Asymmetric synthesis of 4′-C-benzyl-2′,3′-dideoxynucleoside analogues from 3-benzyl-2-hydroxy-2-cyclopenten-1-one

Article abstract of DOI:10.1016/j.tetasy.2008.01.028

Both enantiomers of the key intermediate, 2-benzyl-5-oxo-tetrahydro-furan-2-carboxylic acid were obtained by asymmetric oxidation of 3-benzyl-2-hydroxy-2-cyclopenten-1-one with an ee ≥96%, using the tartaric ester/Ti(OiPr)₄/t-BuOOH complex, and transformed to the corresponding 4′-substituted nucleoside analogues with up to 61% overall yield.

Full text of DOI:10.1016/j.tetasy.2008.01.028

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 19 (2008) 628–634
Asymmetric synthesis of 40-C-benzyl-20,30-dideoxynucleoside
analogues from 3-benzyl-2-hydroxy-2-cyclopenten-1-one
Artur Jogi,a Marit Ilves,a Anne Paju,a Tonis Pehk,b Tiiu Kailas,a,c
˜
˜
Aleksander-Mati Muuriseppa,c and Margus Loppa,*
¨ ¨
aDepartment of Chemistry, Faculty of Science, Tallinn University of Technology, Ehitajate tee 5, 19086 Tallinn, Estonia
bNational Institute of Chemical Physics and Biophysics, Akadeemia tee 23, 12618 Tallinn, Estonia
cCompetence Centre for Cancer Research, Akadeemia tee 15, 12618 Tallinn, Estonia
Received 14 January 2008; accepted 24 January 2008
Available online 4 March 2008
Abstract—Both enantiomers of the key intermediate, 2-benzyl-5-oxo-tetrahydro-furan-2-carboxylic acid were obtained by asymmetric
oxidation of 3-benzyl-2-hydroxy-2-cyclopenten-1-one with an ee P96%, using the tartaric ester/Ti(OiPr)4/t-BuOOH complex, and trans-
formed to the corresponding 40-substituted nucleoside analogues with up to 61% overall yield.
Ó 2008 Elsevier Ltd. All rights reserved.
HO
1. Introduction
B
O
Nucleoside analogues have found use as therapeutic agents
against AIDS and cancer.1 The modifications made in the
structure of the analogue usually hinder the replication of
DNA in infected cells. For that purpose, various substitu-
tions in the furanose ring at the 2-, 3- and 4-positions are
introduced. Also, in many cases the base in the nucleoside
analogue is modified. In recent years, the substitution in
position 4 of the saccharide moiety has intensively been
investigated2a (Fig. 1). Various structures with antiviral
properties bearing ethynyl,2a,b ethenyl,2c methyl,2d,e ethyl,2c
fluoromethylene,2e cyano2f,g and azido2a groups in position
4 have been synthesized and investigated.
R
Figure 1. General structure of 40-substituted-20,30-dideoxynucleoside
analogues.
oxy-2-cyclopenten-1-one 4, which was converted by means
of asymmetric oxidation to the alkyl substituted c-butyro-
lactone skeleton in high enantiomeric purity.3 These com-
pounds were used as key intermediates in the synthesis of
40-alkyl substituted nucleoside analogues.
The preparation of the starting 3-benzyl-2-hydroxy-2-
cyclopenten-1-one was accomplished by using a glutarate
and oxalate condensation approach as shown in Scheme 1.4
Thus, glutarate was condensed with oxalate in THF and
isolated as dipotassium salt 15 in 63% yield. After the direct
alkylation of salt 1 with benzyl bromide in DMF, dialkylat-
ed product 4 was obtained in 40% yield. Salt 1 was hydro-
lyzed with H2SO4 (10% solution) in methanol to afford
intermediate 2 as a 1:1 mixture of 2a/2b (the ratio depends
upon the solvent).5
2. Results and discussion
To alter the lipophilicity of the analogues, we have devel-
oped a new synthesis of 40-alkyl substituted nucleosides
with benzyl substituted compounds.
The preparation of 40-alkyl substituted nucleoside ana-
logues usually starts from natural compounds, such as
L-glutamic acid, D-mannitol or D-ribonolactone.1a In our
approach, we began from a simple achiral 3-alkyl-2-hydr-
The alkylation of tautomeric mixture 2 with benzyl bro-
mide in the presence of excess K2CO3 in acetonitrile affor-
ded 3 in 61% yield. Enol ether 3 was decarboxylated and
hydrolyzed using concentrated HCl, or a mixture of con-
centrated HCl/CH3COOH = 1:1.4b,c The first option gave
*
Corresponding author. Tel.: +372 620 2802; fax: +372 620 2995; e-mail:
lopp@chemnet.ee
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.01.028

A. Jo˜gi et al. / Tetrahedron: Asymmetry 19 (2008) 628–634
629
COOEt
O
COOEt
OK
EtOOC
EtOOC
O
O
EtO
O
HO
OH
iii
40%
EtOOC
i
O
OH
O
O
O
O
+
63%
ii
i
EtO
O
OK
79%
O
1
EtOOC
5b
5a
4
3
ii
v
89%
COOEt
COOEt
OH
iv
Scheme 2. Synthesis of 4-benzyl substituted c-lactone acid enantiomers 5a
and 5b by using (+)- or (ꢀ)-diethyltartrate. Reagents: (i) (+)-DET,
Ti(OiPr)4, t-BuOOH/CH2Cl2; (ii) (ꢀ)-DET, Ti(OiPr)4, t-BuOOH/CH2Cl2.
O
61%
O
OH
EtOOC
OH
4
EtOOC
OH
5 can be determined by the use of either (+)- or (ꢀ)-dieth-
2a
2b
yltartrate in the oxidation process (Scheme 2).
Scheme 1. Synthesis of 3-benzyl-2-hydroxy-2-cyclopenten-1-one 4.
Reagents: (i) t-BuOK/THF; (ii) 10%-H2SO4; (iii) BnBr/DMF; (iv) BnBr/
K2CO3/CH3CN; (v) HCl/CH3COOH.
Thus, we obtained (R)-2-benzyl-5-oxo-tetrahydro-furan 5a
with (+)-diethyltartrate in a Ti-complex in 77% yield and
with ee P96% (as described in previous work3). After
recrystallization, the ee of compound 5a increased to
P99%. Analogously, when using (ꢀ)-diethyltartrate, (S)-
2-benzyl-5-oxo-tetrahydro-furan 5b was obtained in the
same yield and enantiopurity.
4 in 30% yield, while the second option resulted in the tar-
get compound in 89% yield. The improved yield is very
likely due to the increased solubility of 3 in the reaction
mixture.
To transform (ꢀ)-c-lactone acid 5a into the corresponding
nucleoside analogues, literature based methods6 were used
(Scheme 3). First, the carboxyl group of 5a was reduced
to the hydroxyl group using a borane complex in dimethyl-
sulfide.6a Lactone alcohol 6a was obtained in 85% yield. The
hydroxyl group was protected by the tert-butyldimethylsilyl
The asymmetric oxidation of 3-benzyl-2-hydroxy-2-cyclo-
penten-1-one 43 with the t-BuOOH–diethyltartrate–
Ti(OiPr)4 complex enables us to choose the absolute con-
figuration of the target nucleoside analogues, since the
absolute configuration of the key compound c-lactone acid
O
HO
R1O
R1O
O
O
O
O
OR2
i
O
iii
5a
6a: R1 =H
8a: R1=TBDMS,R2 =H
9a: R1=TBDMS,R2 =Ac
ii
iv
7a: R1 =TBDMS
O
HO
O
O
O
N
O
N
O
H
N
O
H
HO
N
vi
N
TBDMSO
v
O
N
H
O
+
12a
11a
10a
NHR3
N
NH2
N
N
HO
R1O
N
HO
O
N
N
vii
O
O
ix
N
N
N
N
+
N
15a
16a
N
NH2
13a: R1 =TBDMS,R3=Bz
14a: R1=H,R3=Bz
viii
Scheme 3. Synthesis of 40-benzyl substituted nucleoside analogues. Reagents: (i) BH3ꢁSMe2/THF; (ii) TBDMSCl, imidazole/CH2Cl2; (iii) DIBAH/toluene,
(iv) Ac2O/Et3N/CH2Cl2; (v) Thymine, BSA, TMSOTf/CH3CN; (vi) TBAF/THF; (vii) N6-benzoyladenine, BSA, TMSOTf/CH3CN; (viii) TBAF/ THF;
(ix) NH3/ MeOH.

630
A. Jo˜gi et al. / Tetrahedron: Asymmetry 19 (2008) 628–634
group with TBDMSCl and imidazole, resulting in TBDMS
derivative 7a in 94% yield. The introduction of the base to
the sugar ring was accomplished via acetate 9a. Thus, the
lactone group was reduced to lactol 8a with DIBAH in
97% yield. The following acetylation with acetic anhydride
and triethylamine, in CH2Cl2 solvent6b (1.0 mmol/mL)
afforded 9a in 88% yield. Without solvent, according to
Ref. 6a the acetal dimer was formed in 14% yield.
tone acids 5a and 5b. These lactone acids were converted
to 40-C-benzyl-20,30-dideoxynucleoside analogues in six
steps. This method can be used for a variety of alkyl substi-
tuted nucleoside analogues, which enables us to tune the
lipophilicity of the substituents and achieve the best antivi-
ral and anticancer properties of the analogue.
4. Experimental
Protected acetates 9a were converted to nucleoside thymine
and adenine analogues with N,O-bis(trimethylsilyl)-acet-
amide (BSA) and trimethylsilyltriflate (TMSOTf).6b–d In
the case of thymine, nucleoside analogues 10a were
obtained in 97% yield. After removal of the silyl group
by tetrabutylammonium fluoride (TBAF),6b the target
nucleoside analogues 11a/12a were obtained in 92% yield.
The b- and a-anomers were separated by column chromato-
graphy to afford 12a:13a in a 1:1 ratio.
1H and 13C NMR spectra were recorded in deuterated
solvents (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 AMX-500 spectrometer. Mass
spectra were determined on a Hitachi M80B spectrometer
using the EI (10 eV and 70 eV) mode. Elemental analyses
were performed on a Perkin–Elmer C, H, N, S-Analyzer
2400. Optical rotations were measured with an A. Kruss
¨
Optronic GmbH polarimeter P 3002. Enantiomeric purities
of the compounds were determined by using a Daicel
Chiracel ODH chiral column. IR spectra were recorded
on a Perkin–Elmer Spectrum BX FTIR spectrometer.
TLC analysis was performed on DC-Alufolien Kieselgel
60 F254 (Merck) plates. For column chromatography,
Merck Silica Gel 60 (0.063–0.200 mm) was used. The re-
agents were purchased from Aldrich and used without
purification. Dichloromethane was distilled from CaH2
To introduce adenine into intermediate 9a, the procedure
described above with N6-benzoyl-protected adenine7 deriv-
ative was used. Nucleoside analogues 13a were obtained in
55% yield. After removal of the silyl group by TBAF in
THF, compound 14a was obtained in quantitative yield.
Target nucleosides were obtained after the removal of the
N-benzoyl group with saturated ammonia in methanol,
to afford nucleoside analogues 15a/16a in 82% yield. The
b- and a-anomers were easily separated by column chroma-
tography, resulting in b-anomer 15a and a-anomer 16a in a
1:1 ratio.
˚
and stored over 3 A molecular sieve pellets before use.
DMF was distilled from CaH2, THF from LiAlH4 before
use. The petroleum ether fraction bp 40–60 °C was used.
For the preparation of enantiomeric nucleoside analogues
the same reaction sequence was repeated with (+)-c-lactone
acid 5b (Scheme 4). In the case of thymine, the analogues
11b (b-anomer) and 12b (a-anomer) were obtained in
59% overall yield from 5b. The corresponding adenine
nucleoside analogues 15b (b-anomer) and 16b (a-anomer)
were obtained in 33% overall yield from 5b.
4.1. 1-Benzyl-4-benzyloxy-5-oxo-cyclopent-3-ene-1,3-dicar-
boxylic acid diethyl ester 3
Ethyl glutarate (6.97 g, 37.1 mmol) was added to a mixture
of diethyl oxalate (5.41 g, 37.1 mmol) and t-BuOK (8.33 g,
74.4 mmol) in dry THF (150 mL) under argon at reflux.
The colour of the reaction mixture changed to brown.
The reaction mixture was boiled at reflux for additional
30 min. After cooling the reaction mixture to room temper-
ature, the precipitate was filtered off, washed with dry ether
and dried, to afford dipotassium salt 1 (7.46 g, 63%).
3. Conclusion
The asymmetric oxidation of 3-benzyl-2-hydroxy-2-cyclo-
penten-1-one 4 easily afforded both enantiomers of c-lac-
Compound 3 was obtained using two different methods.
NH2
O
N
N
H
N
O
OH
N
OH
OH
N
O
N
O
O
OH
O
O
11b
15b
5b
+
+
OH
O
O
O
N
O
N
N
N
N
12b
H
16b
N
H2N
Scheme 4. Synthesis of 40-benzyl substituted nucleoside analogues starting from (+)-c-lactone acid 5b.

A. Jo˜gi et al. / Tetrahedron: Asymmetry 19 (2008) 628–634
631
4.1.1. Method 1. A mixture of dipotassium salt 1 (3.18 g,
10 mmol) and benzyl bromide (5.13 g, 30 mmol) in DMF
(60 mL) was heated for 2 h under argon at 120 °C. DMF
and excess benzyl bromide was removed in vacuum. To
the residue a solution of 30% acetic acid (pH 3) was added
and the solution was extracted with EtOAc (3 ꢂ 15 mL).
The combined extracts were dried over MgSO4. After evap-
oration of the solvent, the residue was purified by column
chromatography (petroleum ether/EtOAc = 20:1) to give
compound 3 (1.67 g, 40%) as a colourless syrup.
6.95 (s, 1H, OH), 3.78 (s, 2H, Ph-CH2–), 2.41–2.39 (m,
2H, H-5), 2.38–2.35 (m, 2H, H-4); 13C NMR (125 MHz,
CDCl3) d 203.8 (CO), 148.8 (C-3), 146.6 (C-2), 137.6 (s),
128.9 (o), 128.5 (m), 126.5 (p), 34.8 (Ph-CH2–), 31.9 (C-
5), 24.6 (C-4); MS (EI, 70 eV): m/z (%) = 188 (100, M+),
159 (20.7), 142 (23.2), 117 (42.5), 104 (20.5), 91 (23.5,
Bn+); Anal. Calcd for C12H12O2: C, 76.57; H, 6.43. Found:
C, 76.63; H, 6.39.
4.3. (R)-5-Benzyl-5-hydroxymethyl-dihydro-furan-2(3H)-
one 6a
4.1.2. Method 2. To dipotassium salt
1
(4.37 g,
13.75 mmol), 10% H2SO4 solution (9.3 mL) was added at
0 °C by portions. The solution was extracted with EtOAc
(8 ꢂ 40 mL). The combined extracts were dried on MgSO4
and the solvents were evaporated on a rotary evaporator,
affording a mixture of tautomers 2a and 2b (2.63 g, 79%).
The ratio of 2a:2b was 1:1 (in CH3OD).
To a solution of 5a (0.88 g, 4.0 mmol) in THF (3.0 mL) at
0 °C BH3ꢁMe2S complex in THF. (0.52 mL, 4.8 mmol) was
added dropwise. The reaction mixture was stirred addition-
ally for 1 h at room temperature and methanol (1.0 mL)
was added after cooling. The mixture was concentrated in
vacuo and purified by column chromatography (petroleum
ether/acetone = 10:2), affording compound 6a (0.702 g,
23
A mixture of tautomers 2a and 2b (1.21 g, 5 mmol), benzyl
bromide (2.57 g, 15 mmol) and K2CO3 (4.12 g, 29.8 mmol)
in CH3CN (20 mL) was boiled at reflux for 16 h. The reac-
tion mixture was cooled to room temperature, K2CO3 was
separated by filtration and CH3CN was removed on a rotary
evaporator. The residue was dissolved in ether (30 mL),
washed with 0.1 M NaOH (10 mL) and with water
(2 ꢂ 10 mL). The ether layer was dried over MgSO4. After
filtration of MgSO4 and ether evaporation, the residue was
purified by column chromatography (petroleum ether/
EtOAc = 20:1) to afford compound 3 (1.29 g, 61%) as a col-
ourless syrup. IR (neat): 3031, 2982, 1743, 1720, 1629, 1604,
85%) as white crystals, mp 80–81 °C; ½aꢃD ¼ þ62:8 (c 3.0,
CHCl3); IR (KBr): 3405, 3026, 2948, 2921, 1753, 1735,
1604, 1498, 1455, 1428, 1236, 1068, 946, 769, 704 cmꢀ1
;
1H NMR (500 MHz, CDCl3) d 7.22–7.32 (m, 5H, Ph),
3.75 and 3.59 (2d, J = 12.1 Hz, 2H, CH2–OH), 3.02 and
2.83 (2d, J = 14.0 Hz, 2H, Ph-CH2), 2.42–2.49 (m, 1H,
H-3), 2.19–2.25 (m, 1H, H-4), 2.00–2.06 (m, 1H, H-4),
1.92–1.99 (m, 1H, H-3); 13C NMR (125 MHz, CDCl3) d
177.7 (C-2), 134.8 (s), 130.3 (o), 128.4 (m), 127.0 (p), 88.5
(C-5), 67.3 (C-6), 41.9 (C-7), 29.3 (C-3), 26.5 (C-4); MS
(EI, 70 eV): m/z (%) = 206 (5.2, M+), 175 (7.9), 157 (1.5),
129 (6.2), 115 (100), 105 (2.1), 91 (58.2, Bn+); Anal. Calcd
for C12H14O3: C, 69.89; H, 6.84. Found: C, 69.83; H, 6.86.
1497, 1455, 1368, 1207, 1159, 745, 702 cmꢀ1 1H NMR
;
(500 MHz, CDCl3) d 7.38–7.30 (m, 5H, Ph-CH2–C), 7.24–
7.19 and 7.11–7.08 (m, 5H, Ph-CH2–O), 5.48 and 5.42 (2d,
J = 12.1 Hz, 2H, Ph-CH2–O), 4.22 (q, J = 7.1 Hz, 2H,
@C–COO–CH2–CH3), 4.14 (q, J = 7.1 Hz, 2H, –C–COO–
CH2–CH3), 3.25 (s, 2H, Ph-CH2–C), 3.08 and 2.72 (2d,
J = 17.9 Hz, 2H, H-2), 1.28 (t, J = 7.1 Hz, 3H, @C–COO–
CH2–CH3), 1.21 (t, J = 7.1 Hz, 3H, –C–COO–CH2–CH3);
13C NMR (125 MHz, CDCl3) d 200.7 (C@O), 169.6 (–C–
COOEt), 163.7 (@C–COOEt), 155.0 (C-4), 136.5 (s, Bn–
C), 135.2 (s, Bn–O), 135.2 (C-3), 129.9 (o, Bn–C), 128.3
(m, Bn–C), 128.3 (m, Bn–O), 128.0 (p, Bn–O), 127.6 (o,
Bn–O), 127.0 (p, Bn–C), 72.2 (Ph-CH2–O), 61.9 (–C–
COO–CH2–CH3), 61.0 (@C–COO–CH2–CH3), 57.3 (C-1),
39.3 (Ph-CH2–C), 31.9 (C-2), 14.0 (@C–COO–CH2–CH3),
13.9 (@C–COO–CH2–CH3).
The (S)-enantiomer 6b was obtained in the same way from
5b in 83% yield. ½aꢃD ¼ ꢀ59:8 (c 3.0, CHCl3).
23
4.4. (R)-5-Benzyl-5-(tert-butyl-dimethyl-silyloxymethyl)-
dihydro-furan-2(3H)-one 7a
To a solution of 6a (0.36 g, 1.75 mmol) and imidazole
(0.16 g, 2.32 mmol) in CH2Cl2 (5.0 mL) at 0 °C TBDMSCl
(0.317 g, 2.1 mmol) was added. Stirring was continued for
15 min at 0 °C and then for 2 h at room temperature.
Water (5.0 mL) was added and the mixture was extracted
with CH2Cl2 (3 ꢂ 5 mL). The combined extracts were dried
over MgSO4 and concentrated in vacuo. The residue was
purified by column chromatography (petroleum ether/ace-
tone = 20:1) to give compound 7a (0.529 g, 94%) as white
23
4.2. 3-Benzyl-2-hydroxy-cyclopent-2-en-1-one 4
crystals, mp 66–67 °C; ½aꢃD ¼ þ24:2 (c 1.0, CHCl3); IR
(KBr): 3032, 2955, 2932, 2857, 1766, 1604, 1496, 1457,
To compound 3 (1.31 g, 3.1 mmol), a mixture of HCl and
CH3COOH (1:1, 12 mL) was added and the resulting mix-
ture heated at reflux for 3 h. The excess acids were neutral-
ized by 20% NaOH solution (to pH 3) and the mixture
extracted with EtOAc (5 ꢂ 10 mL). The combined extracts
were dried over MgSO4 and concentrated in vacuo. The
residue was purified by column chromatography (petro-
leum ether/EtOAc = 10:2) giving compound 4 (0.519 g,
89%). Mp = 99–100 °C (97–99 °C, lit.4d); IR (KBr): 3319,
3023, 2922, 1696, 1651, 1600, 1494, 1451, 1385, 1219,
1253, 1186, 1117, 1080, 945, 845, 778, 704 cmꢀ1 1H
;
NMR (500 MHz, CHCl3) d 7.23–7.32 (m, 5H, Ph), 3.67
and 3.60 (2d, J = 10.6 Hz, 2H, OCH2), 3.02 and 2.83 (2d,
J = 14.1 Hz, 2H, Ph-CH2), 2.44–2.52 (m, 1H, H-3), 2.16–
2.22 (m, 1H, H-4), 1.98–2.08 (m, 2H, H-3, H-4), 0.90 (s,
9H, (CH3)3C–Si), 0.08 and 0.07 (2s, 6H, (CH3)2–Si); 13C
NMR (125 MHz, CDCl3) d 177.0 (C-2), 135.0 (s), 130.4
(o), 128.4 (m), 126.9 (p), 87.7 (C-5), 68.3 (CH2O), 42.0
(CH2Ph), 29.4 (C-3), 27.1 (C-4), 25.7 ((CH3)3C–Si), 18.1
((CH3)3C–Si), ꢀ5.6 ((CH3)2–Si); MS (EI, 10 eV): m/z
(%) = 305 (0.21, M+ꢀCH3), 287 (0.79), 263 (27.9), 245
(71.1), 171 (13.9, M+ꢀBnꢀC4H9), 129 (100.0), 91 (70.2,
1
1195, 1107, 762, 699 cmꢀ1; H NMR (500 MHz, CDCl3)
d 7.33–7.31 (m, 2H, m-Ph), 7.27–7.23 (m, 3H, m,p-Ph),

632
A. Jo˜gi et al. / Tetrahedron: Asymmetry 19 (2008) 628–634
24
Bn+); Anal. Calcd for C18H28SiO3: C, 67,46; H, 8,81.
Found: C, 67,44; H, 9,02.
colourless syrup, ½aꢃD ¼ ꢀ15:3 (c 3.02, CHCl3); IR (neat):
3029, 2954, 2930, 2858, 1747, 1604, 1496, 1462, 1251,
1099, 1004, 959, 838, 778, 702 cmꢀ1; H NMR (500 MHz,
1
The (S)-enantiomer 7b was obtained in the same way from
6b in 97% yield. ½aꢃD ¼ ꢀ24:3 (c 3.0, CHCl3).
CDCl3, data for (2R)-isomer labelled with ꢄ) d 7.22–7.29
(m, 10H, Ph), 6.21 (d, J = 4.7 Hz, 1H, H-2*), 6.19 (d,
J = 4.7 Hz, 1H, H-2), 3.62 and 3.54 (2d, J = 9.8 Hz, 2H,
CH2–OSi), 3.36 and 3.33 (2d, J = 10.0 Hz, 2H,
CHꢄ2–OSi), 2.97 and 2.92 (2d, J = 13.8 Hz, 2H, Ph-CHꢄ2),
2.89 and 2.83 (2d, J = 13.7 Hz, 2H, Ph-CH2–), 2.11–2.19
and 1.91–1.94 (m, 2H, H-3*), 2.02–2.08 and 1.89–1.92 (m,
2H, H-4*), 2.01 (s, 3H, Ac), 1.93 (s, 3H, Ac*), 1.81–1.88
(m, 2H, H-4), 1.72–1.76 and 1.26–1.34 (m, 2H, H-3), 0.96
(s, 9H, (CH3)3C–Si), 0.92 (s, 9H, (CHꢄ3Þ3C–Si), 0.11 and
0.10 (2s, 6H, (CH3)2–Si), 0.04 (2s, 6H ðCHꢄÞ –SiÞ; 13C
23
4.5. (R)-5-Benzyl-5-(tert-butyl-dimethyl-silyloxymethyl)-
tetrahydro-furan-2-ol 8a
To a solution of 7a (1.31 g, 4.1 mmol) in toluene (8.2 mL)
at ꢀ78 °C, a 1.5 M solution of DIBAH in toluene
(3.0 mL, 4.5 mmol) was added dropwise. The reaction mix-
ture was stirred additionally for 15 min at ꢀ76 °C, then
methanol (0.9 mL) was added dropwise and the mixture
was allowed to warm to room temperature. EtOAc
(6.2 mL) and saturated NaHCO3 solution (0.83 mL) were
added and stirring was continued for 2 h. Powdered
Na2SO4 (4.1 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 resi-
due was purified by column chromatography (petroleum
ether/EtOAc = 20:1) to give compound 8a, as a 2:1 mixture
3
2
NMR (125 MHz, CDCl3) d 170.5* and 170.2 (CO–CH3),
137.4 and 137.2* (s), 130.8* and 130.5 (o), 127.9 and
127.8* (m), 126.3 and 126.2* (p), 99.5 and 99.2* (C-2),
89.2 and 88.8* (C-5), 69.5 and 66.5* (C-7), 43.3* and 41.9
(C-6), 32.1 and 32.0* (C-3), 29.0 and 28.9* (C-4), 25.9
and 25.8* ((CH3)3C–Si), 21.4 and 21.3* (CO–CH3), 18.3
and 18.2* ((CH3)3C–Si), ꢀ5.4 and ꢀ5.5 and ꢀ5.6
((CH3)2–Si); MS (EI, 70 eV): m/z (%) = 305 (6.4,
M+ꢀAcꢀCH3), 273 (4.7), 247 (33.8), 213 (16.0), 191
(7.0), 177 (11.0), 173 (10.8), 159 (26.7), 135 (11.6), 129
(64.8), 117 (100.0), 91 (68.4, Bn+); Anal. Calcd for
C20H32SiO4: C, 65.89; H, 8,85. Found: C, 65.92; H, 9.09.
of (2R)- and (2S)-diastereoisomers (1.278 g, 97%) as a col-
24
ourless syrup, ½aꢃD ¼ ꢀ8:3 (c 10.14, CHCl3); IR (neat):
3423, 3029, 2954, 2930, 2858, 1605, 1496, 1462, 1257,
1097, 1079, 1016, 967, 838, 777, 701 cmꢀ1 1H NMR
;
(500 MHz, CDCl3, data for (2S) isomer labelled with ꢄ) d
7.22–7.32 (m, 10H, Ph), 5.45 (t, J = 2 ꢂ 4.4 Hz, 1H, H-
The (5S)-enantiomer 9b was obtained in the same way
from 8b in 89% yield. ½aꢃD ¼ þ12:0 (c 3.01, CHCl3).
22
*
2 ), 5.29 (dd, J = 4.6 and 8.3 Hz, 1H, H-2), 3.90 (d,
J = 8.3 Hz, 1H, OH), 3.65 and 3.54 (2d, J = 10.0 Hz, 4H,
CH2–OSi), 3.34 and 3.30 (2d, J = 10.0 Hz, 4H,
CHꢄ2–OSi), 3.00 and 2.96 (2d, J = 13.5 Hz, 2H,
Ph-CHꢄ2–), 2.84 and 2.64 (2d, J = 13.5 Hz, 2H, Ph-CH2–),
2.45 (d, J = 4.4 Hz, 1H, OH*), 2.04–2.11 and 1.69–1.73
(m, 2H, H-4), 1.92–1.97 (m, 2H, H-4*), 1.97–2.03 and
1.75–1.80 (m, 2H, H-3*), 1.65–1.70 and 1.19–1.28 (m, 2H,
H-3), 0.95 (s, 9H, (CH3)3C–Si), 0.93 (s, 9H, (CHꢄ3Þ3C–Si),
0.13 (2s, 6H, (CH3)2–Si), 0.05 (2s, 6H, (CHꢄÞ –Si); 13C
4.7. 1-[(2RS,5R)-5-Benzyl-5-(tert-butyl-dimethyl-silyloxy-
methyl)-tetrahydro-furan-2-yl]-5-methyl-1H-pyrimidine-
2,4(1H,3H)-dione 10a
To a solution of thymine (0.13 g, 1.03 mmol) in dry
CH3CN (8.6 mL), BSA (0.750 mL, 2.93 mmol) and com-
pound 9a (0.358 g, 0.982 mmol) in CH3CN (5.7 mL) were
added at room temperature. After cooling to 0 °C,
TMSOTf (0.177 mL, 0.982 mmol) was added dropwise,
the reaction mixture was stirred for 2 h at room tempera-
ture and poured into a mixture of CH2Cl2 (50 mL) and sat-
urated NaHCO3 solution (10 mL). The CH2Cl2 layer was
removed and the water layer was extracted with CH2Cl2
(3 ꢂ 10 mL). The combined CH2Cl2 layers were dried over
MgSO4 and, after the solvent was removed, the residue was
purified by column chromatography (petroleum ether/ace-
tone = 10:1) to afford compound 10a as a 5:4 mixture of
(2R)- and (2S)-diastereoisomers (0.411 g, 97%) as white
crystals. IR (KBr): 3183, 3031, 2954, 2929, 2857, 1690,
3
2
NMR (125 MHz, CDCl3) d 137.7* and 136.8 (s), 130.7*
and 130.5 (o), 127.9 (m), 126.3 (p), 99.1* and 99.0 (C-2),
87.2* and 87.1 (C-5), 68.5 and 66.7* (C-7), 43.5* and 42.6
(C-6), 34.9 and 33.5* (C-3), 29.3* and 27.1 (C-4), 25.9
((CH3)3C–Si), 18.3 and 18.2* ((CH3)3C–Si), ꢀ5.5 and
ꢀ5.6 ((CH3)2–Si); Anal. Calcd for C18H30SiO3: C, 67.03;
H, 9.38. Found: C, 67.18; H, 9.63.
The (5S)-enantiomer 8b was obtained in the same way
23
from 7b in 96% yield. ½aꢃD ¼ þ6:5 (c 10.13, CHCl3).
4.6. (R)-5-Benzyl-5-(tert-butyl-dimethyl-silyloxymethyl)-
tetrahydro-furan-2-yl acetate 9a
1496, 1471, 1272, 1098, 1081, 838, 778, 703 cmꢀ1 1H
;
NMR (500 MHz, CDCl3, data for 2S isomer labelled with
ꢄ) d 9.5 (br s, NH), 7.56 and 6.34* (q, J = 1.0 Hz, 2H, H-6),
7.20–7.34 (m, 10H, Ph), 6.23* (dd, J = 5.6 and 6.9 Hz, 1H,
H-20), 5.88 (t, J = 6.5 Hz, 1H, H-20), 3.70 and 3.59 (2d,
J = 10.6 Hz, 4H, CH2–O–Si), 3.56* and 3.49* (2d, J =
10.1 Hz, 2H, CH2–O–Si), 2.95* and 2.86* (2d, J =
13.8 Hz, 2H, Ph-CH2–), 2.86 and 2.72 (2d, J = 13.7 Hz,
2H, Ph-CH2–), 2.37* and 1.51* (m, 2H, H-30), 2.14 and
1.89 (m, 2H, H-30), 2.06* and 1.93* (m, 2H, H-40), 2.05
and 1.89 (m, 2H, H-40), 1.90 and 1.72* (d, J = 1.0 Hz,
6H, CH3–C@), 0.92 and 0.93* (s, 18H, t-Bu), 0.09 (s,
12H, Si–(CH3)2); 13C NMR (125 MHz, CDCl3) d 164.0
To a mixture of compound 8a (0.32 g, 1.0 mmol) and Et3N
(0.42 mL, 3 mmol) in CH2Cl2 (1.0 mL), acetic anhydride
(0.28 mL, 3 mmol) was added dropwise at 0 °C. The reac-
tion mixture was stirred overnight at room temperature.
Water (5 mL) was added and the mixture extracted with
EtOAc (4 ꢂ 5 mL). The combined extracts were dried over
MgSO4. After solvent evaporation in vacuo, the residue
was purified by column chromatography (petroleum
ether/EtOAc = 20:1) to afford compound 9a, as a 5:3 mix-
ture of (2S) and (2R)-diastereoisomers (0.32 g, 88%), as a

A. Jo˜gi et al. / Tetrahedron: Asymmetry 19 (2008) 628–634
633
and 163.8* (C-4), 150.5* and 150.4 (C-2), 136.3* and 136.2
(s), 135.6* and 135.4 (C-6), 131.1* and 130.4 (o), 128.2 and
128.0* (m), 126.7 (p), 110.5* and 110.3 (C-5), 87.2 and 86.8*
(Bn–C–O), 85.5 and 84.5* (C-20), 68.8* and 68.6 (CH2–
OSi), 42.8 and 41.2* (Ph-CH2), 32.4 and 31.3* (C-30), 30.0
and 28.6* (C-40), 25.8 ((CH3)3C–), 18.3 and 18.1*
((CH3)3C–), 12.4 (CH3–C@), ꢀ5.3, ꢀ5.4 and ꢀ5.5
((CH3)2Si).
for C17H20N2O4, C, 64.54; H, 6.37; N, 8.85. Found: C,
64.57; H, 6.36; N, 8.58.
The corresponding enantiomers 11b (b-anomer) and 12b
(a-anomer) were prepared in the same way from 10b and
separated by column chromatography, affording white
crystals in 92% overall yield. Ratio of 11b:12b = 1:1.
24
Compound 11b: ½aꢃD ¼ ꢀ20:7 (c 1.01, MeOH).
The (5S)-enantiomer 10b was obtained in the same way
from 9b in 93% yield.
24
Compound 12b: ½aꢃD ¼ ꢀ62:3 (c 1.0, MeOH).
4.9. (2RS,5R)-N-{9-[5-Benzyl-5-(tert-butyl-dimethyl-silyl-
oxymethyl)-tetrahydro-furan-2-yl]-9H-purin-6-yl}-benzam-
ide 13a
4.8. 1-(5-Benzyl-5-hydroxymethyl-tetrahydro-furan-2-yl)-5-
methyl-1H-pyrimidine-2,4-diones (2R,5R)-11a and (2S,5R)-
12a
To a solution of 6-benzyladenine (0.40 g, 1.67 mmol) in
CH3CN (9.0 mL), BSA (1.17 mL, 4.56 mmol) was added
and the mixture stirred for 20 min at room temperature.
To the mixture a solution of compound 9a (0.554 g,
1.52 mmol) in CH3CN (8.0 mL) was added. After cooling
at 0 °C TMSOTf (0.247 mL, 1.52 mmol) was added drop-
wise and the reaction mixture was stirred for 6 h at room
temperature. Now the mixture was poured into a mixture
of CH2Cl2 (50 mL) and saturated NaHCO3 solution
(10 mL). The CH2Cl2 layer was removed and the water
layer was extracted with CH2Cl2 (3 ꢂ 10 mL). The com-
bined CH2Cl2 extracts were dried over MgSO4. After the
solvent was removed the residue was purified by column
chromatography (CH2Cl2/MeOH = 20:1) on silica gel to
give compound 13a (0.420 g, 51%) as white crystals. IR
(KBr): 3253, 3030, 2954, 2929, 2857, 1699, 1611, 1581,
1-(40-Benzyl-20,30-dideoxy-D-ribo-pentofuranosyl)-thymine
11a (b) and 12a (a). To a solution of compound 10a
(0.375 g, 0.87 mmol) in THF (8.0 mL). 1.0 M TBAF solu-
tion in THF (1.8 mL, 1.8 mmol) was added dropwise.
The reaction mixture was stirred for 2 h at room tempera-
ture and then concentrated in vacuo. The residue was puri-
fied by column chromatography on silica gel (CH2Cl2/
MeOH = 10:1), to afford b-anomer 11a and a-anomer 12a.
Compound 11a (0.127g, 46%) was obtained as white crys-
23
tals; mp = 71–76 °C; ½aꢃD ¼ þ23:5 (c 1.0, MeOH); IR
(KBr): 3431, 3193, 3033, 2928, 1689, 1495, 1472, 1405,
1273, 1070, 704 cmꢀ1 1H NMR (500 MHz, CH3OD) d
;
7.88 (q, J = 1.1 Hz 1H, H-6), 7.18–7.30 (m, 5H, Ph), 5.90
(dd, J = 5.0 and 6.5 Hz, 1H, H-20), 3.64 and 3.59 (2d,
J = 11.7 Hz, 2H, –CH2–OH), 2.84 and 2.76 (2d,
J = 13.7 Hz, 2H, Ph-CH2–), 2.09–2.17 and 1.86–1.92 (m,
2H, H-40), 1.90–2.00 (m, 2H, H-30), 1.84 (s, 3H, CH3–
C@); 13C NMR (125 MHz, CH3OD) d 166.4 (C-4), 152.4
(C-2), 138.5 (C-6), 138.3 (s), 131.6 (o), 129.2 (m), 127.6
(p), 111.1 (C-5), 89.8 (C-50), 87.2 (C-20), 67.7 (–CH2–OH),
43.6 (Ph-CH2–), 32.9 (C-30), 30.0 (C-40), 12.4 (CH3–C@);
MS (EI, 70 eV): m/z (%) = 316 (0.11, M+), 299 (1.9,
M+ꢀOH), 285 (2.5, M+ꢀCH2OH), 249 (2.2), 226 (0.95,
M+ꢀBn), 233 (0.85), 218 (0.77), 191 (33.0), 173 (14.5),
158 (100.0), 129 (28.4), 116 (39.2), 91 (83.0, Bn+); Anal.
Calcd for C17H20N2O4, C, 64.54; H, 6.37; N, 8.85. Found:
C, 64.37; H, 6.31; N, 8.69.
1514, 1455, 1331, 1295, 1253, 1079, 838, 777, 704 cmꢀ1
.
The (5S)-enantiomer 13b was obtained in the same way
from 9b in 55% yield.
4.10. (2RS,5R)-N-[9-(5-Benzyl-5-hydroxymethyl-tetra-
hydro-furan-2-yl)-9H-purin-6-yl]-benzamide 14a
To a solution of 13a (0.32 g, 0.59 mmol) in THF (5.5 mL)
1.0 M TBAF solution (1.22 mL, 1.22 mmol) was added
dropwise. The reaction mixture was stirred for 2 h at room
temperature and concentrated in vacuum. After column
chromatography (CH2Cl2/MeOH = 20:1) compound 14a
(0.254 g, 100%) was obtained as white crystals. IR (KBr):
3268, 3028, 2924, 2855, 1699, 1613, 1582, 1514, 1493,
Compound 12a (0.127 g, 46%) was obtained as white crys-
24
tals; mp = 84–90 °C; ½aꢃD ¼ þ61:6 (c 1.0, MeOH). IR
1454, 1401, 1332, 1296, 1253, 1070, 937, 704 cmꢀ1
.
(KBr): 3412, 3178, 3033, 2926, 1688, 1496, 1469, 1411,
1274, 1062, 704 cmꢀ1
;
1H NMR (500 MHz, CH3OD) d
Compound 14b was obtained in the same way from 13b,
7.20–7.28 (m, 5H, Ph), 6.54 (q, 1H, J = 1.2 Hz, H-6),
6.15 (dd, J = 4.8 and 7.1 Hz, 1H, H-20), 3.49 (s, 2H,
–CH2–OH), 2.99 and 2.86 (2d, J = 13.7 Hz, 2H, Ph-CH2–),
2.34–2.41 and 1.65–1.71 (m, 2H, H-30), 1.95–2.05 (m, 2H,
H-40), 1.66 (d, J = 1.2 Hz, 3H, CH3–C@); 13C NMR
(125 MHz, CH3OD) d 166.2 (C-4), 152.5 (C-2), 138.0 (s),
137.4 (C-6), 132.3 (o), 129.1 (m), 127.7 (p), 111.2 (C-5),
88.6 (C-50), 86.1 (C-20), 68.6 (–CH2–OH), 41.9 (Ph-CH2–),
31.5 (C-30), 29.7 (C-40), 12.7 (CH3–C@); MS (EI, 70 eV):
m/z (%) = 316 (0.22, M+), 299 (2.3, M+ꢀOH), 285 (2.4,
M+ꢀCH2OH), 225 (15.1, M+ꢀBn), 191 (40.7), 173
(20.9), 129 (50.0), 116 (14.2), 91 (100.0, Bn+); Anal. Calcd
also in quantitative yield.
4.11. 5-[(6-Amino-9H-purin-9-yl)-2-benzyltetrahydro-furan-
2-yl]methanol (2R,5R)-15a and (2R,5S)-16a
9-(40-Benzyl-20,30-dideoxy-D-ribo-pentofuranosyl)-adenine
15a (b) and 16a (a). A solution of compound 14a (0.270 g,
0.629 mmol) in MeOH (26 mL) saturated with NH3 was
stirred overnight. After the solvent was removed in vacuo
the residue was purified by column chromatography on sil-
ica gel (CH2Cl2/MeOH = 10:1), affording b-anomer 15a
and a-anomer 16a.

634
A. Jo˜gi et al. / Tetrahedron: Asymmetry 19 (2008) 628–634
22
Compound 15a (0.083 g, 41%) was obtained as white crys-
tals; mp = 158–164 °C; IR (KBr): 3330, 3268, 3113, 2931,
1685, 1644, 1607, 1571, 1495, 1476, 1418, 1338, 1303,
1244, 1215, 1088, 1071, 1005, 940, 704 cmꢀ1; (15a) 1H
NMR (500 MHz, DMSO-d6) d 8.33 (s, 1H, H-80), 8.13 (s,
1H, H-20), 7.27 (br s, 2H, –NH2), 7.21–7.35 (m, 5H, Ph),
6.09 (dd, J = 5.0 and 6.4 Hz, 1H, H-5), 5.32 (dd, J = 5.3
and 6.2 Hz, 1H, –OH), 3.46 (dd, 1H, J = 5.3 and
11.4 Hz, H-1), 3.40 (dd, 1H, J = 6.2 and 11.4 Hz, H-1),
2.82 and 2.81 (2d, 2H, J = 13.8 Hz, Ph-CH2–), 2.32–2.39
and 2.03–2.10 (m, 2H, H-4), 2.22–2.28 (m, 2H, H-3); 13C
NMR (125 MHz, DMSO-d6) d 156.0 (C-60), 152.4 (C-20)
148.8 (C-40), 139.2 (C-80), 137.5 (s), 130.4 (o), 128.0 (m),
126.3 (p), 119.1 (C-50), 88.5 (C-2), 84.6 (C-5), 66.1 (C-1),
42.0 (Ph-CH2–), 31.6 (C-4), 29.7 (C-3); MS (EI, 70 eV):
m/z (%) = 325 (4.17, M+), 295 (17.8, M+ꢀCH2OH), 234
(8.16, M+ꢀBn), 162 (49.5), 136 (89.3), 129 (22.3), 115
(10.4), 117 (10.2), 108 (14.5), 91 (100.0, Bn+); Anal. Calcd
for C17H19N5O2, C, 62.76; H, 5.89; N, 21.52. Found: C,
62.60; H, 5.74; N, 21.55.
Compound 16b: ½aꢃD ¼ ꢀ5:5 (c 4.57, DMSO).
Acknowledgements
We are grateful to the Estonian Ministry of Education and
Research (Grant No. 0142725s06), the Estonian Science
Foundation (Grant Nos. 5628 and 6778) and the Compe-
tence Centre for Cancer Research for financial support of
this research.
References
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Compound 16a (0.084 g, 41%) was obtained as white crys-
22
tals; mp = 137–178 °C; ½aꢃD ¼ þ6:6 (c 4.0, DMSO); IR
(KBr): 3435, 3313, 3137, 2920, 1649, 1601, 1577, 1481,
1454, 1419, 1325, 1303, 1250, 1214, 1091, 1068, 1054,
1
942, 703 cmꢀ1; H NMR (500 MHz, DMSO-d6) d 8.14 (s,
1H, H-20), 7.87 (s, 1H, H-80), 7.25 (br s, 2H, –NH2),
7.08–7.17 (m, 5H, Ph), 6.25 (dd, J = 4.5 and 6.4 Hz, 1H,
H-5), 5.00 (t, J = 5.5 Hz, 1H, –OH), 3.30 and 3.29 (both
dd, J = 5.5 and 11.5 Hz, 2H, H-1), 2.93 and 2.88 (2d,
J = 13.8 Hz, 2H, Ph-CH2–), 2.47–2.53 and 2.33–2.39 (m,
2H, H-4), 2.13–2.19 and 2.05–2.11 (m, 2H, H-3); 13C
NMR (125 MHz, DMSO-d6) d 155.9 (C-60), 152.5 (C-20),
149.1 (C-40), 138.7 (C-80), 137.3 (s), 130.4 (o), 127.6 (m),
126.0 (p), 118.9 (C-50), 87.8 (C-2), 83.9 (C-5), 65.5 (C-1),
41.7 (Ph-CH2–), 31.0 (C-4), 30.0 (C-3); MS (EI, 70 eV):
m/z (%)=325 (14.1, M+), 295 (3.3, M+ꢀCH2OH), 234
(4.8, M+ꢀBn), 162 (5.7), 136 (88.4), 129 (23.1), 115 (5.5),
117 (9.2), 108 (14.6), 91 (100.0, Bn+); Anal. Calcd for
C17H19N5O2, C, 62.81; H, 5.94; N, 20.90. Found: C,
62.72; H, 5.82; N, 21.40.
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4374.
The corresponding enantiomers 15b and 16b were prepared
in the same way from 14b in 86% overall yield. The b-ano-
mer 15b and a-anomer 16b were separated by column chro-
matography on silica gel and isolated as white crystals.
Ratio of 15b:16b = 1:1.
7. Waga, T.; Ohrui, H.; Meguro, H. Nucleosides Nucleotides
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