A general route to 4-C-substituted pyrimidine nucleosides

Article abstract of DOI:10.1055/s-2007-965935

Palladium-catalyzed cross-coupling reactions of tin and zinc nucleophiles with arylsulfonates of pyrimidine nucleosides have been achieved to give a wide range of 4-C-substituted pyrimidine nucleosides. This method also allows the construction of pyrimidi

Full text of DOI:10.1055/s-2007-965935

PAPER
929
A General Route to 4-C-Substituted Pyrimidine Nucleosides
A
G
eneral Route to
l
4-C-S
r
ubstitute
i
d
Pyrim
c
idine Nuc
h
leosides Hennecke, David Kuch, Thomas Carell*
Fakultät für Chemie und Pharmazie, Ludwig-Maximilians-Universität München, Butenandtstr. 5-13 Haus F, 81377 München, Germany
Fax +49(89)218077756; E-mail: thomas.carell@cup.uni-muenchen.de
Received 2 November 2006; revised 21 December 2006
terial we chose the 2,4,6-triisopropylbenzenesulfonates of
Abstract: Palladium-catalyzed cross-coupling reactions of tin and
various uridine derivatives such as 1, 2, 3 (Figure 1 and
Scheme 1). These compounds are conveniently prepared
in high yields from the corresponding uridine nucleosides
zinc nucleophiles with arylsulfonates of pyrimidine nucleosides
have been achieved to give a wide range of 4-C-substituted pyrimi-
dine nucleosides. This method also allows the construction of pyri-
midine-pyrimidinone dinucleosides, containing the carbon skeleton and can be easily purified by column chromatography.
of the (6-4) DNA photo lesion.
The compounds are stable and can be stored at –20 °C for
months.8 In contrast, the corresponding chlorides were, at
Key words: cross-coupling, nucleosides, palladium, pyrimidines,
(6-4) lesion
least in our hands, unstable. In addition, the methods used
for their preparation (using SOCl2 for example) are gener-
ally not compatible with many of the typically used pro-
tecting groups of the sugar hydroxyl groups.
Nucleosides and nucleoside analogues belong to the most
important classes of antiviral and antitumor drugs. Even
today, around 30 years after the discovery of the first suc-
cessful antiviral drug, acyclovir, plenty of new nucleoside
derivatives, many of them pyrimidine derivatives, are
synthesized and tested.1,2 Compared to other substituted
pyrimidine nucleosides, C4-substituted pyrimidines, es-
pecially 2-pyrimidinones, are quite rare in the literature.
In fact, a general method for their synthesis from a com-
mon precursor is missing. Most of the known compounds
have been prepared by glycosylation of the preassembled
heterocycle with a suitable glycosyl donor.3,4 2-Pyrimidi-
none nucleosides are not only of pharmacological interest,
but they occur also in nature, for example as part of the
carbon framework of the (6-4) DNA photo lesion, which
is one of the major mutagenic and cytotoxic lesions
known in DNA.5
1: R = R1
O
S
O
O
2: R = R2
N
3: R = R3
N
R
O
TolO
TBSO
TrO
O
O
O
O
O
Si
O
O
TolO
TBSO
O
O
Si
R1
R2
R3
R4
Figure 1 Structures of the starting materials used
Both 4-N- and 4-O-substituted pyrimidines can be easily
prepared from uridines by conversion of the O4 into a
suitable leaving group (for example a chloride or an aryl-
sulfonate) and substitution of this leaving group by a ni-
trogen or oxygen nucleophile.6,7 For carbon nucleophiles,
however, this reaction is limited to extremely nucleophilic
compounds such as malonic diesters.8 Organometallic nu-
cleophiles like organolithium or organocopper com-
pounds react only sluggishly or, like alkyl Grignard
reagents, add preferentially to the 6-position without sub-
stituting the leaving group.9 We anticipated that these
problems can be overcome by using palladium catalysis,
which is of increasing importance in contemporary purine
nucleoside chemistry.10–14 Two examples for the synthesis
of 4-carbon substituted pyrimidine nucleosides using pal-
ladium-catalyzed cross-coupling are known, but are not
generally applicable, limited to alkyne nucleophiles (So-
nogashira coupling), or low yielding.15,16 As starting ma-
R5
O
S
MR5
N
O
O
[Pd catalysis]
N
R
O
N
N
R
O
Scheme 1 General reaction scheme; M = SnBu3, ZnCl; R5 = alkyl,
alkenyl, aryl, heteroaryl
Initial attempts to use the arylsulfonates in Suzuki cross-
coupling reactions or in Heck reactions were unsuccess-
ful. Under the elevated temperatures needed for the acti-
vation of the arylsulfonates they quickly hydrolyzed back
to uridine. Therefore we focused our attention on Stille
and Negishi couplings as they usually proceed at lower
temperatures and do not need a base. As a first attempt, the
Stille coupling of phenylethynyltributyltin (4) with 1 was
investigated (Table 1, entry 1). Gratifyingly, the reaction
gave the desired product smoothly under fairly standard
conditions [DMF, Pd(PPh3)4, CuI, 55 °C, 24 h]. Without
CuI or with other additives (Bu4NBr), the arylsulfonate
SYNTHESIS 2007, No. 6, pp 0929–0935
x
x
.
x
x
.2
0
0
7
Advanced online publication: 13.02.2007
DOI: 10.1055/s-2007-965935; Art ID: T16506SS
© Georg Thieme Verlag Stuttgart · New York

930
U. Hennecke et al.
PAPER
hydrolysis created problems. The reaction conditions
proved to be quite generally applicable, as under these
conditions other tin nucleophiles and the arylsulfonates 2
and 3 could be applied equally well (Table 1). Alkynyl,
alkenyl and heteroaromatic tin nucleophiles could be used
and, usually, the desired products were obtained after col-
umn chromatography in high purity and good yields.
Table 1 Stille-Type Cross Coupling of 4-(2,4,6-Triisopropylben-
zenesulfonate)pyrimidine Nucleosidesa
Entry Substrate Nucleophile
Product
Yield (%)
SnBu3
Quite surprising was the reaction of the acrylic acid nu-
cleophiles. The reaction of (E)- and (Z)-3-tributylstannyl-
acrylic acid tert-butyl ester (entries 3 and 4) gave
exclusively the same product featuring the E-configured
double bond. Interestingly the reaction of the E-nucleo-
phile was slow and only the use of 2.5 equivalents of the
tin compound gave acceptable yields. To investigate the
influence of the bulky tert-butyl ester, the reaction was
carried out with (E)- and (Z)-3-tributylstannylacrylic acid
methyl ester (entries 5 and 6). Again, the product with the
E-configured double bond was usually the only product.
In one or two cases, however, a E/Z-product mixture was
isolated from the reaction when the Z-configured nucleo-
phile 7 was used. Upon standing at room temperature, the
chloroform solution of Z-configured product isomerized
within two days to the E-compound. This possibly ex-
plains the outcome of our reactions: The Stille coupling
proceeds, as it is generally the case, with retention of con-
figuration at the double bond.17 Afterwards the isomeriza-
tion from the Z- to the E-double bond geometry takes
place in a second step by a yet unknown mechanism.
1
1
64
N
N
O
4
R1
11
S
SnBu3
N
2
3
4
5
2
3
3
2
76
S
N
O
5
R2
12
COOt-Bu
COOt-Bu
N
O
48b
Bu3Sn
N
6
R3
13
COOt-Bu
COOt-Bu
N
71
SnBu3
7
N
O
After the successful application of the tin nucleophiles,
we also investigated the reaction of the arylsulfonates
with zinc organometallics (Negishi coupling, Table 2).
Phenylzinc chloride (derived from phenyl-Grignard and
zinc chloride) reacted with 1 under conditions fairly sim-
ilar to the Stille couplings above [Pd(PPh3)4, THF] even at
room temperature to give the 4-phenyl-2-pyrimidinone
nucleoside 18 in good yield (Table 2, entry 1). The ease of
this reaction prompted us to investigate the cross-coupling
of the sterically more demanding thymidine nucleoside
16. To our surprise the reaction proceeded also smoothly
but required longer reaction times (3 d, entry 2). In this
case, the application of 2.5 mol% Pd(dppf)Cl2 as catalyst
was superior to Pd(PPh3)4, as it allowed easier removal of
the catalyst from the product. Using this protocol, even
sp3-sp2 cross-couplings were possible. Dimethylzinc or n-
butylzinc chloride could be coupled using Pd(PPh3)4.
Here, however, the yields were slightly lower. The cata-
lyst loading for the reaction with dimethylzinc can be as
low as 0.5% without any loss of yield. The use of
Pd(dppf)Cl2, a catalyst known to suppress the problematic
b-hydride elimination, for the reaction with n-butylzinc
chloride did not improve the yield.18
R3
13
COOMe
COOMe
N
O
71b
Bu3Sn
N
8
R2
14
COOMe
COOMe
6
7
2
2
N
O
76
SnBu3
9
N
R2
14
O
O
HN
HN
64c
N
O
O
N
R4
O
N
R4
10
SnBu3
N
R2
15
a Conditions: arylsulfonate (1 equiv), tin nucleophile (1.5 equiv), CuI
(20 mol%), Pd(PPh3)4 (10 mol%), DMF, 24 h, 55 °C. For R1–R4, see
Figure 1.
As our method works under very mild conditions, we pre-
pared the highly functionalized 6-tributylstannyluridine
nucleoside 10 (Table 1, entry 7, two steps from uridine).19
This stannylated nucleoside was anticipated to function as
a precursor for the dihydropyrimidine part of the (6-4)
DNA lesion on the way towards the first total synthesis of
the lesion. Coupling of this compound to arylsulfonate 2
b 2.5 equiv of tin nucleophile was used.
c 1 equiv of tin nucleophile was used.
Synthesis 2007, No. 6, 929–935 © Thieme Stuttgart · New York

PAPER
A General Route to 4-C-Substituted Pyrimidine Nucleosides
931
ficult and needs further optimization (isolated yield 41%).
Deprotection of compound 13 is an especially difficult
task due to the highly electrophilic double bond bearing
two electron-withdrawing substituents.20 Nevertheless
deprotection was possible in our hands using sodium
methoxide and short reaction times. These conditions
gave the unprotected nucleoside, (E)-3-[1-(2¢-deoxyribo-
furanosyl)-2-(1H)-pyrimidinon-4-yl]acrylic acid tert-bu-
tyl ester (23) as the major product (isolated yield 38%).
Minor side products were formed due to Michael-type
addition to the double bond.
Table 2 Negishi-Type Cross-Coupling of 4-(2,4,6-Triisopropyl-
benzenesulfonate)pyrimidine Nucleosidesa
Entry Substrate
Nucleophile Product
Yield (%)
ZnBr
1
1
74
N
N
R1
O
17
18
OSO2Ar
N
In summary, we have developed a new method for the
synthesis of 4-carbon substituted uridines, capable of in-
troducing sp-, sp2- and sp3-carbon substituents. This
method will provide an expedient route towards the as-
sembly of the carbon framework of the (6-4) DNA lesion.
ZnBr
2
3
4
68b
61c
48
N
N
O
O
TBSO
N
O
17
16
R2
OTBS
19
All reactions were carried out in Schlenk glassware under an inert
gas atmosphere. Reactions were monitored by TLC. Yields refer to
isolated yields of analytically pure compounds. Pre-coated silica gel
60F254 (Merck) was used for TLC, silica gel 60 (0.040–0.063 mm,
Merck) was used for column chromatography. NMR spectra were
recorded on Varian or Bruker NMR spectrometers (300, 400 or 600
MHz). Mass spectra were measured on a Finnigan MAT 95 Q
(FAB) or a Finnigan LTQ-FT (ESI). IR spectroscopy was per-
formed on a PerkinElmer FT-IR spectrum 100 or a PerkinElmer
Spectrum BX. The following compounds were prepared by litera-
ture procedures: 2¢,3¢-O-isopropylidene-5¢-O-trityluridine,21 2¢-
deoxy-3¢,5¢-bis-O-(tert-butyldimethylsilyl)-4-O-[(2,4,6-triisopro-
pylbenzene)sulfonyl]uridine (2),22 3¢,5¢-bis-O-(tert-butyldimethyls-
ilyl)-4-O-[(2,4,6-triisopropylbenzene)sulfonyl]thymidine (16),8 2¢-
deoxy-3¢,5¢-O-(1,1,3,3-tetraisopropyl-1,3-disiloxanediyl)uridine,23
(E)- and (Z)-3-tributylstannylacrylic acid methyl ester (8 and 9) and
(E)- and (Z)-3-tributylstannylacrylic acid tert-butyl ester (6 and
7).24
N
2
2
Me2Zn
N
O
R2
20
BuZnCl
N
N
R2
O
21
a Conditions: arylsulfonate (1 equiv), zinc nucleophile (2 equiv),
Pd(PPh3)4 (10 mol%), THF, r.t. Ar = 2,4,6-triisopropylbenzene. For
R1 and R2, see Figure 1.
b Pd(dppf)Cl2 (2.5 mol%) instead of Pd(PPh3)4; reaction time: 3 d.
c 0.5 mol% catalyst was used.
2¢,3¢-O-Isopropylidene-5¢-O-trityl-4-O-[(2,4,6-triisopropylben-
zene)sulfonyl]uridine (1)
gave the interesting pyrimidine-pyrimidinone dinucleo-
side 15 in fairly good 68% yield. This dinucleoside con-
tains the complete carbon framework of the (6-4) lesion
derived from a CC (or UC) dinucleotide and should there-
fore be a highly valuable starting material for the total
synthesis of this biologically interesting lesion (Figure 2).
2¢,3¢-O-Isopropylidene-5¢-O-trityluridine (1.00 g, 1.9 mmol) was
dissolved in THF (25 mL). NaH (60% suspension in mineral oil,
360 mg, 9.0 mmol) was carefully added and the resulting suspen-
sion was stirred for 45 min at r.t. 2,4,6-Triisopropylbenzenesulfo-
nylchloride (983 mg, 3.2 mmol) was added and the suspension was
stirred for 14 h at r.t. Aq sat. NH4Cl (30 mL) was added and the
aqueous phase was extracted with EtOAc (2 × 30 mL). The com-
bined organic phases were washed with brine (40 mL), dried
(MgSO4), filtered and the solvent was removed under vacuum. The
crude product was purified by flash chromatography (silica gel, iso-
hexanes–EtOAc, 4:1) to give the product (820 mg, 54%) as a color-
less oil; Rf = 0.21 (isohexanes–EtOAc, 4:1).
O
O
NH2
N
HN
HN
O
N
O
O
N
O
N
N
N
O
O
O
O
IR (KBr): 3059, 2962, 2932, 2872, 1693, 1631, 1599, 1543, 1450,
1384, 1279, 1196, 1187, 1157, 1113, 1074, 809, 777, 706, 558 cm–1.
OH
OTBS
OTBS
OH
O
TIPDS
OH
O
OH
15
1H NMR (300 MHz, CDCl3): d = 1.23–1.29 [m, 18 H, CH(CH3)3],
1.33 [s, 3 H, C(CH3)2], 1.55 [s, 3 H, C(CH3)2], 2.85–2.96 [m, 1 H,
para CH(CH3)3], 3.36 (dd, J = 10.8, 4.8 Hz, 1 H, H-5¢A), 3.48 (dd,
J = 10.8, 2.7 Hz, 1 H,, H-5¢B), 4.18–4.29 [m, 2 H, ortho CH(CH3)3],
4.42–4.47 (m, 1 H, H-4¢), 4.73–4.80 (m, 2 H, H-2¢, H-3¢), 5.64 (d,
J = 7.2 Hz, 1 H, H-5), 5.89 (d, J = 1.2 Hz, 1 H, H-1¢), 7.20 (s, 2
Figure 2 Comparison of the (6-4) lesion derived from UC or CC
(after imine hydrolysis) and compound 15
Initial deprotection experiments were performed with the
compounds 12 (TBS-protected) 13 (toluoyl-protected).
Compound 12 could be deprotected using HF/pyridine to
give the unprotected nucleoside, 1-(2¢-deoxyribofurano-
syl)-4-thienyl-2-(1H)-pyrimidinone (22). The purification
Harom), 7.26–7.36 (m, 15 H, 3 C6H5), 8.07 (d, J = 7.2 Hz, 1 H, H-6).
13C NMR (75 MHz, CDCl3): d = 23.5 (2 C), 24.5 (2 C), 24.6 (2 C),
25.3, 27.2, 29.6 (2 C), 34.3, 63.3, 80.0, 85.9, 87.0, 87.6, 93.8, 94.7,
114.1, 124.0 (2 C), 127.5 (3 C), 128.0 (6 C), 128.6 (6 C), 130.6,
of the highly polar product, however, was as expected dif- 142.9 (3 C), 146.1, 151.2 (2 C), 153.7, 154.5, 167.1.
Synthesis 2007, No. 6, 929–935 © Thieme Stuttgart · New York

932
U. Hennecke et al.
PAPER
HRMS-ESI (+): m/z [M + HNEt3]+ calcd for C52H68N3O8S:
894.4722; found: 894.4717.
13C NMR (75 MHz, CDCl3): d = 11.6 (3 C), 12.6, 12.7, 13.3 (2 C),
13.6 (3 C), 17.0 (2 C), 17.2, 17.3, 17.4 ( 2C), 17.5, 17.6, 27.1 (3 C),
28.7 (3 C), 39.8, 64.1, 73.6, 85.9, 94.0, 110.7, 149.6, 161.6, 167.8.
2¢-Deoxy-3¢,5¢-bis-O-(4-toluoyl)-4-O-[(2,4,6-triisopropylben-
zene)sulfonyl]uridine (3)
HRMS-ESI (–): m/z [M – H]– calcd for C33H63N2O6Si2Sn: 759.3252;
found: 759.3250.
2¢-Deoxy-3¢,5¢-bis-O-(4-toluoyl)uridine (300 mg, 0.65 mmol) was
dissolved in THF (20 mL). NaH (60% suspension in mineral oil,
129 mg, 3.23 mmol) was carefully added and the resulting suspen-
sion was stirred for 45 min at r.t. 2,4,6-Triisopropylbenzenesulfonyl
chloride (392 mg, 1.29 mmol) was added and the suspension was
stirred for 14 h at r.t. Aq sat. NH4Cl (30 mL) was added and the
aqueous phase was extracted with EtOAc (2 × 30 mL). The com-
bined organic phases were washed with brine (40 mL), dried
(MgSO4), filtered and the solvent was removed under vacuum. The
crude product was purified by flash chromatography (silica gel, iso-
hexanes–EtOAc, 4:1) to give the product (407 mg, 86%) as a white,
amorphous solid.
Stille-Type Cross Couplings; General Procedure
Arylsulfonate (1 equiv), tin reagent (1.5 equiv), CuI (0.2 equiv) and
(Ph3P)4Pd (0.1 equiv) were dissolved in DMF (1 mL per 0.1 mmol
arylsulfonate). The solution was stirred 55 °C for 24 h. After cool-
ing to r.t., the solvent was removed under vacuum and the crude
product was purified by flash chromatography (silica gel, isohex-
anes–EtOAc, 1:1).
1-(2¢,3¢-O-Isopropylidene-5¢-O-tritylribofuranosyl)-4-(phenyl-
ethynyl)-2-(1H)-pyrimidinone (11)
The standard procedure was followed using arylsulfonate 1 (150
mg, 0.19 mmol), (phenylethynyl)tributyltin (98 mL, 0.28 mmol),
CuI (8 mg, 0.04 mmol) and (Ph3P)4Pd (23 mg, 0.02 mmol) affording
the product (74 mg, 64%) as a colorless oil; Rf = 0.30 (isohexanes–
EtOAc, 1:1).
IR (KBr): 2962, 2871, 1717, 1688, 1628, 1611, 1543, 1463, 1382,
1273, 1180, 1101, 1020, 754, 691, 556 cm–1.
1H NMR (600 MHz, CDCl3): d = 1.23–1.32 [m, 18 H, CH(CH3)3]
2.14–2.20 (m, 1 H, H-2¢A), 2.42 (s, 6 H, ArCH3), 2.86–2.94 [m, 1
H, para CH(CH3)3], 3.05 (ddd, J = 14.4, 5.7 Hz, 1.5 Hz, 1 H, H-
2¢B), 4.22–4.28 [m, 2 H, ortho CH(CH3)3], 4.59–4.62 (m, 1 H, H-
4¢), 4.65 (dd, J = 12.0, 3.6 Hz, 1 H, H-5¢A), 4.75 (dd, J = 12.0, 3.0
Hz, 1 H, H-5¢B), 5.54–5.57 (m, 1 H, H-3¢), 5.94 (d, J = 7.2 Hz, 1 H,
H-5), 6.21 (dd, J = 7.8, 5.4 Hz, 1 H, H-1¢), 7.20 (s, 2 Harom), 7.22–
7.27 (m, 4 H, Htol), 7.80–7.83 (m, 2 H, Htol), 7.90–7.93 (m, 2 H,
Htol), 8.07 (d, J = 7.2 Hz, 1 H, H-6).
13C NMR (150 MHz, CDCl3): d = 21.7 (2 C), 23.4 (2 C), 24.4 (2 C),
24.6 (2 C), 29.6 (2 C), 34.2, 39.3, 63.9, 74.8, 84.0, 88.0, 95.0, 124.0
(2 C), 126.2, 126.3, 129.2 (2 C), 129.4 (4 C), 129.8 (2 C), 130.5,
144.5 (2 C), 144.6, 151.2 (2 C), 153.6, 154.5, 166.0, 166.0, 167.1.
IR (film): 3086, 3060, 2988, 2931, 2871, 2217s, 1661, 1611, 1505,
1492, 1448, 1383, 1374, 1314, 1271, 1213, 1158, 1114, 1078, 910,
876, 791, 759, 732, 707, 632, 541 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.36 (s, 3 H, CH3), 1.59 (s, 3 H,
CH3), 3.40 (dd, J = 10.8, 5.1 Hz, 1 H, H-5¢A), 3.51 (dd,
J = 10.8, 2.9 Hz, 1 H, H-5¢B), 4.47–4.52 (m, 1 H, H-4¢), 4.76 (dd,
J = 6.2, 3.5 Hz, 1 H, H-3¢), 4.91 (dd, J = 6.2, 1.5 Hz, 1 H, H-2¢),
5.97 (d, J = 1.5 Hz, 1 H, H-1¢), 6.15 (d, J = 6.9 Hz, 1 H, H-5), 7.25–
7.45 [m, 18 H, C≡CC6H5 + C(C6H5)3], 7.58–7.62 (m, 2 H,
C≡CC6H5), 8.10 (d, J = 6.9 Hz, 1 H, H-6).
13C NMR (75 MHz, CDCl3): d = 25.3, 27.2, 63.5, 80.3, 85.9, 87.1,
87.2, 87.5, 94.5, 95.8, 106.4, 114.0, 120.8, 127.4 (3 C), 128.0 (6 C),
128.5 (8 C), 130.3, 132.7 (2 C), 143.1 (3 C), 143.7, 154.6, 159.2.
HRMS-ESI (+): m/z [M + Na]+ calcd for C40H46N2O9S + Na:
753.2816; found: 753.2829.
HRMS-FAB (+): m/z [M + H]+ calcd for C39H35N2O5: 611.2540;
found: 611.2555.
2¢-Deoxy-3¢,5¢-O-(1,1,3,3-tetraisopropyl-1,3-disiloxanediyl)-6-
(tributylstannyl)uridine (10)
Diisopropylamine (0.35 mL, 2.5 mmol) was dissolved in THF (6
mL) and cooled to 0 °C. n-BuLi (1.6 M in hexanes, 1.58 mL, 2.5
mmol) was added dropwise and the solution was stirred for 1 h at
0 °C. The solution was cooled to –78 °C and 2¢-deoxy-3¢,5¢-O-
(1,1,3,3-tetraisopropyl-1,3-disiloxanediyl)uridine (295 mg, 0.6
mmol) in THF (4 mL) was added dropwise. The resulting yellow
solution was stirred for 2 h at –78 °C. Bu3SnCl (0.34 mL, 1.3 mmol)
was added dropwise and the solution was stirred for 100 min at
–78 °C. Aq sat. NH4Cl solution (20 mL) and EtOAc (20 mL) were
added, the layers were separated and the aqueous phase was extract-
ed with EtOAc (2 × 20 mL). The combined organic phases were
washed with brine (40 mL), dried (MgSO4), filtered and the solvent
was removed under vacuum. The crude product was purified by
flash chromatography (silica gel, isohexanes–EtOAc, 6:1) to give
the product (357 mg, 75%) as a colorless oil; Rf = 0.69 (isohexanes–
EtOAc, 4:1).
1-[2¢-Deoxy-3¢,5¢-bis-O-(tert-butyldimethylsilyl)ribofuranosyl]-
4-thienyl-2-(1H)-pyrimidinone (12)
The standard procedure was followed using arylsulfonate 2 (144
mg, 0.2 mmol), 2-tributyltinthiophene (5; 100 mL, 0.3 mmol), CuI
(8 mg, 0.04 mmol) and (Ph3P)4Pd (23 mg, 0.02 mmol) affording the
crude product. The crude product was purified by flash chromatog-
raphy (silica gel, isohexanes–EtOAc, 2:1) to give the title com-
pound (79 mg, 76%) as a colorless oil; Rf = 0.76 (isohexanes–
EtOAc, 1:1).
IR (ATR): 3087, 2954, 2929, 2856, 1646, 1608, 1530, 1512, 1446,
1417, 1336, 1308, 1249, 1179, 1095, 1065, 1032, 947, 878, 832,
776, 706, 668 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.04 (s, 3 H, SiCH3), 0.05 (s, 3 H,
SiCH3), 0.11 (s, 3 H, SiCH3), 0.12 (s, 3 H, SiCH3), 0.87 (s, 9 H, t-
C4H9), 0.93 (s, 9 H, t-C4H9), 2.18 (ddd, J = 13.5, 6.6, 4.5 Hz, 1 H,
H-2¢A), 2.50–2.61 (m, 1 H, H-2¢B), 3.74–3.82 (m, 1 H, H-5¢A),
3.92–4.00 (m, 2 H, H-4¢, H-5¢B), 4.33–4.42 (m, 1 H, H-3¢), 6.25 (dd,
J = 6.6, 4.5 Hz, 1 H, H-1¢), 6.61 (d, J = 7.1 Hz, 1 H, H-5), 7.13 (dd,
J = 5.1, 3.6 Hz, 1 H, H-4thienyl), 7.57 (dd, J = 5.1, 1.2 Hz, 1 H, H-
IR (ATR): d = 3261, 2924, 2868, 1712, 1680, 1558, 1462, 1428,
1368, 1336, 1231, 1158, 1088, 1065, 1029, 962, 886, 864, 825, 784,
690 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.87–1.69 [m, 55 H, Sn(C4H9)3 +
CH(CH3)3], 2.24–2.35 (m, 1 H, H-2¢A), 2.91–3.02 (m, 1 H, H-2¢B),
3.73–3.81 (m, 1 H, H-4¢), 3.97–4.03 (m, 2 H, H-5¢), 4.94–5.04 (m,
1 H, H-3¢), 5.32 (dd, J = 9.0, 3.3 Hz, 1 H, H-1¢), 5.58–5.70 (m, 1 H,
H-5), 8.09 (br s, 1 H, NH).
3
thienyl), 7.76 (dd, J = 3.6, 1.2 Hz, 1 H, H-5thienyl), 8.41 (d, J = 7.1 Hz,
1 H, H-6).
13C NMR (75 MHz, CDCl3): d = –5.5, –5.5, –5.0, –4.6, 17.9, 18.3,
25.7 (3 C), 25.9 (3 C), 42.2, 61.6, 69.7, 87.0, 87.7, 99.6, 128.3,
129.8, 132.5, 141.8, 143.0, 155.3, 165.4.
HRMS-ESI (+): m/z [M + HNEt3]+ calcd for C31H58N3O4SSi2:
624.3681; found: 624.3660.
Synthesis 2007, No. 6, 929–935 © Thieme Stuttgart · New York

PAPER
A General Route to 4-C-Substituted Pyrimidine Nucleosides
933
(E)-3-1-[2¢-Deoxy-3¢,5¢-bis-O-(4-toluoyl)ribofuranosyl]-2-(1H)-
pyrimidinon-4-yl-acrylic Acid tert-Butyl Ester (13)
Using (Z)-3-Tributyltinacrylic Acid tert-Butyl Ester (7): The stan-
dard procedure was followed using arylsulfonate 3 (730 mg, 0.19
mmol), ester 7 (670 mg, 1.6 mmol), CuI (38 mg, 0.2 mmol) and
(Ph3P)4Pd (116 mg, 0.1 mmol) affording the product (405 mg, 71%)
as a white, amorphous solid; Rf = 0.46 (isohexanes–EtOAc, 1:1).
1-[2¢-Deoxy-3¢,5¢-bis-O-(tert-butyldimethylsilyl)ribofuranosyl]-
4-[2¢-deoxy-3¢,5¢-O-(1,1,3,3-tetraisopropyl-1,3-disiloxanediyl)-
6-uridyl]-2-(1H)-pyrimidinone (15)
The standard procedure was followed except that only 1 equiv of tin
reagent was used and that the reaction time was prolonged to 48 h.
Arylsulfonate (2; 876 mg, 1.2 mmol), tin reagent 10 (920 mg, 1.2
mmol), CuI (46 mg, 0.2 mmol) and (Ph3P)4Pd (140 mg, 0.1 mmol)
afforded the product (706 mg, 64%) as a colorless oil; Rf = 0.72
(isohexanes–EtOAc, 1:1).
IR (KBr): 2978, 1718, 1664, 1612, 1518, 1452, 1370, 1312, 1272,
1179, 1154, 1106, 1020, 976, 843, 794, 754, 692 cm–1.
IR (ATR): 2950, 2930, 2865, 1672, 1518, 1463, 1387, 1364, 1279,
1263, 1091, 1029, 916, 884, 833, 776, 692 cm–1.
1H NMR (600 MHz, CDCl3): d = 1.52 (s, 9 H, t-C4H9), 2.27–2.33
(m, 1 H, H-2¢A), 2.40 (s, 3 H, CH3), 2.44 (s, 3 H, CH3), 3.19–3.24
(m, 1 H, H-2¢B), 4.66 (dd, J = 12.0, 3.0 Hz, 1 H, H-5¢A), 4.67–4.70
(m, 1 H, H-4¢), 4.79 (dd, J = 12.0, 1.8 Hz, 1 H, H-5¢B), 5.59–5.62
(m, 1 H, H-3¢), 6.30 (d, J = 7.2 Hz, 1 H, H-5), 6.33–6.36 (m, 1 H,
1H NMR (600 MHz, CDCl3): d = 0.08 (s, 3 H, SiCH3), 0.09 (s, 3 H,
SiCH3), 0.11 (s, 3 H, SiCH3), 0.12 (s, 3 H, SiCH3), 0.90 (s, 9 H, t-
C4H9), 0.92 (s, 9 H, t-C4H9), 0.97–1.38 [m, 28 H, CH(CH3)3], 2.20–
2.26 (m, 1 H, H-2¢A2Py) 2.36–2.42 (m, 1 H, H-2¢AUr), 2.63–2.69 (m,
1 H, H-2¢B2Py), 2.93–2.99 (m, 1 H, H-2¢BUr), 3.69–3.73 (m, 1 H, H-
4¢Ur), 3.78–3.82 (m, 1 H, H-5¢A2Py), 3.93–3.97 (m, 2 H, H-5¢Ur),
3.98–4.02 (m, 1 H, H-5¢B2Py), 4.02–4.05 (m, 1 H, H-4¢2Py), 4.39–
4.44 (m, 1 H, H-3¢2Py), 4.92–4.98 (m, 1 H, H-3¢Ur), 5.67 (dd,
J = 9.0, 3.0 Hz, 1 H, H1¢Ur), 5.79 (s, 1 H, H-5Ur), 6.18–6.22 (m, 1 H,
H-1¢2Py), 6.54 (d, J = 6.9 Hz, 1 H, H-52Py), 8.15 (s, 1 H, NH), 8.69
(d, J = 6.9 Hz, 1 H, H-62Py).
13C NMR (150 MHz, CDCl3): d = –5.5 (2 C), –4.9, –4.5, 12.5, 12.6,
13.2, 13.6, 17.0 (2 C), 17.1, 17.3, 17.4 (2 C), 17.5, 17.6, 17.9, 18.3,
25.7 (3 C), 25.9 (3 C), 40.2, 42.4, 61.7, 64.1, 70.0, 73.6, 86.4, 87.4,
88.0, 88.4, 102.7, 104.4, 145.8, 149.1 152.1, 154.1, 161.5, 167.0.
HRMS-ESI (+): m/z [M + H]+ calcd for C42H77N4O10Si4: 909.4711;
found: 909.4734.
H-1¢), 6.85 (d, J = 16.2 Hz, 1 H, CH=CH), 7.19–7.30 (m, 5 H, Harom
,
CH=CH), 7.78–7.82 (m, 2 Harom), 7.93–7.98 (m, 2 Harom), 8.13 (d,
J = 7.2 Hz, 1 H, H-6).
13C NMR (150 MHz, CDCl3): d = 21.6, 21.7, 28.0 (3 C), 39.6, 64.1,
75.0, 81.7, 84.2, 88.5, 103.0, 126.2, 126.3, 129.3 (2 C), 129.4 (4 C),
129.8 (2 C), 131.2, 139.4, 142.7, 144.5 (2 C), 155.1, 164.6, 166.0,
166.1, 168.4.
HRMS-ESI (+): m/z [M + H]+ calcd for C32H35N2O8: 575.2388;
found: 575.2379.
Using (E)-3-Tributyltinacrylic Acid tert-Butyl Ester (6): The stan-
dard procedure was followed except that 2.5 equiv of (E)-3-tributyl-
tinacrylic acid tert-butyl ester (6) were used. Arylsulfonate 3 (146
mg, 0.2 mmol), ester 6 (208 mg, 0.5 mmol), CuI (8 mg, 0.04 mmol)
and (Ph3P)4Pd (23 mg, 0.02 mmol) afforded the product 13 (56 mg,
49%) as a white, amorphous solid. For analytical and spectral data,
see above.
Negishi-Type Cross-Coupling Reactions; General Procedure
ZnCl2 (1 M in THF, 2.2 equiv) was dissolved in THF (0.5 mL per
0.1 mmol arylsulfonate) and the solution was cooled to 0 °C. A lith-
ium or magnesium organometallic compound in THF (2 equiv) was
added dropwise and the solution was stirred for 1 h at 0 °C.
(Ph3P)4Pd (0.1 equiv) and the arylsulfonate (1 equiv in 0.5 mL THF
per 0.1 mmol arylsulfonate) were added and the resulting solution
was stirred for 18 h at r.t. Aq sat. NH4Cl (20 mL) and EtOAc (20
mL) were added, the layers were separated and the aqueous phase
was extracted with EtOAc (2 × 20 mL). The combined organic
phases were washed with brine (40 mL), dried (MgSO4), filtered
and the solvent was removed under vacuum. The crude product was
purified by flash chromatography.
(E)-3-1-[2¢-Deoxy-3¢,5¢-bis-O-(tert-butyldimethylsilyl)ribofura-
nosyl]-2-(1H)-pyrimidinon-4-ylacrylic Acid Methyl Ester (14)
Using (Z)-3-Tributyltinacrylic Acid Methyl Ester (9): The standard
procedure was followed using arylsulfonate 2 (620 mg, 0.86 mmol),
ester 9 (810 mg, 2.16 mmol), CuI (33 mg, 0.17 mmol) and
(Ph3P)4Pd (116 mg, 0.1 mmol) affording the product (340 mg, 76%)
as a colorless oil; Rf = 0.69 (isohexanes–EtOAc, 1:1).
IR (ATR): 2953, 2929, 2857, 1728, 1664, 1608, 1520, 1461, 1390,
1362, 1300, 1252, 1110, 1077, 1029, 980, 965, 882, 833, 776, 673
cm–1.
1H NMR (600 MHz, CDCl3): d = 0.03 (s, 3 H, SiCH3), 0.04 (s, 3 H,
SiCH3), 0.09 (s, 3 H, SiCH3), 0.10 (s, 3 H, SiCH3), 0.86 (s, 9 H, t-
C4H9), 0.90 (s, 9 H, t-C4H9), 2.17 (ddd, J = 13.5, 6.6, 4.2 Hz, 1 H,
H-2¢A), 2.54–2.60 (m, 1 H, H-2¢B), 3.76–3.79 (m, 1 H, H-5¢A), 3.80
(s, 3 H, OCH3), 3.94–3.98 (m, 2 H, H-4¢, H-5¢B), 4.33–4.37 (m, 1
H, H-3¢), 6.19 (dd, J = 6.6, 4.2 Hz, 1 H, H-1¢), 6.37 (d, J = 6.6 Hz,
1 H, H-5), 7.02 (d, J = 15.9 Hz, 1 H, CH=CH), 7.39 (d, J = 15.9 Hz
1 H, CH=CH), 8.53 (d, J = 6.6 Hz, 1 H, H-6).
13C NMR (150 MHz, CDCl3): d = –5.5, –5.5, –5.0, –4.6, 17.9, 18.3,
25.6 (3 C), 25.9 (3 C), 42.2, 52.1, 61.5, 69.6, 87.4, 87.9, 103.1,
128.3, 140.7, 144.4, 155.2, 166.1, 167.4.
HRMS-ESI (+): m/z [M + H]+ calcd for C25H45N2O6Si2: 525.2811;
found: 525.2827.
1-(2¢,3¢-O-Isopropylidene-5¢-O-tritylribofuranosyl)-4-phenyl-2-
(1H)-pyrimidinone (18)
The standard procedure was followed using arylsulfonate 1 (141
mg, 0.18 mmol), phenylmagnesium bromide (1 M in THF, 0.38 mL,
0.38 mmol), ZnCl2 solution (0.4 mL, 0.4 mmol) and (Ph3P)4Pd (23
mg, 0.02 mmol) affording the crude product. The crude product was
purified by flash chromatography (silica gel, isohexanes–EtOAc,
1:3) to give the title compound (77 mg, 74%) as a colorless oil;
Rf = 0.71 (isohexanes–EtOAc, 1:3).
IR (Film): 3059, 2986, 2934, 2871, 1674, 1621, 1519, 1494, 1449,
1382, 1374, 1272, 1214, 1158, 1120, 1079, 874, 765, 706, 632 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.36 [s, 3 H, C(CH3)2], 1.59 (s, 3
H, C(CH3)2], 3.46 (dd, J = 10.8, J = 5.1 Hz, 1 H, H-5¢A), 3.52 (dd,
J = 10.8, 3.0 Hz, 1 H, H-5¢B), 4.44–4.50 (m, 1 H, H-4¢), 4.83 (dd,
J = 6.1, 4.0 Hz, 1 H, H-3¢), 4.95 (dd, J = 6.1, 1.4 Hz, 1 H, H-2¢),
6.03–6.06 (m, 1 H, H-1¢), 6.45 (d, J = 7.1 Hz, 1 H, H-5), 7.19–7.54
(m, 18 H, 3H C6H5 + 15 H trityl C6H5), 8.00–8.05 (m, 2 H, C6H5),
8.16 (d, J = 7.1 Hz, 1 H, H-6).
13C NMR (75 MHz, CDCl3): d = 25.4, 27.2, 63.6, 80.2, 85.8, 87.4
(2 C), 94.2, 100.8, 114.0, 127.3 (3 C), 127.9 (8 C), 128.6 (6 C),
128.7 (2 C), 132.0, 135.8, 143.2 (3 C), 144.0, 155.5, 171.7.
Using (E)-3-Tributyltinacrylic Acid Methyl Ester (8): The standard
procedure was followed except that 2.5 equiv of (E)-3-tributyltin-
acrylic acid methyl ester (8) were used. Arylsulfonate 2 (264 mg,
0.37 mmol), ester 8 (383 mg, 0.1 mmol), CuI (15 mg, 0.08 mmol)
and (Ph3P)4Pd (42 mg, 0.04 mmol) afforded the product (136 mg,
71%) as a colorless oil. For analytical and spectral data, see above.
Synthesis 2007, No. 6, 929–935 © Thieme Stuttgart · New York

934
U. Hennecke et al.
PAPER
HRMS-FAB (+): m/z [M + Na]+ calcd for C37H34N2O5 + Na:
1:1) to give the product (48 mg, 48%) as a colorless oil; Rf = 0.66
609.2360; found: 609.2397.
(isohexanes–EtOAc, 1:1).
IR (ATR): 2954, 2929, 2857, 1660, 1620, 1520, 1462, 1390, 1361,
1276, 1252, 1191, 1110, 1076, 1029, 1006, 965, 883, 833, 776, 671
cm–1.
1-[2¢-Deoxy-3¢,5¢-bis-O-(tert-butyldimethylsilyl)ribofuranosyl]-
4-phenyl-5-methyl-2-(1H)-pyrimidinone (19)
The standard general procedure was followed except that 2.5 mol%
of Pd(dppf)Cl2 was used as catalyst with an extended reaction time
of 3 d. Arylsulfonate 8 (649 mg, 0.88 mmol), phenylmagnesium
bromide (0.5 M in THF, 3.52 mL, 1.76 mmol), ZnCl2 solution (1 M
in THF, 1.94 mL, 1.94 mmol) and Pd(dppf)Cl2 (18 mg, 0.022 mmol,
0.025 equiv) afforded the crude product. This was purified by flash
chromatography (silica gel, isohexanes–EtOAc, 1:3) to give the title
compound (316 mg, 68%) as a colorless oil; Rf = 0.67 (isohexanes–
EtOAc, 1:1).
1H NMR (300 MHz, CDCl3): d = 0.03 (s, 3 H, SiCH3), 0.03 (s, 3 H,
SiCH3), 0.08 (s, 3 H, SiCH3), 0.09 (s, 3 H, SiCH3), 0.85 (s, 9 H, t-
C4H9), 0.90 (s, 9 H, t-C4H9), 0.86–0.93 (m, 3 H, CH2CH3), 1.29–
1.42 (m, 2 H, CH2CH3), 1.61–1.73 (m, 2 H, ArCH2CH2), 2.13 (ddd,
J = 13.5, 6.6, 4.5 Hz, 1 H, H-2¢A), 2.48–2.61 (m, 3 H, ArCH2, H-
2¢B), 3.75 (dd, J = 12.0, 2.7 Hz, 1 H, H-5¢A), 3.90–3.97 (m, 2 H, H-
4¢, H-5¢B), 4.31–4.39 (m, 1 H, H-3¢), 6.14 (d, J = 6.8 Hz, 1 H, H-5),
6.19 (dd, J = 6.6, 4.5 Hz, 1 H, H-1¢), 8.28 (d, J = 6.8 Hz, 1 H, H-6).
13C NMR (75 MHz, CDCl3): d = –5.6, –5.5, –5.0, –4.6, 13.8, 17.9,
18.3, 22.4, 25.6 (3 C), 25.8 (3 C), 30.0, 38.4, 42.2, 61.6, 69.8, 86.9,
87.7, 103.7, 142.1, 155.5, 179.6.
HRMS-ESI (+): m/z [M + HNEt3]+ calcd for C31H64N3O4Si2:
598.4430; found: 598.4425.
IR (ATR): 2953, 2929, 2857, 1659, 1489, 1471, 1462, 1390, 1326,
1252, 1190, 1076, 1029, 1003, 990, 968, 885, 831, 775, 711, 698,
670 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.07 (s, 3 H, SiCH3), 0.08 (s, 3 H,
SiCH3), 0.11 (s, 3 H, SiCH3), 0.12 (s, 3 H, SiCH3), 0.89 (s, 9 H, t-
C4H9), 0.92 (s, 9 H, t-C4H9), 2.12 (s, 3 H, 5-CH3), 2.04–2.16 (m, 1
H, H-2¢A), 2.65 (ddd,, J = 13.5, 6.2, 3.9 Hz, 1 H, H-2¢B), 3.80 (dd,
J = 11.5, 2.6 Hz, 1 H, H-5¢A), 3.95 (dd, J = 11.5, 2.6 Hz, 1 H, H-
5¢B), 4.00–4.05 (m, 1 H, H-4¢), 4.43–4.37 (m, 1 H, H-3¢), 6.19 (t, 1
H, J = 6.3 Hz, H-1¢), 7.40–7.46 (m, 3 H, C6H5), 7.57–7.61 (m, 2 H,
C6H5), 8.06 (s, 1 H, H-6).
13C NMR (75 MHz, CDCl3): d = –5.4 (2 C), –4.9, –4.5, 16.7, 18.0,
18.4, 25.7 (3 C), 25.9 (3 C), 42.6, 62.6, 71.6, 87.3, 88.4, 111.0,
128.1 (2 C), 128.5 (2 C), 129.8, 137.9, 142.0, 155.1, 174.5.
HRMS-ESI (+): m/z [M + HNEt3]+ calcd for C34H62N3O4Si2:
632.4273; found: 632.4271.
1-(2¢-Deoxyribofuranosyl)-4-thienyl-2-(1H)-pyrimidinone (22)
Compound 12 (55 mg, 0.1 mmol) was dissolved in EtOAc (2 mL)
and treated with HF/pyridine complex (70 mL). The solution was
shaken for 14 h at r.t. Methoxytrimethylsilane (200 mL) was added
and the solution was shaken for another 2 h at r.t. The solvent was
removed under vacuum and the crude product was purified by flash
chromatography (silica gel, CH2Cl2–MeOH, 9:1) to give the title
compound (12 mg, 41%) as a white, amorphous solid; Rf = 0.43
(CH2Cl2–MeOH, 9:1).
1H NMR (400 MHz, DMSO-d6): d = 2.03–2.11 (m, 1 H, H-2¢A),
2.35 (ddd, J = 13.3, 6.2, 4.3 Hz, 1 H, H-2¢B), 3.56–3.63 (m, 1 H, H-
5¢A), 3.67 (ddd, J = 12.0, 5.2, 4.0 Hz, 1 H, H-5¢B), 3.87–3.91 (m, 1
H, H-4¢), 4.21–4.27 (m, 1 H, H-3¢), 5.11 (t, J = 5.2 Hz, 1 H, 5¢-OH),
5.27 (d, J = 4.4 Hz, 1 H, 3¢-OH), 6.11 (t, J = 6.2 Hz, 1 H, H-1¢), 7.09
(d, J = 7.2 Hz, 1 H, H-5), 7.25 (dd, J = 5.0, 3.8 Hz, 1 H, H-4thienyl),
7.90 (dd, J = 5.0, 1.0 Hz, 1 H, H-3thienyl), 7.25 (dd, J = 3.8, 1.0Hz, 1
H, H-5thienyl), 8.46 (d, J = 7.1 Hz, 1 H, H-6).
1-[2¢-Deoxy-3¢,5¢-bis-O-(tert-butyldimethylsilyl)ribofuranosyl]-
4-methyl-2-(1H)-pyrimidinone (20)
The standard procedure was followed except 0.5 mol% of Pd(PPh3)4
catalyst, double the volume of THF and 4 equiv of MeLi were used.
Arylsulfonate 2 (318 mg, 0.44 mmol), MeLi (1.6 M in Et2O, 4
equiv, 1.1 mL, 1.76 mmol), ZnCl2 solution (1 M in THF, 2.2 equiv,
0.97 mL, 0.97 mmol) and Pd(PPh3)4 (0.005 equiv, 2.5 mg, 0.002
mmol) afforded the crude product. This was purified by flash chro-
matography (silica gel, isohexanes–EtOAc, 1:1, later pure EtOAc)
to give the title compound (121 mg, 61%) as a slightly yellow oil;
Rf = 0.30 (isohexanes–EtOAc, 1:1).
13C NMR (100 MHz, DMSO-d6): d = 40.9, 60.6, 69.5, 86.4, 87.9,
99.5, 128.8, 131.2, 133.3, 141.6, 144.0, 154.2, 164.7.
HRMS-ESI (+): m/z [M + H]+ calcd for C13H15N2O4S: 295.0747;
found: 295.0745.
(E)-3-[1-(2¢-Deoxyribofuranosyl)-2-(1H)-pyrimidinon-4-
yl]acrylic Acid tert-Butyl Ester (23)
IR (ATR): 2953, 2929, 2856, 1658, 1623, 1523, 1462, 1252, 1110,
1077, 833, 775, 671 cm–1.
Compound 13 (49 mg, 0.09 mmol) was dissolved in THF (2.5 mL)
and MeOH (2.5 mL). NaOMe (10 mg, 1.85 mmol) was added and
the solution was stirred for 1 h at r.t. The solution was neutralized
with AcOH, the solvent removed under vacuum and the crude prod-
uct was purified by flash chromatography (silica gel, CH2Cl2–
MeOH, 9:1) to give the title compound (11 mg, 38%) as a white,
amorphous solid; Rf = 0.46 (CH2Cl2–MeOH, 9:1).
1H NMR (400 MHz, CD3CN): d = 1.62 (s, 9 H, t-C4H9), 2.22–2.31
(m, 1 H, H-2¢A), 2.57 (ddd, J = 13.6, 6.4, 4.8 Hz, 1 H, H-2¢B), 3.30–
3.35 (br m, 1 H, 5¢-OH), 3.45–3.49 (br m, 1 H, 3¢-OH), 3.76–3.83
(m, 1 H, H-5¢A), 3.85–3.92 (m, 1 H, H-5¢B), 4.05–4.09 (m, 1 H, H-
4¢), 4.39–4.46 (m, 1 H, H-3¢), 6.19 (t, J = 6.0 Hz, 1 H, H-1¢), 6.72
(d, J = 6.8 Hz, 1 H, H-5), 6.92 (d, J = 16.0 Hz, 1 H, CH=CH), 7.38
(d, J = 16.0 Hz, 1 H, CH=CH), 8.54 (d, J = 6.8 Hz, 1 H, H-6).
1H NMR (300 MHz, CDCl3): d = 0.03 (s, 3 H, SiCH3), 0.04 (s, 3 H,
SiCH3), 0.09 (s, 3 H, SiCH3), 0.10 (s, 3 H, SiCH3), 0.86 (s, 9 H, t-
C4H9), 0.90 (s, 9 H, t-C4H9), 2.09–2.17 (m, 1 H, H-2¢A), 2.39 (s, 3
H, 4-CH3), 2.49–2.58 (m, 1 H, H-2¢B), 3.77 (dd, J = 12.0, 2.4 Hz, 1
H, H-5¢A), 3.93–3.97 (m, 2 H, H-4¢, H-5¢B), 4.32–4.38 (m, 1 H, H-
3¢), 6.16–6.21 (m, 2 H, H-5, H-1¢), 8.31 (d, J = 6.6 Hz, 1 H, H-6).
13C NMR (75 MHz, CDCl3): d = –5.6, –5.6, –5.0, –4.6, 17.8, 18.3,
25.0, 25.6 (3 C), 25.8 (3 C), 42.2, 61.6, 69.7, 86.9, 87.7, 104.2,
142.3, 154.9, 175.8.
HRMS-ESI (+): m/z [M + H]+ calcd for C22H43N2O4Si2: 455.2756;
found: 455.2759.
1-[2¢-Deoxy-3¢,5¢-bis-O-(tert-butyldimethylsilyl)ribofuranosyl]-
4-butyl-2-(1H)-pyrimidinone (21)
The standard procedure was followed using arylsulfonate 2 (144
mg, 0.2 mmol), n-BuLi (1.6 M in hexanes, 0.4 mL, 0.4 mmol),
ZnCl2 solution (0.44 mL, 0.44 mmol) and (Ph3P)4Pd (23 mg, 0.02
mmol) affording the crude product. The crude product was purified
by flash chromatography (silica gel, isohexanes–EtOAc, 2:1, later
13C NMR (100 MHz, CD3CN): d = 28.1 (3 C), 42.0, 61.9, 70.9,
82.1, 88.6, 88.9, 103.5, 130.9, 141.1, 145.8, 156.0, 165.6, 168.8.
HRMS-ESI (+): m/z [M + H]+ calcd for C16H23N2O6: 339.1551;
found: 339.1542.
Synthesis 2007, No. 6, 929–935 © Thieme Stuttgart · New York

PAPER
A General Route to 4-C-Substituted Pyrimidine Nucleosides
935
(10) Havelkova, M.; Dvorak, D.; Hocek, M. Synthesis 2001,
Acknowledgment
1704.
The authors thank the Deutsche Forschungsgemeinschaft, the
Volkswagen Foundation and the Fonds der Chemischen Industrie
for generous financial support. We thank Chris Kuffer for prepara-
tive assistance and Dr. Glenn Burley for carefully reading the ma-
nuscript.
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Synthesis 2007, No. 6, 929–935 © Thieme Stuttgart · New York