Synthesis of 4′-aryl-2′,3′-dideoxynucleoside analogues

Article abstract of DOI:10.1016/j.tet.2009.02.010

A series of 4′-aryl-2′,3′-dideoxynucleoside analogues were synthesized from optically pure 5-oxo-2-aryl-tetrahydrofuran-2-carboxylic acids up to 62% overall yield. 5-Oxo-2-aryl-tetrahydrofuran-2-carboxylic acids were obtained from 2-hydroxy-3-arylcyclopen

Full text of DOI:10.1016/j.tet.2009.02.010

Tetrahedron 65 (2009) 2959–2965
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of 40-aryl-20,30-dideoxynucleoside analogues
,
Artur Jo˜gi a, Anne Paju a, To˜nis Pehk b, Tiiu Kailas a, Aleksander-Mati Mu¨u¨risepp a, Margus Lopp a
*
a Department of Chemistry, Faculty of Science, Tallinn University of Technology, Ehitajate tee 5, 19086 Tallinn, Estonia
b National Institute of Chemical Physics and Biophysics, Akadeemia tee 23, 12618 Tallinn, Estonia
a r t i c l e i n f o
a b s t r a c t
A series of 40-aryl-20,30-dideoxynucleoside analogues were synthesized from optically pure 5-oxo-2-aryl-
tetrahydrofuran-2-carboxylic acids up to 62% overall yield. 5-Oxo-2-aryl-tetrahydrofuran-2-carboxylic
acids were obtained from 2-hydroxy-3-arylcyclopent-2-en-1-ones by asymmetric oxidation in up to 38–
57% yield.
Article history:
Received 18 August 2008
Received in revised form 7 January 2009
Accepted 5 February 2009
lAvailable online 11 February 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
accession to the enzyme active site. On the other hand, the electron
donor/acceptor properties of different substituents in the phenyl
Many therapeutic agents against AIDS and cancer have the
structure of modified nucleosides.1 One of the possibilities to
modify the sugar ring is to introduce substituents to the position
40.2 Some of these 40-substituted compounds have found to be ef-
fective against HIV-drug resistant reverse transcriptase variants.3
On the other hand, many natural aryl-substituted tetrahydrofurans
ring change the electron density in the sugar ring, which may also
influence the biological activity of the compound.
2. Results and discussion
In the preparation of 40-aryl-20,30-dideoxynucleoside analogues
1 with phenyl, p-F-phenyl and o-BnO-phenyl groups in the 40 po-
possess pharmacological activity.4a–c Also, certain
(4-substituted phenyl)- -butyrolactones bearing thymine, uracil
and 5-bromouracil have anticancer activity,4d,e and phenyl-
a-methylene-g-
g
sition,
g-lactone acids 2a–c serve as key intermediates. The
preparation of compounds 2a and 2b by the asymmetric oxidation
of 2-hydroxy-3-arylcyclopent-2-en-1-ones 3a and 3b is described
by us earlier.5 To synthesize 2c, the starting enone 3c was prepared
according to the literature procedure from the corresponding
benzaldehyde in 21% overall yield.7 Compound 3c was subjected to
asymmetric oxidation, analogously to that of 3a and 3b, resulting
substituted g-lactone acids and their derivatives act on the central
nervous system.4f–h
Recently we published the synthesis of optically active 3-aryl-
substituted
g-lactone acids from 3-aryl-2-hydroxy-2-cyclopenten-
1-ones.5
In the present work we describe a stereoselective preparation of
40-aryl-20,30-dideoxynucleoside analogues from 3-aryl-substituted
in the corresponding
(Table 1).
g-lactone acid 2c in 57% yield and 81% ee
g-lactone acids, using the method, which has been developed for
The yield of 2c was higher, however, the enantiomeric purity
was slightly lower than that for lactone acids 2a and 2b (Table 1).
the synthesis of optically active 40-benzyl-substituted nucleoside
analogues6 (Scheme 1). Introduction of the bulky phenyl or
substituted phenyl substituents in the position 40 changes the hy-
drophobic properties of the nucleoside analogue and also its steric
The enantiomeric purity of initial
g-lactone acids 2a–c was in-
creased to ꢀ99% ee by a simple re-crystallisation from petroleum
ether–ethyl acetate. 5-Oxo-2-aryl-tetrahydrofuran-2-carboxylic
acids 2a–c were transformed to 40-aryl-20,30-dideoxynucleoside
analogues 1a–c in the reaction sequence presented in Scheme 2.
O
HO
HOOC
Base
O
O
O
OH
The reduction of the carboxylic group of g-lactone acids 2a–c
was accomplished using a borane complex in dimethylsulfide.8 In
the case of unsubstituted phenyl and p-F-phenyl derivatives, the
corresponding lactone alcohols 4a,b were prepared in 84–86%
yield. In the case of o-BnO-Ph-derivative 2c the yield of lactone
alcohol 4c was only 12%, together with 61% of unreacted starting
compound. The steric hindrance of the bulky ortho-benzyloxy
substituent may be the reason why the reduction of the carboxylic
acid requires higher temperature. The reaction at 50 ꢁC for 30 min
results in lactone alcohol 4c with 44% yield. However, at the same
2
3
1a R=H
R
R
1b R=p-F
1c R= o-OBn
1d R= o-OH
R
Scheme 1. Retrosynthetic route to 40-aryl-20,30-dideoxynucleoside analogues.
* Corresponding author. Tel.: þ372 620 2802; fax: þ372 620 2995.
E-mail address: lopp@chemnet.ee (M. Lopp).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.02.010

2960
A. J˜ogi et al. / Tetrahedron 65 (2009) 2959–2965
Table 1
Synthesis of 40-aryl-20,30-dideoxynucleoside analogues
Entry
Substrate
Substituent R
Yield % (ratio 2R/2S)
2 [ee%]
4
5
6
7
8
b-1Da-1
1
2
3
a
b
c
Ph
p-F-Ph
o-BnO-Ph
38 [86]5
43 [86]5
57 [81]
86
84
44
100
93
78
92 (3.8:1.0)
93 (4.0:1.0)a
88 (2.6:1.0)
90 (3.8:1.0)
81 (3.1:1.0)
67 (1.7:1.0)
87 (1.0:1.0)
100 (1.0:1.1)
91 (1.3:1.0)
100
78
100
a
In the initial solution of 6b the ratio of 2R/2S¼1.0:1.3, after 12 h the ratio changed to 4.0:1.0.
R1O
HOOC
TBDMSO
TBDMSO
iv
O
O
O
O
O
O
OH
OAc
i
iii
R
2a-c
R
R
6a-c
R
7a-c
4a-c R1 = H
ii
5a-c R1 = TBDMS
O
O
HO
O
TBDMSO
N
HO
vi
N
H
O
v
N
H
O
N
O
N
+
O
O
N
O
H
R
8a-c
R
α-1a-c
β-1a-c
R
Scheme 2. Synthesis of 40-aryl-20,30-dideoxynucleoside analogues 1. Reagents: (i) BH3$SMe2/THF, (ii) TBDMSCl, imidazole/CH2Cl2, (iii) DIBAH/toluene, (iv) Ac2O/Et3N/CH2Cl2,
(v) thymine, BSA, TMSOTf/CH3CN, (vi) TBAF/THF.
time, the formation of a considerable amount (33%) of lactone-re-
duced product, dihydroxy acid 9c, was observed. Under the acidic
analogues 8a–c, which do not bear substituents in positions 20 and
30, the difference in 2R/2S ratio (position 10 according to the nu-
meration of nucleosides and position 2 according to that of
substituted furans) is caused by the substituents in the position 40
of ribose. The highest 2R/2S ratio was observed for ortho-benzyl-
oxy-substituted nucleoside analogue 8c (2R/2S¼1.3:1.0; Table 1).
The last stepdthe removal of the protective silyl group with
tetrabutylammonium fluoride (TBAF),9 afforded nucleoside ana-
conditions this compound lactonizes affording
yield (Scheme 3).
d-lactone 10c in 50%
The hydroxyl group in 4c was protected with a TBDMS group
9
using TBDMSCl and imidazole in CH2Cl2 and compounds 5a–c
were reduced with DIBAH at ꢂ78 ꢁC. A mixture of anomeric lactols
6a–c was obtained in 88–93% yield (the ratio of 2R/2S di-
astereomers for compounds 6a–c according to 1H NMR spectra
from CH2–OSi– group is given in Table 1). In the case of the large
ortho-benzyloxy-substituted phenyl derivative 6c, the 2R/2S ratio
was 1.2:1.0, while in the case of the unsubstituted phenyl derivative
6a the ratio was 3.8:1.0 and for the para-fluorophenyl derivative
6b even 1.0:1.3, which changed after 12 h to 4.0:1.0 (Scheme 2;
Table 1).
logues
overall yield. The
chromatography, affording separately
-anomers -1a,b at an approximately 1:1 ratio. In the case of
and -1c the ratio was 1.3:1.0 (Scheme 2).
The benzyl group of compounds -1c and
a
-1a–c and
b
-1a–c as a mixture of anomers, in 78–100%
- and -anomers were separated by column
-anomers -1a,b and
-1c
b
a
b
b
a
a
b
a
b
a
-1c was removed,
-1d and -1d in
using H2 on Pd/C to give the nucleoside analogues
quantitative yield (Scheme 4).
b
a
The acetylation of lactols 6a–c was performed using acetic an-
hydride and triethylamine in CH2Cl2 to afford the corresponding
acetates 7a–c in 67–92% yield (Scheme 2; Table 1).
3. Conclusion
The base was introduced to acetates 7a–c by coupling with
thymine, using N,O-bis(trimethylsilyl)-acetamide (BSA) and tri-
methylsilyltriflate (TMSOTf) as Lewis acids,9 resulting in the
silylated nucleoside analogues 8a–c in 87–100% yield as a mixture
The asymmetric oxidation of 2-hydroxy-3-arylcyclopent-2-en-
1-ones offers a simple route to both enantiomers of 5-oxo-2-aryl-
b- and
a-anomers. The ratio of nucleoside anomers depends on
O
the substituents in the ribose ring.10,11 In the case of nucleoside
HO
O
HO
BnO
N
O
N
O
H
BnO
N
O
HOOC
HO
N
O
HOOC
O
O
OH
O
O
+
OH
H
i
β-1c
α-1c
100%
OBn
2c
OBn
OBn
i
i
100%
9c
4c
33%
44%
O
HO
HO
ii
O
O
HO
HO
N
O
50%
H
N
O
O
N
O
N
O
H
OH
OBn
β-1d
α-1d
10c
Scheme 4. Synthesis of 40-(2-hydroxyphenyl)-20,30-dideoxythymidines 1d, where (i)
H2, 10%Pd/C/MeOH.
Scheme 3. Reduction of
BH3$Me2S/THF, (ii) HCl/CH2Cl2.
g-lactone acid 2c by a borane complex. Reagents: (i)

A. J˜ogi et al. / Tetrahedron 65 (2009) 2959–2965
2961
tetrahydrofuran-2-carboxylic acids, suitable key intermediates for
the preparation of the analogues of 40-aryl-20,30-dideoxynucleo-
sides. The usefulness of the approach is demonstrated by the syn-
thesis of eight new optically active 40-aryl nucleoside analogues
whose antiviral and anticancer properties are currently under
study.
17.5 Hz, 1H, H-4), 2.52 (ddd, J¼4.4, 9.6 and 17.5 Hz, H-4), 2.38 (ddd,
J¼9.2, 9.6 and 14.0 Hz, 1H, H-3); 13C NMR (125 MHz, CDCl3)
d 175.9
(C-5), 173.8 (COOH), 154.9 (Ph C-2), 136.0 (s-Bn), 130.0 (Ph C-4),
128.5 (m-Bn),128.1 (p-Bn), 127.3 (Ph C-1), 127.2 (o-Bn), 125.2 (Ph C-
6), 120.9 (Ph C-5), 112.1 (Ph C-3), 86.0 (C-2), 70.4 (CH2-Ph), 31.2 (C-
3), 28.0 (C-4); MS (EI): m/z (%)¼312 (0.99, Mþ), 294 (0.02), 267
(0.25), 249 (0.05), 224 (0.04), 207 (0.08), 188 (0.06), 178 (1.53), 149
(0.78), 131 (0.81), 121 (5.14), 91 (100, Bnþ). Anal. Calcd for C18H16O5:
C, 69.22; H, 5.16. Found: C, 69.29; H, 5.17.
4. Experimental
4.1. General
4.4. (R)-5-Phenyl-5-hydroxymethyl-dihydro-furan-
2(3H)-one 4a
1H and 13C NMR spectra were recorded using deuterated sol-
vents (CDCl3,
d
7.27 ppm and 77.00 ppm, CD3OD,
d 3.30 ppm and
49.00 ppm, or DMSO-d6,
d
2.50 ppm and 39.50 ppm) on a Bruker
Compound 4a (1.33 g, 86%) was obtained from 2a (1.66 g,
AMX-500 spectrometer. 2D FT methods were used for the full as-
signment of 1H and 13C chemical shifts. Mass spectra were de-
termined on a Hitachi M80B spectrometer using the EI (70 eV)
mode. Elemental analyses were performed on a Perkin–Elmer C, H,
N, S-Analyzer 2400. Optical rotations were measured using an A.
Kru¨ss Optronic GmbH polarimeer P 3002. The enantiomeric purity
of compounds was determined using a Daicel Chiracel ODH chiral
column. IR spectra were recorded on a Perkin–Elmer Spectrum BX
FTIR spectrometer. TLC analysis was performed using DC-Alufolien
Kieselgel 60 F254 (Merck) plates. For column chromatography
Merck Silica gel 60 (0.063–0.200 mm) was used. The reagents were
purchased from Aldrich and used without purification. CH2Cl2 and
CH3CN were distilled from CaH2 before use. THF was distilled from
LiAlH4 before use. The petroleum ether fraction (bp 40–60 ꢁC) was
used.
8.07 mmol) according to the procedure described in Ref. 8 as white
23
crystals; mp¼112–114 ꢁC; [
a
]
þ62.9 (c 3.03, CHCl3); IR (KBr):
D
3412, 3036, 2924, 1737, 1494, 1451, 1213, 1072, 1006, 764, 700 cmꢂ1
;
1H NMR (500 MHz, CDCl3)
d 7.37 (m, 4H, o-Ph, m-Ph), 7.33 (m,1H, p-
Ph), 3.90 (dd, J¼5.4 and 12.4 Hz, 1H, CH2O), 3.73 (dd, J¼8.0 and
12.4 Hz, 1H, CH2O), 3.33 (dd, J¼5.4 and 8.0 Hz, 1H, OH), 2.85 (m, 1H,
H-4), 2.80 (m, 1H, H-3), 2.52 (m, 1H, H-3), 2.38 (m, 1H, H-4); 13C
NMR (125 MHz, CDCl3)
d 177.3 (C-2), 140.6 (s-Ph), 128.6 (m-Ph),
128.0 (p-Ph), 124.7 (o-Ph), 89.7 (C-5), 69.2 (CH2OH), 30.3 (C-4), 29.2
(C-3); MS (EI): m/z (%)¼161 (100.0, MꢂCH2OH), 133 (20.6), 115
(26.1), 105 (89.8), 91 (13.7), 77 (57.2). Anal. Calcd for C11H12O3: C,
68.74; H, 6.29. Found: C, 68.67; H, 6.22.
4.5. (R)-5-(4-Fluorophenyl)-5-hydroxymethyl-dihydro-
furan-2(3H)-one 4b
4.2. 2-Hydroxy-3-(2-benzyloxyphenyl)-cyclopent-
2-en-1-one 3c
Compound 4b (1.29 g, 84%) was obtained from 2b (1.64 g,
7.34 mmol) according to the procedure described in Ref. 8 as white
23
crystals; mp¼79–80 ꢁC; [
a
]
D
þ48.7 (c 3.01, CHCl3); IR (KBr): 3424,
Acetic acid 5-(2-benzyloxyphenyl)-2,5-dioxopentyl ester (9.05 g,
66%) was prepared from 2-benzyloxyphenylbenzaldehyde (8.48 g,
40.0 mmol) and 1-acetoxy-3-buten-2-one (8.7 g, 68.0 mmol)
according to the literature7 as colourless crystals.
3045, 2947, 1749, 1614, 1602, 1516, 1454, 1212, 1078, 1009,
830 cmꢂ1
;
1H NMR (500 MHz, CDCl3)
d
7.33 (dd, J¼5.4 and 8.0 Hz,
2H, Ph H-2,6), 7.06 (dd, J¼8.0 and 9.0 Hz, 2H, Ph H-3,5), 3.84 and
3.70 (both d, J¼12.4 Hz, 2H, CH2–O), 3.29 (br s, 1H, OH), 2.83 and
2.79 (m, 2H, H-3), 2.52 and 2.34 (m, 2H, H-4); 13C NMR (125 MHz,
The title compound 3c (2.28 g, 31%) was prepared from
acetic acid 5-(2-benzyloxyphenyl)-2,5-dioxopentyl ester (8.93 g,
26.3 mmol) according to the method described in Ref. 5 as col-
ourless crystals; mp¼138–140 ꢁC; IR (KBr): 3277, 3033, 2958, 1683,
CDCl3)
d
177.1 (C-2), 162.4 (d, JCF¼247.1 Hz, Ph C-4), 136.4 (d,
JCF¼2.6 Hz, Ph C-1), 126.6 (d, JCF¼8.1 Hz, Ph C-2,6), 115.5 (d,
JCF¼21.6 Hz, Ph C-3,5), 89.2 (C-5), 69.3 (CH2O), 30.3 (C-4), 29.2 (C-
3); MS (EI): m/z (%)¼210 (0.95, Mþ), 179 (88.1), 151 (17.5), 133 (13.2),
123 (100.0), 109 (15.6), 95 (42.2), 75 (17.4). Anal. Calcd for
C11H11FO3: C, 62.85; H, 5.27. Found: C, 62.86; H, 5.22.
1634, 1597, 1488, 1451, 1387, 1286, 1224, 1116, 1018, 753, 696 cmꢂ1
;
1H NMR (500 MHz, CDCl3)
7.38 (m, 4H, o,m-Bn), 7.35 (m, 2H, p-Bn and Ph H-4), 7.09 (m, 1H, Ph
d
7.66 (dd, J¼1.6 and 7.7 Hz, 1H, Ph H-6),
H-5), 7.08 (m, 1H, Ph H-3), 6.81 (s, 1H, OH), 5.16 (s, 2H, CH2-Ph), 2.92
(m, 2H, H-4), 2.51 (m, 2H, H-5); 13C NMR (125 MHz, CDCl3)
d
202.7
4.6. (R)-5-(2-Benzyloxyphenyl)-5-hydroxymethyl-dihydro-
furan-2(3H)-one 4c
(C-1), 155.8 (Ph C-2), 148.8 (C-2), 138.2 (C-3), 135.7 (s-Bn), 130.4 (Ph
C-4), 129.6 (Ph C-6), 128.7 (m-Bn), 128.4 (p-Bn), 127.8 (o-Bn), 124.4
(Ph C-1), 121.9 (Ph C-5), 114.0 (Ph C-3), 71.9 (CH2–Ph), 32.0 (C-5),
25.6 (C-4); MS (EI): m/z (%)¼280 (4.08, Mþ), 224 (0.50), 210 (0.66),
165 (0.10), 147 (0.74), 131 (0.93), 119 (2.51), 105 (1.61), 91 (100, Bnþ).
Anal. Calcd for C18H16O3: C, 77.12; H, 5.75. Found: C, 76.84; H, 5.73.
To a solution of 2c (2.50 g, 8.0 mmol) in THF (6.0 mL) at 0 ꢁC
BH3$Me2S complex in THF (1.23 mL, 11.2 mmol) was added drop-
wise over a period of 8 min. The reaction mixture was stirred at
room temperature for 2 h and then heated at 50 ꢁC for 30 min. After
cooling, the reaction mixture was treated with methanol (3.0 mL).
The mixture was concentrated in vacuum and purified by column
chromatography (petroleum ether/acetone¼10:1 to 10:3) affording
compounds 4c and 9c.
4.3. (R)-5-Oxo-2-(2-benzyloxyphenyl)-tetrahydrofuran-2-
carboxylic acid 2c
Compound 2c (2.99 g, 57%) was prepared from 2-hydroxy-3-(2-
benzyloxyphenyl)-cyclopent-2-en-1-one (4.71 g, 16.8 mmol) 3c
Compound 4c (1.05 g, 44%) was obtained as white crystals;
24
mp¼95–97 ꢁC; [
a
]
þ76.6 (c 3.01, CHCl3); IR (KBr): 3410, 3032,
D
according to the general procedure described in Ref. 5 as white
2941, 2920, 1733, 1600, 1584, 1492, 1445, 1222, 1086, 998, 770, 740,
powder; mp¼44–47 ꢁC; [
a
]
þ67.7 (c 1.73, MeOH); ee¼81%; IR
694 cmꢂ1; 1H NMR (500 MHz, CDCl3)
d
7.54 (dd, J¼1.7, 7.7 Hz,1H, Ph
25
D
(KBr): 3036, 2950, 2627, 1785, 1748, 1602, 1492, 1453, 1382, 1224,
H-6), 7.41 (m, 4H, o,m-Bn), 7.37 (m, 1H, p-Bn), 7.31 (ddd, J¼1.7, 7.7
and 8.3 Hz, 1H, Ph H-4), 7.01 (m, 1H, Ph H-3), 7.00 (m, 1H, Ph H-5),
5.12 and 5.10 (both d, J¼11.5 Hz, 2H, CH2-Ph), 4.10 and 3.91 (both d,
J¼12.2 Hz, 2H, CH2O), 2.66 (br s,1H, OH), 2.78 and 2.50 (m, 2H, H-3),
1175, 1045, 997, 906, 755, 698 cmꢂ1 1H NMR (500 MHz, CDCl3)
;
d
9.05 (br s, 1H, COOH), 7.52 (d, J¼7.6 Hz, 1H, Ph H-6), 7.32 (m, 6H,
o,m,p-Bn, Ph H-4), 7.03 (t, J¼7.6 Hz, 1H, Ph H-5), 6.96 (d, J¼8.1 Hz,
1H, Ph H-3), 5.03 and 4.99 (both d, J¼11.7 Hz, 2H, CH2–Ph), 3.16
(ddd, J¼4.4, 9.5 and 14.0 Hz, 1H, H-3), 2.78 (ddd, J¼9.2, 9.5 and
2.69 and 2.47 (m, 2H, H-2); 13C NMR (125 MHz, CDCl3)
d 177.4 (C-1),
154.5 (Ph C-2),136.2 (s-Bn),129.4 (Ph C-4),128.7 (Ph C-1 and m-Bn),

2962
A. J˜ogi et al. / Tetrahedron 65 (2009) 2959–2965
128.2 (p-Bn),127.4 (o-Bn),126.6 (Ph C-6),121.0 (Ph C-5),112.2 (Ph C-
3), 89.6 (C-4), 70.3 (CH2-Ph), 67.1 (CH2OH), 29.5 (C-3), 29.2 (C-2);
MS (EI): m/z (%)¼298 (0.89, Mþ), 281 (0.36), 267 (7.5), 249 (0.89),
221 (0.66), 207 (2.2), 189 (2.8), 177 (10.0), 161 (2.0), 147 (2.1), 131
(1.7),121 (6.8),105 (1.2), 91 (100.0, Bnþ). Anal. Calcd for C18H18O4: C,
72.47; H, 6.08. Found: C, 72.25; H, 6.06.
JCF¼247.0 Hz, Ph C-4), 137.0 (d, JCF¼3.0 Hz, Ph C-1), 126.7 (d,
JCF¼8.1 Hz, Ph C-2,6), 115.3 (d, JCF¼21.4 Hz, Ph C-3,5), 88.5 (C-5),
70.8 (CH2O), 30.8 (C-4), 29.6 (C-3), 25.7 ((CH3)3C–Si), 18.2 ((CH3)3C–
Si), ꢂ5.6 and ꢂ5.8 ((CH3)2–Si); MS (EI): m/z (%)¼325 (0.11, Mþþ1),
309 (1.0), 299 (0.55), 281 (1.9), 267 (48.8), 253 (0.44), 239 (4.6), 225
(9.7), 207 (2.2), 193 (2.8), 179 (18.2), 165 (4.6), 147 (8.9), 129 (5.8),
123 (19.0), 109 (18.1), 89 (19.9), 75 (100.0). Anal. Calcd for
C17H25FO3Si: C, 62.93; H, 7.77. Found: C, 62.86; H, 7.78.
4.7. (R)-3-(2-Benzyloxy-phenyl)-3-hydroxy-tetrahydro-2H-
pyran-2-one 10c
4.8.3. (R)-5-(2-Benzyloxyphenyl)-5-(tert-butyl-dimethyl-
Compound 10c (0.393 g, 50%) was obtained as white crystals
silyloxymethyl)-dihydro-furan-2(3H)-one 5c
25
from 9c (0.834 g, 2.64 mmol); mp¼150–151 ꢁC; [
a
]
þ121.3 (c 3.00,
Compound 5c (0.964 g, 78%) was obtained as a colourless syrup;
D
25
CHCl3); IR (KBr): 3424, 3323, 3029, 2969, 2940, 1702, 1601, 1588,
[a
]
þ35.4 (c 1.01, CHCl3); IR (neat): 3035, 2953, 2929, 2857, 1779,
D
1483, 1450, 1403, 1280, 1225, 1074, 1014, 964, 753, 732, 696 cmꢂ1
;
1601, 1586, 1489, 1471, 1454, 1243, 1104, 1010, 839, 779, 754,
1H NMR (500 MHz, CDCl3)
d
7.65 (dd, J¼1.7 and 7.8 Hz, 1H, Ph H-6),
698 cmꢂ1; 1H NMR (500 MHz, CHCl3)
d
7.63 (dd, J¼1.7 and 8.1 Hz,1H,
7.47 (m, 2H, o-Bn), 7.42 (m, 2H, m-Bn), 7.39 (m, 1H, p-Bn), 7.30 (dt,
J¼1.7 and 2ꢃ7.8 Hz,1H, Ph H-4), 7.05 (dt, J¼1.0 and 2ꢃ7.8 Hz,1H, Ph
H-5), 6.98 (dd, J¼1.0 and 7.8 Hz, 1H, Ph H-3), 5.05 (s, 2H, Ph-CH2),
4.16 (m, 1H, H-6eq), 3.72 (m, 1H, H-6ax), 2.95 (s, 1H, OH), 2.15 (m,
2H, H-4 and H-5), 2.01 (m, 1H, H-4), 1.60 (m, 1H, H-5); 13C NMR
Ph H-6), 7.43 (m, 4H, o-Bn and m-Bn), 7.39 (m, 1H, p-Bn), 7.31 (ddd,
J¼1.7, 7.5 and 8.1 Hz,1H, Ph H-4), 7.02 (m,1H, Ph H-5), 7.01 (m,1H, Ph
H-3), 5.10 and 5.08 (2d, J¼11.3 Hz, 2H, CH2-Ph), 4.15 and 3.71 (2d,
J¼10.6 Hz, 2H, OCH2), 2.86 and 2.36 (2m, 2H, H-4), 2.72 and 2.43 (2m,
2H, H-3), 0.87 (s, 9H, (CH3)3C–Si), 0.01 and 0.00 (2s, 6H, (CH3)2–Si);
(125 MHz, CDCl3)
d
174.0 (C-2), 153.9 (Ph C-2), 135.8 (s-Bn), 133.2
13C NMR (125 MHz, CDCl3)
d 177.0 (C-2),154.6 (Ph C-2),136.4 (s-Bn),
(Ph C-1), 129.0 (Ph C-4), 128.6 (o-Bn), 128.5 (m-Bn), 128.4 (p-Bn),
125.1 (C-6), 121.1 (Ph C-5), 111.7 (Ph C-3), 73.7 (C-3), 70.8 (CH2–Ph),
69.9 (C-6), 34.7 (C-4), 20.4 (C-5); MS (EI): m/z (%)¼298 (1.2, Mþ),
280 (0.05), 270 (0.28), 252 (0.70), 226 (0.90), 207 (1.3), 192 (2.7), 174
(0.95), 163 (17.5), 146 (1.1), 136 (1.7), 121 (27.8), 107 (2.3), 91 (100.0).
Anal. Calcd for C18H18O4: C, 72.47; H, 6.08. Found: C, 72.23; H, 6.06.
129.4 (Ph C-1), 129.3 (Ph C-4), 128.7 (m-Bn), 128.2 (p-Bn), 127.6 (o-
Bn), 126.7 (Ph C-5), 121.0 (Ph C-5), 112.0 (Ph C-6), 89.2 (C-5), 70.3
(CH2-Ph), 68.4 (CH2OSi), 30.4 (C-4), 29.9 (C-3); 25.8 ((CH3)3C–Si),
18.2 ((CH3)3C–Si), ꢂ5.6 and ꢂ5.8 ((CH3)2–Si); MS (EI): m/z (%)¼355
t
(0.48, Mþꢂ Bu), 337 (5.0), 309 (0.21), 295 (0.72), 277(0.25), 263 (2.1),
249 (0.40), 235 (0.71), 221 (6.3), 205 (1.5), 193 (0.43), 177 (0.39), 161
(1.0),145 (0.71),131 (2.0),121 (1.5),103 (0.46), 91 (100.0). Anal. Calcd
for C24H32O4Si: C, 69.87; H, 7.82. Found: C, 69.82; H, 7.85.
4.8. Typical procedure for preparation of 5a–c
To a solution of 4a–c (3.0 mmol) and imidazole (0.274 g,
4.03 mmol) in CH2Cl2 (1.5 mL) at 0 ꢁC TBDMSCl (0.552 g,
3.66 mmol) was added. Stirring was continued at 0 ꢁC for 15 min
and then for 2 h at room temperature. Water (20 mL) was added
and the mixture was extracted with CH2Cl2 (4ꢃ20 mL). The organic
phase was dried over MgSO4 and concentrated in vacuum. The
residue was purified by column chromatography (petroleum ether/
acetone¼30:1) to give compounds 5a–c.
4.9. Typical procedure for preparation of 6a–c
To a solution of 5a–c (2.6 mmol) in toluene (5.2 mL) at ꢂ78 ꢁC
1.5 M solution of DIBAH in toluene (1.91 mL, 2.87 mmol) was added
dropwise. The reaction mixture was stirred at ꢂ76 ꢁC for 15 min,
then methanol (0.6 mL) was added dropwise and the mixture was
allowed to warm to room temperature. EtOAc (4.0 mL) and satu-
rated NaHCO3 solution (0.5 mL) were added and stirring was con-
tinued for 2 h. Powdered Na2SO4 (3.0 g) was added and the mixture
was stirred overnight. The precipitate was filtered off and washed
with EtOAc. The solvent was removed in vacuum and the residue
was purified by column chromatography (petroleum ether/
acetone¼40:1 to 30:1) to give compounds 6a–c.
4.8.1. (R)-5-Phenyl-5-(tert-butyl-dimethyl-silyloxymethyl)-
dihydro-furan-2(3H)-one 5a
Compound 5a (0.933 g, 100%) was obtained as white crystals;
23
mp¼60–61 ꢁC; [
a
]
þ25.2 (c 2.01, CHCl3); IR (KBr): 3034, 2951,
D
2931, 2859, 1771, 1604, 1499, 1464, 1252, 1215, 1101, 1012, 842, 777,
766, 704 cmꢂ1
;
1H NMR (500 MHz, CHCl3)
d
7.38 (m, 4H, o-Ph and
4.9.1. (R)-5-Phenyl-5-(tert-butyl-dimethyl-silyloxymethyl)-
m-Ph), 7.33 (m, 1H, p-Ph), 3.77 and 3.72 (2d, J¼10.9 Hz, 2H, OCH2),
2.83 and 2.36 (2m, 2H, H-4), 2.82 and 2.51 (2m, 2H, H-3), 0.90 (s,
9H, (CH3)3C–Si), 0.06 and 0.05 (2s, 6H, (CH3)2–Si); 13C NMR
tetrahydro-furan-2-ol 6a
Compound 6a (0.736 g, 92%) was obtained as white crystals;
22
mp¼87–89 ꢁC; [
a]
þ35.4 (c 10.0, CHCl3); 2R/2S¼3.8:1.0; IR (KBr):
D
(125 MHz, CDCl3)
d
176.7 (C-2), 141.1 (s), 128.4 (m), 128.0 (p), 124.9
3274, 3026, 2956, 2930, 2858, 1603, 1492, 1472, 1251, 1138, 1117,
(o), 89.0 (C-5), 70.9 (CH2O), 30.8 (C-4), 29.7 (C-3), 25.8 ((CH3)3C–Si),
18.2 ((CH3)3C–Si), ꢂ5.6 and ꢂ5.7 ((CH3)2–Si); MS (EI): m/z (%)¼291
(0.58, MþꢂCH3), 276 (2.0), 249 (56.4), 231 (3.3), 221 (3.4), 207 (8.4),
189 (0.82), 175 (1.5), 161 (23.5), 145 (3.8), 129 (12.8), 115 (9.3), 105
(15.8), 89 (12.3), 75 (100.0). Anal. Calcd for C17H26SiO3: C, 66.62; H,
8.55. Found: C, 66.60; H, 8.62.
1067, 971, 836, 782, 763, 702 cmꢂ1; 1H NMR (500 MHz, CDCl3, data
for 2S isomer labelled with
7.35 and 7.32
(t, J¼7.6 Hz, 2H, m-Ph), 7.27 and 7.24 (t, J¼7.6 Hz, 1H,
p-Ph), 5.70
(t, J¼4.0 Hz, 1H, H-2), 5.56 (dd, J¼4.1 and 9.4 Hz, 1H, H-
2), 4.10 (d, J¼9.4 Hz, 1H, OH), 3.68 and 3.63 (2d, J¼10.5 Hz, 2H, CH2–
OSi), 3.57 and 3.55 (d,
(2d, J¼10.6 Hz, 2H, CH2–OSi), 2.62
J¼4.0 Hz, 1H, OH), 2.61 and 2.07 (2m, 2H, H-4), 2.52 and 2.27 (2m,
2H, H-4), 2.25 and 1.90 (2m, 2H, H-3), 1.92 and 1.93 (2m, 2H, H-3),
0.95 (s, 9H, (CH3)3C–Si), 0.88
*
)
d
7.43 and 7.46
*
(d, J¼7.6 Hz, 2H, o-Ph),
*
*
*
*
*
*
*
4.8.2. (R)-5-(4-Fluorophenyl)-5-(tert-butyl-dimethyl-
silyloxymethyl)-dihydro-furan-2(3H)-one 5b
*
*
*
(s, 9H, (CH3)3C–Si), 0.13, 0.12, ꢂ0.02
*
Compound 5b (0.904 g, 93%) was obtained as white crystals;
and ꢂ0.04
145.7
125.7
70.8
26.0 and 25.8
*
(4s, 4ꢃ3H, (CH3)2–Si); 13C NMR (125 MHz, CDCl3)
23
mp¼77–81 ꢁC; [
a
]
D
þ20.3 (c 1.01, CHCl3); IR (KBr): 3047, 2955,
d
*
and 143.6 (s), 128.0 and 127.8
*
(m), 127.1 and 126.8 (p),
and 98.8 (C-2), 88.7
*
2931, 2859, 1766, 1602, 1512, 1472, 1464, 1255, 1214, 1114, 1010, 837,
*
and 125.5 (o), 99.56
and 69.6 (CH2O), 34.7 and 34.2
((CH3)3C–Si), 18.4 and 18.3
*
*
and 88.5 (C-5),
and 30.3 (C-4),
781 cmꢂ1
;
1H NMR (500 MHz, CHCl3)
d
7.37 (dd, J¼5.2 and 8.8 Hz,
*
*
(C-3), 31.8
*
2H, Ph H-2,6), 7.06 (t, J¼2ꢃ8.8 Hz, 2H, Ph H-3,5), 3.73 and 3.67 (2d,
J¼11.0 Hz, 2H, OCH2), 2.81 and 2.32 (2m, 2H, H-4), 2.79 and 2.51
(2m, 2H, H-3), 0.90 (s, 9H, (CH3)3C–Si), 0.05 and 0.04 (2s, 6H,
*
*
((CH3)3C–Si), ꢂ5.5 and
ꢂ5.6, ꢂ5.5
*
and ꢂ5.7 ((CH3)2–Si); MS (EI): m/z (%)¼291 (0.19,
*
MþꢂOH), 275 (0.62), 251 (1.0), 233 (21.6), 207 (10.5), 189 (0.9), 177
(CH3)2–Si); 13C NMR (125 MHz, CDCl3)
d
176.5 (C-2), 162.3 (d,
(4.0), 163 (100.0), 145 (8.8), 129 (21.5), 117 (57.6), 105 (11.4), 91

A. J˜ogi et al. / Tetrahedron 65 (2009) 2959–2965
2963
(24.5), 75 (57.0). Anal. Calcd for C17H28SiO3: C, 66.19; H, 9.15. Found:
C, 65.95; H, 9.22.
combined extracts were dried over MgSO4. After solvent evapora-
tion in vacuum the residue was purified by column chromatogra-
phy (petroleum ether/acetone¼20:1) to afford compounds 7a–c.
Yield: 7a (0.458 g, 90%), 7b (0.432 g, 81%), 7c (0.443 g, 67%).
To a solution of thymine (0.171 g, 1.36 mmol) in dry CH3CN
(11.0 mL) BSA (0.998 mL, 3.88 mmol) and compounds 7a–c
(1.30 mmol) in CH3CN (7.6 mL) were added at room temperature.
After cooling to 0 ꢁC TMSOTf (0.235 mL, 1.30 mmol) was added
dropwise, the reaction mixture was stirred at room temperature for
2 h and poured into the mixture of CH2Cl2 (70 mL) and saturated
NaHCO3 solution (15 mL). The CH2Cl2 layer was removed and the
water layer was extracted with CH2Cl2 (3ꢃ10 mL). The combined
CH2Cl2 layers were dried over MgSO4. After evaporation of the
solvent, the residue was purified by column chromatography (pe-
troleum ether/acetone¼10:1 to 10:2) to afford compounds 8a–c.
Yield: 8a (0.472 g, 87%), 8b (0.564 g, 100%), 8c (0.618 g, 91%).
To a solution of compounds 8a–c (1.12 mmol) in THF (10.0 mL)
1.0 M TBAF solution in THF (2.32 mL, 2.32 mmol) was added
dropwise. The reaction mixture was stirred at room temperature
4.9.2. (R)-5-(4-Fluorophenyl)-5-(tert-butyl-dimethyl-
silyloxymethyl)-tetrahydro-furan-2-ol 6b
Compound 6b (0.788 g, 93%) was obtained as white crystals;
23
mp¼65–77 ꢁC; [
a
]
þ26.4 (c 10.1, CHCl3); 2R/2S¼4.0:1.0; IR (KBr):
D
3306, 2932, 2859,1606,1509,1472,1251,1136,1116,1096,1065, 973,
838, 773 cmꢂ1
belled with
7.02 and 6.99
1H, H-2), 5.55 (dd, J¼4.4 and 9.0 Hz, 1H, H-2), 4.01 (d, J¼9.0 Hz, 1H,
OH), 3.63 and 3.60 (2d, J¼10.4 Hz, 2H, CH2–OSi), 3.54 and 3.50
(2d, J¼10.4 Hz, 2H, CH2–OSi), 2.66 (d, J¼4.0 Hz, 1H, OH), 2.59 and
2.03 (2m, 2H, H-4), 2.50 and 2.24 (2m, 2H, H-4 ), 2.20 and 1.92 (2m,
2H, H-3
(CH3)3C–Si), 0.12, 0.11, ꢂ0.03
NMR (125 MHz, CDCl3)
JCF¼244.8 Hz, p), 141.6
127.4
and 127.2 (2d, JCF¼7.8 Hz, o), 114.8 and 114.5
JCF¼21.2 Hz, m), 99.5 and 98.8 (C-2), 88.3 and 88.2 (C-5), 70.5
69.6 (CH2O), 34.6 and 34.0 (C-3), 31.9
25.8
and ꢂ5.7
;
1H NMR (500 MHz, CDCl3, data for 2S isomer la-
7.42
and 7.39 (dd, J¼5.5 and 8.7 Hz, 2ꢃ2H, o-Ph),
(t, 6.97, J¼8.7 Hz, 2ꢃ2H, m-Ph), 5.68 (br t, J¼4 Hz,
*
)
d
*
*
*
*
*
*
*
*
), 1.94 and 1.91 (m, 2H, H-3), 0.94 and 0.86
*
(2s, 2ꢃ9H,
*
and ꢂ0.06
*
(4s, 4ꢃ3H, (CH3)2Si); 13
C
d
162.0 (d, JCF¼245.4 Hz, p), 161.8
*
(d,
*
(d, JCF¼2.7 Hz, s), 139.4 (d, JCF¼2.7 Hz, s),
*
*
(2d,
and
for 2 h and then concentrated in vacuum.
separated by column chromatography on silica gel (CH2Cl2/
MeOH¼40:1 to 20:1) affording anomers -1a–c and -1a–c.
a- and b-Anomers were
*
*
*
*
*
and 30.6 (C-4), 25.9 and
b
a
*
((CH3)3C–Si), 18.4 and 18.2
*
((CH3)3C–Si), ꢂ5.5, ꢂ5.6, ꢂ5.6
*
*
((CH3)2–Si); MS (EI): m/z (%)¼309 (0.25, MþꢂOH), 293
4.10.1. 1-(5-Phenyl-5-hydroxymethyl-tetrahydro-furan-2-yl)-5-
methyl-1H-pyrimidine-2,4-diones -1a (2R,5R) and
(0.72), 269 (1.4), 253 (1.7), 251 (20.9), 225 (10.9), 223 (3.5), 207
(0.71), 195 (2.4), 181 (70.23), 163 (4.7), 149 (6.2), 135 (47.6), 123
(9.7), 109 (37.7), 85 (18.1), 75 (100.0). Anal. Calcd for C17H27FO3Si: C,
62.54; H, 8.34. Found: C, 62.53; H, 8.37.
b
a
-1a (2S,5R)
1-(40-Phenyl-20,30-dideoxy-
D-ribo-pentofuranosyl)-thymines b-1a
and
a-1a. Compound b-1a (0.170 g, 50%) was obtained as white
22
crystals; mp¼86–91 ꢁC; [
a
]
D
þ9.1 (c 5.46, MeOH); IR (KBr): 3427,
4.9.3. (R)-5-(2-Benzyloxyphenyl)-5-(tert-butyl-dimethyl-
3186, 3061, 2954, 1694, 1473, 1448, 1275, 1067, 763, 703 cmꢂ1 1H
;
silyloxymethyl)-tetrahydro-furan-2-ol 6c
NMR (500 MHz, CD3OD)
d
8.19 (s, 1H, H-6), 7.41 (d, J¼7.7 Hz, 2H,
Compound 6c (0.947 g, 88%) was obtained as a colourless syrup,
o-Ph), 7.34 (t, J¼7.7 Hz, 2H, m-Ph), 7.25 (t, J¼7.7 Hz, 1H, p-Ph), 6.16
(dd, J¼3.8 and 6.5 Hz, 1H, H-20), 3.74 and 3.71 (2d, J¼12.2 Hz, 2H,
–CH2OH), 2.60 and 2.17 (2m, 2H, H-40), 2.17 and 2.07 (2m, 2H, H-30),
24
[
a]
þ4.5 (c 10.0, CHCl3);2R/2S¼2.6:1.0;IR (neat):3428, 3034, 2955,
D
2930, 2857, 1600, 1584, 1498, 1486, 1449, 1253, 1223, 1103, 1053,
1004, 837, 778, 754, 697 cmꢂ1; 1H NMR (500 MHz, CDCl3, data for 2S
1.90 (s, 3H, CH3–C]); 13C NMR (125 MHz, CD3OD)
d 166.5 (C-4),
isomer labelled with
(dd, J¼1.8 and 7.8 Hz,1H, Ph H-6), 7.46–7.36 (m, 2ꢃ5H, Bn from both
isomers), 7.28 and 7.24 (2m,
(2m, 2ꢃ1H, Ph H-4), 7.00 and 6.98
2ꢃ1H, Ph H-5), 6.99 and 6.94 (2m, 2ꢃ1H, Ph H-3), 5.72 (t, J¼4.0 Hz,
1H, H-2), 5.55 (ddd, J¼2.3, 3.3 and 10.0 Hz, 1H, H-2), 5.09 and 5.08
(2d, J¼11.4 Hz, 2H, Ph–CH2), 5.08 (s, 2H, Ph–CH2), 4.43 (d, J¼10.0 Hz,
1H, OH), 4.20 and 3.51 (2d, J¼10.1 Hz, 2H, CH2–OSi), 3.96 and 3.57
(2d, J¼10.4 Hz, 2H, CH2–OSi), 2.60 and 2.30 (m, 2H, H-4 ), 2.56 and
2.26 (m, 2H, H-4), 2.42
(d, J¼4.0 Hz,1H, OH), 2.19 and 1.84 (m, 2H, H-
), 1.91 (m, 2H, H-3), 0.88 and 0.86
*
)
d
7.79
*
(dd, J¼1.8 and 7.8 Hz,1H, Ph H-6), 7.74
152.4 (C-2),144.3 (s),138.7 (C-6),129.4 (m),128.5 (p),126.2 (o),111.0
(C-5), 91.7 (C-50), 86.4 (C-20), 68.7 (–CH2OH), 32.9 (C-30), 31.9 (C-40),
12.5 (CH3–C]); MS (EI): m/z (%)¼302 (0.59, Mþ), 271 (40.3), 177
(46.7), 159 (31.5), 146 (50.4), 129 (100.0), 117 (69.4), 105 (94.6), 91
(85.4), 77 (75.3). HRMS-EI calcd for (MꢂCH2OH)þ C15H15O3N2:
271.1083; found: 271.1110.
*
*
*
*
*
*
*
*
Compound a-1a (0.170 g, 50%) was obtained as white crystals;
22
*
mp¼156–168 ꢁC; [
a
]
D
þ4.0 (c 5.46, MeOH). IR (KBr): 3418, 3193,
*
3058, 2954, 1694, 1472, 1448, 1270, 1061, 763, 704 cmꢂ1
;
1H NMR
3
*
*
(2s, 2ꢃ9H, (CH3)3C–Si), 0.00,
(500 MHz, CD3OD) d
7.46 (d, J¼7.7 Hz, 2H, o-Ph), 7.39 (t, J¼7.7 Hz,
ꢂ0.02, ꢂ0.05
CDCl3) 154.7
131.5 (Ph C-1), 128.7 and 128.6
128.1 and 127.9 (p-Bn), 127.7 (2C, Ph C-6), 127.6 and 127.5
120.8 and 120.6
88.6 and 87.8 (C-5), 70.1 and 70.0
OSi), 35.3 and 34.7 (C-3), 31.7
((CH3)3C–Si),18.3 and 18.2
((CH3)3C–Si), ꢂ5.4
*
, ꢂ0.07
*
(4s, 4ꢃ3H, (CH3)2–Si); 13C NMR (125 MHz,
2H, m-Ph), 7.31 (t, J¼7.7 Hz, 1H, p-Ph), 7.02 (q, J¼1.2 Hz, 1H, H-6),
6.38 (dd, J¼4.2 and 6.2 Hz, 1H, H-20), 3.61 and 3.53 (2d, J¼11.9 Hz,
2H, –CH2OH), 2.64 and 2.34 (2m, 2H, H-40), 2.61 and 2.06 (2m, 2H,
H-30), 1.58 (d, J¼1.2 Hz, 3H, CH3–C]); 13C NMR (125 MHz, CD3OD)
d
*
and 154.6 (Ph C-2),136.9
*
and136.6 (s-Bn),133.9
*
and
(Ph C-4),
(o-Bn),
*
(m-Bn), 128.6 and 128.2
*
*
*
*
(Ph C-5), 111.6 (2C, Ph C-3), 99.4
*
and 99.3 (C-2),
and 67.1 (CH2–
d 166.3 (C-4), 152.4 (C-2), 144.7 (s), 138.0 (C-6), 129.4 (m), 128.6 (p),
*
*
(Ph–CH2–), 68.8
*
127.1 (o), 110.9 (C-5), 91.8 (C-50), 88.6 (C-20), 70.8 (–CH2OH), 33.1 (C-
30), 32.4 (C-40), 12.3 (CH3–C]); MS (EI): m/z (%)¼302 (0.94, Mþ),
271 (58.0), 204 (4.0), 177 (47.6), 159 (33.4), 145 (40.3), 129 (100.0),
117 (60.6), 105 (76.8), 91 (69.2), 77 (63.5). HRMS-EI calcd for
(MꢂCH2OH)þ C15H15O3N2: 271.1083; found: 271.1099.
*
*
and 28.9 (C-4), 25.9
*
and 25.8
*
*
, ꢂ5.6, ꢂ5.7
*
and ꢂ5.7
t
((CH3)2–Si); MS (EI): m/z (%)¼339 (0.44, Mþꢂ Bu–OH), 311 (0.12),
295 (0.14), 283 (0.11), 269 (3.8), 251 (3.4), 233 (0.35), 221 (3.3), 205
(1.0), 192 (0.52), 173 (1.1), 161 (0.79), 149 (0.93), 131 (3.8), 115 (1.9),
107 (1.0), 91 (100.0), 85 (7.6), 73 (14.0). Anal. Calcd for C24H34O4Si: C,
69.53; H, 8.27. Found: C, 69.48; H, 8.30.
4.10.2. 1-(5-(4-Fluorophenyl)-5-hydroxymethyl-tetrahydro-furan-
2-yl)-5-methyl-1H-pyrimidine-2,4-diones
(2R,5R) and -1b (2S,5R)
1-(40-(4-Fluorophenyl)-20,30-dideoxy-
b-1b
a
4.10. Typical procedure for preparation of 1a–c
D
-ribo-pentofuranosyl)-thy-
mines b-1b and a-1b. Compound b-1b (0.139 g, 39%) was obtained
24
To
a
mixture of compounds 6a–c (1.45 mmol) and Et3N
as white crystals; mp¼80–86 ꢁC; [
a
]
þ5.0 (c 4.2, MeOH); IR (KBr):
D
(0.610 mL, 4.35 mmol) in CH2Cl2 (1.5 mL) acetic anhydride
(0.410 mL, 4.35 mmol) was added dropwise at 0 ꢁC. The reaction
mixture was stirred at room temperature overnight. Water (5 mL)
was added and the mixture extracted with EtOAc (4ꢃ5 mL). The
3426, 3192, 3063, 2956, 1690, 1604, 1509, 1473, 1275, 1225, 1070,
837 cmꢂ1; 1H NMR (500 MHz, CD3OD)
d 8.15 (s, 1H, H-6), 7.45 (dd,
J¼5.4 and 8.8 Hz, 2H, Ph H-2,6), 7.07 (t, J¼8.8 Hz, 2H, Ph H-3,5), 6.17
(dd, J¼4.2 and 6.3 Hz, 1H, H-20), 3.72 and 3.70 (2d, J¼12.2 Hz, 2H,

2964
A. J˜ogi et al. / Tetrahedron 65 (2009) 2959–2965
–CH2O), 2.60 and 2.18 (2m, 2H, H-40), 2.18 and 2.10 (2m, 2H, H-30),
1.90 (s, 3H, CH3–C]); 13C NMR (125 MHz, CD3OD)
166.5 (C-4),
32.0 (C-30), 31.8 (C-40), 12.4 (CH3–C]). Anal. Calcd for C23H24N2O5,
C, 67.63; H, 5.92; N, 6.86. Found: C, 67.77; H, 5.90; N, 6.83.
d
163.6 (d, JCF¼244.5 Hz, Ph C-4), 152.4 (C-2), 140.4 (d, JCF¼2.9 Hz, Ph
C-1), 138.7 (C-6), 128.3 (d, JCF¼8.1 Hz, Ph C-2,6), 116.0 (d,
JCF¼21.5 Hz, Ph C-3,5), 111.1 (C-5), 91.3 (C-50), 86.4 (C-20), 68.8
(–CH2–OH), 32.9 (C-30), 32.1 (C-40), 12.5 (CH3–C]); MS (EI): m/z
(%)¼320 (0.27, Mþ), 302 (0.12), 289 (33.9), 228 (1.1), 195 (24.8), 177
(17.9), 164 (37.0), 147 (47.7), 135 (75.6), 127 (79.0), 123 (100.0), 109
(98.9), 95 (47.7), 83 (17.9); HRMS-EI calcd for (MꢂCH2OH)þ
C15H14FO3N2: 289.0988; found: 289.0990.
4.11. 1-(5-(2-Hydroxyphenyl)-5-hydroxymethyl-tetra-
hydro-furan-2-yl)-5-methyl-1H-pyrimidine-2,4-diones
b-1d (2R,5R) and a-1d (2S,5R)
1-(40-(2-Hydroxyphenyl)-20,30-dideoxy-
thymines -1d and -1d. To a solution of -1c (a
D
-ribo-pentofuranosyl)-
-1c) (0.25 mmol) in
b
a
b
CH3OH (2.5 mL) 10% Pd/C powder (0.028 g) was added. Through the
reaction mixture H2 was bubbled at room temperature for 5 h. The
reaction mixture was filtered off and concentrated in vacuum. The
residue was purified by column chromatography (CH2Cl2/
Compound
a-1b (0.138 g, 39%) was obtained as white crys-
tals; mp¼191–196 ꢁC; IR (KBr): 3408, 3208, 3072, 2946, 2921,
2864, 2816, 1715, 1668, 1604, 1511, 1474, 1454, 1421, 1274, 1258,
1065, 1052, 989, 961, 894, 839, 816, 776, 760, 724, 676 cmꢂ1 1H
;
MeOH¼30:1 to 20:1) affording compounds
b-1d (a-1d).
NMR (500 MHz, CD3OD)
d
7.47 (dd, J¼5.4 and 8.8 Hz, 2H, Ph H-
Compound b-1d (0.080 g, 100%) was obtained as white crystals;
2,6), 7.11 (t, J¼8.8 Hz, 2H, Ph H-3,5), 7.03 (s, 1H, H-6), 6.38 (dd,
J¼4.1 and 6.1 Hz, 1H, H-20), 3.58 and 3.52 (2d, J¼11.8 Hz, 2H,
–CH2O), 2.62 and 2.33 (2m, 2H, H-40), 2.62 and 2.08 (2m, 2H, H-
mp¼115–119 ꢁC; IR (KBr): 3381, 3218, 1677, 1607, 1471, 1450, 1407,
1274, 1064, 1041, 762 cmꢂ1 1H NMR (500 MHz, CD3OD)
; d 8.17 (q,
J¼1.2 Hz, 1H, H-6), 7.40 (dd, J¼1.7 and 7.7 Hz, Ph H-6), 7.08 (dt, J¼1.7
and 2ꢃ7.7 Hz,1H, Ph H-4), 6.80 (dt, J¼0.8 and 2ꢃ7.7 Hz,1H, Ph H-5),
6.76 (dd, J¼0.8 and 7.7 Hz, 1H, Ph H-3), 6.19 (dd, J¼4.5 and 6.2 Hz,
1H, H-20), 4.18 and 3.71 (2d, J¼12.0 Hz, 2H, –CH2OH), 2.55 and 2.53
(2m, 2H, H-40), 2.15 and 2.03 (m, 2H, H-30), 1.91 (d, J¼1.2 Hz, 3H,
30), 1.63 (s, 3H, CH3–C]); 13C NMR (125 MHz, CD3OD)
d 166.3
(C-4), 163.6 (d, JCF¼245.0 Hz, Ph C-4), 152.5 (C-2), 140.8 (d,
JCF¼2.9 Hz, Ph C-1), 137.9 (C-6), 129.1 (d, JCF¼8.0 Hz, Ph C-2,6),
116.0 (d, JCF¼21.7 Hz, Ph C-3,5), 111.1 (C-5), 91.3 (C-50), 88.5 (C-
20), 70.7 (–CH2–OH), 32.9 (C-30), 32.7 (C-40), 12.4 (CH3–C]); MS
(EI): m/z (%)¼320 (0.27, Mþ), 302 (0.13), 289 (41.9), 195 (31.7),
177 (22.4), 164 (44.3), 147 (58.0), 135 (81.5), 127 (100.0), 123
(80.5), 109 (85.1), 95 (32.7), 83 (15.3); HRMS-EI calcd for (M-
CH2OH)þ C15H14FO3N2: 289.0988; found: 289.0991.
CH3–C]); 13C NMR (125 MHz, CD3OD)
d 166.4 (C-4), 154.7 (Ph C-2),
152.3 (C-2), 138.6 (C-6), 129.7 (Ph C-4), 129.3 (Ph C-1), 127.6 (Ph C-
6), 120.3 (Ph C-5), 117.0 (Ph C-3), 111.0 (C-5), 91.3 (C-50), 86.1 (C-20),
66.0 (–CH2OH), 33.0 (C-30), 30.4 (C-40), 12.5 (CH3–C]); MS (EI): m/z
(%)¼318 (0.23, Mþ), 287 (25.3), 192 (22.6), 175 (11.2), 161 (56.6), 145
(29.0), 131 (100.0), 126 (36.3), 121 (44.1), 115 (23.8), 107 (51.2), 91
(45.0), 77 (46.0); HRMS-EI: calcd for (MꢂCH2OH)þ C15H15O4N2:
287.1032; found: 287.1027.
4.10.3. 1-(5-(2-Benzyloxyphenyl)-5-hydroxymethyl-tetrahydro-
furan-2-yl)-5-methyl-1H-pyrimidine-2,4-diones
b
-1c (2R,5R) and
a-11c (2S,5R)
Compound a-1d (0.079 g, 99%) was obtained as white crystals;
1-(40-(2-Benzyloxyphenyl)-20,30-dideoxy-
D
-ribo-pentofuranosyl)-
22
mp¼93–97 ꢁC; [
a
]
þ31.7 (c 1.00, MeOH); IR (KBr): 3381, 3065,
D
2957, 1690, 1605, 1473, 1451, 1404, 1268, 1059, 822, 758 cmꢂ1
NMR (500 MHz, CD3OD)
;
1H
7.42 (dd, J¼1.7 and 7.7 Hz, 1H, Ph H-6),
thymines
b-1c and a-1c. Compound b-1c (0.260 g, 57%) was
obtained as white crystals; mp¼96–101 ꢁC; IR (KBr): 3419, 3188,
d
3063, 2953, 1690, 1599, 1484, 1447, 1276, 1218, 1067, 756, 698 cmꢂ1
;
7.20 (q, J¼1.2 Hz, 1H, H-6), 7.12 (ddd, J¼1.7, 7.7 and 8.0 Hz, 1H, Ph H-
4), 6.82 (dt, J¼0.8, 2ꢃ7.7 Hz, 1H, Ph H-5), 6.80 (dd, J¼0.8 and 8.0 Hz,
1H, Ph H-3), 6.43 (dd, J¼3.7 and 6.9 Hz, 1H, H-20), 3.84 and 3.60 (2d,
J¼11.8 Hz, 2H, –CH2OH), 2.76 and 2.41 (2m, 2H, H-40), 2.59 and 2.03
(2m, 2H, H-30), 1.65 (d, J¼1.2 Hz, 3H, CH3C]); 13C NMR (125 MHz,
1H NMR (500 MHz, CDCl3)
d
9.25 (s, 1H, NH), 7.70 (q, J¼1.2 Hz, 1H,
H-6), 7.62 (dd, J¼1.7 and 7.7 Hz, Ph H-6), 7.41 (m, 4H, o-Bn and m-
Bn), 7.36 (m, 1H, p-Bn), 7.27 (dt, J¼1.7 and 2ꢃ7.7 Hz 1H, Ph H-4),
7.01 (dt, J¼0.8 and 2ꢃ7.7 Hz, 1H, Ph H-5), 6.98 (dd, J¼0.8 and 7.7 Hz,
1H, Ph H-3), 6.27 (dd, J¼5.4 and 6.6 Hz, 1H, H-20), 5.09 (s, 2H, Ph–
CH2), 4.17 and 3.86 (2d, J¼11.7 Hz, 2H, –CH2–OH), 2.80 (s, 1H, OH),
2.61 and 2.49 (2m, 2H, H-40), 2.31 and 2.08 (m, 2H, H-30), 1.93 (d,
CD3OD)
d 166.3 (C-4), 155.1 (Ph C-2), 152.6 (C-2), 138.2 (C-6), 130.1
(Ph C-1), 129.8 (Ph C-4), 128.3 (Ph C-6), 120.2 (–Ph C-5), 117.2 (Ph C-
3), 111.1 (C-5), 91.8 (C-50), 88.0 (C-20), 68.7 (–CH2OH), 33.0 (C-30),
32.8 (C-40), 12.4 (CH3–C]); MS (EI): m/z (%)¼318 (0.53, Mþ), 287
(23.1), 220 (2.6), 192 (32.1), 175 (14.6), 161 (58.8), 145 (17.4), 131
(100.0), 121 (46.5), 115 (15.3), 107 (42.8), 91 (2.4), 77 (32.0); HRMS-
EI: calcd for (MꢂCH2OH)þ C15H15O4N2: 287.1032; found: 287.1054.
J¼1.2 Hz, 3H, CH3–C]); 13C NMR (125 MHz, CDCl3)
d 164.0 (C-4),
154.7 (Ph C-2), 150.6 (C-2), 136.7 (C-6), 136.5 (s-Bn), 130.1 (Ph C-1),
129.1 (Ph C-4), 128.7 (m-Bn), 128.1 (p-Bn), 127.3 (o-Bn), 127.0 (Ph C-
6), 121.1 (Ph C-5), 112.1 (Ph C-3), 110.8 (C-5), 89.2 (C-50), 85.4 (C-20),
70.1 (Ph–CH2–), 66.3 (–CH2–OH), 31.7 (C-30), 31.0 (C-40), 12.5 (CH3–
C]); MS (EI): m/z (%)¼377 (9.3, MþꢂCH2OH), 282 (3.5), 252 (10.6),
221 (4.3), 207 (2.1), 195 (5.2), 175 (1.6), 161 (9.0), 145 (4.4), 131
(10.5), 126 (11.0), 121 (5.2), 105 (3.3), 91 (100.0), 83(1.9). Anal. Calcd
for C23H24N2O5: C, 67.63; H, 5.92; N, 6.86. Found: C, 67.61; H, 5.90;
N, 6.76.
Acknowledgements
We are grateful to the Estonian Ministry of Education and Re-
search (Grant No: 0142725s06), the Estonian Science Foundation
(Grant No: 5628 and 7114) and the Competence Centre for Cancer
Research for financially supporting to carrying out of this project.
Compound a-1c (0.196 g, 43%) was obtained as white crystals;
25
mp¼73–78 ꢁC; [
a]
þ57.3 (c 1.00, MeOH). IR (KBr): 3421, 3197,
D
3035, 2956,1689,1599,1486,1448,1267,1232,1060, 757, 698 cmꢂ1
;
1H NMR (500 MHz, CDCl3)
d
9.48 (s, 1H, –NH), 7.61 (dd, J¼1.7 and
References and notes
7.8 Hz, 1H, Ph H-6), 7.41 (m, 4H, o-Bn and m-Bn), 7.36 (m, 1H, p-Bn),
7.30 (dt, J¼1.7 and 2ꢃ7.7 Hz, 1H, Ph H-4), 7.09 (q, J¼1.2 Hz, 1H, H-6),
7.02 (m, 1H, Ph H-5), 7.00 (m, 1H, Ph H-3), 6.53 (dd, J¼5.2 and
6.4 Hz, 1H, H-20), 5.10 (s, 2H, Ph-CH2), 3.87 and 3.75 (2d, J¼11.8 Hz,
2H, –CH2OH), 2.91 (s, 1H, OH), 2.67 and 2.42 (2m, 2H, H-40), 2.53
and 1.92 (m, 2H, H-30), 1.77 (d, J¼1.2 Hz 3H, CH3C]); 13C NMR
1. Patrick, G. L. An Introduction to Medicinal Chemistry, 3rd ed.; Oxford University
Press: Oxford, 2005; p 440–557.
2. (a) Sugimoto, I.; Shuto, S.; Mori, S.; Shigeta, S.; Matsuda, A. Bioorg. Med. Chem.
Lett. 1999, 9, 385–388; (b) Sugimoto, I.; Shuto, S.; Matsuda, A. J. Org. Chem. 1999,
64, 7153–7157; (c) Haraguchi, K.; Takeda, S.; Tanaka, H.; Nitanda, T.; Baba, M.;
Dutschman, G. E.; Cheng, Y.-C. Bioorg. Med. Chem. Lett. 2003, 13, 3775–3777; (d)
Haraguchi, K.; Itoh, Y.; Takeda, S.; Honma, Y.; Tanaka, H.; Nitanda, T.; Baba, M.;
Dutschman, G. E.; Cheng, Y.-C. Nucleosides Nucleotides Nucleic Acids 2004, 23,
647–654; (e) Maag, H.; Rydzewski, R. M.; McRoberts, M. J.; Clawford-Ruth, D.;
Verheyden, J. P. H.; Prisbe, E. J. J. Med. Chem. 1992, 35, 1440–1451.
(125 MHz, CDCl3) d 163.9 (C-4), 154.6 (Ph C-2), 150.9 (C-2), 136.4 (s-
Bn), 135.8 (C-6), 130.7 (Ph C-1), 129.1 (Ph C-4), 128.7 (m-Bn), 128.1
(p-Bn), 127.5 (Ph C-6), 127.4 (o-Bn), 120.7 (Ph C-5), 112.2 (Ph C-3),
110.8 (C-5), 89.4 (C-50), 85.7 (C-20), 70.2 (PhCH2), 67.7 (–CH2OH),
3. (a) Boyer, P. L.; Julias, J. G.; Ambrose, Z.; Siddiqui, M. A.;Marquez, V. E.; Hughes, S. H.
J. Mol. Biol. 2007, 371, 873–882; (b) Tanaka, H.; Haraguchi, K.; Kumamoto,

A. J˜ogi et al. / Tetrahedron 65 (2009) 2959–2965
2965
H.; Baba, M.; Cheng, Y.-C. Antiviral Chem. Chemother. 2005, 16, 217–221; (c)
Summerer, D.; Marx, A. Bioorg. Med. Chem. Lett. 2005, 15, 869–871.
4. (a) Yoda, H.; Nakaseko, Y.; Takabe, K. Synlett 2002, 1532–1534; (b) Akiyama, K.;
Yamauchi, S.; Nakato, T.; Maruyama, M.; Sugahara, T.; Kishida, T. Biosci. Bio-
technol. Biochem. 2007, 71, 1028–1035; (c) Yamauchi, S.; Tanaka, T.; Kinoshita, Y.
J. Chem. Soc., Perkin Trans. 1 2001, 2158–2160; (d) Wang, T.-C.; Lee, K.-H.; Chen,
Y.-L.; Liou, S.-S.; Tzeng, C.-C. Bioorg. Med. Chem. Lett. 1998, 8, 2773–2776; (e) Lee,
K.-H.; Huang, B.-R.; Tzeng, C.-C. Bioorg. Med. Chem. Lett. 1999, 9, 241–244; (f)
5. Jo˜gi, A.; Paju, A.; Pehk, T.; Kailas, T.; Mu¨u¨risepp, A.-M.; Kanger, T.; Lopp, M.
Synthesis 2006, 3031–3036.
6. Jo˜gi, A.; Ilves, M.; Paju, A.; Pehk, T.; Kailas, T.; Mu¨u¨risepp, A.-M.; Lopp, M. Tet-
rahedron: Asymmetry 2008, 19, 628–634.
7. Stetter, H.; Schlenker, W. Tetrahedron Lett. 1980, 21, 3479–3482.
8. Okabe, M.; Sun, R.-C.; Tam, S. Y.-K.; Todaro, L. J.; Coffen, D. L. J. Org. Chem. 1988,
53, 4780–4786.
9. Alibe´s, R.; Alva´rez-Larena, A.; De March, P.; Figueredo, M.; Font, J.; Parella, T.;
Rustullet, A. Org. Lett. 2006, 8, 491–494.
´
Pelczarska, A. Arch. Immunol. Ther. Exp. 1967, 15, 271–289; (g) Jakobiec, T. Arch.
Immunol. Ther. Exp. 1969, 17, 125–148; (h) Witkowska, M. Arch. Immunol. Ther.
Exp. 1972, 20, 787–811.
10. Dueholm, K. L.; Pedersen, E. B. Synthesis 1991, 1–22.
11. Huryn, D. M.; Okabe, M. Chem. Rev. 1992, 92, 1745–1768.