Synthesis of a novel aldehyde: 4-O-methyl-5-formylmethyl-2′-deoxyuridine

Article abstract of DOI:10.1081/NCN-120018624

The synthesis of the blocked nucleoside 3′,5′-di-O-p-toluoyl-4-O-methyl-5-formyl-methyl-2′- deoxyuridine (19) was accomplishied in eleven steps from gamma-butyrolactone. This aldehyde, which should facilitate the synthesis of nucleosides containing ¹⁸F, was converted to the corresponding blocked dithianyl nucleoside (21), and also to 5-(2,2-difluoroethyl)-substituted derivatives of 2′-deoxyuridine and 2′-deoxycytidine.

Full text of DOI:10.1081/NCN-120018624

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Synthesis of a Novel Aldehyde: 4-O-Methyl-5-
formylmethyl- 2′-deoxyuridine
Chung-Shan Yu a b & Franz Oberdorfer a c
a Abteilung E0300-Radiochemie und Radiopharmakologie , Deutsches
Krebsforschungszentrum (DKFZ) , Heidelberg, Germany
b Institute of Chemistry , Academia Sinica , 128, Academia Road, Section 2, NanKang Taipei,
11529, Taiwan
c Synthra GmbH–Klausenpfad 23, D-69121, Heidelberg, Germany
Published online: 07 Feb 2007.
To cite this article: Chung-Shan Yu & Franz Oberdorfer (2003) Synthesis of a Novel Aldehyde: 4-O-Methyl-5-formylmethyl- 2′-
deoxyuridine, Nucleosides, Nucleotides and Nucleic Acids, 22:1, 71-84, DOI: 10.1081/NCN-120018624
To link to this article: http://dx.doi.org/10.1081/NCN-120018624
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS
Vol. 22, No. 1, pp. 71–84, 2003
Synthesis of a Novel Aldehyde:
4-O-Methyl-5-formylmethyl-
20-deoxyuridine
#
*
Chung-Shan Yu and Franz Oberdorfer
Abteilung E0300-Radiochemie und Radiopharmakologie, Deutsches
Krebsforschungszentrum (DKFZ), Heidelberg, Germany
ABSTRACT
The synthesis of the blocked nucleoside 30,50-di-O-p-toluoyl-4-O-methyl-5-formyl-
methyl-20-deoxyuridine (19) was accomplishied in eleven steps from gamma-
butyrolactone. This aldehyde, which should facilitate the synthesis of nucleosides
containing 18F, was converted to the corresponding blocked dithianyl nucleoside
(21), and also to 5-(2,2-difluoroethyl)-substituted derivatives of 20-deoxyuridine
and 20-deoxycytidine.
Key Words: Gem-difluoro; Deoxyuridine; Aldehyde; Reductive tritualation;
Dithioacetals.
*Correspondence: Chung-Shan Yu, Institute of Chemistry, Academia Sinica, 128, Academia
Road, Section 2, NanKang Taipei, 11529 Taiwan; Fax: (886) 2-27898670; E-mail: cyu1231@
chem.sinica.edu.tw.
#Franz Oberdorfer, Synthra GmbH–Klausenpfad 23, D-69121 Heidelberg, Germany; Fax:
(49) 6221-502772; E-mail: oberdorfer@synthra.de.
71
DOI: 10.1081/NCN-120018624
Copyright # 2003 by Marcel Dekker, Inc.
1525-7770 (Print); 1532-2335 (Online)
www.dekker.com

72
Yu and Oberdorfer
Suicide gene therapy is one of the most promising clinical protocols in cancer
therapy.[1] The mechanism underlying the therapy starts by delivering the suicide
gene into the target cells, followed by administering the prodrugs. The presence of
the suicide gene in the target cells activates the prodrugs, such as thymidine analogs,
to form toxic metabolites, which then initiate the subsequent suicidal mechanism.
Herpes simplex virus type 1 TK (HSV-1 TK) is the most extensively studied suicide
gene. The success of this protocol relies on a predictable transfection of HSV-1 TK
into cancer cells in vivo. The development of a methodology for monitoring such a
process is of value. One of the most successful approaches is to use 18F-radiolabeled
thymidine analogs as marking substrates for HSV-1 TK on the basis of positron
emission tomography (PET).[2] The previous results have shown that the syntheses
of [18F]-5-(2-fluoroethyl)deoxyuridine 13 and [18F]-5-(2-fluorovinyl)deoxyuridine 24
require tosylate 3 (or triflate 4) and organostannane 5 as precursors, respectively
(Fig. 1). Radiolabeled compounds could be prepared with high specific activity using
nucleophilic or electrophilic radiolabeled fluorination.[3,4] In particular, the gem-
difluoro substituted thymidine analog 6 attracted the most of our attention. It is
known that gem-difluoro compounds always display significant bioactivities[5] and
may serve as alternative candidates of radiotracers. The recent progress in oxidative
desulfurization-fluorination reaction of dithioacetals[6] and the application of
[18F]XeF2 encouraged us to synthesize the compound 6. Furthermore, since tri-
[7]
tium-labeled natural products (e.g., thymidine 7) have been widely used in
enzyme-based assay in vitro, the thymidine analog 8 should be a valuable compound
as well. 5-Formylmethyl deoxyuridine 9 would be a key intermediate for the facial
synthesis of these radioactive molecules mentioned above (Fig. 2).
The preparation of aldehyde 9 has not been reported unlike that of 5-formyl-
methyl uracil 10.[8,9] However, the attempt to repeat the reported [2 þ 2] photo che-
mical reaction of uracil with 1,3-dioxolone was cumbersome.[10] A resulting viscous
gum was obtained after evaporation of the solvent, and the product could not be suc-
cessfully identified by ESI-MS spectra. Such difficulty was probably due to the attack
of the 5-formyl group by the unprotected imino group during the formation of a
cyclized hemiacetal 11. Besides the cyclization, uncontrolled overoxidations were
also observed during treatment of compound 12 with various oxidants[11] including
MnO2, chromium (VI) and activated DMSO. Byproducts such as 5-formyluracil 13
and 5-carboxy uracil 14 were always obtained. To prevent the cyclization and over-
oxidation, the 2,4-dioxo groups were protected with methyl groups, and mild oxidiz-
ing conditions were employed. However, the desired product 16 is still susceptible to
the oxidants (Sch. 1).[10]
The isolation of the desired aldehyde 19 was made possible by modifying the oxi-
dation condition using a 4-methoxy protected nucleoside 18 as the alcohol (Sch. 2).[3]
The preparation of alcohol 18 was a ten-step synthesis using g-butyrolactone as
starting material and this was developed by the separate work of refs[8,12,13] and
our group.[3]
˚
The PDC oxidation in the presence of 4 A MS was more feasible than Swern oxi-
dation in this case. The latter reaction was observed to give a decomposed product.
The successful preparation of the aldehyde 19 allowed us to synthesize the dithiane
derivative 21, gem-difluoro derivatives 6, 23 and 24, as well as tritium-labeled alcohol
18. The dithiolation of aldehyde 19 was carried out by the use of 1,3-propanedithiol

4-O-Methyl-5-formylmethyl-20-deoxyuridine
73
Figure 1. Biologically related radiolabeled thymidine derivatives and precursors.
and BF3 ꢀ 2HOAc. Treatment of aldehyde 19 with DAST provided the gem-difluoro
nucleoside 22 at 80% yield within 10 min (Sch. 3). After selective deprotection,
thymidine derivatives 6, 23 and cytidine derivative 24 were obtained in high yield.
Both fluorine atoms of the methyl rotamers in compound 6 and the a-anomers of
compounds 23, 24 showed different spectroscopical character in 19F-NMR
(JF,F ¼ 10 ꢁ 15 Hz). A hydrogen bond formation was proposed to assist the partial
fixation. The reduction of aldehyde 19 with nonradioactive NaBH4 provided a high
yield of the alcohol 18 (10 min).

74
Yu and Oberdorfer
Figure 2. Aldehydes and the overoxidized by-products.
Scheme 1. Overoxidation reaction.

4-O-Methyl-5-formylmethyl-20-deoxyuridine
75
[3]
Scheme 2. ꢂSee ref , reagents and conditions a: 4 A MS, PDC, CH2Cl2, rt, 25 min.
˚
EXPERIMENTAL SECTION
TLC was performed on Polygram Sil G=UV 254 plates of Machery and Nagel,
Duren. Detection was effective by exposure to UV light or by spraying with molyb-
¨
datophosphoric acid (5% in ethanol). Column chromatography was performed on
silica 60 (40–63 mm), Merck, Darmstadt, at a flow rate ranging from 2–4 mL=min
under atmospheric pressure. Chemicals were purchased from Aldrich. CHCl3 and
CH2Cl2 were dehydrated by passing through a column filled with Al2O3 (neutral).
Cation exchange resin (Hþ form, AG 50W-X8, 200–400 mesh) was purchased from
Bio-Rad. Melting points were determined with a Buchi 535 apparatus and not
¨
corrected. Elemental analysis was performed at the Max Planck Institut fur Medizi-
¨
nische Forschung in Heidelberg. NMR spectra were recorded with a Bruker AC-250
spectrometer at 250 MHz (1H), 63 MHz (13C) and 235 MHz (19F), or AM-500 spec-
trometer at 500 MHz (1H) and 125 MHz (13C) in the Central Department of Spectro-
scopy of DKFZ. DFTCE (C2F2Cl4) was used as external standard for 19F-NMR.
Electrospray ionization mass spectra (ESI-MS) were recorded with a Finnigan
TSQ 7000 triple-quadrupole system. HRMS (FAB) experiment was carried out at
Chemisches Institute der Universita¨t Heidelberg.
1-(3,5-Di-O-p-toluoyl-2-deoxy-b-D-erythro-pentafuranosyl)-5-formylmethyl-4-
methoxypyrimidin-2-one (19). To a flask containing CH2Cl2 (8 mL) was added an a
˚
and b-mixture of 18 (382 mg, 0.732 mmol) and powdered 4 A MS (730 mg) and stirred
under dry N2. PDC (303 mg, 0.8 mmol) was added. After 20 min, the solvent was
removed under reduced pressure to give a dry residue which was purified by the

76
Yu and Oberdorfer
Scheme 3. Reagents and conditions: (a) 1,3-propanedithiol, BF3 ꢀ 2HOAc, CHCl3, rt, 1 h,
65%; (b) DAST, CH2Cl2, rt, 1 h, 80%; (c) NaBH4, THF, rt, 10 min, 90%; (d) (i) NaI, TMSCl,
CH3CN, rt, 5 min; (ii) NaOMe, MeOH, rt, 2 h, 87%; (e) NaOMe, MeOH, rt, 1 h, 64%; (f) NH3,
MeOH, 100ꢃC, 72 h, 83%.
column chromatography with acetone=n-hexane 1:1 to afford b-form of 19 and a-
form of 19 (226 mg, 60%) and 20 (41 mg, 10%). These white solids, which have a plea-
sant odor and are sensitive to moisture, should be carefully stored over P4O10 under
vacuum; mp: 181–183ꢃC, anal. C28H28N2O8 calcd: C 64.62, H 5.39, N 5.39; found: C
64.76, H 5.60, N 5.42; MW: 520.54, ESI þ Q1MS, M1 ¼ 520, M2 ¼ 552 (m=z); MeOH
was used as solvent for ESI-MS analysis. The formyl group was attacked by MeOH.
[M1 þ H]þ ¼ 521.2, [M2 þ H]þ ¼ 553.2, [M2 þ Na]þ ¼ 575.2, [2M1 þ H]þ ¼ 1041.4,
[M1 þ M2 þ H]þ ¼ 1073.4, [2M2 þ H]þ ¼ 1105.4; ESI ꢄ Q1MS, M1 ¼ 520, M2 ¼ 552
(m=z) [M1 ꢄ H]ꢄ ¼ 519.1, [M2 þ Cl]ꢄ ¼ 587.1, [2M1 ꢄ H]ꢄ ¼ 1039.4, [M1 þ M2 ꢄ
H]ꢄ ¼ 1071.4, [2M2 þ Cl]ꢄ ¼ 1139.8 1H-NMR (250 MHz, CDCl3): d 2.24 (ddd,
0
0
0
0
0
0
0
J2 (a),2 (b) ¼ 14.8, J2 (a),1 ¼ 8.3, J2 (a),3 ¼ 6.6 Hz, 1H, H-2 (a)), 2.41 (s, 3H, arom-
CH3), 2.44 (s, 3H, arom-CH3), 2.98–3.19 (m, 3H, H-20(b) þ H-7), 3.94 (s, 3H,
OCH3), 4.58–4.59 (m, 1H, H-40), 4.62 (dd, J5 (a),5 (b) ¼ 11.4, J5 (a),4 ¼ 3.7 Hz, 1H, H-
0
0
0
0
50(a)), 4.83 (dd, J5 (b),5 (a) ¼ 11.4, J5 (b),4 ¼ 2.0 Hz, 1H, H-5 (b)), 5.62 (d, J ¼ 6.6 Hz,
0
0
0
0
0

4-O-Methyl-5-formylmethyl-20-deoxyuridine
77
1H, H-30), 6.45 (dd, J1 ,2 (a) ¼ 8.3, J1 ,2 (b) ¼ 5.5 Hz, 1H, H-10), 7.22–7.30 (m, 4H,
arom), 7.70 (s, 1H, H-6), 7.84–7.97 (m, 4H, arom), 9.43 (s, 1H, H-8 (CHO)). 13C-
NMR (62.90 MHz, CDCl3): d 21.66 (arom-CH3), 21.72 (arom-CH3), 39.31 (C-20),
41.05 (C-7), 54.92 (4-O-CH3), 64.14 (C-50), 75.12 (C-30), 83.61 (C-10), 87.14 (C-40),
100.52 (C-5), 126.30 (C-CH3, arom), 126.51 (C-CH3, arom), 129.28–130.27
(CH ꢅ 8, arom), 141.10 (C-6), 144.55 (C-CO, arom), 144.62 (C-CO, arom), 155.41
(C-2), 166.00 (arom-CO), 166.17 (arom-CO), 170.08 (C-4), 197.15 (C-8, CHO).
0
0
0
0
1-(3,5-Di-O-p-toluoyl-2-deoxy-a-D-erythro-pentafuranosyl)-5-formylmethyl-4-
methoxypyrimidin-2-one (19a). White solids, pleasant odor; mp: 88–90ꢃC, anal.
C28H28N2O8, HRMS (FAB): m=z: calcd 521.1924 [M þ H]þ, found 521.1894,
ꢄ3.0 mmu, calcd 543.1743 [M þ Na]þ; found 543.1733, ꢄ1.0 mmu, MW: 520.54,
ESI þ Q1MS, M1 ¼ 520, M2 ¼ 552 (m=z); MeOH was used as solvent for ESI-MS
analysis. The formyl group of 19a was attacked by MeOH. [M1 þ H]þ ¼ 521.2,
[M2 þ H]þ ¼ 553.2, [M2 þ Na]þ ¼ 575.2, [2M1 þ H]þ ¼ 1041.4, [M1 þ M2 þ H]þ ¼
1073.4, [2M2 þ H]þ ¼ 1105.4; ESI ꢄ Q1MS, M1 ¼ 520, M2 ¼ 552 (m=z) [M1 ꢄ H]ꢄ ¼
519.1, [M2 þ Cl]ꢄ ¼ 587.1, [2M1 ꢄ H]ꢄ ¼ 1039.4, [M1 þ M2 ꢄ H]ꢄ ¼ 1071.4, [2M2 þ
1
Cl]ꢄ ¼ 1139.8 H-NMR (250 MHz, CDCl3) d 2.30 (s, 3H, arom-CH3), 2.36 (s, 3H,
arom-CH3), 2.56–2.64 (m, 1H, H-20(a)), 2.93 (ddd, J2 (b),2 (a) ¼ 15.5, J2 (b),1 ¼ 6.7,
0
0
0
0
0
0
0
J2 (b),3 ¼ 6.4 Hz, 1H, H-2 (b)), 3.26 (m, 2H, H-7), 3.93 (s, 3H, OCH3), 4.50 (dd,
J5 (a),5 (b) ¼ 12.1, J5 (a),4 ¼ 4.3 Hz, 1H, H-50(a)), 4.52 (dd, J5 (b),5 (a) ¼ 12.1,
0
0
0
0
0
00
0
0
0
0
J5 (b),4 ¼ 4.0 Hz, 1H, H-5 (b)), 4.82–4.85 (t, J ¼ 4.2 Hz, 1H, H-4 ), 5.50–5.53 (d,
J ¼ 6.0 Hz, 1H, H-30), 6.26–6.28 (d, J ¼ 6.7, 1H, H-10), 7.09–7.22 (m, 4H, arom),
7.58–7.60 (m, 2H, arom), 7.66 (s, 1H, H-6), 7.85–7.89 (m, 2H, arom), 9.46 (s, 1H,
13
H-8(CHO)). C-NMR (62.896 MHz, CDCl3): d 21.67 (arom-CH3), 38.88 (C-20),
41.11 (C-7), 54.97 (4-O-CH3), 64.02 (C-50), 74.95 (C-30), 85.87 (C-10), 89.22 (C-40),
99.44 (C-5), 126.17 (C-CH3, arom), 126.53 (C-CH3, arom), 129.23 (CH, arom),
129.34 (CH, arom), 129.47 (CH, arom), 129.69 (CH, arom), 141.56 (C-6), 144.28
(C-CO, arom), 144.62 (C-CO, arom), 155.49 (C-2), 165.54 (arom-CO), 166.13
(arom-CO), 170.23 (C-4), 197.19 (C-8, CHO).
1-(3,5-Di-O-p-toluoyl-2-deoxy-b,a-D-erythro-pentafuranosyl)-5-formyl-4-methoxy-
pyrimidin-2-one (20b& þ 20a& ! 20b þ 20a). White solids, pleasant odþor; mp:
161–165ꢃC, anal. C27H26N2O8, HRMS (FAB): m=z: calcd 507.1767 [M þ H] , found
507.1757, ꢄ1.1 mmu, calcd 529.1587, [M þ Na]þ; found 529.1603, 1.7 mmu, MW:
506.51,
ESI þ Q1MS,
M1 ¼ 506,
M2 ¼ 538
(m=z);
[M1 þ H]þ ¼ 507.1,
[M1 þ Na]þ ¼529.1, [M2 þ H]þ ¼ 539.1, [M2 þ Na]þ ¼ 561.1, [2M1 þ H]þ ¼ 1013.3,
þ
1
0
[2M1 þ Na] ¼ 1035.3 H-NMR (250 MHz, CDCl3) d 2.22–2.33 (m, 1H,H-2b (a)),
0
2.38–2.43 (m, 12 H, arom-CH3(a,b)), 2.58–2.64 (m, 1H, H-2a (a)), 2.97–3.16 (m,
2H, H-2a,b0(b)), 4.07 (s, 3H, OCH3), 4.08 (s, 3H, OCH3), 4.55–4.57 (m, 2H, H-
5a,b0(a)), 4.70–4.75 (m, 3H, H-4b þ H-5a,b0(b)), 5.04–5.08 (t, J ¼ 4.2, 1H, H-4a ),
0
0
5.58–5.66 (m, 2H, H-3a,b ), 6.30–6.36 (m, 2H, H-1a,b0), 7.12–7.30 (m, 8H, aroma,b),
0
7.64–7.86 (m, 4H, aroma), 7.92–7.96 (m, 4H, aromb), 8.64 (s, 1H, H-6a), 8.67 (s, 1H,
H-6b), 9.78 (s, 1H, H-7b (CHO)), 9.93 (s, 1H, H-7a (CHO)). 13C-NMR
0
(62.896 MHz, CDCl3): d 21.60 (arom-CH3), 21.65 (arom-CH3), 39.26 (C-2b ),
0
0
0
39.74 (C-2a ), 55.03 (4-O-CH3a,b), 63.86 (C-5a,b0),0 74.53 (C-3a ), 75.03 (C-3b ),
0
0
0
84.32 (C-1b ), 86.06 (C-1a ), 88.35 (C-4b ), 89.72 (C-4a ), 106.38 (C-5b), 106.99 (C-5a),

78
Yu and Oberdorfer
125.86 (C-CH3, arom), 126.23 (C-CH3, arom), 126.37 (C-CH3, arom), 126.41 (C-
CH3, arom), 129.14 (CH, arom), 129.21 (CH, arom), 129.33 (CH, arom), 129.55
(CH, arom), 129.65 (CH, arom), 129.79 (CH, arom), 144.28 (C-CO, arom),
144.31 (C-CO, arom), 144.48 (C-CO, arom), 144.59 (C-CO, arom), 146.65 (C-6b),
146.93 (C-6a), 154.06 (C-2a), 154.24 (C-2b), 165.21 (arom-CO), 165.93 (arom-CO),
165.99 (arom-CO), 169.87 (C-4a,), 170.17 (C-4b,), 183.94 (C-7a, CHO), 184.30 (C-7b,
CHO).
1-(3,5-Di-O-p-toluoyl-2-deoxy-b-D-erythro-pentafuranosyl)-5-[(1,3-dithian-2-yl)
methyl]-4-methoxypyrimidin-2-one (21). To a mixture of a,b form of 19 (184 mg,
0.35 mmol) in dry CHCl3 (5 mL) were added 1,3-propanedithiol (76 mg, 0.70 mmol)
and BF3ꢀ2HOAc (67 mg, 0.35 mmol) sequentially. This reaction was stirred at rt for
1 h, extracted with satd NaHCO3 (2 ꢅ 2 mL) and washed with water (1 mL). The
organic layer was dried over MgSO4 and filtered. The filtrate was concentrated under
reduced pressure at 40ꢃC. The residue obtained was chromatographed with
acetone=n-hexane 1:1 to give b-form of 21 and a-form of 21 (141 mg, 65%). colorless
solid, mp: 64ꢃC (dec.), anal. C31H34N2O7S2, HRMS (FAB): m=z: calcd 611.1886
[M þ H]þ, found 611.1874, ꢄ1.1 mmu, calcd 633.1705 [M þ Na]þ, found 633.1711,
þ 0.6 mmu, MW: 610.75, ESI þ Q1MS, M ¼ 610 (m=z); [M þ H]þ ¼ 611.0,
35
[M þ Na]þ ¼ 633.1; ESIꢄQ1MS, M ¼ 610 (m=z); [Mþ Cl]ꢄ ¼ 644.9. 1H-NMR
(250 MHz, CDCl3) d 1.74–1.88 (m, 1H, H-10a), 2.02–2.11 (m0, 1H, H-10a), 2.31
0
0
0
0
0
0
(ddd, J2 (a),2 (b) ¼ 14.4, J2 (a),1 ¼ 8.3, J2 (a),3 ¼ 6.6 Hz, 1H, H-2 (a)), 2.42 (s, 3H,
arom-CH3), 2–43 (s, 3H, arom-CH3), 2.59 (d, J7,8 ¼ 7.3 Hz, 2H, H-7), 2.71–2.79 (m,
4H, H-9 þ H-11a), 3.00 (ddd, J2 (b),2 (a) ¼ 14.4, J2 (b),1 ¼ 5.5, J2 (b),3 ¼ 1.5 Hz, 1H, H-
0
0
0
0
0
0
20(b)), 3.98 (s, 3H, OCH3), 4.05 (t, J8,7 ¼ 7.3 Hz, H-8), 4.58–4.61 (m, 1H, H-40), 4.65
0
0
0
0
0
0
00
00
(dd, J5 (a) 5 (b) ¼ 12.0, J5 (a),4 ¼ 4.0 Hz, 1H, H-5 (a)), 4.71–4.77 (dd, J5 (b)’5 (a) ¼ 12.0,
0
0
J5 (b),4 ¼ 3.2 Hz, 1 H, H-5 (b)), 5.59–5.61 (d, J ¼ 6.5 Hz, 1H, H-3 ), 6.44 (dd,
J1 ,2 (a) ¼ 8.3, J1 ,2 (b) ¼ 5.5 Hz, 1H, H-10), 7.23–7.29 (m, 4 H, arom), 7.70 (s, 1H, H-
6), 7.87–7.97 (m, 4H, arom). 13C-NMR (62.896 MHz, CDCl3): d 21.67 (arom-CH3),
25.58 (C-7), 29.73 (C-9 or C-11), 29.76 (C-11 or C-9), 32.37 (C-10), 39.15 (C-20),
45.49 (C-8), 54.70 (4-O-CH3), 64.24 (C-50), 75.07 (C-30), 83.35 (C-10), 86.99 (C-40),
104.42 (C-5), 126.35 (C-CH3, arom), 126.61 (C-CH3, arom), 129.21 (CH, arom),
129.40 (CH, arom), 129.59 (CH, arom), 129.83 (CH, arom), 140.51 (C-6), 144.24
(C-CO, arom), 144.41 (C-CO, arom), 155.40 (C-2), 166.06 (arom-CO), 166.08
(arom-CO), 170.16 (C-4).
0
0
0
0
1-(3,5-Di-O-p-toluoyl-2-deoxy-a-D-erythro-pentafuranosyl)-5-[(1,3-dithian-2-yl)
methyl]-4-methoxypyrimidin-2-one (21a). Colorless solid, mp: 69ꢃC (dec.), anal.
C31H34N2O7S2, MW: 610.75, ESI þ Q1MS, M ¼ 610 (m=z); [M þH ]þ ¼ 611.1,
[M þ Na]þ ¼ 633.1, [2M þ H]þ ¼ 1221.5, [2M þ Na]þ ¼ 1243.4; ESI ꢄ Q1MS,
M ¼ 610 (m=z); [M þ 35Cl]ꢄ ¼ 645.0; [2M þ 35Cl]ꢄ ¼ 1255.7 1H-NMR (250 MHz,
CDCl3) d 1.71–1.83 (m, 1H, H-10), 2.00–2.08 (m, 1H, H-10), 2.40 (s, 3H, arom-
CH3), 2.43 (s, 3H, arom-CH3), 2.49–2.80 (m, 7H, H-7 þ H-20(a) þ H-9þH-11),
1
aProtons H-9, H-10 and H-11 were identified by two-dimensional H-NMR (COSY).

4-O-Methyl-5-formylmethyl-20-deoxyuridine
79
0
0
0
0
0
0
0
2.96 (ddd, J2 (b),2 (a) ¼ 15.4, J2 (b),1 ¼ 6.5, J2 (b),3 ¼ 6.4Hz, 1H, H-2 (b)), 3.94–4.09 (m,
4H, -OCH3 þ H-8), 4.57–4.60 (d, 2 H, H-50), 4.88–4.91 (t, J ¼ 3.0 Hz, 1H, H-40),
5.53–5.56 (d, J ¼ 5.2 Hz, H-30), 6.31 (dd, J1 ,2 (b) ¼ 6.5, J1 ,2 (a) ¼ 1.4Hz, 1H, H-10),
7.16–7.30 (m, 4H, arom), 7.55–7.69 (m, 2 H, arom), 7.74 (s, 1H, H-6), 7.92–7.96
(m, 2H, arom). 13C-NMR (62.90 MHz, CDCl3): d 21.66 (arom-CH3), 25.58 (C-7),
29.90 (C-9 or C-11), 30.05 (C-11 or C-9), 32.55 (C-10), 38.76 (C-20), 45.79 (C-8),
54.75 (4-O-CH3), 64.08 (C-50), 75.00 (C-30), 85.72 (C-10), 89.17 (C-40), 103.43 (C-
5), 126.29 (C-CH3, arom), 126.61 (C-CH3, arom), 129.09 (CH, arom), 129.31
(CH, arom), 129.66 (CH, arom), 129.68 (CH, arom), 141.20 (C-6), 144.20 (C-CO,
arom), 144.35 (C-CO, arom), 155.55 (C-2), 165.70 (arom-CO), 166.12 (arom-CO),
170.32 (C-4).
0
0
0
0
1-(3,5-Di-O-p-toluoyl-2-deoxy-b-D-erythro-pentafuranosyl)-5-(2,2-difluoroethyl)-
4-methoxypyrimidin-2-one (22). A mixture of a,b form of 19 (136 mg, 0.26 mmol)
dissolved in dry CH2Cl2 (3 mL) was stirred at rt and treated with DAST (110 mg,
0.68 mmol). The stirring was continued at rt for 1 h. CH2Cl2 (7 mL) was added.
The organic layer was extracted with cold satd NaHCO3 (2 mL), washed once
with water (3 mL), dried over MgSO4 and filtered. The filtrate was concentrated
under reduced pressure at 40ꢃC. The residue obtained was chromatographed with
acetone=n-hexane 2:3 to give b-form of 22 and a-form of 22 (112 mg, 80%). pale
yellow crystals; mp: 168–169ꢃC, anal. C28H28N2O7F2, MW: 542.54, ESI þ Q1MS,
M ¼ 542 (m=z); [M þ H]þ ¼ 543.1, [M þ Na]þ ¼ 565.2; ESI ꢄ Q1MS, M ¼ 542
(m=z); [M þ 35Cl]ꢄ ¼ 577.1. 1H-NMR (500 MHz, CDCl3)
d
2.24 (ddd,
0
0
0
0
0
0
0
J2 (a),2 (b) ¼ 14.7, J2 (a),1 ¼ 8.4, J2 (a),3 ¼ 6.6 Hz, 1H, H-2 (a)), 2.42 (s, 3H, arom-
CH3), 2.44 (s, 3H, arom-CH3), 2.61 (ttd, J7,F ¼ 20.9, J7(a),7(b) ¼ 4.7, J7,8 ¼ 4.7,
0
0
0
0
0 0
J7,6 ¼ 0.7 Hz, 2H, H-7(a), H-7(b)), 3.00 (ddd, J2 (b),2 (a) ¼ 14.7, J2 (b),1 ¼ 5.5,
0
0
J2 (b),3 ¼ 1.5, 1H, H-2 (b)), 3.98 (s, 3H, OCH3), 4.58–4.60 (m, 1H, H-4 ), 4.65
0
0
0
0
0
0
0
(dd, J5 (a),5 (b) ¼ 12.2, J5 (a),4 ¼ 3.8 Hz, 1H, H-5 (a)), 4.79 (dd, J5 (b),5 (a) ¼ 12.2,
0
0
0
0
J5 (b),4 ¼ 2.9 Hz, 1H, H-5 (b)), 5.60–5.62 (m, 1H, H-3 ), 5.73 (tt, J8,F ¼ 56.7,
J8,7 ¼ 4.7 Hz, 1H, H-8), 6.43 (dd, J1 ,2 (a) ¼ 8.4, J1 ,2 (b) ¼ 5.5 Hz, 1H, H-10), 7.23–
0
0
0
0
7.29 (m, 4H, arom), 7.70 (t, J6, ¼ 0.7 Hz, 1H, H-6), 7.86–7.97 (m, 4H,
7
arom).13C-NMR (125.76 MHz, CDCl3) : d 21.65 (arom-CH3), 21.72 (arom-
CH3), 31.89 (t, J7,F ¼ 24.3 Hz, C-7), 39.28 (C-20), 54.95 (4-O-CH3), 64.06 (C-50),
75.09 (C-30), 84.59 (C-10), 87.05 (C-40), 100.24 (t, J5,F ¼ 6.9 Hz, C-5), 114.43 (t,
J8,F ¼ 241.2 Hz, C-8), 126.33 (C-CH3, arom), 126.53 (C-CH3, arom), 129.28
(CH, arom), 129.45 (CH, arom), 129.49 (CH, arom), 129.88 (CH, arom),
141.70 (C-6), 144.52 (C-CO, arom), 144.53 (C-CO, arom), 155.30 (C-2), 166.05
(arom-CO), 166.16 (arom-CO), 170.00 (C-4).19F-NMR (235.34 MHz, CDCl3): d
ꢄ40.77 (dt, JF,H-8 ¼ 56.7, JF,H-7 ¼ 16.3 Hz, CF2H).
1-(3,5-Di-O-p-toluoyl-2-deoxy-a-D-erythro-pentafuranosyl)-5-(2,2-difluoroethyl)-
4-methoxypyrimidin-2-one (22a). White crystals; mp: 135–138ꢃC, anal. C28H28N2-
O7F2 calcd: C 61.99, H 5.17, N 5.17; found: C 62.35, H 5.38, N 5.18; MW: 542.54,
ESI þ Q1MS, M ¼ 542 (m=z); [M þ H]þ ¼ 543.2, [M þ Na]þ ¼ 565.2, [M þ K]þ ¼
581.2; ESI ꢄ Q1MS, M ¼ 542 (m=z); [M þ 35Cl]ꢄ ¼ 577.1 1H-NMR (250 MHz,
0
0
CDCl3) d 2.40 (s, 3H, arom-CH3), 2.43 (s, 3H, arom-CH3), 2.68 (ddd, J2 (a),2 (b) ¼ 15.5,

80
Yu and Oberdorfer
0
0
0
0
0
J2 (a),1 ¼ 1.4, J2 (a),3 ¼ 0.9 Hz, 1H, H-2 (a)), 2.82 (tt, J7,F ¼ 16.4, J7(a),7(b) ¼ 3.7,
0
0
0
0
0
0
J7,8 ¼ 3.7 Hz, 2H, H-7), 3.00 (dt, J2 (b),2 (a) ¼ 15.5, J2 (b),1 ¼ 6.6, J2 (b),3 ¼ 6.5 Hz, 1H,
H-20(b)), 4.03 (s, 3H, OCH3), 4.56–4.58 (d, J ¼ 4.5 Hz, 2H, H-50), 4.88–4.91 (t,
J ¼ 3.9 Hz, 1H, H-40), 5.57–5.59 (d, J ¼ 6.3 Hz, 1H, H-30), 5.75 (tt, J8,F ¼ 56.8,
J8,7 ¼ 3.7 Hz, 1H, H-8), 6.31 (dd, J1 ,2 (b) ¼ 6.6, J1 ,2 (a) ¼ 1.4Hz, 1H, H-10), 7.15–7.30
(m, 4H, arom), 7.66–7.69 (m, 2H, arom), 7.73 (s, 1H, H-6), 7.93–7.96 (m, 2H, arom).
13C-NMR (62.896 MHz, CDCl3): d 21.69 (arom-CH3), 32.02 (t, J7,F ¼ 24.3 Hz, C-7),
38.93 (C-20), 54.97 (4-O-CH3), 64.04 (C-50), 74.92 (C-30), 85.83 (C-10), 89.25 (C-40),
99.14 (t, J5,F ¼ 6.8 Hz, C-5), 114.57 (t, J8,F ¼ 241.2 Hz, C-8), 126.18 (C-CH3, arom),
126.56 (C-CH3, arom), 129.15 (CH, arom), 129.36 (CH, arom), 129.51 (CH, arom),
129.71 (CH, arom), 142.19 (C-6), 144.29 (C-CO, arom), 144.55 (C-CO, arom),
155.62 (C-2), 165.62 (arom-CO), 166.13 (arom-CO), 170.18 (C-4) 19F-NMR
(235.34 MHz, CDCl3): d ꢄ40.33 (dt, JF,H-8 ¼ 56.8, JF,H-7 ¼ 16.4Hz, CF2H).
0
0
0
0
1-(2-Deoxy-b-D-erythro-pentafuranosyl)-5-(2,2-difluoroethyl)pyrimidin-2,4(3H)-
dione (6). A solution of 22 (30 mg, 0.055 mmol) in dry CH3CN (0.5 mL) was stirred
under dry N2 at rt. The reaction was subjected to the sequential addition of NaI
(16.5 mg, 0.11 mmol) and Me3SiCl (10.5 mL, 0.083 mmol). After 5 min the solvent
was evaporated under reduced pressure at 40ꢃC. To the resulting residue was added
MeOH (1 mL) and NaOMe=MeOH (1 mL, 0.2 N). The mixture was stirred at rt for
another 2 h. Cation exchange resin (AG 50WX-8) was added to neutralize to pH 7.
After filtration and concentration under reduced pressure at 40ꢃC, the residue
(61 mg) obtained was chromatographed with silica gel column (MeOH=CHCl3 1:9)
to give 6 in 87% yield (14 mg). Pale yellow crystals, mp: 166–170ꢃC, anal.
C11H14N2O5F2 calcd: C 45.21, H 4.83, N 9.59; found: C 44.80, H 5.01, N 9.35; anal.
C11H14N2O5F2, HRMS (FAB): m=z: calcd 293.0949 [M þ H]þ, found 293.0969,
þ2.0 mmu, calcd 315.0769 [M þ Na]þ; found 315.0776, þ0.8 mmu, MW: 292.24,
ESI þ Q1MS, M ¼ 292 (m=z); [M þ H]þ ¼ 292.9, [M þNa ]þ ¼ 314.9; ESI ꢄ Q1MS,
M ¼ 292 (m=z); [M ꢄ H]ꢄ ¼ 291.0, [2M ꢄ H]ꢄ ¼ 583.1, 1H-NMR (250 MHz,
0
0
0
0
0
0
0
CD3OD) d 2.18 (ddd, J2 (a),2 (b) ¼ 13.6, J2 (a),1 ¼ 7.0, J2 (a),3 ¼ 6.1Hz, 1H, H-2 (a)),
0
0
0
0
0
0
0
2.28 (ddd, J2 (b),2 (a) ¼ 13.6, J2 (b),1 ¼ 6.2, J2 (b),3 ¼ 3.8 Hz, 1H, H-2 (b)), 2.83 (tdd,
0
0
J7,F ¼ 16.5, J7, ¼ 4.6, J7(a),7(b) ¼ 3.9 Hz, 2H, H-7), 3.71 (dd, J5 (a),5 (b) ¼ 12.0,
8
0
0
0
0
0
0
0
J5 (a),4 ¼ 3.6 Hz, 1H, H-5 (a)), 3.79 (dd, J5 (b),5 (a) ¼ 12.0, J5 (b),4 ¼ 3.2 Hz, 1H, H-
50(b)), 3.91 (ddd, J4 ,5 (a) ¼ 3.6, J4 ,3 ¼ 3.4, J4 ,5 (b) = 3.2 Hz, 1H, H-40), 4.38 (ddd,
0
0
0
0
0
0
J3 ,2 (a) ¼ 6.1, J3 ,2 (b) ¼ 3.8, J3 ,4 ¼ 3.4Hz, 1H, H-30), 5.99 (tt, J8,F ¼ 57.1,
0
0
0
0
0
0
J8,7 ¼ 4.6 Hz, 1H, H-8), 6.24 (dd, J1 ,2 (a) ¼ 7.0, J1 ,2 (b) ¼ 6.2 Hz, 1H, H-10), 7.99 (s,
1H, H-6). 13C-NMR (62.896 MHz, CD3OD): d 32.96 (t, J7,F ¼ 24.4 Hz, C-7), 41.47
(C-20), 62.74 (C-50), 72.11 (C-30), 86.64 (C-10), 88.98 (C-40), 107.25 (C-5), 116.50 (t,
J8,F ¼ 239.4Hz, C-8), 141.36 (C-6), 152.06 (C-2), 165.49 (C-4). 19F-NMR
(235.34 MHz, CD3OD): d ꢄ41.77 (dtd, JF,H-8 ¼ 57.1, JF,H-7 ¼ 16.5, JF,F ¼ 10.5 Hz,
CF2H).
0
0
0
0
1-(2-Deoxy-a-D-erythro-pentafuranosyl)-5-(2,2-difluoroethyl)pyrimidin-2,4(3H)-
dione (6a). Pale yellow viscous gum, anal. C11H14N2O5F2, HRMS (FAB): m=z:
calcd 293.0949 [M þ H]þ, found 293.0954, þ0.5 mmu, calcd 315.0769 [M þ Na]þ;
found 315.0770, þ0.1 mmu, MW: 292.24, ESI þ Q1MS, M ¼ 292 (m=z);
[M þ H]þ ¼ 292.9,
[M þ Na]þ ¼ 314.9;
ESI ꢄ Q1MS,
M ¼ 292
(m=z);

4-O-Methyl-5-formylmethyl-20-deoxyuridine
81
[MꢄH]ꢄ ¼ 291.0, [M þ 35Cl]ꢄ ¼ 326.9, [2M ꢄ H]ꢄ ¼ 583.1 1H-NMR (250 MHz,
0
0
0
0
0
0
0
CD3OD) d 2.05 (ddd, J2 (a),2 (b) ¼ 14.6, J2 (a),1 ¼ 2.5, J2 (a),3 ¼ 2.0 Hz, 1H, H-2 (a)),
0
0
0
0
0
0
0
2.65 (ddd, J2 (b),2 (a) ¼ 14.6, J2 (b),1 ¼ 7.3, J2 (b),3 ¼ 6.0 Hz, 1H, H-2 (b)), 2.85 (td,
0
0
0
0
J7,F ¼ 16.7, J7,8 ¼ 4.6 Hz, 2H, H-7), 3.55 (dd, J5 (a),5 (b) ¼ 12.0, J5 (a),4 ¼ 4.5 Hz, 1H,
H-50(a)), 3.60 (dd, J5 (b),5 (a) ¼ 12.0, J5 (b),4 ¼ 4.3 Hz, 1H, H-5 (b)), 4.29 (td,
0
0
0
0
0
J4 ,5 (a) ¼ 4.5, J4 ,5 (b) ¼ 4.3, J4 ,3 ¼ 2.0 Hz, 1H, H-40), 4.34 (dt, J3 ,2 (b) ¼ 6.0,
0
0
0
0
0
0
0
0
0
0
0
0
0
J3 ,2 (a) ¼ 2.0, J3 ,4 ¼ 2.0 Hz, 1H, H-3 ), 5.98 (tt, J8,F ¼ 57.1, J8,7 ¼ 4.6 Hz, 1H, H-8),
6.17 (dd, J1 ,2 (b) ¼ 7.3, J1 ,2 (a) ¼ 2.5 Hz, 1H, H-10), 7.89 (s, 1H, H-6). 13C-NMR
(62.896 MHz, CD3OD): d 32.96 (t, J7,F ¼ 24.1Hz, C-7), 41.76 (C-20), 63.45 (C-50),
72.43 (C-30), 88.59 (C-10), 91.26 (C-40), 106.29 (t, J5,F ¼ 7.0 Hz, C-5), 116.49 (t,
J8,F ¼ 239.5 Hz, C-8), 142.04 (C-6), 152.16 (C-2), 165.76 (C-4). 19F-NMR
(235.34 MHz, CD3OD): d ꢄ41.58 (dtd, JF,H-8 ¼ 57.1, JF,H-7 ¼ 16.6, JF,F ¼ 9.1Hz,
CF2H).
0
0
0
0
1-(2-Deoxy-b-D-erythro-pentafuranosyl)-5-(2,2-difluoroethyl)-4-methoxypyrimi-
din-2-one (23). To a methanol solution of 22 (50 mg, 0.092 mmol, 1 mL) was added
NaOMe=MeOH (1 mL, 0.3 N). After 1 h, a solution of 1N HCl=ether was added to
neutralize the reaction. The solvent was then evaporated under reduced pressure at
40ꢃC. The residue obtained was chromatographed with MeOH=CHCl3 (1:9) to give
23 in 64% (18 mg) yield. Colorless crystals, mp: 155–157.5ꢃC, anal. C12H16N2O5F2,
HRMS (FAB): m=z: calcd 307.1106 [M þ H]þ, found 307.1144, þ3.9 mmu, calcd
329.0925 [M þ Na]þ; found 329.0961, þ3.6 mmu, MW: 306.25, ESI þ Q1MS,
M ¼ 306
(m=z);
[M þ H]þ ¼ 307.0,
[M þ Na]þ ¼ 329,
ESI ꢄ Q1MS,
[2M þ H]þ ¼ 613.2,
[2M þ Na]þ ¼ 635.2,
[3M þ Na]þ ¼ 941.2;
M ¼ 306
(m=z);
[MꢄH]ꢄ ¼ 304.8, [Mþ Cl]ꢄ ¼ 340.9, [2MꢄH]ꢄ ¼ 611.0, [2M þ 35Cl]ꢄ ¼ 647.0,
35
[3MꢄH]ꢄ ¼ 917.0. 1H-NMR (250 MHz, CD3OD) d 2.13 (ddd, J2 (a),2 (b) ¼ 13.6,
0
0
0
0
0
0
0
0
0
0
0
J2 (a),3 ¼ 6.3, J2 (a),1 ¼ 6.0 Hz, 1H, H-2 (a)), 2.43 (ddd, J2 (b),2 (a) ¼ 13.6, J2 (b),1 ¼ 6.2,
0
0
0
J2 (b),3 ¼ 4.4Hz, 1H, H-2 (b)), 2.92 (td, J7,F ¼ 16.6, J7,8 ¼ 4.5 Hz, 2H, H-7), 3.71
0
0
0
0
0
0
0 0
(dd, J5 (a),5 (b) ¼ 12.1, J5 (a),4 ¼ 3.7 Hz, 1H, H-5 (a)), 3.79 (dd, J5 (b),5 (a) ¼ 12.1,
0
0
0
0
0
0
J5 (b),4 ¼ 3.2 Hz, 1H, H-5 (b)), 3.95 (s, 3H, OCH3), 3.98 (ddd, J4 ,3 ¼ 4.1, J4 ,5 (a) ¼ 3.7,
J4 ,5 (b) ¼ 3.2 Hz, 1H, H-40), 4.35 (ddd, J3 ,2 (a) ¼ 6.3, J3 ,2 (b) ¼ 4.4, J3 ,4 ¼ 4.1Hz, 1H,
0
0
0
0
0
0
0
0
H-30), 5.98 (tt, J8,F ¼ 56.7, J8,7 ¼ 4.5 Hz, 1H, H-8), 6.19 (dd, J1 ,2 (b) ¼ 6.2, J1 ,
0
0
0
¼ 6.0 Hz, H-10), 8.30 (s, 1H, H-6). 13C-NMR (62.896 MHz, CD3OD): d 32.66
0
2 (a)
(t, J7,F ¼ 24.1Hz, C-7), 42.41 (C-20), 55.32 (4-O-CH3), 62.38 (C-50), 71.54 (C-30),
88.32 (C-10), 89.29 (C-40), 102.05 (t, J5,F ¼ 6.9 Hz, C-5), 116.52 (t, J8,F ¼ 239.6 Hz,
C-8), 144.95 (C-6), 157.87 (C-2), 171.88 (C-4). 19F-NMR (235.34 MHz, CD3OD):
d ꢄ 40.09 (dtd, JF,H-8 ¼ 56.7, JF,H-7 ¼ 16.5, JF,F ¼ 1.0 Hz, CF2H).
1-(2-Deoxy-a-D-erythro-pentafuranosyl)-5-(2,2-difluoroethyl)-4-methoxypyrimi-
din-2-one (23a). Colorless foam, anal. C12H16N2O5F2, HRMS (FAB): m=z: calcd
307.1106 [M þ H]þ, found 307.1122, þ1.6 mmu, calcd 329.0925 [M þ Na]þ; found
329.0930, þ0.5 mmu, MW: 306.25, ESI þ Q1MS, M ¼ 306 (m=z); [M þ Na]þ ¼ 328.8;
35
1
ESI ꢄ Q1MS, M ¼ 306 (m=z); [Mþ Cl]ꢄ ¼ 340.8 H-NMR (250 MHz, CD3OD) d
0
0
0
0
0
0
0
2.08 (ddd, J2 (a),2 (b) ¼ 14.6, J2 (a),1 ¼ 1.9, J2 (a),3 ¼ 1.7 Hz, 1H, H-2 (a)), 2.65 (ddd,
0
0
0
0
0
0
0
J2 (b),2 (a) ¼ 14.6, J2 (b),1 ¼ 7.0, J2 (b),3 ¼ 5.7 Hz, 1H, H-2 (b)), 2.88 (td, J7,F
¼
16.6, J7,8 ¼ 4.5 Hz, 2H, H-7), 3.55–3.59 (m, 2H, H-50), 3.94 (s, 3H, OCH3), 4.31
0
0
0
0
0
0
0
0
0
(dt, J3 ,2 (b) ¼ 5.7, J3 ,2 (a) ¼ 1.7, J3 ,4 ¼ 1.7 Hz, 1H, H-3 ), 4.36 (td, J4 ,5 ¼ 4.5,

82
Yu and Oberdorfer
0
0
0
J4 ,3 ¼ 1.7 Hz, 1H, H-4 ), 5.95 (tt, J8,F ¼ 56.8, J8,7 ¼ 4.5 Hz, 1H, H-8), 6.10
(dd, J1 ,2 (b) ¼ 7.0, J1 ,2 (a) ¼ 1.9 Hz, 1H, H-10), 8.01 (s, 1H, H-6). 13C-NMR
(62.896 MHz, CD3OD): d 32.62 (t, J7,F ¼ 24.1Hz, C-7), 42.18 (C-20), 55.28 (4-O-
CH3), 63.48 (C-50), 72.53 (C-30), 90.36 (C-10), 91.85 (C-40), 101.24 (t, J5,F ¼ 6.6 Hz,
C-5), 116.63 (t, J8,F ¼ 239.7 Hz, C-8), 145.38 (C-6), 157.98 (C-2), 171.98 (C-4). 19F-
0
0
0
0
NMR (235.34 MHz, CD3OD):
d
ꢄ41.62 (dtd, JF,H-8 ¼ 56.7, JF,H-7 ¼ 16.6,
JF,F ¼ 16.1Hz, CF2H).
1-(2-Deoxy-b-D-erythro-pentafuranosyl)-4-amino-5-(2,2-difluoroethyl)pyrimidin-
2-one (24). Compound 23 (14 mg, 0.046 mmol) was dissolved in the methanol solu-
tion (15 mL) which had been saturated with ammonia at 0ꢃC. The solution was
transferred to a Teflon tube which was sealed in a stainless reaction vessel. The reac-
tion was heated at 100ꢃC for 72 h. The solvent was then evaporated under reduced
pressure at 40ꢃC, while pale yellow crystals was formed on the inner wall of the flask.
These crystals were washed with cold methanol and dried under vacuum (4 mbar).
The yield of 24 was 83% (11 mg). Pale yellow crystals, mp: 185–191ꢃC, anal.
C11H15N3O4F2, HRMS (FAB): m=z: calcd 292.1109 [M þ H]þ, found 292.1099,
ꢄ1.0 mmu, calcd 314.0928 [M þ Na]þ, found 314.0930, þ0.2 mmu, MW: 291.26,
ESI þ Q1MS, M ¼ 291 (m=z); [M þ H]þ ¼ 291.8, [2M þ H]þ ¼ 583.0, [2M þ Na]þ ¼
35
605.0; ESI ꢄ Q1MS, M ¼ 291 (m=z); [MꢄH]ꢄ ¼ 289.9, [Mþ Cl]ꢄ ¼ 325.8,
35
[2MꢄH]ꢄ ¼ 581.1, [2Mþ Cl]ꢄ ¼ 617.0. 1H-NMR (250 MHz, CD3OD) d 2.13
0
0
0
0
0
0
0
(ddd, J2 (a),2 (b) ¼ 13.6 Hz, J2 (a),1 ¼ 6.9 Hz, J2 (a),3 ¼ 6.7 Hz, 1H, H-2 (a)), 2.34 (ddd,
0
0
0
0
0
0
0
J2 (b),2 (a) ¼ 13.6, J2 (b),1 ¼ 6.1, J2 (b),3 ¼ 4.1Hz, 1H, H-2 (b)), 2.92 (td, J7,F ¼ 16.9, J7,
0
0
0
0
0
¼ 4.3 Hz, 2H, H-7), 3.69 (dd, J5 (a),5 (b) ¼ 12.1, J5 (a),4 ¼ 3.8 Hz, 1H, H-5 (a)), 3.79
8
0
0
0
0
0
0
0
0
0
(dd, J5 (b),5 (a) ¼ 12.1, J5 (b),4 ¼ 3.2 Hz, 1H, H-5 (b)), 3.91 (td, J4 ,3 ¼ 3.8, J4 ,5 (a) ¼ 3.8,
J4 ,5 (b) ¼ 3.2 Hz, 1H, H-40), 4.34 (ddd, J3 ,2 (a) ¼ 6.7, J3 ,2 (b) ¼ 4.1, J3 ,4 ¼ 3.8 Hz, 1H,
0
0
0
0
0
0
0
0
H-30), 5.96 (tt, J8,F ¼ 56.4, J8,7 ¼ 4.3 Hz, 1H, H-8), 6.19 (dd, J1 ,2 (a) ¼ 6.9,
0
0
J1 ,2 (b) ¼ 6.1Hz, 1H, H-10), 8.00 (s, 1H, H-6). 13C-NMR (62.896 MHz, CD3OD): d
33.11 (t, J7,F ¼ 23.6 Hz, C-7), 42.20 (C-20), 62.61 (C-50), 71.79 (C-30), 87.66 (C-10),
88.95 (C-40), 99–100.5 (C-5)b, 116.75 (t, J8,F ¼ 240.2 Hz, C-8), 143.64 (C-6), 157.81
0
0
(C-2)b, 166.80 (C-4). 19F-NMR (235.34 MHz, CD3OD): d ꢄ39.82 (dtd, JF,H-8
56.4, JF,H-7 ¼ 16.9, JF,F ¼ 3.2 Hz, CF2H).
¼
1-(2-Deoxy-a-D-erythro-pentafuranosyl)-4-amino-5-(2,2-difluoroethyl)pyrimidin-
2-one (24a). Colorless crystals, mp: 173–177ꢃC, anal. C11H15N3O4F2, HRMS
(FAB): m=z: calcd 292.1109 [M þ H]þ, found 292.1100, ꢄ0.8 mmu, calcd 314.0928
[M þ Na]þ, found 314.0902, ꢄ2.6 mmu, MW: 291.26, ESI þ Q1MS, M ¼ 291
(m=z); [M þ H]þ ¼ 291.7, [M þ Na]þ ¼ 313.7, [2M þ H]þ ¼ 583.0, [2M þ Na]þ ¼
605.0, [3Mþ H]þ ¼ 874.1, [3M þ Na]þ ¼ 896.2; ESI ꢄ Q1MS, M ¼ 291 (m=z);
35
35
[MꢄH]ꢄ ¼ 289.7, [Mþ Cl]ꢄ ¼ 325.7, [2MꢄH]ꢄ ¼ 581.0, [2Mþ Cl]ꢄ ¼ 617.0,
35
[3MꢄH]ꢄ ¼ 872.1, [3Mþ Cl]ꢄ ¼ 907.8 1H-NMR (250 MHz, CD3OD) d 2.04 (d,
J2 (a),2 (b) ¼ 14.3 Hz, 1H, 0 H-20(a)), 2.64 (ddd, J2 (b),2 (a) ¼ 14.3, J2 (b),1 ¼ 7.1,
0
0
0
0
0
0
0
0
J2 (b),3 ¼ 6.3 Hz, 1H, H-2 (b)), 2.94 (td, J7,F ¼ 16.9, J7,8 ¼ 4.2 Hz, 2H, H-7), 3.52–
bThe signal of C-5 was very broad due to coupling with the two F’s. The signal of C-2 was
broad.

4-O-Methyl-5-formylmethyl-20-deoxyuridine
83
3.63 (m, 2H, H-50), 4.30–4.32 (m, 2H, H-30þH-4), 5.95 (tt, J8,F ¼ 56.5, J8,7 ¼ 4.3 Hz,
1H, H-8), 6.10 (dd, J1 ,2 (b) ¼ 7.1, J1 ,2 (a) ¼ 2.1Hz, 1H, H-10), 7.82 (s, 1H, H-6). 13C-
NMR (62.896 MHz, CD3OD): d 33.19 (t, J7,F ¼ 23.4Hz, C-7), 42.24 (C-20), 63.51
(C-50), 72.55 (C-30), 89.57 (C-10), 91.27 (C-40), 98.0–99.5 (C-5)b, 116.75 (t,
J8,F ¼ 240.3 Hz, C-8), 144.12 (C-6), 157.89 (C-2)b, 166.91 (C-4). 19F-NMR
(235.34 MHz, CD3OD): d ꢄ39.62 (dtd, JF,H-8 ¼ 56.5, JF,H-7 ¼ 16.9, JF,F ¼ 14.8 Hz,
CF2H).
0
0
0
0
Reduction of a,b form of aldehyde19 to a,b form of alcohol 18 with NaBH4
A a and b-mixture of 19 (10 mg, 0.019 mmol) in THF (1 mL) under dry N2 was
treated with NaBH4 (0.3 mg, 0.007 mmol). The solution color changed from color-
less to pale yellow. The stirring was continued at rt for 10 min. TLC (acetone=n-hex-
ane 1:1) indicated consumption of the starting material 19 (Rf ¼ 0.45) and 19a
(Rf ¼ 0.41) and formation of the product 18 (Rf ¼ 0.31) and 18a (Rf ¼ 0.24).[3]
After completion of the reaction, the solvent was evaporated under reduced pressure
at 40ꢃC. The residue obtained was chromatographed with acetone=n-hexane 1:1 to
1
give 18 and 18a (90%, 9 mg). The analytical data[10] of H- and 13C-NMR spectra
and mass spectra was consistent with the published data.
ACKNOWLEDGMENTS
We thank German Academic Exchange Service (DAAD) and DKFZ for the
financial support. We thank Prof. Chun-Hung Lin (Institute of Biological Chemis-
try, Academia Sinica, Taiwan) for his reviewing this manuscript.
REFERENCES
1. Springer, C.J.; Niculescu-Duvaz, I. Molecular imaging and gene therapy. Clin.
Invest. 2000, 105, 1161.
2. For reviews see (a) Nichol, C.; Kim, E.E. Imaging transgene expression with
radionuclide imaging technologies. J. Nucl. Med. 2001, 42, 1368. (b) Gambhir,
S.S.; Herschman, H.R.; Cherry, S.R.; Barrio, J.R.; Satyamurthy, N.; Toyokuni,
T.; Phelps, M.E.; Larson, S.M.; Balatoni, J.; Finn, R.; Sadelain, M.; Tjuvajev,
J.; Blasberg, R. Non-invasive radiotracer imaging as a tool for drug develop-
ment. Neoplasia 2000, 2, 118. (c) Gibson, R.E.; Burns, H.D.; Hamill, T.G.;
Eng, W.S.; Francis, B.E.; Ryan, C. Assays for noninvasive imaging of reporter
gene expression—Noninvasive radiotracer imaging as a tool for drug develop-
ment. Curr. Pharm. Design 2000, 6, 973. (d) Gambhir, S.S.; Bario, J.R.;
Herschman, H.R.; Phelps, M.E. Assays for noninvasive imaging of reporter
gene expression. Nucl. Med. Biol. 1999, 26, 481.
3. Yu, C.S.; Oberdorfer, F. Synthesis of 4-O-methyl-protected 5-(2-hydro-
xyethyl)-20-deoxyuridine derivatives and their nucleophilic fluorination to 5-
(2-Fluoroethyl)-20-deoxyuridine. Synthesis 1999, 2057.

84
Yu and Oberdorfer
4. (a) Yu, C.S.; Oberdorfer, F. Synthesis of (E)-5-[2-(tri-n-butylstannyl)vinyl]
substituted 20-deoxyuridine derivatives for use in halogenation and radiohalo-
genation reactions. Synlett 2000, 86. (b) Yu, C.S.; Eisenbarth, J.; Runz, A.;
Weber, K.; Zeisler, S.; Oberdorfer, F. Syntheses of 5-(2-radiohaloethyl)- and
5-(2-radiohalovinyl)-20-deoxyuridines: Novel types radiotracer for monitoring
cancer gene therapy with PET. J. Label. Compd. Radiopharm. 2003, 46, 1–19.
5. For reviews, see: (a) Kitazume, T.; Yamazaki, T. Chambers R.D., Ed.; Organo-
fluorine chemistry: techniques and synthons. Topics in Current Chemistry;
Springer Verlag: 1997; Vol. 193, 91–130. (b) Percy, J.M. Building block
approaches to aliphatic organofluorine compounds. Top. Curr. Chem. 1997,
193, 131.
6. Kuroboshi, M.; Kanie, K.; Hiyama, T. Oxidative desulfurization-fluorination:
A facile entry to a wide variety of organofluorine compounds leading to novel
liquid-crystalline materials. Adv. Synth. Catal. 2001, 343, 235.
7. Constantinou, M.; Aigbirhio, F.I.; Smith, R.G.; Ramsden, C.A.; Pike, V.W.
Xenon difluoride exchanges fluoride under mild conditions: A simple prepara-
tion of [F-18]Xenon difluoride for PET and mechanistic studies. J. Am. Chem.
Soc. 2001, 123, 1780.
8. Fissekis, J.D.; Sweet, F. The chemistry of some 5-(2-hydroxyalkyl)uracil deri-
vatives and a synthesis of 5-vinyluracil. J. Org. Chem. 1973, 38, 264–269.
Though 5-(2-hyroxyethyl)uracil 12 has been reported as early as in 1973 by Fis-
sekis et al., they failed in oxidation of the primary hydroxyl to obtain 5-formyl-
methyl uracil 10.
9. Bergstrom, D.E.; Agosta, W.C. The photosensitized cycloaddition of uracil to
vinylene carbonate: A route to 5-(formylmethyl)uracil and (þ)-5-(40,50-dihy-
droxypentyl)uracil. Tetrahedron Lett. 1974, 13, 1087.
10. Yu, C.S. PhD Thesis ‘‘Organic Preparative Requirements for Investigations on
the Preparation of 18F- and 80Br-Labelled Nucleoside Analogues. Useful Tools
for Monitoring Gene Therapy.’’ University of Heidelberg, Apr. 1999.
11. (a) Tidwell, T.T. In organic reactions. Paquette L.A. Ed.; Oxidation of Alcohols
to Carbonyl Compounds via Alkoxysulfonium Ylides: The Moffatt, Swern
and Related Oxidations John Wiley & Sons, 1990, Vol. 39, pp 304–307. (b)
Brossmer, R.; Ziegler, D. Zur darstellung heterocyclischer aldehyde. Tetrahe-
dron Lett. 1966, 5253.
12. Griengl, H.; Wanek, E.; Schwarz, W.; Streicher, W.; Rosenwirth, B.; De
Clercq, E. 20-fluorinated arabinonucleosides of 5-(2-haloalkyl)uracil: synthesis
and antiviral activity. J. Med. Chem. 1987, 30, 1199.
13. Wong, J.L.; Fuchs, D.S. Competitive isomerization and dealkylation of 2,4-
dialkoxy pyrimidines in aqueous and nonaqueous media. J. Org. Chem.
1970, 35, 3786.
Received March 29, 2002
Accepted October 22, 2002