3), 4.63e4.72 (m, 1H,
H4), 4.82e4.87 (m, 2H, H5; H50), 5.68 (d, J¼2.0 Hz,1H, H1), 6.05e6.28
(m, 2H, H2; H3), 7.3e7.5 (m, 9H, ArH), 7.9e8.1 (m, 6H, ArH); 13C NMR
(100.4 MHz, CDCl3): d 14.0,16.8, 61.3, 64.3, 64.5, 71.1, 71.6, 72.6, 75.0,
76.7, 77.0, 79.1, 84.3, 88.3, 91.2, 95.4, 97.0, 101.5, 109.8, 111.3, 128.3,
128.4,128.4,129.7,129.8,129.8,132.9,133.2,137.0,139.9,150.6,163.5,
165.0, 165.2, 165.4, 165.6, 166.0, 166.2; HRMS [ESIþ]: m/z calcd for
C
35H32N2NaO10: 663.1955 [MþNa]þ. Found: 663.1953.
3.2.4. 1-(20,30,50-Tri-O-benzoyl-
ycarbonyl)-4,6-dimethylpyrimidin-2-one (
orless solid; mp 162e163 ꢀC (from EtOAc/hexane); [
CHCl3); IR (KBr):
1024, 708; 1H NMR (400 MHz, CDCl3):
b-D-ribo-pentofuranosyl)-5-(ethox-
b
-5b). 120 mg (63%), col-
a
]
D
28 þ6.57 (c 0.5,
y
(cmꢁ1) 1718, 1674, 1602, 1515, 1451, 1263, 1097,
d
1.39 (t, J¼7.2 Hz, 3H,
OCH2CH3), 2.45 (s, 3H, Me), 2.48 (s, 3H, Me), 4.37 (q, J¼7.2 Hz, 2H,
OCH2CH3), 4.71 (dd, J¼5.8 Hz, J¼10.2 Hz, 1H, H4), 4.77e4.86 (m, 2H,
H5; H50), 5.97 (d, J¼2.0 Hz,1H, H1), 6.15 (d, J¼1.8 Hz, J¼7 Hz,1H, H2),
6.24 (dd, J¼7.0, 7.0 Hz,1H, H3), 7.2e7.6 (m, 9H, ArH), 7.85 (d, J¼7.6 Hz,
3.2. General procedure to synthesize nucleosides having
a pyrimidin-2-one moiety
2H, ArH), 8.92 (d, J¼7.2 Hz, 2H, ArH), 8.07 (d, J¼7.2 Hz, 2H, ArH); 13
C
To a MeCN solution (3 mL) of 2,3,5-tri-O-benzoyl-
D-ribo-furanosyl
NMR (100.4 MHz, CDCl3): d 14.1,17.5, 25.0, 62.0, 64.5, 72.5, 75.1, 76.7,
fluoride as the substrate (0.8 mmol) was added ethyl 4,6-
diphenylpyrimidin-(1H)-one-5-carboxylate (1.0 mmol) and BSA
(1.9 mmol). The mixture was stirred at 50 ꢀC for 1 h and then cooled to
0 ꢀC. BF3$OEt2 (3.0 mmol) wasadded tothemixture slowlyand stirred
for 1 h, followed by quenching with satd NaHCO3. The mixture was
extracted with ethyl acetate. The combined organic layer was washed
with brine, dried over Na2SO4, and then filtered and evaporated. The
residue was chromatographed on silica gel with hexane/ethyl acetate
ratios of 7:1 and then 3:1 as the eluent to afford product 5a.
77.0, 80.7, 92.7, 113.5, 128.3, 128.4, 128.5, 128.7, 129.0, 129.7, 129.8,
129.8,133.1, 133.4,133.7,153.8,156.0,165.1,166.1,166.2,166.3,174.1;
MS [ESIþ] m/z 663.1 [MþNa]þ. Anal. calcd for C35H32N2O10: C, 65.62;
H, 5.03; N, 4.37. Found: C, 65.47; H, 4.92; N, 4.10.
3.2.5. 1-(20,30,50-Tri-O-benzoyl-
a-D-ribo-pentofuranosyl)-4,6-
diphenylpyrimidin-2-one (a-5c). 19 mg (9%), colorless solid; mp
60e61 ꢀC; [
a
]
28 þ0.06 (c 0.5, CHCl3); IR (KBr):
y
(cmꢁ1) 1722, 1587,
D
1533, 1451, 1092, 1069, 972, 764, 705; 1H NMR (400 MHz, CDCl3):
d
4.65e4.77 (m, 2H, H5; H50), 4.88e4.92 (m, 1H, H4), 6.16 (d,
3.2.1. 1-(20,30,50-Tri-O-benzoyl-
ycarbonyl)-4,6-diphenylpyrimidin-2-one (
a
-
D
-ribo-pentofuranosyl)-5-(ethox-
-5a). 91 mg (15%), col-
ꢁ0.04 (c 0.5, CHCl3); IR (KBr):
J¼4.8 Hz, 1H, H2), 6.20 (dd, J¼4.8 Hz, 7.4 Hz, 1H, H3) 7.02 (s, 1H, H1),
a
7.2e7.6 (m, 8H, ArH), 7.84 (s, 1H, ArH), 7.9e8.1 (m, 7H, ArH); 13C
28
orless solid, mp 68e69 ꢀC; [
a
]
y
NMR (100.4 MHz, CDCl3): d 64.6, 72.6, 74.6, 76.7, 77.0, 80.6, 93.9,
D
(cmꢁ1) 2979, 1722, 1536, 1450, 1410, 1249, 1093, 1062, 1025, 707; 1H
103.5, 128.1, 128.3, 128.7, 128.8, 128.9, 129.0, 129.4, 129.7, 129.7,
129.8, 130.5, 132.3, 133.0, 133.2, 133.4, 135.7, 155.8, 160.0, 165.0,
166.3; HRMS [ESIþ]: m/z calcd for C42H32N2NaO8: 715.2056
[MþNa]þ. Found: 715.2057.
NMR (400 MHz, CDCl3):
d
0.94 (t, J¼7.0 Hz, 3H, OCH2CH3), 3.9e4.1
(m, 2H, OCH2CH3), 4.6e4.7 (m, 2H, H5; H50), 4.85e4.90 (m, 1H, H4),
6.09 (d, J¼4.8 Hz,1H, H2), 6.15 (dd, J¼4.8, 7.2 Hz,1H, H3), 6.94 (s,1H,
H1), 7.2e7.7 (m,17H, ArH), 7.89 (d, J¼0.8 Hz, 3H, ArH), 8.04e8.07 (m,
4H, ArH); 13C NMR (100.4 MHz, CDCl3):
d
13.4, 61.9, 63.9, 71.5, 75.3,
3.2.6. 1-(20,30,50-Tri-O-benzoyl-
diphenylpyrimidin-2-one (
99e100 ꢀC (from THF/hexane); [
b-D-ribo-pentofuranosyl)-4,6-
76.7, 77.0, 79.9, 101.2, 121.2, 128.3, 128.4, 128.5, 128.5, 128.5, 128.8,
129.0, 129.1, 129.5, 129.6, 129.8, 129.9, 129.9, 130.3, 132.9, 133.4,
133.6,137.2,162.3,165.0,165.2,166.2,167.5,167.9; HRMS [ESIþ]: m/z
calcd for C45H36N2NaO10: 787.2268 [MþNa]þ. Found: 787.2268.
b-5c). 194 mg (84%), colorless solid; mp
a
]
28 ꢁ28.0 (c 1.0, CHCl3); IR (KBr):
y
D
(cmꢁ1) 1718, 1674, 1602, 1515, 1451, 1263, 1097, 1024, 708; 1H NMR
(400 MHz, CDCl3):
d
4.68 (dd, J¼5.6, 12.8 Hz, 1H, H4), 4.79e4.87 (m,
2H, H5; H50), 5.72 (d, J¼1.6 Hz, 1H, H1), 6.27 (dd, J¼7.2, 7.2 Hz, 1H,
H3), 6.31 (dd, J¼2.0, 8.0 Hz,1H, H2), 6.75 (s,1H, ArH), 7.2e7.6 (m,17H,
ArH), 7.71 (d, J¼7.2 Hz, 2H, ArH), 7.93 (d, J¼7.6 Hz, 2H, BzH), 8.04 (d,
J¼8.0 Hz, 2H, BzH) 8.17 (d, J¼6.0 Hz, 2H, BzH); 13C NMR (100.4 MHz,
3.2.2. 1-(20,30,50-Tri-O-benzoyl-
ycarbonyl)-4,6-diphenylpyrimidin-2-one (
orless solid, mp 171e172 ꢀC (from THF/hexane); [
CHCl3); IR (KBr):
(cmꢁ1) 2978, 2338, 2058, 1722, 1665, 1594, 1482,
1255, 712, 701; 1H NMR (400 MHz, CDCl3):
0.74 (t, J¼7.4 Hz, 3H,
b
-
D
-ribo-pentofuranosyl)-5-(ethox-
-5a). 478 mg (78%), col-
b
28
a]
ꢁ1.28 (c 1.0,
D
y
CDCl3): d 64.6, 72.6, 74.6, 76.7, 77.0, 80.6, 93.9, 103.5, 128.1, 128.3,
d
128.7, 128.8, 128.9, 129.0, 129.4, 129.7, 129.7, 129.8, 130.5, 132.3,
133.0,133.2,133.4,135.7,155.8,160.0,165.0,166.3; HRMS [ESIþ]: m/z
calcd for C42H32N2NaO8: 715.2056 [MþNa]þ. Found: 715.2056.
OCH2CH3), 3.74 (q, J¼6.9 Hz, 2H, OCH2CH3), 4.59e4.63 (m, 1H, H4),
4.78 (ddd, J¼19.3, 11.9, 5.5 Hz, 2H, H5; H50), 5.51 (d, J¼2.0 Hz, 1H,
H1), 6.19 (dd, J¼7.6 Hz, J¼7.6 Hz, 1H, H3), 6.32 (dd, J¼2.0 Hz,
J¼6.8 Hz, 1H, H2), 7.2e7.8 (m, 17H, ArH), 7.73 (dd, J¼8.0, 8.0 Hz, 4H,
ArH), 7.93 (d, J¼7.2 Hz, 2H, BzH), 8.08 (d, J¼6.8 Hz, 2H, BzH); 13C
3.3. General procedure to synthesize nucleosides having
a pyrimidin-2-thione moiety
NMR (100.4 MHz, CDCl3):
d 13.3, 61.6, 64.4, 72.4, 74.2, 76.7, 77.0,
80.6, 94.2, 95.5, 113.6, 128.2, 128.2, 128.3, 128.3, 128.4, 128.7, 128.8,
129.0, 129.2, 129.5, 129.7, 129.9, 130.2, 130.6, 131.1, 133.0, 133.3,
To a MeCN solution (3 mL) of 2,3,5-tri-O-benzoyl-
anosyl fluoride as the substrate (0.5 mmol) was added ethyl 4,6-
b-D-ribo-fur-

K. Michigami et al. / Tetrahedron 69 (2013) 595e599
599
diphenylpyrimidin-2(1H)-thione-5-carboxylate (0.6 mmol) and the
solution was cooled to 0 ꢀC. BF3$OEt2 (1.5 mmol) was added slowly
to the mixture and stirred at 0 ꢀC for 1 h, followed by quenching
with satd NaHCO3. The mixture was extracted with ethyl acetate.
The combined organic layer was washed with brine, dried over
Na2SO4, and then filtered and evaporated. The residue was chro-
matographed on silica gel using hexane/ethyl acetate ratios of 15:1
and then 7:1 as the eluent to afford product 6a.
Directed toward Straightforward Synthesis’, Ministry of Educa-
tion, Culture, Sports, Science and Technology (MEXT), Japan and
by Special Coordination Funds for Promoting Science and Tech-
nology, Creation of Innovation Centers for Advanced In-
terdisciplinary Research Areas (Innovative Bioproduction Kobe),
MEXT, Japan.
Supplementary data
3.3.1. 1-(20,30,50-Tri-O-benzoyl-
ycarbonyl)-4,6-diphenylpyrimidin-2-thione (
colorless needle, mp 102e104 ꢀC (from EtOAc/hexane); [
(c 1.0, CHCl3); IR (KBr):
1069, 1057, 864, 697; 1H NMR (400 MHz, CDCl3):
b-D-ribo-pentofuranosyl)-5-(ethox-
b
-6a). 304 mg (78%),
Detailed experimental procedures and characterization data
(1H, 13C, IR, mass spectrometry). Supplementary data related to this
article can be found online at http://dx.doi.org/10.1016/
j.tet.2012.11.017.
a
]
30 þ21.8
D
y
(cmꢁ1) 1722, 1515, 1491, 1263, 1214, 1092,
d
0.91 (t, J¼7.2 Hz,
3H, OCH2CH3), 4.01 (q, J¼7.2 Hz, 2H, OCH2CH3), 4.57 (dd, J¼11.4,
3.5 Hz, 1H, H5), 4.7e4.8 (m, 2H, H4; H50), 6.01 (dd, J¼6.8, 5.0 Hz, 1H,
H3), 6.14 (dd, J¼5.0, 2.4 Hz,1H, H2), 6.56 (d, J¼2.4 Hz,1H, H1), 7.2e7.6
(m,19H, ArH), 7.86 (d, J¼8.0 Hz, 2H, ArH), 7.98 (d, J¼7.2 Hz, 2H, ArH),
References and notes
8.11 (d, J¼7.2 Hz, 2H, ArH); 13C NMR (100.4 MHz, CDCl3):
d 13.39,
1. (a) Tan, X.; Chu, C. K.; Boudinot, F. D. Adv. Drug Delivery Rev. 1999, 39,
117e151; (b) Huryn, D. M.; Okabe, M. Chem. Rev. 1992, 92, 1745e1768; (c)
Romeo, G.; Chicchio, U.; Corsaro, A.; Merino, P. Chem. Rev. 2010, 110,
3337e3370.
2. (a) Isono, K. J. Antibiot. 1988, 41, 1711e1739; (b) Wang, W. S.; Tzeng, C. H.; Chiou,
T. J.; Liu, J. H.; Hsieh, R. K.; Yen, C. C.; Chen, P. M. Jpn. J. Clin. Oncol. 1997, 27,
154e157.
61.87, 63.74, 71.74, 79.64, 86.13,121.2,128.4,128.8,129.1,129.5,129.7,
129.9,130.2,133.2,133.3,133.4,137.0,164.8,165.0,165.2,166.2,167.6,
169.6; MS [ESIþ] m/z: 781 [MþH]þ. Anal. calcd for C45H36N2O9S: C,
69.22; H, 4.65; N, 3.59. Found: C, 68.86; H, 4.71; N, 3.93.
3. Bretner, M.; Kulikowski, T.; Dzik, M. J.; Balinska, M.; Rode, W.; Shugr, D. J. Med.
Chem. 1993, 36, 3611e3617.
4. (a) Pískara, A.; Sorm, F. Collect. Czech. Chem. Commun. 1964, 29, 2060e2076;
(b) Robin, A.; Julienne, K.; Meslin, J. C.; Deniaud, D. Eur. J. Org. Chem. 2006,
634e643; (c) Person, M. S. M.; Robin, A.; Bourgougnon, N.; Meslin, J. C.;
Deniaud, D. J. Org. Chem. 2003, 68, 8583e8587.
5. (a) Koenig, W.; Knorr, E. Ber. Dtsch. Chem. Ges. 1901, 34, 957e981 Review;
(b) Schmidt, R. R. In Comprehensive Organic Synthesis; Trost, B. M., Fleming,
3.3.2. 1-(20,30,50-Tri-O-benzoyl-
ycarbonyl)-4,6-dimethylpyrimidin-2-thione (
b
-
D
-ribo-pentofuranosyl)-5-(ethox-
-6b). 217 mg (66%),
þ24.3 (c 1.0, CHCl3); IR (KBr):
ꢀ
b
26
white solid, mp 62e63 ꢀC; [
(cmꢁ1) 1719, 1262, 1225, 1092, 1068, 1024, 705, 686; 1H NMR
(400 MHz, CDCl3):
a
]
D
y
d
1.38 (t, J¼6.9 Hz, 3H, OCH2CH3), 2.48 (s, 6H,
Me), 4.40 (q, J¼6.9 Hz, 2H, OCH2CH3), 4.56 (dd, J¼12.0, 4.4 Hz, 1H,
H5), 4.67e4.78 (m, 2H, H4; H50), 5.97 (dd, J¼7.0, 5.0 Hz,1H, H3), 6.08
(dd, J¼4.8, 2.8 Hz, 1H, H2), 6.45 (d, J¼2.8 Hz, 1H, H1), 7.30e7.59 (m,
9H, ArH), 7.88 (d, J¼7.2 Hz, 2H, ArH), 8.03 (d, J¼7.6 Hz, 2H, ArH), 8.09
I., Eds.; Pergamon: Oxford, U.K., 1991; vol. 6,
p 33; (c) Schmidt, R. R.
Angew. Chem. 1986, 98, 213e236; (d) Paulsen, H. Angew. Chem., Int. Ed.
Engl. 1982, 21, 155e173; (e) Igarashi, K. Adv. Carbohydr. Chem. Biochem.
1977, 34, 243e283.
6. (a) Hashimoto, S.; Hayashi, M.; Noyori, R. Tetrahedron Lett. 1984, 25,
(d, J¼7.2 Hz, 2H, ArH); 13C NMR (100.6 MHz, CDCl3):
d 14.10, 22.92,
1379e1382; (b) Noyori, R.; Hayashi, M. Chem. Lett. 1987, 57e60; (c) Review:
€
Vorbruggen, H.; Ruh-Pohlenz, C. Org. React. 2000, 55, 1e630; (d) Lazrek, H.
30.88, 61.69, 63.82, 71.92, 75.96, 76.69, 77.00, 77.32, 79.73, 85.98,
122.7, 128.33, 128.38, 128.4, 128.8, 129.1, 129.5, 129.7, 129.8, 133.1,
133.4, 133.5, 164.9, 165.2, 165.4, 166.2, 167.0, 169.0; HRMS [ESIþ]:
m/z calcd for C35H32N2O9S: 679.1726 [MþNa]þ. Found: 679.1726.
B.; Ouzebla, D.; Baddi, L.; Vasseur, J. J. Nucleosides, Nucleotides Nucleic Acids
2007, 26, 1095e1098; (e) Hadd, M. J.; Gervay, J. Carbohydr. Res. 1999, 320,
61e69; (f) Sugimura, H.; Osumi, k.; Yamazaki, T.; Yamaya, T. Tetrahedron Lett.
1991, 32, 1813e1816; (g) Mukaiyama, T.; Kobashi, Y. Chem. Lett. 2004, 33,
10e11; (h) Knapp, S.; Shieh, W.-C. Tetrahedron Lett. 1991, 32, 3627e3630; (i)
Hanessian, S.; Sato, K.; Liak, T. J.; Dahn, N.; Dixit, D. J. Am. Chem. Soc. 1984,
106, 6114e6115; (j) Knapp, S. Chem. Rev. 1995, 95, 1859e1876 and references
cited therein.
3.3.3. 1-(20,30,50-Tri-O-benzoyl-
diphenylpyrimidin-2-thione ( -6c). 138 mg (47%), white solid, mp
163e164 ꢀC (from MeCN); [
(cmꢁ1) 1582, 1564, 1510, 1494, 1436, 1365, 1233, 1139, 746, 686; 1H
b-D-ribo-pentofuranosyl)-4,6-
b
27
€
7. (a) Vorbruggen, H.; Niedballa, U. Angew. Chem., Int. Ed. Engl. 1970, 9,
a
]
þ17.3 (c 1.0, CHCl3); IR (KBr):
y
D
€
461e462; (b) Vorbruggen, H.; Ruh-Pohlenz, C. J. Org. Chem. 1974, 39,
€
3654e3660; (c) Vorbruggen, H.; Ruh-Pohlenz, C. J. Org. Chem. 1974, 39,
€
NMR (400 MHz, CDCl3):
d
4.61 (dd, J¼4.2, 12.2 Hz, 1H, H5),
3660e3663; (d) Vorbruggen, H.; Ruh-Pohlenz, C. J. Org. Chem. 1974, 39,
4.81e4.71 (m, 2H, H4; H50), 6.07 (dd, J¼7.0, 4.8 Hz, 1H, H3), 6.18 (dd,
J¼4.8, 2.7 Hz, 1H, H2), 6.70 (d, J¼2.7 Hz, 1H, H1), 7.30e7.61 (m, 12H,
ArH), 7.82 (s, 1H, ArH), 7.90 (d, J¼7.2 Hz, 2H, ArH), 8.04e8.14 (m,
€
3664e3667; (e) Vorbruggen, H.; Ruh-Pohlenz, C. J. Org. Chem. 1974, 39,
€
3668e3671; (f) Vorbruggen, H.; Ruh-Pohlenz, C. J. Org. Chem. 1974, 39,
3672e3674.
8. (a) Kappe, C. O.; Falsone, S. F. Synlett 1998, 718e720; (b) Kappe, C. O. Acc. Chem.
Res. 2000, 879e888 For synthesis of 4,6-diphenyl-3,4-dihydropyrimidin-2(1H)-
one: see; (c) Sabri, S. S.; Hussein, A. Q.; Al-Hajjar, F. H. J. Chem. Eng. Data 1985,
30, 512e514.
9. (a) Hayashi, M. Chem. Rec. 2008, 8, 252e267; (b) Okunaga, K.; Nomura, Y.;
Kawamura, K.; Nakamichi, N.; Eda, K.; Hayashi, M. Heterocycles 2008, 76,
715e726.
10. Hayashi, M.; Hashimoto, S.; Noyori, R. Chem. Lett. 1984, 1747e1750.
11. (a) Klebe, J. F. Acc. Chem. Res. 1970, 3, 299e305; (b) Sell, T. B.; Nair, V. Tetrahedron
1994, 50, 117e138.
12. Zeng, Y.; Ning, J.; Kong, F. Tetrahedron Lett. 2002, 43, 3729e3733.
13. (a) Shimizu, B.; Miyaki, M. Tetrahedron Lett. 1968, 7, 855e859; (b) Beranek, J.;
Hrebabecky, H. Nucleic Acids Res. 1976, 3, 1387e1399; (c) Azuma, T.; Isono, K.
Chem. Pharm. Bull. 1977, 25, 3347e3353.
11H, ArH); 13C NMR (100.6 MHz, CDCl3):
d 63.90, 71.88, 79.62, 86.11,
95.26, 108.9, 127.2, 128.3, 128.4, 128.5, 128.82, 128.88, 129.0, 129.2,
129.6,129.7,129.8,129.9,131.1, 133.1, 133.4, 133.5, 136.4,165.0,165.1,
165.2, 166.3, 169.9; HRMS [ESIþ]: m/z calcd for C42H32N2O9S:
731.1828 [MþNa]þ. Found: 731.1825.
Acknowledgements
This work was supported by a Grant-in-Aid (No. B23350043)
for Scientific Research on Innovative Areas ‘Molecular Activation