Efficient and β-stereoselective synthesis of pyrazole C-nucleosides

Article abstract of DOI:10.1055/s-2006-926319

3(5)-(β-D-Ribofuranosyl)pyrazole 1 and 3(5)-(2-deoxy-β-D- ribofuranosyl)pyrazole (2) were stereoselectively synthesized by cyclization of 1,2-diazafulvene intermediates obtained from 2,3,5-tri-O-benzyl-D-ribose (5) and 3,5-di-O-benzyl-2-deoxy-D-ribose (10

Full text of DOI:10.1055/s-2006-926319

PAPER
793
Efficient and b-Stereoselective Synthesis of Pyrazole C-Nucleosides
b-Stereoselecth
i
of Pyr
n
azole
C
-Nuc
y
leosides a Harusawa, Chiharu Matsuda, Lisa Araki, Takushi Kurihara*
Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan
Fax +81(726)901086; E-mail: kurihara@gly.oups.ac.jp
Received 5 September 2005; revised 6 October 2005
for pyrazofurin and formycin (Figure 2).4 In 1995, Wight-
man et al. reported a stereoselective synthesis of 1 starting
from 5-(tert-butyldiphenylsilyl)-2,3-O-isopropylidene-D-
ribono-1,4-lactone in 6 steps and about 20% overall yield.4a
They used the first synthetic approach mentioned above,
in which treatment of diol 3 (a 6:1 diastereomeric mix-
ture) with TsCl afforded the desired b-alkyne 4b (52%),
together with a-anomer 4a (10%) and b-L-lyxo isomer
(7%) (Scheme 1).4a However, the yield and b-stereoselec-
tivity in glycosylation reaction still remain to be opti-
mized.
Abstract: 3(5)-(b-D-Ribofuranosyl)pyrazole 1 and 3(5)-(2-deoxy-
b-D-ribofuranosyl)pyrazole (2) were stereoselectively synthesized
by cyclization of 1,2-diazafulvene intermediates obtained from
2,3,5-tri-O-benzyl-D-ribose (5) and 3,5-di-O-benzyl-2-deoxy-D-ri-
bose (10), respectively.
Key words: pyrazole, C-nucleoside, b-anomer, stereoselective
synthesis, diazafulvene
Pyrazofurin1a and formycin1b,c are two naturally occurring
nucleosides possessing significant antitumor and antiviral
activities (Figure 1).2 These two nucleosides belong to the
family of C-nucleosides in which the ribofuranosyl moi-
ety is linked to the heterocyclic base by a carbon–carbon
bond at the anomeric center.1,2 With this C-glycosidic
linkage, they are enzymatically stable to the action of nu-
cleoside phosphorylase.1 However, the high toxicity asso-
ciated with these compounds has restricted development
as potential therapeutic agents.1a–c,2
H
N
N
HO
O
HO
R
1 : R = OH
2 : R = H
NH2
H
H
Figure 2 3(5)-(b-D-ribofuranosyl)pyrazole 1
N
N
N
CONH2
N
N
HO
HO
N
CH(OEt)2
O
O
OH
CH(OEt)2
C
C
HO
OH
HO
OH
C
TPSO
O
OH HO
TPSO
C
TsCl
pyridine
Pyrazofurin
Formycin
1
O
O
Figure 1 Pyrazofurin and formycin
O
O
4β (52%)
4α (10%)
Synthetic methods for C-nucleosides were classified into
two major synthetic approaches:3 (1) the introduction of a
functional group at the anomeric position of a sugar deriv-
ative, followed by the construction of a heterocyclic base;
and (2) direct attachment of a pre-formed aglycon unit to
an appropriate carbohydrate moiety.1,3 As the first ap-
proach involves many steps, it results in rather low yields
and poor stereoselectivity. The second strategy was devel-
oped to overcome the drawbacks of the first approach.
3
β-L-lyxo isomer (7%)
Scheme 1 Synthetic approach to 1 by Wightman et al.
We previously reported an efficient synthesis of 4(5)-b-D-
ribofuranosylimidazoles with high stereoselectivity, using
the cyclization of 1,3-diazafulvenes generated in situ.6
This synthetic method belongs to the second approach in
the current synthesis of C-nucleosides. The second strate-
gy has not been done for the synthesis of b-D-ribofurano-
sylpyrazole to date.3 Taking account of the analogies
between imidazoles7 and pyrazoles,8 the synthesis of
pyrazole C-nucleosides is feasible. Further, C-nucleosides
are suitable candidates for use as building blocks of oligo-
nucleotides in gene therapy.3,6e We herein describe effi-
cient and b-stereoselective synthesis of 3(5)-(b-D-
ribofuranosyl)pyrazole 1, which was obtained from 2,3,5-
Systematic studies on the synthetic methods of pyrazole
C-nucleosides4 and their conversion into pyrazofurin5a–c
and formycin5a,d were continued for about two decades by
Buchanan and Wightman et al. In this context, 3(5)-(b-D-
ribofuranosyl)pyrazole 1 is used as a common precursor
SYNTHESIS 2006, No. 5, pp 0793–0798
x
x
.
x
x
.2
0
0
6
Advanced online publication: 07.02.2006
DOI: 10.1055/s-2006-926319; Art ID: F14805SS
© Georg Thieme Verlag Stuttgart · New York

794
S. Harusawa et al.
PAPER
OH
BnO
BnO
OH
BnO
OH
OH
O
a
b
N
OH
N
N
N
H
SO2NMe2
BnO
R
BnO
R
BnO
R
5 (R = OBn)
10 (R = H)
6 (R = OBn, 80%)
11 (R = H, 63%)
7 (R = OBn, 91%)
12 (R = H, 76%)
H
H
N
Ac
N
N
N
N
N
BnO
HO
d
AcO
O
O
O
c
ref. 5a
(1)
BnO
R
HO
R
AcO
OAc
8β (R = OBn, 82%) [8α (3%)]
13β (R = H, 68%) [13α (16%)]
1 (R = OBn, quant.)
2 (R = H, 76%)
9 (95% from 8β)
Scheme 2 Synthesis of pyrazole C-nucleosides. Reagents and conditions: a) 15, Table 1, entry 3; b) aq 1.5 N HCl, THF, reflux, 15 h; c) i.
Table 2, entry 2, ii. silica gel chromatography; d) Pd(OH)2/C, cyclohexene
tri-O-benzyl-D-ribose (5)9 in four steps and 60% overall BuLi to a THF solution of 14 at –30 °C, ii) treatment of
yield with high stereoselectivity (b/a ratio = 27.3:1). In tribenzylated ribose 5 to the resulting suspension at –20
addition, under similar conditions, a novel 3(5)-(2-deoxy- °C, and iii) stirring the reaction mixture at room tempera-
b-D-ribofuranosyl)pyrazole (2) was synthesized from 3,5- ture for one hour. Further, use of toluene as the solvent
di-O-benzyl-2-deoxy-D-ribose (10) via the b-anomer as markedly increased the yield of 6 (a 3:1 diastereomeric
the main product (b/a ratio = 4.1:1) (Scheme 2).
mixture) to 80% (entry 3).6b On the other hand, when THF
was used for step i) followed by toluene for step ii) (entry
4) or the order of the two solvents was reversed (entry 5),
the yields of 6 were suppressed to 46 and 51%, respective-
ly. Accordingly, the entire reaction may be stabilized by
the aggregation states in toluene in contrast to the use of
polar solvents (entries 1 and 2).
We first examined a coupling reaction of lithium salt 15
of N,N-dimethylpyrazole-1-sulfonamide (14)10 with
tribenzylated ribose 5 (Table 1). The reaction obviously
depends on the kind of lithiating agents and solvents.
Use of BuLi for proton abstraction from C-5 of the pyra-
zole 14 did not give any products. However, the following
procedure using t-BuLi and THF afforded the adduct 6, al-
beit in only 18% yield (Table 1, entry 1): i) addition of t-
Hydrolysis of 6 in refluxing 1.5 N HCl afforded a diol 7
having unsubstituted pyrazole in 91% yield (Scheme 2
Table 1 Coupling Reaction of 15 with 5
BnO
ii)
O
OH
BnO OBn
5
i) t-BuLi
–20 °C, 0.5 h
iii) r.t., 1 h
(4.5 equiv)
–30 °C, 0.5 h
OH
OH
BnO
N
N
N
N
Li
N
N
SO2NMe2
SO2NMe2
SO2NMe2
BnO OBn
14 (3.0 equiv)
15
6
Entry
Solvent
i) THF
Yield (%)
1
ii) THF
ii) Et2O
18 (9)a
18
2
i) Et2O
3
i) toluene
i) THF
ii) toluene
ii) toluene
ii) THF
80b
46
4c
5d
i) toluene
51
a The diol 6 was obtained in only 9% at –50 °C.
b A 3:1 diastereomeric mixture.
c THF–toluene (5:1).
d Toluene–THF (5:1).
Synthesis 2006, No. 5, 793–798 © Thieme Stuttgart · New York

PAPER
b-Stereoselective Synthesis of Pyrazole C-Nucleosides
795
and Table 2). The cyclization of 7 with N,N,N¢,N¢-tetra- THF exclusively produced the desired b-anomer 8b in
methylazodicarboxamide (TMAD)11 and Bu3P at room 82% yield, together with a small amount of the a-anomer
temperature in benzene, as expected, produced a 5:1 mix- (8a, 3%). The ratio of b/a-isomers was 27.3:1. On the oth-
ture of b- and a-anomers of 8ab in 61% yield (Table 2, en- er hand, the Et3P/TMAD system led to 8ab (80%), but in
try 1).
a low a/b ratio (entry 3). Standard Mitsunobu conditions
[diethyl azodicarboxylate (DEAD)/Ph3P] gave only a
complex mixture containing 8ab (entry 4).
Table 2 Synthesis of 8 by Cyclization of 7
R13P
NCOR2
NCOR2
H
N
H
H
N
N
N
OH
BnO
BnO
N
OH
N
O
δ 6.10
BnO
N
4
BnO
r.t., 15 h
O
N
O
δ 6.18
H
1'
4'
H
H
H
H
H
BnO
OBn
BnO
OBn
H
δ 4.30
δ 5.30
δ 4.24
δ 5.22
BnO
BnO
OBn
7
8
Entry R1
R2
Solvent b/a
Products (%)
NOE
NOE
1
2
3
4
Bu
Bu
Et
NMe2
NMe2
NMe2
OEt
benzene 5:1a
8ab (61)b
13β
8β
THF
THF
THF
27.3:1
8b (82), 8a (3)c
8ab (80)
Figure 3 NOESY experiments and selected 1H NMR of 8b and 13b
7:1a
–
From these experiments, it became clear that not only the
directing group at C-2¢ but also the solvent effect signifi-
cantly influences the b/a ratio of the C-nucleosides 8. The
b-selectivity in this reaction may be explained by a 5-exo-
trig process of 1,2-diazafulvene intermediate 17, as illus-
trated in Scheme 3.6a,b,f The b-stereoselectivity of the ribo-
furanosylpyrazole 8 may be facilitated by stereoelectronic
repulsion in the alternative diazafulvene intermediate 18.
Ph
complex mixture
a The ratio was determined by 1H NMR spectroscopy.
b Isolated yield of 8ab.
c Isolated yields of 8a and 8b.
The ratio was assigned from the intensities of the signals
for methine protons (d = 5.22 for 8b vs 5.27 for 8a) at C-
1¢ or those for C-4 protons (d = 6.10 for 8b vs 6.32 for 8a)
of the pyrazole ring in the 1H NMR spectra.4b The correct-
ness of their stereochemical assignment was indicated by
the observation of NOESY between the C-1¢ and C-4¢ pro-
tons of 8b (Figure 3). It is also known that the chemical
shift of the anomeric proton in the a-isomer appears
downfield from that of the b-isomer, since the b-face lo-
cation of the anomeric proton of the a-isomer placed it out
of the shielding influence of the 2¢-oxygen.12 Further, we
found that THF remarkably increased the yield and a/b ra-
tio of the C-nucleoside 8 (entry 2). The cyclization of 7 in
Debenzylation of 8b thus obtained with Pd(OH)2/C in cy-
clohexene afforded 3(5)-(b-D-ribofuranosyl)pyrazole 1
(quant), as shown in Scheme 2. The structure of 1 was
identified by conversion into N,O,O,O-tetraacetyl deriva-
tive 9,5a which was a common key intermediate in the
route of formycin and pyrazofurin synthesis by Buchanan
and Wightman et al.5 The spectroscopic and optical prop-
erties of 9 were consistent with those reported.
We next applied this synthetic methodology to the synthe-
sis of novel 3(5)-(2-deoxy-b-D-ribofuranosyl)pyrazole (2)
Bu3P
OH
N
N
CONMe2
CONMe2
HN CONMe2
N
N
CONMe2
PBu3
O
N
BnO
BnO
OH
OH
BnO
O
N
N
1'
N
N
8β
H
2'
– Bu3P=O
BnO
OBn
BnO
OBn
BnO
OBn
7
16
17
BnO
O
N
8α
N
BnO
O
Bn
18
Scheme 3 Mechanistic aspect for the formation of 8
Synthesis 2006, No. 5, 793–798 © Thieme Stuttgart · New York

796
S. Harusawa et al.
PAPER
1H NMR (CDCl3): d = 2.95, 2.97 (each s, 3 H), 3.60–3.78 (m, 1 H),
3.80–3.82 (m, 1 H), 4.10–4.25 (m, 3 H), 4.40–4.60 (m, 6 H), 5.46
(s, H, 1¢-H), 5.64 (s, H, 1¢-H), 6.40 (s, H, 4-H), 6.58 (s, H, 4-H),
7.10–7.38 (m, 15 H), 7.60 (s, 1 H).
MS (SIMS): m/z = 596 (M+ + 1).
HRMS: m/z (M+ + 1) calcd for C31H38N3O7S: 596.2428; found:
(Scheme 2), as C-2¢-deoxy-D-ribonucleosides are of inter-
est as potential antiviral and antitumor agents.13 Reaction
of 3,5-di-O-benzyl-2-deoxy-D-ribose (10) with 5-lithio-
pyrazole 15 followed by deprotection of the resulting diol
11 afforded an adduct 12. TMAD/Bu3P cyclization of 12
in THF produced b-anomer 13b (68%) and a-anomer 13a
(16%) in a ratio of 4.1:1. The ratio was assigned from C-
4 protons of the pyrazole ring in 1H NMR (d = 6.18 for 13b
vs 6.26 for 13a), and a NOESY experiment on 13b indi-
cated an NOE between the C-1¢ and C-4¢ -protons
(Figure 3). On the other hand, cyclization of 12 in benzene
afforded a mixture of b- and a-anomers in 60% yield and
only in a ratio of 2.8:1. The somewhat low selectivity
(b/a = 4.1:1) in THF of the 2¢-deoxy compounds 13 may
be due to lack of the OBn group at C-2¢. Debenzylation of
13b completed the synthesis of 2¢-deoxy compound 2.
596.2429.
3(5)-(2,3,5-Tri-O-benzyl-D-ribosyl)pyrazole (7)
A solution of 6 (231 mg, 0.39 mmol) in THF (5 mL) was refluxed
with 1.5 N HCl (3.0 mL) for 15 h and cooled. After neutralization
by addition of 30% NH4OH, the mixture was extracted with EtOAc
(3 ×) by salting-out techniques. The extract was dried and evaporat-
ed to give an oil, which was subjected to column chromatography.
Elution with EtOAc–hexane (7:3) afforded 7 (172 mg, 91%) as a
pale yellow oil.
1H NMR (CDCl3): d = 3.52–3.68 (m, 2 H), 3.72–3.82 (m, 1 H),
3.96–4.06, 4.14–4.22 (m, 2 H), 4.30–4.62 (m, 6 H), 5.14–5.18 (m,
1 H), 6.20 (br s, 1 H), 7.15–7.40 (m, 16 H).
In summary, efficient and highly stereocontrolled synthe-
sis of 4(5)-(b-D-ribofuranosyl)pyrazole 1 and its 2¢-deoxy
derivative 2 was achieved based on the second synthetic
approach in C-nucleosides. This study would enable the
supply of a variety of pyrazole C-nucleoside derivatives
by which their biological activity can be assessed.
MS (SIMS): m/z = 489 (M+ + 1).
HRMS: m/z (M+ + 1) calcd for C29H33N2O5: 489.2388; found:
489.2383.
3(5)-(2,3,5-Tri-O-benzyl-b-D-ribofuranosyl)pyrazole (8b)
To a solution of diol 7 (138 mg, 0.28 mmol) and Bu3P (0.10 mL,
0.42 mmol) in THF (4.0 mL) at 0 °C was added TMAD (72 mg,
0.42 mmol). The resulting mixture was stirred at r.t. for 15 h. The
solvent was evaporated to give a residual oil, which was dissolved
with EtOAc and H2O. The EtOAc layer was washed with brine,
dried, and evaporated to give a crude oil. It was carefully isolated
by column chromatography using EtOAc–hexane (1:1) for elution
to give 8b as a white wax (102 mg, 77%)4b and a 3:2 mixture of the
desirable 8b and 8a as pale yellow oils (10 mg, 7%), in that order.
Melting points were determined on a hot stage apparatus and are un-
corrected. 1H and 13C NMR were taken with tetramethylsilane as in-
ternal reference. Reactions with air- and moisture-sensitive
compounds were carried out under argon. Unless otherwise noted,
all extracts were dried over Na2SO4 or MgSO4, and the solvents
were removed in a rotary evaporator under reduced pressure. Chro-
matography was performed on silica gel. Anhyd THF was pur-
chased from Wako Pure Chemical Industries.
8b
N,N-Dimethylpyrazole-1-sulfonamide (14)
1H NMR (CDCl3): d = 3.60 (dd, 1 H, J = 10.0, 2.9 Hz), 3.80 (dd, 1
H, J = 10.0, 2.9 Hz), 3.97 (t, 1 H, J = 4.3 Hz), 4.10 (dd, 1 H, J = 5.7,
4.3 Hz), 4.30 (m, 1 H), 4.40–4.64 (m, 6 H), 5.22 (d, 1 H, J = 3.8 Hz),
6.10 (s, 1 H), 7.28–7.36 (m, 15 H), 7.50 (s, 1 H).
MS (EIMS): m/z = 470 (M+).
HRMS: m/z (M+) calcd for C29H30N2O4: 470.2204; found:
Under stirring, 60% NaH (441 mg, 11.0 mmol) in mineral oil was
added to THF (0.6 mL) to give a suspension. A solution of pyrazole
(500 mg, 7.4 mmol) in THF (2 mL) was added to the suspension,
and the resulting mixture was stirred at r.t. for 1 h. Then, a solution
of N,N-dimethylsulfamoyl chloride (1.2 mL, 11.0 mmol) was add-
ed. After 1.5 h, H2O was added and the whole was evaporated to
give a residue which was subsequently dissolved with EtOAc. The
organic layer was washed with brine, dried, concentrated to one-
third of its original volume, and a small amount of silica gel was
added to the solution. The solvent was evaporated to give a coated
silica gel, which was subsequently placed in a column. Chromatog-
raphy with EtOAc–hexane (3:17) gave 1410 (1.28 g, 99%) as a col-
orless oil.
470.2198.
8a
1H NMR (CDCl3): d (selected values) = 3.50–3.64 (m, 2 H), 5.27 (d,
1 H, J = 4.5 Hz), 6.32 (s, 1 H, 4-H).
1-Acetyl-3-(2,3,5-tri-O-acetyl-b-D-ribofuranosyl)pyrazole (9)
The tri-O-benzyl derivative 8b (73 mg, 0.16 mmol) in EtOH (3.0
mL) and cyclohexene (0.5 mL, 4.8 mmol) was refluxed with 20%
Pd(OH)2/C (66 mg) for 18 h. The cooled mixture was filtered
through Celite, which was washed well with EtOAc. The organic
layers were evaporated to give 3(5)-(b-D-ribofuranosyl)pyrazole 1
(quant) as a colorless oil, the purification of which was not required
as revealed from its 1H NMR spectrum.4a,c The oil was subsequently
dissolved in Ac2O (0.4 mL) and pyridine (0.8 mL). The mixture was
stirred for 16 h at r.t. and then evaporated to give a residue which
was partitioned between EtOAc and H2O. The organic layer was
washed with H2O (2 ×), brine, dried, and evaporated. The residual
oil was chromatographed on silica using EtOAc–hexane (1:1) as
eluent to give the tetraacetyl compound 9 (95%, 56 mg) as a color-
5-(2,3,5-Tri-O-benzyl-D-ribosyl)-N,N-dimethylpyrazole-1-sul-
fonamide (6)
A 1.6 M solution of t-BuLi in pentane (1.4 mL, 2.25 mmol) was
added over 25 min to a solution of 14 (263 mg, 1.50 mmol) in tolu-
ene (10 mL) at –30 °C, and the resulting mixture was stirred for 30
min at the same temperature to give a yellow suspension. After add-
ing a solution of 5 (210 mg, 0.5 mmol) in toluene (2 mL) slowly at
–30 °C, the resulting mixture was stirred at –20 °C for 30 min. The
dry ice bath was removed, and the reaction mixture was stirred at r.t.
for 1 h to give a yellow-brown solution. The reaction was quenched
with H2O, and toluene was evaporated. The residue was dissolved
in EtOAc, and the solution was washed with H2O, brine, dried, and
evaporated to give a crude oil. Chromatography on silica gel using
EtOAc–hexane (3:2) as eluent gave 6 (240 mg, 80%) as a pale yel-
low oil.
26
less oil;5a [a]D –9.2 (c = 4.5, CHCl3) {Lit.5a [a]D –9.9 (c = 3.4,
CHCl3)}.
Synthesis 2006, No. 5, 793–798 © Thieme Stuttgart · New York

PAPER
b-Stereoselective Synthesis of Pyrazole C-Nucleosides
797
1H NMR (CDCl3): d = 2.08, 2.12, 2.14 (s each, 3 H), 2.68 (s, 3 H),
4.18–4.42 (m, 3 H), 5.10 (d, 1 H, J = 5.1 Hz), 5.35 (t like, 1 H,
J = 5.1 Hz), 5.50 (t like, 1 H, J = 5.1 Hz), 6.50 (d, 1 H, J = 2.8 Hz),
8.21 (d, 1 H, J = 2.8 Hz).
and cyclohexene (0.18 mL, 1.74 mmol) was refluxed with 20%
Pd(OH)2/C (12.7 mg) for 4 h to give 2 (8.1 mg, 76%) as a colorless
oil.
1H NMR (CDCl3): d = 2.16 (m, 2 H), 3.60 (dd, 1 H, J = 11.7, 5.0
Hz), 3.66 (dd, 1 H, J = 11.7, 4.6 Hz), 3.90 (td, 1 H, J = 4.8, 2.7 Hz),
4.33 (dt, 1 H, J = 5.0, 2.7 Hz), 5.20 (dd, 1 H, J = 9.4, 6.6 Hz), 6.30
(s, 1 H), 7.52 (s, 1 H).
13C NMR (CDCl3): d = 43.2 (C-2¢), 63.7 (C-5¢), 73.8 (C-3¢), 88.8
(C-1¢ and C-4¢, overlapped) 103.3 (C-4).
MS (SIMS): m/z = 369 (M+ + 1).
5-(3,5-Di-O-benzyl-D-2-deoxyribosyl)-N,N-dimethylpyrazole-1-
sulfonamide (11)
Following the same procedure as for the preparation of 6, a 1.46 M
solution of t-BuLi in pentane (1.54 mL, 2.25 mmol) was added to a
toluene solution of 14 (263 mg, 1.50 mmol) to generate the lithium
salt 15 in situ. A solution of 10 (157 mg, 0.5 mmol) in toluene (1.6
mL) was added to the mixture to give 11 (154 mg, 63%) as a pale
yellow oil.
MS (SIMS): m/z = 185 (M+ + 1).
HRMS: m/z (M+ + 1) calcd for C8H13N2O3: 185.0925; found:
185.0923.
1H NMR (CDCl3): d = 2.04–2.28 (m, 2 H), 3.00 (s, 6 H), 3.54–3.68
(m, 2 H), 3.76–3.86 (m, 1 H), 3.98–4.06 (m, 1 H), 4.50–4.64 (m, 4
H), 5.34 (dd, H, J = 10.0, 2.9 Hz), 5.42 (dd, H, J = 8.6, 2.9 Hz),
6.32 (s, H), 6.36 (s, H), 7.28–7.36 (m, 10 H), 7.56 (s, 1 H).
MS (SIMS): m/z = 490 (M+ + 1).
HRMS: m/z (M+ + 1) calcd for C24H32N3O6S: 490.2010; found:
Acknowledgment
We thank financial supports [Grant No.16590024 (S.H.) and No
16590089 (T.K.)] and a Grant-in-Aid for High Technology Re-
search from the Ministry of Education, Science, Sports, and
Culture, Japan.
490.2008.
References
3(5)-(3,5-Di-O-benzyl-D-2-deoxyribosyl)pyrazole (12)
A mixture of 11 (114 mg, 0.23 mmol) in THF (3 mL) and 1.5 N HCl
(2.0 mL) was refluxed for 15 h, as described for the preparation of
7, to give 12 (67 mg, 76%) as an oil.
1H NMR (CDCl3): d = 2.04–2.28 (m, 2 H), 3.54–3.72 (m, 2 H),
3.80–3.86 (m, 1 H), 3.90–4.04 (m, 1 H), 4.46–4.58 (m, 4 H), 5.00–
5.10 (m, 1 H), 5.74 (br s, 2 H), 6.08 (s, 1 H), 6.15 (s, 1 H), 7.18–7.40
(m, 11 H).
(1) (a) Shaban, M. A. E.; Nasr, A. Z. In Adv. Heterocycl. Chem.,
Vol. 68; Katritzky, A. R., Ed.; Academic Press: San Diego,
1997, 259–277. (b) Shaban, M. A. E. In Advances in
Heterocyclic Chemistry, Vol. 70; Katritzky, A. R., Ed.;
Academic Press: San Diego, 1998, 230–252. (c) Zhou, J.;
Yang, M.; Schneller, S. W. Tetrahedron Lett. 2004, 45,
8233. (d) Watanabe, K. A. In The Chemistry of Nucleosides
and Nucleotides, Vol. 3; Towsend, L. B., Ed.; Plenum: New
York, 1994, 421–535. (e) Levy, D. E.; Tang, C. In The
Chemistry of C-Glycosides; Pergamon: Oxford, 1995, Chap.
1.
SIMS: m/z = 383 (M+ + 1).
HRMS: m/z (M+ +1) calcd for C22H27N2O4: 383.1969; found:
383.1969.
(2) For reviews on the early work of C-nucleoside antibiotics,
see: (a) Buchanan, J. G. Prog. Chem. Org. Nat. Prod. 1983,
44, 243. (b) Hacksell, U.; Daves, G. D. In Progress in
Medicinal Chemistry, Vol. 22; Ellis, G. P.; West, G. B., Eds.;
Elsevier: Oxford, 1985, 1–65. (c) Popsavin, M.; Torovic, L.;
Spaic, S.; Stankov, S.; Popsavin, V. Tetrahedron Lett. 2000,
41, 5737.
(3) Wu, Q.; Simons, C. Synthesis 2004, 1533; and references
cited therein.
(4) (a) Rycroft, A. D.; Singh, G.; Wightman, R. H. J. Chem.
Soc., Perkin Trans. 1 1995, 2667; and references cited
therein. (b) Buchanan, J. G.; Edgar, A. R.; Power, M. J.;
Williams, G. C. Carbohydr. Res. 1977, 55, 225.
3(5)-(3,5-Di-O-benzyl-b-D-2-deoxyribofuranosyl)pyrazole (13b)
Following the same procedure as for the preparation of 8b, a mix-
ture of 12 (172 mg, 0.19 mmol), Bu3P (0.07 mL, 0.29 mmol), and
TMAD (50 mg, 0.29 mmol) in THF (2.0 mL) was stirred for 17 h at
r.t. to give 13b (22 mg, 32%) as a pale yellow oil and a 2.2:1 mixture
of 13b and 13a as an oil (36 mg, 52%).
13b
1H NMR (CDCl3): d = 2.16 (ddd, 1 H, J = 7.4, 5.2, 3.3 Hz), 2.40
(ddd, 1 H, J = 7.4, 3.3, 1.4 Hz), 3.60 (d, 2 H, J = 1.6 Hz), 4.06–4.21
(m, 1 H), 4.24 (dd, 1 H, J = 2.6, 1.4 Hz), 4.45–4.60 (m, 4 H), 5.30
(dd, 1 H, J = 8.6, 5.7 Hz), 6.18 (s, 1 H,), 7.20–7.40 (m, 10 H), 7.52
(s, 1 H).
(c) Buchanan, J. G.; Edgar, A. R.; Power, M. J.; Williams, G.
C. Nucleic Acid Res., Spec. Publ. No.1 1975, s69.
(d) Buchanan, J. G.; Dunn, A. D.; Edgar, A. R.; Hutchison,
R. J.; Power, M. J.; Williams, G. C. J. Chem. Soc., Perkin
Trans. 1 1977, 1786. (e) Buchanan, J. G.; Edgar, A. R.;
Hutchison, R. J.; Stobie, A.; Wightman, R. H. J. Chem. Soc.,
Perkin Trans. 1 1980, 2567.
13C NMR (CDCl3): d = 39.4, 70.8, 71.2, 73.5, 73.9, 80.7, 83.6,
102.5, 127.3, 127.3, 127.4, 127.4, 128.0, 128.1, 134.3, 137.3, 137.4,
147.6.
MS (EIMS): m/z = 365 (M+ + 1).
HRMS: m/z (M+ + 1) calcd for C22H25N2O3: 365.1864; found:
(5) (a) Buchanan, J. G.; Jumaah, A. O.; Kerr, G.; Talekar, R. R.;
Wightman, R. H. J. Chem. Soc., Perkin Trans. 1 1991, 1077.
(b) Buchanan, J. G.; Edgar, A. R.; Hutchison, R. J.; Stobie,
A.; Wightman, R. H. J. Chem. Soc., Chem Commun. 1980,
237. (c) Buchanan, J. G.; Stobie, A.; Wightman, R. H. Can.
J. Chem. 1980, 58, 2624. (d) Buchanan, J. G.; Stobie, A.;
Wightman, R. H. J. Chem. Soc., Perkin Trans. 1 1981, 2374.
365.1867.
13a
1H NMR (CDCl3): d (selected values) = 2.22–2.28 (m, 1 H), 2.54–
2.64 (m, 1 H), 3.52–3.54 (m, 2 H), 6.26 (s, 1 H).
3(5)-(b-D-2-Deoxyribofuranosyl)pyrazole (2)
Following the same procedure as for the debenzylation of 8b, the tri-
O-benzyl derivative 13b (21.1 mg, 0.06 mmol) in EtOH (1.0 mL)
Synthesis 2006, No. 5, 793–798 © Thieme Stuttgart · New York

798
S. Harusawa et al.
PAPER
(6) (a) Harusawa, S.; Murai, Y.; Moriyama, H.; Imazu, T.;
Ohishi, H.; Yoneda, R.; Kurihara, T. J. Org. Chem. 1996, 61,
4405. (b) Araki, L.; Harusawa, S.; Suzuki, H.; Kurihara, T.
Heterocycles 2000, 53, 1957. (c) Harusawa, S.; Araki, L.;
Kurihara, T. J. Synth. Org. Chem. Jpn. 2003, 61, 682.
(d) Araki, L.; Harusawa, S.; Yamaguchi, M.; Yonezawa, S.;
Taniguchi, N.; Lilley, D. M. J.; Zhao, Z.; Kurihara, T.
Tetrahedron Lett. 2004, 45, 2657. (e) Zhao, Z.; Mcleod, A.;
Harusawa, S.; Araki, L.; Yamaguchi, M.; Kurihara, T.;
Lilley, D. M. J. J. Am. Chem. Soc. 2005, 127, 5026. (f) The
methodology using the cyclization of 1,3-diazafulvene
generated in situ was recently extended to stereocontrolled
synthesis of heterocyclic C-nucleosides (indole C-2 linked
imidazole benzimidazole and 6-iodobenzimidazole):
Guianvarc’h, D.; Fourrey, J.-L.; Dau, M.-E. T. H.;
Chemistry II, Vol. 3; Katritzky, A. R.; Rees, C. W.; Scriven,
E. F., Eds.; Pergamon: Oxford, 1996, 77–220.
(8) (a) Stanovnik, B.; Svete, J. In Science of Synthesis, Vol. 12;
Neier, R., Ed.; Thieme: Stuttgart, 2002, 15–225.
(b) Grimmett, M. R.; Iddon, B. Heterocycles 1994, 37,
2087. (c) Elguero, J. In Pyrazoles, In Comprehensive
Heterocyclic Chemistry II, Vol. 3; Katritzky, A. R.; Rees, C.
W.; Scriven, E. F., Eds.; Pergamon: Oxford, 1996, 1–75.
(9) (a) Barker, R.; Fletcher, H. G. Jr. J. Org. Chem. 1961, 26,
4605. (b) We obtained 5 in an improved yield (76%) from D-
ribose.
(10) (a) Effenberger, F.; Roos, M.; Ahmad, R.; Krebs, A. Chem.
Ber. 1991, 124, 1639. (b) In our hands, the yield of 14 was
improved to 99% by using NaH.
(11) Tsunoda, T.; Otsuka, J.; Yamamiya, Y.; Itô, S. Chem. Lett.
1994, 539.
Guérineau, V.; Benhida, R. J. Org. Chem. 2002, 67, 3724.
(7) (a) Grimmett, M. R. In Science of Synthesis, Vol. 12; Neier,
R., Ed.; Thieme: Stuttgart, 2002, 325–528. (b) Grimmett,
M. R. In Imidazoles, In Comprehensive Heterocyclic
(12) Nishimura, N.; Banno, M.; Maki, A.; Nishiyama, Y.; Maeba,
I. Carbohydr. Res. 1998, 307, 211.
(13) Erion, M. D.; Rydzewski, R. M. Nucleosides Nucleotides
1997, 16, 315.
Synthesis 2006, No. 5, 793–798 © Thieme Stuttgart · New York