Chemical modification of the sugar moiety of pyrimidine nucleosides VIA a 4′,5′-epoxyuridine intermediate

Article abstract of DOI:10.3987/COM-05-10551

The reaction of 4′,5′-unsaturated nucleoside (5) with m-CPBA provided different products depending on the solvent. 4′,5′-Epoxynucleoside (6) was generated as a key intermediate although 6 was not stable enough to isolate and further reaction progressed. W

Full text of DOI:10.3987/COM-05-10551

HETEROCYCLES, Vol. 65, No. 12, 2005
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HETEROCYCLES, Vol. 65, No. 12, 2005, pp. 2991 - 2999
Received, 1st September, 2005, Accepted, 13th October, 2005, Published online, 14th October, 2005
CHEMICAL MODIFICATION OF THE SUGAR MOIETY OF
PYRIMIDINE NUCLEOSIDES VIA A 4',5'-EPOXYURIDINE
INTERMEDIATE
Hideki Takasu,† Hironao Sajiki,‡* and Kosaku Hirota‡*
†Medicinal Chemistry Research Institute, Otsuka Pharmaceutical Co., Ltd.,
‡
463-10 Kagasuno, Kawauchi, Tokushima 771-0192, Laboratory of Medicinal
Chemistry, Gifu Pharmaceutical University, 5-6-1 Mitahora-higashi, Gifu
502-8585, Japan, E-mail: sajiki@gifu-pu.ac.jp
Abstract – The reaction of 4',5'-unsaturated nucleoside (5) with m-CPBA
provided different products depending on the solvent. 4',5'-Epoxynucleoside (6)
was generated as a key intermediate although 6 was not stable enough to isolate
and further reaction progressed. When the reaction was performed in CH2Cl2,
2,4'-cyclonucleoside (7) and 4'-ketonucleoside (8) were obtained. On the other
hand, 4'-alkoxy derivatives (9 and 11) together with their epimers (10 and 12)
were aquired as a mixture by the nucleophilic attack of alcohol.
INTRODUCTION
Nucleosides modified in the sugar moiety have been recognized as attractive synthetic targets for the
development of potential antiviral and antitumor agents.1 Recently, 4'-substituted nucleosides (1) have
received much attention because of the discovery of potent anti-HIV agents such as 4'-azidothymidine
(1a)2 and 4'-cyanothymidine (1b).3 The modification of the 4'-position of the sugar moiety using
4',5'-unsaturated derivatives (2) was reported previously.2,4,5 In these cases, 4'-substituted 5'-halogeno
derivatives (3)2,4 were key intermediates and it is quite important to transform the 5'-halogen to the OH
group, because the 5'-hydroxy group of nucleosides is supposed to be important for their biological
activities. We considered that 4',5'-epoxynucleosides (4)2,5 are very useful intermediates for the synthesis
B
B
B
B
X
HO
O
O
B : pyrimidine derivatives
X : halogen
O
O
O
R
R
HO
HO
HO
(1a) B = thymine R = N3
(1b) B = thymine R = CN
HO
1
4
2
3

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HETEROCYCLES, Vol. 65, No. 12, 2005
of 4'-substituted nucleosides (1). Here, we report the synthesis of 4'-alkoxyuridine derivatives via
4',5'-epoxyuridine starting from the 4',5'-unsaturated uridine derivative (5).6
RESULTS AND DISCUSSION
The oxidation reaction of 4',5'-didehydro-5'-deoxy-2',3'-O-isopropylideneuridine (5) using m-CPBA in
CH2Cl2 at room temperature was completed within 30 min and gave unexpected
2,4'-didehydro-(2,3-O-isopropylidene-α-L-lyxosyl)uracil (7) and 1-[4-(2,3-O-isopropylidene-β-D-
erythrolactonyl)]uracil (8) in 30 and 18% yields, respectively, together with uracil formed by the glycosyl
bond cleavage under acidic conditions (Scheme 1). A plausible reaction mechanism of the conversion of
5 into 7 and 8 via 4',5'-epoxy compound (6) is shown in Scheme 2. It was assumed that the anticipated
4',5'-epoxy intermediate (6) was obtained by the reaction of 5 with m-CPBA. The subsequent
ring-opening of the epoxide by the nucleophilic attack of the oxygen atom at the 2-position of the uracil
ring gave the corresponding 2,4'-cyclo compound (7) (path a). On the other hand, 4'-keto compound (8)
was generated by the nucleophilic attack of another m-CPBA to 4',5'-epoxy compound (6) or 2,4'-cyclo
compound (7) (path b). The 4'-keto compound (8) was not stable and the formation of uracil by the
acid-catalyzed (silica gel) hydrolytic cleavage of the glycosyl bond proceeded during the two-dimensional
development of TLC analysis.
U
U
m-CPBA
O
O
O
CH Cl
2
2
O
O
O
O
6
5
O
N
O
m-CPBA
U
O
CH Cl
O
N
2
2
O
O
HO
O
O
O
7 (30%)
8 (18%)
Scheme 1
1
To confirm the formation of intermediary 6, the reaction of 5 with m-CPBA was followed by H NMR
spectrum in CDCl3. Consequently, the complete conversion of the starting material (5) was observed
1
within 30 min and the formation of the expected epoxide (6) was confirmed by H NMR spectrum5a,7
although 6 decomposed gradually in the NMR tube. Therefore, the epoxide (6) is quite labile under the
acidic reaction conditions2 and it is extremely difficult to isolate.

HETEROCYCLES, Vol. 65, No. 12, 2005
2993
O
N
O
O
N
O
H
O O
HN
H
N
N
O
R
O
N
O
O
O
O
O
m-CPBA
CH Cl
a
a
O
O
2
2
HO
O
O
b
O
O
H O
O
O
5
6
7
R
b
b
O
O
HN
HN
O
N
O
N
O
O
O
O
H
O
O
O O
O
O
O
R
8
Scheme 2
Next, we examined the epoxidation reaction of 5 in MeOH, as a solvent and a nucleophile.8 As the result,
the 4'-methoxy derivative (9) and its epimer (10) were obtained as a mixture (Scheme 3). The use of
EtOH instead of MeOH as a solvent gave the corresponding 4'-ethoxy derivative (11) and its epimer (12).
The ratio of α- to β-isomer was roughly 1:1.
U
U
U
HO
RO
RO
O
O
O
m-CPBA
HO
ROH
O
O
O
O
O
O
5
9 (47%)*
11 (47%)
10 (42%)*
12 (37%)
R = Me
R = Et
*not isolated
Scheme 3
The mixture of 9 and 10 was not separable. To isolate each isomer (9 and 10), the purified mixture was at
first protected at the 5'-position as the trityl ether and benzoic acid ester while the corresponding 5'-O-Bz
and 5'-O-Tr derivatives were also not separable. On the other hand, when the mixture of 9 and 10 was
converted to the 5'-O-DMTr(4,4'-dimethoxytrityl) derivatives (13 and 14), the separation of 13 and 14
could be achieved easily by silica gel column chromatography in 45 and 39% isolated yields based upon
the original starting material (5), respectively (Scheme 4). The stereochemistry of these compounds was
1
determined by H NMR and NOE5a spectral analysis in CDCl3. The 5-H resonance of 13 appeared at a
significantly higher field (δ 5.34 ppm) compared with that of 14 (δ 5.70 ppm) due to the anisotropic effect
of the benzene ring of β-5'-O-DMTr group reported by Haraguchi et al.9 (Figure. 1).

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HETEROCYCLES, Vol. 65, No. 12, 2005
U
O
U
O
MeO
U
O
DMTrO
DMTr-Cl
U
O
HO
O
O
MeO
O
O
DMTrO
MeO
MeO
HO
pyridine
O
O
O
O
9 + 10 (mixture)
13 (45%)
14 (39%)
Scheme 4
1
1
O
N
H NMR
H NMR
O
H
δ 5.70 ppm
δ 5.34 ppm
H
NH
NH
NOE 3.6%
O
H
MeO
N
O
O
DMTrO
O
O
H
NOE 1.2%
MeO
H
H
DMTrO
O
O
O
NOE 5.1%
14
13
Figure 1
Concomitantly, the 5'-O-DMTr group of 13 was cleaved by 80% AcOH and a 90% yield of
1
2',3'-O-isopropyliden-4'-methoxyuridine (9) was isolated and its H NMR spectral data was consistent
with the data of 9 in the crude mixture together with 10 (Scheme 3).
Next, we investigated deprotection of the 2',3'-O-isopropylidene group of 12. The deprotection reaction
was carried out at 50 °C in 80% AcOH although the yield of 15 was not satisfactory (12%) because of the
formation of uracil arising from the acid-catalyzed cleavage of the glycosyl bond.
The epoxidation reaction of 4',5'-didehydro-5'-deoxy-2',3'-O-isopropylideneuridine (5) afforded different
products depending on the kind of solvent used. The reaction of 5 with m-CPBA in CH2Cl2 solvent
afforded 2,4'-cyclonucleoside derivative (7) and 4'-ketonucleoside derivative (8). On the other hand, the
reaction of 5 with m-CPBA in an alcohol solvent afforded 4'-alkoxide derivatives (9), (10), (11) and (12).
EXPERIMENTAL
1H and 13C NMR spectra were recorded on a JEOL EX 400 spectrometer or a JEOL GX 270 spectrometer
(1H: 400 or 270 MHz, 13C: 100 MHz). Chemical shifts (δ) are given in ppm relative to residual solvent or
tetramethylsilane as an internal standard. Low and high-resolution MS spectra were taken on a JEOL
JMS-SX 102 or JMS-D300 machine. Melting points were determined on a Yanagimoto micro melting
point apparatus and were uncorrected. IR spectra were recorded on a Perkin Elmer model 1600 FT-IR
spectrophotometer. All reagents were commercially available and used without further purification.
Compounds known in the literature were characterized by comparison of their 1H NMR spectral data with
the previously reported data.
1-(2,3-Isopropylidene-5-deoxy-β-D-erythro-pent-4-enofuranosyl)uracil (5)6

HETEROCYCLES, Vol. 65, No. 12, 2005
2995
To a stirred solution of 2',3'-isopropylidene-5'-O-tosyluridine6 (5.7 g, 13 mmol) in dry THF (10 mL) was
added t-BuOK (4.5 g, 40 mmol) at rt under argon atmosphere. The reaction mixture was stirred for 30
min at rt and the solvent was evaporated in vacuo. The residue was subjected to silica gel column
chromatography (CHCl3 : MeOH = 200 : 1) to give 5 (3.0 g, 87%) as a white foam.
IR (KBr) νmax/cm-1: 1688, 1459, 1381, 1222 and 1071. MS (EI) m/z: 266 (M+, 13%), 155 (S+, 4%), 113
(B++2, 14%). 1H NMR (DMSO-d6) δ: 11.42 (1H, br s, N3-H), 7.71 (1H, d, J=7.8 Hz, 6-H), 5.89 (1H, br s,
1'-H), 5.62 (1H, d, J=7.8 Hz, 5-H), 5.24 (1H, d, J=6.1 Hz, 3'-H), 5.10 (1H, d, J=6.1 Hz, 2'-H), 4.36 (1H,
br s, 5'-Ha), 4.18 (1H, br s, 5'-Hb), 1.39 (3H, s, 2',3'-O-isopropylidene-CH3), 1.30 (3H, s,
2',3'-O-isopropylidene-CH3). 13C NMR (DMSO-d6) δ: 163.37 (4-C and 4'-C) 150.29 (2-C), 143.96 (6-C),
112.43 (2',3'-O-isopropylidene), 101.62 (5-C), 95.22 (1'-C), 84.95 (5'-C), 82.06 (2'-C), 79.48 (3'-C), 26.46
(2',3'-O-isopropylidene-CH3). HRMS (FAB+) m/z Calcd for C12H15N2O5 (M++1): 267.0981. Found:
267.0992.
2,4'-Didehydro-(2,3-O-isopropylidene-α-L-lyxosyl)uracil (7) and 1-[4-(2,3-O-isopropylidene-β-D-
erythrolactonyl)]uracil (8)
To a stirred solution of 5 (133 mg, 0.5 mmol) in dry CH2Cl2 (10 mL) was added m-CPBA (65%, 172 mg,
0.65 mmol) at rt under argon atmosphere. The reaction mixture was stirred for 30 min at rt. The
precipitate was collected to give 7 (42 mg, 30%). The filtrate was evaporated in vacuo and the residue
was subjected to silica gel column chromatography (CHCl3 : MeOH = 80 : 1) to afford 8 (24 mg, 18%) as
a pale yellow oil.
1
7: mp: 171 °C (CH2Cl2). MS (EI) m/z: 267 (M+-CH3, 12%), 113 (100%). H NMR (DMSO-d6) δ: 7.71
(1H, d, J=7.3 Hz, 6-H), 6.21 (1H, s, 1'-H), 5.93 (1H, d, J=7.3 Hz, 5-H), 5.57 (1H, t, J=6.4 Hz, 5'-OH),
5.08 (1H, d, J=5.4 Hz, 2'-H), 4.95 (1H, d, J=5.4 Hz, 3'-H), 3.94 (1H, dd, J=6.4 and 12.7 Hz, 5'-Ha), 3.87
(1H, dd, J=6.4 and 12.7 Hz, 5'-Hb), 1.45 (3H, s, 2',3'-O-isopropylidene-CH3), 1.26 (3H, s,
2',3'-O-isopropylidene-CH3). Anal. Calcd for C12H14N2O6: C, 51.07; H, 5.00; N, 9.92. Found: C, 50.80; H,
4.96; N, 9.82.
8: IR (KBr) νmax/cm-1: 1807(lactone), 1698, 1459, 1386, 1280 and 1064. MS (EI) m/z: 253 (M+-CH3,
1
30%), 113 (B++2, 31%). H NMR (CDCl3) δ: 9.21 (1H, br s, N3-H), 7.24 (1H, d, J=8.3 Hz, 6-H), 5.82
(1H, d, J=8.3 Hz, 5-H), 5.55 (1H, s, 1'-H), 5.20 (1H, d, J=6.1 Hz, 2'-H), 5.06 (1H, d, J=6.1 Hz, 3'-H), 1.51
(3H, s, 2',3'-O-isopropylidene-CH3), 1.45 (3H, s, 2',3'-O-isopropylidene-CH3). 13C NMR (CDCl3) δ:
171.84 (4'-C), 162.79 (4-C), 150.17 (2-C), 143.40 (6-C), 114.93 (2',3'-O-isopropylidene-C(CH3)), 103.55
(5-C), 93.53 (1'-C), 80.15 (3'-C), 76.25 (2'-C), 26.29 (2',3'-O-isopropylidene-CH3), 25.08
(2',3'-O-isopropylidene-CH3). HRMS (FAB+) m/z Calcd for C11H13N2O6 (M++1): 269.0774. Found:
269.0780.
5'-Deoxy-4',5'-epoxy-2',3'-O-isopropylideneuridine (6)

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The solution of 5 (13 mg, 0.05 mmol) and m-CPBA (65%, 17 mg, 0.065 mmol) in CDCl3 (0.7 mL) was
allowed to stand at rt under argon atmosphere in the NMR tube. The mixture was monitored periodically
1
by measuring the H NMR spectrum. After 30 min, the disappearance of the starting material (5) and
1
formation of expected (6) were detected by the H NMR spectrum although 6 decomposed gradually
under the same conditions.
1H NMR (CDCl3) δ: 9.50 (1H, br s, N3-H), 7.42 (1H, d, J=7.9 Hz, 6-H), 5.81 (1H, s, 1'-H), 5.80 (1H, d,
J=7.9 Hz, 5-H), 5.16 (1H, d, J=6.0 Hz, 2'-H), 4.87 (1H, d, J=6.0 Hz, 3'-H), 3.29 (1H, d, J=3.5 Hz, 5'-Ha),
3.15 (1H, d, J=3.5 Hz, 5'-Ha), 1.56 (3H, s, 2',3'-O-isopropylidene-CH3), 1.38(3H, s,
2',3'-O-isopropylidene -CH3).
2',3'-O-Isopropyliden-4'-methoxyuridine
(9)
and
1-(2,3-O-isopropylidene-4-methoxy-α-L-
lyxofuranosyl)uracil (10)
To a stirred solution of 5 (2.66 g, 10 mmol) in dry MeOH (50 mL) was added m-CPBA (65%, 4.31 g,
16.3 mmol) at rt under argon atmosphere. The reaction mixture was stirred for 24 h and the mixture was
concentrated in vacuo. The residue was subjected to silica gel column chromatography (CHCl3 : MeOH =
200 : 1) to afford 9 (1.55 g, 49%) and 10 (1.33 g, 43%) as a mixture. Yields were estimated by the
integration ratios of the 1H NMR spectra of the mixture.
1
9: H NMR (CDCl3) δ: 9.09 (1H, br s, N3-H), 7.43 (1H, d, J=8.3 Hz, 6-H), 5.77 (1H, d, J=8.3 Hz, 5-H),
5.70 (1H, d, J=2.4 Hz, 1'-H), 5.13 (1H, d, J=6.8 Hz, 3'-H), 5.03 (1H, dd, J=2.4 and 6.8 Hz, 2''-H),
3.78-3.93 (2H, m, 5'-H x 2), 3.46 (3H, s, 4'-OCH3), 1.62 (3H, s, 2',3'-O-isopropylidene-CH3), 1.37 (3H, s,
2',3'-O-isopropylidene-CH3).
10: 1H NMR (CDCl3) δ: 8.87 (1H, br s, N3-H), 7.32 (1H, d, J=8.3 Hz, 6-H), 6.36 (1H, br s, 1'-H), 5.77
(1H, d, J=8.3 Hz, 5-H), 4.98 (1H, d, J=5.9 Hz, 2'-H), 4.75 (1H, d, J=5.9 Hz, 3'-H), 3.78-3.93 (2H, m, 5'-H
x
2), 3.28 (3H, s, 4'-OCH3), 1.58 (3H, s, 2',3'-O-isopropylidene-CH3), 1.37 (3H, s,
2',3'-O-isopropylidene-CH3).
2',3'-O-Isopropyliden-4'-ethoxyuridine
lyxofuranosyl)uracil (12)
(11)
and
1-(2,3-O-isopropylidene-4-ethoxy-α-L-
To a stirred solution of 5 (133 mg, 0.5 mmol) in dry EtOH (50 mL) was added m-CPBA (65%, 130 mg,
0.49 mmol) at rt under argon atmosphere. The reaction mixture was stirred for 15 h and the mixture was
concentrated in vacuo. The residue was subjected to silica gel column chromatography (CHCl3 : MeOH =
100 : 1) to give 12 (60 mg, 37%) as the first fraction (white foam) and 11 (77 mg, 47%) as the second
fraction (white foam).
1
11: MS (EI) m/z: 313 (M+-CH3, 14%), 217 (S+, 4%), 138 (100%). H NMR (CDCl3) δ: 9.65 (1H, br s,
N3-H), 7.38 (1H, d, J=7.8 Hz, 6-H), 5.78 (1H, d, J=7.8 Hz, 5-H), 5.75 (1H, d, J=2.4 Hz, 1'-H), 5.12 (1H,
d, J=6.8 Hz, 3'-H), 4.98 (1H, dd, J=6.8 and 2.4 Hz, 2'-H), 3.45-3.85 (4H, m, 4'-OCH2CH3 and 5'-H x 2),

HETEROCYCLES, Vol. 65, No. 12, 2005
2997
2.87 (1H, br s, 5'-OH), 1.63 (3H, s, 2',3'-O-isopropylidene-CH3), 1.37 (3H, s, 2',3'-O-isopropylidene-CH3),
1.18-1.29 (3H, m, 4'-OCH2CH3). Anal. Calcd for C14H20N2O7: C, 51.21; H, 6.14; N, 8.53. Found: C,
51.05; H, 6.25; N, 8.32.
1
12: MS (EI) m/z: 313 (M+-CH3, 5%), 217 (S+, 9%), 112 (B+-1, 44%), 59(100%). H NMR (CDCl3) δ:
9.40 (1H, br s, N3-H), 7.49 (1H, d, J=8.1 Hz, 6-H), 6.34 (1H, d, J=1.5 Hz, 1'-H), 5.78 (1H, d, J=8.1 Hz,
5-H), 4.98 (1H, dd, J=6.3 and 1.5 Hz, 2'-H), 4.77 (1H, d, J=6.3 Hz, 3'-H), 3.83-3.95 (2H, m,
4'-OCH2CH3), 3.64-3.75 (1H, m, 5'-Ha), 3.45-3.56 (1H, m, 5'-Hb), 2.27 (1H, br s, 5'-OH), 1.58 (3H, s,
2',3'-O-isopropylidene-CH3), 1.36 (3H, s, 2',3'-O-isopropylidene-CH3), 1.18 (3H, t, J=6.8 Hz,
4'-OCH2CH3). HRMS (FAB+) m/z Calcd for C14H21N2O7 (M++1): 329.1348. Found: 329.1353.
5'-O-(4,4'-Dimethoxytrityl)-2',3'-O-isopropyliden-4'-methoxyuridine
(13)
and
1-[5-O-(4,4'-
dimethoxytrityl)-2,3-O-isopropylidene-4-methoxy-α-L-lyxofuranosyl]uracil (14)
To a stirred solution of a mixture of 9 and 10 (314 mg, 1.0 mmol; 9 : 10 = 9 : 8) in dry pyridine (5 mL)
was added DMTr-Cl(4,4'-dimethoxytrityl chloride) (508 mg, 1.5 mmol) at rt under argon atmosphere.
The reaction mixture was stirred for 9 h and the mixture was concentrated in vacuo and remaining
pyridine was removed as a toluene azeotrope. The residue was partitioned between CHCl3 and sat.
NaHCO3. The organic layer was washed with water and dried over MgSO4. The solvent was evaporated
in vacuo and the residue was subjected to silica gel column chromatography (CHCl3 : MeOH = 100 : 1) to
afford 13 (275 mg, 45%) as the first fraction (white foam) and 14 (243 mg, 39%) as the second fraction
(white foam).
13: IR (KBr) νmax/cm-1: 1693, 1508, 1458, 1380, 1249 and 1087. MS (EI) m/z: 616 (M+, 2%), 303
(DMTr+, 100%). 1H NMR (CDCl3) δ: 8.72 (1H, br s, N3-H), 7.63 (1H, d, J=8.1 Hz, 6-H), 7.23-7.36 (9H,
m, DMTr-H), 6.82-6.85 (4H, m, DMTr-H), 6.22 (1H, d, J=2.4 Hz, 1'-H), 5.34 (1H, d, J=8.1 Hz, 5-H),
5.10 (1H, d, J=6.8 Hz, 3'-H), 4.75 (1H, dd, J=6.8 and 2.4 Hz, 2'-H), 3.80 (6H, s, DMTr-OCH3), 3.56 (1H,
d, J=9.8 Hz, 5'-Ha), 3.36 (1H, d, J=9.8 Hz, 5'-Hb), 3.31 (3H, s, 4'-OCH3), 1.61 (3H, s,
2',3'-O-isopropylidene-CH3), 1.38 (3H, s, 2',3'-O-isopropylidene-CH3). 13C NMR (CDCl3) δ: 162.69 (4-C),
158.78 (DMTr-C), 149.83 (2-C), 144.04 (DMTr-C), 140.42 (6-C), 134.91 (DMTr-C), 130.21 (DMTr-C),
130.17 (DMTr-C), 128.20 (DMTr-C), 128.02 (DMTr-C), 127.25 (DMTr-C), 116.26 (DMTr-C), 113.31
(DMTr-C), 106.33 (2',3'-O-isopropylidene), 102.94 (5-C), 88.77 (1'-C), 87.36 (4'-C), 84.67 (2'-C), 80.85
(3'-C), 62.87 (5'-C), 55.27 (DMTr-OCH3), 50.62 (4'-OCH3), 25.99 (2',3'-O-isopropylidene-CH3), 25.88
(2',3'-O-isopropylidene-CH3). HRMS (EI) m/z Calcd for C34H36N2O9 (M+): 616.2421. Found: 616.2414.
14: IR (KBr) νmax/cm-1: 1690, 1508, 1458, 1380, 1250 and 1099. MS (EI) m/z: 616 (M+, 2%), 303
(DMTr+, 100%). 1H NMR (CDCl3) δ: 8.68 (1H, br s, N3-H), 7.56 (1H, d, J=7.8 Hz, 6-H), 7.20-7.45 (9H,
m, DMTr-H), 6.80-6.83 (4H, m, DMTr-H), 6.24 (1H, d, J=1.5 Hz, 1'-H), 5.70 (1H, d, J=7.8 Hz, 5-H),
4.98 (1H, dd, J=5.4 and 1.5 Hz, 2'-H), 4.88 (1H, d, J=5.4 Hz, 3'-H), 3.79 (6H, s, DMTr-OCH3), 3.56 (1H,

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HETEROCYCLES, Vol. 65, No. 12, 2005
d, J=10.3 Hz, 5'-Ha), 3.17 (1H, d, J=10.3 Hz, 5'-Hb), 2.86 (3H, s, 4'-OCH3), 1.50 (3H, s,
2',3'-O-isopropylidene-CH3), 1.42 (3H, s, 2',3'-O-isopropylidene-CH3). 13C NMR (CDCl3) δ: 162.53 (4-C),
158.58 (DMTr-C), 158.54 (DMTr-C), 150.60 (2-C), 144.35 (DMTr-C), 140.76 (6-C), 135.66 (DMTr-C),
135.19 (DMTr-C), 130.38 (DMTr-C), 130.21 (DMTr-C), 128.29 (DMTr-C), 128.71 (DMTr-C), 126.86
(DMTr-C), 113.92 (DMTr-C), 112.97 (DMTr-C), 112.07 (2',3'-O-isopropylidene), 102.65 (5-C), 91.28
(1'-C), 86.14 (4'-C), 84.77 (2'-C), 83.72 (3'-C), 57.55 (5'-C), 55.21 (DMTr-OCH3), 48.56 (4'-OCH3),
26.06 (2',3'-O-isopropylidene-CH3), 25.42 (2',3'-O-isopropylidene-CH3). HRMS (EI) m/z Calcd for
C34H36N2O9 (M+): 616.2421. Found: 616.2410.
2',3'-O-Isopropyliden-4'-methoxyuridine (9)
13 (50 mg, 0.05 mmol) was dissolved in 80% AcOH (10 mL) and the mixture was stirred for 9 h at rt
under argon atmosphere. The reaction mixture was concentrated in vacuo and remaining AcOH was
removed as a toluene azeotrope. The residue was subjected to silica gel column chromatography (CHCl3 :
MeOH = 50 : 1) to afford 9 (23 mg, 90%) as a pale yellow oil.
1
MS (EI) m/z: 299 (M+-CH3, 18%), 203 (S+, 6%), 138 (100%), 113 (B++2, 29%). H NMR (CDCl3) δ:
9.56 (1H, br s, N3-H), 7.35 (1H, d, J=7.8 Hz, 6-H), 5.78 (1H, d, J=7.8 Hz, 5-H), 5.73 (1H, d, J=2.4 Hz,
1'-H), 5.12 (1H, d, J=6.8 Hz, 3'-H), 5.02 (1H, dd, J=6.8 and 2.4 Hz, 2'-H), 3.76-3.85 (2H, m, 5'-H x 2),
3.46 (3H, s, 4'-OCH3), 1.62 (3H, s, 2',3'-O-isopropylidene-CH3), 1.37 (3H, s, 2',3'-O-isopropylidene-CH3).
13C NMR (CDCl3) δ: 163.27 (4-C), 150.21 (2-C), 142.71 (6-C), 115.95 (2',3'-O-isopropylidene), 107.14
(4'-C), 102.93 (5-C), 93.64 (1'-C), 83.55 (2'-C), 81.24 (3'-C), 62.37 (5'-C), 50.48 (4'-OCH3), 26.05
(2',3'-O-isopropylidene-CH3), 25.55 (2',3'-O-isopropylidene-CH3). HRMS (FAB+) m/z Calcd for
C13H19N2O7 (M++1): 315.1192. Found: 315.1185.
1-(4-Ethoxy-α-L-lyxofuranosyl)uracil (15)
12 (210 mg, 0.61 mmol) was dissolved in 80% AcOH (10 mL) and the mixture was stirred at 50 °C for 30
h under argon atmosphere. The reaction mixture was concentrated in vacuo and remaining AcOH was
removed as a toluene azeotrope. The residue was subjected to silica gel column chromatography (CHCl3 :
MeOH = 15 : 1) to afford 15 (23 mg, 12%) as a white foam.
1H NMR (DMSO-d6) δ: 11.37 (1H, br s, N3-H), 7.35 (1H, d, J=8.2 Hz, 6-H), 6.00 (1H, d, J=7.3 Hz, 1'-H),
5.80 (1H, d, J=8.2 Hz, 5-H), 5.41-5.43 (2H, m, 2'-OH and 3'-OH), 4.67 (1H, t, J=5.6 Hz, 5'-OH),
4.37-4.43 (1H, m, 2'-H), 3.82 (1H, d, J=4.5 Hz, 3'-H), 3.39-3.71 (4H, m, 4'-OCH2CH3 and 5'-H x 2), 1.15
(3H, t, J=7.0 Hz, 4'-OCH2CH3). HRMS (FAB+) m/z Calcd for C11H17N2O7 (M++1): 289.1036. Found:
289.1046.
REFERENCES AND NOTES
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