Sugar-modified derivatives of cytostatic 7-(het)aryl-7-deazaadenosines: 2′-C-methylribonucleosides, 2′-deoxy-2′- fluoroarabinonucleosides, arabinonucleosides and 2′-deoxyribonucleosides

Article abstract of DOI:10.1016/j.bmc.2012.07.003

A series of novel sugar-modified derivatives of cytostatic 7-hetaryl-7-deazaadenosines (2′-C-methylribonucleosides, 2′-deoxy-2′-fluoroarabinonucleosides, arabinonucleosides and 2′-deoxyribonucleosides) was prepared and screened for biological activity. Th

Full text of DOI:10.1016/j.bmc.2012.07.003

Bioorganic & Medicinal Chemistry 20 (2012) 5202–5214
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Sugar-modified derivatives of cytostatic 7-(het)aryl-7-deazaadenosines:
20-C-methylribonucleosides, 20-deoxy-20-fluoroarabinonucleosides,
arabinonucleosides and 20-deoxyribonucleosides
a
a
a
a
a
a
ˇ
Petr Nauš , Pavla Perlíková , Aurelie Bourderioux , Radek Pohl , Lenka Slavetínská , Ivan Votruba ,
b
b
a,c,
ˇ b
⇑
Gina Bahador , Gabriel Birkuš , Tomáš Cihlár , Michal Hocek
a 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
b Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA
c Department of Organic Chemistry, Faculty of Science, Charles University in Prague, Hlavova 8, CZ-12843 Prague 2, Czech Republic
a r t i c l e i n f o
a b s t r a c t
A series of novel sugar-modified derivatives of cytostatic 7-hetaryl-7-deazaadenosines (20-C-methylribo-
nucleosides, 20-deoxy-20-fluoroarabinonucleosides, arabinonucleosides and 20-deoxyribonucleosides)
was prepared and screened for biological activity. The synthesis consisted of preparation of the corre-
sponding sugar-modified 7-iodo-7-deazaadenine nucleosides and their aqueous-phase Suzuki-Miyaura
cross-coupling reactions with (het)arylboronic acids or Stille couplings with hetarylstannanes in DMF.
The synthesis of 7-iodo-7-deazaadenine nucleosides was based on a glycosidation of 6-chloro-7-iodo-
7-deazapurine with a suitable sugar synthon or on an interconversion of 20-OH stereocenter (for arabino-
nucleosides). Several examples of 20-C-Me-ribonucleosides showed moderate anti-HCV activities in a rep-
licon assay accompanied by cytotoxicity. Several 7-hetaryl-7-deazaadenine fluoroarabino- and
arabinonucleosides exerted moderate micromolar cytostatic effects. The most active was 7-ethynyl-7-
deazaadenine fluoroarabinonucleoside which showed submicromolar antiproliferative activity. However,
all the sugar-modified derivatives were less active than the parent ribonucleosides.
Article history:
Received 8 June 2012
Revised 2 July 2012
Accepted 2 July 2012
Available online 20 July 2012
Keywords:
Nucleosides
Fluorine
Deazapurines
Pyrrolo[2,3-d]pyrimidine
Cytostatics
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
indicating that ribo-configuration of the sugar might be crucial for
the activity in this particular class of compounds. Here we report
Nucleoside cytostatic or cytotoxic agents1 are one of the most
important classes of drugs clinically used for treatment of solid or
hematological malignancies. Within our long-term program2 on
new biologically active base-modified nucleosides, we have recently
discovered two novel types of nucleoside cytostatic: 6-hetaryl-7-
deazapurine ribonucleosides3 1 and 7-hetaryl-7-deazaadenosines4
2. Both types of compounds displayed nanomolar cytostatic activi-
ties towards a wide panel of leukemia and cancer cell-lines. Our
on-going study on mechanism of action is still under way but in par-
allel we systematically study the SAR. In both series, the most active
compounds were derivatives bearing furyl or thienyl groups at the
position 6 or 7 of the 7-deazapurine. In the 6-hetaryl-7-deazapurine
ribonucleoside series we were able to prepare their cycloSal-phos-
phate and phosphoramidate prodrugs5 to find that they are less ac-
tive due to increased efflux from the cells and a series of sugar
modified derivatives:6 20-C-methylribonucleosides, arabinonucleo-
sides and 20-fluoroarabinonucleosides that were all entirely inactive
the synthesis and biological activity profiling of analogous sugar-
modified derivatives derived from 7-hetaryl-7-deazaadenine (Chart
1).
7-Deazaadenosine (tubercidin) is a natural cytostatic antibiotic7
and extensive studies have focused8 on its diverse derivatives.
Some 7-substituted derivatives of tubercidin bearing halogens, car-
boxamides or alkynes were reported9 to exert cytotoxic, antipara-
sitic, and/or antiviral activities mostly through inhibition of
adenosine kinase. An important class of derivatives are 7-substi-
tuted 20-C-methylribonucleosides that are selective inhibitors of
HCV replication.10 Therefore, our present study also complements
the SAR of the base- and sugar-modified derivatives of tubercidin11
.
2. Results and discussion
2.1. Chemistry
The synthesis of 7-substituted 7-deaza-20-C-methyladenosines
7 began with the Vorbrüggen-type condensation of 6-chloro-7-
iodo-7-deazapurine 3 with 1,2,3,5-tetra-O-benzoyl-2-C-methyl-b-
⇑
Corresponding author.
E-mail address: hocek@uochb.cas.cz (M. Hocek).
0968-0896/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmc.2012.07.003

P. Nauš et al. / Bioorg. Med. Chem. 20 (2012) 5202–5214
Cl
5203
Cytostatic nucleosides from our lab:
X, Y = O, S, NH, N, CH
I
Cl
N
I
N
N
X
Y
N
Y
i)
X
NH2
N
N
R
N
BzO
N
H
3
O
48%
+
BzO
O
OBz
CH3
CH3
OBz
HO
HO
N
N
N
N
O
O
BzO
ii)
5
BzO
OBz
4
69%
I
HO
1
OH
(R = H or F)
HO
OH
NH2
N
NH2
N
2
R
Commercial nucleoside cytostatics:
NH2
Anti-HCV nucleoside in
clinical trials:
HO
HO
NH2
N
N
iii)
N
NH2
N
O
O
N
N
N
N
N
N
CH3
OH
CH3
OH
HO
HO
N
N
F
N
Cl
HO
HO
HO
O
O
N
N
O
7a-i
6
Products
(yields)
Products
(yields)
7
a
7
f
-R (-R')
-R (-R')
CH3
OH
HO
OH
HO
F
HO
Clofarabine
cytostatic
Fludarabine
cytostatic
7a
7f
2'-C-Me-7-deazaA
(70%)
(77%)
S
anti-HCV
OMe
O
This work:
7b
7g
b
c
d
g
h
i
Y
Y
(67%)
(59%)
X
X
NH2
N
NH2
N
S
7c
7h
HO
HO
(41%)
(62%)
N
N
R
N
N
O
O
CH3
OH
7d
7i
HO
HO
O
(65%)
(66%)
R = OH or F
Chart 1.
e
7e
(55%)
O
D
-ribofuranose 4 (Scheme 1). Among the conditions screened, the
one-pot DBU/TMSOTf procedure12 was found to be the best, afford-
ing protected 20-C-methyl-b-
-ribofuranoside 5 in 48% yield. Ami-
Scheme 1. Reagents and conditions: (i) TMSOTf, DBU, MeCN, 70 °C; (ii) aq NH3 (26%
w/w), dioxane, 120 °C; (iii) R-B(OH)2, Na2CO3, Pd(OAc)2, TPPTS, H2O/MeCN (2:1),
100 °C.
D
nation/deprotection of compound 5 by heating with aqueous
ammonia in dioxane provided 7-deaza-7-iodo-20-C-methyladeno-
sines 6 in 69% yield. Finally, aqueous Suzuki–Miyaura reactions13
of 6 with a series of boronic acids gave desired 7-(het)aryl substi-
tuted 7-deaza-20-C-methyladenosines 7a–i in good yields.
A synthetic path to 7-hetaryl-7-deazaadenine arabinonucleo-
sides was developed starting from the corresponding ribonucleo-
side 1418 (Scheme 4). At first, the 30- and 50-hydroxy groups of
7-iodotubercidin 14 were protected using the Markiewicz reagent.
As the starting material 14 is poorly soluble in pyridine, it was nec-
essary to co-evaporate it several times with pyridine prior to silyla-
tion to obtain the silylated derivative 15 in good yield (89%).
Oxidation by Dess-Martin periodinane that provided high yields
with a similar substrate in our previous study of 7-deazapurine
nucleosides6 did not proceed with 15. Therefore, the 20-hydroxyl
group was oxidized with CrO3 in presence of acetic anhydride and
pyridine to give ketone 16 (59%). The crude ketone 16 was subse-
quently selectively reduced by sodium borohydride to arabinoside
17 (85%). The key intermediate, free arabinoside 18, was prepared
by deprotection of compound 17 by Et3Nꢀ3HF in high yield (93%).
Arabinoside 18 was used as a starting material for a series of Su-
zuki cross-coupling reactions with hetarylboronic acids in pres-
ence of sodium carbonate, TPPTS and palladium acetate in
acetonitrile:water (1:2) at 100 °C. A set of five 6-amino-7-het-
aryl-7-deazapurine arabinonucleosides 19a,e–h was obtained in
good yields (64–92%) (Scheme 5).
The route towards 7-substituted 7-deazaadenine 20-deoxy-20-
fluoroarabinonucleosides commenced with nucleobase-anion
glycosylation14 of 6-chloro-7-iodo-7-deazapurine
3 with 2-
deoxy-2-fluoroarabinosyl bromide 9 (Scheme 2). The bromide 915
was obtained by treatment of 2-deoxy-2-fluoro-1,3,5-tri-O-ben-
zoyl-a-D-arabinofuranose 8 with 30% HBr in acetic acid. The
reaction of deazapurine 3 with bromose 9 in the presence of
KOH, TDA-1 {TDA-1 = tris[2-(2-methoxyethoxy)ethyl]amine)} in
acetonitrile provided protected 6-chloro-7-iodo-7-deazapurine
20-deoxy-20-fluoro-b-
D-arabinofuranoside 10 in excellent 85%
yield. Nucleoside 10 was converted to unprotected 7-iodo-7-
deazaadenine 20-deoxy-20-fluoroarabinoside 11 by treatment with
aqueous ammonia in dioxane in steel bomb in 84% yield.
Palladium-catalyzed cross-coupling reactions of iodide 11 with
(het)arylboronic acids under aqueous-phase conditions or with
stannanes in DMF afforded the corresponding 7-(het)aryl
substituted 7-deazaadenine 20-deoxy-20-fluoroarabinonucleosides
12a,e–h,j in good yields. The 4-pyrazolyl derivative 12j was syn-
thesized by the Stille reaction of 11 with 1-dimethylsulfamoyl-4-
tributylstannylpyrazole16 followed by acid catalyzed deprotection
(1 M aq HCl) of dimethylsulfamoyl group (80% yield in two steps).
The Sonogashira reaction of 11 with (trimethylsilyl)acetylene
and subsequent base promoted protodesilylation of intermediate
13 afforded ethynyl derivative 12k in high yield (Scheme 3). 7-
Triazolyl derivative 12l was prepared by copper mediated [3+2]
cycloadition17 of ethynyl compound 12k with trimethylsilylazide
in moderate yield of 27%.
An ethynyl group was introduced to the position 7 of 7-dea-
zaadenine arabinoside 18 by the Sonogashira reaction of 18 with
(trimethylsilyl)acetylene in presence of copper(I) iodide, Et3N and
PdCl2(PPh3)2 in DMF to obtain TMS-ethynyl derivative 20 (51%
yield) which was deprotected using potassium carbonate in meth-
anol. 7-Ethynyl-7-deazaadenine arabinoside 19k was obtained in
77% yield (Scheme 6).
A series of 7-hetaryl-7-deazaadenine 2-deoxyribonucleosides
was
synthesized
from
20-deoxy-7-iodo–tubercidin
2119

5204
P. Nauš et al. / Bioorg. Med. Chem. 20 (2012) 5202–5214
BzO
BzO
NH2
N
I
NH2
N
O
O
i)
I
OBz
Br
i)
99%
N
BzO
F
BzO
F
N
HO
O
92 %
O
N
N
O
8
9
(iPr)2Si
Cl
I
O
OH
15
ii)
O
(iPr)2
Si
Cl
OH
HO
14
I
N
ii)
85%
BzO
N
9
N
N
O
59%
N
N
NH2
N
NH2
N
I
H
I
BzO
F
iii)
3
10
RO
iv)
N
N
O
N
N
O
iii)
O
84%
HO
O
NH2
N
NH2
N
I
R
(iPr)2Si
OH
RO
O
O
(iPr)2
R'-M
iv)
Si
HO
N
N
N
N
O
17
O
, R = TIPDS, 85%
16
18, R = H, 93%
HO
F
11
HO
F
Scheme 4. Reagents and conditions: (i) TIPDSCl2/py; (ii) CrO3, Ac2O, py/CH2Cl2,
0 °C; (iii) NaBH4/EtOH, 0 °C; (iv) Et3Nꢀ3HF/THF, rt.
12a, e-h,j
Products
(yields)
12
R (R')
M
NH2
N
NH2
N
I
R
a
B(OH)2
SnBu3
SnBu3
B(OH)2
12a (86%)
12e (75%)
i)
HO
HO
N
N
N
N
O
O
e
O
S
OH
OH
19a,e-h
HO
HO
f
12f (82%)
12g (89%)
12h (90%)
18
Product
(yield)
Product
(yield)
O
R
R
19
a
19
g
g
h
19a
19g
O
S
(73%)
S
(73%)
B(OH)2
SnBu3
N
19e
19h
NH
e
f
h
j
12j (80%)
(64%)
(92%)
O
S
19f
Scheme 2. Reagents and conditions: (i) HBr, AcOH; (ii) KOH, TDA-1, MeCN; (iii) aq
NH3 (26% w/w), dioxane, 120 °C; (iv) For M = B(OH)2: R-B(OH)2, Na2CO3, Pd(OAc)2,
TPPTS, H2O/MeCN (2:1), 100 °C; For M = SnBu3: R(R0)-SnBu3, PdCl2(PPh3)2, DMF,
100 °C.
(77%)
Scheme 5. Reagents and conditions: (i) R-B(OH)2, Na2CO3, TPPTS, Pd(OAc)2, CH3CN/
H2O (1:2), 100 °C.
R
O
N
N
HN
R
NH2
N
NH2
I
NH2
N
i)
iii)
11
NH2
N
82%
HO
27%
HO
i)
N
HO
N
N
N
F
N
N
N
O
O
HO
N
N
O
HO
F
12l
OH
HO
13
HO
OH
, R = TMS
12k, R = H, 97%
HO
ii)
18
20, R = TMS, 51%
19k, R = H, 77%
ii)
Scheme 3. Reagents and conditions: (i) Trimethylsilylacetylene, PdCl2(PPh3)2, CuI,
NEt3, DMF, rt; (ii) K2CO3, MeOH; (iii) TMSN3, CuI, DMF/MeOH.
Scheme 6. Reagents and conditions: (i) (Trimethylsilyl)acetylene, PdCl2(PPh3)2,
CuI, Et3N, DMF, rt; (ii) K2CO3, MeOH, rt.
(Scheme 7). The Suzuki cross-coupling reactions with hetarylbo-
ronic acids were performed in the presence of sodium carbonate,
TPPTS and palladium acetate in acetonitrile:water (1:2) at 100 °C.
Target 7-hetaryl-7-deazaadenine 20-deoxyribonucleosides 22e–h
were prepared in good yields (72–89%).
following cell cultures: (i) human promyelocytic leukemia HL60
cells (ATCC CCL 240); (ii) human cervix carcinoma HeLa S3 cells
(ATCC CCL 2.2); (iii) human T lymphoblastoid CCRF-CEM cell line
(ATCC CCL 119), and (iv) hepatocellular carcinoma cells HepG2
(ATCC HB 8065). Cell viability was determined following a 3-day
incubation using metabolic 2,3-bis-(2-methoxy-4-nitro-5-sulf-
ophenyl)-2H-tetrazolium-5-carboxanilide (XTT) based method.20
Table 1 shows the activities of selected most potent compounds.
Several examples of 7-hetaryl-7-deazaadenine 20-C-methyl-ribo-
2.2. Biological activity profiling
All the title nucleosides were subjected to biological activity
screening. The cytotoxic activity in vitro was studied on the

P. Nauš et al. / Bioorg. Med. Chem. 20 (2012) 5202–5214
5205
Table 2
NH2
N
NH2
N
I
R
Further cytostatic activities of selected nucleosides (SRB)
Compound
GIC50
NCI-H23
(l
M)a
Hs 578
i)
HO
HO
N
N
N
N
O
O
HCT 116
Du 145
6
7e
12e
12k
12l
6.65
>10
>10
0.108
7.64
0.79
6.08
>10
0.048
5.36
4.39
9.05
8.49
0.065
1.82
3.38
8.89
8.52
0.002
9.41
HO
HO
22e-h
21
Product
(yield)
Product
(yield)
R
R
22
e
22
g
a
Cytostatic activity was determined by SRB (GIC50) following a 3-day incubation
with tested compounds. Values represent 2–4 independent experiments.
22g
22e
O
S
(72%)
(89%)
O
22f
22h
f
h
Table 3
(75%)
(88%)
S
Anti-HCV activities of title nucleosides
Compound
HCV replicon 1A
M) CC50
HCV replicon 1B
M) CC50
26.27
>44
Scheme 7. Reagents and conditions: (i) R-B(OH)2, Na2CO3, TPPTS, Pd(OAc)2, CH3CN/
H2O (1:2), 100 °C.
EC50
0.37
(l
(lM)
EC50
(
l
(lM)
6
7a
7b
7c
7d
7e
7f
7g
19.75
>44
>44
>44
20.13
nd
0.38
27.07
9.44
35.43
11.99
24.67
4.91
>44
>44
29.59
nucleosides 7, and 20-fluoro-20-deoxyribonucleosides 12 and arabi-
24.13
5.31
nonucleosides 19 exerted
lM cytostatic effects. The most active
was the 7-ethynyl-7-deazaadenine 20-fluoro-20-deoxyribonucleo-
side 12k which showed submicromolar effects. The 20-deoxyribo-
nucleosides 22 were entirely inactive.
nd
nd
8.96
49.63
48.09
>44
>44
38.77
nd
14.19
12.28
15.54
6.13
18.33
36.31
6.15
26.36
15.70
2.80
>44
>44
29.42
>44
>44
7h
7i
Cytostatic activity of selected nucleosides was also evaluated
against further four cell-lines derived from various human solid tu-
mors including lung (NCI-H23), prostate (Du145), colon (HCT 116),
and breast (Hs 578) carcinomas. Concentrations inhibiting the cell
growth by 50% (GIC50) were determined using a quantitative cellu-
lar staining with sulforhodamine B (SRB)21 following a 5-day treat-
ment. The SRB method allowed for a quantitative measurement of
a net effect on cell growth by subtracting the background signal
generated by the cell culture inoculum at the beginning of treat-
ment. Again, several compounds exerted micromolar effects (Table
2). The 7-ethynyl fluoroarabinonucleoside 12k displayed nanomo-
lar activity against Du145.
12a
12e
12f
12g
12h
12j
12k
12l
18
19a
19e
19f
19g
19h
19k
22e
22f
22g
22h
43.47
12.05
4.07
16.994
10.81
8.45
>44
>44
>44
42.85
>44
24.35
>44
2.68
36.98
10.94
22.36
0.36
>44
33.65
>44
12.11
21.66
13.72
>44
0.36
1.83
1.39
>44
3.41
0.92
1.39
10.91
9.97
>44
>44
>44
3.02
20.64
22.47
33.98
1.75
>44
>44
>44
>44
35.32
25.16
37.75
1.54
11.08
7.58
>44
>44
>44
23.05
>44
The title modified nucleosides were also tested up to 100 lM
17.43
for antiviral activities in HCV genotype 1A and 1B replicons22 (Ta-
ble 3). They generally displayed micromolar antiviral activities in
the HCV replicon. Unfortunately, in most cases the compounds
lacked selectivity and the antiviral effect was accompanied by
cytotoxicity. With the exception of 7-iododeazaadenine 20-C-Me-
ribonucleoside 6 (which showed ca 65-fold selectivity), in most
compounds the selectivities were <10-fold. These results suggest
that, similarly to the previously reported ribonucleosides, these
4.16
5.16
5.26
5.91
>44
>44
>44
>44
>44
24.03
11.39
>44
>44
nd, not determined.
sugar-modified deazapurine ribonucleosides interfere with critical
cell growth processes and most of the activity toward HCV viral
replication is non-specific. Shortly before submission of this work,
a paper by Di Francesco et al.23 appeared reporting micromolar
anti-HCV activities of related (but different derivatives) 7-het-
aryl-7-deazaadenine 20-C-Me-ribonucleosides but no cytotoxicity
data were reported.
Table 1
Cytotoxic activities of title nucleosides (XTT)
Compound
IC50
(
l
M)a
CCRF-CEM
HL60
HeLa S3
HepG2
6
7d
7i
>10
>10
>10
>10
>10
0.20
>10
6.44
>10
13.51
>10
12.99
>10
7.50
>10
>10
5.60
>10
0.22
6.66
3.19
7.62
5.38
8.36
7.03
3.77
4.38
3.95
7.81
7.50
9.07
0.18
3.45
7.02
6.64
4.25
4.67
3.10
ndb
nd
nd
>10
nd
nd
2.3. Conclusions
12f
12j
12k
12l
18
19e
19f
19g
19h
19k
We have prepared a large series of new sugar-modified deriva-
tives of previously reported4 nanomolar cytostatic agents, 7-het-
aryl-7-deazaadenine ribonucleosides. In all cases, the synthesis
was based on preparation of key 7-iodo-7-deazaadenine nucleo-
side followed by cross-coupling reactions. All compounds were
tested on cytostatic and anti-HCV effects. Many examples of 7-het-
aryl-7-deazaadenine 20-C-methyl-ribonucleosides 7, and 20-fluoro-
nd
6.12
6.62
12.23
6.10
>15
9.86
20-deoxyribonucleosides 12 and arabinonucleosides 19 exerted
lM
>10
cytostatic effects, whereas the 20-deoxyribonucleosides 22 were
entirely inactive. In all cases, the level of activities is significantly
lower than the activities of the ribonucleosides.4 However, these
a
Cytostatic activity was determined by XTT assay following a 3-day incubation
with tested compounds. Values represent 2–4 independent experiments.
b
nd, not determined.

5206
P. Nauš et al. / Bioorg. Med. Chem. 20 (2012) 5202–5214
results are interesting because these compounds are the first
examples of biologically active hetaryl-7-deazapurine nucleosides
(please note that the corresponding 6-hetaryl-7-deazapurine su-
gar-modified nucleosides were all inactive6). They also clearly indi-
cate that the mechanism of action of 7-hetaryl-7-deazaadenosines4
is different from the second class of related nanomolar cytostatics,
6-hetaryl-7-deazapurine ribonucleosides reported3 earlier. Our
deeper studies on the mechanisms are under way.
the crude product was purified by chromatography on silica
(CHCl3?CHCl3/MeOH, 8:2) and then re-purified by reverse phase
chromatography (0?100% MeOH in H2O) to afford title compound
6 as white solid (76 mg, 69%). Product was recrystallized from
MeOH/MeCN. Mp 207–208 °C. ½a D20
ꢁ
ꢂ39.0 (c 0.274, MeOH). 1H
NMR (600 MHz, DMSO-d6): 0.67 (s, 3H, CH3); 3.65 (ddd, 1H,
Jgem = 12.1, J5 b,OH = 4.8, J5 b,4 = 2.7, H-50b); 3.81 (ddd, 1H,
0
0
0
Jgem = 12.1, J5 a,OH = 4.8, J5 a,4 = 2.0, H-50a); 3.79 (ddd, 1H,
0
0
0
J4 ,3 = 9.1, J4 ,5 = 2.7, 2.0, H-40); 3.93 (bd, 1H, J3 ,4 = 9.1, H-30); 5.14
0
0
0
0
0
0
(s, 1H, OH-20); 5.16 (bs, 1H, OH-30); 5.22 (t, 1H, JOH,5 = 4.8, OH-
0
3. Experimental part
50); 6.10 (s, 1H, H-10); 6.67 (bs, 2H, NH2); 7.82 (s, 1H, H-6); 8.10
(s, 1H, H-2). 13C NMR (151 MHz, DMSO-d6): 19.89 (CH3); 51.68
(C-5); 59.46 (CH2-50); 71.76 (CH-30); 78.87 (C-20); 82.39 (CH-40);
90.71 (CH-10); 103.11 (C-4a); 126.81 (CH-6); 149.88 (C-7a);
152.23 (CH-2); 157.43 (C-4). MS (FAB): m/z 407 [M+H]. HRMS
(FAB) for C12H16IN4O4 [M+H] Calcd: 407.0216. Found: 407.0225.
Anal. Calcd for C12H15IN4O4: C, 35.48; H, 3.72; N, 13.79. Found: C,
35.37; H 3.72; N 13.39.
Melting points were determined on a Kofler block and are uncor-
rected. Optical rotations were measured at 25 °C, ½a D20
ꢁ
values are gi-
ven in 10ꢂ1 deg cm2 gꢂ1. NMR spectra were measured at 400.1 MHz
for 1H and 100.6 MHz for 13C nuclei, or at 499.8 MHz for 1H and
125.7 MHz for 13C, or at 600.1 MHz for 1H and 150.9 MHz for 13C
in CDCl3 (TMS was used as internal standard), DMSO-d6 (referenced
to the residual solvent signal). 19F spectra were recorded at
470.3 MHz. Chemical shifts are given in ppm (d-scale), coupling
constants (J) in Hz. Complete assignment of all NMR signals was
performed using a combination of H,H-COSY, H,H-ROESY, H,C-
HSQC and H,C-HMBC experiments. High resolution mass spectra
were measured using electrospray ionization. Reverse phase high
performance flash chromatography (HPFC) purifications were per-
formed with Biotage SP1 apparatus on KP-C18-HS columns. 2-
3.3. 4-Amino-7-(2-C-methyl-b-D-ribofuranosyl)-5-phenyl-7H-
pyrrolo[2,3-d]pyrimidine (7a)
An argon purged mixture of compound 6 (49 mg, 0.12 mmol),
phenylboronic acid (23 mg, 0.18 mmol), Na2CO3 (144 mg,
1.36 mmol), TPPTS (9 mg, 0.016 mmol) and Pd(OAc)2 (1.4 mg,
Deoxy-2-fluoro-1,3,5-tri-O-benzoyl-
a
-D
-arabinofuranose
8
and
6.2 lmol) in H2O/MeCN (2:1, 1.8 ml) was stirred at 80 °C for 1 h.
1,2,3,5-tetra-O-benzoyl-2-C-methyl-b-
chased from Nucleo Chemisty Co. (Shenzhen, China).
D
-ribofuranose 4 were pur-
After cooling, volatiles were removed by evaporation and the resi-
due was purified by reverse phase chromatography (0?100%
MeOH in H2O) affording title compound 7a as white solid
(30 mg, 70%). Mp >129 °C (slow melting due to dehydration).
3.1. 4-Chloro-5-iodo-7-(2-C-methyl-2,3,5-tri-O-benzoyl-b-
ribofuranosyl)-7H-pyrrolo [2,3-d]pyrimidine (5)
D-
½
a 2D0
ꢁ
ꢂ55.7 (c 0.226, MeOH). 1H NMR (600 MHz, DMSO-d6): 0.75
(s, 3H, CH3); 3.65 (bdd, 1H, Jgem = 12.2, J5 b,4 = 2.9, H-50b); 3.82
0
0
(bdd, 1H, Jgem = 12.2, J5 a,4 = 2.1, H-50a); 3.86 (ddd, 1H, J4 ,3 = 9.1,
0
0
0
0
To a mixture of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine 3
(903 mg, 3.23 mmol), 2-C-methyl-1,2,3,5-tetra-O-benzoyl-b-
J4 ,5 = 2.9, 2.1, H-40); 4.02 (d, 1H, J3 ,4 = 9.1, H-30); 5.15 (bs, 3H,
OH-20,30,50); 6.10 (bs, 2H, NH2); 6.23 (s, 1H, H-10);7.36 (m, 1H, H-
p-Ph); 7.44–7.50 (m, 4H, H-o,m-Ph); 7.70 (s, 1H, H-6); 8.16 (s,
1H, H-2). 13C NMR (151 MHz, DMSO-d6): 20.00 (CH3); 59.60
(CH2-50); 72.01 (CH-30); 78.88 (C-20); 82.39 (CH-40); 90.51 (CH-
10); 100.09 (C-4a); 116.41 (C-5); 120.75 (CH-6); 127.05 (CH-p-
Ph); 128.64 (CH-o-Ph); 129.23 (CH-m-Ph); 134.89 (C-i-Ph);
150.67 (C-7a); 151.94 (CH-2); 157.49 (C-4). MS (FAB) m/z 357
[M+H]. HRMS (FAB) for C18H21N4O4: [M+H] Calcd: 357.1563.
Found: 357.1557. Anal. Calcd for C18H20N4O4ꢀ1.6H2O: C, 56.13; H,
6.07; N, 14.54. Found: C, 56.52; H, 5.74; N, 14.14.
0
0
0
0
D
-
ribofuranose 4 (1.7 g, 2.93 mmol) and DBU (1.3 ml, 8.69 mmol) in
MeCN (20 ml), TMSOTf (2.1 ml, 11.62 mmol) was added dropwise
at 0 °C and the mixture was then stirred at 70 °C for 24 h. After
cooling, the mixture was diluted with AcOEt (100 ml), washed with
aq NaHCO3 (sat., 25 ml), H2O (25 ml) and brine (25 ml). The organic
layer was dried over MgSO4 and evaporated. The residue was chro-
matographed on silica (hexanes/toluene, 1:1; then hexanes/tolu-
ene/MeCN, 49:49:2?3:3:4) affording title compound 5 as a white
foam (1.04 g, 48%). Product was recrystallized from EtOH. Mp 95–
97 °C. ½a 2D0
ꢁ
ꢂ69.3 (c 0.280, CHCl3). 1H NMR (500 MHz, CDCl3):
1.59 (s, 3H, CH3); 4.72 (td, 1H, J4 ,3 = J4 ,5 b = 5.8, J4 ,5 a = 3.4, H-40);
0
0
0
0
0
0
4.85 (dd, 1H, Jgem = 12.2, J5 b,4 = 5.8, H-50b); 4.95 (dd, 1H, Jgem = 12.2,
0
0
3.4. 4-Amino-5-(4-methoxyphenyl)-7-(2-C-methyl-b-
ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine (7b)
D-
J5 a,4 = 3.4, H-50a); 6.03 (d, 1H, J3 ,4 = 5.8, H-30); 6.95 (s, 1H, H-10);
7.34, 7.46 and 7.47 (3 ꢃ m, 3 ꢃ 2H, H-m-Bz); 7.54, 7.59 and 7.61
(3 ꢃ m, 3 ꢃ 1H, H-p-Bz); 7.69 (s, 1H, H-6); 7.96, 8.10 and 8.11
(3 ꢃ m, 3 ꢃ 2H, H-o-Bz); 8.75 (s, 1H, H-2). 13C NMR (125.7 MHz,
CDCl3): 17.92 (CH3); 52.68 (C-5); 63.33 (CH2-50); 75.55 (CH-30);
80.04 (CH-40); 84.93 (C-20); 88.95 (CH-10); 117.71 (C-4a); 128.49,
128.54 and 128.63 (CH-m-Bz); 128.65, 129.50 and 129.61 (C-i-
Bz); 129.78, 129.83 and 129.92 (CH-o-Bz); 132.66 (CH-6); 133.38,
133.66, 133.72 (CH-p-Bz); 150.68 (C-7a); 151.17 (CH-2); 153.15
(C-4); 165.09, 165.33 and 166.32 (CO). MS (FAB): m/z 738 [M+H].
HRMS (FAB) for C33H26ClIN3O7 [M+H] Calcd: 738.0504. Found:
738.0491. Anal. Calcd for C33H25ClIN3O7: C, 53.71; H, 3.41; N,
5.69. Found: C 53.91; H 3.29; N 5.38.
0
0
0
0
Compound 7b was prepared as described for 7a by the reaction
of compound 6 (73 mg, 0.18 mmol) and 4-methoxyphenylboronic
acid. Yield 47 mg (67%). White solid, mp 127–129 °C. ½a D20
ꢂ48.4
ꢁ
(c 0.225, MeOH). 1H NMR (600 MHz, DMSO-d6): 0.74 (s, 3H, CH3);
3.64 (bdd, 1H, Jgem = 12.21, J5 b,4 = 2.9, H-50b); 3.80 (s, 3H, CH3O);
0
0
3.81 (bdd, 1H, Jgem = 12.1, J5 a,4 = 2.1, H-50a); 3.85 (ddd, 1H,
0
0
J4 ,3 = 9.1, J4 ,5 = 2.9, 2.1, H-40); 4.01 (d, 1H, J3 ,4 = 9.1, H-30); 5.13
(bs, 3H, OH-20,30,50); 6.08 (bs, 2H, NH2); 6.22 (s, 1H, H-10); 7.04
(m, 2H, H-m-C6H4OMe); 7.36 (m, 2H, H-o-C6H4OMe); 7.60 (s, 1H,
H-6); 8.14 (s, 1H, H-2). 13C NMR (151 MHz, DMSO-d6): 19.99
(CH3); 55.39 (CH3O); 59.61 (CH2-50); 72.03 (CH-30); 78.87 (C-20);
82.34 (CH-40); 90.47 (CH-10); 100.31 (C-4a); 114.65 (CH-m-
C6H4OMe); 116.06 (C-5); 120.14 (CH-6); 127.04 (C-i-C6H4OMe);
129.91 (CH-o-C6H4OMe); 150.45 (C-7a); 151.85 (CH-2); 157.51
(C-4); 158.58 (C-p-C6H4OMe). MS (FAB) m/z 387 [M+H]. HRMS
(FAB) for C19H23N4O5 [M+H] Calcd: 387.1668. Found: 387.1665.
Anal. Calcd for C19H22N4O5ꢀ1.6H2O: C, 54.96; H, 6.12; N, 13.49.
Found: C, 55.30; H, 5.91; N, 13.18.
0
0
0
0
0
0
3.2. 4-Amino-5-iodo-7-(2-C-methyl-b-
pyrrolo[2,3-d]pyrimidine (6)
D-ribofuranosyl)-7H-
A mixture of compound 5 (200 mg, 0.27 mmol) and aq ammo-
nia (25% w/w, 3 ml) in dioxane (3 ml) was stirred in a sealed tube
at 120 °C for 10 h. After cooling, the volatiles were evaporated and

P. Nauš et al. / Bioorg. Med. Chem. 20 (2012) 5202–5214
5207
0
0
3.5. 4-Amino-7-(2-C-methyl-b-D-ribofuranosyl)-5-(naphthalen-
1-yl)-7H-pyrrolo[2,3-d]pyrimidine (7c)
and 3.85 (2 ꢃ bd, 2H, Jgem = 12.0, H-50); 3.87 (ddd, 1H, J4 ,3 = 9.1,
J4 ,5 = 2.9, 2.0, H-40); 4.00 (bd, 1H, J3 ,4 = 9.1, H-30); 5.16 (bs, 2H,
OH-20,30); 5.25 (bs, 1H, OH-50); 6.19 (s, 1H, H-10); 6.58 (dd, 1H,
J3,4 = 3.3, J3,5 = 0.8, H-3-furyl); 6.60 (dd, 1H, J4,3 = 3.3, J4,5 = 1.9, H-
4-furyl); 6.90 (bs, 2H, NH2); 7.78 (dd, 1H, J5,4 = 1.9, J5,3 = 0.8, H-5-
furyl); 8.01 (s, 1H, H-6); 8.14 (s, 1H, H-2). 13C NMR (151 MHz,
DMSO-d6): 19.91 (CH3); 59.66 (CH2-50); 71.92 (CH-30); 78.85 (C-
20); 82.48 (CH-40); 90.60 (CH-10); 99.03 (C-4a); 105.22 (CH-3-fur-
yl); 106.10 (C-5); 112.13 (CH-4-furyl); 120.07 (CH-6); 142.17
(CH-5-furyl); 148.98 (C-2-furyl); 150.60 (C-7a); 152.35 (CH-2);
157.46 (C-4). MS (ESI) m/z 347 [M+H], 369 [M+Na]. HRMS (ESI)
for C16H19N4O5 [M+H] Calcd: 347.1355. Found: 347.1347. Anal.
Calcd for C16H18N4O5ꢀ0.7H2O: C, 53.54; H, 5.45; N, 15.61. Found:
C, 53.86; H, 5.48; N, 15.22.
0
0
0
0
Compound 7c was prepared as described for 7a by the reaction
of compound 6 (92 mg, 0.23 mmol) and naphthalene-1-boronic
acid. Yield 38 mg (41%). Crude product was prepurified by chroma-
tography on silica (0?20% MeOH in CHCl3), before final reverse
phase chromatography. Tan solid, mp 142–144 °C. ½a D20
ꢂ58.6 (c
ꢁ
0.239, MeOH). 1H NMR (500 MHz, DMSO-d6, T = 353 K): 0.90 (s,
3H, CH3); 3.67 (dd, 1H, Jgem = 12.2, J5 b,4 = 3.5, H-50b); 3.83 (dd,
0
0
1H, Jgem = 12.2, J5 a,4 = 2.3, H-50a); 3.91 (ddd, 1H, J4 ,3 = 8.9,
0
0
0
0
J4 ,5 = 3.5, 2.3, H-40); 4.04 (d, 1H, J3 ,4 = 8.9, H-30); 4.89 (bs, 3H,
OH-20,30,50); 5.39 (bs, 2H, NH2); 6.34 (s, 1H, H-10); 7.500 (ddd, 1H,
J7,8 = 8.3, J7,6 = 6.9, J7,5 = 1.3, H-7-naphth); 7.502 (dd, 1H, J2,3 = 6.9,
J2,4 = 1.3, H-2-naphth); 7.56 (ddd, 1H, J6,5 = 8.1, J6,7 = 6.9, J6,8 = 1.3,
H-6-naphth); 7.60 (dd, 1H, J3,4 = 8.3, J3,2 = 6.9, H-3-naphth); 7.63
(s, 1H, H-6); 7.75 (dddd, 1H, J8,7 = 8.3, J8,6 = 1.3, J8,4 = 1.0, J8,5 = 0.8,
H-8-naphth); 7.98 (ddd, 1H, J4,3 = 8.3, J4,2 = 1.3, J4,8 = 1.0, H-4-naph-
th); 8.01 (ddd, 1H, J5,6 = 8.1, J5,7 = 1.3, J5,8 = 0.8, H-5-naphth); 8.19
(s, 1H, H-2). 13C NMR (151 MHz, DMSO-d6, T = 353 K): 19.73
(CH3); 59.70 (CH2-50); 72.30 (CH-30); 78.69 (C-20); 82.28 (CH-40);
90.64 (CH-10); 102.10 (C-4a); 113.02 (C-5); 121.50 (CH-6);
125.27 (CH-8-naphth); 125.38 (CH-3-naphth); 125.98 (CH-6-
naphth); 126.42 (CH-7-naphth); 127.82 (CH-4-naphth); 128.12
(CH-2,5-naphth); 131.63 (C-1-naphth); 132.13 (C-8a-naphth);
133.39 (C-4a-naphth); 150.05 (C-7a); 151.61 (CH-2); 156.96 (C-
4). MS (ESI) m/z 407 [M+H], 429 [M+Na]. HRMS (ESI) for
0
0
0
0
3.8. 4-Amino-7-(2-C-methyl-b-D-ribofuranosyl)-5-(thiophen-2-
yl)-7H-pyrrolo[2,3-d]pyrimidine (7f)
Compound 7f was prepared as described for 7a by the reaction
of compound 6 (100 mg, 0.25 mmol) and thiophene-2-boronic
acid. Yield 69 mg (77%). White solid. Mp 130–132 °C. ½a D20
ꢂ51.4
ꢁ
(c 0.255, MeOH). 1H NMR (600 MHz, DMSO-d6): 0.73 (s, 3H, CH3);
3.65 (dd, 1H, Jgem = 12.3, J5 b,4 = 2.9, H-50b); 3.83 (dd, 1H,
0
0
Jgem = 12.3, J5 a,4 = 2.1, H-50a); 3.86 (ddd, 1H, J4 ,3 = 9.1, J4 ,5 = 2.9,
0
0
0
0
0
0
2.1, H-40); 4.00 (bd, 1H, J3 ,4 = 9.1, H-30); 5.20 (bs, 3H, OH-20,30,50);
6.19 (s, 1H, H-10); 6.30 (bs, 2H, NH2); 7.13 (dd, 1H, J3,4 = 3.5,
J3,5 = 1.2, H-3-thienyl); 7.16 (dd, 1H, J4,5 = 5.2, J4,3 = 3.5, H-4-thie-
nyl); 7.55 (dd, 1H, J5,4 = 5.2, J5,3 = 1.1, H-2-thienyl); 7.82 (s, 1H, H-
6); 8.16 (s, 1H, H-2). 13C NMR (151 MHz, DMSO-d6): 19.96 (CH3);
59.37 (CH2-50); 71.76 (CH-30); 78.88 (C-20); 82.38 (CH-40); 90.53
(CH-10); 100.27 (C-4a); 108.51 (C-5); 121.64 (CH-6); 125.93 (CH-
5-thienyl); 126.42 (CH-3-thienyl); 128.53 (CH-4-thienyl); 136.04
(C-2-thienyl); 150.40 (C-7a); 152.26 (CH-2); 157.47 (C-4). MS
(ESI) m/z 363 [M+H], 385 [M+Na]. HRMS (ESI) for C16H19N4O4S
[M+H] Calcd: 363.1127. Found: 363.1121. Anal. Calcd for
0
0
C22H23N4O4 [M+H] Calcd: 407.1714. Found: 407.1704. Anal. Calcd
for C22H22N4O4ꢀ1.5H2O: C, 60.96; H, 5.81; N, 12.93. Found: C,
61.30; H, 5.72; N, 13.28.
3.6. 4-Amino-7-(2-C-methyl-b-D-ribofuranosyl)-5-(naphthalen-
2-yl)-7H-pyrrolo[2,3-d]pyrimidine (7d)
Compound 7d was prepared as described for 7a by the reaction
of compound 6 (91 mg, 0.22 mmol) and naphthalene-2-boronic
acid. Yield 58 mg (65%). Crude product was prepurified by chroma-
tography on silica (0?20% MeOH in CHCl3), before final reverse
C
16H18N4O4Sꢀ0.95H2O: C, 50.64; H, 5.28; N, 14.76. Found: C,
51.03; H, 5.06; N, 14.40.
phase chromatography. Cream solid, mp 143–145 °C. ½a D20
ꢁ
ꢂ64.3
3.9. 4-Amino-5-(furan-3-yl)-7-(2-C-methyl-b-
7H-pyrrolo[2,3-d]pyrimidine (7g)
D-ribofuranosyl)-
(c 0.253, MeOH). 1H NMR (500 MHz, DMSO-d6): 0.79 (s, 3H, CH3);
3.66 (ddd, 1H, Jgem = 12.6, J5 b,OH = 5.0, J5 b,4 = 2.9, H-50b); 3.84
0
0
0
(ddd, 1H, Jgem = 12.6, J5 a,OH = 5.0, J5 a,4 = 2.1, H-50a); 3.88 (ddd, 1H,
Compound 7g was prepared as described for 7a by the reaction
of compound 6 (50 mg, 0.12 mmol) and furan-3-boronic acid.
Reaction time 2.5 h. Yield 25 mg (59%) of white solid. Mp >123 °C
0
0
0
J4 ,3 = 9.1, J4 ,5 = 2.9, 2.1, H-40); 4.06 (bdd, 1H, J3 ,4 = 9.1,
0
0
0
0
0
0
J3 ,OH = 4.6, H-30); 5.11–5.17 (bm, 3H, OH-20,30,50); 6.19 (bs, 2H,
0
NH2); 6.27 (s, 1H, H-10); 7.52 (m, 1H, H-6-naphth); 7.55 (m, 1H,
H-7-naphth); 7.62 (dd, 1H, J3,4 = 8.5, J3,1 = 1.8, H-3-naphth); 7.81
(s, 1H, H-6); 7.94–7.97 (m, 3H, H-1,5,8-naphth); 8.01 (d, 1H,
J4,3 = 8.5, H-4-naphth); 8.18 (s, 1H, H-2). 13C NMR (125.7 MHz,
DMSO-d6): 20.03 (CH3); 59.66 (CH2-50); 72.08 (CH-30); 78.90 (C-
20); 82.41 (CH-40); 90.57 (CH-10); 100.24 (C-4a); 116.45 (C-5);
121.14 (CH-6); 126.10 (CH-6-naphth); 126.76 (CH-7-naphth);
126.82 (CH-1-naphth); 127.23 (CH-3-naphth); 127.87 and 128.02
(CH-5,8-naphth); 128.70 (CH-4-naphth); 132.00 (C-4a-naphth);
132.35 (C-1-naphth); 133.46 (C-8a-naphth); 150.82 (C-7a);
152.02 (CH-2); 157.61 (C-4). MS (ESI) m/z 407 [M+H], 429
[M+Na]. HRMS (ESI) for C22H23N4O4 [M+H] Calcd: 407.1714.
Found: 407.1715. Anal. Calcd for C22H22N4O4ꢀ1.3H2O: C, 61.47; H,
5.77; N, 13.03. Found: C, 61.83; H, 5.51; N, 12.65.
(slow melting due to dehydration). ½a D20
ꢂ54.5 (c 0.217, MeOH).
ꢁ
1H NMR (600 MHz, DMSO-d6): 0.72 (s, 3H, CH3); 3.65 (dd, 1H,
Jgem = 12.2, J5 b,4 = 3.0, H-50b); 3.82 (dd, 1H, Jgem = 12.2, J5 a,4 = 2.1,
0
0
0
0
H-50a); 3.85 (ddd, 1H, J4 ,3 = 9.1, J4 ,5 = 3.0, 2.1, H-40); 3.99 (d, 1H,
0
0
0
0
J3 ,4 = 9.1, H-30); 5.16 (bs, 3H, OH-20,30,50); 6.19 (s, 1H, H-10); 6.25
(bs, 2H, NH2); 6.66 (dd, 1H, J4,5 = 1.7, J4,2 = 0.8, H-4-furyl); 7.65 (s,
1H, H-6); 7.79 (t, 1H, J5,2 = J5,4 = 1.7, H-5-furyl); 7.80 (dd, 1H,
J2,5 = 1.7, J2,4 = 0.8, H-2-furyl); 8.13 (s, 1H, H-2). 13C NMR
(151 MHz, DMSO-d6): 19.99 (CH3); 59.74 (CH2-50); 72.08 (CH-30);
78.87 (C-20); 82.41 (CH-40); 90.56 (CH-10); 100.67 (C-4a); 106.27
(C-5); 111.78 (CH-4-furyl); 119.00 (C-3-furyl); 120.61 (CH-6);
139.79 (CH-2-furyl); 144.43 (CH-5-furyl); 150.52 (C-7a); 152.03
(CH-2); 157.68 (C-4). MS (ESI) m/z 347 [M+H]. HRMS (ESI) for
0
0
C
16H19N4O5 [M+H] Calcd: 347.1350. Found: 347.1349. Anal. Calcd
for C16H18N4O5ꢀ1.7H2O: C, 50.98; H, 5.72; N, 14.86. Found: C,
3.7. 4-Amino-5-(furan-2-yl)-7-(2-C-methyl-b-
D
-ribofuranosyl)-
51.30; H, 5.33; N, 14.46.
7H-pyrrolo[2,3-d]pyrimidine (7e)
3.10. 4-Amino-7-(2-C-methyl-b-D-ribofuranosyl)-5-(thiophen-3-
Compound 7e was prepared as described for 7a by the reaction
of compound 6 (97 mg, 0.24 mmol) and furan-2-boronic acid. Yield
yl)-7H-pyrrolo[2,3-d]pyrimidine (7h)
46 mg (55%). White solid, mp 130–132 °C. ½a D20
ꢁ
ꢂ53.3 (c 0.250,
Compound 7h was prepared as described for 7a by the reaction
of compound 6 (101 mg, 0.25 mmol) and thiophene-3-boronic
MeOH). 1H NMR (600 MHz, DMSO-d6): 0.72 (s, 3H, CH3); 3.68

5208
P. Nauš et al. / Bioorg. Med. Chem. 20 (2012) 5202–5214
acid. Yield 56 mg (62%) of white solid. Mp 128–130 °C. ½a D20
ꢁ
ꢂ60.3
hexanes/AcOEt as colorless needles. Mp 202–204 °C. 1H NMR
(c 0.222, MeOH). 1H NMR (600 MHz, DMSO-d6): 0.74 (s, 3H, CH3);
(499.8 MHz, DMSO-d6): 4.67 (dddd, 1H, J4 ,5 = 5.5, 3.7, J4 ,3 = 4.9,
0
0
0
0
3.65 (ddd, 1H, Jgem = 12.1, J5 b,OH = 4.8, J5 b,4 = 2.9, H-50b); 3.82
JH,F = 0.4, H-40); 3.72 (dd, 1H, Jgem = 12.0, J5 b,4 = 5.5, H-50b); 4.79
0
0
0
0
0
(ddd, 1H, Jgem = 12.1, J5 a,OH = 4.8, J5 a,4 = 2.1, H-50a); 3.85 (ddd, 1H,
(dd, 1H, Jgem = 12.0, J5 a,4 = 3.7, H-50a); 5.74 (ddd, 1H, JH,F = 50.8,
0
0
0
0
0
J4 ,3 = 9.0, J4 ,5 = 2.9, 2.1, H-40); 4.00 (dd, 1H, J3 ,4 = 9.0, J3 ,OH = 7.1,
J2 ,1 = 4.2, J2 ,3 = 2.5, H-2’); 5.89 (ddd, 1H, JH,F = 19.3, J3 ,4 = 4.9,
0
0
0
0
0
0
0
0
0
0
0
0
0
H-30); 5.12 (d, 1H, JOH,3 = 7.1, OH-30); 5.13 (s, 1H, OH-20); 5.16 (t,
J3 ,2 = 2.5, H-30); 6.90 (dd, 1H, JH,F = 17.7, J1 ,2 = 4.2, H-1’); 7.53 (m,
2H, H-m-Bz-50); 7.59 (m, 2H, H-m-Bz-30); 7.67 (m, 1H, H-p-Bz-
50); 7.73 (m, 1H, H-p-Bz-30); 8.00 (bs, 1H, H-6); 8.01 (m, 2H, H-o-
Bz-50); 8.09 (m, 2H, H-o-Bz-30); 8.72 (s, 1H, H-2). 13C NMR
(125.7 MHz, DMSO-d6): 54.59 (C-5); 63.82 (CH2-50); 76.43 (d,
JC,F = 28.6, CH-30); 78.34 (d, JC,F = 3.4, CH-40); 82.39 (d, JC,F = 16.6,
CH-10); 93.44 (d, JC,F = 192.1, CH-20); 116.61 (C-4a); 128.84 (C-i-
Bz-30); 129.03, 129.04 (CH-m-Bz-30,50); 129.42 (CH-o-Bz-50);
129.44 (C-i-Bz-50); 129.87 (CH-o-Bz-30); 133.80 (CH-p-Bz-50);
134.19 (CH-p-Bz-30); 134.64 (d, JC,F = 4.6, CH-6); 150.75 (C-7a);
151.29 (CH-2); 151.65 (C-4); 165.01 (CO-Bz-30); 165.70 (CO-Bz-
50). 19F NMR (470.3 MHz, DMSO-d6):-193.91. MS (ESI) m/z 622
[M+H], 644 [M+Na]. HRMS (ESI) for C25H19N3ClFIO5 [M+H] Calcd:
622.0036. Found: 622.00365.
0
0
0
0
0
1H, JOH,5 = 4.8, OH-50); 6.20 (s, 1H, H-10); 6.20 (bs, 2H, NH2); 7.24
0
(dd, 1H, J4,5 = 4.9, J4,2 = 1.4, H-4-thienyl); 7.49 (dd, 1H, J2,5 = 2.9,
J2,4 = 1.4, H-2-thienyl); 7.698 (dd, 1H, J5,4 = 4.9, J5,2 = 2.9, H-5-thie-
nyl); 7.70 (s, 1H, H-6); 8.14 (s, 1H, H-2). 13C NMR (151 MHz,
DMSO-d6): 20.01 (CH3); 59.67 (CH2-50); 72.04 (CH-30); 78.89 (C-
20); 82.41 (CH-40); 90.55 (CH-10); 100.44 (C-4a); 111.08 (C-5);
120.73 (CH-6); 122.11 (CH-2-thienyl); 127.66 (CH-5-thienyl);
128.72 (CH-4-thienyl); 135.16 (C-3-thienyl); 150.38 (C-7a);
151.96 (CH-2); 157.57 (C-4). IR (KBr): 3475, 3351, 3240, 3200,
3120, 3107, 1621, 1594, 1575, 1549, 1510, 1465, 1409, 1378,
1346, 1297, 1139, 1123, 1072, 1045, 861, 788. MS (ESI) m/z 363
[M+H], 385 [M+Na]. HRMS (ESI) for C16H19N4O4S [M+H] Calcd:
363.1122. Found: 363.1122. Anal. Calcd for C16H18N4O4Sꢀ1.1H2O:
C, 50.28; H, 5.33; N, 14.66. Found: C, 50.42; H, 5.20; N, 14.45.
3.13. 4-Amino-5-iodo-7-(2-deoxy-2-fluoro-b-D-
3.11. 4-Amino-5-(benzofuran-2-yl)-7-(2-C-methyl-b-
D
-
arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine (11)
ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine (7i)
A suspension of nucleoside 10 (3.31 g, 5.32 mmol) in aq ammo-
nia (25% w/w, 15 ml) and dioxane (15 ml) was stirred in a steel
bomb at 120 °C for 16 h. After cooling the volatiles were evapo-
rated and the residue was co-evaporated with silica and chromato-
graphed on the column of silica (4% MeOH in CHCl3) affording
7-iodo-7-deazaadenine nucleoside 11 as white crystalline solid
(1.77 g, 84%). Compound was recrystallized from H2O. Mp 214–
Compound 7i was prepared as described for 7a by the reaction
of compound 6 (100 mg, 0.25 mmol) and benzofuran-2-boronic
acid. Yield 64 mg (66%). White solid. Mp 248 °C (dec). ½a D20
ꢂ55.0
ꢁ
(c 0.220, MeOH). 1H NMR (500 MHz, DMSO-d6): 0.76 (s, 3H, CH3);
3.72 (ddd, 1H, Jgem = 12.5, J5 b,OH = 5.0, J5 b,4 = 2.9, H-50b); 3.88
0
0
0
(ddd, 1H, Jgem = 12.5, J5 a,OH = 5.0, J5 a,4 = 2.0, H-50a); 3.90 (ddd, 1H,
0
0
0
J4 ,3 = 9.2, J4 ,5 = 2.9, 2.0, H-40); 4.04 (dd, 1H, J3 ,4 = 9.2, J3 ,OH = 7.0,
216 °C. ½a D
ꢁ
+28 (c 0.429, DMSO). 1H NMR (499.8 MHz, DMSO-
0
0
0
0
0
0
0
H-30); 5.17 (d, 1H, JOH,3 = 7.0, OH-30); 5.19 (s, 1H, OH-20); 5.28 (t,
d6): 3.60 (dddd, 1H, Jgem = 11.9, J5 b,OH = 5.7, J5 b,4 = 5.1, JH,F = 0.9,
0
0
0
0
1H, JOH,5 = 5.0, OH-50); 6.23 (s, 1H, H-10); 6.98 (bs, 2H, NH2); 7.04
H-50b); 3.66 (dddd, 1H, Jgem = 11.9, J5 a,OH = 5.7, J5 a,4 = 4.1,
0
0
0
0
0
0
0
0
(d, 1H, J3,7 = 1.0, H-3-benzofuryl); 7.27 (td, 1H, J5,4 = J5,6 = 7.3,
J5,7 = 1.4, H-5-benzofuryl); 7.29 (td, 1H, J6,5 = J6,7 = 7.3, J6,4 = 1.7,
H-6-benzofuryl); 7.61–7.67 (m, 2H, H-4,7-benzofuryl); 8.19 (s,
1H, H-2); 8.26 (s, 1H, H-6). 13C NMR (125.7 MHz, DMSO-d6):
19.96 (CH3); 59.72 (CH2-50); 71.97 (CH-30); 78.91 (C-20); 82.59
(CH-40); 90.74 (CH-10); 99.19 (C-4a); 101.58 (CH-3-benzofuryl);
105.47 (C-5); 111.30 (CH-7-benzofuryl); 120.81 (CH-4-benzofu-
ryl); 122.32 (CH-6); 123.73 (CH-5-benzofuryl); 124.08 (CH-6-
benzofuryl); 129.01 (C-3a-benzofuryl); 150.94 (C-7a); 151.45
(C-2-benzofuryl); 152.58 (CH-2); 154.00 (C-7a-benzofuryl);
157.50 (C-4). MS (ESI, negative mode) m/z 395 (M-H). HRMS (ESI,
negative mode) for C20H19N4O5: [M-H] Calcd: 395.1350. Found:
JH,F = 1.5, H-50a); 3.79 (tdd, 1H, J4 ,5 = 5.1, 4.1, J4 ,3 = 5.1, JH,F = 0.8,
H-40); 4.35 (dtd, 1H, JH,F = 19.0, J3 ,4 = J3 ,OH = 5.1, J3 ,2 = 3.8, H-30);
0
0
0
0
0
5.08 (t, 1H, JOH,5 = 5.7, OH-50); 5.10 (ddd, 1H, JH,F = 52.7, J2 ,1 = 4.5,
0
0
0
J2 ,3 = 3.8, H-20); 5.90 (d, 1H, JOH,3 = 5.1, OH-30); 6.53 (dd, 1H,
0
0
0
JH,F = 14.9, J1 ,2 = 4.5, H-10); 6.71 (bs, 2H, NH2); 7.53 (d, 1H,
JH,F = 2.1, H-6); 8.12 (s, 1H, H-2). 13C NMR (125.7 MHz, DMSO-
d6): 52.24 (C-5); 60.48 (CH2-50); 72.78 (d, JC,F = 23.3, CH-30); 81.25
(d, JC,F = 16.9, CH-10); 83.19 (d, JC,F = 5.4, CH-40); 95.89 (d,
JC,F = 191.7, CH-20); 102.91 (C-4a); 127.88 (d, JC,F = 3.5, CH-6);
149.96 (C-7a); 152.36 (CH-2); 157.38 (C-4). 19F NMR (470.3 MHz,
DMSO-d6): ꢂ194.45. MS (ESI) m/z 395 [M+H], 417 [M+Na]. HRMS
(ESI) for C11H13N4FIO3 [M+H] Calcd: 395.0011. Found: 395.0010.
Calcd for C11H12N4FIO3ꢀH2O: C, 32.06; H, 3.42; N, 13.59. Found: C,
32.40; H, 3.23; N, 13.21.
0
0
1
395.1358. Anal. Calcd for C20H20N4O5ꢀ 3H2O: C, 59.70; H, 5.18; N,
13.92. Found: C, 59.98; H, 5.13; N, 13.46.
3.12. 4-Chloro-5-iodo-7-(2-deoxy-2-fluoro-3,5-di-O-benzoyl-b-
3.14. 4-Amino-7-(2-deoxy-2-fluoro-b-D-arabinofuranosyl)-5-
D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine (10)
phenyl-7H-pyrrolo[2,3-d]pyrimidine (12a)
A mixture of powdered KOH (875 mg, 85%, 13.28 mmol), TDA-1
An argon purged mixture of compound 11 (276 mg, 0.70 mmol),
phenylboronic acid (127 mg, 1.04 mmol), Na2CO3 (221 mg,
2.08 mmol), TPPTS (49 mg, 0.086 mmol) and Pd(OAc)2 (8 mg,
0.035 mmol) in H2O/MeCN (2:1, 5 ml) was stirred at 80 °C for
3 h. After cooling, the mixture was co-evaporated with silica and
column chromatography on silica (3% MeOH in CHCl3) afforded
product 12a as colorless foam (207 mg, 86%). Crystallization from
H2O (little MeOH) gave long colorless needles. Mp 118–120 °C.
(0.13 ml, 0.4 mmol) in dry MeCN (50 ml) was stirred at rt for
10 min before 6-chloro-7-iodo-7-deazapurine (1.75 g,
6.26 mmol) was added. Stirring was continued for 15 min and then
2-deoxy-2-fluoro-3,5-di-O-benzoyl-b- -arabinofuranosyl bromide
3
D
915 (3.17 g, 7.5 mmol, prepared from 8) in MeCN (50 ml) was
added at once. The mixture was vigorously stirred at rt for
45 min (during that time highly insoluble product precipitated
out). The mixture was quenched with aq NH4Cl (sat, 200 ml) and
extracted with dichloromethane (200 ml, then 2 ꢃ 50 ml). Com-
bined organics were dried over MgSO4 and volatiles removed in va-
cuo. Resulting solid was crystallized from chloroform/2-propanol
affording nucleoside 10 as beige powder (3.32 g, 85%). Alterna-
tively the crude product can be purified by column chromatogra-
phy on silica (hexanes/AcOEt, 6:1). Product 10 crystallizes from
½
a D
+26.8 (c 0.574, DMSO). 1H NMR (499.8 MHz, DMSO-d6): 3.62
ꢁ
(ddd, 1H, Jgem = 11.8, J5 b,OH = 5.8, J5 b,4 = 5.4, H-50b); 3.67 (dddd,
0
0
0
1H, Jgem = 11.8, J5 a,OH = 5.8, J5 a,4 = 4.4, JH,F = 1.4, H-50a); 3.79 (m,
0
0
0
1H, J4 ,5 = 5.4, 4.4, J4 ,3 = 5.0, JH,F = 0.8, H-40); 4.40 (dtd, 1H,
0
0
0
0
JH,F = 19.0, J3 ,4 = J3 ,OH = 5.0, J3 ,2 = 3.7, H-30); 5.06 (t, 1H, JOH,5 = 5.8,
0
0
0
0
0
0
OH-5’); 5.16 (ddd, 1H, JH,F = 52.8, J2 ,1 = 4.5, J2 ,3 = 3.7, H-20); 5.90 (t,
0
0
0
0
1H, JOH,3 = 5.0, OH-30); 6.16 (bs, 2H, NH2); 6.64 (dd, 1H, JH,F = 15.4,
0

P. Nauš et al. / Bioorg. Med. Chem. 20 (2012) 5202–5214
5209
J1 ,2 = 4.5, H-10); 7.38 (m, 1H, H-p-Ph); 7.42 (d, 1H, JH,F = 2.2, H-6);
7.48 (m, 4H, H-o,m-Ph); 8.18 (s, 1H, H-2). 13C NMR (125.7 MHz,
DMSO-d6): 60.60 (CH2-50); 72.97 (d, JC,F = 23.3, CH-30); 81.15 (d,
JC,F = 16.8, CH-10); 83.17 (d, JC,F = 5.2, CH-40); 96.02 (d, JC,F = 191.7,
CH-20); 100.06 (C-4a); 116.60 (C-5); 121.81 (d, JC,F = 3.4, CH-6);
127.16 (CH-p-Ph); 128.59 (CH-o-Ph); 129.21 (CH-m-Ph); 134.49
(C-i-Ph); 150.82 (C-7a); 152.12 (CH-2); 157.46 (C-4). 19F NMR
(470.3 MHz, DMSO-d6): -197.87. MS (ESI) m/z 345 [M+H], 367
[M+Na]. HRMS (ESI) for C17H18N4FO3 [M+H] Calcd: 345.1357.
Found: 345.1357. Calcd for C17H17N4FO3ꢀH2O: C, 56.35; H, 5.29;
N, 15.46. Found: C, 56.05; H, 5.14; N, 15.22.
DMSO-d6): 60.46 (CH2-50); 72.80 (d, JC,F = 23.3, CH-30); 81.17 (d,
JC,F = 16.7, CH-10); 83.17 (d, JC,F = 5.4, CH-40); 96.02 (d, JC,F = 191.8,
CH-20); 100.22 (C-4a); 108.84 (C-5); 122.65 (d, JC,F = 3.4, CH-6);
126.09 (CH-5-thienyl); 126.64 (CH-3-thienyl); 128.57 (CH-4-thie-
nyl); 135.54 (C-2-thienyl); 150.57 (C-7a); 152.49 (CH-2); 157.47
(C-4). 19F NMR (470.3 MHz, DMSO-d6): -194.41. MS (ESI) m/z 351
[M+H], 373 [M+Na]. HRMS (ESI) for C15H16N4FO3S [M+H] Calcd:
0
0
351.0922.
Found:
351.0922.
Calcd
for
C
15H15N4FO3Sꢀ0.5H2Oꢀ0.15CH4O: C, 49.97; H, 4.59; N, 15.38.
Found: C, 50.08; H, 4.38; N, 15.16.
3.17. 4-Amino-7-(2-deoxy-2-fluoro-b-
D
-arabinofuranosyl)-5-
(furan-3-yl)-7H-pyrrolo[2,3-d]pyrimidine (12g)
3.15. 4-Amino-7-(2-deoxy-2-fluoro-b-D-arabinofuranosyl)-5-
(furan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine (12e)
Compound 12g was prepared as described for 12a from comp-
und 11 (197 mg, 0.5 mmol) and furan-3-boronic acid. Yield 149 mg
(89%). Compound crystallized from H2O/MeOH as beige needles of
An argon purged mixture of iodide 11 (197 mg, 0.5 mmol), 2-
(tributylstannyl)furan (232 mg, 0.65 mmol) and PdCl2(PPh3)2
(18 mg, 0.025 mmol) in DMF (2 ml) was stirred at 100 °C for 2 h.
After cooling volatiles were removed in vacuo and the residue
was several times co-evaporated with toluene and finally with sil-
ica. Column chromatography on silica (0?4% MeOH in CHCl3)
afforded product 12e as a solid foam (125 mg, 75%). Compound
crystallized from MeOH/H2O as beige microcrystalline needles.
trihydrate. Mp >102 °C (slow melting due to dehydration). ½a D
ꢁ
+27.1 (c 0.591, DMSO). 1H NMR (500.0 MHz, DMSO-d6): 3.61
(ddd, 1H, Jgem = 11.9, J5 b,OH = 5.8, J5 b,4 = 5.0, H-50b); 3.67 (dddd,
0
0
0
1H, Jgem = 11.9, J5 a,OH = 5.8, J5 a,4 = 4.4, JH,F = 1.5, H-50a); 3.80 (ddd,
0
0
0
1H, J4 ,3 = 5.2, J4 ,5 = 5.0, 4.4, H-40); 4.38 (dddd, 1H, JH,F = 19.0,
0
0
0
0
J3 ,4 = 5.2, J3 ,OH = 5.0, J3 ,2 = 3.6, H-30); 5.09 (t, 1H, JOH,5 = 5.8, OH-
0
0
0
0
0
0
50); 5.13 (ddd, 1H, JH,F = 52.8, J2 ,1 = 4.5, J2 ,3 = 3.6, H-20); 5.93 (d,
0
0
0
0
Mp 209–211 °C. ½a D
ꢁ
+39.1 (c 0.417, DMSO). 1H NMR (499.8 MHz,
1H, JOH,3 = 5.0, OH-30); 6.32 (bs, 2H, NH2); 6.60 (dd, 1H,
0
0
0
0
DMSO-d6): 3.65 (dddd, 1H, Jgem = 11.9, J5 b,OH = 5.8, J5 b,4 = 5.3,
JH,F = 15.6, J1 ,2 = 4.5, H-10); 6.70 (dd, 1H, J4,5 = 1.8, J4,2 = 1.0, H-4-
furyl); 7.38 (d, 1H, JH,F = 2.2, H-6); 7.81 (dd, 1H, J5,4 = 1.8,
J5,2 = 1.5, H-5-furyl); 7.84 (dd, 1H, J2,5 = 1.5, J2,4 = 1.0, H-2-furyl);
8.15 (s, 1H, H-2). 13C NMR (125.7 MHz, DMSO-d6): 60.70 (CH2-
50); 73.07 (d, JC,F = 23.3, CH-30); 81.17 (d, JC,F = 16.8, CH-10); 83.20
(d, JC,F = 5.1, CH-40); 96.05 (d, JC,F = 191.6, CH-20); 100.63 (C-4a);
106.64 (C-5); 111.72 (d, JC,F = 6, CH-4-furyl); 118.63 (C-3-furyl);
121.67 (d, JC,F = 3.5, CH-6); 139.97 (CH-2-furyl); 144.47 (CH-5-fur-
yl); 150.72 (C-7a); 152.25 (CH-2); 157.67 (C-4). 19F NMR
(470.3 MHz, DMSO-d6): -194.23. MS (ESI) m/z 335 [M+H], 357
[M+Na]. HRMS (ESI) for C15H16N4FO4 [M+H] Calcd: 335.1150.
Found: 335.1150. Calcd for C15H15N4FO4ꢀ3H2O: C, 46.39; H, 5.45;
N, 14.43. Found: C, 46.66; H, 5.43; N, 14.22.
0
0
JH,F = 0.7, H-50b); 3.70 (dddd, 1H, Jgem = 11.9, J5 a,OH = 5.8, J5 a,4
=
0
0
0
4.3, JH,F = 1.5, H-50a); 3.83 (dddd, 1H, J4 ,5 = 5.3, 4.3, J4 ,3 = 5.0, JH,F
0
0
0
0
= 0.8, H-40); 4.39 (dtd, 1H, JH,F = 19.1, J3 ,OH = J3 ,4 = 5.0, J3 ,2 = 3.7,
0
0
0
0
0
H-30); 5.11 (t, 1H, JOH,5 = 5.8, OH-50); 5.15 (ddd, 1H, JH,F = 52.8,
0
J2 ,1 = 4.5, J2 ,3 = 3.7, H-20); 5.92 (d, 1H, JOH,3 = 5.0, OH-30); 6.61
0
0
0
0
0
(dd, 1H, JH,F = 15.3, J1 ,2 = 4.5, H-10); 6.61 (dd, 1H, J4,3 = 3.3,
J4,5 = 1.8, H-4-furyl); 6.70 (dd, 1H, J3,4 = 3.3, J3,5 = 0.8, H-3-furyl);
6.93 (bs, 2H, NH2); 7.71 (d, 1H, JH,F = 2.1, H-6); 7.78 (dd, 1H,
J5,4 = 1.8, J5,3 = 0.8, H-5-furyl); 8.16 (s, 1H, H-2). 13C NMR
(125.7 MHz, DMSO-d6): 60.68 (CH2-50); 73.03 (d, JC,F = 23.4, CH-
30); 81.34 (d, JC,F = 16.9, CH-10); 83.32 (d, JC,F = 5.0, CH-40); 95.96
(d, JC,F = 191.8, CH-20); 98.96 (C-4a); 105.58 (CH-3-furyl); 106.52
(C-5); 112.14 (CH-4-furyl); 121.15 (d, JC,F = 3.2, CH-6); 142.27
(CH-5-furyl); 148.62 (C-2-furyl); 150.77 (C-7a); 152.54 (CH-2);
157.46 (C-4). 19F NMR (470.3 MHz, DMSO-d6): -194.40. MS (ESI)
m/z 335 [M+H], 357 [M+Na]. HRMS (ESI) for C15H16N4FO4 [M+H]
Calcd: 335.1150. Found: 335.1150. Calcd for C15H15N4FO4ꢀ0.1H2O:
C, 53.6; H, 4.56; N, 16.67. Found: C, 53.44; H, 4.40; N, 16.52.
0
0
3.18. 4-Amino-7-(2-deoxy-2-fluoro-b-D-arabinofuranosyl)-5-
(thiophen-3-yl)-7H-pyrrolo[2,3-d]pyrimidine (12h)
Compound 12h was prepared as described for 12a from comp-
und 11 (276 mg, 0.7 mmol) and thiophene-3-boronic acid. Yield
222 mg (90%). Compound crystallized from H2O/MeOH as off-
white needles. Mp 105–107 °C. ½a D
ꢁ
+16.6 (c 0.525, DMSO). 1H
NMR (499.8 MHz, DMSO-d6): 3.62 (dt, 1H, Jgem = 12.1,
3.16. 4-Amino-7-(2-deoxy-2-fluoro-b-D-arabinofuranosyl)-5-
(thiophen-2-yl)-7H-pyrrolo[2,3-d]pyrimidine (12f)
J5 b,OH = J5 b,4 = 5.7, H-50b); 3.68 (dddd, 1H, Jgem = 12.1, J5 a,OH = 5.7,
0
0
0
0
J5 a,4 = 4.3, JH,F = 1.4, H-50a); 3.82 (m, 1H, J4 ,5 = 5.7, 4.3, J4 ,3 = 5.2,
An argon purged mixture of iodide 11 (197 mg, 0.5 mmol), 2-
(tributylstannyl)thiophene (242 mg, 0.65 mmol) and PdCl2(PPh3)2
(18 mg, 0.025 mmol) in DMF (2 ml) was stirred at 100 °C for 2 h.
After cooling volatiles were removed in vacuo and the residue
was several times co-evaporated with toluene and finally with sil-
ica. Column chromatography on silica (0?4% MeOH in CHCl3)
afforded product 12f as beige solid (144 mg, 82%). Mp 99–101 °C.
0
0
0
0
0
0
JH,F = 0.5, H-40); 4.40 (dddd, 1H, JH,F = 19.0, J3 ,4 = 5.2, J3 ,OH = 5.0,
0
0
0
J3 ,2 = 3.8, H-30); 5.09 (t, 1H, JOH,5 = 5.7, OH-50); 5.15 (ddd, 1H,
0
0
0
JH,F = 52.8, J2 ,1 = 4.5, J2 ,3 = 3.8, H-20); 5.93 (d, 1H, JOH,3 = 5.0, OH-
0
0
0
0
0
30); 6.25 (bs, 2H, NH2); 6.63 (dd, 1H, JH,F = 15.4, J1 ,2 = 4.5, H-10);
7.27 (dd, 1H, J4,5 = 4.9, J4,2 = 1.3, H-4-thienyl); 7.43 (d, 1H,
JH,F = 2.2, H-6); 7.53 (dd, 1H, J2,5 = 2.9, J2,4 = 1.3, H-2-thienyl); 7.71
(dd, 1H, J5,4 = 4.9, J5,2 = 2.9, H-5-thienyl); 8.17 (s, 1H, H-2). 13C
NMR (125.7 MHz, DMSO-d6): 60.67 (CH2-50); 73.03 (d, JC,F = 23.3,
CH-30); 81.19 (d, JC,F = 16.7, CH-10); 83.20 (d, JC,F = 5.2, CH-40);
96.06 (d, JC,F = 191.6, CH-20); 100.44 (C-4a); 111.35 (C-5); 121.78
(d, JC,F = 3.5, CH-6); 122.37 (CH-2-thienyl); 127.69 (CH-5-thienyl);
128.65 (CH-4-thienyl); 134.76 (C-3-thienyl); 150.59 (C-7a);
152.23 (CH-2); 157.60 (C-4). 19F NMR (470.3 MHz, DMSO-d6): -
194.25. MS (ESI) m/z 351 [M+H], 373 [M+Na]. HRMS (ESI) for
0
0
½
a D
+35.4 (c 0.475, DMSO). 1H NMR (499.8 MHz, DMSO-d6): 3.61
ꢁ
(dddd, 1H, Jgem = 12.1, J5 b,OH = 5.7, J5 b,4 = 5.0, JH,F = 0.6, H-50b);
0
0
0
0
0
0
3.67 (dddd, 1H, Jgem = 12.1, J5 a,OH = 5.7, J5 a,4 = 4.0, JH,F = 1.3, H-
50a); 3.81 (m, 1H, J4 ,3 = 5.4, J4 ,5 = 5.0, 4.0, JH,F = 0.9, H-40); 4.39
0
0
0
0
(dddd, 1H, JH,F = 19.2, J3 ,4 = 5.4, J3 ,OH = 5.0, J3 ,2 = 3.8, H-30); 5.12
0
0
0
0
0
(t, 1H, JOH,5 = 5.7, OH-50); 5.17 (ddd, 1H, JH,F = 52.8, J2 ,1 = 4.6,
0
0
0
J2 ,3 = 3.8, H-20); 5.93 (d, 1H, JOH,3 = 5.0, OH-30); 6.39 (bs, 2H,
0
0
0
NH2); 6.61 (dd, 1H, JH,F = 14.9, J1 ,2 = 4.6, H-10); 7.16 (dd, 1H,
J3,4 = 3.4, J3,5 = 1.2, H-3-thienyl); 7.18 (dd, 1H, J4,5 = 5.1, J4,3 = 3.4,
H-4-thienyl); 7.49 (d, 1H, JH,F = 2.1, H-6); 7.57 (dd, 1H, J5,4 = 5.1,
J5,3 = 1.2, H-5-thienyl); 8.18 (s, 1H, H-2). 13C NMR (125.7 MHz,
0
0
C15H16N4FO3S [M+H] Calcd: 351.0922. Found: 351.0922. Calcd for
C
15H15N4FO3Sꢀ3.35H2Oꢀ0.1CH4O: C, 43.82; H, 5.38; N, 13.54.
Found: C, 44.14; H, 5.03; N, 13.21.

5210
P. Nauš et al. / Bioorg. Med. Chem. 20 (2012) 5202–5214
3.19. 4-Amino-7-(2-deoxy-2-fluoro-b-
(1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine (12j)
D
-arabinofuranosyl)-5-
12k as white crystalline solid (219 mg, 97%). Compound was
recrystallized from MeOH. Mp 220–222 °C. ½a D +41.6 (c 0.370,
DMSO). 1H NMR (499.8 MHz, DMSO-d6): 3.62 (dddd, 1H,
ꢁ
An argon purged mixture of iodide 11 (276 mg, 0.7 mmol),
1-dimethylsulfamoyl-4-tributylstannylpyrazole16 (488 mg, 1.05
mmol), PdCl2(PPh3)2 (25 mg, 0.035 mmol) in DMF (3 ml) was stir-
red at 100 °C for 3 h. Volatiles were removed under reduced pres-
sure, the residue was several times co-evaporated with toluene/
MeOH and finally with silica. Column chromatography on silica
(0?8% MeOH in CHCl3) afforded product protected on pyrazole
nitrogen by dimethylsulfamoyl group. This material was directly
deprotected by the addition of aq HCl (1 M, 17 ml) and stirring at
100 °C for 6 h. Volatiles were removed in vacuo, and the residue
was co-evaporated with H2O/MeOH (5ꢃ), once with aq ammonia
(25% w/w), then with H2O (3ꢃ) and finally with silica. Column
chromatography on silica (10% MeOH, 2% aq ammonia in CHCl3)
afforded product 12j as solid foam (187 mg, 80%). Compound crys-
Jgem = 12.1, J5 b,OH = 5.6, J5 b,4 = 5.2, JH,F = 0.7, H-50b); 3.68 (dddd,
0
0
0
1H, Jgem = 12.1, J5 a,OH = 5.6, J5 a,4 = 4.0, JH,F = 1.6, H-50a); 3.81 (dddd,
0
0
0
1H, J4 ,3 = 5.4, J4 ,5 = 5.2, 4.0, JH,F = 0.7, H-40); 4.28 (s, 1H, HC„C);
0
0
0
0
4.37 (dddd, 1H, JH,F = 19.0, J3 ,4 = 5.4, J3 ,OH = 5.0, J3 ,2 = 4.0, H-30);
0
0
0
0
0
5.11 (t, 1H, JOH,5 = 5.6, OH-50); 5.14 (ddd, 1H, JH,F = 52.8, J2 ,1 = 4.7,
0
0
0
0
J2 ,3 = 4.0, H-20); 5.91 (d, 1H, JOH;3 = 5.0, OH-30); 6.54 (dd, 1H,
0
0
JH,F = 14.0, J1 ,2 = 4.7, H-10); 6.71 (bs, 2H, NH2); 7.69 (d, 1H,
JH,F = 1.9, H-6); 8.15 (s, 1H, H-2). 13C NMR (125.7 MHz, DMSO-
d6): 60.42 (CH2-50); 72.65 (d, JC,F = 23.2, CH-30); 77.30 (C„CH);
81.34 (d, JC,F = 16.8, CH-10); 83.23 (d, JC,F = 5.4, CH-40); 83.36
(HC„C); 94.34 (C-5); 95.81 (d, JC,F = 192.2, CH-20); 101.99 (C-4a);
128.11 (d, JC,F = 2.9, CH-6); 149.44 (C-7a); 153.23 (CH-2); 157.69
(C-4). 19F NMR (470.3 MHz, DMSO-d6):-194.82. MS (ESI) m/z 293
[M+H], 315 [M+Na]. HRMS (ESI) for C13H14N4FO3 [M+H] Calcd:
293.10445. Found: 293.10458. Calcd for C13H13N4FO3: C, 53.42;
H, 4.48; N, 19.17. Found: C, 53.16; H, 4.42; N, 18.83.
0
0
tallized from H2O/MeOH as white needles. Mp 157–159 °C. ½a D
ꢁ
+31.8 (c 0.535, DMSO). 1H NMR (499.8 MHz, DMSO-d6): 3.61
(dddd, 1H, Jgem = 11.8, J5 b,OH = 5.8, J5 b,4 = 5.3, JH,F = 0.9, H-50b);
0
0
0
0
0
0
3.66 (dddd, 1H, Jgem = 11.8, J5 a,OH = 5.8, J5 a,4 = 4.3, JH,F = 1.5, H-
3.22. 4-Amino-7-(2-deoxy-2-fluoro-b-D-arabinofuranosyl)-5-
(1H-1,2,3-triazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine (12l)
50a); 3.79 (td, 1H, J4 ,5 = 5.3, 4.3, J4 ,3 = 5.3, H-40); 4.37 (dddd, 1H,
0
0
0
0
JH,F = 19.0, J3 ,4 = 5.3, J3 ,OH = 5.0, J3 ,2 = 3.6, H-30); 5.05 (t, 1H,
0
0
0
0
0
JOH,5 = 5.8, OH-50); 5.12 (ddd, 1H, JH,F = 52.8, J2 ,1 = 4.5, J2 ,3 = 3.6,
An argon purged mixture of ethynyl compound 12k (178 mg,
0.609 mmol), CuI (6 mg, 0.031 mmol) and TMSN3 (240
0
0
0
0
0
H-20); 5.89 (d, 1H, JO0 H;3 = 5.0, OH-30); 6.18 (bs, 2H, NH2); 6.60 (dd,
ll,
1H, JH,F = 16.0, J1 ,2 = 4.5, H-10); 7.28 (d, 1H, JH,F = 2.4, H-6); 7.62
and 7.90 (2 ꢃ bs, 2 ꢃ 1H, H-3,5-pyrazole); 8.13 (s, 1H, H-2);
13.04 (bs, 1H, NH-pyrazole). 13C NMR (125.7 MHz, DMSO-d6):
60.74 (CH2-50); 73.13 (d, JC,F = 23.3, CH-30); 81.11 (d, JC,F = 16.8,
CH-10); 83.17 (d, JC,F = 5.1, CH-40); 96.07 (d, JC,F = 191.5, CH-20);
100.91 (C-4a); 107.16 (C-5); 113.40 (C-4-pyrazole); 121.24 (d,
JC,F = 3.6, CH-6); 127.31 and 138.42 (CH-3,5-pyrazole); 150.47 (C-
7a); 152.05 (CH-2); 157.73 (C-4). 19F NMR (470.3 MHz, DMSO-
d6): -194.17. MS (ESI) m/z 335 [M+H], 357 [M+Na]. HRMS (ESI)
for C14H16N6FO3 [M+H] Calcd: 335.12624. Found: 335.12625. Calcd
for C14H15N6FO3ꢀ1.2H2O: C, 47.24; H, 4.93; N, 23.61. Found: C,
47.43; H, 4.71; N, 23.36.
1.83 mmol) in MeOH (130 l)/DMF (1 ml) was stirred at 100 °C
l
0
0
for 24 h. Volatiles were evaporated under reduced pressure, the
residue was twice co-evaporated with MeOH, suspended in MeOH
and filtered through celite. Filtrate was co-evaporated with silica
and column chromatography on silica (10% MeOH in CHCl3) affor-
ded triazolyl derivative 12l as yellowish solid (56 mg, 27%). Com-
pound was recrystallized from MeOH as white solid. Mp 288–
290 °C. ½a D
ꢁ
+42.5 (c 0.386, DMSO). 1H NMR (499.8 MHz, DMSO-
d6+DCl): 3.67 (ddd, 1H, Jgem = 12.1, J5 b,4 = 5.5, JH,F = 1.0, H-50b);
0
0
3.71 (ddd, 1H, Jgem = 12.1, J5 a,4 = 4.4, JH,F = 1.4, H-50a); 3.90 (dddd,
0
0
1H, J4 ,5 = 5.5, 4.4, J4 ,3 = 5.3, JH,F = 0.8, H-40); 4.40 (ddd, 1H,
0
0
0
0
JH,F = 18.7, J3 ,4 = 5.3, J3 ,2 = 3.8, H-30); 5.22 (ddd, 1H, JH,F = 52.5,
0
0
0
0
J2 ,1 = 4.5, J2 ,3 = 3.8, H-20); 6.62 (dd, 1H, JH,F = 14.4, J1 ,2 = 4.5, H-
10); 8.26 (d, 1H, JH,F = 1.8, H-6); 8.50 (s, 1H, H-2); 8.65 (s, 1H, H-tri-
azole). 13C NMR (125.7 MHz, DMSO-d6+DCl): 60.80 (CH2-50); 73.00
(d, JC,F = 23.2, CH-30); 82.26 (d, JC,F = 16.9, CH-10); 84.10 (d, JC,F = 5.0,
CH-40); 95.78 (d, JC,F = 192.8, CH-20); 99.24 (C-4a); 108.96 (C-5);
124.05 (CH-6); 124.80 (CH-triazole); 139.76 (C-triazole); 143.80
(CH-2); 147.57 (C-7a); 151.84 (C-4). MS (ESI) m/z 336 [M+H],
0
0
0
0
0
0
3.20. 4-Amino-7-(2-deoxy-2-fluoro-b-D-arabinofuranosyl)-5-
[(trimethylsilyl)ethynyl]-7H-pyrrolo[2,3-d]pyrimidine (13)
An argon purged mixture of iodide 11 (394 mg, 1 mmol),
PdCl2(PPh3)2 (35 mg, 0.05 mmol), CuI (19 mg, 0.1 mmol), trimeth-
ylsilylacetylene (1.4 ml, 10 mmol) and triethylamine (1 ml) was
stirred in DMF (4 ml) at rt for 16 h. Volatiles were removed in va-
cuo and the rest was twice co-evaporated with EtOH and loaded on
silica by co-evaporation from EtOH. Column chromatography on
silica (0?3% MeOH in CHCl3) afforded white solid, which after
recrystallization from chloroform gave product 13 (297 mg, 82%).
Mp 211–213 °C. 1H NMR (400.1 MHz, DMSO-d6): 0.24 (s, 9H,
CH3-TMS); 3.57–3.72 (m, 2H, H-50b & H-50a); 3.80 (tdd, 1H,
358 [M+Na]. HRMS (ESI) for
C13H15N7FO3 [M+H] Calcd:
336.12149. Found: 336.12145. Calcd for C13H14N7FO3ꢀ0.4H2O: C,
45.59; H, 4.36; N, 28.63. Found: C, 45.92; H, 4.10; N, 28.36.
3.23. 4-Amino-5-iodo-7-[3,5-O-(tetraisopropyldisiloxan-1,3-
diyl)-b-D-ribofuranosyl]-7H-pyrrolo[2,3-d]pyrimidine (15)
J4 ,5 = 5.1, 4.1, J4 ,3 = 5.0, JH,F = 0.8, H-40); 4.37 (dtd, 1H, JH,F = 19.0,
7-Iodotubercidin (14) (4.00 g, 10.2 mmol) was co-evaporated
twice with anhydrous pyridine (20 ml) and dissolved in anhydrous
pyridine (80 ml). TIPDSCl2 (10.2 mmol, 3.26 ml) was added to the
solution and the reaction mixture was stirred for 4 h at rt Then,
volatiles were removed in vacuo, the residue was dissolved in
EtOAc (100 ml) and extracted with water (60 ml). The organic
phase was dried over MgSO4 and evaporated under reduced pres-
sure. The crude product was purified by column chromatography
on silica (hexane-EtOAc 1:1) to afford silylated product 15
(5.98 g, 92%). 1H NMR (500 MHz, CDCl3): 0.97–1.18 (m, 28H,
0
0
0
0
J3 ,4 = J3 ,OH = 5.0, J3 ,2 = 4.8, H-30); 5.10 (t, 1H, JOH,5 = 5.7, OH-50);
0
0
0
0
0
0
5.13 (ddd, 1H, JH,F = 52.7, J2 ,1 = 4.7, J2 ,3 = 4.8, H-20); 5.92 (d, 1H,
0
0
0
0
JOH,3 = 5.0, OH-30); 6.53 (dd, 1H, JH,F = 13.8, J1 ,2 = 4.7, H-10); 6.71
(bs, 2H, NH2); 7.71 (d, 1H, JH,F = 1.8, H-6); 8.15 (s, 1H, H-2). MS
(ESI) m/z 365 [M+H], 387 [M+Na]. HRMS (ESI) for C16H22N4FO3Si
[M+H] Calcd: 365.1440. Found: 365.1440.
0
0
0
3.21. 4-Amino-7-(2-deoxy-2-fluoro-b-D-arabinofuranosyl)-5-
ethynyl-7H-pyrrolo[2,3-d]pyrimidine (12k)
((CH3)2CH); 4.03 (dd, 1H, Jgem = 12.4 Hz, J5 a,4 = 3.0 Hz, H-50a);
0
0
4.09 (bddd, 1H, J4 ,3 = 8.0 Hz, J4 ,5 b = 3.8 Hz, J4 ,5 a = 3.0 Hz, H-40);
0
0
0
0
0
0
A mixture of the TMS compound 13 (282 mg, 0.77 mmol) and
K2CO3 (107 mg, 0.77 mmol) in MeOH (10 ml) was stirred at rt for
1 h, followed by the co-evaporation with silica. Column chroma-
tography on silica (4% MeOH in CHCl3) provided title compound
4.14 (dd, 1H, Jgem = 12.4 Hz, J5 b,4 = 3.8 Hz, H-50b); 4.37 (dd, 1H,
0
0
J2 ,3 = 5.4 Hz, J2 ,1 = 1.6 Hz, H-20); 4.80 (dd, 1H, J3 ,4 = 7.9 Hz,
0
0
0
0
0
0
J3 ,2 = 5.4 Hz, H-30); 5.78 (bs, 2H, NH2); 6.09 (d, 1H, J1 ,2 = 1.6 Hz,
0
0
0
0

P. Nauš et al. / Bioorg. Med. Chem. 20 (2012) 5202–5214
5211
H-10); 7.31 (s, 1H, H-6); 8.24 (s, 1H, H-2). 13C NMR (125.7 MHz,
CDCl3): 12.59, 12.80, 13.04 and 13.35 ((CH3)2CH); 16.89, 16.95,
17.00, 17.08, 17.29, 17.43, 17.45 and 17.53 ((CH3)2CH); 50.25 (C-
5); 61.41 (CH2-50); 70.23 (CH-30); 75.34 (CH-20); 81.81 (CH-40);
89.63 (CH-10); 104.74 (C-4a); 126.97 (CH-6); 149.48 (C-7a);
152.00 (CH-2); 156.74 (C-4). MS (ESI) m/z (%): 635 (100) [M+H],
657 (85) [M+Na]; HRMS (ESI) Calcd for C23H40O5N4ISi2 [M+H]:
635.15764. Found: 635.15753.
(btd, 1H, J4 ,5 a = J4 ,3 = 4.8 Hz, J4 ,5 b = 4.1 Hz, H-40); 4.02–4.09 (m,
0
0
0
0
0
0
2H, H-20,30); 5.07 (m, 1H, OH-50); 5.45 (bd, 1H, JOH,3 = 3.6 Hz, OH-
0
30); 5.47 (d, 1H, JOH,2 = 5.3 Hz, OH-20); 6.40 (d, 1H, J1 ,2 = 4.5 Hz,
H-10); 6.61 (bs, 2H, NH2); 7.51 (s, 1H, H-6); 8.09 (s, 1H, H-2). 13C
NMR (125.7 MHz, DMSO-d6): 50.63 (C-5); 61.05 (CH2-50); 75.26
(CH-30); 76.04 (CH-20); 83.46 (CH-10); 83.88 (CH-40); 102.87 (C-
4a); 128.98 (CH-6); 150.04 (C-7a); 151.92 (CH-2); 157.20 (C-4).
MS (ESI) m/z (%): 393 (90) [M+H], 415 (100) [M+Na]; HRMS (ESI)
Calcd for C11H14O4N4I [M+H]: 393.00542. Found: 393.00547.
0
0
0
3.24. 4-Amino-5-iodo-7-[3,5-O-(tetraisopropyldisiloxan-1,3-
diyl)-b-
D
-erythro-pentofuran-2-ulosyl] -7H-pyrrolo[2,3-
3.27. 4-Amino-5-phenyl-7-(b-D-arabinofuranosyl)-7H-
d]pyrimidine (16)
pyrrolo[2,3-d]pyrimidine (19a)
Mixture of chromium (VI) oxide (2.36 g, 23.6 mmol), pyridine
(3.79 ml, 47.1 mmol) and acetic anhydride (2.22 ml, 23.6 mmol)
in anhydrous dichloromethane (60 ml) was cooled to 0 °C and stir-
red for 30 min until chromium oxide was completely dissolved.
Then solution of compound 15 (5.98 g, 9.42 mmol) in dichloro-
methane (60 ml) was slowly added. The reaction mixture was stir-
red at 0 °C for 1.5 h. Then ice-cold EtOAc (235 ml) was added. The
precipitate was filtered off through a pad of silica (46 g). The fil-
trate was evaporated under reduced pressure. The residue was
purified by column chromatography on silica (hexane-EtOAc 3:2).
Ketone 16 (3.51 g, 59%) was obtained as yellow foam. 1H NMR
(400.0 MHz, CDCl3): 1.06–1.17 (m, 28H, (CH3)2CHSi); 3.99 (dt,
An argon purged mixture of compound 18 (150 mg, 0.38 mmol),
phenylboronic acid (58 mg, 0.48 mmol), Na2CO3 (122 mg,
1.14 mmol), Pd(OAc)2 (4.3 mg, 19 lmol) and TPPTS (33 mg,
0.057 mmol) in water–MeCN (2:1, 2.5 ml) was stirred at 100 °C
for 3 h. After cooling, the mixture was neutralized by the addition
of aq HCl (1 M), volatiles were removed in vacuo. The residue was
purified twice by reverse phase HPFC on C-18 column (0?100%
MeOH in water). Compound 19a (96 mg, 73%) was obtained as a
white crystalline solid after recrystallization (MeOH-water 1:4).
Mp 140–142 °C. ½a D20
ꢁ
ꢂ18.8 (c 0.202, DMSO). IR (ATR): 3337,
1623, 1591, 1458, 1084, 1005 cmꢂ1
.
1H NMR (500 MHz, DMSO-
d6): 3.61 (bdm, 1H, Jgem = 11.8 Hz, H-50a); 3.68 (bdm, 1H,
1H, J4 ,3 = 9.6, J4 ,5 = 3.2, H-40); 4.12, 4.19 (2 ꢃ dd, 2 ꢃ 1H,
Jgem = 11.8 Hz, H-50b); 3.75 (btd, 1H, J4 ,5 a = J4 ,3 = 4.7 Hz,
0
0
0
0
0
0
0
0
Jgem = 12.8, J5 ,4 = 3.2, H-50); 5.44 (d, 1H, J3 ,4 = 9.6, H-30); 5.65 (s,
1H, H-10); 6.10 (bs, 2H, NH2); 7.11 (s, 1H, H-6); 8.07 (s, 1H, H-2).
MS (ESI) m/z (%): 633 (62) [M+H], 655 (100) [M+Na]; HRMS (ESI)
Calcd for C23H38O5N4ISi2 [M+H]: 633.14199. Found: 633.14215.
J4 ,5 b = 4.1 Hz, H-40); 4.11 (q, 1H, J3 ,4 = J3 ,2 = J3 ,OH = 4.5 Hz, H-30);
0
0
0
0
0
0
0
0
0
0
0
4.13 (m, 1H, H-20); 5.07 (bt, 1H, JOH,5 a = JOH,5 b = 4.8 Hz, OH-50);
0
0
5.47 (d, 1H, JOH,3 = 4.5 Hz, OH-30); 5.50 (d, 1H, JOH,2 = 5.6 Hz, OH-
0
0
20); 6.07 (bs, 2H, NH2); 6.51 (d, 1H, J1 ,2 = 4.8 Hz, H-10); 7.36 (m,
1H, H-p-Ph); 7.44 (s, 1H, H-6); 7.44–7.51 (m, 2 ꢃ 2H, H-o,m-Ph);
8.15 (s, 1H, H-2). 13C NMR (125.7 MHz, DMSO-d6): 61.18 (CH2-
50); 75.48 (CH-30); 76.21 (CH-20); 83.26 (CH-10); 83.82 (CH-40);
100.06 (C-4a); 115.40 (C-5); 123.10 (CH-6); 126.94 (CH-p-Ph);
128.53 (CH-o-Ph); 129.22 (CH-m-Ph); 134.97 (C-i-Ph); 150.91 (C-
7a); 151.66 (CH-2); 157.29 (C-4). MS (ESI) m/z (%): 343 (100)
[M+H], 365 (8) [M+Na]; HRMS (ESI) Calcd for C17H19O4N4 [M+H]:
343.14008. Found: 343.14007. For C17H18O4N4 Calcd: 59.64% C,
5.30% H, 16.37% N. Found: 59.50% C, 5.65% H, 16.45% N.
0
0
3.25. 4-Amino-5-iodo-7-[3,5-O-(tetraisopropyldisiloxan-1,3-
diyl)-b-D-arabinofuranosyl]-7H-pyrrolo[2,3-d]pyrimidine (17)
Ketone 16 (2.85 g, 4.50 mmol) was dissolved in ethanol (99%,
170 ml) and the solution was cooled to 0 °C. Sodium borohydrate
(340 mg, 9.00 mmol) was added. The reaction mixture was stirred
at 0 °C for 1.5 h. The reacion was quenched with aq NH4Cl (sat.,
50 ml) and extracted with EtOAc (150 ml). The organic phase was
dried over MgSO4 and evaporated under reduced pressure. The
crude product was purified by column chromatography on silica
(hexane-EtOAc 1:1) to give arabinoside 17 (2.43 g, 85%) as a yel-
lowish foam. 1H NMR (500 MHz, CDCl3): 0.95–1.29 (m, 28H,
3.28. 4-Amino-5-(furan-2-yl)-7-(b-D-arabinofuranosyl)-7H-
pyrrolo[2,3-d]pyrimidine (19e)
((CH3)2CH); 3.83 (dt, 1H, J4 ,3 = 8.6 Hz, J4 ,5 a = J4 ,5 b = 2.7 Hz, H-40);
Compound 19e was prepared as described for compound 19a
from compound 18 (150 mg, 0.38 mmol) and furan-2-boronic acid.
The crude product was purified by reverse phase HPFC on C-18 col-
umn (water-MeOH 0?100%). Arabinoside 19e (81 mg, 64%) was
obtained as a yellowish lyophilizate (t-BuOH). Mp 117–119 °C.
0
0
0
0
0
0
4.03 (dd, 1H, Jgem = 13.2 Hz, J5 a,4 = 3.0 Hz, H-50a); 4.10 (dd, 1H,
0
0
Jgem = 13.2 Hz, J5 b,4 = 2.5 Hz, H-50b); 4.45 (t, 1H, J3 ,4 = J3 ,2 = 8.4 Hz,
0
0
0
0
0
0
H-30); 4.65 (dd, 1H, J2 ,3 = 8.1 Hz, J2 ,1 = 6.3 Hz, H-20); 6.34 (d, 1H,
0
0
0
0
J1 ,2 = 6.2 Hz, H-10); 6.83 (bs, 2H, NH2); 7.60 (s, 1H, H-6); 8.13 (s,
1H, H-2). 13C NMR (125.7 MHz, CDCl3): 12.40, 12.92, 13.00 and
13.54 ((CH3)2CH); 16.89, 16.92, 16.95, 17.06, 17.33, 17.42, 17.53
and 17.74 ((CH3)2CH); 50.89 (C-5); 60.67 (CH2-50); 72.90 (CH-30);
76.39 (CH-20); 80.96 (CH-40); 83.97 (CH-10); 103.63 (C-4a);
129.13 (CH-6); 147.03 (CH-2); 148.65 (C-7a); 154.74 (C-4). MS
(ESI) m/z (%): 635 (100) [M+H], 657 (30) [M+Na]; HRMS (ESI) Calcd
for C23H40O5N4ISi2 [M+H]: 635.15764. Found: 635.15782.
0
0
½
a 2D0
ꢁ
ꢂ41.0 (c 0.056, DMSO). IR (ATR): 3462, 1626, 1558, 1472,
1310, 1221, 1068, 1013 cmꢂ1 1H NMR (500 MHz, DMSO-d6): 3.64
(dm, 1H, Jgem = 11.8 Hz, H-50a); 3.70 (dm, 1H, Jgem = 11.8 Hz, H-
.
50b); 3.76 (btd, 1H, J4 ,5 a = J4 ,3 = 4.8 Hz, J4 ,5 b = 3.9 Hz, H-40); 4.09
0
0
0
0
0
0
(q, 1H, J3 ,4 = J3 ,2 = J3 ,OH = 4.5 Hz, H-30); 4.11 (m, 1H, H-20); 5.09
0
0
0
0
0
(m, 1H, OH-50); 5.47 (d, 1H, JOH,3 = 4.6 Hz, OH-30); 5.48 (d, 1H,
0
JOH,2 = 5.6 Hz, OH-20); 6.47 (d, 1H, J1 ,2 = 4.7 Hz, H-10); 6.60 (dd,
1H, J4,3 = 3.3 Hz, J4,5 = 1.8 Hz, H-4-furyl); 6.62 (dd, 1H, J3,4 = 3.3 Hz,
J3,5 = 0.9 Hz, H-3-furyl); 6.83 (bs, 2H, NH2); 7.70 (s, 1H, H-6); 7.77
(dd, 1H, J5,4 = 1.8 Hz, J5,3 = 0.9 Hz, H-5-furyl); 8.13 (s, 1H, H-2). 13C
NMR (125.7 MHz, DMSO-d6): 61.19 (CH2-50); 75.41 (CH-30); 76.09
(CH-20); 83.45 (CH-10); 83.92 (CH-40); 98.99 (C-4a); 105.06 (CH-
3-furyl); 105.28 (C-5); 112.07 (CH-4-furyl); 122.43 (CH-6);
142.00 (CH-5-furyl); 149.10 (C-2-furyl); 150.77 (C-7a); 152.02
(CH-2); 157.25 (C-4). MS (ESI) m/z (%): 333 (100) [M+H], 355
0
0
0
3.26. 4-Amino-5-iodo-7-(b-
d]pyrimidine (18)
D-arabinofuranosyl)-7H-pyrrolo[2,3-
Arabinoside 17 (670 mg, 1.06 mmol) was dissolved in anhy-
l, 2.11 mmol) was added.
drous THF (12 ml) and Et3Nꢀ3HF (344
l
The reaction mixture was stirred overnight at rt The precipitate
of compound 18 was filtered off and washed with methanol. Ara-
binoside 18 (385 mg, 93%) was obtained as white crystalline solid.
Mp 218–220 °C. 1H NMR (500 MHz, DMSO-d6): 3.60 (dm, 1H,
Jgem = 11.7 Hz, H-50a); 3.66 (dm, 1H, Jgem = 11.7 Hz, H-50b); 3.72
(10) [M+Na]; HRMS (ESI) Calcd for
C15H17O5N4 [M+H]:
333.11935. Found: 333.11934. For C15H16O5N4 Calcd: 54.21% C,
4.85% H, 16.86% N. Found: 54.08% C, 4.70% H, 16.63% N.

5212
P. Nauš et al. / Bioorg. Med. Chem. 20 (2012) 5202–5214
3.29. 4-Amino-5-(thiophen-2-yl)-7-(b-
pyrrolo[2,3-d]pyrimidine (19f)
D
-arabinofuranosyl)-7H-
92%) was obtained as a white crystalline solid after recrystalliza-
tion (MeOH-water 1:4). Mp 214–217 °C. ½a D20
ꢂ37.2 (c 0.207,
ꢁ
DMSO). IR (ATR): 3442, 1619, 1599, 1554, 1083, 1038,
Compound 19f was prepared as described for compound 19a
from compound 18 (150 mg, 0.38 mmol) and thiophene-2-boronic
acid. The crude product was purified twice by reverse phase HPFC
on C-18 column (0?100% MeOH in water). Compound 19f
(103 mg, 77%) was obtained as an off-white crystalline solid after
1001 cmꢂ1
.
1H NMR (500 MHz, DMSO-d6): 3.61 (dd, 1H,
Jgem = 11.7 Hz, J5 a,4 = 5.0 Hz, H-50a); 3.68 (dd, 1H, Jgem = 11.7 Hz,
0
0
J5 b,4 = 4.0 Hz, H-50b); 3.74 (btd, 1H, J4 ,5 a = J4 ,3 = 4.8 Hz,
0
0
0
0
0
0
J4 ,5 b = 4.1 Hz, H-40); 4.07–4.14 (m, 2H, H-20,30); 5.08 (bs, 1H, OH-
0
0
50); 5.47 (bd, 1H, JOH,3 = 4.3 Hz, OH-30); 5.50 (bd, 1H, JOH,2 = 5.4 Hz,
0
0
recrystallization (MeOH-water 1:4). Mp 150–154 °C. ½a D20
ꢁ
ꢂ26.8 (c
OH-20); 6.24 (bs, 2H, NH2); 6.49 (d, 1H, J1 ,2 = 4.8 Hz, H-10); 7.29
(dd, 1H, J4,5 = 4.9 Hz, J4,2 = 1.3 Hz, H-4-thienyl); 7.46 (s, 1H, H-6);
7.49 (dd, 1H, J2,5 = 2.9 Hz, J2,4 = 1.3 Hz, H-2-thienyl); 7.71 (dd, 1H,
J5,4 = 4.9 Hz, J5,2 = 2.9 Hz, H-5-thienyl); 8.15 (s, 1H, H-2). 13C NMR
(125.7 MHz, DMSO-d6): 61.15 (CH2-50); 75.36 (CH-30); 76.18 (CH-
20); 83.26 (CH-10); 83.80 (CH-40); 100.30 (C-4a); 110.22 (C-5);
121.94 (CH-2-thienyl); 123.09 (CH-6); 127.62 (CH-5-thienyl);
128.61 (CH-4-thienyl); 135.13 (C-3-thienyl); 150.46 (C-7a);
151.31 (CH-2); 157.10 (C-4). MS (ESI) m/z (%): 349 (100) [M+H],
371 (10) [M+Na]; HRMS (ESI) Calcd for C15H17O4N4S [M+H]:
349.09650. Found: 349.09648. For C15H16O4N4ꢀ1H2O Calcd:
49.17% C, 4.95% H, 15.29% N. Found: 49.05% C, 4.64% H, 15.09% N.
0
0
0.205, DMSO). IR (ATR): 3441, 1616, 1596, 1552, 1456, 1351, 1305,
1181, 1068, 1049, 1015 cmꢂ1
.
1H NMR (600 MHz, DMSO-d6): 3.61
0
(dt, 1H, Jgem = 11.7 Hz, J5 a,4 = J5 a,OH = 5.1 Hz, H-50a); 3.68 (ddd, 1H,
0
0
Jgem = 11.7 Hz, J5 b,OH = 5.5 Hz, J5 b,4 = 4.1 Hz, H-50b); 3.75 (btd, 1H,
0
0
0
J4 ,5 a = J4 ,3 = 4.7 Hz, J4 ,5 b = 4.2 Hz, H-40); 4.09 (q, 1H, J3 ,4 = J3 ,2
=
=
0
0
0
0
0
0
0
0
0
0
J3 ,OH = 4.6 Hz, H-30); 4.12 (bdt, 1H, J2 ,OH = 5.6 Hz, J2 ,3 = J2 ,1
0
0
0
0
0
0
4.7 Hz, H-20); 5.08 (t, 1H, JOH,5 a = JOH,5 b = 5.4 Hz, OH-50); 5.47 (d,
0
0
1H, JOH,3 = 4.5 Hz, OH-30); 5.52 (d, 1H, JOH,2 = 5.6 Hz, OH-20); 6.27
0
0
(s, 2H, NH2); 6.48 (d, 1H, J1 ,2 = 4.8 Hz, H-10); 7.12 (dd, 1H,
J3,4 = 3.5 Hz, J3,5 = 1.2 Hz, H-3-thienyl); 7.17 (dd, 1H, J4,5 = 5.2 Hz,
J4,3 = 3.5 Hz, H-4-thienyl); 7.50 (s, 1H, H-6); 7.55 (dd, 1H,
J5,4 = 5.2 Hz, J5,3 = 1.2 Hz, H-5-thienyl); 8.15 (s, 1H, H-2). 13C NMR
(150.9 MHz, DMSO-d6): 61.04 (CH2-50); 75.32 (CH-30); 76.11
(CH-20); 83.28 (CH-10); 83.83 (CH-40); 100.19 (C-4a); 107.55 (C-
5); 123.87 (CH-6); 125.72 (CH-5-thienyl); 126.20 (CH-3-thienyl);
128.45 (CH-4-thienyl); 136.16 (C-2-thienyl); 150.63 (C-7a);
152.01 (CH-2); 157.28 (C-4). MS (ESI) m/z (%): 349 (100) [M+H],
371 (18) [M+Na]; HRMS (ESI) Calcd for C15H17O4N4S [M+H]:
349.09650. Found: 349.09647. For C15H16O4N4ꢀ0.75H2O Calcd:
49.78% C, 4.87% H, 15.48% N. Found: 50.05% C, 4.66% H, 15.12% N.
0
0
3.32. 4-Amino-5-[(trimethylsilyl)ethynyl]-7-(b-D-
arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine (20)
An argon purged mixture of compound 18 (150 mg, 0.38 mmol),
CuI (7.3 mg, 0.038 mmol), PdCl2(PPh3)2 (13 mg, 0.019 mmol), tri-
methylsilylacetylene (545
l
l, 3.83 mmol) and triethylamine
l) was stirred over-
(150 l, 1.07 mmol) in anhydrous DMF (600
l
l
night at rt Volatiles were removed in vacuo and the residue was
twice co-evaporated with EtOH. The crude product was purified
by silicagel column chromatography (3.5% MeOH in CHCl3) to ob-
tain compound 20 (70 mg, 51%) as a colorless foam. 1H NMR
(400 MHz, DMSO-d6): 0.24 (s, 9H, CH3Si); 3.59–3.69 (2H, H-50a,
3.30. 4-Amino-5-(furan-3-yl)-7-(b-D-arabinofuranosyl)-7H-
pyrrolo[2,3-d]pyrimidine (19g)
H-50b); 3.73 (bq, 1H, J4 ,5 a = J4 ,3 = J4 ,5 b = 4.4 Hz, H-40); 4.03–4.11
0
0
0
0
0
0
Compound 19f was prepared as described for compound 19a
from compound 18 (150 mg, 0.38 mmol) and furan-3-boronic acid.
The crude product was purified by reverse phase HPFC on C-18 col-
umn (0?100% MeOH in water). Compound 19g (93 mg, 73%) was
(m, 2H, H-30, H-20); 5.09 (t, 1H, JOH,5 a = JOH,5 b = 5.6 Hz, OH-50);
0
0
5.45–5.47 (m, 2H, OH-30, OH-20); 6.38 (d, 2H, J1 ,2 = 4.8 Hz, H-10);
7.64 (s, 1H, H-6); 8.11 (s, 1H, H-2). MS (ESI) m/z (%): 363 (100)
[M+H], 385 (15) [M+Na]; HRMS (ESI) Calcd for C16H23O4N4Si
[M+H]: 363.14831. Found: 363.14828.
0
0
obtained as
a yellow crystalline solid after recrystallization
(MeOH-water 1:4). Mp 148–152 °C. ½a D20
ꢁ
ꢂ21.0 (c 0.205, DMSO).
IR (ATR): 3433, 1626, 1592, 1559, 1446, 1068, 1003 cmꢂ1
.
1H
3.33. 4-Amino-5-ethynyl-7-(b-
D-arabinofuranosyl)-7H-
NMR (500 MHz, DMSO-d6): 3.61 (dd, 1H, Jgem = 11.7 Hz,
pyrrolo[2,3-d]pyrimidine (19k)
J5 a,4 = 5.1 Hz, H-50a); 3.68 (dd, 1H, Jgem = 11.7 Hz, J5 b,4 = 4.1 Hz,
0
0
0
0
H-50b); 3.74 (btd, 1H, J4 ,5 a = J4 ,3 = 4.9 Hz, J4 ,5 b = 4.1 Hz, H-40);
0
0
0
0
0
0
A solution of compound 20 (70 mg, 0.19 mmol) and K2CO3
(13.3 mg, 0.97 mmol) in methanol (5 ml) was stirred for 1 h at rt
Then the reaction mixture was co-evaporated with silica under re-
duced pressure and chromatographed on silicagel column (5%
MeOH in CHCl3). Product 19k (43 mg, 77%) was obtained as white
crystalline solid after recrystallization (MeOH:CHCl3:hexane). Mp
4.08 (bq, 1H, J3 ,4 = J3 ,2 = J3 ,OH = 4.4 Hz, H-30); 4.10 (m, 1H, H-20);
0
0
0
0
0
5.06 (bs, 1H, OH-50); 5.46 (d, 1H, JOH,3 = 4.3 Hz, OH-30); 5.48 (d,
0
1H, JOH,2 = 5.5 Hz, OH-20); 6.21 (bs, 2H, NH2); 6.47 (d, 1H,
0
J1 ,2 = 4.6 Hz, H-10); 6.67 (dd, 1H, J4,5 = 1.8 Hz, J4,2 = 1.0 Hz, H-4-fur-
yl); 7.41 (s, 1H, H-6); 7.80 (bt, 1H, J5,4 = J5,2 = 1.6 Hz, H-5-furyl);
7.81 (bdd, 1H, J2,5 = 1.6 Hz, J2,4 = 1.0 Hz, H-2-furyl); 8.12 (s, 1H, H-
0
0
198–201 °C. ½a 2D0
ꢁ
ꢂ21.8 (c 0.072, DMSO). IR (ATR): 3472, 1635,
1H NMR
Jgem = 11.7 Hz,
J5 a,4 = J5 a,OH = 5.2 Hz, H-50a); 3.67 (bddd, 1H, Jgem = 11.7 Hz,
13
2). C NMR (125.7 MHz, DMSO-d6): 61.25 (CH2-50); 75.52 (CH-
1592, 1570, 1482, 1455, 1314, 1303, 1035 cmꢂ1
.
30); 76.16 (CH-20); 83.23 (CH-10); 83.80 (CH-40); 100.58 (C-4a);
105.27 (C-5); 111.70 (CH-4-furyl); 119.00 (C-3-furyl); 122.85
(CH-6); 139.63 (CH-2-furyl); 144.34 (CH-5-furyl); 150.71 (C-7a);
151.64 (CH-2); 157.38 (C-4). MS (ESI) m/z (%): 333 (100) [M+H];
HRMS (ESI) Calcd for C15H17O5N4 [M+H]: 333.11935. Found:
333.11934. For C15H16O5N4ꢀ0.25CH3OHꢀ0.5H2O Calcd: 52.43% C,
5.19% H, 16.04% N. Found: 52.22% C, 4.95% H, 15.75% N.
(500 MHz,
DMSO-d6):
3.62
(bdt,
1H,
0
0
0
J5 b,OH = 5.5 Hz,
J5 b,4 = 4.0 Hz,
H-50b);
J4 ,5 a = J4 ,5 b = J4 ,3 = 4.4 Hz, H-40); 4.06 (m, 1H, H-30); 4.09 (m, 1H,
3.74
(bq,
1H,
0
0
0
0
0
0
0
0
0
H-20); 4.23 (s, 1H, CH„C); 5.09 (t, 1H, JOH,5 a = JOH,5 b = 5.4 Hz, OH-
0
0
50); 5.47 (d, 1H, JOH,3 = 4.4 Hz, OH-30); 5.48 (d, 1H, JOH,2 = 5.4 Hz,
0
0
OH-20); 6.40 (d, 1H, J1 ,2 = 4.8 Hz, H-10); 6.60 (bs, 2H, NH2); 7.65
(s, 1H, H-6); 8.11 (s, 1H, H-2). 13C NMR (125.7 MHz, DMSO-d6):
60.95 (CH2-50); 75.10 (CH-30); 76.02 (CH-20); 77.86 (CH„C);
82.82 (CH„C); 83.57 (CH-10); 83.94 (CH-40); 93.02 (C-5); 102.06
(C-4a); 129.25 (CH-6); 149.49 (C-7a); 152.79 (CH-2); 157.56 (C-
4). MS (ESI) m/z (%): 291 (100) [M+H], 313 (20) [M+Na]; HRMS
(ESI) Calcd for C13H15O4N4 [M+H]: 291.10878. Found: 291.10882.
For C13H14O4N4 Calcd: 53.79% C, 4.86% H, 19.30% N. Found:
53.66% C, 4.99% H, 18.98% N.
0
0
3.31. 4-Amino-5-(thiophen-3-yl)-7-(b-D-arabinofuranosyl)-7H-
pyrrolo[2,3-d]pyrimidine (19h)
Compound 19h was prepared as described for compound 19a
from compound 18 (150 mg, 0.38 mmol) and thiophene-3-boronic
acid. The crude product was purified by reverse phase HPFC on C-
18 column (0?100% MeOH in water). Compound 19h (123 mg,

P. Nauš et al. / Bioorg. Med. Chem. 20 (2012) 5202–5214
5213
3.34. 4-Amino-5-(furan-2-yl)-7-(2-deoxy-b-
7H-pyrrolo[2,3-d]pyrimidine (22e)
D
-ribofuranosyl)-
silica (2% MeOH in CHCl3). Compound 22g (94 mg, 72%) was ob-
tained as
a yellowish crystalline solid after recrystallization
(MeOH-water 1:4). Mp 184–190 °C. ½a D20
ꢁ
ꢂ20.2 (c 0.218, DMSO).
Compound 22e was prepared as described for compound 19a
from compound 21 (150 mg, 0.40 mmol) and furan-2-boronic acid.
The crude product was purified by reverse phase HPFC on C-18 col-
umn (0?100% MeOH in water). Compound 22e (108 mg, 89%) was
obtained as a beige crystalline solid after recrystallization (MeOH-
IR (ATR): 3233, 1616, 1581, 1554, 1456, 1049, 1021 cmꢂ1 1H
.
NMR (500 MHz, DMSO-d6): 2.18 (ddd, 1H, Jgem = 13.1 Hz,
J2 a,1 = 6.0 Hz, J2 a,3 = 2.7 Hz, H-20a); 2.52 (ddd, 1H, Jgem = 13.1 Hz,
0
0
0
0
J2 b,1 = 8.3 Hz, J2 b,3 = 5.8 Hz, H-20b); 3.51 (ddd, 1H, Jgem = 11.7 Hz,
0
0
0
0
J5 a,OH = 5.9 Hz, J5 a,4 = 4.4 Hz, H-50a); 3.57 (ddd, 1H, Jgem = 11.7 Hz,
0
0
0
water 1:4). Mp 205–208 °C. ½a D20
ꢁ
ꢂ24.9 (c 0.181, DMSO). IR (ATR):
J5 b,OH = 5.3 Hz,
J5 b,4 = 4.8 Hz,
H-50b);
3.83
(td,
1H,
0
0
0
3381, 1629, 1557, 1496, 1458, 1219, 1161, 1072, 1054, 1017 cmꢂ1
.
J4 ,5 a = J4 ,5 b = 4.5 Hz, J4 ,3 = 2.5 Hz, H-40); 4.35 (m, 1H, H-30); 5.05
0
0
0
0
0
0
1H NMR (500 MHz, DMSO-d6): 2.21 (ddd, 1H, Jgem = 13.1 Hz,
(bt, 1H, JOH,5 a = JOH,5 b = 5.6 Hz, OH-50); 5.25 (d, 1H, JOH,3 = 4.1 Hz,
0
0
0
J2 a,1 = 6.0 Hz, J2 a,3 = 2.8 Hz, H-20a); 2.52 (ddd, 1H, Jgem = 13.1 Hz,
OH-30); 6.24 (bs, 2H, NH2); 6.55 (dd, 1H, J1 ,2 b = 8.3 Hz,
0
0
0
0
0
0
J2 b,1 = 8.1 Hz, J2 b,3 = 5.8 Hz, H-20b); 3.53 (ddd, 1H, Jgem = 11.7 Hz,
J1 ,2 a = 5.9 Hz, H-10); 6.70 (dd, 1H, J4,5 = 1.8 Hz, J4,2 = 0.9 Hz, H-4-
furyl); 7.48 (s, 1H, H-6); 7.80 (t, 1H, J5,4 = J5,2 = 1.7 Hz, H-5-furyl);
7.83 (dd, 1H, J2,5 = 1.6 Hz, J2,4 = 0.9 Hz, H-2-furyl); 8.12 (s, 1H, H-
0
0
0
0
0
0
J5 a,OH = 5.9 Hz, J5 a,4 = 4.5 Hz, H-50a); 3.60 (dt, 1H, Jgem = 11.7 Hz,
0
0
0
J5 b,OH = J5 b,4 = 5.0 Hz, H-50b); 3.84 (td, 1H, J4 ,5 a = J4 ,5 b = 4.5 Hz,
0
0
0
0
0
0
0
13
J4 ,3 = 2.6 Hz, H-40); 4.37 (m, 1H, H-30); 5.05 (t, 1H,
2). C NMR (125.7 MHz, DMSO-d6): 39.84 (CH2-20); 62.19 (CH2-
0
0
JOH,5 a = JOH,5 b = 5.6 Hz, OH-50); 5.27 (d, 1H, JOH,3 = 4.1 Hz, OH-30);
50); 71.22 (CH-30); 83.06 (CH-10); 87.50 (CH-40); 101.06 (C-4a);
106.47 (C-5); 111.73 (CH-4-furyl); 118.76 (C-3-furyl); 120.64
(CH-6); 139.82 (CH-2-furyl); 144.31 (CH-5-furyl); 150.49 (C-7a);
151.94 (CH-2); 157.62 (C-4). MS (ESI) m/z (%): 317 (17) [M+H],
339 (100) [M+Na]; HRMS (ESI) Calcd for C15H17O4N4 [M+H]:
317.12443. Found: 317.12445. For C15H16O4N4 Calcd: 59.96% C,
5.10% H, 17.71% N. Found: 57.72% C, 5.26% H, 17.63% N.
0
0
0
6.56 (dd, 1H, J1 ,2 b = 8.1 Hz, J1 ,2 a = 6.0 Hz, H-10); 6.61 (dd, 1H,
J4,3 = 3.3 Hz, J4,5 = 1.9 Hz, H-4-furyl); 6.68 (dd, 1H, J3,4 = 3.3 Hz,
J3,5 = 0.9 Hz, H-3-furyl); 6.89 (bs, 2H, NH2); 7.78 (dd, 1H,
J5,4 = 1.9 Hz, J5,3 = 0.9 Hz, H-5-furyl); 7.82 (s, 1H, H-6); 8.13 (s, 1H,
H-2). 13C NMR (125.7 MHz, DMSO-d6): 39.87 (CH2-20); 62.11
(CH2-50); 71.11 (CH-30); 83.11 (CH-10); 87.58 (CH-40); 99.38 (C-
4a); 105.47 (CH-3-furyl); 106.38 (C-5); 112.06 (CH-4-furyl);
120.18 (CH-6); 142.12 (CH-5-furyl); 148.80 (C-2-furyl); 150.63
(C-7a); 152.28 (CH-2); 157.42 (C-4). MS (ESI) m/z (%): 317 (100)
0
0
0
0
3.37. 4-Amino-5-(thiophen-3-yl)-7-(2-deoxy-b-D-
ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine (22h)
[M+H], 339 (62) [M+Na]; HRMS (ESI) Calcd for
C15H17O4N4
[M+H]: 317.12443. Found: 317.12442. For C15H16O4N4 Calcd:
59.96% C, 5.10% H, 17.71% N. Found: 59.66% C, 4.94% H, 17.47% N.
Compound 22h was prepared as described for compound 19a
from compound 21 (150 mg, 0.40 mmol) and thiophene-3-boronic
acid. The crude product was purified by reverse phase HPFC on C-
18 column (0?100% MeOH in water). Compound 22h (112 mg,
88%) was obtained as a white crystalline solid after recrystalliza-
3.35. 4-Amino-5-(thiophen-2-yl)-7-(2-deoxy-b-D-
ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine (22f)
tion (MeOH-water 1:4). Mp 105–108 °C. ½a D20
ꢂ14.3 (c 0.231,
ꢁ
Compound 22f was prepared as described for compound 19a
from compound 21 (150 mg, 0.40 mmol) and thiophene-2-boronic
acid. The crude product was purified by reverse phase HPFC on C-
18 column (0?100% MeOH in water). Compound 22f (99 mg, 75%)
DMSO). IR (ATR): 3441, 1616, 1596, 1552, 1456, 1351, 1305,
1181, 1068, 1048, 1015 cmꢂ1
.
0
1H NMR (600 MHz, DMSO-d6): 2.19
(ddd, 1H, Jgem = 13.1 Hz, J2 a,1 = 6.0 Hz, J2 a,3 = 2.7 Hz, H-20a); 2.54
0
0
0
(ddd, 1H, Jgem = 13.1 Hz, J2 b,1 = 8.3 Hz, J2 b,3 = 5.9 Hz, H-20b); 3.51
0
0
0
0
was obtained as a white lyophilizate (t-BuOH). Mp 88–92 °C. ½a D20
ꢁ
(btd, 1H, Jgem = 11.8 Hz, J5 a,OH = J5 a,4 = 5.0 Hz, H-50a); 3.58 (bdt,
0
0
0
1H, Jgem = 11.8 Hz, J5 b,OH = J5 b,4 = 4.9 Hz, H-50b); 3.83 (td, 1H,
0
0
0
ꢂ17.5 (c 0.223, DMSO). IR (ATR): 3461, 1623, 1589, 1576, 1548,
1463, 1191, 1092, 1051 cmꢂ1
.
0
1H NMR (600 MHz, DMSO-d6): 2.20
J4 ,5 a = J4 ,5 b = 4.5 Hz, J4 ,3 = 2.5 Hz, H-40); 4.36 (m, 1H, H-30); 5.05
0
0
0
0
0
0
(ddd, 1H, Jgem = 13.1 Hz, J2 a,1 = 6.0 Hz, J2 a,3 = 2.7 Hz, H-20a); 2.54
(bt, 1H, JOH,5 a = JOH,5 b = 5.4 Hz, OH-50); 5.26 (bd, 1H, JOH,3 = 3.0 Hz,
0
0
0
0
0
0
(ddd, 1H, Jgem = 13.1 Hz, J2 b,1 = 8.3 Hz, J2 b,3 = 5.8 Hz, H-20b); 3.52
OH-30); 6.19 (s, 2H, NH2); 6.57 (dd, 1H, J1 ,2 b = 8.3 Hz, J1 ,2 a = 6.0 Hz,
H-10); 7.27 (dd, 1H, J4,5 = 4.9 Hz, J4,2 = 1.3 Hz, H-4-thienyl); 7.51
(dd, 1H, J2,5 = 2.9 Hz, J2,4 = 1.3 Hz, H-2-thienyl); 7.53 (s, 1H, H-6);
7.70 (dd, 1H, J5,4 = 4.9 Hz, J5,2 = 2.9 Hz, H-5-thienyl); 8.14 (s, 1H,
H-2). 13C NMR (150.9 MHz, DMSO-d6): 39.87 (CH2-20); 62.18
(CH2-50); 71.23 (CH-30); 83.09 (CH-10); 87.53 (CH-40); 100.85 (C-
4a); 111.21 (C-5); 120.77 (CH-6); 122.18 (CH-2-thienyl); 127.49
(CH-5-thienyl); 128.70 (CH-4-thienyl); 134.93 (C-3-thienyl);
150.35 (C-7a); 151.92 (CH-2); 157.54 (C-4). MS (ESI) m/z (%): 333
(100) [M+H], 355 (56) [M+Na]; HRMS (ESI) Calcd for C15H17O3N4S
[M+H]: 333.10159. Found: 333.10162. For C15H16O3N4SꢀH2O Calcd:
51.42% C, 5.18% H, 15.99% N. Found: 51.45% C, 5.07% H, 15.73% N.
0
0
0
0
0
0
0
0
(ddd, 1H, Jgem = 11.7 Hz, J5 a,OH = 5.8 Hz, J5 a,4 = 4.2 Hz, H-50a); 3.58
0
0
0
(bdt, 1H, Jgem = 11.7 Hz, J5 b,OH = J5 b,4 = 4.8 Hz, H-50b); 3.84 (td,
0
0
0
1H, J4 ,5 a = J4 ,5 b = 4.4 Hz, J4 ,3 = 2.5 Hz, H-40); 4.36 (m, 1H, H-30);
0
0
0
0
0
0
5.06 (t, 1H, JOH,5 a = JOH,5 b = 5.6 Hz, OH-50); 5.26 (d, 1H,
0
0
JOH,3 = 4.1 Hz, OH-30); 6.31 (s, 2H, NH2); 6.57 (dd, 1H,
0
J1 ,2 b = 8.2 Hz,J1 ,2 a = 5.9 Hz, H-10); 7.15 (dd, 1H, J3,4 = 3.5 Hz,
J3,5 = 1.3 Hz, H-3-thienyl); 7.18 (dd, 1H, J4,5 = 5.1 Hz, J4,3 = 3.5 Hz,
H-4-thienyl); 7.57 (dd, 1H, J5,4 = 5.1 Hz, J5,3 = 1.2 Hz, H-5-thienyl);
7.59 (s, 1H, H-6); 8.15 (s, 1H, H-2). 13C NMR (150.9 MHz, DMSO-
d6): 39.97 (CH2-20); 62.09 (CH2-50); 71.18 (CH-30); 83.21 (CH-10);
87.61 (CH-40); 100.70 (C-4a); 108.67 (C-5); 121.79 (CH-6);
126.00 (CH-5-thienyl); 126.56 (CH-3-thienyl); 128.41 (CH-4-thie-
nyl); 135.72 (C-2-thienyl); 150.36 (C-7a); 152.19 (CH-2); 157.42
(C-4). MS (ESI) m/z (%): 333 (100) [M+H], 355 (23) [M+Na]; HRMS
(ESI) Calcd for C15H17O3N4S [M+H]: 333.10159. Found: 333.10160.
For C15H16O3N4S Calcd: 54.20% C, 4.85% H, 16.86% N. Found: 54.28%
C, 5.12% H, 16.58% N.
0
0
0
0
Acknowledgments
This work was supported by the Academy of Sciences of the
Czech Republic (RVO: 61388963), Czech Science Foundation
(P207/11/0344) and by Gilead Sciences, Inc.
3.36. 4-Amino-5-(furan-3-yl)-7-(2-deoxy-b-
7H-pyrrolo[2,3-d]pyrimidine (22g)
D-ribofuranosyl)-
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The crude product was purified by column chromatography on

5214
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