Synthesis of diverse 6-(1,2-disubstituted ethyl)purine bases and nucleosides via 6-(oxiran-2-yl)purines

Article abstract of DOI:10.1016/j.tet.2008.08.074

Dihydroxylation of 6-vinylpurines with t-BuOOH and OsO₄ gave 6-(1,2-dihydroxyethyl)purines 2, while the epoxidation with H₂WO₄ and t-BuOOH afforded 6-(oxiran-2-yl)purines 3. Oxirane ring-opening reactions of 3 with diverse nucleophiles gave a series of title 6-(1,2-disubstituted ethyl)purine bases and nucleosides, which were tested for cytostatic and antiviral activities.

Full text of DOI:10.1016/j.tet.2008.08.074

Tetrahedron 64 (2008) 10355–10364
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Tetrahedron
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Synthesis of diverse 6-(1,2-disubstituted ethyl)purine bases and nucleosides
via 6-(oxiran-2-yl)purines
*
ˇ
´ˇ
´
Martin Kuchar, Radek Pohl, Blanka Klepetarova, Michal Hocek
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Gilead Sciences & IOCB Research Center, Flemingovo nam. 2,
CZ-16610 Prague 6, Czech Republic
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 23 June 2008
Received in revised form 6 August 2008
Accepted 21 August 2008
Available online 30 August 2008
Dihydroxylation of 6-vinylpurines with t-BuOOH and OsO4 gave 6-(1,2-dihydroxyethyl)purines 2, while
the epoxidation with H2WO4 and t-BuOOH afforded 6-(oxiran-2-yl)purines 3. Oxirane ring-opening
reactions of 3 with diverse nucleophiles gave a series of title 6-(1,2-disubstituted ethyl)purine bases and
nucleosides, which were tested for cytostatic and antiviral activities.
Ó 2008 Published by Elsevier Ltd.
1. Introduction
have also reported dihydroxylation of 9-ethyl-6-vinylpurine to
6-(1,2-dihydroxypropyl)-9-ethylpurine15 by treatment with an
Purine bases and nucleosides bearing diverse C-substituents
(aryl, alkenyl, alkynyl or alkyl groups) in position 6 are an
important class of compounds possessing a broad spectrum of
biological effects: e.g., cytostatic,1 antiviral2 and antimicrobial3
activities or receptor modulation.4 6-Methylpurine and its ribo-
nucleoside are highly cytotoxic5 and its liberation by purine
nucleoside phosphorylases from its non-toxic deoxyribonucleo-
side was proposed as a novel principle in the gene therapy of
cancer.6 We have been interested in the synthesis of purines
bearing functionalized alkyl substituents, and reported syntheses
and cytostatic effects of 6-(hydroxymethyl)-,7 6-(fluoromethyl)-8
and 6-(difluoromethyl)purine,9 6-(2-hydroxyethyl)purine10 bases
and nucleosides and (purin-6-yl)alanines11 and -phenylalanines.12
Very recently, we have finished syntheses of a large series
of 6-(dialkylamino)methyl-, 6-alkoxymethyl- and 6-(alkylsulfa-
nylmethyl)purine derivatives,13 as well as homologous 6-(dia-
lkylamino)ethyl-, 6-(dialkylamino)vinyl-, 6-alkoxyethyl- and
6-[2-(alkylsulfanyl)ethyl]purines14 that also exerted significant
cytostatic effects and moderate non-selective anti-HCV activities.
Epoxides are among the most widely used intermediates in
organic synthesis, easily leading to 1,2-disubstituted compounds
via ring-opening reactions with nucleophiles. Surprisingly, so far
there was only one reported example of epoxidation of an alkene in
position 6 of purine by Nair and Chamberlain.15 6-(Prop-1-en-1-yl)-
9-ethylpurine was epoxidized using m-chloroperbenzoic acid in
dichloromethane to give the epoxide in a low yield of 16% accom-
panied by unwanted formation of 1-N-oxides. No further trans-
formations of the oxirane were reported. Nair and Chamberlain
equimolar amount of osmium tetroxide. More examples of dihy-
droxylations were performed in position 2 with 2-vinylpurine,
-adenine and -hypoxanthine nucleosides.16
As a logical extension of our previous studies on cytostatic
purine nucleosides bearing functionalized C-substituents (Fig. 1),
we have decided to prepare a series of 6-(1,2-disubstituted
ethyl)purines, which can be considered as derivatives of cytostatic
6-(hydroxymethyl)purines, via 6-(oxiran-2-yl)purine intermediates.
2. Results and discussion
In order to gain access to the title purines bearing 1,2-difunc-
tionalized ethyl groups, we have tested two approaches: (i) direct
X
Ar
N
Ar = aryl
hetaryl
X =
H
CH3
OH
N
N
N
N
N
N
F
NRR'
CH2NRR'
N
O
HO
HO
O
OH OH
OH OH
HO
N
cytostatic, anti-HCV
HO
cytostatic
X
N
N
N
O
subject of this study
OH OH
Figure 1. Biologically active 6-substituted purine nucleosides.
* Corresponding author. Tel.: þ420 220183324; fax: þ420 220183559.
E-mail address: hocek@uochb.cas.cz (M. Hocek).
0040-4020/$ – see front matter Ó 2008 Published by Elsevier Ltd.
doi:10.1016/j.tet.2008.08.074

ˇ
10356
M. Kuchar et al. / Tetrahedron 64 (2008) 10355–10364
Table 2
dihydroxylation of 6-vinylpurines and (ii) epoxidation of 6-vinyl-
purines followed by ring opening (Scheme 1).
Reactivity of epoxides 3 with sodium methoxide and ethoxide
Entry Starting compd Reagentsa
Product (yield)
1
2
3
4
5
6
7
8
9
3a
3a
3a
3a
3a
3a
3b
3c
3a
MeOH, MeONa
4a (32%), 5a (25%)
OH
MeOH, MeONa, ZnCl2 (1)
MeOH, MeONa, ZnCl2 (3)
MeOH, MeONa, ZnCl2 (4)
MeOH, ZnCl2
MeOH, MeONa, ZnCl2 (3.6) 6a (43%), 7a (7%)
MeOH, MeONa, ZnCl2 (3.6) 6b (37%)
MeOH, MeONa, ZnCl2 (3.6) 6c (15%)
4a (27%), 5a (15%), 3a (30%)
4a (2%), 6a (24%), 7a (8%)
6a (21%), 7a (16%)
O
OH
N
N
N
N
N
6a (28%), 7a (24%)
N
N
t-BuOOH
t-BuOOH
OsO4
N
H2WO4, CHCl3
N
R
N
N
N
R
R
2a, b
1a, b
3a, b
EtOH, EtONa
8a (32%), 9a (31%)
a
In all cases, 3 equiv of MeONa or EtONa has been used, numbers of equivalents of
ZnCl2 are given in parentheses.
TBSO
HO
R=
O
NEt3.3HF
THF
O
Reactions of 3a with sodium methoxide were performed in all
cases at 60 ꢀC for 2 h. Reaction with 3 equiv of sodium methoxide
without further additive led to a mixture of 9-benzyl-6-(2-hydroxy-
1-methoxyethyl)purine (4a) and unexpected 6-(2-hydroxyethyl)-8-
methoxypurine (5a), apparently formed as a product of an attack of
the nucleophile to position 8 (entry 1). Further, we have studied the
effect of additive ZnCl2. When using 1 equiv of ZnCl2 (entry 2), lower
conversion to the same products 4a and 5a was observed. On the
other hand, in the presence of a larger amount of ZnCl2, the same
reaction proceeded to form the other ring-opened isomer: 9-benzyl-
6-(2-methoxy-1-hydroxyethyl)purine (6a), accompanied by 6-ace-
tyl-9-benzylpurine (7a)22 formed by a rearrangement of 3a catalyzed
by excessive zinc chloride (entries 4 and 5). Based on this result, we
found the best conditions to be with a more diluted reaction mixture
and a special ratio of sodium methoxide (3 equiv) and zinc chloride
(3.6 equiv) (entry 6) leading more selectively to the formation of 9-
benzyl-6-(1-hydroxy-2-methoxyethyl)purine (6a) in an acceptable
yield of 43%. An analogous reaction was also performed on protected
and free nucleosides 3b,c to give the corresponding nucleosides 6b,c
in moderate yields. This interesting dichotomy of regioselectivity of
epoxide opening by either sodium or zinc methoxide leading to 2-
hydroxy-1-methoxyethyl or 1-hydroxy-2-methoxyethyl derivatives,
b
a
Bn
c
TBSO OTBS
Scheme 1. Dihydroxylation and epoxidation.
OH OH
Dihydroxylation of vinylpurines was described only with an
equimolar amount of osmium tetroxide in dry pyridine.15,16 In order
to avoid the use of stoichiometric amounts of this toxic reagent, we
have tested several reagents and conditions (Table 1). The reactions
of 9-benzyl-6-vinylpurine (1a) with a ruthenium catalyst17 (entry 1)
or with potassium permanganate18 (entry 2) led to complex mix-
tures of degradation products. On the other hand, the reaction
with catalytic amount (2 mol %) of osmium tetroxide19 with
tert-butylhydroperoxide as a reoxidant at rt gave the desired
vicinal diol 2a in a good yield of 67% (entry 3). This successful
dihydroxylation protocol was then applied for silyl-protected 6-
vinylpurine ribonucleoside 1b giving rise to the 6-(1,2-dihy-
droxyethyl)purine nucleoside 2b in 58% yield (entry 4). Epoxi-
dation of 6-vinylpurines was also pursued using several
reagents and conditions. The reaction of 6-vinylpurine 1a with
m-chloroperbenzoic acid in dichloromethane15 was slow and
unselective, and after 1 day formation of diol and other side
products was observed by TLC and NMR spectroscopy (entry 5).
Transition metal catalysts (i.e., H2WO4) often dramatically en-
hance the speed and selectivity of epoxidations.20 The reaction
of 1a was therefore performed with 5 mol % of H2WO4 in
chloroform with dry tert-butylhydroperoxide as oxidant (entry
6). Epoxidation was performed at rt for 16 h to give the oxirane
3a in a good yield of 62%. It should be noted here that both
dihydroxylation and epoxidation of nucleoside 1b did not pro-
ceed diastereoselectively, and due to the presence of homochiral
ribose moiety, the products 2b and 3b (as well as all other
nucleoside derivatives in this paper) were isolated as 1:1
diastereomeric mixtures.
CH3
O
HO
OH
N
CH3
N
N
N
N
O
+
N
R
N
N
R
4a
5a
NaOMe
MeOH
H3C
O
O
O
OH
N
N
N
Having access to the epoxide intermediates 3a,b, we have further
studied the regioselectivity of ring-opening reactions of these epox-
ides with diverse nucleophiles (Table 2, Scheme 2). In most cases the
nucleophilic reagent is expected to attack the less hindered epoxide
carbon.21 However, as purine is a strongly electron withdrawing
substituent, electronic effects could also play an important role in the
regioselectivity. Initially, we studied the reaction of sodium meth-
oxide with an epoxide under various conditions (Table 2, Scheme 2).
Zn(OMe)2
MeOH
N
N
N
+
N
R
N
R
N
N
N
N
R
7a
6a, b, c
3a, b, c
NaOEt
EtOH
CH2CH3
HO
O
CH2CH3
O
N
N
N
N
N
Table 1
+
N
R
Dihydroxylation and epoxidation of 6-vinylpurines
N
N
R
Entry Starting compd Reagents
Product (yield)
8a
9a
1
2
3
4
5
6
7
1a
1a
1a
1b
1a
1a
1b
RuCl3, NaIO4, H2SO4, H2O, EtOAc, CH3CN Decomposition
KMnO4, acetone
t-BuOOH/OsO4
t-BuOOH/OsO4
m-CPBA, DCM
t-BuOOH/H2WO4
t-BuOOH/H2WO4
Decomposition
2a (67%)
2b (58%)
R= TBSO
HO
O
NEt3.3HF
THF
O
a
Bn
b
c
2aþdegradation
TBSO OTBS
OH OH
3a (62%)
3b (80%)
Scheme 2. Reactivity of epoxides 3 with sodium methoxide and ethoxide.

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M. Kuchar et al. / Tetrahedron 64 (2008) 10355–10364
10357
Table 3
Transformations of epoxides
respectively, is unprecedented in the literature to the best of our
knowledge. Furthermore, we have examined the reactivity of sodium
ethoxide with epoxide. The reaction with 3 equiv of sodium ethoxide
(entry 9) led to the formation of 9-benzyl-6-(2-hydroxy-1-ethoxy-
ethyl)purine (8a) and 9-benzyl-8-ethoxy-6-vinylpurine (9a) as
products of attack of ethoxide to position 8 followed by dehydration.
We have also studied the reactions of epoxides 3 with other
nucleophiles (Scheme 3, Table 3). The treatment of 3a with etha-
nolic ammonia proceeded slowly and after 5 days we isolated 6-(2-
amino-1-hydroxyethyl)-9-benzylpurine (10a) in a moderate yield
of 34% (entry 1). The analogous reaction of the free nucleoside 3c
led to the 2-amino derivative 10c (entry 2). Reaction of 3a with
methylmagnesium chloride in THF gave 6-acetyl-9-benzylpurine
(7a) formed by a rearrangement of 3a catalyzed by magnesium
chloride present in the Grignard reagent21 (entry 3). Therefore, we
tried the reaction of 3a with the organocuprate reagent prepared
from CuI and methyl lithium, which gave the desired product 9-
benzyl-6-(1-hydroxypropyl)purine 11a in good yield of 60%. The
analogous reaction with nucleoside 3b gave 11b in a low yield of
21%. Reaction with the sodium salt of diethylmalonate generated in
situ proceeded with simultaneous intramolecular lactonization
leading to lactone 12a in a low yield of 22%. The lactonization
proceeded stereoselectively to give a racemic product with a trans-
relative configuration. Reaction with sodium methanethiolate led
to a mixture of two isomers 13a (60%) and 14a (13%). In the case of
nucleosides 3b, this reaction gave 13b, as the product of nucleo-
philic attack at the more hindered carbon, as the main product (the
other isomer was only detected on TLC in trace amounts but not
isolated). Reaction with sodium thiophenolate proceeded almost
quantitatively and led to a mixture of two products: dehydrated
product 15a and 1-hydroxy isomer 16a. On the other hand, reaction
with sodium benzoxide led only to one isomer 18a accompanied by
its dehydrated byproduct 17a.
Entry
Starting compd
Reagents
Product (yield)
1
2
3
4
5
6
7
8
3a
3c
3a
3a
3b
3a
3a
3b
3a
3a
3a
3a
NH3/EtOH, rt, 5 days
NH3/EtOH, rt, 5 days
MeMgCl
Me2CuLi/THF
Me2CuLi/THF
CH2(COOEt)2, EtONa,
MeSNa/THF aq
MeSNa/THF aq
PhSNa, THF aq
t-BuOH, NaH, THF
PhOH, NaH, THF
BnOH, NaH, THF
10a (34%)
10c (42%)
7a (71%)
11a (60%)
11b (21%)
12a (22%)
13a (60%), 14a (13%)
13b (74%)
15a (35%), 16a (63%)
No reaction
No reaction
17a (26%), 18a (14%)
9
10
11
12
The whole series of TBS-protected nucleosides (2b, 3b, 6b, 11b
and 13b) was deprotected by treatment with Et3N$3HF in THF
(Table 4) to give the free nucleosides 2c, 6c, 11c and 13c in good
yields. In the case of silylated epoxide 3b, the above mentioned
desilylation gave the nucleoside 3c in low yield accompanied by
6-(acetyl)-9-(b-D-ribofuranosyl)purine 7c. However, the use of
TBAF in THF gave cleanly the desired nucleoside 3c in good yield.
All compounds were fully characterized. Crystal structures of
epoxide 3a, methylsulfanyl 14a and 8-methoxy derivatives 5a were
determined by X-ray crystallography (Fig. 2). No significant anti-
viral (HCV replicon) or cytostatic effect was observed in any of the
new purine bases or nucleosides reported here, with the exception
of parent epoxide 3c, which exerted a moderate cytostatic activity:
IC50¼3.6–9
mM for CEM, HL60 and HeLa cell lines.
In conclusion, a practical synthesis of 6-(oxiran-2-yl)purine
bases and nucleosides was developed based on epoxidation of
6-vinylpurines. The epoxides are reactive towards nucleophilic
ring-opening reactions leading to diverse types of products. Apart
from the expected addition products, in some cases (hard sodium
alkoxides) we have observed rather unexpected by-products
formed by attack of the nucleophile to position 8 and in some other
cases products of elimination or rearrangements. Despite the
moderate yields and poor selectivities of some of these reactions,
the presented methodology significantly extends the portfolio of
purines bearing functionalized C-substituents in position 6 to many
novel derivatives not accessible by the established methodologies.
O
NH2
OH
N
N
H3C
N
OH
N
N
N
R
N
7a
N
MeMgCl
THF
N
N
N
R
N
R
11a, b
10a, c
NH3/EtOH
Me2CuLi
O
THF
3. Experimental
3.1. General
N
N
O
O
COOEt
COOEt
N
R
O
O
N
MeSNa
H2O/THF
3a, b, c
N
N
N
Melting points were determined on a Kofler block and are un-
corrected. Mass spectra were measured on a ZAB-EQ (VG Analyti-
cal) spectrometer. IR spectra were measured on a Bruker equinox
55 and FTIR spectrometer Nicolet 6700. NMR spectra were recorded
on Bruker Avance 600 (1H at 600 MHz, 13C at 151 MHz), Bruker
Avance 500 (1H at 500 MHz, 13C at 125.8 MHz) and Bruker Avance
400 (1H at 400 MHz, 13C at 100.6 MHz). 1H and 13C NMR spectra
were referenced to the signal of TMS or to the solvent residual
H3C
+
EtONa
CH3
S
HO
S
N
OH
Bn
12a
BnOH
NaH, THF
PhSNa
THFaq
N
N
N
N
N
N
N
N
R
R
13a, b
14a, b
HO
PhS
OBn
OBn
N
SPh
OH
N
N
N
N
N
N
N
N
N
Bn
17a
N
Bn
N
N
Table 4
N
Bn
16a
N
N
Deprotections of silylated nucleosides
Bn
18a
15a
Entry
Starting compd
Reagent
Product (yield)
1
2
3
4
5
6
2b
3b
3b
6b
11b
13b
Et3N$3HF
Et3N$3HF
TBAF
Et3N$3HF
Et3N$3HF
Et3N$3HF
2c (93%)
3c (39%), 7c (20%)
3c (82%)
6c (67%)
11c (75%)
13c (92%)
TBSO
HO
R=
O
NEt3.3HF
THF
O
b
a
Bn
c
TBSO OTBS
OH OH
Scheme 3. Other transformations of epoxides 3.

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M. Kuchar et al. / Tetrahedron 64 (2008) 10355–10364
10358
reduced pressure. The residue was purified by column chroma-
tography on silica gel to give the product.
3.3.1. 9-Benzyl-6-(1,2-dihydroxyethyl)purine (2a)
Chromatography methanol/chloroform 0–3%, crystallized from
chloroform/heptane, colourless crystals, yield 70%. Mp 118–120 ꢀC.
1H NMR (500 MHz, CDCl3): 4.12 and 4.16 (2ꢁdd, 2H, Jgem¼11.5,
Jvic¼4.6, CH2O); 4.23 and 5.22 (2ꢁbr s, 2ꢁ1H, OH); 5.35 (t, 1H,
Jvic¼4.6, CHO); 5.44 (s, 2H, CH2Ph); 7.29–7.37 (m, 5H, H-o,m,p-Ph);
8.09 (s, 1H, H-8); 8.95 (s, 1H, H-2). 13C NMR (125.7 MHz, CDCl3):
47.36 (CH2Ph); 65.65 (CH2O); 71.69 (CHO); 127.89 (CH-o-Ph);
128.62 (CH-p-Ph); 128.08 (CH-m-Ph); 130.36 (C-5); 134.64 (C-i-Ph);
144.32 (CH-8); 151.15 (C-4); 151.83 (CH-2); 159.37 (C-6). ESI MS:
m/z (%) (65) [Mþ Na], (100) [Mþ H]. HRMS calcd for C14H15N4O2 [Mþ
H] 271.1190, found 271.1190. Anal. Calcd for C14H14N4O2$0.25H2O: C
61.19, H 5.32, N 20.39. Found: C 61.27, H 5.17, N 20.34. IR (CHCl3):
3587, 3411, 3114, 3092, 3070, 1596, 1585, 1456, 1406, 1333, 1095,
1080, 1052, 1031, 998, 699, 647, 455.
3.3.2. 9-(2,3,5-Tri-O-tert-butyldimethylsilyl-b-D-ribofuranosyl)-6-
[(R,S)-1,2-dihydroxyethyl]purine (2b)
Purified by column chromatography (silica gel, ethyl acetate/
hexane 20–50%) to give yellowish foam, yield 58%, mixture of di-
astereoisomers 1:1. 1H NMR (500 MHz, CDCl3): ꢂ0.21, ꢂ0.17, ꢂ0.02,
ꢂ0.01, 0.101, 0.103, 0.107, 0.112, 0.144, 0.146 and 0.154 (11ꢁs, 36H,
CH3Si); 0.80, 0.81, 0.94, 0.961 and 0.962 (5ꢁs, 54H, (CH3)3C); 3.58
and 3.64 (2ꢁbr t, 2ꢁ1H, J¼6.5, OH); 3.81 (dd, 2H, Jgem¼11.4,
0
0
0
0
0
J5 b,4 ¼2.6, H-5 b); 4.03 and 4.06 (2ꢁdd, 2ꢁ1H, Jgem¼11.4, J5 a,4 ¼3.6,
H-50a); 4.11–4.19 (m, 6H, H-40 and CH2O); 4.31 and 4.33 (2ꢁt, 2ꢁ1H,
J3 ,2 ¼J3 ,4 ¼4.0, H-30); 4.59 and 4.62 (2ꢁdd, 2ꢁ1H, J2 ,1 ¼4.6,
0
0
0
0
0
0
0
0
0
J2 ,3 ¼4.0, H-2 ); 4.91 (br m, 2H, OH); 5.30 (br m, 2H, CHO); 6.14 and
0
0
0
6.16 (2ꢁd, 2ꢁ1H, J1 ,2 ¼4.6, H-1 ); 8.541 and 8.543 (2ꢁs, 2ꢁ1H, H-8);
8.93 and 8.94 (2ꢁs, 2ꢁ1H, H-2).13C NMR (125.7 MHz, CDCl3): ꢂ5.40,
ꢂ5.39, ꢂ5.36, ꢂ5.35, ꢂ5.04, ꢂ5.01, ꢂ4.75, ꢂ4.71, ꢂ4.69, ꢂ4.38 and
ꢂ4.33 (CH3Si); 17.83, 17.84, 18.05, 18.06 and 18.53 ((CH3)3C); 25.61,
25.62, 25.81 and 26.08 ((CH3)3C); 62.09 and 62.28 (CH2-50); 65.66
and 65.70 (CH2O); 71.34, 71.60 and 71.66 (CH-30 and CHO); 76.15
and 76.35 (CH-20); 85.24 and 85.46 (CH-40); 88.38 and 88.69 (CH-
10); 130.93 and 131.01 (C-5); 143.29 and 143.37 (CH-8); 150.89 and
150.98 (C-4); 151.53 and 151.61 (CH-2); 159.26 and 159.29 (C-6). ESI
MS: m/z (%) (35) [Mþ H]. HRMS calcd for C30H59N4O6Si3 [Mþ H]
655.3737, found 655.3723. IR (CHCl3): 3589, 3413, 3120, 3074, 2956,
1597, 1584, 1497, 1472, 1464, 1408, 1391, 1334, 1257, 1083, 1071, 938,
839, 682, 648.
Figure 2. ORTEP drawings of crystal structures of 3a (a), 14a (b) and 5a (c) with atom
numbering scheme. Thermal ellipsoids are drawn at the 50% probability level.
signal [DMSO-d6: 2.50 ppm (1H), 39.70 ppm
(
13C); CD3OD:
3.31 ppm (1H); 49.00 ppm (13C)]. H,C-HSQC and H,C-HMBC exper-
iments were performed for complete assignment of all signals.
Starting compounds were prepared according to the literature
procedures: 1a22 and 1b.23
3.4. General method for epoxidation of 6-vinylpurines
3.2. Preparation of starting t-BuOOH solution
A mixture of a vinylpurine 1 (2 mmol) and H2WO4 (25 mg,
0.1 mmol) in a solution of tert-butylhydroperoxide in tert-butanol
and chloroform (30 ml) was stirred at rt for 16 h. After completion,
the reaction mixture was filtered and concentrated under reduced
pressure. The residue was purified by column chromatography on
silica gel to give the product.
Anhydrous Na2SO4 (50 g) was added to a mixture of tert-butanol
(100 ml) and aqueous H2O2 (30% in H2O, 200 ml) and the two
phases were separated. The organic layer was dried over anhydrous
MgSO4 and filtered. This solution was sufficiently dry for dihy-
droxylations but not for epoxidations. For the use in epoxidations,
chloroform (100 ml) was added to the solution, which was again
dried over anhydrous MgSO4 and filtered.
3.4.1. 9-Benzyl-6-(oxiran-2-yl)purine (3a)
Purified by column chromatography (silica gel, ethyl acetate/
hexane 30–60%), crystallized from chloroform/heptane to give
colourless crystals, yield 62%. Mp 105–108 ꢀC. 1H NMR (500 MHz,
CDCl3): 3.34 (dd, 1H, Jgem¼6.4, J3b,2¼4.2, H-3b-ox); 3.60 (dd, 1H,
Jgem¼6.4, J3a,2¼2.5, H-3a-ox); 4.56 (dd, 1H, J2,3¼4.2, 2.5, H-2-ox);
5.46 (s, 2H, CH2Ph); 7.30 (m, 2H, H-o-Ph); 7.32–7.39 (m, 3H, H-
m,p-Ph); 8.08 (s, 1H, H-8); 8.97 (s, 1H, H-2). 13C NMR (125.7 MHz,
CDCl3): 47.30 (CH2Ph); 49.27 (CH-2-ox); 49.53 (CH2-3-ox); 127.80
(CH-o-Ph); 128.65 (CH-p-Ph); 129.15 (CH-m-Ph); 132.49 (C-5);
134.87 (C-i-Ph); 144.80 (CH-8); 151.56 (C-4); 152.74 (CH-2); 156.01
(C-6). ESI MS: m/z (%) (100) [Mþ Na], (32) [Mþ H]. HRMS calcd for
3.3. General method for dihydroxylation of 6-vinylpurines
A mixture of a vinylpurine 1 (1 mmol) and OsO4 (1 ml of 2%
solution in t-BuOH, 0.02 mmol) in a solution of tert-butylhy-
droperoxide in tert-butanol (50 ml) was stirred at rt for 2 days. After
completion, the reaction mixture was diluted with a 10% aqueous
solution of Na2S2O4 (500 ml) and then washed with ethyl acetate
(3ꢁ50 ml). The collected organic layers were washed with brine,
dried over anhydrous MgSO4, filtered and concentrated under

ˇ
M. Kuchar et al. / Tetrahedron 64 (2008) 10355–10364
10359
C14H13N4O [Mþ H] 253.1084, found. 253.1088. Anal. Calcd for
14H12N4O: C 66.65, H 4.79, N 22.21. Found: C 66.23, H 4.62, N 21.88.
IR (CHCl3): 3113, 3092, 3069, 3034, 1598, 1586, 1501, 1456, 1411,
1331, 1078, 1030, 1003, 728, 699, 644, 456.
151.17 (C-4); 154.53 (C-6); 157.82 (C-8). ESI MS: m/z (%) (90) [Mþ
Na], (100) [Mþ H]. HRMS calcd for C15H17N4O2 [Mþ H] 285.13460,
found 285.13446. Anal. Calcd for C15H16N4O2: C 63.37, H 5.67, N
19.71. Found: C 63.36, H 5.78, N 19.88. IR (CHCl3): 3620, 3361, 3092,
3069, 3036, 1614, 1592, 1553, 1497, 1485, 1484, 1455, 1403, 1334,
1059, 1038, 1030, 699, 458.
C
3.4.2. 9-(2,3,5-Tri-O-tert-butyldimethylsilyl-b-D-ribofuranosyl)-6-
[(R,S)-oxiran-2-yl]purine (3b)
Purified by column chromatography (silica gel, ethyl acetate/
hexane 0–30%) to give white foam, yield 80%, mixture of di-
astereoisomers 1:1. 1H NMR (600 MHz, CDCl3): ꢂ0.27, ꢂ0.25, ꢂ0.04,
0.102, 0.106, 0.109, 0.144, 0.147, 0.153 and 0.158 (10ꢁs, 36H, CH3Si);
0.78, 0.79, 0.94, 0.96 and 0.97 (5ꢁs, 54H, (CH3)3C); 3.336 and 3.339
(2ꢁdd, 2ꢁ1H, Jgem¼6.4, J3b,2¼4.2, H-3b-ox); 3.55 and 3.58 (2ꢁdd,
2ꢁ1H, Jgem¼6.4, J3a,2¼2.5, H-3a-ox); 3.81 (dd, 2H, Jgem¼11.5,
3.5.3. 9-Benzyl-6-(1-hydroxy-2-methoxyethyl)purine (6a)
A
mixture of 9-benzyl-6-(oxiran-2-yl)purine (3a) (126 mg,
0.5 mmol), dry ZnCl2 (245 mg, 1.8 mmol) and sodium methoxide
(1.5 mmol) in methanol (20 ml) was stirred at 60 ꢀC for 2 h. After
completion, the reaction mixture was diluted with water (150 ml)
and then washed with ethyl acetate (3ꢁ50 ml). The collected or-
ganic layers were washed with brine, dried over anhydrous MgSO4,
filtered and concentrated under reduced pressure. The residue was
purified by column chromatography (silica gel, methanol/chloro-
form 0–5%) and crystallized from chloroform/heptane to give white
crystals 61 mg (43%). Mp 115–116 ꢀC. 1H NMR (500 MHz, CDCl3):
3.39 (s, 3H, CH3O); 4.00 (dd, 2H, Jgem¼10.1, Jvic¼3.8, CHaHbO); 4.02
(dd, 2H, Jgem¼10.1, Jvic¼4.9, CHaHbO); 4.75 (br d, 1H, J¼5.2, OH); 5.45
(br ddd, 1H, J¼5.2, 4.9, 3.8, CHO); 5.46 (s, 2H, CH2Ph); 7.31–7.40 (m,
5H, H-o,m,p-Ph); 8.05 (s, 1H, H-8); 8.99 (s, 1H, H-2). 13C NMR
(125.7 MHz, CDCl3): 47.43 (CH2Ph); 59.50 (CH3O); 70.61 (CHO);
75.84 (CH2O); 127.97 (CH-o-Ph); 128.72 (CH-p-Ph); 129.19 (CH-m-
Ph); 130.74 (C-5); 134.83 (C-i-Ph); 144.14 (CH-8); 151.28 (C-4);
151.94 (CH-2); 158.95 (C-6). ESI MS: m/z (%) (100) [Mþ Na], (45)
[Mþ H]. HRMS calcd for C15H17N4O2Na [Mþ Na] 307.1166, found
307.1162. Anal. Calcd for C15H16N4O2: C 63.37, H 5.67, N 19.71.
Found: C 63.51, H 5.54, N 19.38. IR (CHCl3): 3565, 3440, 3112, 3092,
3069, 3033, 2830, 1594, 1586, 1498, 1456, 1405, 1332, 1328, 1122,
1099, 1079, 1031, 1004, 699, 646, 456.
0
0
0
0
0
J5 b,4 ¼2.9, H-5 b); 4.02 and 4.03 (2ꢁdd, 2ꢁ1H, Jgem¼11.5, J5 a,4 ¼3.9,
0
H-50a); 4.15 and 4.16 (2ꢁddd, 2ꢁ1H, J4 ,5 ¼3.9, 2.9, 0J4 ,3 ¼3.8, H-4 );
0
0
0
0
0
0
0
0
4.31 and 4.33 (2ꢁdd, 2ꢁ1H, J3 ,2 ¼4.0, J3 ,4 ¼3.8, H-3 ); 4.58 and 4.60
(2ꢁdd, 2ꢁ1H, J2,3¼4.2, 02.5, H-2-ox); 4.65 and 4.66 (2ꢁdd, 2ꢁ1H,
0
0
0
0
0
0
J2 ,1 ¼5.2, J2 ,3 ¼4.0, H-2 ); 6.138 and 6.144 (2ꢁd, 2ꢁ1H, J1 ,2 ¼5.2,
H-10); 8.47 and 8.49 (2ꢁs, 2ꢁ1H, H-8); 8.92 (s, 2H, H-2). 13C NMR
(151 MHz, CDCl3): ꢂ5.38, ꢂ5.11, ꢂ5.06, ꢂ4.74, ꢂ4.68 and ꢂ4.43
(CH3Si); 17.79, 17.81, 18.06, 18.52 and 18.53 ((CH3)3C); 25.60, 25.81
and 26.07 ((CH3)3C); 48.88 and 49.14 (CH-2-ox); 49.60 and 49.63
(CH2-3-ox); 62.43 and 62.48 (CH2-50); 71.85 and 71.93 (CH-30);
75.87 and 76.08 (CH-20); 85.57 and 85.69 (CH-40); 88.18 and 88.22
(CH-10); 133.26 and 133.35 (C-5); 143.93 and 144.00 (CH-8); 151.26
(C-4); 152.53 and 152.57 (CH-2); 155.84 and 155.91 (C-6). ESI MS:
m/z (%) (65) [Mþ Na], (100) [Mþ H]. HRMS calcd for C30H57N4O5Si3
[Mþ H] 637.3631, found 637.3634. IR (CHCl3): 3119, 3068, 2956,
1599,1586,1499, 1472,1464,1411,1391,1362,1331,1258,1083,1071,
938, 839, 682, 646.
3.5. Reaction of 9-benzyl-6-(oxiran-2-yl)purine (3a) with
sodium methoxide
3.5.4. 9-(2,3,5-Tri-O-tert-butyldimethylsilyl-
[(R,S)-1-hydroxy-2-methoxyethyl]purine (6b)
A mixture of 9-(2,3,5-tri-O-tert-butyldimethylsilyl-
b-D-ribofuranosyl)-6-
b-D-ribofur-
A mixture of 9-benzyl-6-(oxiran-2-yl)purine (3a) (252 mg,
1 mmol) and sodium methoxide (3 mmol) in methanol (20 ml) was
stirred at 60 ꢀC for 2 h. After completion, the reaction mixture was
concentrated under reduced pressure. The residue was purified by
column chromatography (silica gel, methanol/chloroform 0–5%) to
give two isomers: 90 mg (32%) of 9-benzyl-6-(hydroxyethyl)-8-
methoxypurine (5a) and 70 mg (25%) of 9-benzyl-6-(2-hydroxy-1-
methoxyethyl)purine (4a). Both isomers were crystallized from
chloroform/heptane to give white crystals.
anosyl)-6-(oxiran-2-yl)purine (3b) (637 mg, 1 mmol), dry ZnCl2
(170 mg, 1.25 mmol) and sodium methoxide (1 mmol) in metha-
nol (15 ml) was stirred at ambient temperature for 1 day. After
completion, the reaction mixture was diluted with water (150 ml)
and then washed with ethyl acetate (3ꢁ50 ml). The collected
organic layers were washed with brine, dried over anhydrous
MgSO4, filtered and concentrated under reduced pressure. The
residue was purified by column chromatography (silica gel, ethyl
acetate/hexane 0–20%) to give product 6b (250 mg, 37%), mixture
of diastereoisomers 1:1. 1H NMR (500 MHz, CDCl3): ꢂ0.28, ꢂ0.27,
ꢂ0.05, ꢂ0.04, 0.109, 0.113, 0.116, 0.139, 0.142 and 0.149 (10ꢁs,
36H, CH3Si); 0.77, 0.94 and 0.96 (3ꢁs, 54H, (CH3)3C); 3.361 and
3.362 (2ꢁs, 2ꢁ3H, CH3O); 3.804 and 3.806 (2ꢁdd, 2H, Jgem¼11.4,
3.5.1. 9-Benzyl-6-(2-hydroxy-1-methoxyethyl)purine (4a)
Mp 94–96 ꢀC. 1H NMR (500 MHz, CDCl3): 3.51 (s, 3H, CH3O); 4.10
(d, 2H, Jvic¼5.0, CH2O); 5.01 (t, 1H, Jvic¼5.0, CHO); 5.46 (s, 2H,
CH2Ph); 7.33–7.41 (m, 5H, H-o,m,p-Ph); 8.09 (s,1H, H-8); 9.02 (s,1H,
H-2). 13C NMR (125.7 MHz, CDCl3): 47.37 (CH2Ph); 58.09 (CH3O);
64.17 (CH2O); 81.23 (CHO); 127.99 (CH-o-Ph); 128.70 (CH-p-Ph);
129.16 (CH-m-Ph); 131.95 (C-5); 134.76 (C-i-Ph); 144.60 (CH-8);
151.65 (C-4); 152.58 (CH-2); 158.19 (C-6). ESI MS: m/z (%) (100) [Mþ
Na], (45) [Mþ H]. HRMS calcd for C15H17N4O2 [Mþ H] 285.1346,
found 285.1345. IR (CHCl3): 3589, 3358, 3113, 3092, 3069, 3033,
2831, 1589, 1500, 1456, 1440, 1405, 1331, 1115, 1077, 1044, 1030,
1004, 699, 456.
0
0
0
J5 b,4 ¼2.7, H-5 b); 3.99–4.01 (m,04H, CH2O); 4.02 and 04.04 (2ꢁdd,
0
0
2ꢁ1H, Jgem¼11.4, J5 a,4 ¼4.0, H-5 a); 4.16 (m, 2H, H-4 ); 4.33 (dd,
2H, J3 ,2 ¼4.3, J3 ,4 ¼3.6, H-30); 4.65 and 4.69 (2ꢁdd, 2ꢁ1H,
0
0
0
0
0
0
0
0
0
J2 ,1 ¼5.3, J2 ,3 ¼4.3, H-2 ); 4.758 and 4.761 (2ꢁd, 2ꢁ1H, J¼6.3,
0
0
OH); 5.46 (m, 2H, CHO); 6.13 and 6.15 (2ꢁd, 2ꢁ1H, J1 ,2 ¼5.3, H-
10); 8.44 and 8.45 (2ꢁs, 2ꢁ1H, H-8); 8.93 and 8.94 (2ꢁs, 2ꢁ1H,
H-2). 13C NMR (125.7 MHz, CDCl3): ꢂ5.39, ꢂ5.21, ꢂ5.18, ꢂ4.73,
ꢂ4.70, ꢂ4.69, ꢂ4.43 and ꢂ4.41 (CH3Si); 17.80, 18.06, 18.51 and
18.52 ((CH3)3C); 25.59, 25.81 and 26.06 ((CH3)3C); 59.43 and
59.44 (CH3O); 62.41 and 62.50 (CH2-50); 70.48 and 70.59 (CHO);
71.84 and 71.93 (CH-30); 75.83 (CH2O); 75.92 and 76.07 (CH-20);
85.65 and 85.71 (CH-40); 88.16 and 88.38 (CH-10); 131.29 and
131.39 (C-5); 143.24 and 143.33 (CH-8); 150.92 and 150.97 (C-4);
151.60 and 151.65 (CH-2); 158.81 and 158.87 (C-6). ESI MS: m/z
(%) (100) [Mþ Na], (80) [Mþ H]. HRMS calcd for C31H61N4O6Si3
[Mþ H] 669.3893, found 669.3889. IR (CHCl3): 3440, 3119, 3071,
2956, 1597, 1585, 1497, 1472, 1464, 1408, 1391, 1362, 1333, 1258,
1122, 1083, 1073, 939, 839, 682, 648.
3.5.2. 9-Benzyl-6-(2-hydroxyethyl)-8-methoxypurine (5a)
Mp 98–100 ꢀC. 1H NMR (500 MHz, DMSO-d6): 3.13 (t, 2H,
Jvic¼7.0, CH2-pur); 3.88 (td, 2H, Jvic¼7.0, 5.6, CH2-O); 4.17 (s, 3H,
CH3O); 4.75 (t,1H, Jvic¼5.6, OH); 5.22 (s, 2H, CH2Ph); 7.26 (m, 2H, H-
o-Ph); 7.28 (m, 1H, H-p-Ph); 7.33 (m, 2H, H-m-Ph); 8.64 (s, 1H, H-2).
13C NMR (125.7 MHz, DMSO-d6): 36.26 (CH2-pur); 44.26 (CH2Ph);
57.90 (CH3O); 59.54 (CH2O); 127.55 (CH-o-Ph); 128.02 (CH-p-Ph);
128.98 (CH-m-Ph); 130.24 (C-5); 136.34 (C-i-Ph); 150.44 (CH-2);

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M. Kuchar et al. / Tetrahedron 64 (2008) 10355–10364
10360
3.5.5. 6-[(R,S)-1-Hydroxy-2-methoxyethyl]-9-(
ribofuranosyl)purine (6c)
b
-
D
-
144.50 (CH-8); 151.57 (C-4); 152.55 (CH-2); 158.71 (C-6). ESI MS:
m/z (%) (85) [Mþ Na], (50) [Mþ H]. HRMS calcd for
C
16H18N4O2Na [Mþ Na] 321.1322, found 321.1322. IR (CHCl3):
A mixture of 6-(oxiran-2-yl)-9-(
b-
D-ribofuranosyl)purine (3c)
(294 mg, 1 mmol), dry ZnCl2 (170 mg, 1.25 mmol) and sodium
methoxide (1 mmol) in methanol (15 ml) was stirred at 60 ꢀC for
2 h. After completion, the reaction mixture was concentrated under
reduced pressure. The residue was purified by column chroma-
tography (reverse phase, ethyl methanol/water 0–100%) and ly-
ophilized from water to give 6c (50 mg, 15%) as white foam,
diastereoisomeric mixture 1:1. 1H NMR (500 MHz, DMSO-d6): 3.23
(s, 6H, CH3O); 3.572, 3.576, 3.687 and 3.688 (4ꢁddd, 4ꢁ1H,
3585, 3381, 3092, 3069, 3035, 2987, 1591, 1499, 1456, 1404,
1389, 1331, 1078, 1063, 1052, 1040, 1031, 1003, 647.
3.6.3. 9-Benzyl-6-(2-amino-1-hydroxyethyl)purine (10a)
A mixture of 9-benzyl-6-(oxiran-2-yl)purine (3a) (252 mg,
1 mmol) and saturated ethanolic ammonia (25 ml) was stirred at
ambient temperature for 5 days. After completion, the reaction
mixture was concentrated under reduced pressure. The residue was
purified by crystallization from chloroform/methanol/heptane to
giving 90 mg (34%) of white crystals. Mp 179–182 ꢀC. 1H NMR
(500 MHz, DMSO-d6): 3.36 (m, 2H, CH2N); 5.40 (dd, 1H, J¼6.8, 5.7,
CHO); 5.54 (s, 2H, CH2Ph); 7.29 (m, 1H, H-p-Ph); 7.34 (m, 2H, H-m-
0
0
0
0
Jgem¼12.0, J5 ,OH¼6.0, J5 ,4 ¼4.0, H-5 ); 3.782 and 3.783 (2ꢁdd, 2ꢁ1H,
Jgem¼9.8, Jvic¼6.2, CHaHbO); 3.85 (dd, 2H, Jge0m¼9.8, Jvic¼5.8,
0
0
0
0
CHaHbO); 3.98 (td, 2H, J4 ,5 ¼4.0, J4 ,3 ¼3.5, H-4 ); 4.19 (td, 2H,
J3 ,2 ¼J3 ,OH¼4.9, J3 ,4 ¼3.5, H-30); 4.65 and 4.66 (2ꢁddd,
0
0
0
0
0
2ꢁ1H, J2 ,OH¼6.0, J2 ,1 ¼05.9, J2 ,3 ¼4.9, H-2 ); 5.112 and 5.113 (2ꢁt,
Ph); 7.38 (m, 2H, H-o-Ph); 8.83 (s, 1H, H-8); 8.95 (s, 1H, H-2). 13
C
0
0
0
0
0
0
0
0
0
2ꢁ1H, JOH,5 ¼6.0, OH-5 ); 5.25 (d, 2H, JOH,3 ¼4.9, OH-3 ); 5.32 (ddd,
NMR (125.7 MHz, DMSO-d6): 43.01 (CH2N); 46.77 (CH2Ph); 66.77
(CHO); 127.95 (CH-o-Ph); 128.21 (CH-p-Ph); 128.98 (CH-m-Ph);
131.04 (C-5); 136.62 (C-i-Ph); 146.78 (CH-8); 151.65 (C-4); 152.07
(CH-2); 157.90 (C-6). ESI MS: m/z (%) (8) [Mþ Na], (100) [Mþ H].
HRMS calcd for C14H16N5O [Mþ H] 270.1349, found 253.1351. IR
(KBr): 3260, 3150, 3100, 3064, 3027, 1587, 1501, 1454, 1402, 1329,
1077, 1057, 1030, 727, 699, 461.
0
2H, Jvic¼6.2, 6.0, 5.8, CHO); 5.547 and 5.549 (2ꢁd, 2ꢁ1H, JOH,2 ¼6.0,
OH-20); 5.6120 and 5.614 (2ꢁd, 2ꢁ1H, Jvic¼6.0, OH); 6.04 (d, 2H,
J1 ,2 ¼5.9, H-1 ); 8.81 (s, 2H, H-8); 8.92 (s, 2H, H-2).13C NMR
(125.7 MHz, DMSO-d6): 58.61 (CH3O); 61.52 (CH2-50); 68.52 (CHO);
70.58 (CH-30); 73.76 and 73.85 (CH-20); 75.21 (CH2O); 85.97 (CH-
40); 87.76 and 87.77 (CH-10); 131.91 and 131.93 (C-5); 144.87
and 144.89 (CH-8); 151.17 (C-4); 151.95 (CH-2); 160.20 (C-6). ESI
MS: m/z (%) (100) [Mþ Na], (27) [Mþ H]. HRMS calcd for
0
0
3.6.4. 6-[(R,S)-2-Amino-1-hydroxyethyl]-9-(b-D-
ribofuranosyl)purine (10c)
C
C
13H18N4O6Na [Mþ Na] 349.1117, found 349.1112. Anal. Calcd for
13H18N4O6$0.5H2O: C 46.57, H 5.77, N 16.71. Found: C 46.51, H 5.68,
A mixture of 6-(oxiran-2-yl)-9-(b-D-ribofuranosyl)purine (3c)
N 16.48. IR (KBr): 3400–2400, 2829, 1598, 1585, 1500, 1406, 1334,
1211, 1119, 1084, 1054, 1100, 811, 645. [
ꢂ39.8 (c 0.26, MeOH).
(294 mg, 1 mmol) and saturated ethanolic ammonia (25 ml) was
stirred at ambient temperature for 5 days. After completion, the
reaction mixture was concentrated under reduced pressure. The
residue was purified by column chromatography (reverse phase,
water/methanol 0–100%) and lyophilized from water to give
130 mg (42%) of white foam, diastereoisomic mixture 1:1. 1H NMR
(600 MHz, DMSO-d6): 3.37 (m, 4H, CH2N); 3.57 (br ddd, 2H,
a
]
D
3.6. Reaction of 9-benzyl-6-(oxiran-2-yl)purine (3a) with
sodium ethoxide
A mixture of 9-benzyl-6-(oxiran-2-yl)purine (3a) (252 mg,
1 mmol) and sodium ethoxide (3 mmol) in ethanol (20 ml) was
stirred at 60 ꢀC for 2 h. Sodium ethoxide was generated from so-
dium hydride (3 mmol) and ethanol. After completion, the reaction
mixture was concentrated under reduced pressure. The residue was
purified by column chromatography (silica gel, ethyl acetate/
methanol 0–10%) to give two product: 96 mg (32%) of 9-benzyl-8-
ethoxy-6-vinylpurine (9a) and 88 mg (31%) of 9-benzyl-6-(2-hy-
droxy-1-ethoxyethyl)purine (8a).
0
0
0
0
0
Jgem¼12.0, J5 b,OH¼5.2, J5 b,4 ¼4.0, H-5 b); 3.69 (m, 2H, H-5 a); 3.986
0
0
0
0
0
and 3.988 (2ꢁtd, 2ꢁ1H, J4 ,5 ¼4.0, J4 ,3 ¼3.5, H-4 ); 4.19 (br m, 2H, H-
30); 4.65 (br m, 2H, H-20); 5.128 and 5.131 (2ꢁbr t, 2ꢁ1H, JOH,5 ¼5.2,
0
OH-50); 5.31 (br s, 2H, OH-30); 5.41 (dd, 2H, Jvic¼7.3, 5.2, CHO); 5.56
(br s, 2H, OH-20); 6.056 and 6.058 (2ꢁd, 2ꢁ1H, J1 ,2 ¼5.8, H-1 ); 6.35
0
0
0
(br s, 2H, OH); 8.00 (br s, 4H, NH2); 8.90 (s, 2H, H-8); 8.98 (s, 2H, H-
13
2). C NMR (151 MHz, DMSO-d6): 42.90 (CH2N); 61.48 (CH2-50);
66.57 (CHO); 70.55 (CH-30); 73.91 and 73.95 (CH-20); 86.03 (CH-40);
87.76 and 87.81 (CH-10); 131.65 and 131.67 (C-5); 145.29 and 145.34
(CH-8); 151.62 and 151.65 (C-4); 152.12 (CH-2); 158.13 and 158.14
(C-6). ESI MS: m/z (%) (100) [Mþ H]. HRMS calcd for C12H18N5O5 [Mþ
H] 312.1303, found 312.1303. IR (KBr): 3293, 3116, 3065–2400,
3.6.1. 9-Benzyl-8-ethoxy-6-vinylpurine (9a)
Yellow oil. 1H NMR (600 MHz, CDCl3): 1.48 (t, 3H, Jvic¼7.2,
CH3CH2); 4.67 (q, 2H, Jvic¼7.2, CH3CH2); 5.24 (s, 2H, CH2Ph); 5.83
(dd, 1H, Jvic¼11.0, Jgem¼1.8, CHaHb); 6.88 (dd, 1H, Jvic¼17.5, Jgem¼1.8,
]CHaHb); 7.16 (dd, 1H, Jvic¼17.5, 11.0, ]CH); 7.29 (m, 1H, H-p-Ph);
1596,1498,1404,1335,1211,1120,1078,1054, 811, 643. [
0.22, MeOH).
a]
D ꢂ40.3 (c
7.31 (m, 2H, H-m-Ph); 7.35 (m, 2H, H-o-Ph); 8.75 (s, 1H, H-2). 13
C
NMR (151 MHz, CDCl3): 14.47 (CH3CH2); 44.61 (CH2Ph); 66.89
(CH2CH3); 124.27 (]CH2); 128.00 (CH-o-Ph); 128.03 (CH-p-Ph);
128.72 (CH-m-Ph); 128.98 (C-5); 132.31 (]CH); 135.68 (C-i-Ph);
148.63 (C-6); 150.54 (CH-2); 152.62 (C-4); 157.95 (C-8). ESI MS: m/z
(%) (100) [Mþ H]. HRMS calcd for C16H17N4O [Mþ H] 281.1398, found
281.1397. IR (CHCl3): 3092, 3068, 3036, 2987, 1640, 1601, 1588, 1537,
1482, 1398, 1330, 1094, 1045, 1028, 921, 699, 455.
3.6.5. 6-Acetyl-9-benzylpurine (7a)22
Methylmagnesium chloride (2 ml, 3 M in THF) was added
dropwise to a mixture of 9-benzyl-6-(oxiran-2-yl)purine (3a)
(252 mg, 1 mmol) in dry THF (5 ml) under an argon atmosphere at
ꢂ30 ꢀC. The resulting mixture was stirred for 1 day at rt. After
completion, the reaction mixture was diluted with water (100 ml)
and then washed with ethyl acetate (3ꢁ30 ml). The collected or-
ganic layers were washed with brine, dried over anhydrous MgSO4,
filtered and concentrated under reduced pressure. The residue was
purified by column chromatography (silica gel, methanol/chloro-
form 0–2%) and crystallized from chloroform/heptane to give 7a as
white crystals (190 mg, 71%). Mp 117–123 ꢀC. 1H NMR (500 MHz,
DMSO-d6): 2.80 (s, 3H, CH3); 5.58 (s, 2H, CH2Ph); 7.29 (m, 1H, H-p-
Ph); 7.31 (m, 2H, H-o-Ph); 7.36 (m, 2H, H-m-Ph); 9.09 (s, 1H, H-8);
9.12 (s, 1H, H-2). 13C NMR (125.7 MHz, DMSO-d6): 28.53 (CH3);
47.08 (CH2Ph); 127.97 (CH-o-Ph); 128.31 (CH-p-Ph); 129.03 (CH-m-
Ph); 129.72 (C-5); 136.26 (C-i-Ph); 148.49 (C-6); 149.50 (CH-8);
3.6.2. 9-Benzyl-6-(2-hydroxy-1-ethoxyethyl)purine (8a)
Yellow oil. 1H NMR (600 MHz, CDCl3): 1.25 (t, 3H, Jvic¼7.0,
CH3CH2); 3.64 and 3.66 (2ꢁdq, 2H, Jgem¼11.7, Jvic¼7.0, CH2CH3); 4.07
(dd, 1H, Jgem¼11.8, Jvic¼4.6, CHaHbO); 4.10 (dd, 1H, Jgem¼11.8,
Jvic¼5.9, CHaHbO); 5.13 (dd, 1H, Jvic¼5.9, 4.6, CHO); 5.45 (s, 2H,
CH2Ph); 7.28–7.40 (m, 5H, H-o,m,p-Ph); 8.09 (s,1H, H-8); 9.01 (s,1H,
H-2). 13C NMR (151 MHz, CDCl3): 15.22 (CH3CH2); 47.32 (CH2Ph);
64.34 (CH2O); 65.87 (CH2CH3); 79.19 (CHO); 127.98 (CH-o-Ph);
128.66 (CH-p-Ph); 129.12 (CH-m-Ph); 131.94 (C-5); 134.77 (C-i-Ph);

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M. Kuchar et al. / Tetrahedron 64 (2008) 10355–10364
10361
151.94 (CH-2); 154.14 (C-4); 198.44 (CO). ESI MS: m/z (%) (100) [Mþ
3.7.3. 9-Benzyl-6-[(4RS,3RS)-4-(ethoxycarbonyl)-5-
oxotetrahydrofuran-3-yl]purine (12a)
Na], (53) [Mþ H]. HRMS calcd for C14H13N4O [Mþ H] 253.1084, found
253.1086. IR (CHCl3): 3112, 3092, 3069, 1704, 1584, 1496, 1456, 1401,
1358, 1326, 1077, 1029, 699, 646, 457.
9-Benzyl-6-(oxiran-2-yl)purine (3a) (380 mg, 1.5 mmol) was
added to a mixture of diethylmalonate (720 mg, 4.5 mmol) and NaH
(216 mg, 4.5 mmol) in ethanol (20 ml). The resulting mixture was
stirred for 2 h at rt. After completion, the reaction mixture was di-
luted with water (150 ml) and then washed with ethyl acetate
(3ꢁ50 ml). The collected organic layers were washed with brine,
dried over anhydrous MgSO4, filtered and concentrated under re-
duced pressure. The residue was purified by column chromatography
(silica gel, ethyl acetate/hexane 0–50%) to give 120 mg (22%) of col-
ourless oil, racemic compound of trans-relative configuration. 1H
NMR (500 MHz, CDCl3): 1.30 (t, 3H, Jvic¼7.2, CH3CH2O); 4.26 and 4.29
(2ꢁdq, 2ꢁ1H, Jgem¼10.8, Jvic¼7.2, CH3CH2O); 4.47 (d, 1H, J3,4¼8.8, H-
3-THF); 4.53 (dd, 1H, Jgem¼8.5, J5b,4¼7.8, H-5b-THF); 4.95 (t, 1H,
Jgem¼J5a,4¼8.5, H-5a-THF); 5.01 (ddd, 1H, J4,3¼8.8, J4,5¼8.5, 7.8, H-4-
THF); 5.45 (s, 2H, CH2Ph); 7.31–7.40 (m, 5H, H-o,m,p-Ph); 8.06 (s, 1H,
H-8); 8.96 (s, 1H, H-2). 13C NMR (125.7 MHz, CDCl3): 14.01
(CH3CH2O); 42.37 (CH-4-THF); 47.47 (CH2Ph); 50.11 (CH-3-THF);
62.37 (CH3CH2O); 70.21 (CH2-5-THF); 127.96 (CH-o-Ph); 128.76 (CH-
p-Ph); 129.20 (CH-m-Ph); 132.10 (C-5); 134.76 (C-i-Ph); 144.63 (CH-
8); 151.50 (C-4); 152.72 (CH-2); 156.36 (C-6); 166.91 (COOEt); 171.21
(C-2-THF). ESI MS: m/z (%) (100) [Mþ Na], (65) [Mþ H]. HRMS calcd for
3.7. Reaction of the epoxide with methylcuprate
THF (8 ml) was added to vacuum dried copper iodide
(950 mg, 5 mmol) under an argon atmosphere. The mixture was
stirred at ꢂ30 ꢀC and a solution of methyl lithium (5 ml, 1.4 M in
THF) was added dropwise. The mixture was stirred for 20 min at
ꢂ30 ꢀC and then a solution of 6-(oxiran-2-yl)purine (3a or 3b,
1 mmol) in THF (7 ml) was added. The resulting mixture was
stirred for 12 h at rt. After completion, the reaction mixture was
diluted with water (150 ml) and then washed with ethyl acetate
(3ꢁ50 ml). The collected organic layers were washed with 10%
aqueous solution of EDTA (100 ml) and then with brine, dried
over anhydrous MgSO4, filtered and concentrated under reduced
pressure.
3.7.1. 9-Benzyl-6-(1-hydroxypropyl)purine (11a)
Purified by column chromatography (silica gel, methanol/
chloroform 0–5%) and crystallized from chloroform/heptane to
give 160 mg (60%) of white crystals. Mp 82–84 ꢀC. 1H NMR
(500 MHz, CDCl3): 1.02 (t, 3H, Jvic¼7.4, CH3CH2); 1.92 (dq, 1H,
Jgem¼13.9, Jvic¼7.4, CH3CHaHb); 2.20 (dqd, 1H, Jgem¼13.9, Jvic¼7.4,
4.2 CH3CHaHb); 4.50 (d, 1H, Jvic¼6.5, OH); 5.27 (ddd, 1H, Jvic¼7.4,
6.5, 4.2, CHO); 5.47 (s, 2H, CH2Ph); 7.33 (m, 2H, H-o-Ph); 7.35–
7.40 (m, 3H, H-m,p-Ph); 8.04 (s, 1H, H-8); 8.96 (s, 1H, H-2). 13C
NMR (125.7 MHz, CDCl3): 9.42 (CH3CH2); 30.53 (CH2CH3); 47.40
(CH2Ph); 71.65 (CHO); 127.92 (CH-o-Ph); 128.71 (CH-p-Ph);
129.20 (CH-m-Ph); 130.27 (C-5); 134.90 (C-i-Ph); 143.90 (CH-8);
151.21 (C-4); 151.86 (CH-2); 162.03 (C-6). ESI MS: m/z (%) (100)
[Mþ Na], (75) [Mþ H]. HRMS calcd for C15H17N4O [Mþ H]
269.1397, found 269.1401. Anal. Calcd for C15H16N4O: C 67.15, H
6.01, N 20.88. Found: C 66.88, H 5.97, N 20.43. IR (CHCl3): 3450,
3112, 3092, 3070, 3035, 1595, 1585, 1499, 1456, 1407, 1380, 1332,
1076, 1053, 1030, 699, 647, 455.
C
19H19N4O4 [Mþ H] 367.1401, found 367.1404. IR (CHCl3): 3112, 3092,
3069, 3031, 2941, 2875, 1787, 1737, 1596, 1586, 1501, 1477, 1445, 1407,
1332, 1153, 1115, 1097, 1079, 699, 644, 619, 456.
3.8. Reaction of the epoxide with sodium methanethiolate
A mixture of 9-benzyl-6-(oxiran-2-yl)purine (3a) (252 mg,
1 mmol) and sodium methanethiolate (210 mg, 3 mmol) in THF
(20 ml) and water (5 ml) was sonicated at rt for 3 h. After com-
pletion, the reaction mixture was concentrated under reduced
pressure. The residue was purified by column chromatography
(silica gel, methanol/chloroform 0–5%) to give two isomers, 20 mg
(13%) of 14a and 90 mg (60%) of 13a. Both isomers were crystallized
from chloroform/heptane to give the product.
3.7.2. 9-(2,3,5-Tri-O-tert-butyldimethylsilyl-
[(R,S)-1-hydroxypropyl]purine (11b)
b
-
D
-ribofuranosyl)-6-
3.8.1. 9-Benzyl-6-[1-hydroxy-2-(methylsulfanyl)ethyl]purine (14a)
White crystals, mp 99–103 ꢀC. 1H NMR (500 MHz, DMSO-d6):
2.04 (s, 3H, CH3S); 3.02 (dd, 1H, Jgem¼13.2, Jvic¼6.6, CHaHbS); 3.15
(dd, 1H, Jgem¼13.2, Jvic¼7.1, CHaHbS); 5.33 (ddd, 1H, Jvic¼7.1, 6.6, 6.0,
CHO); 5.52 (s, 2H, CH2Ph); 5.76 (d, 1H, Jvic¼6.0, OH); 7.29 (m, 1H, H-
p-Ph); 7.35 (m, 2H, H-m-Ph); 7.37 (m, 2H, H-o-Ph); 8.73 (s, 1H, H-8);
8.92 (s, 1H, H-2). 13C NMR (125.7 MHz, DMSO-d6): 15.62 (CH3S);
38.68 (CH2S); 46.72 (CH2Ph); 68.96 (CHO); 127.92 (CH-o-Ph);
128.19 (CH-p-Ph); 129.01 (CH-m-Ph); 131.28 (C-5); 136.72 (C-i-Ph);
146.42 (CH-8); 151.34 (C-4); 152.09 (CH-2); 160.55 (C-6). ESI MS: m/
z (%) (100) [Mþ Na], (35) [Mþ H]. HRMS calcd for C15H16N4OSNa [Mþ
Na] 323.0937, found 323.0933. Anal. Calcd for C15H16N4OS: C 59.98,
H 5.37, N 18.65, S 10.67. Found: C 59.71, H 5.48, N 18.34, S 10.28. IR
(CHCl3): 3439, 3113, 3092, 3070, 3035, 2923, 1595, 1586, 1500, 1456,
1427, 1405, 1333, 1079, 1030, 1004, 699, 647, 455.
Purified by column chromatography (silica gel, ethyl acetate/
hexane 0–20%) to give 135 mg (21%) of light yellow foam, mix-
ture of diastereoisomers 1:1. 1H NMR (500 MHz, CDCl3): ꢂ0.32,
ꢂ0.31, ꢂ0.06, 0.113, 0.114, 0.116, 0.118, 0.137, 0.140, 0.143 and
0.147 (11ꢁs, 36H, CH3Si); 0.75, 0.76, 0.945, 0.946, 0.955 and 0.958
(6ꢁs, 54H, (CH3)3C); 0.982 and 0.983 (2ꢁt, 2ꢁ3H, Jvic¼7.3,
CH3CH2); 1.93 and 2.18 (2ꢁm, 2ꢁ2H, CH2CH3); 3.81 (dd, 2H,
Jgem¼11.4, J5 b,4 ¼2.6, H-50b); 4.02 and 4.03 (2ꢁdd, 2ꢁ1H,
0
0
0
0
0
0
Jgem¼11.4, J5 a,4 ¼4.0, H-5 a); 4.16 (m,0 2H, H-4 ); 4.32 and 4.33
0
0
0
0
(2ꢁdd, 2ꢁ1H, J3 ,2 ¼4.4, J3 ,4 ¼3.2, H-3 ); 4.51 (d, 2H, 0J¼6.6, OH);
0
0
0
0
4.69 and 4.70 (2ꢁdd, 2ꢁ1H, J2 ,1 ¼5.5, J2 ,3 ¼4.4, H-2 ); 5.28 (m,
0
0
0
2H, CHO); 6.13 and 6.15 (2ꢁd, 2ꢁ1H, J1 ,2 ¼5.5, H-1 ); 8.40 and
8.41 (2ꢁs, 2ꢁ1H, H-8); 8.909 and 8.911 (2ꢁs, 2ꢁ1H, H-2). 13C
NMR (125.7 MHz, CDCl3): ꢂ5.39, ꢂ5.37, ꢂ5.28, ꢂ5.22, ꢂ4.70,
ꢂ4.69, ꢂ4.67 and ꢂ4.44 (CH3Si); 9.20 (CH3CH2); 17.80, 18.07,
18.51 and 18.52 ((CH3)3C); 25.57, 25.58, 25.82 and 26.06
((CH3)3C); 30.46 and 30.49 (CH2CH3); 62.59 and 62.61 (CH2-50);
71.51 and 71.62 (CHO); 72.11 (CH-30); 75.96 and 75.99 (CH-20);
85.88 and 85.91 (CH-40); 88.08 and 88.19 (CH-10); 130.89 and
130.94 (C-5); 143.06 and 143.11 (CH-8); 150.94 and 150.96 (C-4);
151.58 (CH-2); 161.90 and 161.96 (C-6). ESI MS: m/z (%) (80) [Mþ
Na], (100) [Mþ H]. HRMS calcd for C31H61N4O5Si3 [Mþ H]
653.3944, found 653.3948. IR (CHCl3): 3606, 3453, 3118, 3070,
2957, 1596, 1583, 1496, 1472, 1464, 1409, 1391, 1379, 1362, 1332,
1258, 1083, 1072, 1053, 939, 839, 683, 648.
3.8.2. 9-Benzyl-6-[2-hydroxy-1-(methylsulfanyl)ethyl]purine (13a)
Yellowish crystals, mp 98–101 ꢀC. 1H NMR (500 MHz, CDCl3):
2.17 (s, 3H, CH3S); 4.30 (dd, 1H, Jgem¼11.7, Jvic¼5.7, CHaHbO); 4.33
(dd, 1H, Jgem¼11.7, Jvic¼4.4, CHaHbO); 4.41 (br s, 1H, OH); 4.51 (dd,
1H, Jvic¼5.7, 4.4, CHS); 5.45 (s, 2H, CH2Ph); 7.32–7.42 (m, 5H, H-
o,m,p-Ph); 8.05 (s, 1H, H-8); 8.95 (s, 1H, H-2). 13C NMR (125.7 MHz,
CDCl3): 14.58 (CH3S); 47.48 (CH2Ph); 49.16 (CHS); 62.95 (CH2S);
128.04 (CH-o-Ph); 128.77 (CH-p-Ph); 129.21 (CH-m-Ph); 131.11 (C-
5); 134.72 (C-i-Ph); 144.04 (CH-8); 151.54 (C-4); 152.35 (CH-2);
160.55 (C-6). ESI MS: m/z (%) (100) [Mþ Na], (75) [Mþ H]. HRMS
calcd for C15H16N4OSNa [Mþ Na] 323.0937, found 323.0933. IR

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M. Kuchar et al. / Tetrahedron 64 (2008) 10355–10364
10362
(CHCl3): 3610, 3396, 3112, 3092, 3069, 3035, 3001, 2924, 1587, 1498,
1456, 1405, 1329, 1079, 1050, 1030, 1003, 647.
(CH-o-SPh); 130.54 (C-5); 134.73 (C-i-Ph); 135.73 (C-i-SPh); 144.10
(CH-8); 151.18 (C-4); 151.73 (CH-2); 159.22 (C-6). ESI MS: m/z (%)
(25) [MþNa], (100) [MþH]. HRMS calcd for C20H19N4OS [Mþ H]
363.1274, found 363.1273. IR (CHCl3): 3438, 3112, 3068, 3035, 1594,
1587,1499, 1456, 1405, 1333, 1288, 1180, 1156,1079, 1026, 1000, 843,
698, 646, 617, 456.
3.8.3. 9-(2,3,5-Tri-O-tert-butyldimethylsilyl-b-D-ribofuranosyl)-6-
[(R,S)-2-hydroxy-1-(methylsulfanyl)ethyl]purine (13b)
A mixture of 3b (637 mg, 1 mmol) and sodium methanethiolate
(210 mg, 3 mmol) in THF (20 ml) and water (5 ml) was sonicated at
rt for 3 h. After completion, the reaction mixture was concentrated
under reduced pressure. The residue was purified by column
chromatography (silica gel, ethyl acetate/hexane 0–20%) to give
508 mg (74%) of white foam, mixture of diastereoisomers 1:1. 1H
NMR (500 MHz, CDCl3): ꢂ0.23, ꢂ0.20, ꢂ0.025, ꢂ0.019, 0.110, 0.106,
0.113, 0.139, 0.141 and 0.146 (10ꢁs, 36H, CH3Si); 0.79, 0.80, 0.939,
0.940, 0.957 and 0.963 (6ꢁs, 54H, (CH3)3C); 2.145 and 2.150 (2ꢁs,
3.10. Reaction of the epoxide with sodium benzoxide
A mixture of benzylalcohol (540 mg, 5 mmol) and NaH (72 mg,
1.5 mmol) in THF (4 ml) was stirred under an argon atmosphere.
After 30 min, epoxide 3a (127 mg, 0.5 mmol) in THF (2 ml) was
added dropwise. The resulting mixture was stirred at ambient
temperature for 8 h. After completion, the reaction mixture was
concentrated under reduced pressure. The residue was purified by
column chromatography (silica gel, ethyl acetate/hexane 0–30%) to
give two products 17a and 18a.
0
0
2ꢁ3H, CH3S); 3.808 and 3.810 (2ꢁdd, 2ꢁ1H, Jgem¼11.5, J5 b,4 ¼2.6,
0
H-50b); 4.03 and 4.04 (2ꢁdd, 2ꢁ1H, Jgem¼11.5, J5 a,4 ¼3.8, H-5 a);
0
0
4.16 (td, 2H, J4 ,3 ¼J4 ,5 a¼3.8, J4 ,5 b¼2.6, H-40); 4.25–4.36 (m, 6H, H-
0
0
0
0
0
0
30 and CH2O); 4.47–4.58 (m, 4H, CHS and OH); 4.63 and 4.640(2ꢁdd,
0
0
0
0
0
0
0
2ꢁ1H, J2 ,1 ¼4.9, J2 ,3 ¼4.3, H-2 ); 6.13 (d, 2H, J1 ,2 ¼4.9, H-1 ); 8.48
and 8.50 (2ꢁs, 2ꢁ1H, H-8); 8.90 (s, 2H, H-2). 13C NMR (125.7 MHz,
CDCl3): ꢂ5.38, ꢂ5.36, ꢂ5.11, ꢂ5.04, ꢂ4.75, ꢂ4.74, ꢂ4.70, ꢂ4.38 and
ꢂ4.37 (CH3Si); 14.46 and 14.50 (CH3S); 17.83, 17.84, 18.06, 18.52 and
18.53 ((CH3)3C); 25.61, 25.81 and 26.07 ((CH3)3C); 49.04 and 49.33
(CHS); 62.22 and 62.32 (CH2-50); 63.00 and 63.08 (CH2O); 71.52 and
71.67 (CH-30); 76.02 and 76.14 (CH-20); 85.35 and 85.51 (CH-40);
88.36 and 88.46 (CH-10); 131.69 and 131.75 (C-5); 143.26 (CH-8);
151.20 and 151.22 (C-4); 152.11 and 152.13 (CH-2); 160.56 and
160.58 (C-6). ESI MS: m/z (%) (100) [MþNa], (95) [MþH]. HRMS
3.10.1. 9-Benzyl-6-[1-(benzyloxy)vinyl]purine (17a)
Colourless oil, yield 26%. 1H NMR (500 MHz, CDCl3): 4.99 (dt, 1H,
Jgem¼2.7, 5J¼0.5, ]CHaHb); 5.19 (s, 2H, OCH2Ph); 5.45 (s, 2H,
NCH2Ph); 6.18 (d, 1H, Jgem¼2.7, ]CHaHb); 7.29 (m, 2H, H-o-NBn);
7.32–7.38 (m, 6H, H-m,p-NBn and H-m,p-OBn); 7.52 (m, 2H, H-o-
OBn); 8.07 (s, 1H, H-8); 9.04 (s, 1H, H-2).13C NMR (125.7 MHz,
CDCl3): 47.25 (NCH2Ph); 70.05 (OCH2Ph); 95.72 (]CH2); 127.12
(CH-o-OBn); 127.69 (CH-p-OBn); 127.79 (CH-o-NBn); 128.47 (CH-
m-OBn); 128.57 (CH-p-NBn); 129.11 (CH-m-NBn); 130.31 (C-5);
135.01 (C-i-NBn); 136.65 (C-i-OBn); 144.51 (CH-8); 151.81 (C-6);
152.27 (CH-2); 152.37 (C-4); 155.36 (]C). ESI MS: m/z (%) (10) [Mþ
H]. HRMS calcd for C21H19N4O [Mþ H] 343.1553, found 343.1555. IR
(CHCl3): 3112, 3092, 3068, 3035, 3010, 2932, 2876, 1616, 1582, 1576,
1498, 1455, 1334, 1149, 1202, 1128, 1106, 645.
calcd for
C
31H61N4O5SSi3 [Mþ H] 685.3665, found 685.3674.
IR (CHCl3): 3607, 3307, 3120, 3065, 2956, 1592, 1580, 1497, 1472,
1463, 1405, 1391, 1362, 1332, 1311, 1258, 1082, 1072, 935, 839, 704,
680, 647.
3.9. Reaction of the epoxide with sodium benzenethiolate
3.10.2. 9-Benzyl-6-[1-(benzyloxy)-2-hydroxyethyl]purine (18a)
Yellow oil, yield 14%. 1H NMR (500 MHz, CDCl3): 3.39 (br s, 1H,
OH); 4.11 (br m, 2H, CH2O); 4.60 and 4.75 (2ꢁd, 2H, Jgem¼11.8,
OCH2Ph); 5.19 (dd,1H, Jvic¼5.6, 4.5, CHO); 5.44 (s, 2H, NCH2Ph); 7.22
(m, 1H, H-p-OBn); 7.25 (m, 2H, H-m-OBn); 7.32–7.41 (m, 7H, H-o-
OBn and H-o,m,p-NBn); 8.06 (s, 1H, H-8); 9.01 (s, 1H, H-2). 13C NMR
(125.7 MHz, CDCl3): 47.38 (NCH2Ph); 64.45 (CH2O); 72.74
(OCH2Ph); 78.83 (CHO); 127.77 (CH-o-NBn); 128.03 (CH-p-OBn);
128.16 (CH-o-OBn); 128.27 (CH-m-OBn); 128.73 (CH-p-NBn);
129.19 (CH-m-NBn); 132.04 (C-5); 134.81 (C-i-NBn); 137.58 (C-i-
OBn); 144.50 (CH-8); 151.69 (C-4); 152.56 (CH-2); 158.42 (C-6). ESI
MS: m/z (%) (100) [Mþ Na], (20) [Mþ H]. HRMS calcd for C21H21N4O2
[Mþ H] 361.1659, found 361.1662. IR (CHCl3): 3592, 3347, 3112,
3034, 3009, 1589, 1499, 1455, 1405, 1331, 1210, 1077, 1029, 1002,
699, 646, 609, 459.
A mixture of 3a (127 mg, 0.5 mmol) and sodium benzenethio-
late (200 mg, 1.5 mmol) in THF (10 ml) and water (2.5 ml) was
sonicated at rt for 3 h. After completion, the reaction mixture was
concentrated under reduced pressure. The residue was purified by
column chromatography (silica gel, ethyl acetate/hexane 0–20%) to
give two products 15a (60 mg, 35%) and 16a (115 mg, 63%).
3.9.1. 9-Benzyl-6-[1-(phenylsulfanyl)vinyl]purine (15a)
Crystallized from chloroform/heptane to give yellowish crystals.
Mp 131–135 ꢀC. 1H NMR (500 MHz, CDCl3): 5.474 (s, 2H, CH2Ph);
5.475 and 7.27 (2ꢁd, 2H, Jgem¼0.8, ]CH2); 7.28–7.44 (m, 8H, H-
o,m,p-Ph and H-m,p-SPh); 7.63 (m, 2H, H-o-SPh); 8.06 (s, 1H, H-8);
9.04 (s, 1H, H-2). 13C NMR (125.7 MHz, CDCl3): 47.36 (CH2Ph);
121.61 (]CH2); 127.83 (CH-o-Ph); 128.66 (CH-p-Ph); 128.88 (CH-p-
SPh); 129.18 (CH-m-Ph); 129.49 (CH-m-SPh); 130.14 (C-5); 131.48
(C-i-SPh); 134.99 (C-i-Ph); 135.46 (CH-o-SPh); 143.14 (]C); 144.49
(CH-8); 152.06 (CH-2); 152.11 (C-4); 153.26 (C-6). ESI MS: m/z (%)
(25) [MþH]. HRMS calcd for C20H17N4S [Mþ H] 345.1168, found
345.1162. IR (CHCl3): 3112, 3065, 3036, 1626, 1606, 1580, 1572, 1496,
1455, 1440, 1405, 1329, 1305, 1106, 1079, 1026, 1001, 972, 897, 883,
699, 694, 617, 476, 456, 425.
3.10.3. 6-[(R,S)-Oxiran-2-yl]-9-(b-D-ribofuranosyl)-purine (3c)
Epoxide 3b (450 mg, 0.71 mmol) was dissolved in a solution of
TBAF (674 mg, 2.17 mmol) in THF (3 ml). The mixture was stirred at
ambient temperature for 2 h, evaporated and the residue was pu-
rified by column chromatography (silica gel methanol/chloroform
0–10%) to give 170 mg (82%) of light yellow foam (1:1 di-
astereoisomeric mixture). 1H NMR (500 MHz, DMSO-d6): 3.30 (dd,
2H, Jgem¼6.4, J3b,2¼4.1, H-3b-ox); 3.56 and 3.57 (2ꢁdd, 2ꢁ1H,
Jgem¼6.4, J3a,2¼2.6, H-3a-ox); 3.58 and 3.70 (2ꢁbr m, 2ꢁ2H, H-50);
3.9.2. 9-Benzyl-6-[1-hydroxy-2-(phenylsulfanyl)ethyl]purine (16a)
Yellow oil, 1H NMR (500 MHz, CDCl3): 3.65 (dd, 1H, Jgem¼13.8,
Jvic¼5.9, CHaHbS); 3.78 (dd, 1H, Jgem¼13.8, Jvic¼4.3, CHaHbS); 4.89 (br
s, 1H, OH); 5.39 (s, 2H, CH2Ph); 5.55 (bdd, 1H, Jvic¼5.9, 4.3, CH-O);;
7.00 (m, 1H, H-p-SPh); 7.08 (m, 2H, H-m-SPh); 7.26 (m, 2H, H-o-
SPh); 7.31 (m, 2H, H-o-Ph); 7.34–7.40 (m, 3H, H-m,p-Ph); 7.99 (s, 1H,
H-8); 8.93 (s, 1H, H-2). 13C NMR (125.7 MHz, CDCl3): 41.06 (CH2S);
47.38 (CH2Ph); 69.50 (CHO); 125.92 (CH-p-SPh); 128.02 (CH-o-Ph);
128.43 (CH-m-SPh); 128.74 (CH-p-Ph); 129.17 (CH-m-Ph); 129.68
0
0
0
0
0
0
0
3.98 (td, 2H, 0J4 ,5 ¼4.5, J4 ,3 ¼3.4, H-4 ); 4.19 (br dd, 2H, J3 ,2 ¼5.0,
0
0
J3 ,4 ¼3.4, H-3 ); 4.43 and 4.44 (2ꢁdd, 02ꢁ1H, J2,3¼4.1, 2.6, H-2-ox);
0
0
0
0
0
4.61 (br dd, 2H, J2 ,1 ¼5.5, J2 ,3 ¼5.0, H-2 ); 5.12 (br s, 2H, OH-5 ); 5.28
(br s, 2H, OH-30); 5.57 (br s, 2H, OH-20); 6.05 (d, 2H, J1 ,2 ¼5.5, H-1 );
8.88 (s, 2H, H-8); 8.90 (s, 2H, H-2). 13C NMR (125.7 MHz, DMSO-d6):
48.50 (CH2-3-ox); 48.78 and 48.84 (CH-2-ox); 61.39 (CH2-50); 70.44
(CH-30); 73.96 and 73.98 (CH-20); 85.90 (CH-40); 87.87 and 87.89
(CH-10); 133.08 and 133.13 (C-5); 145.60 and 145.62 (CH-8); 151.37
0
0
0

ˇ
M. Kuchar et al. / Tetrahedron 64 (2008) 10355–10364
10363
0
0
0
0
0
0
and 151.38 (C-4); 152.18 (CH-2); 155.20 and 155.21 (C-6). ESI MS:
m/z (%) (50) [Mþ H]. HRMS calcd for C12H13N4O5 [Mþ H] 293.0881,
found 293.0887. IR (KBr): 3291, 3116, 1599, 1585, 1500, 1414, 1333,
and 4.651 (2ꢁddd, 2ꢁ1H, J2 ,OH¼6.0, J2 ,1 ¼5.8, J2 ,3 ¼4.9, H-2 ); 5.07
(ddd, 2H, Jvic¼7.0, 6.3, 5.9, CHO); 5.121 and 5.123 (2ꢁdd, 2ꢁ1H,
0
0
0
0
JOH,5 ¼6.0, 5.2, OH-5 ); 5.25 (d, 2H, JOH,3 ¼4.9, OH-3 ); 5.332 and
5.334 (2ꢁd, 2ꢁ1H, Jvic¼5.9, OH); 5.540 and 5.543 (2ꢁd, 2ꢁ1H,
1210, 1119, 1083, 1055, 812, 644.[
a
]
D ꢂ44.5 (c 0.24, MeOH).
0
0
0
0
0
JOH,2 ¼6.0, OH-2 ); 6.04 (d, 2H, J1 ,2 ¼5.8, H-1 ); 8.79 (s, 2H, H-8);
8.91 (s, 2H, H-2). 13C NMR (125.7 MHz, DMSO-d6): 10.21 and 10.23
(CH3CH2); 29.21 (CH2CH3); 61.51 and 61.53 (CH2-50); 70.58 and
70.59 (CH-30); 70.82 and 70.85 (CHO); 73.80 and 73.84 (CH-20);
85.94 and 85.97 (CH-40); 87.73 (CH-10); 131.35 and 131.37 (C-5);
144.65 (CH-8); 151.13 (C-4); 151.96 (CH-2); 162.49 and 162.51 (C-6).
ESI MS: m/z (%) (100) [Mþ Na]. HRMS calcd for C13H18N4O5Na [Mþ
Na] 333.1169, found 333.1166. IR (KBr): 3411, 1631, 1598, 1500, 1407,
3.11. General method for the cleavage of the TBS groups
A TBS-protected nucleoside (1 mmol) was dissolved in a solu-
tion of NEt3$3HF (1 ml, 6 mmol) in THF (3 ml). The mixture was
stirred at ambient temperature for 1 day, evaporated and the res-
idue was purified by column chromatography (silica gel methanol/
chloroform 0–10% and then reverse phase methanol/water 0–100%)
and lyophilized from water.
1334, 1211, 1115, 1082, 1050, 811, 645. [
a
]
ꢂ40.0 (c 0.11, MeOH).
D
3.11.1. 6-[(R,S)-1,2-Dihydroxyethyl]-9-(b-D-ribofuranosyl)-
3.12. Single crystal X-ray structure analysis
purine (2c)
Yellowish foam, yield 93%, mixture of diastereoisomers 1:1. 1H
The diffraction data of single crystals of 3a (colourless,
0.15ꢁ0.22ꢁ0.60 mm), 5a (colourless, 0.04ꢁ0.15ꢁ0.76 mm) and 14a
(colourless, 0.14ꢁ0.19ꢁ0.69 mm) were collected on an Xcalibur X-
NMR (500 MHz, DMSO-d6): 3.561, 3.562, 3.670 and 3.671 (4ꢁdd,
0
0
0
4ꢁ1H, Jgem¼11.9, J5 ,4 ¼4.0, H-5 ); 3.81 (dd, 2H, Jgem¼10.8, Jvic¼6.1,
CHaHbO); 3.860 and 3.864 (2ꢁdd, 2ꢁ1H, Jgem¼10.8, Jvic¼5.6,
ray diffractometer with Cu K
a
(
l
¼1.54180 Å) at 150 K (3a, 5a) and
0
0
0
0
0
CHaHbO); 3.97 (td, 2H, J4 ,5 ¼4.0, J4 ,3 ¼3.8, H-4 ); 4.18 (dd, 2H,
298 K (14a). All three structures were solved by direct methods
with SIR9224 and refined by full-matrix, least-squares methods
based on F with CRYSTALS.25 The hydrogen atoms were located in
a difference map, but those attached to carbon atoms were repo-
sitioned geometrically and then refined with riding constraints,
while all other atoms were refined anisotropically in all cases.
0
0
0
0
0
0
0
J3 ,2 ¼5.1, J3 ,4 ¼3.8, H-3 ); 4.587 and 4.594 (2ꢁdd, 2ꢁ1H, J2 ,1 ¼5.6,
0
0
0
0
J2 ,3 ¼5.1, H-2 ); 4.90 (br s, 2H, OH-5 ); 5.17 (dd, 2H, Jvic¼6.1, 5.6,
CHO); 5.22 (br s, 2H, OH-30); 5.54 (br s, 2H, OH-20); 6.03 (d, 2H,
0
0
0
J1 ,2 ¼5.6, H-1 ); 6.26 (br s, 4H, OH); 8.81 (s, 2H, H-8); 8.90 (s, 2H, H-
2). 13C NMR (125.7 MHz, DMSO-d6): 61.55 (CH2-50); 64.91 and 64.93
(CH2O); 70.46 (CH-30); 71.24 (CHO); 74.04 and 74.12 (CH-20); 85.99
(CH-40); 87.94 (CH-10); 131.99 and 132.01 (C-5); 144.63 and 144.65
(CH-8); 151.04 (C-4); 151.83 (CH-2); 160.88 and 160.89 (C-6). ESI
MS: m/z (%) (80) [Mþ Na], (100) [Mþ H]. HRMS calcd for
3.12.1. Crystal datad3a
C
14H12N4O1, monoclinic, space group P21/n, a¼9.8178(11) Å,
b¼4.7574(6) Å, c¼25.341(3) Å,
b
¼92.184(9)ꢀ, V¼1182.7(2) Å3, Z¼4,
C
C
12H16N4O6Na [Mþ H] 335.0962, found 335.0953. Anal. Calcd for
12H16N4O6$1.5H2O: C 42.48, H 5.64, N 16.51. Found: C 42.46, H
M¼252.28, 17,490 reflections measured, 2468 independent re-
flections. Final R¼0.0451, wR¼0.0143, GoF¼1.20 for 1947 reflections
5.29, N 16.15. IR (KBr): 3339, 1631, 1587,1496, 1401,1332,1212,1106,
1084, 1055, 808, 645. [
ꢂ58.5 (c 0.08, MeOH).
with I>2
s(I) and 173 parameters. CCDC 689513.
a]
D
3.12.2. Crystal datad5a
3.11.2. 6-[(R,S)-2-Hydroxy-1-(methylsulfanyl)ethyl]-9-(b-D-
C
15H18N4O3, monoclinic, space group P21/c, a¼18.0503(9) Å,
ribofuranosyl)purine (13c)
b¼4.5943(3) Å, c¼18.0503(9) Å,
b
¼98.5414(2)ꢀ, V¼1480.28(14) Å3,
White foam, yield 75%, diastereoisomeric mixture 1:1. 1H NMR
Z¼4, M¼302.33, 9099 reflections measured, 3016 independent re-
flections. Final R¼0.0644, wR¼0.0748, GoF¼1.15 for 2134 reflections
(500 MHz, DMSO-d6): 2.08 and 2.09 (2ꢁs, 2ꢁ3H, CH3S); 3.57 (br dd,
2H, Jgem¼12.1, J5 b,4 ¼4.0, H-50b); 3.69 (br dd, 2H, Jgem¼12.1,
0
0
with I>2s(I) and 200 parameters. CCDC 689512.
0
0
0
J5 a,4 ¼4.5, H-5 a); 3.97 (br dd, 2H, Jgem¼10.3, Jvic¼5.7, CHaHbO); 3.98
0
0
0
0
0
0
0
(ddd, 2H, J4 ,5 ¼4.5, 4.0, J4 ,3 ¼3.6, H-4 ); 4.19 (dd, 2H, J3 ,2 ¼4.9,
3.12.3. Crystal datad14a
0
0
0
J3 ,4 ¼3.6, H-3 ); 4.22 (dd, 2H, Jgem¼10.3, Jvic¼9.1, CHaHbO); 4.44 and
C15H16N4O1S1, monoclinic, space group P21/n, a¼10.1334(1) Å,
0
0
4.45 (2ꢁddd,0 2ꢁ1H, Jvic¼9.1, 5.7, CHS); 4.67 (br dd, 2H, J2 ,1 ¼5.9,
b¼8.0744(1) Å, c¼18.9298(2) Å,
b
¼98.5948(11)ꢀ, V¼1531.46(3) Å3,
0
0
0
J2 ,3 ¼4.9, H-2 ); 5.03 (br s, 2H, OH); 5.12 (br s, 2H, OH-5 ); 5.27 (br s,
Z¼4, M¼300.39, 23,406 reflections measured, 3136 independent
reflections. Final R¼0.0464, wR¼0.0757, GoF¼1.10 for 1529 re-
2H, OH-30); 5.57 (br s, 2H, OH-20); 6.033 and 6.034 (2ꢁd, 2ꢁ1H,
J1 ,2 ¼5.9, H-1 ); 8.79 (s, 2H, H-8); 8.88 (s, 2H, H-2). 13C NMR
(125.7 MHz, DMSO-d6): 14.25 and 14.26 (CH3S); 48.03 and 48.07
(CHS); 61.55 (CH2-50); 62.29 (CH2O); 70.63 (CH-30); 73.76 (CH-20);
86.01 (CH-40); 87.81 (CH-10); 132.43 and 132.46 (C-5); 144.76
and 144.78 (CH-8); 151.05 (C-4); 152.02 (CH-2); 159.96 (C-6). ESI
MS: m/z (%) (98) [Mþ Na], (28) [Mþ H]. HRMS calcd for
0
0
0
flections with I>2s(I) and 190 parameters. CCDC 689514.
Acknowledgements
This work is a part of the research project Z4 055 0506. It was
supported by the ‘Centre for New Antivirals and Antineoplastics’
(1M0508), by the Programme for Targeted Research
(1QS400550501) and by Gilead Sciences, Inc. (Foster City, CA,
U.S.A.). Antiviral activity was studied by E. Mabery and Dr. I. Shih
and Dr. R. Mackman (Gilead) and cytostatic activity by Dr. I. Votruba
(IOBC). The contribution of these scientists is gratefully
acknowledged.
C
C
13H18N4O5SNa [Mþ Na] 365.0890, found 365.0880. Anal. Calcd for
13H18N4O5S$0.5H2O: C 44.44, H 5.45, N 15.94. Found: C 44.73,
H 5.55, N 15.86. IR (KBr): 3413, 1594, 1499, 1475, 1468, 1433, 1400,
1333, 1212, 1123, 1080, 1057, 1038, 813, 646. [
MeOH).
a
]
D
ꢂ31.9 (c 0.19,
3.11.3. 6-[(R,S)-1-Hydroxypropyl]-9-(b-D-ribofuranosyl)purine
(11c)
White foam, yield 75%, diastereoisomeric mixture 1:1. 1H NMR
(500 MHz, DMSO-d6): 0.847 and 0.852 (2ꢁt, 2ꢁ3H, Jvic¼7.4,
CH3CH2); 1.85–2.00 (m, 4H, CH2CH3); 3.570 0 and 3.574 (2ꢁddd,
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0
0
0
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J4 ,3 ¼3.5, H-4 ); 4.19 (td, 2H, J3 ,2 ¼J3 ,OH¼4.9, J3 ,4 ¼3.5, H-3 ); 4.646
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