Synthesis of pseudo-C-nucleosides from β-formyl-α,β- unsaturated ester bearing a β-furanosidic moiety

Article abstract of DOI:10.1007/s00706-009-0171-1

Pseudo-C-nucleosides have potential biological activity, and an efficient synthesis of new pseudo-C-nucleosides has been developed via the reaction of a β-formyl-α,β-unsaturated ester bearing a β-sugar moiety with hydrazines in neutral and acidic conditio

Full text of DOI:10.1007/s00706-009-0171-1

Monatsh Chem (2009) 140:1237–1244
DOI 10.1007/s00706-009-0171-1
ORIGINAL PAPER
Synthesis of pseudo-C-nucleosides from b-formyl-a,b-unsaturated
ester bearing a b-furanosidic moiety
Jorge M. Pinheiro Æ M. Isabel Ismael Æ
J. Albertino Figueiredo Æ Artur M. S. Silva
Received: 25 November 2008 / Accepted: 29 July 2009 / Published online: 11 September 2009
Ó Springer-Verlag 2009
Abstract Pseudo-C-nucleosides have potential biological
activity, and an efficient synthesis of new pseudo-C-nucleo-
sides has been developed via the reaction of a b-formyl-a,b-
unsaturated ester bearing a b-sugar moiety with hydrazines in
neutral and acidic conditions. The preparation of the b-for-
myl-a,b-unsaturated ester was accomplished by oxidation of
the secondary hydroxyl group of 3-O-benzyl-1,2-O-isopro-
pylidene-a-D-glucofuranose, followed by elongation of its
carbon chain with (ethoxycarbonylmethylene)triphenylphos-
phorane and oxidation of the hydroxymethyl group.
of both moieties [2]. Due to structural similarities with the
C-nucleosides, these compounds may have interesting
biological properties.
Compounds that have heterocyclic rings with two or more
nitrogen atoms, such as triazole [3], pyrazole [4], and pyr-
idazine [5] derivatives, present a wide range of biological
activity, including anti-angiogenesis, antimetastatic, herbi-
cidal, antibacterial, and fungicidal properties [6]. Pyrazoles
are the most representative of five-membered heterocyclic
systems [7]. Despite the fact that pyrazole rings are rarely a
constituent of natural products, numerous synthetic pyrazole
derivatives have found use in pharmaceutical, agrochemical,
photographic, and various other applications [8]. The pyra-
zole motif makes up the core structure of numerous
biologically active compounds, such as Celebrex and Viagra
[9]. One of the most commonly used synthetic methods to
synthesize pyrazoles involves the reaction of 1,3-dicarbonyl
compounds with hydrazine derivatives, leading to a mixture
of regioisomers via hydrazone formation and loss of water
molecules. Occasionally, 3-hydroxy-3,4-dihydropyrazoles
or hydroxypyrazolines can be observed as stable, isolable
intermediates that can be fully characterized prior to the loss
of the second molecule of water, which gives rise to pyrazole
derivatives [10].
Keywords Carbohydrates ꢀ Heterocycles ꢀ
Pseudo-C-nucleosides ꢀ Pyridazinone ꢀ Wittig reaction
Introduction
Pseudo-C-nucleosides are C-nucleoside analogs that have a
C–C linkage between C-40 and C-50 of a furanose or C-60
of a pyranose sugar moiety and a heterocyclic base [1].
Their synthesis can be accomplished by two pathways:
by heterocyclic ring construction in the sugar moiety
bearing an appropriate functional group or by the reaction
Many pyrazoline derivatives have found clinical appli-
cation as non-steroidal anti-inflammatory drugs (NSAIDs).
For example, antipyrine, 2,3-dimethyl-1-phenyl-3-pyr-
azolin-5-one, was the first pyrazolone derivative used in the
management of pain and inflammation [11].
J. M. Pinheiro ꢀ M. Isabel Ismael (&) ꢀ J. A. Figueiredo
Department of Chemistry, Paper and Textile Research Unity,
´
University of Beira Interior, Rua Marques d’Avila e Bolama,
Pyridazines are interesting compounds due to their
important pharmacological activities [12, 13], resulting in
many of them being used as drugs [14]. Pyridazine deriv-
atives can be synthesized by several methods [15],
including reactions of 3-amino-2H-pyran-2-ones and chal-
cones with hydrazine hydrate [14].
ˆ
6201-001 Covilha
˜, Portugal
e-mail: iismael@ubi.pt; isabel.c.ismael@gmail.com
A. M. S. Silva
Department of Chemistry and QOPNA, University of Aveiro,
3810-193 Aveiro, Portugal
123

1238
J. M. Pinheiro et al.
Microwave irradiation has been successfully applied as
oxidation of the 5-hydroxymethyl group of 3 with pyridi-
˚
nium chlorochromate (PCC)/molecular sieves 4 A
an alternative source of energy in organic chemistry.
Spectacular accelerations, higher yields under milder
reaction conditions, and higher product purities have been
reported. Indeed, a number of authors have described
success in reactions that do not occur by conventional
heating, and even modifications of selectivity (chemo-,
regio-, and stereoselectivity) have been found. The effects
of microwave irradiation on organic synthesis reactions are
caused by a combination of thermal effects, including the
heating rate, superheating or ‘‘hot spots,’’ and the selective
absorption of radiation by polar substances. Such phe-
nomena are not usually accessible by classical heating, and
the existence of non-thermal effects such as highly polar-
izing radiation—the ‘‘specific microwave effect’’—is still a
controversial topic [16].
(powder).
The attempt to synthesize 3-O-benzyl-1,2-O-isopropyl-
idene-a-D-allo-hexafuran-5-ulose, an isomer of 2 bearing
another configuration at C-3, was not successful. The
oxidation of 5 with Bu2SnO and NBS led to a new com-
pound that was detected by TLC, but not isolated after
workup, probably due to degradation. An alternative
method involving the primary alcohol tritylation of 3-O-
benzyl-1,2-O-isopropylidene-a-D-allo-furanose (5) was
considered, and the protected derivative 6 was obtained in
90% yield (Scheme 2) [17]. The 5-hydroxyl group of 6 was
oxidized with PCC to give 7 in 73% yield. Elongation of
the carbon chain of 7, using the same reaction conditions
presented in Scheme 1, led to the formation of lactone 8 in
62% yield instead of the expected compound, ethyl 3-O-
benzyl-5,6-dideoxy-5-C-hydroxymethyl-1,2-O-isopropyl-
idene-a-D-allo-hept-5-(E)-enofuranuronate. The formation
of this compound can be envisaged by considering a carbon
chain elongation, then cleavage of the trityl group followed
by lactone ring formation.
Continuing our work on the synthesis of pseudo-C-
nucleosides bearing a pyrazole moiety, including the
reaction of a,b-unsaturated esters with diazomethane fol-
lowed by dehydrogenation of the intermediate pyrazoline
with Cl2/CCl4, and the reaction of b-ketoesters with
hydrazines [17], led us to study the reaction of a b-fura-
nosidic b-formyl-a,b-unsaturated ester with hydrazine
derivatives.
The reactivity of ethyl 3-O-benzyl-5,6-dideoxy-5-C-
formyl-1,2-O-isopropylidene-a-D-xylo-hept-5-enofura-
nuronate (4) with methyl hydrazinocarboxylate (9),
benzoylhydrazine (10), phenylhydrazine (11), and hydra-
zine hydrate (12) was studied by three methods (Scheme 3;
Table 1). The treatment of 4 with hydrazine derivatives 9-
11 in refluxing ethanol for 5 h (Method A) led to the for-
mation of corresponding hydrazone derivatives 13-15.
However, when using hydrazine hydrate (12) a pyridazin-6-
one 16 was obtained. These results indicate that the pres-
ence of electron-withdrawing groups on the hydrazone
moiety of 13-15 prevents the formation of an heterocyclic
ring, while in the absence of substitution on the hydrazone
moiety the formation of a pyridazin-6-one ring 16 occurred.
In this case the reaction was also faster; the product was
obtained after 1 h, since longer reaction times led to the
degradation of pyridazinone 16. The formation of 16 can be
envisaged by hydrazone formation followed by the attack of
the nitrogen atom of the NH2 group to the ester carbonyl
Results and discussion
Chemistry
Our synthetic strategy started with the preparation of
ethyl 3-O-benzyl-5,6-dideoxy-5-C-formyl-1,2-O-isopro-
pylidene-a-D-xylo-hept-5-enofuranuronate (4, Scheme 1).
The 5-hydroxyl group of 3-O-benzyl-1,2-isopropylidene-a-
D-xylo-hexofuran-5-ulose (1) was oxidized with dibutyltin
oxide (Bu2SnO), followed by addition of NBS, and product
2 was obtained in 77% yield [18]. The carbon chain
elongation of 2 was achieved using a Wittig type reaction
with a stabilized phosphorane [(ethoxycarbonylmethyl-
ene)triphenylphosphorane], leading to 3 in 80% yield.
Compound 4 was then obtained in 72% yield after
Scheme 1
CO2Et
CH2OH
CO2Et
CHO
CH2OH
CH2OH
HO
O
O
OBn
O
O
OBn
O
OBn
A
B
C
OBn
O
O
O
O
80%
77%
72%
O
O
O
O
1
2
3
4
A: 1) Bu2SnO, PhCH3, 120 °C, 6 h
2) NBS, CHCl3, rt, 5 min
B: Ph3P=CHCO2Et, CHCl3, 30 °C, 30 min
C: PCC, mol. sieves 4Å, CH2Cl2, rt, 10 min
123

Synthesis of pseudo-C-nucleosides
1239
Scheme 2
O
O
CH2OTr
O
CH2OTr
O
CH2OH
O
HO
O
HO
A
B
C
O
O
O
90%
O
73%
62%
BnO
O
O
BnO
O
BnO
O
BnO
O
6
5
7
8
A: TrCl, Et3N, DMF, rt, 14 h
B: PCC, mol. sieves 4Å, CH2Cl2, 40 °C, 1 h
C: Ph3P=CHCO2Et, CHCl3, 30 °C, 30 min
Scheme 3
COPh
EtO2C
6
NNHR
1'
HN N
EtO2C
CHO
CO2Et
O
OBn
5
O
OBn
O
OBn
A, B, C
9 or 10
1
Ac2O, NaOAc,
100 °C, 4 h
4
O
O
O
3
O
O
O
4
13 R= CO2Me
18
14
R=COPh
(72 % from 14)
12
A, C
11 A, B
11
C
H
Ph
9
H2NNHCO2Me
O
6
5
N
N
N
EtO2C
NNHPh
1
N
10 H2NNHCOPh
11 H2NNHPh
12 H2NNH2 . H2O
5
3
EtO2C
3
4
4
O
OBn
O
O
1'
1'
OBn
OBn
4'
4'
O
O
O
3'
3'
O
O
O
17
15
16
Table 1 Formation yields and
reaction conditions in the
treatment of 4 with hydrazine
derivatives 9–12
Method
A EtOH, reflux
Hydrazine derivatives
Time (min)
Product
13
Yield (%)
Methyl hydrazinocarboxylate (9)
300
300
300
60
81
64
64
45
86
73
71
66
61
69
45
Benzoylhydrazine (10)
14
15
16
13
14
15
13
14
17
16
Phenylhydrazine (11)
Hydrazine hydrate (12)
B EtOH, MW (450 W)
C EtOH, AcOH, 80°C
9
6
10
11
9
6
6
180
180
180
60
10
11
12
group, which then undergoes ethoxyl group elimination and
intramolecular ring closure.
shorter reaction time, and using roughly half the amount of
solvent (Method B).
The reaction of 4 with the hydrazine derivatives 9–11
under microwave irradiation led to the formation of the
same hydrazone derivatives 13–15 in better yields, a
The reaction of ethyl 3-O-benzyl-5,6-dideoxy-5-C-
formyl-1,2-O-isopropylidene-a-D-xylo-hept-5-enofuranuro-
nate (4) with hydrazine derivatives 9, 10, and 12 in
123

1240
J. M. Pinheiro et al.
The 1H NMR spectrum of 7 showed a multiplet at
dH = 7.45–7.18 ppm, due to the aromatic protons of the
benzyl and trityl groups, while the methylene protons of
the benzyl group appear as an AB spin system
(J = 11.7 Hz) at dH = 4.52 and 4.37 ppm, and the H-6
resonance appears in a multiplet at dH = 3.34–3.20 ppm.
The resonance of the ketone carbonyl group of 7 appears at
dC = 201.5 ppm in the 13C NMR spectrum. Besides the
resonances of the aromatic and furanosidic carbons, it is
possible to assign the signals at dC = 71.4 and 63.6 ppm to
the resonances of the benzyl group and C-6 methylene
carbons. In the 1H NMR spectrum of 8 the signals from the
trityl group disappeared, and no signals from the ethyl
group were detected. The vinyl and methylene protons of
the lactone moiety of 8 appear, respectively, as a singlet at
dH = 6.05 ppm and as a multiplet at dH = 4.81–4.51 ppm.
The carbonyl carbon of the lactone moiety of 8 appears in
the 13C NMR spectrum at dC = 173.2 ppm, whereas the
signals of the other lactone carbons C-3, C-4, and C-5
appear at dC = 115.8, 166.3, and 70.8 ppm.
H N
3
Ph
H N
Ph
2
N
N
EtO C
2
EtO C
2
EtO C
2
PhNHNH
3
CHO
OH
G
G
G
19
20
4
G = 3-O-benzyl-1,2-O-isopropylidene- -D-threo-furanos-4-yl
Ph
Ph
N
N
HN N
[oxid]
EtO C
EtO C
2
2
G
G
21
17
Scheme 4
refluxing ethanol and using glacial acetic acid as catalyst
(Method C) also led to the formation of 13, 14, and 16 as
referred to in Method A. However, the reaction of 4 with
phenylhydrazine (11) led to the formation of a new pyra-
zole-type compound 17. The formation of this product 17
can be envisaged by the mechanism depicted in Scheme 4.
In the acidic medium protonation of the more nucleophilic
nitrogen of the phenylhydrazine occurs, the secondary
nitrogen atom then attacks the formyl group of 4 leading to
the hydrazonium compound 20, which gives 17 after
cyclization and oxidation processes.
The 1H NMR spectra of hydrazones 13, 14, and 15
showed three singlets at dH = 10.41–8.68, 8.19–7.78, and
6.85–6.34 ppm due to the resonances of NH, H-10, and H-
6, respectively. The 13C NMR spectra of these compounds
present the carbonyl carbon resonances of the unsaturated
ester groups at dC = 166.6–165.3 ppm and those of the
hydrazone moiety at dC = 164.2–154.0 ppm. Other
important carbon resonances to be noticed are those of C-10
and C-5 appearing at dC = 145.2–133.8 and 146.6–
Intramolecular cyclization of 13 and 14 was tried, since
it is known that compounds bearing hydrazone and a,b-
unsaturated ester moieties in their structure can be cyclized
with Ac2O/NaOAc [17]. The TLC analysis of the reaction
of 13 with Ac2O/NaOAc, at 100°C for 8 h, revealed that no
reaction occurred, and 13 was recovered. This reaction was
repeated with 14, and a new compound was detected. The
product was identified as 18 (72%). It is possible to con-
clude that the intramolecular cyclization of 13 did not
occur because the hydrazone moiety of this molecule is less
reactive than the corresponding moiety of 14.
1
145.8 ppm, respectively. The H and 13C NMR spectra of
13, 14, and 15 indicate the presence of only one isomer,
which was assumed to be the (E) isomer of the hydrazone
double bond, based on the literature data of other hydra-
zones [19, 20].
1
The H NMR spectrum of 16 presented the proton res-
onances of the NH (broad singlet), H-3 (doublet), and H-5
(singlet) at, respectively, dH = 12.12, 7.75, and 6.89 ppm.
In the 13C NMR spectrum the signals of the pyridazinone
ring appear at dC = 162.0, 142.7, 137.0, and 126.6 ppm
and were assigned to the resonances of C-6, C-4, C-3, and
C-5, respectively. In its HMBC spectrum, it was possible to
observe connectivities of H-3 with C-4 and C-5, H-5 with
C-3 and C-40, and of H-40 with C-4 and C-5 (Fig. 1).
Characterization of the obtained products
The main features of the 1H NMR spectrum of compound 3
are the singlet at dH = 6.06 ppm, due to the resonance of
H-6, and a multiplet at dH = 4.59–4.56 ppm, which is
assigned to the methylene signals of the hydroxymethyl
group. The 13C NMR spectrum of 3 presented two qua-
ternary carbon signals at dC = 165.5 and 156.8 ppm,
which were assigned to C-7 and C-5, while the signals
at dC = 115.5 and 63.5 ppm were attributed to C-6 and to
the methylene carbon of the hydroxymethyl group. The 1H
and 13C NMR spectra of 4 present new signals at
dH = 9.86 ppm, as a singlet, and dC = 192.0 ppm, due to
the proton and carbon resonances of the formyl group that
has been formed.
Fig. 1 Most important correla-
tions in HMBC spectrum of 16
H
O
H
N
N
3
H
5
O
4'
OBn
H
O
O
16
123

Synthesis of pseudo-C-nucleosides
1241
In the NMR spectra of 17, the pyrazole signals appear at
dH = 8.12 ppm (H-5, as a singlet) and at dC = 140.7, 129.1,
and 122.1 ppm, assigned to C-4, C-5, and C-3, respectively.
Compound 18 was characterized by a 1H NMR spectrum
that showed two singlets at dH = 7.03 and 5.94 ppm,
which were assigned to the resonances of H-3 and H-5. The
NH signal was not detected, but the IR spectrum showed a
sample at a v/v ratio of 1–5% to give the best signal-to-
noise ratio. Data acquisition and data processing were
performed using the XMASS software version 6.1.2
(Bruker Daltonics). HRMSs were in good agreement
( 0.5 ppm) with the calculated values. Elemental analyses
were obtained with a Vario EL CHN analyzer (University
of Beira Interior) and were in good agreement ( 0.4%)
with the calculated values. A domestic microwave oven
(Electrolux, 850 W, 20-l capacity) was used in the reac-
tions carried out under microwave irradiation. The progress
of all reactions was monitored by thin-layer chromatogra-
phy using aluminium sheets pre-coated with silica gel
60F254 to a thickness of 0.2 mm (Merck), and spots were
developed in a UV chamber (256 nm) or with 3% of
vanillin in ethanol/H2SO4 (100 cm3/1.5 cm3) followed by
heating. Column chromatography (CC) was conducted
under low pressure by elution of the columns filled with
silica gel (0.040–0.063 mm, Merck). All other chemicals
and solvents used were obtained from commercial sources
and used as received or dried using standard procedures.
band at 3,241 cm-1 attributed to the NH vibration. The 13
C
NMR spectrum presented signals at dC = 149.2, 119.8, and
89.3 ppm, which were assigned to C-4, C-5, and C-3 of the
pyrazoline ring.
Conclusions
We have prepared new pseudo-C-nucleosides bearing pyra-
zole and pyridazinone rings by the reaction of the appropri-
ate b-sugar-b-formyl-a,b-unsaturated ester with hydrazine
derivatives. Under neutral conditions (with classical heating
or with microwave irradiation), hydrazones and a pseudo-C-
nucleoside 16 were formed, while under acidic conditions the
reaction with phenylhydrazine and hydrazine hydrate led to
pseudo-C-nucleosides bearing a pyrazole and a pyridazinone
ring, respectively. The cyclization of a c-phenylhydrazono-
a,b-unsaturated ester derivative with Ac2O/NaOAc also leads
to a pseudo-C-nucleoside.
3-O-Benzyl-1,2-O-isopropylidene-a-D-xylo-
hexafuran-5-ulose (2)
Yield: 0.24 g (77%); syrup; Rf = 0.64 (1:1 ethyl ace-
1
tate:toluene); IR and H NMR spectra were found to be
identical with the ones described in Ref. [18].
Ethyl 3-O-benzyl-5,6-dideoxy-5-C-hydroxymethyl-1,
2-O-isopropylidene-a-D-xylo-hept-5-(E)-enofuranuronate
(3, C20H26O7)
Experimental
A solution of 0.72 g ethoxycarbonylmethylene triphenyl-
phosphorane (2.03 mmol) in 5 cm3 dry CHCl3 was added
dropwise to a solution of 1.11 g 2 (3.6 mmol) in 5.0 cm3
dry CHCl3. The mixture was stirred for 30 min at 30°C,
concentrated, and the obtained residue was purified by CC
eluting with a 1:5 mixture of ethyl acetate:toluene. Yield
0.28 g (80%); syrup; Rf = 0.57 (1:2 ethyl acetate:toluene);
1H NMR (250.13 MHz, CDCl3): d = 7.32–7.22 (m, C6H5),
6.06 (s, H-6), 5.95 (d, J = 3.4 Hz, H-1), 4.59–4.56 (m,
CH2C6H5, CH2OH, H-2, H-3, H-4), 4.05 (q, J = 7.2 Hz,
CH2CH3), 2.92 (br s, CH2OH), 1.48 and 1.31 [2 s,
C(CH3)2], 1.22 (t, J = 7.2 Hz, CH2CH3) ppm; 13C NMR
(62.9 MHz, CDCl3): d = 165.5 (C-7), 156.8 (C-5), 137.0
(C-1, C6H5), 128.2, 128.0, 127.7 (CH, C6H5), 115.5 (C-6),
111.7 [C(CH3)2], 104.7 (C-1), 83.1 (C-3), 82.4 (C-2), 79.7
(C-4), 72.1 (CH2C6H5), 63.5 (CH2OH), 59.9 (CH2CH3),
26.7 and 26.2 [C(CH3)2], 14.0 (CH2CH3) ppm; IR (neat):
vꢀ = 3,500 (OH), 1,700 (C=O), 1,685 (C=C) cm-1; ESI(?)-
HRMS: found 379.1754 (379.1757 calcd for C20H27O7).
Melting points were determined on a Leitz-Biomed with
platinum plate apparatus. Infrared (IR) spectral data were
obtained using a FT-IR Mattson Genesis II spectropho-
tometer. NMR spectra were recorded on Bruker AC-P 250
1
(250.13 MHz for H and 62.9 MHz for 13C) and Bruker
Avance 300 spectrometers (300.13 MHz for 1H and
75.47 MHz for 13C), with CDCl3 as solvent if not stated
otherwise. Chemical shifts (d) are reported in ppm values
and coupling constants (J) in Hz. The internal standard was
TMS. 13C NMR assignments of compound 16 and 17 were
made using 2D gHSQC and gHMBC (delays for one bond
and long-range J C/H couplings were optimized for 145
and 7 Hz, respectively) experiments. Mass spectra were
performed on an APEX III FT-ICR MS (Bruker Daltonics,
Billerica, MA), equipped with a 7-T actively shielded
magnet. Ions were generated using an Apollo API elec-
trospray ionization (ESI) source. Ionization was achieved
by an electrospray ionization source (Bruker Daltonics,
Billerica, MA), with a voltage of between 1,800 and
2,200 V (to optimize ionization efficiency) applied to the
needle, and counter voltage of 450 V applied to capillary.
Samples were prepared by adding a spray solution of
50:49.5:0.5 (v/v/v) water/methanol/formic acid to the
Ethyl 3-O-benzyl-5,6-dideoxy-5-C-formyl-1,2-O-isopropyl-
idene-a-D-xylo-hept-5-enofuranuronate (4, C20H24O7)
A solution of 0.38 g 3 (1.00 mmol) in 0.8 cm3 dry CH2Cl2
was added to a suspension of 0.63 g PCC (2.92 mmol) and
3
˚
1.20 g molecular sieves 4 A (powder) in 3.0 cm dry
123

1242
J. M. Pinheiro et al.
CH2Cl2, and the resulting mixture stirred for 10 min at
room temperature. The reaction mixture was added to
40 cm3 diethyl ether and strongly stirred for 20 min. The
inorganic salts were separated by filtration, and the
obtained solution was purified by florisil. Yield 0.27 g
4-(3-O-Benzyl-1,2-O-isopropylidene-a-D-ribo-furanos-4-
yl)-2(5H)-furanone (8, C18H20O6)
Compound 8 was obtained by the method used in the
preparation of 3, followed by CC purification, eluting with a
1:5 mixture of ethyl acetate:toluene. Yield 0.21 g (62%);
1
1
(72%); syrup; Rf = 0.73 (1:2 ethyl acetate:methanol); H
m.p.: 153–154°C; Rf = 0.62 (1:1 ethyl acetate:toluene); H
NMR (250.13 MHz, CDCl3): d = 9.86 (s, CHO), 7.37–
7.23 (m, C6H5), 6.60 (s, H-6), 6.06 (d, J = 3.7 Hz, H-1),
5.86 (d, J = 2.9 Hz, H-4), 4.69 (d, J = 3.7 Hz, H-2), 4.60
and 4.43 (AB system, J = 12.0 Hz, CH2C6H5), 4.32 (d,
J = 2.9 Hz, H-3), 4.16 (q, J = 7.0 Hz, CH2CH3) 1.53 and
1.35 [2 s, C(CH3)2], 1.28 (t, J = 7.0 Hz, CH2CH3) ppm;
13C NMR (62.9 MHz, CDCl3): d = 192.0 (CHO), 165.3
(CO2Et), 143.4 (C-5), 136.9 (C-1, C6H5), 128.5, 127.9,
127.6 (CH, C6H5), 126.4 (C-6), 113.1 [C(CH3)2], 105.7 (C-
1), 83.7 (C-4), 83.0 (C-2), 78.1 (C-3), 72.4 (CH2C6H5),
61.3 (CH2CH3), 27.1 and 26.5 [C(CH3)2], 14.2 (CH2CH3)
NMR (250.13 MHz, CDCl3): d = 7.41–7.22 (m, 5H, C6H5),
6.05 (s, H-3), 5.82 (d, J = 3.6 Hz, H-10), 4.87 and 4.21 (AB
system, J = 8.6 Hz, CH2C6H5), 4.81–4.51 (m, H-20, H-40,
CH2-5), 3.64 (dd, J = 4.1, 9.3 Hz, H-30), 1.61 and 1.38 [2 s,
C(CH3)2] ppm; 13C NMR (62.9 MHz, CDCl3): d = 173.2
(C-2), 166.3 (C-4), 136.4 (C-1, C6H5), 128.7, 128.6, 128.3
(CH, C6H5), 115.8 (C-3), 113.6 [C(CH3)2], 104.4 (C-10), 81.4
(C-20), 76.8 (C-30), 74.4 (C-40), 72.4 (CH2C6H5), 70.8 (C-5),
26.7 and 26.4 [C(CH3)2] ppm; IR (KBr): vꢀ = 1,710 (C=O),
1,675 (C=C) cm-1
; ESI(?)-HRMS: found 333.1333
(333.1338 calcd for C18H21O6).
ppm; IR (neat): vꢀ = 1,720 (C=O), 1,691 (C=C) cm-1
;
ESI(?)-HRMS: found 377.1600 (377.1599 calcd for
General procedure for preparation of hydrazone
derivatives
C20H25O7).
3-O-Benzyl-1,2-O-isopropylidene-6-O-triphenylmethyl-a-
D-ribo-hexafuranose (6)
Yield: 2.35 g (90%); syrup; Rf = 0.69 (2:1 ethyl ace-
Method A
A
solution of the appropriate hydrazine derivative
(1.10 mmol) in 1 cm3 ethanol was added dropwise to a
solution of 0.38 g compound 4 (1.00 mmol) in 1.0 cm3
ethanol. The mixture was stirred for the appropriate time
(see Table 1) at 80°C, and then cooled to room tempera-
ture, concentrated, and the obtained residue was purified by
CC. Reaction of methyl hydrazinocarboxylate (9) led to 13
in 81% yield (0.36 g); benzoylhydrazine (10) led to 14 in
64% yield (0.32 g); phenylhydrazine (11) led to 15 in 64%
yield (0.30 g), and hydrazine hydrate (12) yielded 16 in
45% yield (0.16 g).
1
tate:toluene); IR and H NMR spectra were found to be
identical with the ones described in Ref. [17].
3-O-Benzyl-1,2-O-isopropylidene-6-O-triphenylmethyl-a-
D-ribo-hexafuran-5-ulose (7, C35H34O6)
A solution of 0.54 g 6 (1.00 mmol) dissolved in 1.5 cm3
dry CH2Cl2 was added to a suspension of 1.0 g activated
˚
powdered molecular sieves 4 A, and 0.66 g PCC
(3.05 mmol) in 3.0 cm3 dry CH2Cl2. The reaction mixture
was stirred at 40°C for 1 h, and then added to 60 cm3
diethyl ether under vigorous stirring. Inorganic salts were
filtered, and the mixture was passed by florisil in vacuum
until the filtrate was colorless. The solvent was evaporated
at low temperature to give 0.38 g (73%) pure 7 (this
compound is unstable and must be conserved at low
temperature and freshly prepared to be used in the
synthesis of 8). Syrup; Rf = 0.71 (2:1 ethyl acetate:tolu-
Method B
A mixture of hydrazine derivative (1.10 mmol) in 0.5 cm3
ethanol was added dropwise to a solution of 0.38 g com-
pound 4 (1.00 mmol) in 0.5 cm3 ethanol. The mixture was
heated in a microwave oven at 450 W for 6 min, the dis-
appearance of the starting material being monitored every
2 min by TLC. The obtained residue, after concentration,
was purified by CC. Reaction of 9 led to 13 in 86% yield
(0.39 g); 10 led to 14 in 73% yield (0.36 g); 11 yielded 15
in 71% yield (0.33 g).
1
ene); H NMR (250.13 MHz, CDCl3): d = 7.45–7.18 (m,
20H, C6H5), 5.67 (d, J = 3.6 Hz, H-1), 4.52 and 4.37 (AB
system, J = 11.7 Hz, CH2C6H5), 4.42 (t, J = 4.0 Hz,
H-2), 4.03 (d, J = 8.7 Hz, H-4), 3.85 (dd, H-3, J = 4.0,
8.7 Hz), 3.34–3.20 (m, CH2-6), 1.54 and 1.31 [2 s,
C(CH3)2] ppm; 13C NMR (62.9 MHz, CDCl3): d = 201.5
(C-5), 143.9, 143.7, 142.4 (C-1, C6H5), 137.1 (C-1,
CH2C6H5), 128.3, 128.0, 127.6, 127.5, 127.4, 127.1,
126.3, 124.6 (CH, C6H5), 112.1 [C(CH3)2], 103.4 (C-1),
86.1 [C(C6H5)3], 77.8 (C-4), 77.0 (C-2), 76.1 (C-3), 71.4
(CH2C6H5), 63.6 (CH2-6), 26.2 and 25.9 [C(CH3)2] ppm;
Method C
A solution of hydrazine derivative (1.10 mmol) in 1 cm3
ethanol was added dropwise to a solution of 0.38 g 4
(1.00 mmol) in 1.0 cm3 ethanol. Then glacial acetic acid
(0.10 mmol) was added to the reaction mixture, which was
heated at 80°C for the appropriate time (see Table 1). The
disappearance of the starting material was monitored every
IR (neat): vꢀ = 1,710 (C=O) cm-1
.
123

Synthesis of pseudo-C-nucleosides
1243
ethyl acetate:toluene); 1H NMR (250.13 MHz, CDCl3):
d = 8.68 (s, NH), 8.04 (s, H-10), 7.26–6.87 (m, 10H,
C6H5), 6.34 (s, H-6), 6.03 (d, J = 3.7 Hz, H-1), 5.44 (d,
J = 3.2 Hz, H-4), 4.64 (d, J = 3.7 Hz H-2,), 4.50 and 4.35
(AB system, J = 11.7 Hz, CH2C6H5), 4.43 (d, J = 3.2 Hz,
H-3), 4.17 (q, J = 6.9 Hz, CH2CH3), 1.56 and 1.37 [2 s,
C(CH3)2], 1.27 (t, J = 6.9 Hz, CH2CH3) ppm; 13C NMR
(62.9 MHz, CDCl3): d = 166.6 (CO2Et), 146.6 (C-5),
143.4 (C-1, CH2C6H5), 137.1 (C-1, C6H5), 133.8 (C-10),
129.2, 128.1, 128.0, 127.9, 127.6, 120.7, 112.7 (CH, C6H5),
116.6 (C-6), 111.8 [C(CH3)2], 104.1 (C-1), 83.1 (C-2), 82.8
(C-3), 78.7 (C-4), 72.3 (CH2C6H5), 60.0 (CH2CH3), 27.0,
26.4 [C(CH3)2], 14.2 (CH2CH3) ppm; IR (neat): vꢀ = 3,241
hour by TLC. The mixture was concentrated after cooling
and purified by CC. 13 was obtained in 66% yield (0.30 g)
by reaction with 9; 10 reacted with 4 to form 14 in 61%
yield (0.27 g); 11 led to 17 in 69% yield (0.31 g); 12 led to
16 in 45% yield (0.16 g).
Ethyl 3-O-benzyl-5,6-dideoxy-5-C-(methoxycarbonylhy-
drazonomethyl)-1,2-O-isopropylidene-a-D-xylo-hept-5-
enofuranuronate (13, C22H28N2O8)
The obtained residue was purified by CC eluted with a 1:10
mixture of ethyl acetate:toluene. Syrup; Rf = 0.63 (4:1
ethyl acetate:toluene); 1H NMR (250.13 MHz, CDCl3):
d = 8.95 (s, NH), 7.78 (s, H-10), 7.50–7.30 (m, C6H5), 6.74
(br s, H-6), 5.97 (d, J = 3.7 Hz, H-1), 5.91 (d, J = 2.9 Hz,
H-4), 4.60 (d, J = 3.7 Hz, H-2), 4.53 and 4.40 (AB system,
J = 11.8 Hz, CH2C6H5), 4.33 (d, 1H, H-3), 4.10 (q,
J = 7.0 Hz, CH2CH3), 3.79 (s, OCH3), 1.50 and 1.30
[2 s, C(CH3)2], 1.24 (t, CH2CH3) ppm; 13C NMR
(62.9 MHz, CDCl3): d = 165.3 (CO2Et), 154.0 (CO2Me),
146.3 (C-5), 142.2 (C-10), 136.8 (C-1, C6H5), 128.1, 128.0,
127.6 (CH, C6H5), 117.8 (C-6), 112.0 [C(CH3)2], 104.8 (C-
1), 83.3 (C-3), 82.8 (C-2), 76.6 (C-4), 72.2 (CH2C6H5),
60.2 (CH2CH3), 52.6 (OCH3), 26.7, 26.2 [C(CH3)2], 13.9
(CH2CH3) ppm; IR (neat): vꢀ = 3,239 (NH), 1,782 (C=O),
(NH), 1,723 (C=O) cm-1
.
4-(3-O-Benzyl-1,2-O-isopropylidene-a-D-threo-furanos-4-
yl)pyridazin-6-one (16, C18H20N2O5)
The obtained residue was purified by CC eluted with a 1:3
mixture of ethyl acetate:toluene. Syrup; Rf = 0.22 (5:1
1
ethyl acetate:methanol); H NMR (250.13 MHz, CDCl3):
d = 12.12 (br s, H-1), 7.75 (d, J = 1.9 Hz, H-3), 7.30–7.06
(m, C6H5), 6.89 (s, H-5), 6.09 (d, J = 3.7 Hz, H-10), 5.05
(d, J = 2.5 Hz, H-40), 4.72 (d, J = 3.7 Hz, H-20), 4.56 and
4.34 (AB system, J = 12.1 Hz, CH2C6H5), 4.29 (d,
J = 2.5 Hz, H-30), 1.54 and 1.37 [2 s, C(CH3)2] ppm;
13C NMR (62.9 MHz, CDCl3): d = 162.0 (C-6), 142.7 (C-
4), 137.0 (C-3), 136.2 (C-1, C6H5), 128.6, 128.3, 127.8
(CH, C6H5), 126.6 (C-5), 112.3 [C(CH3)2], 105.2 (C-10),
82.4 (C-30), 82.4 (C-20), 78.8 (C-40), 72.1 (CH2C6H5), 26.8
and 26.1 [C(CH3)2] ppm; IR (neat): vꢀ = 3,241 (NH), 1,784
1,721 (C=O) cm-1
.
Ethyl 5-C-(benzoylhydrazonomethyl)-3-O-benzyl-5,6-dide-
oxy-1,2-O-isopropylidene-a-D-xylo-hept-5-enofuranur-
onate (14, C27H30N2O7)
The obtained residue was purified by CC eluted with a 1:5
mixture of ethyl acetate:toluene. Syrup; Rf = 0.39 (1:2
ethyl acetate:toluene); 1H NMR (250.13 MHz, CDCl3):
d = 10.41 (s, NH), 8.19 (s, H-10), 7.86 (d, J = 7.5 Hz,
C6H5), 7.46–7.16 (m, 8H, C6H5), 6.85 (s, H-6), 5.91 (d,
J = 3.9 Hz, H-1), 5.82 (d, J = 2.9 Hz, H-4), 4.54–4.49
(m, H-2, CH2C6H5), 4.39 (AB system, J = 11.8 Hz,
CH2C6H5), 4.30 (d, H-3), 4.07 (q, J = 6.9 Hz, CH2CH3),
1.44 and 1.25 [2 s, C(CH3)2], 1.23 (t, CH2CH3) ppm; 13C
NMR (62.9 MHz, CDCl3): d = 165.5 (CO2Et), 164.2
(COPh), 145.8 (C-5), 145.2 (C-10), 136.7 (C-1, CH2C6H5),
132.6 (C-1, C6H5), 131.8, 128.5, 128.2, 127.8, 127.7,
127.6, 127.5 (CH, C6H5), 118.9 (C-6), 111.9 [C(CH3)2],
104.9 (C-1), 83.4 (C-3), 82.9 (C-2), 78.0 (C-4), 72.4
(CH2C6H5), 60.3 (CH2CH3), 26.7 and 26.2 [C(CH3)2], 13.9
(CH2CH3) ppm; IR (neat): vꢀ = 3,243 (NH), 1,780 (C=O),
1,720 (C=O) cm-1; ESI(?)-HRMS: found 495.2119
(495.2126 calcd for C27H31N2O7).
(C=O), 1,592 (C=C) cm-1
; ESI(?)-HRMS: found
345.1442 (345.1450 calcd for C18H21N2O5).
Ethyl 4-(3-O-benzyl-1,2-O-isopropylidene-a-D-threo-
furanos-4-yl)-1-phenylpyrazole-3-carboxylate
(17, C26H28N2O6)
The obtained residue was purified by CC eluted with a 1:20
mixture of ethyl acetate:toluene. Syrup; Rf = 0.58 (1:2
ethyl acetate:toluene); 1H NMR (250.13 MHz, CDCl3):
d = 8.12 (s, H-5), 7.75–7.04 (m, C6H5), 6.07 (d,
J = 3.8 Hz, H-10), 5.74 (d, J = 2.9 Hz, H-40), 4.74 (d,
J = 3.8 Hz, H-20), 4.48 and 4.23 (AB system, J = 12 Hz,
CH2C6H5), 4.36–4.28 (m, H-30, CH2CH3), 1.57 and 1.37
[2 s, C(CH3)2], 1.33 (t, J = 7.2 Hz, CH2CH3) ppm; 13C
NMR (62.9 MHz, CDCl3): d = 162.2 (CO2Et), 140.7 (C-
4), 139.5 (C-1, C6H5-N), 137.2 (C-1, C6H5), 129.1 (C-5),
129.4, 128.3, 127.8, 127.7, 127.5, 119.9 (CH, C6H5), 122.1
(C-3), 111.8 [C(CH3)2], 104.5 (C-10), 83.4 (C-20), 81.6 (C-
30), 76.0 (C-40), 72.2 (CH2C6H5), 61.1 (CH2CH3), 26.9 and
26.3 [C(CH3)2], 14.2 (CH2CH3) ppm; IR (neat): vꢀ = 1,723
Ethyl 3-O-benzyl-5,6-dideoxy-5-C-(phenylhydrazonometh-
yl)-1,2-O-isopropylidene-a-D-xylo-hept-5-enofuranuronate
(15, C26H30N2O6)
(C=O), 1,595 (C=C) cm-1
465.2008 (465.2026 calcd for C26H29N2O6).
; ESI(?)-HRMS: found
The obtained residue was purified by CC eluted with a 1:10
mixture of ethyl acetate:toluene. Syrup, Rf = 0.47 (1:2
123

1244
J. M. Pinheiro et al.
2. Watanabe KA (1994). In: Townsend LB (ed) Chemistry of
nucleosides and nucleotides, vol 3. Plenum Press, New York,
p 421
3. Lange JHM, Stuivenberg HH, Coolen HKAC, Adolfs TJP,
McCreary AC, Keizer HG, Wals HC, Veerman W, Borst AJM,
Looff W, Verveer PC, Kruse CG (2005) J Med Chem 48:1823
4. Abele E, Abele R, Lukevics E (2007) Chem Heterocycl Compd
43:945
5. Heinisch G, Kopelent-Frank H (1992) Pharmacologically active
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6. Omran OA, Amer AA, Khodairy A (2006) Synth Commun
36:3647
Ethyl 2-benzoyl-4-(3-O-benzyl-1,2-O-isopropylidene-a-D-
threo-furanos-4-yl)-2,3-dihydro-1H-pyrazole-3-carbox-
ylate (18, C27H30N2O7)
A solution of 0.149 g sodium acetate (1.80 mmol) and
2.57 cm3 acetic anhydride (2.73 mmol) was added dropwise
with stirring to a mixture of 0.49 g hydrazone 14
(1.00 mmol) in 2.0 cm3 dry CHCl3. The mixture was stirred
for 4 h at 100°C and then cooled to room temperature. The
crude mixture was concentrated in a vacuum and extracted
with CHCl3 (3 9 45.0 cm3). The organic layer was dried and
the solvent evaporated. The obtained residue was purified by
CC with a 1:10 mixture of ethyl acetate:toluene, and 18 was
obtained as syrup. Yield 0.36 g (72%); Rf = 0.48 (2:1 ethyl
acetate:toluene); 1H NMR (250.13 MHz, CDCl3): d = 7.75–
7.04 (m, 10H, C6H5), 7.03 (s, H-3), 6.12 (d, J = 3.7 Hz,
H-10), 5.94 (s, H-5), 5.89 (dd, J = 4.0, 2.0 Hz, H-40), 4.63
(d, J = 3.7 Hz, H-20), 4.50 (d, J = 4.0 Hz, H-30), 4.43 and
4.30 (AB system, J = 12.2 Hz, CH2C6H5), 4.00–3.95 (m,
CH2CH3), 1.51 and 1.34 [2 s, C(CH3)2], 1.22 (t, J = 7.2 Hz,
CH2CH3) ppm; 13C NMR (62.9 MHz, CDCl3): d = 164.8
(CO2Et), 156.5 (COPh), 149.2 (C-4), 137.3 (C-1, CH2C6H5),
131.9 (C-1, C6H5), 131.5, 128.6, 128.2, 128.1, 127.7, 127.2
(CH, C6H5), 119.8 (C-5), 112.2 [C(CH3)2], 104.0 (C-10), 89.3
(C-3), 83.4 (C-20), 82.8 (C-30), 80.1 (C-40), 72.2 (CH2C6H5),
60.7 (CH2CH3), 27.3 and 26.7 [C(CH3)2], 14.1 (CH2CH3)
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