Synthesis of 2′-deoxy-2′-fluororibo- and 2′-deoxy- 2′,2′-difluororibonucleosides derived from 6-(het)aryl-7- deazapurines

Article abstract of DOI:10.1016/j.tet.2012.07.033

A series of novel sugar-modified derivatives of cytostatic 6-hetaryl-7-deazapurine ribonucleosides (2′-deoxy-2′-fluororibo- and 2′-deoxy-2′,2-difluororibonucleosides) bearing an aryl or hetaryl group in position 6, was prepared and screened for biological activity. The fluororibo derivatives were prepared by aqueous palladium catalyzed cross-coupling reactions of the corresponding 6-chloro-7-deazapurine 2′-deoxy-2′-fluororibonucleoside 11 with (het)arylboronic acids. The key intermediate 11 was prepared by a six-step sequence from the corresponding arabinonucleoside by selective protection of 3′- and 5′-hydroxyls by acid-labile groups followed by stereoselective S_N2 fluorination and deprotection. The difluororibo-series was prepared by non-stereoselective glycosidation of 6-chloro-7-deazapurine with benzoyl-protected 2-deoxy-2,2-difluoro-d-erythro-pentofuranosyl-1-mesylate followed by cross-couplings, separation of anomers and deprotection. The title nucleosides did not show considerable cytostatic or antiviral activity.

Full text of DOI:10.1016/j.tet.2012.07.033

Tetrahedron 68 (2012) 8300e8310
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of 20-deoxy-20-fluororibo- and 20-deoxy-20,20-difluororibonucleosides
derived from 6-(het)aryl-7-deazapurines
a
a,b,
*
ꢀ a
ꢁ
ꢀ a
Pavla Perlíkova , Neus Jornet Martínez , Lenka Slavetínska , 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 Department of Organic and Nuclear 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 6-hetaryl-7-deazapurine ribonucleosides (20-
deoxy-20-fluororibo- and 20-deoxy-20,2-difluororibonucleosides) bearing an aryl or hetaryl group in
position 6, was prepared and screened for biological activity. The fluororibo derivatives were prepared by
aqueous palladium catalyzed cross-coupling reactions of the corresponding 6-chloro-7-deazapurine 20-
deoxy-20-fluororibonucleoside 11 with (het)arylboronic acids. The key intermediate 11 was prepared by
a six-step sequence from the corresponding arabinonucleoside by selective protection of 30- and 50-
hydroxyls by acid-labile groups followed by stereoselective SN2 fluorination and deprotection. The
difluororibo-series was prepared by non-stereoselective glycosidation of 6-chloro-7-deazapurine with
Article history:
Received 27 April 2012
Received in revised form 18 June 2012
Accepted 10 July 2012
Available online 20 July 2012
benzoyl-protected 2-deoxy-2,2-difluoro-D-erythro-pentofuranosyl-1-mesylate followed by cross-
couplings, separation of anomers and deprotection. The title nucleosides did not show considerable
cytostatic or antiviral activity.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
represented by gemcitabine5 (20,20-difluorodeoxycytidine), which
is a clinical anti-cancer drug with a broad spectrum of activity. It is
As a result of our long-term interest in synthesis and biological
activity of modified purine ribonucleoside derivatives and ana-
logues,1 we have recently discovered a new group2 of nucleoside
cytostatics: 6-hetaryl-7-deazapurine ribonucleosides (Fig. 1). These
nucleosides showed a potent in vitro cytostatic effect against
a broad spectrum of leukaemia and tumour cell-lines in nanomolar
concentrations, as well as non-selective anti-HCV activities (prob-
ably caused by cytotoxicity). Attempts to improve their activities
and/or pharmacokinetic properties by the preparation of cycloSal-
phosphate and ProTide prodrugs3 were not efficient due to efflux
from the cells. Further efforts to modulate the activities and/or to
achieve selectivity to HCV RNA-polymerase were focused on sugar
modifications. In our recent study,4 we have prepared 20-C-methyl-
ribonucleosides, arabinonucleosides and 20-fluoroarabinonucleo-
sides (Fig. 1). None of these derivatives showed any cytostatic or
anti-HCV activities indicating that the ribo-configuration of the
sugar might be crucial for the activity. However, there are as yet
unexplored types of derivatives that should be tested to prove or
disprove this hypothesis and to complete the structureeactivity
relationship of this class of cytostatics: nucleosides with a fluorine
in the ribo-configuration. The 20,20-difluororibo motif is
the only nucleoside analogue that is used for the treatment of solid
tumours (pancreas and lung cancer). Also some 20-deoxy-20-fluo-
roribonucleosides were reported to show cytostatic activities.6
Therefore, we report here the synthesis of the title 20-deoxy-20-
fluororibo- and 20-deoxy-20,20-difluororibonucleosides derived
from 6-hetaryl-7-deazapurines.
2. Results and discussion
The synthetic route to 7-deazapurine 20-deoxy-20-fluoror-
ibonucleosides was similar to the literature procedure for the
synthesis of purine 20-deoxy-20-fluororibonucleosides.7 The syn-
thesis was based on selective acid-labile tetrahydropyran-2-yl
(THPe) protection of the 30- and 50-hydroxy groups in the ara-
bino-derivative followed by fluorination with DAST (Scheme 1). The
starting material for the synthesis was silyl-protected arabinonu-
cleoside 5.4 First, the 20-hydroxyl group was protected by acetyla-
tion with acetic anhydride in the presence of Et3N and catalytic
amount of DMAP in acetonitrile to obtain acetate 6 in 98% yield.
Then, the silyl groups were removed using Et3N$3HF in THF8 to
prepare nucleoside 7 (95%). Subsequently, THP-protecting groups
were introduced to positions 30 and 50 by reaction with 2,3-
dihydropyran in presence of TsOH in DMF. THP-protected acetate
8 was obtained in a high yield of 97%. The synthesis continued with
* Corresponding author. E-mail address: hocek@uochb.cas.cz (M. Hocek).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.07.033

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P. Perlíkova et al. / Tetrahedron 68 (2012) 8300e8310
8301
to obtain free 20-fluoro-20-deoxyribonucleoside 11 in moderate
yield (33% over two steps).
X, Y, Z = O, S, N, NH, CH
Y
X
Y
X
Y
X
Fluoroderivative 11 was then used as a starting material for
R = H or F
R
a series of aqueous-phase Suzuki cross-coupling reactions9 to
Z
Z
Z
synthesize
6-(het)aryl-7-deazapurine
20-fluoro-20-deoxy-
ribonucleosides 12aef (Scheme 2). The Suzuki cross-coupling re-
actions with (het)arylboronic acids were performed in the presence
of sodium carbonate, TPPTS and palladium acetate in acetonitrile/
water (2:1) at 100 ꢀC. The desired title 6-(het)aryl-7-deazapurine
20-fluoro-20-deoxyribonucleosides 12aef were obtained in mod-
erate to good yields (37e89%).
N
N
N
N
N
N
N
N
N
O
O
O
HO
HO
HO
CH3
OH
R'
The synthesis of 6-hetaryl-7-deazapurine 20-deoxy-20,20-difluoro-
HO
OH
HO
HO
D-erythro-pentofuranosyl nucleosides 18 was based on glycosylation
1
3, R' = OH
4, R' = F
inactive
2
of 6-chloro-7-deazapurine (14) with commercially available mesylate
nanomolar cytostatic
unselective anti-HCV
13 (Scheme 3). Catalysis with TMSOTf that was previously used10 for
inactive
the synthesis of purine 20-deoxy-20,20-difluoro-
L-erythro-pentofur-
This work:
anosyl nucleosides did not lead to formation of any product. There-
fore, we decided to use a glycosylation protocol utilizing KOH and
TDA-1 in toluene that was successfully used for glycosylation of 7-
deazapurine derivatives with halogenoses.2,11 At ambient tempera-
ture, the conversion was very low. Only at 50 ꢀC and with prolonged
reactiontimewastheyieldofnucleoside15 raised to maximum of 19%
(Table 1). However, any higher temperatures led to degradation.
Crude difluoronucleoside 15 was always obtained as an inseparable
Y
Y
X
X
N
Z
Z
N
N
F
N
F
N
N
O
O
mixture of a- and b-anomers (1:2).
HO
HO
As attempts to separate anomers of nucleoside 15 failed, we de-
cided to directly use the crude glycosylation product mixture 15 for
the cross-coupling reactions to introduce the heterocyclic group to
position 6 of the 7-deazapurine moiety. We supposed that the pres-
ence of a bulky group might help the separation of anomers. Thus the
mixture 15 was subjected to a series of the Stille and Suzuki couplings.
The Suzuki cross-coupling reactions of nucleoside 15 with hetar-
ylboronic acids were performed in the presence of Pd(PPh3)4 and
K2CO3 in toluene at 85 ꢀC and the Stille cross-coupling reactions with
hetarylstannanes under Pd(PPh3)2Cl2 catalysis in DMF at 105 ꢀC and
proceeded with full conversion. The separation of anomers of the
protected fluorinated 6-hetaryl-7-deazapurine nucleosides 16 and 17
was again very difficult and several repeated HPFC chromatographies
F
fluorine in
ribo-configuration
HO
HO
Fig. 1. Structures of biologically active 6-hetaryl-7-deazapurine nucleosides and their
sugar-modified derivatives.
aminolysis of the acetyl group in position 20 using methanolic
ammonia at 0 ꢀC to obtain 30,50-O-protected arabinoside 9 in
quantitative yield. Fluorine was stereoselectively introduced to 20-
position by SN2-reaction of arabinoside 9 with DAST in presence of
pyridine in dichloromethane. The crude 20-fluoro-20-deoxy-
ribonucleoside 10 was directly deprotected under acidic conditions
Cl
Cl
N
Cl
N
N
N
N
N
N
N
ii
i
N
O
O
O
O
O
RO
(iPr)2Si
(iPr)2Si
O
O
OAc
OH
N
O
(iPr)2
O
(iPr)2
Si
Si
RO
OAc
7, R = H, 95 %
8, R = THP, 97 %
6, 98 %
5
iii
Cl
N
Cl
Cl
N
N
N
N
F
N
N
iv
v
N
vi
O
O
O
8
THPO
THPO
HO
THPO
9, 100 %
OH
THPO
HO
F
10
11, 33 % (over 2 steps)
Scheme 1. (i): Ac2O, Et3N, DMAP/CH3CN, rt; (ii) Et3N$3HF/THF, rt; (iii) DHP, TsOH/DMF, rt; (iv) NH3/MeOH, 0 ꢀC; (v) DAST, Py/DCM, rt; (vi) AcOH/THF/H2O 4:2:1, reflux.

ꢀ
P. Perlíkova et al. / Tetrahedron 68 (2012) 8300e8310
8302
Cl
N
R
N
N
N
N
F
i
N
F
O
O
HO
HO
HO
HO
12a-f
11
yield
R
12a 2-furyl
12b 3-furyl
47 %
39 %
12c 2-thienyl
12d 3-thienyl
12e phenyl
65 %
37 %
89 %
89 %
12f
2-benzofuryl
Scheme 2. (i) ReB(OH)2, Na2CO3, TPPTS, Pd(OAc)2, CH3CN/H2O, (2:1), 100 ꢀC.
were required for successful isolation and purification of the
anomers 16a,b,def and -anomers 17a,b. Nucleosides 16c and 17def
were obtained as crude compounds and were used in the following
stepwithoutfurtherpurification. Although -anomer17c was formed
b
-
inthe reactionwith2-thienyl-tributylstannane, we did not manage to
separate it from the -anomer 16c. The moderate isolated yields of
benzoylated difluoronucleosides 16 and 17 (11e33%) were caused by
significant loss of the material by repeated chromatographic
a
b
a
Scheme 3.

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P. Perlíkova et al. / Tetrahedron 68 (2012) 8300e8310
8303
Table 1
was removed under reduced pressure. The residue was dissolved in
EtOAc (60 ml), extracted with water and saturated aqueous
NaHCO3. The organic phase was dried over MgSO4 and evaporated
to give acetate 6 (3.61 g; 98%) as a colourless foam. IR (ATR): 1749,
1587, 1545, 1509, 1455, 1357, 1224, 1204, 1058, 1034 cmꢁ1. 1H NMR
(400 MHz, CDCl3): 0.97e1.30 (m, 28H, (CH3)2CH); 1.62 (s, 3H,
Optimization of synthesis of difluoroderivative 15
Base (equiv)
PTC (equiv)
Solvent
Other
conditions
Yield (%)
a/b ratio
KOH (2)
KOH (2)
KOH (2)
KOH (2.5)
TDA-1 (0.5)
TDA-1 (0.5)
TDA-1 (0.5)
TDA-1 (2)
Toluene
Toluene
Toluene
Toluene
rt, 24 h
3
10
19
6
1:2
1:2
1:2
1:2
50 ꢀC, 24 h
50 ꢀC, 48 h
50 ꢀC, 48 h
CH3CO); 3.90 (dt, 1H, J4 ,3 ¼8.6 Hz, J4 ,5 a¼J4 ,5 b¼3.1 Hz, H-40); 4.07
0
0
0
0
0
0
(dd, 1H, Jgem¼13.0 Hz, J5 a,4 ¼3.1 Hz, H-50a); 4.19 (dd, 1H,
0
0
0
0
0
0
0
0
0
Jgem¼13.0 Hz, J5 b,4 ¼3.1 Hz, H-5 b); 4.80 (t,1H, J3 ,4 ¼0 J3 ,2 ¼8.4 Hz, H-
separations. The deprotection of benzoyl groups with sodium meth-
oxide in methanol led to the target free 6-hetaryl-7-deazapurine 20-
30); 5.57 (dd, 1H, J2 ,3 ¼8.2 Hz, J2 ,1 ¼6.6 Hz, H-20); 6.62 (d, 1H,
0
0
0
0
0
0
J5,6¼3.8 Hz, H-5); 6.70 (d, 1H, J1 ,2 ¼6.6 Hz, H-1 ); 7.55 (d, 1H,
J6,5¼3.8 Hz, H-6); 8.61 (s, 1H, H-2). MS (ESI) m/z (%): 592 (100)
[(35Cl)MþNa], 594 (48) [(37Cl)MþNa]; HRMS (ESI) calcd for
C25H40O6N3ClNaSi2 [MþNa]: 592.20364; found: 592.20348.
deoxy-20,20-difluoro-
-erythro-pentofuranosyl nucleosides 18aef
D
and 19a,b,def in moderate to good yields (40e73%). Relative config-
uration of selected compounds 15e19 was established by two-
dimensional ROESY NMR spectra, where it was possible to observe
typical spacial contacts between some protons in a molecule. The
4.3. 4-Chloro-7-[2-O-acetyl-
[2,3-d]pyrimidine (7)
b-D-arabinofuranosyl]-7H-pyrrolo
characteristic spacial interactions for b-anomer found in the spectra
were between protons H-10 and H-40, further between H-6 and H-30
and sometimes also between proton H-6 and proton from hydroxyl
group OH-50. On the other hand, crosspeaks observed in the spectra of
Silylated acetate 6 (1.30 g, 2.28 mmol) was dissolved in anhy-
drous THF (40 ml) and Et3N$3HF (743 l, 4.56 mmol) was added.
The reaction mixture was stirred overnight. Then, the mixture was
co-evaporated with silica gel (10 g) and chromatographed on silica
m
a-anomer usually correspond with spacial contacts between proton
H-6 and H-40 and H-10 and H-30, respectively.
in 2% methanol in CHCl3. The title compound 7 (710 mg; 95%) was
3. Conclusion
20
obtained as a white solid. Mp 166e168 ꢀC. [
a]
þ4.9 (c 0.387,
D
DMSO). IR (ATR): 3468, 3269, 1733, 1592, 1551, 1507, 1460, 1412,
1363, 1223, 1203, 1136, 1096, 1047, 1021 cmꢁ1. 1H NMR (500 MHz,
DMSO-d6): 1.63 (s, 3H, CH3CO); 3.66 (br dt, 1H, Jgem¼12.2 Hz,
We have developed a synthesis of two new series of fluorinated
sugar-modified derivatives of previously discovered cytostatic 6-
hetaryl-7-deazapurine ribonucleosides. The synthesis of the fluo-
roribo derivatives was a seven-step (but efficient) sequence con-
cluded by aqueous Suzuki cross-coupling reactions of 6-chloro-7-
deazapurine 20-deoxy-20-fluororibonucleoside 11 with (het)aryl-
boronic acids. The synthesis of the 20,20-difluororibonucleosides
was more straightforward but much less selective and efficient. The
glycosidation of 14 with the sugar mesylate 13 gave a low yield of
an unseparable anomeric mixture of products. Only after the
follow-up cross-coupling and/or deprotection, the desired anom-
erically pure title nucleosides were obtained in moderate yields. All
the title compounds were tested for in vitro cytostatic (HL60, HeLa
S3, CCRF-CEM, Hep G2) and for anti-HCV activity. None of them
showed any considerable activity in any of these assays, apart from
J5 a,OH¼J5 a,4 ¼5.0 Hz, H-50a); 3.74 (br dt, 1H, Jgem¼12.2 Hz,
0
0
0
J5 b,OH¼J5 b,4 ¼4.3 Hz, H-50b); 3.87 (ddd, 1H, J4 ,3 ¼6.5 Hz,
0
0
0
0
0
J4 ,5 a¼4.8 Hz, J4 ,5 b¼3.6 Hz, H-40); 4.38 (br dt, 1H, J3 ,4 ¼6.5 Hz,
0
0
0
0
0
0
0
0
0
0
0
0
J3 ,OH¼J3 ,2 ¼5.5 Hz, H-3 ); 5.08 (br t, 1H, JOH,5 a¼JOH,5 b¼5.5 Hz, OH-
0
50); 5.30 (t, 1H, J2 ,1 ¼J2 ,3 ¼5.8 Hz, H-2 ); 5.83 (d, 1H, JOH,3 ¼5.3 Hz,
0
0
0
0
0
0
OH-30); 6.72 (d,1H, J1 ,2 ¼5.9 Hz, H-1 ); 6.73 (br d,1H, J5,6¼3.7 Hz, H-
5); 7.88 (d, 1H, J6,5¼3.8 Hz, H-6); 8.65 (s, 1H, H-2). 13C NMR
(125.7 MHz, DMSO-d6): 20.05 (CH3); 60.27 (CH2-50); 71.78 (CH-30);
77.87 (CH-20); 81.56 (CH-10); 83.00 (CH-40); 99.61 (CH-5); 117.00 (C-
4a); 129.72 (CH-6); 150.77 (CH-2); 150.85 and 150.88 (C-4, 7a);
169.19 (CO). MS (ESI) m/z (%): 328 (50) [(35Cl)MþH], 330 [(37Cl)
MþH] (22), 350 (100) [(35Cl)MþNa], 352 (46) [(37Cl)MþNa]; HRMS
(ESI) calcd for C13H14O5N3ClNa [MþNa]: 350.05142; found:
350.05136.
0
0
ca. mM cytotoxic and anti-HCV activities of bulky benzofuran-linked
nucleosides 18f and 9f. This lack of activity confirms that the potent
cytostatic effect of 6-hetaryl-7-deazapurine nucleosides is only
limited to ribonucleosides and sugar modification does not bring
any selectivity in this particular class of compounds.
4.4. 4-Chloro-7-[2-O-acetyl-3,5-di-O-(tetrahydropyran-2-yl)-
b-
D-arabinofuranosyl]-7H-pyrrolo[2,3-d]pyrimidine (8)
4. Experimental
4.1. General
Acetate
7 (658 mg, 2.01 mmol) and TsOH$H2O (764 mg,
4.02 mmol) were dissolved in anhydrous DMF (60 ml). The solution
was cooled to 0 ꢀC and 3,4-dihydro-2H-pyran (2.75 ml,
30.12 mmol) was added. The reaction mixture was stirred at 0 ꢀC
for 1 h and then was allowed to warm to rt and stirred overnight.
Afterwards, the reaction mixture was diluted with EtOAc (50 ml)
and extracted with saturated aqueous NaHCO3. The organic phase
was dried over MgSO4 and evaporated under reduced pressure. The
crude product was purified by column chromatography on silica
(hexane/EtOAc 4:1) to give title compound 8 (968 mg; 97%) as
a colourless oil. Mixture of four diastereomers (1:1:1:1). 1H NMR
(400 MHz, CDCl3): 1.46e1.97 (m, 48H, H-3,4,5-THP); 1.73,1.75,1.781
and 1.783 (4ꢂs, 4ꢂ3H, CH3CO); 3.45e3.60 (m, 8H, H-6a-THP);
3.66e3.77 (m, 4H, H-50a); 3.78e3.95 (m, 8H, H-6b-THP); 3.99e4.30
(m, 8H, H-40,50b); 4.46e4.62 (m, 4H, H-30); 4.67e4.91 (m, 8H, H-2-
THP); 5.39e5.42 and 5.58e5.64 (2ꢂm, 4H, H-20); 6.60e6.63 (m, 4H,
H-5); 6.80e6.86 (m, 4H, H-10); 7.58, 7.616, 7.620 and 7.64 (4ꢂd, 4H,
4ꢂJ6,5¼3.8 Hz, H-6); 8.63 and 8.64 (4ꢂs, 4H, H-2). MS (ESI) m/z (%):
518 (100) [(35Cl)MþNa], 520 (32) [(37Cl)MþNa]; HRMS (ESI) calcd
for C23H30O7N3ClNa [MþNa]: 518.16700; found: 518.16721.
NMR spectra were recorded using a 400 MHz (400 MHz for 1H),
500 MHz (500 MHz for 1H, 125.7 MHz for 13C, 470.3 MHz for 19F), or
600 MHz (600 MHz for 1H, 151 MHz for 13C) spectrometer. Melting
points were determined using a Kofler block and are uncorrected.
High-resolution mass spectra were measured using electrospray
ionization. High performance flash chromatography (HPFC) puri-
fications were performed either using silica gel columns with
hexane/EtOAc gradient or C-18 columns with H2O/MeOH gradient.
4.2. 4-Chloro-7-[2-O-acetyl-3,5-O-(tetraisopropyldisiloxan-1,3-
diyl)-b-D-arabinofuranosyl]-7H-pyrrolo[2,3-d]pyrimidine (6)
Arabinoside 54 (3.41 g, 6.46 mmol) was dissolved in anhydrous
acetonitrile (127 ml) and DMAP (79 mg, 0.65 mmol), triethylamine
(1.08 ml, 7.75 mmol) and acetic anhydride (731
added. The reaction mixture was stirred for 1 h. Then, the solvent
ml, 7.75 mmol) were

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P. Perlíkova et al. / Tetrahedron 68 (2012) 8300e8310
8304
0
0
0
0
4.5. 4-Chloro-7-[3,5-di-O-(tetrahydropyran-2-yl)-
furanosyl]-7H-pyrrolo[2,3-d]pyrimidine (9)
b
-
D
-arabino-
1H, Jgem¼12.2 Hz, J5 b,OH¼5.2 Hz, J5 b,4 ¼2.9 Hz, H-5 b); 3.97e4.01
(m, 1H, H-40); 4.43 (dtd, 1H, J3 ,F¼16.5 Hz, J3 ,4 ¼J3 ,OH¼6.0 Hz,
0
0
0
0
J3 ,2 ¼4.6 Hz, H-3 ); 5.16 (t, 1H, JOH,5 a¼JOH,5 b¼5.4 Hz, OH-50); 5.34
0
0
0
0
0
0
0
0
0
0
0
THP-protected acetate 8 (968 mg, 1.95 mmol) was dissolved in
methanolic ammonia (50 ml, 27%) at 0 ꢀC and stirred for 3 h. Then
the solution was evaporated in vacuo, resulting in arabinoside 9
(886 mg, 100%) as colourless foam. Mixture of four diastereomers
(1:1:1:1). 1H NMR (400 MHz, CDCl3): 1.50e1.93 (m, 48H, H-3,4,5-
THP); 3.51e3.69, 3.74e3.98, 4.01e4.57 and 4.66e4.86 (4ꢂm, 44H,
H-20,30,40,50 and H-2,6-THP); 6.57e6.065 (m, 6H, H-10, 5); 6.72 and
(ddd, 1H, J2 ,F¼53.00Hz, J2 ,3 ¼4.6 Hz, J2 ,1 ¼3.3 Hz, H-2 ); 5.73 (d, 10H,
0
0
0
0
JOH,3 ¼6.0 Hz, OH-3 ); 6.52 (dd, 1H, J1 ,F¼16.7 Hz, J1 ,2 ¼3.4 Hz, H-1 );
6.79 (dd, 1H, J4,3¼3.5 Hz, J4,5¼1.8 Hz, H-4-furyl); 7.08 (d, 1H,
J5,6¼3.8 Hz, H-5); 7.49 (dd, 1H, J3,4¼3.5 Hz, J3,5¼0.8 Hz, H-3-furyl);
7.94 (d, 1H, J6,5¼3.8 Hz, H-6); 8.06 (dd, 1H, J5,4¼1.8 Hz, J5,3¼0.8 Hz,
H-5-furyl); 8.80 (s, 1H, H-2). 13C NMR (150.9 MHz, DMSO-d6): 60.57
(CH2-50); 68.62 (d, JC,F¼15.8 Hz, CH-30); 84.01 (d, JC,F¼1.8 Hz, CH-
40); 85.30 (d, JC,F¼32.7 Hz, CH-10); 93.89 (d, JC,F¼187.2 Hz, C-20);
101.71 (CH-5); 112.80 (C-4a); 112.87 (CH-4-furyl); 113.62 (CH-3-
furyl); 128.01 (CH-6); 146.61 (CH-5-furyl); 146.74 (C-4); 151.36
(CH-2); 151.73 (C-7a); 152.51 (C-2-furyl). 19F NMR (470.3 MHz,
DMSO-d6): ꢁ200.36 (s, 1F, F-20). MS (ESI) m/z (%): 320 (100) [MþH],
342 (15) [MþNa]; HRMS (ESI) calcd for C15H15O4N3F [MþH]:
320.10411; found: 320.10413. For C15H14O4N3F$H2O calcd: 53.41% C,
4.78% H, 12.46% N; found: 53.43% C, 4.70% H, 12.06% N.
0
0
6.75 (2ꢂdd, 2H, 2ꢂJ1 ,2 ¼5.6 Hz, H-1 ); 7.73, 7.847, 7.850 and 7.75
(4ꢂd, 4H, 4ꢂJ6,5¼3.8 Hz, H-6); 8.631, 8.633 and 8.64 (4ꢂs, 4H, H-2).
MS (ESI) m/z (%): 454 (11) [(35Cl)MþH], 476 (100) [(35Cl)MþNa], 478
(32) [(37Cl)MþNa]; HRMS (ESI) calcd for C21H28O6N3ClNa [MþNa]:
476.15588; found: 476.15585.
4.6. 4-Chloro-7-[2-deoxy-2-fluoro-
rolo[2,3-d]pyrimidine (11)
b-D-ribofuranosyl]-7H-pyr-
Arabinoside 9 (575 mg, 1.27 mmol) was dissolved in anhydrous
4.8. 4-(Furan-3-yl)-7-[2-deoxy-2-fluoro-b-D-ribofuranosyl]-7H-
dichloromethane (35 ml) in a plastic vial. Anhydrous pyridine
pyrrolo[2,3-d]pyrimidine (12b)
(765
Then DAST (836
m
l, 9.50 mmol) was added and the solution was cooled to 0 ꢀC.
m
l, 6.33 mmol) was added. The reaction mixture
Compound 12b was prepared as described for compound 12a
from compound 11 (100 mg, 0.54 mmol) and furan-3-boronic acid.
The crude product was purified by column chromatography on
silica (1% methanol in CHCl3) and by reverse phase HPFC on C-18
(0/100% MeOH in water). Compound 12b (43 mg, 39%) was
obtained as an off-white crystalline solid after recrystallization
was allowed to warm to rt and was stirred overnight. The reaction
mixture was diluted with CHCl3 (30 ml) and extracted with aque-
ous NaHCO3 (saturated, 30 ml) and water (30 ml). The organic
phase was dried over MgSO4 and evaporated under reduced pres-
sure to obtain crude fluoroderivative 10, which was subsequently
dissolved in AcOH/THF/water mixture (4:2:1; 80.5 ml) and the
solution was heated to reflux for 1 h. The reaction mixture was co-
evaporated several times with toluene and the residue was chro-
matographed on silica gel column in 1.5% methanol in CHCl3. 2-
Deoxy-2-fluororibonucleoside 11 (120 mg, 33%) was obtained as
(10% MeOH in water). Mp 69e71 ꢀC. [
a
]
20 ꢁ32.2 (c 0.205, DMSO). IR
D
(ATR): 3243, 1580, 1518, 1454, 1432, 1102, 1079, 1020 cmꢁ1. 1H NMR
0
(500 MHz, DMSO-d6): 3.61 (ddd, 1H, Jgem¼12.2 Hz, J5 a,OH¼5.5 Hz,
0
0
0
0
J5 a,4 ¼3.9 Hz, H-50a); 3.76 (ddd, 1H, Jgem¼12.02 Hz, J5 b,OH¼5.2 Hz,
0
0
J5 b,4 ¼2.9 Hz, H-5 b); 3.97e4.01 (m, 1H, H-4 ); 4.43 (br dq, 1H,
J3 ,F¼16.7 Hz, J3 ,4 ¼J3 ,OH¼J3 ,2 ¼5.4 Hz, H-30); 5.17 (t, 1H,
0
0
0
0
0
0
a white crystalline solid after recrystallization (methanol/water
20
1:2). Mp 165e167 ꢀC. [
a]
ꢁ25.0 (c 0.395, DMSO). IR (ATR): 3187,
JOH,5 a¼JOH,5 b¼5.4 Hz, OH-500); 5.33 (ddd, 1H, J2 ,F¼53.0 Hz,
0
0
0
D
0
0
0
0
0
0
1590, 1546, 1503, 1452, 1419, 1354, 1274, 1201, 1086, 1057,
J2 ,3 ¼4.6 Hz, J2 ,1 ¼3.3 Hz, H-2 ); 5.73 (d, 1H, JOH,3 ¼5.7 Hz, OH-3 );
1025 cmꢁ1. 1H NMR (500 MHz, CD3OD): 3.78 (dd, 1H, Jgem¼12.4 Hz,
6.52 (dd, 1H, J1 ,F¼16.7 Hz, J1 ,2 ¼3.3 Hz, H-10); 7.12 (d, 1H,
J5,6¼3.8 Hz, H-5); 7.26 (dd, 1H, J4,5¼1.9 Hz, J4,2¼0.8 Hz, H-4-furyl);
7.90 (dd, 1H, J5,4¼1.8 Hz, J5,2¼1.6 Hz, H-5-furyl); 7.93 (d, 1H,
J6,5¼3.9 Hz, H-6); 8.74 (dd, 1H, J2,5¼1.5 Hz, J2,4¼0.8 Hz, H-2-furyl);
8.81 (s, 1H, H-2). 13C NMR (125.7 MHz, DMSO-d6): 60.56 (CH2-50);
68.60 (d, JC,F¼15.8 Hz, CH-30); 83.98 (d, JC,F¼1.8 Hz, CH-40); 85.35 (d,
JC,F¼32.6 Hz, CH-10); 93.94 (d, JC,F¼187.2 Hz, C-20); 101.28 (CH-5);
109.53 (CH-4-furyl); 114.65 (C-4a); 125.11 (C-3-furyl); 127.57 (CH-
6); 144.82 (CH-5-furyl); 145.14 (CH-2-furyl); 150.40 (C-4); 151.24
(C-7a); 151.35 (CH-2). 19F NMR (470.3 MHz, DMSO-d6): ꢁ200.28 (s,
1F, F-20). MS (ESI) m/z (%): 320 (100) [MþH], 342 (95) [MþNa];
HRMS (ESI) calcd for C15H15O4N3F [MþH]: 320.10411; found:
320.10412. For C15H14O4N3F$2.4H2O calcd: 49.70% C, 5.23% H,
11.59% N; found: 50.09% C, 4.89% H, 11.15% N.
0
0
0
0
0
0
0
0
J5 a,4 ¼3.5 Hz, H-5 a); 3.93 (dd, 1H, Jgem¼12.4 Hz, J5 b,4 ¼2.5 Hz, H-
50b); 4.11 (br dddd, 1H, J4 ,3 ¼6.5 Hz, J4 ,5 a¼3.5 Hz, J4 ,5 b¼2.5 Hz,
0
0
0
0
0
0
J4 ,F¼1.5 Hz, H-40); 4.57 (ddd, 1H, J3 ,F¼16.5 Hz, J3 ,4 ¼6.5 Hz,
0
0
0
0
J3 ,2 ¼4.7 Hz, H-30); 5.30 (ddd, 1H, J2 ,F¼53.0 Hz, J2 ,3 ¼4.7 Hz,
0
0
0
0
0
0
0
0
0
0
0
0
J2 ,1 ¼3.0 Hz, H-2 ); 6.53 (dd, 1H, J1 ,F¼16.8 Hz, J1 ,2 ¼3.0 Hz, H-1 );
6.72 (d, 1H, J5,6¼3.8 Hz, H-5); 7.88 (d, 1H, J6,5¼3.8 Hz, H-6); 8.60 (s,
13
1H, H-2). C NMR (125.7 MHz, CD3OD): 61.89 (CH2-50); 70.36 (d,
JC,F¼16.2 Hz, CH-30); 85.26 (CH-40); 88.25 (d, JC,F¼33.2 Hz, CH-10);
95.21 (d, JC,F¼188.5 Hz, CH-20); 101.36 (CH-5); 119.61 (C-4a); 129.64
(CH-6); 151.59 (CH-2); 152.22 (C-7a); 152.96 (C-4). 19F NMR
(470.3 MHz, CD3OD): ꢁ202.12. MS (ESI) m/z (%): 288 (8) [(35Cl)
MþH], 310 (100) [(37Cl)MþNa], 312 (48) [(37Cl)MþNa]; HRMS (ESI)
calcd for C11H12O3N3ClF [MþH]: 288.05457; found: 228.05457.
4.7. 4-(Furan-2-yl)-7-[2-deoxy-2-fluoro-
b
-D
-ribofuranosyl]-
4.9. 4-(Thiophene-2-yl)-7-[2-deoxy-2-fluoro-b-D-ribofuranosyl]-
7H-pyrrolo[2,3-d]pyrimidine (12a)
7H-pyrrolo[2,3-d]pyrimidine (12c)
An argon purged mixture of compound 11 (100 mg, 0.35 mmol),
furan-2-boronic acid (52 mg, 0.43 mmol), Na2CO3 (37 mg,
0.35 mmol), Pd(OAc)2 (3.9 mg, 0.017 mmol) and TPPTS (30 mg,
0.053 mmol) in water/MeCN (1:2, 2 ml) was stirred at 100 ꢀC for
2 h. After cooling the mixture was neutralized by the addition of
aqueous HCl (1 M), and volatiles were removed in vacuo. Purifica-
tion of the residue by column chromatography on silica (1%
methanol in CHCl3) and crystallization (H2O/methanol 2:1) affor-
ded compound 12a (52 mg, 47%) as a white crystalline solid. Mp
Compound 12c was prepared as described for compound 12a
from compound 11 (100 mg, 0.54 mmol) and thiophene-2-boronic
acid. The crude product was purified by reverse phase HPFC on C-18
(0/100% MeOH in water). Compound 12c (76 mg, 65%) was
obtained as a white crystalline solid after recrystallization (H2O/
20
MeOH 2:1). Mp 177e179 ꢀC. [
a
]
ꢁ37.0 (c 0.181, DMSO). IR (ATR):
D
3352, 1567, 1514, 1459, 1352, 1078, 1031, 1017 cmꢁ1 1H NMR
.
0
(500 MHz, DMSO-d6): 3.62 (ddd, 1H, Jgem¼12.3 Hz, J5 a,OH¼5.5 Hz,
0
0
0
0
J5 a,4 ¼3.8 Hz, H-5 0a); 3.76 (ddd, 1H, Jgem¼12.30Hz, J5 b,OH¼5.3 Hz,
159e161 ꢀC. [
a]
20 ꢁ42.7 (c 0.145, DMSO). IR (ATR): 3426, 1597, 1561,
J5 b,4 ¼2.9 Hz, H-5 b); 3.97e4.02 (m, 1H, H-4 ); 4.44 (dtd, 1H,
0
0
D
1458, 1080, 1019 cmꢁ1
.
1H NMR (600 MHz, DMSO-d6): 3.61 (ddd,
J3 ,F¼16.8 Hz, J3 ,4 ¼J3 ,OH¼6.1 Hz, J3 ,2 ¼4.6 Hz, H-3 ); 5.17 (t, 1H,
0
0
0
0
0
0
0
0
1H, Jgem¼12.2 Hz, J5 a,OH¼5.5 Hz, J5 a,4 ¼3.9 Hz, H-5 a); 3.75 (ddd,
JOH,5 a¼JOH,5 b¼5.4 Hz, OH-50); 5.34 (ddd, 1H, J2 ,F¼53.0 Hz,
0
0
0
0
0
0

ꢀ
P. Perlíkova et al. / Tetrahedron 68 (2012) 8300e8310
8305
0
0
0
0
0
0
0
J2 ,3 ¼4.5 Hz, J2 ,1 ¼3.3 Hz, H-2 ); 5.73 (d, 1H, JOH,3 ¼6.0 Hz, OH-3 );
(d, 1H, J6,5¼3.8 Hz, H-6); 8.17 (m, 2H, H-o-Ph); 8.92 (s, 1H, H-2). 13
C
NMR (125.7 MHz, DMSO-d6): 60.58 (CH2-50); 68.64 (d, JC,F¼15.8 Hz,
CH-30); 84.03 (d, JC,F¼1.8 Hz, CH-40); 85.43 (d, JC,F¼32.6 Hz, CH-10);
93.97 (d, JC,F¼187.2 Hz, C-20); 101.53 (CH-5); 115.66 (C-4a); 128.09
(CH-6); 128.87 (CH-o-Ph); 129.16 (CH-m-Ph); 130.58 (CH-p-Ph);
137.57 (C-i-Ph); 151.42 (CH-2); 151.66 (C-7a); 156.54 (C-4). 19F NMR
(470.3 MHz, DMSO-d6): ꢁ200.36 (s, 1F, F-20). MS (ESI) m/z (%): 330
(100) [MþH]; HRMS (ESI) calcd for C17H17O3N3F [MþH]: 330.12485;
found: 330.12484. For C17H16O3N3F$2.2H2O calcd: 55.34% C, 5.57%
H, 11.39% N; found: 55.42% C, 5.38% H, 11.08% N.
6.53 (dd, 1H, J1 ,F¼16.7 Hz, J1 ,2 ¼3.3 Hz, H-10); 7.21 (d, 1H,
J5,6¼3.9 Hz, H-5); 7.31 (dd, 1H, J4,5¼5.0 Hz, J4,3¼3.8 Hz, H-4-
thienyl); 7.87 (dd, 1H, J5,4¼5.0 Hz, J5,3¼1.1 Hz, H-5-thienyl); 7.98
(d, 1H, J6,5¼3.9 Hz, H-6); 8.18 (dd, 1H, J3,4¼3.8 Hz, J3,5¼1.1 Hz, H-3-
thienyl); 8.78 (s, 1H, H-2). 13C NMR (125.7 MHz, DMSO-d6): 60.52
(CH2-50); 68.58 (d, JC,F¼15.8 Hz, CH-30); 83.99 (d, JC,F¼1.8 Hz, CH-
40); 85.41 (d, JC,F¼32.6 Hz, CH-10); 93.96 (d, JC,F¼187.1 Hz, C-20);
101.33 (CH-5); 113.12 (C-4a); 128.18 (CH-6); 129.26 (CH-4-thienyl);
129.87 (CH-3-thienyl); 131.05 (CH-5-thienyl); 142.42 (C-2-thienyl);
150.45 (C-4); 151.12 (CH-2); 151.64 (C-7a). 19F NMR (470.3 MHz,
DMSO-d6): ꢁ200.19 (s, 1F, F-20). MS (ESI) m/z (%): 336 (100) [MþH];
HRMS (ESI) calcd for C15H15O3N3FS [MþH]: 336.08127; found:
336.08121. For C15H14O3N3FS calcd: 53.72% C, 4.21% H, 12.53% N;
found: 53.45% C, 4.10% H, 12.18% N.
0
0
0
4.12. 4-(Benzofuran-2-yl)-7-[2-deoxy-2-fluoro-b-D-ribofur-
anosyl]-7H-pyrrolo[2,3-d]pyrimidine (12f)
Compound 12f was prepared as described for compound 12a
from compound 11 (100 mg, 0.54 mmol) and benzofuran-2-boronic
acid. The crude product was purified by reverse phase HPFC on C-18
4.10. 4-(Thiophene-3-yl)-7-[2-deoxy-2-fluoro-
anosyl]-7H-pyrrolo[2,3-d]pyrimidine (12d)
b-D-ribofur-
(0/100% MeOH in water). Compound 12f (114 mg, 89%) was
20
obtained as an off-white amorphous solid. Mp 189e193 ꢀC. [
a]
D
Compound 12d was prepared as described for compound 12a
from compound 11 (100 mg, 0.54 mmol) and thiophene-3-boronic
acid. The crude product was purified by column chromatography
on silica (1% methanol in CHCl3) and by reverse phase HPFC on C-18
(0/100% MeOH in water). Compound 12d (43 mg, 37%) was
ꢁ47.8 (c 0.209, DMSO). IR (ATR): 3241, 1599, 1567, 1549, 1461, 1228,
1101, 1057 cmꢁ1 1H NMR (500 MHz, DMSO-d6): 3.63 (br dm, 1H,
.
Jgem¼12.2 Hz, H-50a); 3.76 (br dm, 1H, Jgem¼12.2 Hz, H-50b);
3.98e4.03 (m, 1H, H-40);0 4.46 (br dq, 1H, J3 ,F¼16.8 Hz,
0
0
0
0
0
0
0
J3 ,4 ¼J3 ,OH¼J3 ,2 ¼5.0 Hz, H-3 ); 4.98e5.24 (m, 1H, OH-5 ); 5.37
obtained as an off-white crystalline solid after recrystallization
0
0
0
0
0
0
(ddd, 1H, J2 ,F¼53.0 Hz,0 J2 ,3 ¼4.6 Hz, J2 ,1 ¼3.4 Hz, H-2 ); 5.78 (br d,
20
(H2O/EtOH 3:1). Mp 179e181 ꢀC. [
a
]
ꢁ41.3 (c 0.234, DMSO). IR
D
0
0
0
0
1H, JOH,3 ¼5.5 Hz, OH-3 ); 6.56 (dd,1H, J1 ,F¼16.8 Hz, J1 ,2 ¼3.3 Hz, H-
10); 7.30 (d, 1H, J5,6¼3.8 Hz, H-5); 7.36 (br td, 1H, J5,4¼J5,6¼7.5 Hz,
J5,7¼0.9 Hz, H-5-benzofuryl); 7.48 (ddd, 1H, J6,7¼8.3 Hz, J6,5¼7.2 Hz,
J6,4¼1.3 Hz, H-6-benzofuryl); 7.81 (br dq, 1H, J7,6¼8.4 Hz,
J7,5¼J7,4¼J7,3¼0.8 Hz, H-7-benzofuryl); 7.82 (br dm, 1H, J4,5¼7.8 Hz,
H-4-benzofuryl); 7.94 (d, 1H, J3,7¼1.0 Hz, H-3-benzofuryl); 8.05 (d,
1H, J6,5¼3.8 Hz, H-6); 8.90 (s,1H, H-2). 13C NMR (125.7 MHz, DMSO-
d6): 60.33 (CH2-50); 68.59 (d, JC,F¼15.8 Hz, CH-30); 84.03 (d,
JC,F¼1.7 Hz, CH-40); 85.43 (d, JC,F¼32.7 Hz, CH-10); 93.98 (d,
JC,F¼187.3 Hz, C-20); 102.02 (CH-5); 109.33 (CH-3-benzofuryl);
112.12 (CH-7-benzofuryl); 114.16 (C-4a); 122.66 (CH-4-benzofuryl);
124.02 (CH-5-benzofuryl); 126.77 (CH-6-benzofuryl); 127.94 (C-3a-
benzofuryl); 128.74 (CH-6); 146.64 (C-4); 151.42 (CH-2); 152.00 (C-
7a); 154.10 (C-2-benzofuryl); 155.52 (C-7a-benzofuryl). 19F NMR
(470.3 MHz, DMSO-d6): ꢁ200.18 (s, 1F, F-20). MS (ESI) m/z (%): 370
(100) [MþH]; HRMS (ESI) calcd for C19H17O4N3F [MþH]: 370.11976;
found: 370.11969. For C19H16O4N3F calcd: 61.79% C, 4.37% H, 11.38%
N; found: 61.50% C, 4.12% H, 11.09% N.
(ATR): 3351, 1566, 1518, 1463, 1350, 1079, 1033, 1019 cmꢁ1. 1H NMR
0
(500 MHz, DMSO-d6): 3.62 (ddd, 1H, Jgem¼12.2 Hz, J5 a,OH¼5.5 Hz,
0
0
0
0
J5 a,4 ¼3.9 Hz, H-50a); 3.76 (ddd, 1H, Jgem¼12.2 Hz, J5 b,OH¼5.2 Hz,
0
0
0
J5 b,4 ¼2.9 Hz, H-5 b); 3.98e4.02 (m, 1H, H-4 ); 4.44 (br dq, 1H,
J3 ,F¼16.7 Hz, J3 ,4 ¼J3 ,OH¼J3 ,2 ¼5.5 Hz, H-30); 5.17 (t, 1H,
0
0
0
0
0
0
JOH,5 a¼JOH,5 b¼5.4 Hz, OH-500); 5.34 (ddd, 1H, J2 ,F¼53.0 Hz,
0
0
0
0
0
0
0
0
0
J2 ,3 ¼4.6 Hz, J2 ,1 ¼3.4 Hz, H-2 ); 5.73 (d, 1H, JOH,3 ¼5.9 Hz, OH-3 );
6.54 (dd, 1H, J1 ,F¼16.8 Hz, J1 ,2 ¼3.4 Hz, H-10); 7.17 (d, 1H,
J5,6¼3.8 Hz, H-5); 7.75 (dd, 1H, J5,4¼5.1 Hz, J5,2¼2.9 Hz, H-5-
thienyl); 7.96 (dd, 1H, J4,5¼5.1 Hz, J4,2¼1.3 Hz, H-4-thienyl); 7.96
(d, 1H, J6,5¼3.8 Hz, H-6); 8.55 (dd, 1H, J2,5¼2.9 Hz, J2,4¼1.3 Hz, H-2-
thienyl); 8.84 (s, 1H, H-2). 13C NMR (125.7 MHz, DMSO-d6): 60.56
(CH2-50); 68.62 (d, JC,F¼15.9 Hz, CH-30); 83.99 (d, JC,F¼1.8 Hz, CH-
40); 85.36 (d, JC,F¼32.7 Hz, CH-10); 93.94 (d, JC,F¼187.2 Hz, C-20);
101.51 (CH-5); 114.68 (C-4a); 127.37 (CH-5-thienyl); 127.58 (CH-4-
thienyl); 127.86 (CH-6); 128.88 (CH-2-thienyl); 139.93 (C-3-
thienyl); 151.30 (CH-2); 151.68 (C-7a); 151.81 (C-4). 19F NMR
(470.3 MHz, DMSO-d6): ꢁ200.27 (s, 1F, F-20). MS (ESI) m/z (%): 336
(100) [MþH]; HRMS (ESI) calcd for C15H15O3N3FS [MþH]:
336.08127; found: 336.08141. For C15H14O3N3FS calcd: 53.72% C,
4.21% H, 12.53% N; found: 53.54% C, 4.11% H, 12.21% N.
0
0
0
4.13. 4-Chloro-7-[3,5-di-O-benzoyl-2-deoxy-2,2-difluoro-
a,b-
D-erythro-pentofuranosyl]-7H-pyrrolo[2,3-d]pyrimidine (15)
4.11. 4-Phenyl-7-[2-deoxy-2-fluoro-
pyrrolo[2,3-d]pyrimidine (12e)
b
-
D
-ribofuranosyl]-7H-
6-Chloro-7-deazapurine (14) (5 g, 32.6 mmol) was dissolved in
anhydrous toluene (250 ml) and KOH (3.71 g, 65.1 mmol), TDA-1
(5.21 ml, 16.3 mmol) and mesylate 13 (29.71 g, 65.1 mmol) were
added. The reaction mixture was stirred at 50 ꢀC for 48 h. Then, the
reaction mixture was diluted with EtOAc (100 ml) and extracted
with aqueous HCl (1 M, 150 ml) and water (150 ml). Organic phase
was dried over MgSO4 and evaporated under reduced pressure. The
crude reaction product was purified by column chromatography on
silica (hexane/EtOAc 10:1) to obtain crude nucleoside 15 (3.16 g,
Compound 12e was prepared as described for compound 12a
from compound 11 (100 mg, 0.54 mmol) and phenylboronic acid.
The crude product was purified by reverse phase HPFC on C-18
(0/100% MeOH in water). Compound 12e (102 mg, 89%) was
obtained as a white crystalline solid after recrystallization (H2O/
20
MeOH 2:1). Mp 70e73 ꢀC. [
a
]
ꢁ31.6 (c 0.263, DMSO). IR (ATR):
D
3273, 1560, 1521, 1467, 1360, 1238, 1113, 1061, 1041 cmꢁ1. 1H NMR
19%) as a mixture of anomers (a/b 1:2). Colourless amorphous solid.
(500 MHz, DMSO-d6): 3.62 (ddd, 1H, Jgem¼12.3 Hz, J5 a,OH¼5.4 Hz,
1H NMR (400 MHz, CDCl3): 4.63e4.68 (m, 2H, -H-40); 4.71e4.75
b
0
0
J5 a,4 ¼3.9 Hz, H-5 0a); 3.76 (ddd, 1H, Jgem¼12.2 0Hz, J5 b,OH¼5.3 Hz,
(m, 4H, b a a
-H-50a, -H-50a,
-H-50b); 4.85 (dd, 2H, Jgem¼12.4 Hz,
0
0
0
J5 b,4 ¼2.9 Hz, H-5 b); 3.98e4.02 (m, 1H, H-4 ); 4.45 (dtd, 1H,
J4 ,5 ¼3.6 Hz,
b a
-H-50b); 4.96e5.02 (m, 1H, -H-40); 5.84e5.92 (m,
0
0
0
0
0
J3 ,F¼16.6 Hz, J3 ,4 ¼J3 ,OH¼6.1 Hz, J3 ,2 ¼4.6 Hz, H-3 ); 5.18 (t, 1H,
3H,
a
-H-30,
b
-H-30); 6.69e6.76 (m, 5H, -H-10,
b a-H-5, b
-H-5); 6.98
-H-
-H-p-Bz); 8.02e8.14 (m,
0
0
0
0
0
0
JOH,5 a¼JOH,5 b¼5.4 Hz, OH-500); 5.36 (ddd, 1H, J2 ,F¼53.0 Hz,
(dd, 1H, J1 ,F¼12.4 Hz, J1 ,F¼6.4 Hz,
a a
-H-10); 7.44e7.68 (m, 21H,
0
0
0
0
0
0
0
0
0
0
0
J2 ,3 ¼4.6 Hz, J2 ,1 ¼3.4 Hz, H-2 ); 5.75 (d, 1H, JOH,3 ¼6.0 Hz, OH-3 );
6,
b
-H-6,
a
-H-m-Bz,
b
-H-m-Bz,
a-H-p-Bz,
b
6.56 (dd, 1H, J1 ,F¼16.7 Hz, J1 ,2 ¼3.4 Hz, H-10); 7.04 (d, 1H,
12H,
a-H-o-Bz,
b
-H-o-Bz); 8.68 (s, 2H,
b
-H-2), 8.69 (s, 1H, a-H-2).
0
0
0
J5,6¼3.8 Hz, H-5); 7.58 (m, 1H, H-p-Ph); 7.60 (m, 2H, H-m-Ph); 7.98
MS (ESI) m/z (%): 514 (36) [(35Cl)MþH], 516 (9) [(37Cl)MþH], 536

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P. Perlíkova et al. / Tetrahedron 68 (2012) 8300e8310
8306
(100) [(35Cl)MþNa], 538 (32) [(37Cl)MþNa]; HRMS (ESI) calcd for
C25H19O5N3ClF2 [MþH]: 514.09758, found 514.09760.
Jgem¼246.0 Hz). MS (ESI) m/z (%): 546 (75) [MþH], 568 (100)
[MþNa]; HRMS (ESI) calcd for C29H22O6N3F2 [MþH]: 546.14712,
found 536.14740. Compound 17b: IR (ATR): 1725, 1601, 1572, 1452,
1264, 1108, 1095, 1070, 1026 cmꢁ1. 1H NMR (400 MHz, CDCl3): 4.73
4.14. 4-(Furan-2-yl)-7-[3,5-di-O-benzoyl-2-deoxy-2,2-difluoro-
0
0
0
0
0
b-D-erythro-pentofuranosyl]-7H-pyrrolo[2,3-d]pyrimidine (16a)
(br d, 2H, J4 ,5 ¼4.4 Hz, H-5 a, H-5 b); 4.97e5.01 (m, 1H, H-4 ); 5.92
(dt, 1H, J3 ,F¼12.0 Hz, J3 ,F¼J3 ,4 ¼5.2 Hz, H-30); 6.87 (d, 1H,
0
0
0
0
and 4-(furan-2-yl)-7-[3,5-di-O-benzoyl-2-deoxy-2,2-difluoro-
erythro-pentofuranosyl]-7H-pyrrolo[2,3-d]pyrimidine (17a)
a-D-
J5,6¼4.0 Hz, H-5); 7.07 (dd, 1H, J1 ,F¼8.8 Hz, J1 ,F¼6.4 Hz, H-10); 7.19
(br s, 1H, H-4-furyl); 7.44e7.67 (m, 8H, H-6, H-m-Bz, H-p-Bz, H-5-
furyl); 8.07e8.13 (m, 4H, H-o-Bz); 8.34 (br s, 1H, H-2-furyl); 8.93
(s, 1H, H-2). 13C NMR (125.7 MHz, CDCl3): 63.35 (CH2-50); 72.51 (dd,
JC,F¼33.2 and 17.1 Hz, CH-30); 80.23 (dd, JC,F¼5.3 and 1.9 Hz, CH-40);
83.63 (dd, JC,F¼41.3 and 21.0 Hz, CH-10); 102.23 (CH-5); 109.45 (CH-
4-furyl); 114.88 (C-4a); 121.90 (dd, JC,F¼268.6 and 256.7 Hz, C-20);
124.85 (C-3-furyl); 126.36 (CH-6); 127.99 (C-i-Bz); 128.53, 128.77
(CH-m-Bz); 129.12 (C-i-Bz); 129.82, 130.03 (CH-o-Bz); 133.48,
134.21 (CH-p-Bz); 144.14, 144.17 (CH-2,5-furyl); 151.30 (C-4);
151.84 (CH-2); 152.46 (C-7a); 164.75, 166.06 (CO-Bz). 19F{1H} NMR
(470.3 MHz, CDCl3): ꢁ116.41 and ꢁ104.41 (2ꢂd, 2ꢂ1F,
Jgem¼249.2 Hz). MS (ESI) m/z (%): 546 (55) [MþH], 568 (100)
[MþNa]; HRMS (ESI) calcd for C29H22O6N3F2 [MþH]: 546.14712,
found 536.14742.
0
0
An argon purged mixture of compound 15 (750 mg, 1.46 mmol),
2-(tributylstannanyl)furan (781 mg, 2.19 mmol) and PdCl2(PPh3)2
(51 mg, 0.073 mmol) in anhydrous DMF (5 ml) was stirred at 105 ꢀC
for 2 h. After cooling, volatiles were removed in vacuo. The residue
was purified by multiple HPFC on silica column (0e100% EtOAc in
hexane) to give 16a (262 mg, 33%) and 17a (86 mg, 11%) as yel-
lowish oils. Compound 16a: IR (ATR): 1730, 1602, 1453, 1270, 1095,
1071 cmꢁ1
.
1H NMR (400 MHz, CDCl3): 4.66 (br q, 1H,
J4 ,5 b¼J4 ,5 a¼J3 ,4 ¼4.4 Hz, H-40); 4.74 (dd, 1H, Jgem¼12.0 0Hz,
0
0
0
0
0
0
0
0
0
0
0
J4 ,5 ¼4.4 Hz, H-5 a); 4.86 (dd,1H, Jgem¼12.0 Hz, J4 ,5 ¼3.2 Hz,0H-5 b);
0
0
0
0
5.85 (ddd, 1H, J3 ,F¼14.0 Hz, J3 ,F¼5.2 Hz, J3 ,4 ¼3.2 Hz, H-3 ); 6.67
(dd, 1H, J3,4¼3.6 Hz, J4,5¼2.0 Hz, H-4-furyl); 6.83 (dd, 1H,
J1 ,F¼12.4 Hz, J1 ,F¼6.4 Hz, H-10); 7.16 (d, 1H, J5,6¼4.0 Hz, H-5);
7.44e7.68 (m, 8H, H-6, H-m-Bz, H-p-Bz, H-3-furyl); 7.74 (d, 1H,
J5,4¼0.9 Hz, H-5-furyl); 8.07e8.16 (m, 4H, H-o-Bz); 8.90 (s, 1H, H-2).
MS (ESI) m/z (%): 546 (40) [MþH], 568 (100) [MþNa]; HRMS (ESI)
calcd for C29H22O6N3F2 [MþH]: 546.14712, found 536.14685. 17a: IR
(ATR): 1730, 1453, 1266, 1109, 1096, 1071 cmꢁ1. 1H NMR (400 MHz,
0
0
4.16. 4-(Thiophene-2-yl)-7-[3,5-di-O-benzoyl-2-deoxy-2,2-
difluoro-b-D-erythro-pentofuranosyl]-7H-pyrrolo[2,3-d]pyrimi-
dine (16c)
0
0
0
0
CDCl3): 4.73 (br d, 2H, J4 ,5 ¼4.4 Hz, H-5 a, H-5 b); 4.97e05.01 (m, 1H,
Compound 16c was prepared as described for compounds 16a
and 17a from compound 15 (750 mg, 1.46 mmol) and 2-(tributyl-
stannyl)thiophene. The crude reaction mixture was partially sepa-
rated by multiple HPFC on silica gel column (0/100% EtOAc in
hexane). Crude compound 16c (121 mg) was used for the next step
without further purification.
H-40); 5.91 (dt, 1H, J3 ,F¼11.6 Hz, J3 ,F¼J3 ,4 ¼4.8 Hz, H-3 ); 6.67 (dd,
0
0
0
0
0
1H, J3,4¼3.6 Hz, J4,5¼2.0 Hz, H-4-furyl); 7.06 (dd, 1H, J1 ,F¼8.8 Hz,
J1 ,F¼6.4 Hz, H-10); 7.21 (d, 1H, J5,6¼4.0 Hz, H-5); 7.44e7.67 (m, 8H,
0
H-6, H-m-Bz, H-p-Bz, H-3-furyl); 7.74 (d, 1H, J5,4¼1.2 Hz, H-5-furyl);
8.06e8.12 (m, 4H, H-o-Bz); 8.90 (s, 1H, H-2). MS (ESI) m/z (%): 546
(35) [MþH], 568 (100) [MþNa]; HRMS (ESI) calcd for C29H22O6N3F2
[MþH]: 546.14712, found 536.14666.
4.17. 4-(Thiophene-3-yl)-7-[3,5-di-O-benzoyl-2-deoxy-2,2-
difluoro-
dine (16d) and 4-(thiophene-3-yl)-7-[3,5-di-O-benzoyl-2-deoxy-
2,2-difluoro- -erythro-pentofuranosyl]-7H-pyrrolo[2,3-d]py-
rimidine (17d)
b-D-erythro-pentofuranosyl]-7H-pyrrolo[2,3-d]pyrimi-
4.15. 4-(Furan-3-yl)-7-[3,5-di-O-benzoyl-2-deoxy-2,2-difluoro-
b-D-erythro-pentofuranosyl]-7H-pyrrolo[2,3-d]pyrimidine (16b)
a-D
and 4-(furan-3-yl)-7-[3,5-di-O-benzoyl-2-deoxy-2,2-difluoro-
a-D-
erythro-pentofuranosyl]-7H-pyrrolo[2,3-d]pyrimidine (17b)
Compounds 16d and 17d were prepared as described for com-
pounds 16b and 17b from compound 15 (1.00 g, 1.95 mmol) and
thiophene-3-boronic acid. The crude reaction mixture was partially
separated by multiple HPFC on silica gel column (0/100% EtOAc in
hexane). Compounds 16d (337 mg, 31%) and crude compound 17d
(210 mg) were obtained as yellowish oils. Compound 17d was used
for the next step without further purification. Compound 16d: IR
(ATR): 1725, 1568, 1519, 1453, 1265, 1094, 1070, 1027 cmꢁ1. 1H NMR
(400 MHz, CDCl3): 4.65e4.70 0 (m, 1H, H-40); 4.74 (dd, 1H,
An argon purged mixture of compound 15 (1.00 g, 1.95 mmol),
furan-3-boronic acid (326 mg, 2.92 mmol), K2CO3 (537 mg,
3.89 mmol) and Pd(PPh3)4 (112 mg, 0.097 mmol) in anhydrous
toluene (16 ml) was stirred at 85 ꢀC for 2 h. After cooling, the re-
action mixture was diluted with EtOAc (30 ml) and extracted with
aqueous HCl (1 M, 20 ml) and water (20 ml). The organic phase was
dried over MgSO4 and evaporated under reduced pressure. The
residue was purified by multiple HPFC on silica column (0e100%
EtOAc in hexane) to give 16b (298 mg, 28%) and 17b (120 mg, 11%)
as yellowish oils. Compound 16b: IR (ATR): 1722, 1600, 1572, 1518,
1452, 1263, 1090, 1068, 1025 cmꢁ1. 1H NMR (400 MHz, CDCl3): 4.67
0
0
Jgem¼12.0 Hz, J4 ,5 ¼4.4 Hz, H-5 a); 4.86 (dd, 1H, Jgem¼12.0 Hz,
J4 ,5 ¼3.2 Hz, H-50b); 5.86 (ddd, 1H, J3 ,F¼14.0 Hz, J3 ,F¼5.2 Hz,
0
0
0
0
J3 ,4 ¼2.8 Hz, H-3 ); 6.86 (dd, 1H, J1 ,F¼12.4 Hz, J1 ,F¼6.4 Hz, H-10);
6.93 (d, 1H, Ji¼3.6 Hz, H-5); 7.43e7.68 (m, 8H, H-6, H-m-Bz, H-p-Bz,
H-5-thienyl); 7.90 (br d, 1H, J5,4¼4.8, H-4-thienyl); 8.07e8.16 (m,
4H, H-o-Bz); 8.29 (br s, 1H, H-2-thienyl); 8.97 (s, 1H, H-2). MS (ESI)
m/z (%): 562 (100) [MþH], 584 (70) [MþNa]; HRMS (ESI) calcd for
C29H22O5N3F2S [MþH]: 562.12427, found 562.12425.
0
0
0
0
0
(br q, 1H, J4 ,5 b¼J4 ,5 a¼J3 ,4 ¼0 4.4 Hz, H-40); 4.74 (dd, 1H,
0
0
0
0
0
0
0
0
Jgem¼12.4 Hz, J4 ,5 ¼4.8 Hz, H-5 a); 4.86 (dd, 1H, Jgem¼12.0 Hz,
J4 ,5 ¼3.2 Hz, H-50b); 5.85 (ddd, 1H, J3 ,F¼14.0 Hz, J3 ,F¼5.2 Hz,
0
0
0
0
0
0
0
0
J3 ,4 ¼3.2 Hz, H-3 ); 6.81e6.87 (m, 2H, H-1 , H-5); 7.18 (br s, 1H, H-4-
furyl); 7.44e7.68 (m, 8H, H-6, H-m-Bz, H-p-Bz, H-5-furyl);
8.08e8.15 (m, 4H, H-o-Bz); 8.34 (br s, 1H, H-2-furyl); 8.90 (s, 1H, H-
2). 13C NMR (125.7 MHz, CDCl3): 62.88 (CH2-50); 71.75 (dd, JC,F¼34.6
and 16.8 Hz, CH-30); 77.80 (dd, JC,F¼4.0 and 2.3 Hz, CH-40); 82.33
(dd, JC,F¼37.0 and 21.1 Hz, CH-10); 102.22 (CH-5); 109.41 (CH-4-
furyl); 115.11 (C-4a); 120.69 (dd, JC,F¼265.0 and 259.1 Hz, C-20);
124.89 (C-3-furyl); 126.83 (d, JC,F¼4.1 Hz, CH-6); 127.95 (C-i-Bz);
128.53, 128.67 (CH-m-Bz); 129.21 (C-i-Bz); 129.70, 130.11 (CH-o-
Bz); 133.46, 134.15 (CH-p-Bz); 144.08, 144.10 (CH-2,5-furyl); 151.35
(C-4); 151.81 (CH-2); 152.34 (C-7a); 164.84, 166.01 (CO-Bz). 19F{1H}
NMR (470.3 MHz, CDCl3): ꢁ117.00 and ꢁ110.74 (2ꢂd, 2ꢂ1F,
4.18. 4-Phenyl-7-[3,5-di-O-benzoyl-2-deoxy-2,2-difluoro-
erythro-pentofuranosyl]-7H-pyrrolo[2,3-d]pyrimidine (16e)
and 4-phenyl-7-[3,5-di-O-benzoyl-2-deoxy-2,2-difluoro-
erythro-pentofuranosyl]-7H-pyrrolo[2,3-d]pyrimidine (17e)
b-D-
a-D-
Compounds 16e and 17e were prepared as described for com-
pounds 16b and 17b from compound 15 (750 mg, 1.46 mmol) and
phenylboronic acid. The crude reaction mixture was partially sep-
arated by multiple HPFC on silica gel column (0/100% EtOAc in

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P. Perlíkova et al. / Tetrahedron 68 (2012) 8300e8310
8307
hexane). Compounds 16e (267 mg, 32%) and crude compound 17e
(236 mg) were obtained as yellowish oils. Compound 17e was used
for the next step without further purification. Compound 16e: IR
(ATR): 1724, 1568, 1519, 1452, 1264, 1093, 1069, 1026 cmꢁ1. 1H NMR
(400 MHz, CDCl3): 4.65e4.70 0 (m, 1H, H-40); 4.75 (dd, 1H,
(2ꢂd, 2ꢂ1F, Jgem¼234.3 Hz). MS (ESI) m/z (%): 338 (50) [MþH], 360
(100) [MþNa]; HRMS (ESI) calcd for C15H14O4N3F2 [MþH]:
338.09469; found: 338.09466. For C15H13O4N3F2 calcd: 53.42% C,
3.88% H, 12.46% N; found: 53.03% C, 4.12% H, 12.20% N.
0
0
Jgem¼12.0 Hz, J4 ,5 ¼4.4 Hz, H-5 a); 4.86 (dd, 1H, Jgem¼12.4 Hz,
J4 ,5 ¼3.6 Hz, H-50b); 5.87 (ddd, 1H, J3 ,F¼14.0 Hz, J3 ,F¼5.2 Hz,
4.21. 4-(Furan-3-yl)-7-[2-deoxy-2,2-difluoro-b-D-erythro-pen-
0
0
0
0
0
J3 ,4 ¼3.2 Hz, H-3 ); 6.87 (dd, 1H, J1 ,F¼12.4 Hz, J1 ,F¼6.4 Hz, H-10);
6.93 (d, 1H, J5,6¼3.6 Hz, H-5); 7.44e7.68 (m, 10H, H-6, H-m-Bz, H-p-
Bz, H-m-Ph, H-p-Ph); 8.08e8.15 (m, 6H, H-o-Bz, H-o-Ph); 9.04 (s,
1H, H-2). MS (ESI) m/z (%): 556 (80) [MþH], 578 (100) [MþNa];
HRMS (ESI) calcd for C31H24O5N3F2 [MþH]: 556.16785, found
556.16784.
tofuranosyl]-7H-pyrrolo[2,3-d]pyrimidine (18b)
0
0
0
0
Compound 18b was prepared as described for compound 18a.
Compound 16b (193 mg, 0.35 mmol) was used. The crude product
was purified by column chromatography (2% MeOH in CHCl3) and
reverse phase HPFC on C-18 column (methanol in H2O 0e100%) to
give compound 18b (92 mg, 78%) as a yellowish crystalline solid after
20
4.19. 4-(Benzofuran-2-yl)-7-[3,5-di-O-benzoyl-2-deoxy-2,2-
recrystallization (H2O/methanol 2:1). Mp 85e86 ꢀC. [
a]
D
þ17.1 (c
difluoro-
dine (16f) and 4-(benzofuran-2-yl)-7-[3,5-di-O-benzoyl-2-deoxy-
2,2-difluoro- -erythro-pentofuranosyl]-7H-pyrrolo[2,3-d]py-
rimidine (17f)
b-D-erythro-pentofuranosyl]-7H-pyrrolo[2,3-d]pyrimi-
0.211, DMSO). IR (ATR): 3432, 1596, 1574, 1512, 1212, 1071, 1056, 1030,
1010 cmꢁ1 1H NMR (500 MHz, DMSO-d6): 3.70 (ddd, 1H,
.
0
0
0
0
a-D
Jgem¼12.6 Hz, J5 a,OH¼5.9 Hz, J5 a,4 ¼4.1 Hz, H-5 a); 3.82 (br dm, 1H,
Jgem¼12.6 Hz, H-50b); 3.93e3.97 (m, 1H, H-40); 4.42e4.51 (m, 1H, H-
30); 5.27 (t, 1H,0 JOH,5 a¼JOH,5 b¼5.5 Hz, OH-50); 6.35 (d, 1H,
0
0
JOH,3 ¼6.5 Hz, OH-3 ); 6.60 (dd,1H, J1 ,F¼10.9 and 5.1 Hz, H-10); 7.18 (d,
1H, J5,6¼3.9 Hz, H-5); 7.27 (dd,1H, J4,5¼1.9 Hz, J4,2¼0.8 Hz, H-4-furyl);
7.89 (dd,1H, J6,5¼3.9 Hz, J6,F¼0.9 Hz, H-6); 7.91 (br dd,1H, J5,4¼1.8 Hz,
J5,2¼1.5 Hz, H-5-furyl); 8.76 (dd, 1H, J2,5¼1.5 Hz, J2,4¼0.8 Hz, H-2-
furyl); 8.83 (s, 1H, H-2). 13C NMR (125.7 MHz, DMSO-d6): 59.63
(CH2-50); 68.82 (dd, JC,F¼25.8 and 18.8 Hz, CH-30); 81.23 (d,
JC,F¼8.0 Hz, CH-40); 82.53 (dd, JC,F¼39.5 and 24.6 Hz, CH-10); 101.79
(CH-5); 109.51 (CH-4-furyl); 114.32 (C-4a); 123.24 (dd, JC,F¼260.5 and
255.8 Hz, C-20); 124.98 (C-3-furyl); 127.45 (CH-6); 144.87 (CH-5-
furyl); 145.27 (CH-2-furyl); 150.60 (C-4); 151.59 (C-7a); 151.62 (CH-
2).19F NMR (470.3 MHz, DMSO-d6): ꢁ113.94 and ꢁ113.03 (2ꢂd, 2ꢂ1F,
Jgem¼234.1 Hz). MS (ESI) m/z (%): 338 (82) [MþH], 360 (100) [MþNa];
HRMS (ESI) calcd for C15H14O4N3F2 [MþH]: 338.09469; found:
338.09457. For C15H13O4N3F2$1.3H2O calcd: 49.95% C, 4.36% H, 11.65%
N; found: 50.05% C, 4.33% H, 11.42% N.
0
0
Compounds 16f and 17f were prepared as described for com-
pounds 16b and 17b from compound 15 (750 mg, 1.46 mmol) and
benzofuran-2-boronic acid. The crude reaction mixture was par-
tially separated by multiple HPFC on silica gel column (0/100%
EtOAc in hexane). Compounds 16f (262 mg, 30%) and crude com-
pound 17f (289 mg) were obtained as yellowish oils. Compound 17f
was used for the next step without further purification. Compound
16f: IR (ATR): 1725, 1600, 1573, 1453, 1264, 1248, 1094, 1070,
1027 cmꢁ1 1H NMR (400 MHz, CDCl3): 4.65e4.469 (m, 1H, H-40);
.
0
0
0
4.75 (dd, 1H, Jgem¼12.4 Hz, J40,5 ¼4.8 Hz, H-5 a); 4.87 (dd, 1H,
0
0
0
Jgem¼12.4 Hz, J4 ,5 ¼3.6 Hz, H-5 b); 5.88 (ddd, 1H, J3 ,F¼14.0 Hz,
J3 ,F¼5.2 Hz, J3 ,4 ¼3.2 Hz, H-30); 6.85 (dd, 1H, J1 ,F¼12.4 Hz,
0
0
0
0
J1 ,F¼6.4 Hz, H-10); 7.28e7.34 (m, 2H, H-5, H-5-benzofuryl);
0
7.40e7.67 (m, 9H, H-6, H-m-Bz, H-p-Bz, H-6-benzofuryl, H-4-
benzofuryl); 7.73 (d, 1H, J6,7¼7.6 Hz, H-7-benzofuryl); 7.79 (s, 1H,
H-3-benzofuryl); 8.07e8.17 (m, 4H, H-o-Bz); 8.97 (s, 1H, H-2). MS
(ESI) m/z (%): 596 (52) [MþH], 618 (100) [MþNa]; HRMS (ESI) calcd
for C33H24O6N3F2 [MþH]: 596.16277, found 596.16276.
4.22. 4-(Thiophene-2-yl)-7-[2-deoxy-2,2-difluoro-b-D-er-
ythro-pentofuranosyl]-7H-pyrrolo[2,3-d]pyrimidine (18c)
4.20. 4-(Furan-2-yl)-7-[2-deoxy-2,2-difluoro-b-D-erythro-pento-
furanosyl]-7H-pyrrolo[2,3-d]pyrimidine (18a)
Compound 18c was prepared as described for compound 18a.
Crude product 16c (121 mg) was used. The crude product was pu-
rified by column chromatography (1.5% MeOH in CHCl3) to give
compound 18c (50 mg, 10% over two steps) as a white crystalline
Compound 16a (171 mg, 0.31 mmol) was dissolved in anhydrous
methanol (5 ml) and a solution of sodium methoxide in methanol
(1 M, 940
ml, 0.94 mmol) was added. The reaction mixture was
solid after recrystallization (H2O/methanol 10:1). Mp 176e179 ꢀC.
20
stirred at rt for 1 h, then it was neutralized with aqueous HCl (1 M)
and co-evaporated with silica (10 g). The residue was purified by
column chromatography on silica (2% of methanol in CHCl3) to
[a
]
þ5.0 (c 0.06, DMSO). IR (ATR): 3333, 1559, 1518, 1353, 1196,
D
1058, 1035 cmꢁ1 1H NMR (500 MHz, DMSO-d6): 3.71 (ddd, 1H,
.
0
0
0
0
Jgem¼12.6 Hz, J5 a,OH¼5.9 Hz, J5 a,4 ¼4.1 Hz, H-5 a); 3.83 (br dm, 1H,
obtain compound 18a (75 mg, 67%) as an off-white crystalline solid
Jgem¼12.5 Hz, H-50b); 3.94e3.98 (m, 1H, H-40); 4.47 (tdd, 1H,
20
after recrystallization (H2O/methanol 10:1). Mp 184e186 ꢀC. [
a]
2ꢂJ3 ,F¼12.6 Hz, J3 ,4 ¼8.1 Hz, J3 ,OH¼6.5 Hz, H-30); 5.28 (t, 10H,
0
0
0
0
D
JOH,5 a¼JOH,5 b¼5.6 Hz, OH-50); 6.36 (d, 1H, JOH,3 ¼6.5 Hz, OH-3 );
0
0
0
þ14.8 (c 0.200, DMSO). IR (ATR): 3145, 1587, 1566, 1487, 1263, 1205,
1069, 1052, 1022 cmꢁ1 1H NMR (500 MHz, DMSO-d6): 3.70 (ddd,
6.60 (dd, 1H, J1 ,F¼11.0 and 5.0 Hz, H-10); 7.27 (d, 1H, J5,6¼3.9 Hz, H-
0
.
0
0
0
0
1H, Jgem¼12.6 Hz, J5 a,OH¼5.9 Hz, J5 a,4 ¼4.2 Hz, H-5 a); 3.82 (br dm,
5); 7.32 (dd, 1H, J4,5¼5.1 Hz, J4,3¼3.8 Hz, H-4-thienyl); 7.89 (dd, 1H,
J5,4¼5.1 Hz, J5,3¼1.1 Hz, H-5-thienyl); 7.94 (dd, 1H, J6,5¼3.9 Hz,
J6,F¼1.1 Hz, H-6); 8.20 (dd, 1H, J3,4¼3.8 Hz, J3,5¼1.1 Hz, H-3-thienyl);
8.80 (s, 1H, H-2). 13C NMR (125.7 MHz, DMSO-d6): 59.60 (CH2-50);
68.80 (dd, JC,F¼25.7 and 18.6 Hz, CH-30); 81.26 (d, JC,F¼8.0 Hz, CH-
40); 82.58 (dd, JC,F¼39.9 and 24.5 Hz, CH-10); 101.87 (CH-5); 112.80
(C-4a); 123.24 (dd, JC,F¼260.2 and 255.5 Hz, C-20); 128.05 (CH-6);
129.30 (CH-4-thienyl); 130.05 (CH-3-thienyl); 131.25 (CH-5-
thienyl); 142.22 (C-2-thienyl); 150.65 (C-4); 151.41 (CH-2); 151.99
(C-7a). 19F NMR (470.3 MHz, DMSO-d6): ꢁ113.93 and ꢁ112.99 (2ꢂd,
2ꢂ1F, Jgem¼234.3 Hz). MS (ESI) m/z (%): 354 (63) [MþH], 376 (100)
[MþNa]; HRMS (ESI) calcd for C15H14O3N3F2S [MþH]: 354.07184;
found: 354.07189. For C15H13O3N3F2S calcd: 50.99% C, 3.71% H,
11.89% N; found: 50.82% C, 3.76% H, 11.43% N.
1H, Jgem¼12.5 Hz, H-50b); 3.94e3.98 (m, 1H, H-40); 4.42e4.51 (m,
1H, H-30); 5.26 (t, 01H, JOH,5 a¼JOH,5 b¼5.6 Hz, OH-50); 6.35 (d, 1H,
0
0
JOH,3 ¼6.5 Hz, OH-3 ); 6.60 (dd, 1H, J1 ,F¼11.0 and 5.2 Hz, H-10); 6.80
(dd, 1H, J4,3¼3.5 Hz, J4,5¼1.8 Hz, H-4-furyl); 7.14 (d, 1H, J5,6¼3.8 Hz,
H-5); 7.51 (dd, 1H, J3,4¼3.5 Hz, J3,5¼0.8 Hz, H-3-furyl); 7.90 (dd, 1H,
J6,5¼3.8 Hz, J6,F¼1.3 Hz, H-6); 8.08 (dd, 1H, J5,4¼1.8 Hz, J5,3¼0.8 Hz,
H-5-furyl); 8.82 (s, 1H, H-2). 13C NMR (125.7 MHz, DMSO-d6): 59.63
(CH2-50); 68.88 (dd, JC,F¼25.9 and 18.3 Hz, CH-30); 81.26 (d,
JC,F¼8.3 Hz, CH-40); 82.50 (dd, JC,F¼39.9 and 23.8 Hz, CH-10); 102.24
(CH-5); 112.47 (C-4a); 112.92 (CH-4-furyl); 113.82 (CH-3-furyl);
123.23 (dd, JC,F¼260.3 and 255.1 Hz, C-20); 127.93 (CH-6); 146.75
(CH-5-furyl); 146.91 (C-4); 151.66 (CH-2);152.09 (C-7a); 152.38 (C-
2-furyl). 19F NMR (470.3 MHz, DMSO-d6): ꢁ113.94 and ꢁ112.88
0
0

ꢀ
P. Perlíkova et al. / Tetrahedron 68 (2012) 8300e8310
8308
20
4.23. 4-(Thiophene-3-yl)-7-[2-deoxy-2,2-difluoro-
ythro-pentofuranosyl]-7H-pyrrolo[2,3-d]pyrimidine (18d)
b
-
D
-er-
recrystallization (H2O/methanol 9:1). Mp 209e211 ꢀC. [
a]
D
þ8.3 (c
0.216, DMSO). IR (ATR): 3317, 1598, 1576, 1548, 1461, 1360, 1345, 1197,
1078, 1055, 1037 cmꢁ1. 1H NMR (500 MHz, DMSO-d6): 3.72 (ddd, 1H,
0
0
0
0
Compound 18d was prepared as described for compound 18a.
Compound 16d (322 mg, 0.59 mmol) was used. The crude product
was purified by column chromatography (2% MeOH in CHCl3) and
reverse phase HPFC on C-18 column (methanol in H2O 0e100%) to
Jgem¼12.6 Hz, J5 a,OH¼5.8 Hz, J5 a,4 ¼4.1 Hz, H-5 a); 3.84 (br dm, 1H,
Jgem¼12.6 Hz, H-50b); 3.96e4.00 (m, 1H, H-40); 4.44e4.53 (m, 1H, H-
30); 5.30 (t,1H, JOH,5 a¼JOH,5 b¼5.6 Hz, OH-50); 6.38 (d,1H, JOH,3 ¼6.5 Hz,
0
0
0
OH-30); 6.64 (dd, 1H, J1 ,F¼10.9 and 5.1 Hz, H-10); 7.36 (d, 1H,
0
give compound 18d (104 mg, 51%) as a white crystalline solid after
J5,6¼3.8 Hz, H-5); 7.37 (ddd,1H, J5,4¼7.8 Hz, J5,6¼7.2 Hz, J5,7¼0.9 Hz, H-
5-benzofuryl); 7.49 (ddd, 1H, J6,7¼8.4 Hz, J6,5¼7.2 Hz, J6,4¼1.3 Hz, H-6-
benzofuryl); 7.81 (dq, 1H, J7,6¼8.4 Hz, J7,5¼J7,4¼J7,3¼0.9 Hz, H-7-
benzofuryl); 7.83 (dm, 1H, J4,5¼7.8 Hz, H-4-benzofuryl); 7.96 (d, 1H,
J3,7¼1.0 Hz, H-3-benzofuryl); 8.00 (dd, 1H, J6,5¼3.8 Hz, J6,F¼1.0 Hz, H-
6); 8.93 (s, 1H, H-2). 13C NMR (125.7 MHz, DMSO-d6): 59.65 (CH2-50);
68.87 (dd, JC,F¼25.9 and 18.3 Hz, CH-30); 81.32 (d, JC,F¼8.2 Hz, CH-40);
82.60 (dd, JC,F¼39.9 and 24.0 Hz, CH-10); 102.56 (CH-5); 109.51 (CH-3-
benzofuryl); 112.12 (CH-7-benzofuryl); 113.82 (C-4a); 122.70 (CH-4-
benzofuryl); 123.26 (dd, JC,F¼260.2 and 255.8 Hz, C-20);124.03 (CH-
5-benzofuryl); 126.84 (CH-6-benzofuryl); 127.90 (C-3a-benzofuryl);
128.61 (CH-6); 146.85 (C-4); 151.71 (CH-2); 152.35 (C-7a); 153.95 (C-2-
benzofuryl); 155.56 (C-7a-benzofuryl). 19F NMR (470.3 MHz, DMSO-
d6): ꢁ113.92 andꢁ112.82 (2ꢂd, 2ꢂ1F, Jgem¼234.2 Hz, F-20). MS (ESI) m/
z (%): 388 (58) [MþH], 410 (100) [MþNa]; HRMS (ESI) calcd for
C19H16O4N3F2 [MþH]: 388.11034; found: 388.11031. For C19H15O4N3F2
calcd: 58.92% C, 3.90% H, 10.85% N; found: 58.92% C, 4.17% H, 11.35% N.
20
recrystallization (H2O/methanol 2:1). Mp 87e90 ꢀC. [
a
]
þ14.0 (c
D
0.214, DMSO). IR (ATR): 3422, 1578, 1568, 1515, 1466, 1201, 1066,
1043, 1032 cmꢁ1 1H NMR (500 MHz, DMSO-d6): 3.71 (ddd, 1H,
.
0
0
0
0
Jgem¼12.6 Hz, J5 a,OH¼5.8 Hz, J5 a,4 ¼4.1 Hz, H-5 a); 3.83 (br dm, 1H,
Jgem¼12.6 Hz, H-50b); 3.94e3.98 (m, 1H, H-40); 4.42e4.52 (m, 1H, H-
30); 5.27 (t, 1H, JOH,5 a¼JOH,5 b¼5.5 Hz, OH-50); 6.36 (d, 1H,
0
0
JOH,3 ¼3.9 Hz, OH-3 ); 6.61 (dd, 1H, J1 ,F¼11.0 and 5.1 Hz, H-10); 7.23
(d, 1H, J5,6¼3.9 Hz, H-5); 7.76 (dd, 1H, J5,4¼5.1 Hz, J5,2¼2.9 Hz, H-5-
thienyl); 7.92 (dd, 1H, J6,5¼3.9 Hz, J6,F¼1.1 Hz, H-6); 7.96 (br dd, 1H,
J4,5¼5.1 Hz, J4,2¼1.3 Hz, H-4-thienyl); 8.58 (dd, 1H, J2,5¼2.9 Hz,
J2,4¼1.3 Hz, H-2-thienyl); 8.86 (s, 1H, H-2). 13C NMR (125.7 MHz,
DMSO-d6): 59.63 (CH2-50); 68.84 (br dd, JC,F¼26.0 and 18.1 Hz, CH-
30); 81.24 (d, JC,F¼7.9 Hz, CH-40); 82.55 (br dd, JC,F¼39.9 and 24.2 Hz,
CH-10); 102.04 (CH-5); 114.35 (C-4a); 123.27 (br t, JC,F¼258.0 Hz, C-
20); 127.43 (CH-5-thienyl); 127.57 (CH-4-thienyl); 127.75 (CH-6);
129.07 (CH-2-thienyl); 139.75 (C-3-thienyl); 151.58 (CH-2); 151.98
and 152.02 (C-4,7a). 19F NMR (470.3 MHz, DMSO-d6): ꢁ113.93 and
ꢁ112.96 (2ꢂd, 2ꢂ1F, Jgem¼234.2 Hz). MS (ESI) m/z (%): 354 (100)
[MþH], 376 (82) [MþNa]; HRMS (ESI) calcd for C15H14O3N3F2S
[MþH]: 354.07184; found: 354.07179. For C15H13O3N3F2S calcd:
50.99% C, 3.71% H, 11.89% N; found: 50.81% C, 3.70% H, 11.72% N.
0
0
0
4.26. 4-(Furan-2-yl)-7-[2-deoxy-2,2-difluoro-a-D-erythro-
pentofuranosyl]-7H-pyrrolo[2,3-d]pyrimidine (19a)
Compound 19a was prepared as described for compound 18a.
Compound 17a (68 mg, 0.12 mmol) was used. The crude product
was purified by column chromatography (1.5% MeOH in CHCl3) to
give compound 19a (17 mg, 40%) as an off-white lyophilizate (tert-
4.24. 4-Phenyl-7-[2-deoxy-2,2-difluoro-
b-D-erythro-pentofur-
anosyl]-7H-pyrrolo[2,3-d]pyrimidine (18e)
butanol). Mp 88e90 ꢀC. [
a]
20 þ30.0 (c 0.033, DMSO). IR (ATR): 3257,
D
Compound 18e was prepared as described for compound 18a.
Compound 16e (227 mg, 0.41 mmol) was used. The crude product
was purified by column chromatography (1.5% MeOH in CHCl3) to
1600, 1567, 1458, 1244, 1054, 1016 cmꢁ1. 1H NMR (500 MHz, DMSO-
d6): 3.62 (br dm, 1H, Jgem¼12.5 Hz, H-50a); 3.70 (br dm, 1H,
Jgem¼12.5 Hz, H-50b); 4.31e4.35 (m, 1H, H-40); 4.46e4.55 (m, 1H, H-
30); 5.12 (br t, 1H, JOH,5 a¼JOH,5 b¼5.8 Hz, OH-50); 6.47 (d, 1H,
0
0
give compound 18e (104 mg, 73%) as a white crystalline solid after
20
recrystallization (H2O/methanol 9:1). Mp 201e202 ꢀC. [
a]
þ12.0
JOH,3 ¼6.0 Hz, OH-3 ); 6.78 (dd, 1H, J1 ,F¼10.1 and 7.2 Hz, H-10); 6.80
(dd, 1H, J4,3¼3.5 Hz, J4,5¼1.8 Hz, H-4-furyl); 7.14 (d, 1H, J5,6¼3.8 Hz,
H-5); 7.50 (dd, 1H, J3,4¼3.5 Hz, J3,5¼0.8 Hz, H-3-furyl); 7.81 (dd, 1H,
J6,5¼3.8 Hz, J6,F¼2.8 Hz, H-6); 8.08 (dd, 1H, J5,4¼1.8 Hz, J5,3¼0.8 Hz,
H-5-furyl); 8.81 (s, 1H, H-2). 13C NMR (125.7 MHz, DMSO-d6): 60.37
(CH2-50); 69.79 (dd, JC,F¼26.1 and 17.8 Hz, CH-30); 82.24 (dd,
JC,F¼40.0 and 20.1 Hz, CH-10); 84.06 (d, JC,F¼7.3 Hz, CH-40); 102.30
(CH-5); 112.27 (C-4a); 112.94 (CH-4-furyl); 113.81 (CH-3-furyl);
123.15 (dd, JC,F¼261.3 and 255.2 Hz, C-20); 128.65 (d, JC,F¼3.0 Hz,
CH-6); 146.77 (CH-5-furyl); 146.86 (C-4); 151.67 (CH-2);152.39 and
152.42 (C-7a, 2-furyl). 19F NMR (470.3 MHz, DMSO-d6): ꢁ119.04
and ꢁ110.38 (2ꢂd, 2ꢂ1F, Jgem¼233.6 Hz). MS (ESI) m/z (%): 338 (62)
[MþH], 360 (100) [MþNa]; HRMS (ESI) calcd for C15H14O4N3F2
[MþH]: 338.09469; found: 338.09466. For C15H13O4N3F2 calcd:
53.42% C, 3.88% H, 12.46% N; found: 53.15% C, 3.92% H, 12.06% N.
0
0
0
D
(c 0.283, DMSO). IR (ATR): 3271, 1575, 1557, 1463, 1429, 1338, 1201,
1061, 1034 cmꢁ1 1H NMR (500 MHz, DMSO-d6): 3.71 (ddd, 1H,
.
0
0
0
0
Jgem¼12.5 Hz, J5 a,OH¼5.9 Hz, J5 a,4 ¼4.1 Hz, H-5 a); 3.83 (br dm, 1H,
Jgem¼12.5 Hz, H-50b); 3.95e3.99 (m, 1H, H-40); 4.48 (tdd, 1H,
2ꢂJ3 ,F¼12.5 Hz, J3 ,4 ¼8.1 Hz, J3 ,OH¼6.5 Hz, H-30); 5.27 (br dd, 1H,
0
0
0
0
JOH,5 a¼5.8 Hz, JOH,5 b¼5.3 Hz, OH-50); 6.37 (d, 1H, JOH,3 ¼6.5 Hz, OH-
0
0
0
30); 6.64 (dd, 1H, J1 ,F¼11.0 and 5.1 Hz, H-10); 7.10 (d, 1H, J5,6¼3.9 Hz,
0
H-5); 7.56e7.63 (m, 3H, H-m,p-Ph); 7.93 (dd, 1H, J6,5¼3.9 Hz,
J6 ,F¼1.3 Hz, H-6); 8.16e8.20 (m, 2H, H-o-Ph); 8.95 (s, 1H, H-2). 13
C
0
NMR (125.7 MHz, DMSO-d6): 59.63 (CH2-50); 68.87 (dd, JC,F¼26.1
and 18.4 Hz, CH-30); 81.28 (d, JC,F¼8.2 Hz, CH-40); 82.60 (dd,
JC,F¼40.0 and 24.1 Hz, CH-10); 102.02 (CH-5); 115.32 (C-4a); 123.26
(dd, JC,F¼260.3 and 255.3 Hz, CH-20); 127.97 (CH-6); 128.86 (CH-o-
Ph); 129.13 (CH-m-Ph); 130.62 (CH-p-Ph); 137.37 (C-i-Ph); 151.65
(CH-2); 151.99 (C-7a); 156.70 (C-4). 19F NMR (470.3 MHz, DMSO-
d6): ꢁ113.93 and ꢁ ꢁ112.86 (2ꢂd, 2ꢂ1F, Jgem¼234.3 Hz). MS (ESI)
m/z (%): 338 (100) [MþH], 370 (56) [MþNa]; HRMS (ESI) calcd for
C17H16O3N3F2 [MþH]: 348.11542; found: 348.11543. For
C17H15O3N3F2 calcd: 58.79% C, 4.35% H, 12.10% N; found: 58.57% C,
4.53% H, 11.71% N.
4.27. 4-(Furan-3-yl)-7-[2-deoxy-2,2-difluoro-
tofuranosyl]-7H-pyrrolo[2,3-d]pyrimidine (19b)
a-D-erythro-pen-
Compound 19b was prepared as described for compound 18a.
Compound 17b (163 mg, 0.30 mmol) was used. The crude product
was purified by column chromatography (2% MeOH in CHCl3) and
reverse phase HPFC on C-18 column (methanol in H2O 0e100%) to
give compound 19b (40 mg, 40%) as a yellowish crystalline solid
4.25. 4-(Benzofuran-2-yl)-7-[2-deoxy-2,2-difluoro-b-D-er-
ythro-pentofuranosyl]-7H-pyrrolo[2,3-d]pyrimidine (18f)
after recrystallization (H2O/methanol 4:1). Mp 75e79 ꢀC. [
a
]
20 þ4.3
D
Compound 18f was prepared as described for compound 18a.
Compound 16f (214 mg, 0.36 mmol) was used. The crude product was
purified by column chromatography (1.5% MeOH in CHCl3) to give
compound 18f (86 mg, 61%) as a white crystalline solid after
(c 0.087, DMSO). IR (ATR): 3348, 1571, 1514, 1465, 1239, 1096, 1067,
1034 cmꢁ1
.
1H NMR (500 MHz, DMSO-d6): 3.62 (ddd, 1H,
0
0
0
0
Jgem¼12.3 Hz, J5 a,OH¼6.2 Hz, J5 a,4 ¼4.5 Hz, H-5 a); 3.70 (br dm, 1H,
Jgem¼12.3 Hz, H-50b); 4.32e4.37 (m, 1H, H-40); 4.46e4.56 (m, 1H, H-

ꢀ
P. Perlíkova et al. / Tetrahedron 68 (2012) 8300e8310
8309
30); 5.12 (br t, 1H, JOH,5 a¼JOH,5 b¼5.7 Hz, OH-50); 6.46 (d, 1H,
JC,F¼40.2 and 20.4 Hz, CH-10); 84.12 (d, JC,F¼7.4 Hz, CH-40); 102.04
(CH-5); 115.11 (C-4a); 123.19 (dd, JC,F¼261.5 and 255.2 Hz, CH-20);
128.65 (d, JC,F¼2.8 Hz, CH-6); 128.86 (CH-o-Ph); 129.12 (CH-m-Ph);
130.61 (CH-p-Ph); 137.39 (C-i-Ph); 151.64 (CH-2); 152.29 (C-7a);
156.65 (C-4). 19F NMR (470.3 MHz, DMSO-d6): ꢁ118.91 and ꢁ110.27
(2ꢂd, 2ꢂ1F, Jgem¼233.8 Hz). MS (ESI) m/z (%): 348 (100) [MþH], 370
(93) [MþNa]; HRMS (ESI) calcd for C17H16O3N3F2 [MþH]:
348.11542; found: 348.11540. For C17H15O3N3F2 calcd: 58.79% C,
4.35% H, 12.10% N; found: 58.47% C, 4.46% H, 11.71% N.
0
0
JOH,3 ¼6.0 Hz, OH-3 ); 6.78 (dd, 1H, J1 ,F¼9.9 and 7.3 Hz, H-10); 7.18
(d, 1H, J5,6¼3.9 Hz, H-5); 7.27 (dd, 1H, J4,5¼1.9 Hz, J4,2¼0.8 Hz, H-4-
furyl); 7.80 (dd, 1H, J6,5¼3.8 Hz, J6,F¼2.9 Hz, H-6); 7.91 (br t, 1H,
J5,4¼J5,2¼1.7 Hz, H-5-furyl); 8.76 (dd, 1H, J2,5¼1.5 Hz, J2,4¼0.8 Hz, H-
2-furyl); 8.83 (s, 1H, H-2). 13C NMR (125.7 MHz, DMSO-d6): 60.35
(CH2-50); 69.80 (dd, JC,F¼26.2 and 16.2 Hz, CH-30); 82.28 (dd,
JC,F¼40.0 and 20.3 Hz, CH-10); 84.04 (d, JC,F¼7.4 Hz, CH-40); 101.80
(CH-5); 109.51 (CH-4-furyl); 114.10 (C-4a); 123.15 (dd, JC,F¼261.4
and 255.4 Hz, C-20); 124.99 (C-3-furyl); 128.16 (CH-6); 144.85 (CH-
5-furyl); 145.25 (CH-2-furyl); 150.54 (C-4); 151.62 (CH-2); 151.88
(C-7a). 19F NMR (470.3 MHz, DMSO-d6): ꢁ119.02 and ꢁ110.44 (2ꢂd,
2ꢂ1F, Jgem¼233.6 Hz). MS (ESI) m/z (%): 338 (100) [MþH], 360 (80)
[MþNa]; HRMS (ESI) calcd for C15H14O4N3F2 [MþH]: 338.09469;
found: 338.09460. For C15H13O4N3F2$2.3H2O calcd: 47.57% C, 4.68%
H, 11.10% N; found: 47.75% C, 4.56% H, 10.74% N.
0
0
0
4.30. 4-(Benzofuran-2-yl)-7-[2-deoxy-2,2-difluoro-a-D-er-
ythro-pentofuranosyl]-7H-pyrrolo[2,3-d]pyrimidine (19f)
Compound 19f was prepared as described for compound 18a. Crude
compound 17f (289 mg) was used. The crude product was by column
chromatography on silica (1.5% methanol in CHCl3) to give compound
19f (51 mg, 9% over two steps) as a white crystalline solid after re-
20
crystallization (H2O/methanol 9:1). Mp 230e232 ꢀC. [
a
]
þ34.9 (c
4.28. 4-(Thiophene-3-yl)-7-[2-deoxy-2,2-difluoro-
pentofuranosyl]-7H-pyrrolo[2,3-d]pyrimidine (19d)
a-D-erythro-
D
0.109, DMSO). IR (ATR): 3122, 1599, 1571, 1458, 1363, 1084, 1053 cmꢁ1
.
1H NMR (500 MHz, DMSO-d6): 3.63 (ddd, 1H, Jgem¼12.3 Hz,
0
Compound 19d was prepared as described for compound 18a.
Crude compound 17d (210 mg) was used. The crude product was
purified by column chromatography (2% MeOH in CHCl3) and re-
verse phase HPFC on C-18 column (methanol in H2O 0e100%) to
give compound 19d (62 mg, 9% over two steps) as a pale pink
crystalline solid after recrystallization (H2O/methanol 4:1). Mp
0
0
0
J5 a,OH¼6.2 Hz, J5 a,4 ¼4.5 Hz, H-5 a); 3.72 (br dm, 1H, Jgem¼12.4 Hz, H-
50b); 4.35e4.39 (m, 1H, H-40); 4.49e4.58 (m, 1H, H-30); 5.15 (dd, 1H0 ,
JOH,5 a¼6.2 Hz, JOH,5 b¼5.3 Hz, OH-50); 6.49 (d,1H, JOH,3 ¼6.0 Hz, OH-3 );
0
0
0
6.82 (dd, 1H, J1 ,F¼10.2 and 7.2 Hz, H-10); 7.36 (d, 1H, J5,6¼3.9 Hz, H-5);
0
7.37 (ddd, 1H, J5,4¼7.8 Hz, J5,6¼7.2 Hz, J5,7¼0.8 Hz, H-5-benzofuryl); 7.49
(ddd,1H, J6,7¼8.3 Hz, J6,5¼7.2 Hz, J6,4¼1.3 Hz, H-6-benzofuryl); 7.82 (dq,
1H, J7,6¼8.4 Hz, J7,5¼J7,4¼J7,3¼0.9 Hz, H-7-benzofuryl); 7.83 (br dm, 1H,
J4,5¼7.8 Hz, H-4-benzofuryl); 7.92 (dd, 1H, J6,5¼3.8 Hz, J6,F¼2.8 Hz, H-
6); 7.96 (d, 1H, J3,7¼1.0 Hz, H-3-benzofuryl); 8.92 (s, 1H, H-2). 13C NMR
(125.7 MHz, DMSO-d6): 60.38 (CH2-50); 69.79 (dd, JC,F¼26.1 and
17.7 Hz, CH-30); 82.34 (dd, JC,F¼39.7 and 20.2 Hz, CH-10); 84.08 (d,
Ji¼7.4 Hz, CH-40); 102.58 (CH-5); 109.47 (CH-3-benzofuryl); 112.11 (CH-
7-benzofuryl); 113.61 (C-4a); 122.69 (CH-4-benzofuryl); 123.15 (dd,
JC,F¼261.4 and 255.8 Hz, C-20);124.03 (CH-5-benzofuryl); 126.82 (CH-
6-benzofuryl); 127.90 (C-3a-benzofuryl); 129.31 (d, JC,F¼3.3 Hz, CH-6);
146.78 (C-4); 151.71 (CH-2); 152.65 (C-7a); 153.99 (C-2-benzofuryl);
155.56 (C-7a-benzofuryl). 19F NMR (470.3 MHz, DMSO-d6): ꢁ119.08
and ꢁ110.67 (2ꢂd, 2ꢂ1F, Ji¼233.4 Hz, F-20). MS (ESI) m/z (%): 388 (67)
[MþH], 410 (100) [MþNa]; HRMS (ESI) calcd for C19H16O4N3F2 [MþH]:
388.11034; found: 388.11029. For C19H15O4N3F2 calcd: 58.92% C, 3.90%
H, 10.85% N; found: 59.13% C, 4.24%H, 10.59% N.
157e160 ꢀC. [
a
]
D
20 þ47.1 (c 0.193, DMSO). IR (ATR): 3336, 1585, 1569,
1514, 1260, 1240, 1115, 1059, 1038, 1009 cmꢁ1. 1H NMR (500 MHz,
0
DMSO-d6): 3.62 (ddd, 1H, Jgem¼12.3 Hz, J5 a,OH¼6.2 Hz,
J5 a,4 ¼4.5 Hz, H-50a); 3.70 (br dm, 1H, Jgem¼12.4 Hz, H-50b);
0
0
4.32e4.37 (m, 1H, H-40); 4.47e4.56 (m, 1H, H-30); 5.12 (dd, 1H,
JOH,5 a¼6.2 Hz, JOH,5 b¼5.2 Hz, OH-50); 6.47 (d, 1H, JOH,3 ¼3.8 Hz, OH-
0
0
0
30); 6.80 (dd, 1H, J1 ,F¼9.9 and 7.3 Hz, H-10); 7.23 (d, 1H, J5,6¼3.9 Hz,
0
H-5); 7.76 (dd, 1H, J5,4¼5.1 Hz, J5,2¼2.9 Hz, H-5-thienyl); 7.83 (dd,
1H, J6,5¼3.9 Hz, J6,F¼2.9 Hz, H-6); 7.96 (dd, 1H, J4,5¼5.1 Hz,
J4,2¼1.3 Hz, H-4-thienyl); 8.58 (dd, 1H, J2,5¼2.9 Hz, J2,4¼1.3 Hz, H-2-
thienyl); 8.86 (s, 1H, H-2). 13C NMR (125.7 MHz, DMSO-d6): 60.35
(CH2-50); 69.81 (br dd, JC,F¼26.5 and 18.1 Hz, CH-30); 82.31 (dd,
JC,F¼40.1 and 20.2 Hz, CH-10); 84.07 (d, JC,F¼7.2 Hz, CH-40); 102.05
(CH-5); 114.13 (C-4a); 123.17 (br dd, JC,F¼261.8 and 255.0 Hz, C-20);
127.42 (CH-5-thienyl); 127.56 (CH-4-thienyl); 128.45 (CH-6);
129.05 (CH-2-thienyl); 139.76 (C-3-thienyl); 151.57 (CH-2); 151.93
(C-4); 152.31 (C-7a). 19F NMR (470.3 MHz, DMSO-d6): ꢁ118.98 and
ꢁ110.33 (2ꢂd, 2ꢂ1F, Jgem¼233.5 Hz). MS (ESI) m/z (%): 354 (100)
[MþH], 376 (60) [MþNa]; HRMS (ESI) calcd for C15H14O3N3F2S
[MþH]: 354.07184; found: 354.07176. For C15H13O3N3F2S calcd:
50.99% C, 3.71% H, 11.89% N; found: 50.59% C, 3.71% H, 11.41% N.
Acknowledgements
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. The authors thank to Dr. I.
Votruba (IOCB) and Dr. Tomas Cihlar, Dr. Gabriel Birkus and Dr.
Richard Mackman (Gilead) for cytostatic and antiviral screening.
4.29. 4-Phenyl-7-[2-deoxy-2,2-difluoro-a-D-erythro-pentofur-
anosyl]-7H-pyrrolo[2,3-d]pyrimidine (19e)
References and notes
Compound 19e was prepared as described for compound 18a.
Crude compound 17e (236 mg) was used. The crude product was
purified by reverse phase HPFC on C-18 column (methanol in H2O
ꢀ
ꢁꢀ
ꢀ
1. (a) Hocek, M.; Holy, A.; Votruba, I.; Dvorakova, H. J. Med. Chem. 2000, 43,
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ꢁꢀ
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Furman, P. A.; Tharnish, P. M.; Otto, M. J. J. Med. Chem. 2005, 48, 5869e5873; (d)
20
a white lyophilizate (tert-butanol/benzene 2:1). Mp 39e41 ꢀC. [
a]
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Hocek, M.; Silhar, P.; Shih, I.; Mabery, E.; Mackman, R. Bioorg. Med. Chem. Lett.
D
ꢁ
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2006, 16, 5290e5293; (e) Bourderioux, A.; Naus, P.; Perlíkova, P.; Pohl, R.;
þ30.7 (c 0.101, DMSO). IR (ATR): 3150, 1562, 1517, 1459, 1359, 1238,
1054, 1032 cmꢁ1 1H NMR (500 MHz, DMSO-d6): 3.63 (ddd, 1H,
ꢀ
ꢁ
ꢀ
ꢁ
ꢀ
ꢀ
Pichova, I.; Votruba, I.; Dzubak, P.; Konecny, P.; Hajduch, M.; Stray, K. M.; Wang,
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5498e5507.
.
0
0
0
0
Jgem¼12.4 Hz, J5 a,OH¼5.8 Hz, J5 a,4 ¼4.5 Hz, H-5 a); 3.71 (ddd, 1H,
0
0
ꢁ
ꢁ
ꢀ
ꢀ
2. Naus, P.; Pohl, R.; Votruba, I.; Dzubak, P.; Hajduch, M.; Ameral, R.; Birkus, G.;
Wang, T.; Ray, A. S.; Mackman, R.; Cihlar, T.; Hocek, M. J. Med. Chem. 2010, 53,
460e470.
0
0
0
Jgem¼12.4 Hz, J5 b,OH¼J5 b,4 ¼4.0 Hz, H-5 b); 4.33e4.37 (m, 1H, H-4 );
4.48e4.56(m, 1H, H-30); 5.14 (br t, 1H, JOH,5 a¼JOH,5 b¼5.6 Hz, OH-
0
0
50); 6.50 (br d, 1H, JOH,3 ¼5.5 Hz, OH-3 ); 6.83 (dd, 1H, J1 ,F¼10.0 and
0
0
0
ꢀꢁ
ꢀ
ꢁ
ꢀꢁ
ꢀ
ꢀ
ꢀ
3. (a) Spacilova, P.; Naus, P.; Pohl, R.; Votruba, I.; Snasel, J.; Zabranska, H.; Pichova,
7.4 Hz, H-10); 7.10 (d, 1H, J5,6¼3.9 Hz, H-5); 7.56e7.63 (m, 3H, H-
ꢁ
ꢀꢁ
I.; Ameral, R.; Birkus, G.; Cihlar, T.; Hocek, M. ChemMedChem 2010, 5,
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1386e1396; (b) Perlíkova, P.; Pohl, R.; Votruba, I.; Shih, R.; Birkus, G.; Cihlar, T.;
Hocek, M. Bioorg. Med. Chem. 2011, 19, 229e242.
0
m,p-Ph); 7.84 (dd, 1H, J6,5¼3.9 Hz, J6 ,F¼2.8 Hz, H-6); 8.17e8.20 (m,
2H, H-o-Ph); 8.94 (s, 1H, H-2). 13C NMR (125.7 MHz, DMSO-d6):
ꢁ
ꢀ
4. Naus, P.; Perlíkova, P.; Pohl, R.; Hocek, M. Collect. Czech. Chem. Commun. 2011,
76, 957e988.
60.36 (CH2-50); 69.83 (dd, JC,F¼26.5 and 18.0 Hz, CH-30); 82.39 (dd,

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