Synthesis of 4-O-methyl-protected 5-(2-hydroxyethyl)-2'-deoxyuridine derivatives and their nucleophilic fluorination to 5-(2-fluoroethyl)-2'- deoxyuridine

Article abstract of DOI:10.1055/s-1999-3641

The novel pyrimidine base, 5-(2-hydroxyethyl)-4-methoxypyrimidin-2(1H)- one (7) was prepared from the pyrimidine derivative 2 via a three step synthesis in 72% yield. Glycosylation of 7 with an α-chlorosugar provided the 4-O-methyl-protected pyrimidine nucleoside 8 in 78% yield with a β:α ratio ranging from 1.5:1 to 2:1. A complete cleavage of the 4-methoxy group of alcohol 8 was achieved using NaI and trimethylsilyl chloride. The synthesis of 14, an analog of 8, was also possible by using N,O- bis(trimethylsilyl)trifluoroacetimide as silylating reagent and 3,5-di-O-p- chlorobenzoyl-2-deoxy-α-D-erythro-pentofuranosyl chloride as the sugar moiety. A slightly improved ratio of β/α (>2:1) and a yield of 54% of 14 was obtained. The two key precursors for nucleophilic fluorination, the tosylate 9 and triflate 10, were obtained in 87 and 17% yield, respectively. NOE results of 10β and 10α indicated that H-1' of the deoxyribosyl residue interacted strongly with one of the two protons on C-8 of the 5-ethyl side chain. This interaction was even stronger than that between H-1' and H-2'. The unusual downfield chemical shift of C-1' in ¹³C NMR can not be explained by the structure shown in Scheme 3. Nucleophilic fluorination of the tosylate 9α under phase transfer catalyzed conditions provided the fluorinated product 11α (5%), the base-induced elimination product 12α (24%), and unexpectedly the chloro-substituted product 13α (26%).

Full text of DOI:10.1055/s-1999-3641

PAPER
2057
Synthesis of 4-O-Methyl-Protected 5-(2-Hydroxyethyl)-2´-deoxyuridine
Derivatives and their Nucleophilic Fluorination to 5-(2-Fluoroethyl)-2´-
deoxyuridine
Chung-Shan Yu,1 Franz Oberdorfer*
EUROPET GmbH, PET-Zentrum im Klinikum der Albert-Ludwigs-Universität, Hugstetter Strasse 55, D-79106 Freiburg, Germany
Fax +49(761)2709200, E-mail: Franz.Oberdorfer@t-online.de
Received 18 January 1999; revised 7 July 1999
5-(2-Fluoroethyl)-2'-deoxyuridine (1, FEDU) was first re-
ported by Griengl et al.6 The synthesis of 1 starting from
γ-butyrolactone consisted of a ten-step procedure. First 5-
(2-fluoroethyl)uracil was prepared7,6 and then converted
Abstract: The novel pyrimidine base, 5-(2-hydroxyethyl)-4-meth-
oxypyrimidin-2(1H)-one (7) was prepared from the pyrimidine de-
rivative 2 via a three step synthesis in 72% yield. Glycosylation of
7 with an a-chlorosugar provided the 4-O-methyl-protected pyrim-
idine nucleoside 8 in 78% yield with a b:a ratio ranging from 1.5:1 into 1 via glycosylation with the a-chlorosugar, 3,5-di-O-
p-toluoyl-2-deoxy-a-D-erythro-pentofuranosyl chloride.8
to 2:1. A complete cleavage of the 4-methoxy group of alcohol 8
was achieved using NaI and trimethylsilyl chloride. The synthesis
FEDU (1) was obtained in an overall yield of 5% based on
of 14, an analog of 8, was also possible by using N,O-bis(trimethyl-
the γ-butyrolactone.
silyl)trifluoroacetimide as silylating reagent and 3,5-di-O-p-chlo-
robenzoyl-2-deoxy-a-D-erythro-pentofuranosyl chloride as the
sugar moiety. A slightly improved ratio of b/a (>2:1) and a yield of
54% of 14 was obtained. The two key precursors for nucleophilic
O
F
fluorination, the tosylate 9 and triflate 10, were obtained in 87 and
17% yield, respectively. NOE results of 10b and 10a indicated that
H-1’ of the deoxyribosyl residue interacted strongly with one of the
two protons on C-8 of the 5-ethyl side chain. This interaction was
even stronger than that between H-1’ and H-2’. The unusual down-
field chemical shift of C-1’ in 13C NMR can not be explained by the
structure shown in Scheme 3. Nucleophilic fluorination of the tosyl-
ate 9a under phase transfer catalyzed conditions provided the flu-
orinated product 11a (5%), the base-induced elimination product
12a (24%), and unexpectedly the chloro-substituted product 13a
(26%).
NH
N
O
HO
O
OH
1
We did not follow this synthetic route since the 4-oxo
group competitively attacks the C-8 position during the
nucleophilic fluorination. Wong et al.9 and Prystaš10 re-
ported a selective dealkylation of the 2-methoxy group of
2,4-dimethoxypyrimidine in non-aqueous acid. We used
this procedure after protecting the 5-(2-hydroxyethyl)
group of 2 using acetic anhydride in pyridine (Scheme 1).
The acetyl-protected 2,4-dimethoxypyrimidine 3 was
then reacted with acetyl chloride for 20 hours in order to
obtain 4. After column chromatography on silica gel, two
fractions were identified. First fraction was 5-(2-acetoxy-
ethyl)-4-methoxypyrimidin-2(1H)-one (5), the second
one being 5-(2-acetoxyethyl)uracil (6). The chemical shift
of C-4 and C-2 of 5 in 13C NMR spectrum was 170.73
Key words: 5-(2-hydroxyethyl) pyrimidine nucleosides, tosylates,
triflates, NOE, phase transfer catalyzed nucleophilic fluorination
The “suicide” gene therapy is one of the most promising
approaches in cancer therapy.2 The suicide gene is insert-
ed into tumor cells in situ, followed by initiation of the
suicide mechanism.3 Herpes simplex virus type 1 thymi-
dine kinase (HSV-1 TK) is the most intensively studied
suicide gene.4 HSV-1 TK can activate prodrugs5 such as a
nucleoside analog, which we report in this work, to form
toxic drugs that may kill the cell.
OCH3
N
OCH3
N
O
OCH3
OCH3
AcO
AcO
AcO
AcO
HO
b
a
NH
N
N
N
N
+
+
N
Ac
O
N
H
O
N
H
O
OCH3
OCH3
2
3
4
6
5
c
Reagents and conditions: (a) Ac2O/pyridine, r.t., 1 h, 90% (b) acetyl chloride, r.t., 20 h (c) chromatography on silica gel, 5: 80%, 6: ~5%
Scheme 1
Synthesis 1999, No. 12, 2057–2064 ISSN 0039-7881 © Thieme Stuttgart · New York

2058
C.-S. Yu, F. Oberdorfer
PAPER
Table 1 13C NMR Data (62.90 MHz, CDCl3/TMS, d) of the Carbon Atoms in Pyrimidine Bases and Nucleosidesa
Product
C-2
C-4
C-5
C-6
C-7
C-8
C-1´
C-2´
C-3´
C-4´
C-5´
3
164.41
159.62
156.63
155.57
155.64
155.50
155.26
155.36
156.31
156.22
155.49
155.55
154.94
155.50
169.29
170.73
170.37
170.52
170.68
170.54
169.78
170.00
170.16
170.13
170.26
170.38
169.43
170.31
110.93
104.88
103.25
105.72
104.60
105.86
103.23
102.31
119.03
119.38
104.06
103.15
106.91
103.94
157.67
142.77
143.87
139.90
140.74
139.84
140.76
141.24
158.46
158.50
140.33
140.89
138.94
140.96
26.06
26.07
29.24
29.81
29.97
29.75
26.82
26.97
26.91
27.07
27.92
28.01
127.11
30.44
62.53
62.33
59.46
60.96
61.14
60.76
67.70
67.81
65.41
65.01
81.40
81.59
114.66
42.64
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
5
7b
8bc
8ac
14b
9b
83.50
85.83
83.12
83.46
85.62
104.63
104.14
83.48
85.76
85.76
85.70
39.15
38.86
38.88
39.04
38.87
39.23
39.27
39.22
38.91
39.06
38.84
75.16
75.03
75.38
75.09
74.87
75.31
74.54
75.17
74.94
74.74
75.00
87.07
89.19
87.10
86.88
88.94
82.24
81.40
87.00
89.15
89.24
89.06
64.31
64.10
64.52
64.08
64.07
64.98
64.18
64.19
64.07
64.03
64.03
9a
10b
10a
11bd
11ac,e
12a
13a
a Protecting groups are exempted.
b Recorded in DMSO-d6.
c Recorded at 125.76 MHz.
d 13C-19F coupling constants: 3J5,F = 6.1 Hz (d), 2J7,F = 21.6 Hz (d), 1J8,F = 168.7 Hz (d).
e 13C-19F coupling constants: 3J5,F = 5.5 Hz (d), 2J7,F = 21.3 Hz (d), 1J8,F = 168.4 Hz (d).
ppm and 159.62 ppm, respectively (Tables 1 and 2). This found the presence of chlorine in 7. It is assumed that 7
corresponded to reported data11 (169.35 ppm for C-4 of 4- formed an adduct with HCl.
methoxypyrimidine; 159.25 ppm for C-2 of 2-hydroxypy-
The silylation of compound 7 was tried under the usual
rimidine) . We did not isolate the other product, 5-(2-ace-
conditions, i.e. hexamethyldisilazane (HMDS), and a
toxyethyl)-1-acetyl-4-methoxypyrimidin-2-one
(4),
trace amount of trimethylsilyl chloride (TMSCl) under re-
flux. Such a relatively harsh condition probably would
cleave the 4-methoxy group of the pyrimidine base 7. We
indeed observed a white precipitate [supposed to be 5-(2-
hydroxyethyl)uracil] during heating, instead of the ex-
which was not stable during column chromatography. The
enhanced basicity of 4 allowed a proton-mediated
deacetylation of N-1. Compound 5 was obtained in 80%
yield.
Finally deprotection of the 5-(2-acetoxyethyl) group in 5 pected homogeneous solution. Therefore, a milder silyla-
delivered 5-(2-hydroxyethyl)-4-methoxypyrimidin- tion method with N,O-bis-trimethylsilylacetimid (BSA)
2(1H)-one (7) in quantitative yield (Scheme 2) which was was applied and silylation was complete within 10 min-
the expected 4-O-protected pyrimidine base meeting the utes. The a-chlorosugar was then added. Again, in the el-
requirements for condensation with an a-chlorosugar to emental analyses we found the presence of chlorine in
yield the b,a-nucleoside 8. From elemental analysis, we both the b- and a-anomer of 8. This contamination was as-
OCH3
OCH3
RO
RO
OCH3
N
N
N
N
N
HO
b, c
a
O
O
5
+
OTol
TolO
N
H
O
O
O
7
TolO
OTol
8α
9α
R = H
8β R = H
9β R = Ts
10β R = Tf
d
d
O
e
e
R = Ts
Tol =
H3C
C
10α R = Tf
Reagents and conditions: (a) NaOMe/MeOH, r.t., 1 h, HCl/Et2O, quantitative, (b) BSA/CHCl3, r.t., 10 min; (c) 3,5-di-O-p-toluoyl-2-deoxy-a-
D-erythro-pentofuranosyl chloride, 1 h, 78%, b/a = 1.5:1~2:1; (d) p-toluenesulfonyl chloride/pyridine, 4°C, 20 h, 87%; (e) (CF3SO2)2O/pyri-
dine/CH2Cl2, 0°C, 1 h, 17%
Scheme 2
Synthesis 1999, No. 12, 2057–2064 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of 4-O-Methyl-Protected 5-(2-Hydroxyethyl)-2’-deoxyuridine Derivatives
2059
sumed to arise from not identified chlorosilyl compounds ing observations. The H-1’ exhibited an unusual upfield
formed by the reaction of the silylating reagent (BSA) chemical shift at 5.30 ppm as compared to 6.0–6.5 ppm
with the chloride ion. The impurity could not be removed for “normal” nucleosides. On the other hand, the C-1’car-
completely by column chromatography. The 4-O-methyl- bon resonance was shifted downfield from the normal val-
protected nucleoside 8 finally was transformed into tosy- ue of 84 to 104 ppm. The triflates were further analysed
late 9 and triflate 10 in 87 and 17% yields, respectively.
with steady-state 1H-NOE difference experiments (Table
3). The H-1’ proton was found to have an unexpected in-
teraction with one of the methylene protons at C-8 (Fig-
ure). The NOE values are 6.6 and 4.3% for 10b and 10a,
For the b-anomeric and a-anomeric triflates 10b, 10a, in-
spection of 1H and 13C NMR spectra led to some interest-
Table 2 13C NMR Data of the Carbon Atoms in Protecting Groups Present in Pyrimidine Bases and Nucleosides
Product
13C NMR (62.90 MHz, CDCl3/TMS)
δ
3
20.67 (COCH3), 53.76 (2-OCH3), 54.49 (4-OCH3), 170.70 (COCH3)
20.76 (COCH3), 54.49 (4-OCH3), 171.47 (COCH3)
53.43 (4-OCH3)
5
7a
8bb
21.69 (arom-CH3), 21.72 (arom-CH3), 53.69 (4-OCH3), 126.37 (C-CH3, arom), 126.62 (C-CH3, arom), 129.28 (CH,
arom), 129.41(CH, arom), 129.60 (CH, arom), 129.88 (CH, arom), 144.51 (C-CO, arom), 166.20 (arom-CO), 166.23
(arom-CO)
8ab
21.62 (arom-CH3), 21.72 (arom-CH3), 54.72 (4-OCH3), 126.30 (C-CH3, arom), 126.61 (C-CH3, arom), 129.17 (CH,
arom), 129.35 (CH, arom), 129.57 (CH, arom), 129.72 (CH, arom), 144.27 (C-CO, arom), 144.55 (C-CO, arom), 165.58
(arom-CO), 166.17 (arom-CO)
14b
9b
54.73 (4-OCH3), 127.43 (C-Cl, arom), 127.70 (C-Cl, arom), 128.94 (CH, arom), 129.02 (CH, arom), 130.92 (CH, arom),
131.18 (CH, arom), 140.27 (C-CO, arom), 165.21 (arom-CO), 165.34 (arom-CO)
21.60 (arom-CH3), 21.68 (arom-CH3), 54.58 (4-OCH3), 126.33 (C-CH3, arom), 126.54 (C-CH3, arom), 127.68 (CH,
arom), 129.23 (CH, arom), 129.42 (CH, arom), 129.48 (CH, arom), 129.72 (CH, arom), 129.83 (CH, arom), 132.82 (C-
CH3, arom), 144.43 (C-CO, arom), 144.46 (C-CO, arom), 144.99 (C-SO, arom), 165.95 (arom-CO), 166.07 (arom-CO)
9a
21.62 (arom-CH3), 21.69 (arom-CH3), 54.69 (4-OCH3), 126.22 (C-CH3, arom), 126.60 (C-CH3, arom), 127.69 (CH,
arom), 129.16 (CH, arom), 129.36 (CH, arom), 129.51 (CH, arom), 129.73 (CH, arom), 129.77 (CH, arom), 132.80 (C-
CH3, arom), 144.26 (C-CO, arom), 144.58 (C-CO, arom), 145.11 (C-SO, arom), 165.45 (arom-CO), 166.16 (arom-CO)
10bc
10ad
11b
11ab
12a
13a
21.63 (arom-CH3), 21.67 (arom-CH3), 55.15 (4-OCH3), 118 (CF3), 126.81 (C-CH3, arom), 127.11 (C-CH3, arom), 129.10
(CH, arom), 129.14 (CH, arom), 129.70 (CH, arom), 129.76 (CH, arom), 143.86 (C-CO, arom), 144.10 (C-CO, arom),
166.11 (arom-CO), 166.20 (arom-CO)
21.63 (arom-CH3), 55.17 (4-OCH3), 118 (CF3), 126.86 (C-CH3, arom), 127.02 (C-CH3, arom), 129.11 (CH, arom), 129.15
(CH, arom), 129.65 (CH, arom), 129.69 (CH, arom), 143.84 (C-CO, arom), 144.09 (C-CO, arom), 166.21 (arom-CO),
166.39 (arom-CO)
21.66 (arom-CH3), 21.71 (arom-CH3), 54.75 (4-O-CH3), 126.36 (C-CH3, arom), 126.59 (C-CH3, arom), 129.26 (CH,
arom), 129.36 (CH, arom), 129.38 (CH, arom), 129.46 (CH, arom), 129.52 (CH, arom), 144.40 (C-CO, arom), 144.49
(C-CO, arom), 165.06 (arom-CO), 166.16 (arom-CO)
21.67 (arom-CH3), 54.75 (4-OCH3), 126.24 (C-CH3, arom), 126.57 (C-CH3, arom), 129.10 (CH, arom), 129.33 (CH,
arom), 129.55 (CH, arom), 129.69 (CH, arom), 144.24 (C-CO, arom), 144.44 (C-CO, arom), 165.60 (arom-CO), 166.13
(arom-CO)
21.68 (arom-CH3), 54.77 (4-OCH3), 126.06 (C-CH3, arom), 126.52 (C-CH3, arom), 129.23 (CH, arom), 129.34 (CH,
arom), 129.54 (CH, arom), 129.70 (CH, arom), 144.28 (C-CO, arom), 144.43 (C-CO, arom), 165.50 (arom-CO), 166.12
(arom-CO)
21.66 (arom-CH3), 54.75 (4-OCH3), 126.23 (C-CH3, arom), 126.55 (CCH3, arom), 129.12 (CH, arom), 129.32 (CH,
arom), 129.51 (CH, arom), 129.67 (CH, arom), 144.23 (C-CO, arom), 144.52 (C-CO, arom), 165.60 (arom-CO), 166.10
(arom-CO)
a Recorded in DMSO-d6.
b Recorded at 125.76 MHz.
c 13C-19F coupling constant: 1JC,F = 320.8 Hz (q).
d 13C-19F coupling constant: 1JC,F = 320.2 Hz (q).
Synthesis 1999, No. 12, 2057–2064 ISSN 0039-7881 © Thieme Stuttgart · New York

2060
C.-S. Yu, F. Oberdorfer
PAPER
respectively. The unusual downfield chemical shift of we still found some unexpected results when treating the
C-1’ in 13C NMR can not be explained by the structure tosylate 9a with KF/Kryptofix[2.2.2] as shown in Scheme
shown in the Figure.
3. In addition to the fluorinated product 11a and the base-
induced elimination product 12a, the chloro-substituted
nucleoside 13a was also formed. We reexamined the pro-
cedure for the preparation of the precursor tosylate 9a.
Apparently the contaminating chlorosilyl compounds in
our starting material 8a are the source of chloride for this
side-reaction. Compounds 11a and 13a were not resolved
by column chromatography. The approximate yields of
compounds 11a and 13a were therefore estimated by
TLC.
OCH3
OCH3
8
F3CO2SO
8
F3CO2SO
7
N
H
7
N
N
Ha Hb
Ha Hb
OTol
N
O
O
Ha
TolO
Hb
O
2´
1´
1´
2´
O
H
Hb
TolO
OTol
Ha
6.6%
4.3%
Relatively few references were available concerning the
cleavage of the O-alkyl group from a pyrimidine, e.g. 2,4-
dibenzyloxypyrimidine.12 Neither acids such as HCl and
CF3CO2H13, nor cationic exchange resins (H+)14 were
practical in our case to hydrolyse the 4-methoxy group of
pyrimidine nucleosides. Hydrolysis proceeded either in-
completely or glycosidic bonds were also cleaved. Trime-
thylsilyl iodide (TMSI) was demonstrated as a mild and
4.0%
6.8%
10β
10α
Figure 1H-NOE results between H-1’ and H-8a
The contamination with chlorosilyl compounds in 8b,a
did not seriously interfere with the next reaction step but
OCH3
H
OCH3
OCH3
F
H
Cl
N
N
N
N
N
H
N
O
9α
O
+
+
O
OTol
OTol
OTol
O
O
O
TolO
TolO
TolO
11α
12α
13α
Reagents and conditions: KF/Kryptofix[2.2.2]/MeCN, 85°C, 72 h, 11a: 5% (approximate yield), 12a: 24%, 13a: 26% (approximate yield)
Scheme 3
Table 3 NOE Results (%)a
Effected
Protons
Irradiated Protons
10b
10a
H-1’
H-8a
H-8b
H-7a,b
H-1’
H-8a
H-7a,b
H-6
H-4’
0.6b
0.8
1.5
-
24.3
-
2.4 (2H)
-
-
1.4
-
-
25.0
5.0 (2H)
-
-
9.9c
0.7
8.5
5.4
-
-
-
0.8
1.8
0.3b
-
1.6
4.3b
-
4.0
0.4
-
0.5
-
25.5
-
3.9 (2H)
-
-
8.1
-
8.5c
-
9.1
8.3
-
-
-
1.5
1.8
H-8b
H-8a
H-7a,b
H-2’b
H-2’a
H-1’
0.5
6.6b
0.6
6.8
-
10.4
1.4
1.4
-
OCH3
-
-
a Protons H-1’, H-8a, H-8b (10b) and H-7a,b were irradiated individually. The irradiated protons induce a Nuclear Overhauser Effect (NOE)
on nearby protons (distance < 5 Å). The NOE is expressed as the % change in the observed proton integral and is approximately proportional
to r-6. For example, in the case of 10b, the geminal protons H-8a,b gave the largest observed NOE (ca. 25%), and H-1’gave an NOE of 6.8%
with H-2’a (cis relationship) but only 0.6% with H-2’b (trans relationship).
b The very small NOE between H-1’ and H-6 is consistent with an anti conformation of the pyrimidine ring. The suprisingly large NOE between
H-1’ and H-8a can not be explained by the structure shown in the Figure.
c The significant NOE between H-7a,b and H-6 is consistent with their proximity.
Synthesis 1999, No. 12, 2057–2064 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of 4-O-Methyl-Protected 5-(2-Hydroxyethyl)-2’-deoxyuridine Derivatives
2061
efficient cleaving reagent.12,15 NaI and TMSCl in acetoni-
trile has been used as alternative to TMSI as the sole agent
and we observed a complete cleavage of the 4-methoxy
group of 8b,a within 1 minute (yield: 90%).
weight equivalents of silica gel to the amount of the crude product;
yield: 4.0 g (80%). Byproduct 6 (approximate yield ~5%) was con-
firmed by comparison of the Rf value (TLC, MeOH/CHCl3 1:19)
with the reference sample.7a
Optimization of the synthesis of 8 was achieved when
the more volatile silylating reagent N,O-bistrimethyl-
silyltrifluoroacetimide (BSTFA)16 and crystallized 3,5-
di-O-p-chlorobenzoyl-2-deoxy-a-D-erythro-pentofurano-
syl chloride17 were used. Compound 14b was obtained
pure as colourless needles with satisfactory elemental
analyses and 1H and 13C NMR spectra free from signals of
contaminating products.
5-(2-Hydroxyethyl)-4-methoxypyrimidin-2(1H)-one (7):
Compound 5 (1.2 g, 5.65 mmol) was dissolved in methanol (80 ml)
with stirring at rt. NaOMe/MeOH (20 ml, 11.4 mmol, 2 eq) was
added. The stirring was continued for 1 h. Product 7 (Rf = 0.22) was
formed as observed by TLC (MeOH/CHCl3 1:9). The Rf value of
educt 5 was 0.81. After completion of the reaction, the pH of the so-
lution was slowly adjusted to neutral with 1M HCl/ether. The sol-
vent was evaporated under vacuum (4 mbar). The residue was
chromatographed with MeOH/CHCl3 1:9 to give product 7 in quan-
titative yield (0.960 g, 5.64 mmol).
TLC was carried out with Polygram Sil G/UV 254 plates of Mach-
ery and Nagel, Düren. Spots were developed by applying molyb-
datophosphoric acid (5% in EtOH). Column chromatography was
performed on silica gel 60 (40–63 µm), Merck, Darmstadt, with a
flow rate ranging from 2–4 mL/min under atmospheric pressure.
Chemicals were purchased from Aldrich. CHCl3 and CH2Cl2 were
dried by passing down a column filled with Al2O3 (neutral). MeCN
was of DNA-synthesis grade from Merck-Schuchardt. Melting
points were determined with a Büchi 535 apparatus and are not cor-
rected. Elemental analysis was performed at the Max Planck Institut
für Medizinische Forschung in Heidelberg. Electron ionizaion mass
spectra (EI-MS) and high resolution mass spectra (HRMS) were re-
corded on a Varian MAT 711 device. Electrospray ionization mass
spectra (ESI-MS) were carried out with a Finnigan TSQ 7000 triple-
quadrupole system. HRMS (FAB) were carried out at Institute of
Organic Chemistry, University of Heidelberg. 1H NMR, 13C NMR
(DEPT-135), and 19F NMR were recorded on a Bruker AC-250 or
AM-500 spectrometer in the Central Department of Spectroscopy
of the German Cancer Research Center (DKFZ). 13C NMR data
of pyrimidine bases and nucleosides are presented in Table 1, data
of protecting groups and functional groups in Table 2. 1H and
19F NMR data and physical data of the compounds prepared are
given in Tables 4–6.
1-(3,5-Di-O-p-toluoyl-2-deoxy-b,a-D-erythro-pentofuranosyl)-5-
(2-hydroxyethyl)-4-methoxypyrimidin-2-ones (8b,a)
To a stirred solution of 7 (250 mg, 1.47 mmol) in anhyd CHCl3 (15
mL) under exclusion of moisture was added BSA (741 mg, 3.64
mmol). The mixture was stirred until a clear solution appeared
(about 10 min). 3,5-Di-O-p-toluoyl-2-deoxy-a-D-erythro-pento-
furanosyl chloride (890 mg, 2.29 mmol)8 and TMSOTf (40 µL, 0.2
mmol) were added sequentially. The colourless solution turned to
pale yellow. The reaction was complete after 1 h. CHCl3 (40 mL)
was added and the mixture was extracted with aq satd NaHCO3 so-
lution (130 mL) and the aqueous layer further extracted with CHCl3
(60 mL). The combined organic extracts were washed with H2O (20
mL), dried (MgSO4), filtered and the filtrate was concentrated under
reduced pressure at 40°C. The residue (ca 1.8 g) was chromato-
graphed (acetone/hexane, 1:1, column: 4.5 î 24 cm, silica gel: 190
g) to give 8b (95 mg, 0.18 mmol) and a mixture of 8b,a (500 mg,
0.96 mmol). The mixture was rechromatographed under the same
conditions (acetone/hexane, 1:1). Total yield of 8: 78% with a ratio
of b/a = 2:1.
1-(3,5-Di-O-p-chlorobenzoyl-2-deoxy-b-D-erythro-pentofurano-
syl)-5-(2-hydroxyethyl)-4-methoxypyrimidin-2-one (14b)
To a stirred solution of 7 (10 mg, 0.059 mmol) in anhyd CHCl3 (0.5
mL) was added BSTFA (99 mg, 0.38 mmol) at r.t. under exclusion
of mositure and the stirring was continued for 10 min. No clear so-
lution was obtained. 3,5-Di-O-p-chlorobenzoyl-2-deoxy-a-D-eryth-
ro-pentofuranosyl chloride17 (51 mg, 0.118 mmol) and TMSOTf (2
µL, 0.012 mmol) were added sequentially and the stirring was con-
tinued for 1 h. The workup and chromatography (acetone/hexane,
1:1) were carried out under the same conditions used for 8. Products
14b (10 mg, 0.017 mmol), 14a (3 mg, 0.005 mmol) and a mixture
of 14b,a (5 mg, 0.009 mmol) were obtained. The proportion of
product 14b,a (> 2:1) could be roughly determined by TLC (ace-
tone/hexane, 1:1). Total yield of 14: 54%.
5-(2-Acetoxyethyl)-2,4-dimethoxypyrimidine (3)
To a stirred solution of 2 (4.9 g, 26.6 mmol)6 in pyridine (25 mL)
was added Ac2O (15 mL) at r.t. and the stirring was continued for 1
h. After completion of the reaction (TLC monitoring: product 3, Rf
0.68; starting material 2, Rf 0.32; solvent: acetone/toluene, 1:1),
CHCl3 (3 mL) was added. The solvent was evaporated at 40°C un-
der vacuum, and the evaporation was continued overnight until no
odour of AcOH was detectable (4 mbar); yield: 5.36 g (90%).
5-(2-Acetoxyethyl)-4-methoxypyrimidin-2(1H)-one (5)
A 100 mL round-bottomed two-necked flask, dried at 110°C in an
oven for 24 h, was flushed with dry N2 at r.t. To this flask was added
compound 3 (5.36 g, 23.69 mmol) and commercial fresh AcCl (50
g, 637 mmol) with stirring. The reaction was continued for ~ 20 h.
A small amount (about 5 µL) of the aliquot was taken after 10 h and
coevaporated with toluene (0.2 mL) at 35°C under reduced presure
and used as reference for TLC (MeOH/CHCl3, 1:19). The product 5
(Rf 0.30) was observed but the amount was low, although 3 (Rf 0.79)
was almost consumed. The intermediate 4 (Rf 0.58) was assumed to
be the major product. The best reaction time was 20 h. A longer re-
action time or traces of moisture increased the amount of the hydro-
lyzed product 5-(2-acetoxyethyl)uracil (6) (Rf 0.21).7a After the
reaction was complete, the solvent was evaporated at 35°C under
vacuum (4 mbar) and coevaporated twice by addition of toluene (2
î 4 mL). The residue was chromatographed using MeOH/CHCl3
(1:19) as eluent. During this step, the intermediate 4 was deacetylat-
ed to form the polar product 5. Pure 5 was obtained by using 200
1-(3,5-Di-O-p-toluoyl-2-deoxy-b,a-D-erythro-pentofuranosyl)-5-
(2-p-toluenesulfonyloxyethyl)-4-methoxypyrimidin-2-ones
(9b,a)
A stirred solution of a mixture of 8b,a (553 mg, 1.06 mmol) in py-
ridine (5 mL) at r.t. was cooled to 0°C in an ice-bath. To this solu-
tion was added p-toluenesulfonyl chloride (243 mg, 1.27 mmol)
and the stirring was continued at 0°C for 10 min. The mixture was
then placed in a refrigerator at 4°C for 20 h. The proceeding of the
reaction was monitored by TLC (acetone/hexane, 2:3; starting ma-
terials 8b and 8a, Rf 0.31 and 0.26 and products 9b and 9a, 0.48 and
0.42). After completion of the reaction, the mixture was concentrat-
ed at 35°C under vacuum (4 mbar). The residue was chromato-
graphed using acetone/hexane (1:1) as eluent to give 9b (225 mg,
0.33 mmol), 9a (280 mg, 0.41 mmol) and a mixture of 9b,a (120
mg, 0.18 mmol) in 87% total yield. The 9b,a mixture was rechro-
matographed under the same conditions (acetone/hexane, 1:1).
Synthesis 1999, No. 12, 2057–2064 ISSN 0039-7881 © Thieme Stuttgart · New York

2062
C.-S. Yu, F. Oberdorfer
PAPER
Table 4 1H NMR Data of Pyrimidine Bases and Nucleosides
Prod-
uct
1H NMR (250 MHz, CDCl3/TMS)
δ, J (Hz)
3
1.94 (s, 3 H, COCH3), 2.72 (t , 2 H, J7,8 = 6.7, H-7), 3.90 (s, 3 H, OCH3), 3.92 (s, 3 H, OCH3), 4.15 (t, 2 H, J8,7 = 6.7, H-8), 7.95
(s, 1 H, H-6)
5
2.00 (s, 3 H, COCH3), 2.69 (t, 2 H, J7,8 = 6.4, H-7), 4.02 (s, 3 H, OCH3), 4.19 (t, 2 H, J8,7 = 6.4, H-8), 7.44 (s, 1 H, H-6), 12.74
(br s, 1 H, NH)
7a
8b
2.39 (t, 2 H, J7,8 = 6.6, H-7), 2.7–3.9 (br s, 1 H, OH),b 3.45 (t, 2 H, J8,7 = 6.6, H-8), 3.80 (s, 3 H, OCH3), 7.46 (s, 1 H, H-6), 8.49
(br s, 1 H, NH)
1.45 (t, 1 H, JOH,8 = 5.6, OH), 2.24 (ddd, 1 H, J2´a,2´b = 15.8, J2´a,1´ = 8.2, J2´a,3´ = 6.7, H-2’a), 2.37 (t, 2 H, J7,8 = 6.2, H-7), 2.42 (s,
3 H, arom-CH3), 2.44 (s, 3 H, arom-CH3), 3.00 (dd, 1 H, J2´b,2´a = 15.8, J2´b,1´ = 5.4, H-2'b), 3.57–3.61 (m, 2 H, H-8), 3.96 (3 H, s,
OCH3), 4.60–4.61 (m, 1 H, H-4'), 4.66 (dd, 1 H, J5´a,5´b = 12.0, J5´a,4´ = 4.1, H-5’a), 4.78 (dd, 1 H, J5´b,5´a = 12.0, J5´b,4´ = 2.9,
H-5’b), 5.60 (d, 1 H, J = 6.5, H-3’), 6.45 (dd, 1 H, J1´,2´a = 8.2, J1´,2´b = 5.4, H-1'), 7.23–7.29 (m, 4 Harom), 7.68 (s, 1 H, H-6), 7.87–
7.98 (m, 4 Harom
)
8a
1.56 (br s, 1 H, OH), 2.40 (s, 3 H, arom-CH3), 2.43 (s, 3 H, arom-CH3), 2.46–2.63 (m, 2 H, H-7), 2.70 (dd, 1 H, J2´a,2´b = 15.5,
J
2´a,1´ = 1.3, H-2’a), 2.96 (ddd, 1 H, J2´b,2´a = 15.5, J2´b,1´ = 6.7, J2´b,3´ = 6.2, H-2'b), 3.57–3.66 (m, 2 H, H-8), 4.02 (s, 3 H, OCH3),
4.55–4.57 (m, 2 H, H-5'), 4.89 (t, 1 H, J = 4.0, H-4'), 5.57 (d, 1 H, J = 6.2, H-3'), 6.33 (dd, 1 H, J1´, 2´b = 6.7, J1´, 2´a = 1.3, H-1’),
7.16–7.30 (m, 4 Harom), 7.30–7.69 (m, 2 Harom), 7.70 (s, 1 H, H-6), 7.87–7.98 (m, 2 Harom
)
14b
9b
1.73 (br s, 1 H, OH), 2.26 (ddd, 1 H, J2´a,2´b = 14.8, J2´a,1´ = 8.2, J2´a,3´ = 6.7, H-2’a), 2.45 (t, 2 H, J7,8 = 6.3, H-7), 2.99 (ddd, 1 H,
2´b,2´a = 14.8, J2´b,1´ = 5.6, J2´b,3´ = 1.6, H-2'b), 3.64–3.70 (m, 2 H, H-8), 3.97 (s, 3H, OCH3), 4.57–4.60 (td, 1 H, J4´,5´a = 4.0, J4´,5´b
= 4.0, J4´,3´ = 1.8, H-4’), 4.71 (dd, 2 H, J5´a,5´b = 12.1, J5´,4´ = 4.0, H-5’), 5.57 (ddd, 1 H, J3´,2´a = 6.7, J3´, 4´ = 1.8, J3´,2´b =1.6, H-3’),
6.41 (dd, 1 H, J1´, 2´a = 8.2, J1´, 2´b = 5.6, H-1'), 7.40–7.48 (m, 4 Harom), 7.68 (s, 1 H, H-6), 7.91–8.03 (m, 4 Harom
J
)
2.23 (ddd, 1 H, J2´a,2´b = 14.4, J2´a,1´ = 8.4, J2´a,3´ = 6.6, H-2'a), 2.40–2.44 (m, 2 H, H-7), 2.41(s, 3 H, arom-CH3), 2.43(s, 3 H, arom-
CH3), 2.44(s, 3 H, arom-CH3), 2.95 (ddd, 1 H, J2´b,2´a = 14.4, J2´b,1´ = 5.5, J2´b,3´ = 1.5, H-2’b), 3.96 (s, 3 H, OCH3), 4.01 (t, 2 H,
J
8,7 = 6.4, H-8), 4.57–4.62 (m, 1 H, H-4'), 4.65 (dd, 1 H, J5´a,5´b = 12.0, J5´a,4´ = 4.0, H-5’a), 4.78 (dd, 1 H, J5´b,5´a = 12.0, J5´b,4´
3.0, H-5'b), 5.58–5.61 (m, 1 H, H-3'), 6.42 (dd, 1 H, J1´, 2´a = 8.4, J1´, 2´b = 5.5, H-1'), 7.22–7.31 (m, 6 Harom), 7.59 (s, 1 H, H-6),
7.64–7.67 (m, 2 Harom), 7.87–7.98 (m, 4 Harom
=
)
9a
2.39 (s, 3 H, arom-CH3), 2.44 (s, 6 H, arom-CH3), 2.49-2.71 (m, 3 H, H-2'a + H-7), 2.98 (dt, 1 H, J2´b,2´a = 15.8, J2´b,1´ = 6.5, J2´b,3´
= 6.5, H-2’b), 3.91 (s, 3 H, OCH3), 4.07 (t, 2 H, J8,7 = 6.1, H-8), 4.56 (d, 2 H, J = 4.6, H-5’), 4.91 (t, 1 H, J = 4.0, H-4’), 5.57 (d,
1 H, J = 6.1, H-3’), 6.30 (dd, 1 H, J1´, 2´b = 6.5, J1´,2´a = 1.4, H-1'), 7.14–7.17 (m, 2 Harom), 7.25–7.30 (m, 4 Harom), 7.61–7.67 (m, 5
H
arom + H-6), 7.94–7.97 (m, 2 Harom
)
10b
2.33 (ddd, 1 H, J2´a,2´b = 14.2, J2´a,1´ = 5.4, J2´a,3´ = 4.8, H-2’a), 2.40 (s, 3 H, arom-CH3), 2.41 (s, 3 H, arom-CH3), 2.52 (ddd, 1 H,
J
2´b,2´a = 14.2, J2´b,3´ = 7.1, J2´b,1´ = 2.6, H-2'b), 2.72–2.79 (m, 2 H, H-7), 3.56 (ddd, 1 H, J8a,8b = 9.5, J8a,7a = 7.3, J8a,7b = 6.3, H-8a),
3.93 (ddd, 1 H, J8b,8a = 9.5, J8b,7b = 6.4, J8b,7a = 6.1, H-8b), 3.99 (s, 3 H, OCH3), 4.42 (dd, 1 H, J5´a,5´b = 12.4, J5´a,4´ = 7.7, H-5’a),
4.50 (ddd, 1 H, J4´,5´a = 7.7, J4´,5´b = 4.6, J4´,3´ = 2.8, H-4’), 4.52 (dd, 1 H, J5´b, 5´a= 12.4, J5´b,4´ = 4.6, H-5’b), 5.30 (dd, 1 H, J1´,2´a
=
5.4, J1´,2´b = 2.6, H-1’), 5.56 (ddd, 1 H, J3´,2´b = 7.1, J3´,2´a = 4.8, J3´,4´ = 2.8, H-3'), 7.20–7.27 (m, 4 Harom), 7.83-7.98 (m, 4 Harom),
8.14 (s, 1 H, H-6)
10a
11b
2.17 (d, 1 H, J2´a,2´b = 14.6, H-2’a), 2.40 (s, 3 H, arom-CH3), 2.42 (s, 3 H, arom-CH3), 2.51 (ddd, 1 H, J2´b,2´a = 14.6, J2´b,3´ = 8.0,
J
2´b,1´ = 5.4, H-2’b), 2.84 (t, 2 H, J7, 8a = 6.1, J7, 8b = 6.1, H-7), 3.68 (dt, 1H, J8a,8b = 9.9, J8a,7 = 6.1, H-8a), 3.97 (dt, 1H, J8b,8a = 9.9,
J8b,7 = 6.1, H-8b), 4.02 (s, 3H, OCH3), 4.43 (ddd, 1H, J4´,5´a = 4.3, J4´,5´b = 3.6, J4´,3´ = 3.5 Hz, H-4’), 4.48 (dd, 1 H, J5´a,5´b = 11.7,
5´a,4´ = 4.3 Hz, H-5’a), 4.59 (dd, 1H, J5´b, 5´a= 11.7 Hz, J5´b,4´ = 3.6 Hz, H-5’b), 5.27 (d, 1H, J = 4.6, H-1’), 5.39 (ddd, 1H, J3´,2´b
8.0, J3´,4´ = 3.5 Hz, J3´,2´a = 2.0, H-3’), 7.20-7.26 (m, 4Harom), 7.89-7.92 (m, 4Harom), 8.29 (s, 1H, H-6)
J
=
2.24 (ddd, 1 H, J2´a,2´b = 15.8, J2´a,1´ = 8.4, J2´a,3´ = 6.6, H-2’a), 2.41 (s, 3 H, arom-CH3), 2.44 (s, 3 H, arom-CH3), 2.51 (dt, 2 H, J7,F
= 23.2, J7,8 = 6.2, H-7), 2.98 (ddd, 1 H, J2´b,2´a = 15.8, J2´b,1´ = 5.5, J2´b,3´ = 1.4, H-2’b), 3.97 (s, 3 H, OCH3), 4.10–4.50 (m, 2 H, H-
8), 4.55–4.60 (m, 1 H, H-4'), 4.65 (dd, 1 H, J5´a,5´b = 12.1, J5´a,4´ = 3.7 Hz, H-5´a), 4.78 (dd, 1 H, J5´b,5´a = 12.1, J5´b,4´ = 3.0, H-
5’b), 5.60 (d, 1 H, J = 6.6, H-3’), 6.45 (dd, 1 H, J1´,2´a = 8.4, J1´,2´b = 5.5, H-1'), 7.22–7.30 (m, 4 Harom), 7.66 (s, 1 H, H-6), 7.86–
7.97 (m, 4 Harom
)
11a
12a
2.40 (s, 3 H, arom-CH3), 2.43 (s, 3 H, arom-CH3), 2.60–2.76 (m, 3 H, H-7 + H-2'a), 2.88–3.04 (m, 1 H, H-2'b), 4.02 (s, 3 H,
OCH3), 4.22–4.53 (m, 2 H, H-8), 4.55 (m, 2 H, H-5´), 4.89 (t, 1 H, J = 4.0, H-4'), 5.58 (d, 1 H, J = 6.2, H-3'), 6.32 (dd, 1 H, J1´,2´b
= 6.7, J1´,2´a = 1.3, H-1'), 7.15–7.18 (m, 2 Harom), 7.25–7.30 (m, 2 Harom), 7.67–7.69 (m, 3 Harom + H-6), 7.92–7.96 (m, 2 Harom
)
2.38 (s, 3 H, arom-CH3), 2.43 (s, 3 H, arom-CH3), 2.64 (d, 1 H, J2´a,2´b = 15.6, H-2’a), 3.00 (ddd, 1 H, J2´b,2´a = 15.6, J2´b,1´ = 6.7,
J
2´b,3´ = 6.4, H-2’b), 4.02 (s, 3 H, OCH3), 4.55 (m, 2 H, H-5’), 4.93 (t, 1 H, J = 4.1, H-4’), 5.13 (dd, 1 H, J8a,7 = 11.3, J8a,8b = 0.9, H-
8a), 5.51 (dd, 1 H, J8b,7 = 17.6, J8b,8a = 0.9, H-8b), 5.64 (d, 1 H, J = 5.9, H-3’), 6.36 (dd, 1 H, J1´,2´b = 6.7, J1´,2´a = 1.4, H-1’), 6.44
(dd, 1 H, J7,8b = 17.6, J7,8a = 11.3, H-7), 7.12–7.29 (m, 4 Harom), 7.64–7.67 (m, 2 Harom), 7.88 (s, 1 H, H-6), 7.93–7.96 (m, 2 Harom
)
13a
2.40 (s, 3 H, arom-CH3), 2.43 (s, 3 H, arom-CH3), 2.61–2.81 (m, 3 H, H-7 + H-2'a), 3.00 (ddd, 1 H, J2´b,2´a = 15.6, J2´b,1´ = 6.7,
J
2´b,3´ = 6.5, H-2'b), 3.36–3.57 (m, 2 H, H-8), 4.02 (s, 3 H, OCH3), 4.56–4.58 (m, 2 H, H-5'), 4.91 (t, 1 H, J = 3.9 Hz, H-4'), 5.57
(d, 1 H, J = 6.2, H-3'), 6.33 (dd, 1 H, J1´,2´b = 6.7, J1´,2´a = 1.3, H-1'), 7.16–7.29 (m, 4 Harom), 7.66–7.70 (m, 3 Harom + H-6), 7.93–
7.96 (m, 2 Harom
)
a DMSO-d6. b The integration of proton (11H) was affected by the presence of HCl.
Synthesis 1999, No. 12, 2057–2064 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of 4-O-Methyl-Protected 5-(2-Hydroxyethyl)-2’-deoxyuridine Derivatives
2063
Table 5 19F NMR Data of Compounds 10 and 11
added (CF3SO2)2O (82 mg, 0.29 mmol) and anhyd CH2Cl2 (1.7 mL)
while stirring and the other was charged with a mixture of 8b,a (150
mg, 0.29 mmol), pyridine (23 mg, 0.29 mmol) and anhyd CH2Cl2
(1.1 mL) while stirring. The solution of 8b,a was then added slowly
to the solution containing (CF3SO2)2O within 3 min via a syringe.
Stirring was continued at 0°C under exclusion of moisture for 1 h.
The reaction was monitored by TLC (acetone/hexane, 1:1; 8b and
8a, Rf 0.32 and 0.27; 10b,a, Rf 0.73). After completion of the reac-
tion, CH2Cl2 (20 mL) was added and the organic layer was washed
with H2O (10 mL), dried (MgSO4) and filtered. The filtrate was con-
centrated under reduced pressure at 30°C and the residue (ca 190
mg) was chromatographed (silica gel: 29 g; EtOAc/hexane, 1:4) to
give 10b (14 mg, 0.021 mmol) and 10a (17 mg, 0.026 mmol) in
17% yield.
Product
19F NMR (235.4, CDCl3/C2F2Cl4)
δ, J (Hz)
10b
10a
11b
11a
2.29 (CF3)
2.22 (CF3)
–141.77 (tt, 2JF,H-8 = 46.8, 3JF,H-7 = 23.2, CFH2)
–141.59 (tt, 2JF,H-8 = 47.0, 3JF,H-7 = 24.6, CFH2)
1-(3,5-Di-O-p-toluoyl-2-deoxy-b,a-D-erythro-pentofuranosyl)-5-
(2-trifluoromethanesulfonyloxyethyl)-4-methoxypyrimidin-2-
ones (10b,a)
Two 10 mL two-necked round-bottomed flasks were cooled to 0°C
in an ice bath and flushed with dry N2. To one of the two flasks was
Table 6 Physical Data of Compounds Pyrimidine Bases and Nucleotides Prepareda
Prod-
uct
Appearance
mp (oC)
ESI + Q1MS
m/z
ESI – Q1MS
m/z
3
5
colourless oil
white solid
-
226 [M]+, 227.1 [M + H]+, 249.0 [M+Na]+
-
119–120
212 [M]+, 213.0 [M + H]+, 235.0 [M + Na]+, 425.1 [2 M + 212 [M-], 211.0 [M – H]- , 247.0
H]+, 447.1 [2 M + Na]+, 463.1 [2 M + K]+
170 [M]+, 171.0 [M + H]+, 192.9 [M + Na]+
522 [M]+, 523.2 [M + H]+, 545.2 [M + Na]+
[M + 35Cl]-, 423.1 [2 M – H]-,
445.1 [2 M – 2 H + Na]-
7
silver-white
fine needles
152.7–153.7
170 [M-], 169.0 [M – H]- , 205.0
[M + 35Cl]-
8b
8a
white foam
white solid
-
522 [M-], 557.2 [M + 35Cl]-
187–189
522 [M]+, 523.2 [M + H]+, 545.2 [M + Na]+, 561.2 [M + K]+, 522 [M-], [M + 35Cl]-
795.8 [3 M + H + Na]2+, 803.5 [3 M + H + K]2+ , 1045.5 [2
M + H]+ , 1067.5 [2 M + Na]+
14bb
9b
white needles
white solid
216–218
71–73
562 [M]+, 562.9 [M + H]+, 584.9 [M + Na]+, 1125.1 [2 M + 562 [M-], 596.8 [M + Cl]-
H]+, 1148.9 [2 M + Na]+
676 [M]+, 677.2 [M + H]+, 699.2 [M + Na]+, 1353.6 [2 M +
H]+, 1376.6 [2 M + Na]+
-
9a
colourless fine 137.0–137.5
needles
676 [M]+, 677.3 [M + H]+, 699.2 [M + Na]+, 1353.7 [2 M +
H]+, 1375.7 [2 M + Na]+
-
10b
10a
11b
11a
12a
13a
colourless
foam
-
654 [M]+, 655.2 [M + H]+, 677.1 [M + Na]+
654 [M-], 689.1 [M + 35Cl]-
654 [M-], 689.1 [M + 35Cl]-
colourless
foam
-
654 [M]+, 655.2 [M + H]+, 677.2 [M + Na]+
pale yellow
crystals
157–158
181.0–182.8
113–115
189–192
524 [M]+, 525.2 [M + H]+, 547.2 [M + Na]+, 563.2 [M + K]+ 524 [M-], 559.1 [M + 35Cl]-
colourless
crystals
524 [M]+, 525.2 [M + H]+, 547.2 [M + Na]+, 1049.4 [2 M +
H]+, 1071.4 [2 M + Na]+
-
-
white solid
504 [M]+, 505.1 [M + H]+, 527.1 [M + Na]+, 1009.4 [2 M +
H]+, 1031.4 [2 M + Na]+
white solid
540 [M]+, 541.2 [M + H]+, 563.1 [M + Na]+, 1081.4 [2 M + 540 [M-], 575.1 [M + 35Cl]-
H]+ , 1103.4 [2 M + Na]+
a Satisfactory microanalyses (C ± 0.16; H ± 0.23; N ± 0.12) or HRMS values (± 0.0191 amu) were obtained.
b Isotope clusters centered at M = 562 amu were observed in the mass spectra. The isotope clusters are in accordance with the proposed formula.
Synthesis 1999, No. 12, 2057–2064 ISSN 0039-7881 © Thieme Stuttgart · New York

2064
C.-S. Yu, F. Oberdorfer
PAPER
1-(3,5-Di-O-p-toluoyl-2-deoxy-a-D-erythro-pentofuranosyl)-5-
(2-fluoroethyl)-4-methoxypyrimidin-2-one (11a), 1-(3,5-Di-O-p-
toluoyl-2-deoxy-a-D-erythro-pentofuranosyl)-5-vinyl-4-meth-
oxypyrimidin-2-one (12a) and 1-(3,5-Di-O-p-toluoyl-2-deoxy-a-
D-erythro-pentofuranosyl)-5-(2-chloroethyl)-4-methoxypyrimi-
din-2-one (13a)
Acknowledgement
We acknowledge gratefully the German Academic Exchange Ser-
vice (DAAD) for providing financial support in the form of a scho-
larship to C-S Yu to carry out the research at the German Cancer
Research Center (DKFZ). We thank Dr. W. E. Hull, Mrs. G. Schwe-
bel-Schilling and Mr. G. Erben who carried out the NMR and mass
spectroscopic analyses and contributed fruitful discussions. We are
particularly grateful to Priv.-Doz. Dr. J. Jens Wolff, Department of
Organic Chemistry, University of Heidelberg, for helpful discussi-
ons.
KF (26 mg, 0.44 mmol) was dried overnight at 120 °C. Then it was
added together with 9a (100 mg, 0.15 mmol) and kryptofix[2.2.2]
(6 mg, 0.015 mmol) to MeCN (3 mL) at r.t. while stirring. The mix-
ture was heated to 85°C and the stirring was continued for 24 h. The
yellow colour of the solution became colourless. According to TLC
(acetone/hexane, 1:1), three products were formed:11a (Rf 0.41),
12a (Rf 0.48) and 13a (Rf 0.43) (1a, Rf 0.38). Another portion of KF
(80 mg, 1.35 mmol) and Kryptofix[2.2.2] (54 mg, 0.135 mmol) was
added, while the colour of the solution turned to pale yellow. Stir-
ring at 85°C was continued for 48 h and then the solvent was evap-
orated under reduced pressure. The residue was chromatographed
using acetone/hexane (1:2) as eluent to give 12a (18 mg, 24%), 13a
(15 mg) and a mixture of 11a/13a (10 mg). Separation of 11a from
the mixture of 11a/13a under the same conditions (silica gel, ace-
tone/hexane, 1:2) failed. The composition of the mixture of 11a/13a
was evaluated by TLC (11a: 4 mg, 13a: 6 mg). Thus, the approxi-
mate yield of 11a and 13a was 5 and 26% (6 and 15 mg), respec-
tively. In the 19F NMR of the mixture of 11a/13a, the typical 19F-
signal and the coupling patterns of the fluorine with H-8 and H-7
were observed (Table 5). The analytical data of compound 11a were
obtained from the reaction of 8b,a with diethylaminosulfur trifluo-
ride (DAST).
References
(1) Permanent address: 3rd. Fl. no. 26 Lane 434, Ankang Road,
11414 Taipei, Taiwan. E-mail:
Yu610202@venus.seed.net.tw.
(2) Haberkorn, U.; Altmann, A.; Morr, I.; Knopf, K.-W.;
Germann, C.; Haeckel, R.; Oberdorfer, F.; Kaick, G. V. J.
Nucl. Med. 1997, 38, 287.
(3) Anderson, W. F. Human Gene Therapy 1994, 5, 1.
(4) Rogulski, K. R.; Kim, J. H.; Kim, S. H.; Freytag, S. O. Human
Gene Therapy 1997, 8, 73.
(5) (a) Tjuvajev, J. G.; Stockhammer, G.; Desai, R.; Uehara, H.;
Watanabe, K.; Gansbacher, B.; Blasberg, R. G. Cancer Res.
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(b) Tjuvajev, J. G.; Finn, R.; Watanabe K.; Joshi, R.; Oku T.;
Kennedy, J.; Beattie, B.; Koutcher, J.; Larson, S.; Blasberg, R.
G. Cancer Res. 1996, 56, 4087.
1-(3,5-Di-O-p-toluoyl-2-deoxy-b-D-erythro-pentofuranosyl)-5-
(2-fluoroethyl)-4-methoxypyrimidin-2-one (11b)
(c) Blasberg, R. G.; Tjuvajev, J. G. Int. Appl. WO 96 28,190,
1995; Chem Abstr 1996, 125, 321864.
(6) Griengl, H.; Wanek, E.; Schwarz, W.; Streicher, W.;
Rosenwirth, B.; De Clercq, E. J. Med. Chem. 1987, 30, 1199.
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1964, 29, 2670.
A mixture of 8b,a (100 mg, 0.19 mmol) was dissolved in dry
CH2Cl2 (1 mL) at rt with stirring and under exclusion of moisture.
The solution was cooled to –20°C. Et3N (106 µL, 0.76 mmol) and
DAST (49 mg, 0.30 mmol) were added sequentially. After 10 min,
the cooling was removed. Stirring was continued at r.t. for 3 h.
CHCl3 (5 mL) was added. The organic layer was extracted with cold
satd aq NaHCO3 solution (2 î 2 mL), washed with H2O (2 mL),
dried (MgSO4) and filtered. The filtrate was concentrated under re-
duced pressure at 40°C. The residue was chromatographed with
EtOAc/CH2Cl2 (1:4) to give 11b (25 mg, 0.048 mmol) and 11a (14
mg, 0.027 mmol) in 39% yield.
(b) Fissekis, J. D.; Sweet, F. J. Org. Chem. 1973, 28, 264.
(c) Chkhikvadze, K. A.; Magidson, O. Y. J. Gen. Chem. USSR
(Engl. Transl.) 1964, 34, 2599.
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Volume The chemistry of Heterocyclic Compounds,
Weissberger, A.; Taylor, E. C., Ed.; Wiley: New York, 1985,
p 509.
Removal of the 4-Methoxy Group of the 4-Methoxy-Substituted
Pyrimidine Nucleosides; Preparation of 1-(3,5-di-O-p-toluoyl-2-
deoxy-b-D-erythro-pentafuranosyl)-5-(2-hydroxyethyl)pyrimi-
din-2,4(3H)-dione from 1-(3,5-Di-O-p-toluoyl-2-deoxy-b-D-
erythro-pentofuranosyl)-5-(2-hydroxyethyl)-4-methoxypyrimi-
din-2-one (8b); Typical Procedure
To a stirred solution of 8b (30 mg, 0.058 mmol) in MeCN (0.5 mL)
in a 10 mL two-necked round-bottomed flask were added NaI (18
mg, 0.12 mmol) and Me3SiCl (11 µL, 0.087 mmol) sequentially un-
der exclusion of moisture. After 1 min, TLC (MeOH/CHCl3, 1:19)
indicated complete consumption of 8b (Rf 0.52). Only one product
1-(3,5-di-O-p-toluoyl-2-deoxy-b-D-erythro-pentofuranosyl)-5-(2-
hydroxyethyl)pyrimidin-2,4(3H)-dione (Rf 0.41) was formed as
confirmed by comparison with an authentic sample prepared ac-
cording to literature.18 After evaporation of the solvent under re-
duced pressure, the residue was chromatographed using acetone/
hexane (1:1) as eluent. The product was obtained in 90% yield (26
mg). Analytical data (1H and13C NMR) were consistent with that of
an authentic sample.18
(12) Silverman, R. B.; Radak, R. E.; Hacker, N. P. J. Org. Chem.
1979, 44, 4970.
(13) Trost, B. M.; Shi, Z. J. Am. Chem. 1996, 118, 3037.
(14) Sujino, K.; Sugimura, H. Tetrahedron Lett. 1994, 35, 1883.
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(b) Schmidt, A. H. Aldrichimica Acta 1981, 14, 31.
(c) Olah, G. A.; Prakash, G. K. S.; Krishnamurti, R.
Adv.Silicon Chem.1991, 1, 1.
(16) Cristalli, G.; Volpini, R.; Vittori, S.; Camaioni, E.; Rafaiani,
G.; Potenza, S.; Vita, A. Nucleosides & Nucleotides 1996, 15,
1567.
(17) Eger, K.; Jalalian, M.; Schmidt, M. Tetrahedron 1994, 50,
8371.
(18) Griengl, H.; Bodenteich, M.; Hayden, W.; Wanek, E.;
Streicher, W.; Stütz, P.; Bachmayer, H.; Ghazzouli, I.;
Rosenwirth, B. J. Med. Chem. 1985, 28, 1679.
Article Identifier:
1437-210X,E;1999,0,12,2057,2064,ftx,en;Z00699SS.pdf
Synthesis 1999, No. 12, 2057–2064 ISSN 0039-7881 © Thieme Stuttgart · New York