Synthesis of "reversed" pyrazole-C-nucleoside precursors from push-pull activated monosaccharide derivatives

Article abstract of DOI:10.1080/07328300500471770

3-O-Benzyl-6-deoxy-1,2-O-isopropylidene-α-D-xylo-hept-5- ulofuranurononitrile (1) was reacted with N,N-dimethylformamide dimethylacetal in tetrahydrofuran to furnish the (E)-3-O-benzyl-6-deoxy-6- dimethylaminomethylene-1,2-O-isopropylidene-α-D-xylo-hept-5

Full text of DOI:10.1080/07328300500471770

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Synthesis of “Reversed”
Pyrazole‐C‐nucleoside Precursors from
Push‐pull Activated Monosaccharide
Derivatives
Imran Ali Hashmi a , Holger Feist a , Manfred Michalik b , Helmut Reinke a &
Klaus Peseke a
a Institut für Chemie, Universität Rostock , Rostock, Germany
b Leibniz‐Institut für Organische Katalyse an der Universität Rostock e. V. ,
Rostock, Germany
Published online: 21 Aug 2006.
To cite this article: Imran Ali Hashmi , Holger Feist , Manfred Michalik , Helmut Reinke & Klaus Peseke
(2006) Synthesis of “Reversed” Pyrazole‐C‐nucleoside Precursors from Push‐pull Activated Monosaccharide
Derivatives, Journal of Carbohydrate Chemistry, 25:1, 19-32, DOI: 10.1080/07328300500471770
To link to this article: http://dx.doi.org/10.1080/07328300500471770
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Journal of Carbohydrate Chemistry, 25:19–32, 2006
Copyright # Taylor & Francis Group, LLC
ISSN: 0732-8303 print 1532-2327 online
DOI: 10.1080/07328300500471770
Synthesis of “Reversed”
Pyrazole-C-nucleoside
Precursors from Push-pull
Activated Monosaccharide
Derivatives
Imran Ali Hashmi and Holger Feist
¨
Institut fu¨r Chemie, Universitat Rostock, Rostock, Germany
Manfred Michalik
¨
Leibniz-Institut fu¨r Organische Katalyse an der Universitat Rostock e. V.,
Rostock, Germany
Helmut Reinke and Klaus Peseke
¨
Institut fu¨r Chemie, Universitat Rostock, Rostock, Germany
3-O-Benzyl-6-deoxy-1,2-O-isopropylidene-a-D-xylo-hept-5-ulofuranurononitrile (1) was
reacted with N,N-dimethylformamide dimethylacetal in tetrahydrofuran to furnish
the (E)-3-O-benzyl-6-deoxy-6-dimethylaminomethylene-1,2-O-isopropylidene-a-D-xylo-
hept-5-ulofuranurononitrile (2) as a major product. Furthermore, treatment of
compound 1 with carbon disulphide and methyl iodide under basic conditions
afforded 3-O-benzyl-6-deoxy-1,2-O-isopropylidene-6-[bis(methylsulfanyl)methylene]-
a-D-xylo-hept-5-ulofuranurononitrile (6). Reaction of
2 and 6 with hydrazines
yielded the “reversed” pyrazole-C-nucleoside analogs 4, 5a, 5b, 7, 8, and 9,
respectively.
Keywords Deoxyuloses, Nucleoside analogs, Pyrazoles, Push-pull alkenes, Enones,
a-Oxoketene-S,S-acetals
Received October 11, 2004; accepted September 15, 2005.
¨
Address correspondence to Klaus Peseke, Institut fu¨r Chemie, Universitat Rostock,
Albert-Einstein-Str. 3a, D-18051 Rostock, Germany. E-mail: klaus.peseke@
uni-rostock.de
19

I. A. Hashmi et al.
20
INTRODUCTION
The synthesis of “reversed” or “iso-” nucleosides and C-nucleosides has been
carried out in a search for compounds having anticancer and antiviral activi-
ties.[1–3] “Reversed” C-nucleosides constitute a class of nucleoside analogs in
which the nucleobase is linked by a carbon-carbon bond to a ribose carbon
other than C-1. It is anticipated that “reversed” C-nucleosides may have
increased chemical and enzymatic stability under physiologic conditions. The
synthesis of “reversed” C-nucleosides has been reported by several
laboratories.[4,5]
In recent years, we have reported the preparation of C-branched monosac-
charides with push-pull functionality that could be used as precursors for the
synthesis of “reversed” C-nucleoside analogs.[6,7] In this paper, we describe
the synthesis of such compounds with a pyrazole moiety starting from
D-glucose.
RESULTS AND DISCUSSION
The 3-O-benzyl-6-deoxy-1,2-O-isopropylidene-a-D-xylo-hept-5-ulofuranurono-
nitrile 1 was synthesized starting from D-glucose.[8–13] We have reported
the reaction of 4,6-O-benzylidene-3-deoxy-a-D-erythro-hexopyranosid-2-ulose
with acetals of amides to yield the 4,6-O-benzylidene-3-deoxy-3-dimethylami-
nomethylen-a-D-erythro-hexopyranosid-2-ulose.[14] Similarly, compound
1
was reacted with N,N-dimethylformamide dimethylacetal in THF to furnish
the crystalline (E)-3-O-benzyl-6-deoxy-6-dimethylaminomethylene-1,2-O-iso-
propylidene-a-D-xylo-hept-5-ulofuranurononitrile (2) in 72% yield and the
noncrystalline (Z)-3-O-benzyl-6-deoxy-6-dimethylaminomethylene-1,2-O-iso-
propylidene-a-D-xylo-hept-5-ulofuranurononitrile (3) in 5% yield (Sch. 1).
The spectroscopic data of 2 were in accordance with the push-pull character
of C,C-double bond.[15] In the 13C NMR spectra the signal for C-6 appeared at
d ¼ 77.6 and for C-10 at d ¼ 157.3. The CO resonance gave a signal at d ¼ 187.4,
which is shifted upfield compared with this of 1 (d ¼ 196.9). Similarly, in IR
spectrum the CN vibrations could be observed at a lower wave number
(2192 cm21; for 1: 2257 cm21).
Furthermore, compound 2 was subjected to X-ray analysis at 293 K. The
crystallographic data are given below. An ORTEP drawing of compound 2 is
shown in Fig. 1 clearly demonstrating the (E)-configuration of the double
bond. It is known from the literature[15,16] that the bond length of push-pull
functionalized double bonds is increased and the single bonds to the donor sub-
stituents are shortened. Also in compound 2 this effect can be seen. The bond
distance for C6-C8 is 1.38 pm longer than for a noninfluenced C,C-double
bond. The interatomic distance C5-C6 (1.46 pm) and C6-C7 (1.41 pm) are
shorter than for comparable typical single bonds.

“Reversed” Pyrazole-C-nucleoside Precursors
21
Scheme 1: Synthesis of push-pull activated a-D-xylo-hept-5-ulofuranurononitriles.
4,6-O-Benzylidene-3-deoxy-3-dimethylaminomethylen-a-D-erythro-hexo-
pyranosid-2-ulose easily reacts with hydrazine to form a pyrazolo anellated
pyranoside.[14] The corresponding reaction of the a-dimethylaminomethylene
ulofuranurononitrile 2 was performed in ethanol at room temperature using
hydrazine hydrate. After 15 min the TLC indicated the absence of starting
material. The “reversed” pyrazole-C-nucleoside 4 was isolated in a yield of
94% (Sch. 2).
The pyrazole 4 can exist in the tautomeric forms 4a and 4b but, due to the
fast NH-proton exchange, they were not distinguishable. In the 13C NMR
spectrum of compound 4, absence of a carbonyl carbon signal and appearance
Figure 1: ORTEP drawing of compound 2.

I. A. Hashmi et al.
22
Scheme 2: Synthesis of “reversed” pyrazole-C-nucleoside.
of two broad singlets of C-5 (d ¼ 139.2) and C-3 (d ¼ 146.8) confirmed that
cyclization had taken place.
The reaction of compound 2 with 2-hydrazinoethanol in ethanol at room
temperature afforded after chromatography the isomeric products 5a and 5b
in yields of 35% each (Sch. 3). The EI-MS spectra of both compounds
supplied an Mþ signal at m/z 386. In the 13C NMR spectra of both compounds
signals of a hydroxyethyl group were visible at d ¼ 54.8, d ¼ 60.8, and d ¼ 53.8,
d ¼ 61.4. All the other spectral data of these two compounds were quite similar
and in accordance with the structures of 5a and 5b.
By recording a NOESY spectrum, we were able to assign the position of
2-hydroxyethyl group in compound 5a. Cross peaks between the protons H-5
and H-100 were observed (Sch. 3), which confirmed the attachment of the
2-hydroxyethyl group at the nitrogen atom in the neighborhood of C-5.
As it is well known, a-oxoketene dithioacetals can be prepared by the
reaction of cyclic or acyclic ketones with carbon disulphide in the presence of
a base and an alkylating agent.[17–19] To synthesize the first type of furanosyl
substituted push-pull activated ketene-S,S-acetal, compound 1 was reacted
with carbon disulphide and methyl iodide in the presence of sodium hydride
in dimethylformamide to give 6 as a yellow syrup in 52% yield (Sch. 4).
The 1H NMR spectrum of compound 6 shows two sharp S-methyl signals at
d ¼ 2.46 and d ¼ 2.62. In the 13C NMR spectrum, S-methyl signals appeared
at d ¼ 19.7 and d ¼ 20.8, the CO signal was shifted upfield to d ¼ 186.3 (for 2:
d ¼ 187.4), and C-10 gave a strong downfield shift signal at d ¼ 183.7. The IR
spectrum showed CN and CO vibrations at 2201 cm21 and 1683 cm21
,
respectively. All these spectroscopic data indicate the formation of required
compound 6.
a-Oxoketene dithioacetals react easily with hydrazines to form pyra-
zoles.[6,17,18] To prove the suitability of the a-oxoketene dithioacetal 6 for this

“Reversed” Pyrazole-C-nucleoside Precursors
23
Scheme 3: Synthesis of “reversed” hydroxyethyl-pyrazole-C-nucleosides.
Scheme 4: Synthesis of a push-pull activated bis(methylsulfanyl)methylene-a-D-xylo-hept-5-
ulofuranurononitrile and of “reversed” pyrazole-C-nucleoside.

I. A. Hashmi et al.
24
transformation, we studied its reaction with hydrazine hydrate in ethanol. In a
simple way the pyrazole 7 was obtained in 87% yield (Sch. 4).
The spectroscopic data confirmed the proposed structure, but it was not
possible to determine which of the two tautomers had been formed. As
already mentioned for compound 4, 1H-pyrazoles normally constitute an equi-
librium of the two possible tautomeric forms in solution (Sch. 4).
Treatment of compound 6 with 2-hydrazinoethanol and methylhydrazine,
in ethanol resulted in formation of the substituted 2-hydroxyethylpyrazole 8
and the methylpyrazole 9, respectively, in good yields (Sch. 5). Always, in
these reactions only one main product was obtained in contrast to the
reaction of enaminoketone 2 with hydrazinoethanol (Sch. 3) in which two
isomers were obtained. Generally, the reactions of such push-pull alkenes 2
and 6, respectively, proceed according to an addition-elimination mechanism.
It seems the reaction of compound 6 afforded a higher nucleophility as 2 and,
therefore, 2-hydrazinoethanol and methylhydrazine attack the C-10 stereose-
lectively with the substituted N-atom.
The HRMS of compound 8 showed the expected molecular ion peak at m/z
431.15298. The 13C NMR displayed resonances for three CH2-groups at
d ¼ 51.6, d ¼ 61.0, and d ¼ 72.1. Two CH2 groups belong to 2-hydroxyethyl
Scheme 5: Reactions bis(methylsulfanyl)methylene-a-D-xylo-hept-5-ulofuranurononitrile 6
with hydrazine derivatives.

“Reversed” Pyrazole-C-nucleoside Precursors
25
and one to benzyl. Two signals at d ¼ 144.0 (C-3) and d ¼ 151.0 (C-5) corre-
spond to a pyrazole ring formation.
Similarly, the spectroscopic data proved the structure of pyrazole 9.
Compound 9 showed a molecular ion peak at m/z 401.14177 in the HRMS.
The 13C NMR spectrum displayed a signal at d ¼ 37.2, which was in agreement
with a methyl group attached to an electron-withdrawing nitrogen atom. Two
signals at d ¼ 143.0 (C-3) and d ¼ 150.6 (C-5) confirmed the pyrazole ring
formation.
Furthermore, we were able to check by NOESY experiments which
nitrogen atom is carrying the methyl group. Cross peaks were observed
between the N-methyl and S-methyl protons in compound 9 (Sch. 5), indicating
their vicinal arrangement. With this result in mind and in accordance with the
identical chemical shifts for the C-3 and C-5 in the compounds 8, 9, also in
pyrazole 8, the 2-hydroxy ethyl group should be linked at the same nitrogen
atom.
For the deprotection of isopropylidene group of compound 4 (Sch. 6), we
used a mixture of acetic acid and water with a few drops of trifloroacetic
acid. The reaction mixture was stirred at room temperature for 8 h. The depro-
1
tected compound 10 was obtained in a yield of 68%. The H and 13C NMR
spectra of compound 10 proved the existence of a mixture of two isomers
having the a-D-xylo- and b-D-xylo-configuration in a ratio of 2 : 1.
EXPERIMENTAL
General Procedures
¨
Melting points were determined with a Boetius melting point apparatus
and are corrected. Optical rotations were measured with a Polar LmP (IBZ
Meßtechnik) polarimeter. IR spectra were recorded with a Nicolet 205 FT-IR
spectrometer. 1H and 13C NMR spectra were recorded with Bruker spec-
trometers AC 250 (250.13 MHz and 62.9 MHz, respectively), ARX 300
(300.13 MHz and 75.5 MHz, respectively), and AVANCE 500 (500.13 MHz and
125.8 MHz, respectively). The calibration of spectra was carried out by
Scheme 6: Deisopropylidenation of “reversed” pyrazole-C-nucleoside 4.

I. A. Hashmi et al.
26
means of solvent signals (CDCl3: d 1H ¼ 7.25, d 13C ¼ 77.0; acetone-d6: d
1H ¼ 2.05, d 13C ¼ 29.8). For the assignment of 1H and 13C NMR signals,
DEPT and two-dimensional 1H, 1H COSY, and NOESYas well as 1H, 13C corre-
lation spectra were recorded. Mass spectra were obtained with an AMD 402/3
spectrometer (AMD Intectra GmbH). Elemental analyses were performed with
a Leco CHNS-932. Column chromatography was carried out on silica gel 60
(230-400 mm, Merck). Thin-layer chromatography (TLC) was performed on
silica gel 60 GF254 foils (Merck) with detection by UV–light and by charring
with sulphuric acid. Solvents and liquid reagents were purified and dried
according to recommended procedures.
3-O-Benzyl-6-deoxy-1,2-O-isopropylidene-a-D-xylo-hept-5-ulofuranur-
ononi-trile (1). 3-O-Benzyl-6-deoxy-1,2-O-isopropylidene-a-D-gluco-heptfur-
anurononitrile (1.824 g, 5.68 mmol) was added to a suspension of PCC (3.59 g,
17.04 mmol) with molecular sieves 0.3 nm (5.68 g) in dichloromethane
(35 mL). The mixture was stirred for 3 h and the reaction followed by TLC.
When the oxidation was completed, the reaction mixture was diluted with
diethylether and filtered through a glass filter filled with silica gel (silicagel
40, Merck Darmstadt). Removal of the solvent gave slightly impure
compound 1, which was purified by column chromatography (toluene/EtOAc
9 : 1) to obtain 1 as a colorless syrup. Yield: 1.19 g (65.7%, colorless syrup); Rf
0.51 (toluene/ethyl acetate 9 : 1); [a]2D2 2116 (c ¼ 1.0, CHCl3); IR (capillary), n
1
(cm21): 1739 (C55O), 2257 (CN); H NMR (250.1 MHz, CDCl3): d 1.32, 1.45 (2s,
6H, CMe2), 3.74 (s, 2H, CH2CN), 4.29 (d, 1H, J3,4 ¼ 3.8 Hz, H-3), 4.46 (d, 1H,
JCH(a),CH(b) ¼ 11.6 Hz, CHHPh), 4.58 (d, 1H, CHHPh), 4.61 (d, 1H, J1,2 ¼ 3.5 Hz,
H-2), 4.70 (d, 1H, H-4), 6.06 (d, 1H, H-1), 7.14–7.35 (m, 5H, Ph); 13C NMR
(62.9 MHz, CDCl3): d 26.2, 26.8 (CMe2), 31.1 (CH2CN), 72.8 (CH2Ph), 81.5 (C-2),
83.7 (C-3), 84.5 (C-4), 106.2 (C-1), 112.9 (CMe2), 113.4 (CN), 128.1, 128.4, 129.6
(Ph), 136.0 (i-Ph), 196.9 (CO); MS, (EI), m/z (%): 317 [M]þ.
Anal. Calcd for C17H19NO5(317.339): C, 64.34; H, 6.03; N, 4.41. Found: C,
64.21; H, 5.92; N, 4.33.
(E)-3-O-Benzyl-6-deoxy-6-dimethylaminomethylene-1,2-O-isopropyli-
dene-a-D-xylo-hept-5-ulofuranurononitrile (2) and (Z)-3-O-Benzyl-6-
deoxy-6-dimethylaminomethylene-1,2-O-isopropylidene-a-D-xylo-hept-
5-ulofuranurononi-trile (3). 1 (100 mg, 0.32 mmol) and N,N-dimethylforma-
mide dimethylacetal (0.1 mL, 0.64 mmol) in anhydrous THF (5 mL) were
stirred at rt for 2 h. After completion of the reaction (monitored by TLC),
the solvent was evaporated in vacuo and the residue purified by column
chromatography (100% ethyl acetate) to furnish the crystalline 2 and the
noncrystalline 3.
Compound 2: Yield: 85 mg (72%, colorless crystals); mp 1288C; Rf 0.48
(ethyl acetate); [a]2D1–86 (c ¼ 0.2, CHCl3); IR (capillary), n (cm21): 1681

“Reversed” Pyrazole-C-nucleoside Precursors
27
1
(C55O), 2192 (CN); H NMR (250.1 MHz, CDCl3): d 1.32, 1.49 (2s, 6H, CMe2),
3.20, 3.30 (2s, 6H, NMe2), 4.52 (d, 1H, JCH(a),CH(b) ¼ 12.2 Hz, CHHPh), 4.61
(d, 1H, J3,4 ¼ 3.8 Hz, H-3), 4.63 (d, 1H, J1,2 ¼ 3.5 Hz, H-2), 4.67 (d, 1H,
CHHPh), 5.22 (d, 1H, H-4), 6.11 (d, 1H, H-1), 7.28 (m, 5H, Ph), 7.83 (s, 1H,
H-10); 13C NMR (75.5 MHz, CDCl3): d 26.2, 26.8 (CMe2), 38.6, 47.8 (NMe2),
71.9 (CH2Ph), 77.6 (C-6), 82.5, 82.7 (C-2, C-3), 82.9 (C-4), 105.0 (C-1), 112.0
(CMe2), 118.8 (CN), 127.4, 127.6, 127.9 (Ph), 137.1 (i-Ph), 157.3 (C-10), 187.4
(CO); MS (EI), m/z (%): 372 [M]þ.
Anal. Calcd for C20H24N2O5 (372.415): C, 64.50; H, 6.50; N, 7.52; Found: C,
64.91; H, 6.68; N, 7.45.
1
Compound 3: Yield: 6 mg (5%, colorless syrup); Rf 0.46 (ethyl acetate); H
NMR (250.1 MHz, CDCl3): d 1.30, 1.48 (2s, 6H, CMe2), 3.25, 3.43 (2s, 6H,
NMe2), 4.62 (d, 1H, J2,3 ¼ 2.0 Hz, H-3), 4.64 (d, 1H, J1,2 ¼ 4.0 Hz, H-2), 4.70
(center of qAB, 2H, JCH(a),CH(b) ¼ 11.5 Hz, CH2Ph), 5.01 (d, 1H, H-4), 6.03
(d, 1H, H-1), 7.25–7.41 (m, 5H, Ph), 7.93 (s, 1H, H-10); 13C NMR (62.9 MHz,
CDCl3): d 25.9, 26.3 (CMe2), 38.9, 48.1 (NMe2), 72.4 (CH2Ph), 78.7 (C-6), 83.8,
84.0 (C-2, C-3), 87.2 (C-4), 106.6 (C-1), 113.1 (CMe2), 118.9 (CN), 127.8, 127.8,
128.4 (Ph), 137.3 (i-Ph), 158.2 (C-10), 189.7 (CO); MS(EI), m/z (%): 372 [M]þ.
X-ray Structure Determination of 2
The data collection was performed on a Bruker P4 four-circle diffract-
˚
ometer with Mo-Ka radiation (l ¼ 0.71073 A) and a graphite monochromator
in routine v-scan after checking the crystal quality by a rotational photo and
determining a reasonable reduced cell. Further data: Temperature: 293(2) K;
Crystal system: Orthorhombic; Space group: P212121; Unit cell dimensions:
˚
˚
˚
a ¼ 9.913(4) A, a ¼ 908, b ¼ 10.735(4) A, b ¼ 908, c ¼ 18.848(6) A, g ¼ 908;
3
3
˚
Volume: 2005.7(13) A ; Z: 4; Density (calculated): 1.233 Mg/m ; Absorption
coefficient: 0.089 mm21; F(000): 792; Crystal size: 0.78 ꢀ 0.76 ꢀ 0.42 mm3; Q
range for data collection: 2.18 to 23.018; Index ranges: 210 ꢁ h ꢁ 10,
211 ꢁ k ꢁ 11, 220 ꢁ l ꢁ 20; Reflections collected: 3218; Independent reflec-
tions: 2781 [R(int) ¼ 0.0237]; Completeness to Q ¼ 23.018: 99.4%; Absorption
correction: None; Data/restraints/parameters: 2781/0/245; Goodness of fit
on F2: 1.028: Final R indices [I . 2s(I)]: R1 ¼ 0.0360, wR2 ¼ 0.0943; R
indices (all data): R1 ¼ 0.0435, wR2 ¼ 0.0993; Absolute structure parameter:
0.6(14); Extinction coefficient: 0.029(3); Largest diff. peak and hole: 0.153 and
23
˚
.
20.125 e A
.
The weighting scheme was calculated according to
w21 ¼ s2(Fo2) þ (0.0558 P)2 þ 0.1523 P with P ¼ (Fo2þ2 F2c)/3. The structure
was solved by direct methods (Bruker SHELXTL) and refined by the full
matrix least-squares method of the Bruker SHELXTL software package. All
nonhydrogen atoms were refined anisotropically with the hydrogen atoms
introduced into theoretical positions and refined according to the riding
model. CCDC 252045 contains the supplementary crystallographic data for

I. A. Hashmi et al.
28
this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/
conts/retrieving.html (or from the CCDC, 12 Union Road, Cambridge CB2
1EZ, UK; fax: þ44 1223 336033; e-mail: deposit@ccdc.cam.ac.uk).
3-(3-O-Benzyl-1,2-O-isopropylidene-a-D-xylo-tetrofuranos-4-yl)-1H-
pyrazole-4-carbonitrile (4). To a solution of 2 (100 mg, 0.26 mmol) in MeOH
(2 mL) was added hydrazine hydrate (0.03 mL, 0.62 mmol) at rt. The resulting
mixture was stirred for 15 min. After completion of the reaction (monitored by
TLC), the solvent was evaporated in vacuo and the residue purified by column
chromatography (toluene/EtOAc 9 : 1) to obtain 4 as a colorless syrup. Yield:
86 mg (94%, colorless syrup); Rf 0.48 (toluene/EtOAc 8 : 2); [a]2D2 280 (c ¼ 1.0,
1
CHCl3); IR (capillary), n (cm21): 3357 (NH), 2235 (CN); H NMR (250.1 MHz,
CDCl3): d 1.36, 1.56 (2s, 6H, CMe2), 4.31 (d, 1H, J3 ,4 ¼ 3.3 Hz, H-30), 4.37
(d, 1H, JCH(a),CH(b) ¼ 11.6 Hz, CHHPh), 4.50 (d, 1H, CHHPh), 4.73 (d, 1H,
0
0
J1 ,2 ¼ 3.8 Hz, H-20), 5.50 (d, 1H, H-40), 6.06 (d, 1H, H-10), 7.01–7.07 (m, 2H,
o-Ph), 7.21–7.28 (m, 3H, m-, p-Ph), 7.91 (s, 1H, H-5), 12.40 (br, 1H, NH); 13C
NMR (62.9 MHz, CDCl3): d 26.1, 26.8 (CMe2), 72.6 (CH2Ph), 75.5 (C-40), 82.2,
82.6 (C-20, C-30), 90.2 (C-4), 104.8 (C-10), 112.7 (CMe2), 113.1 (CN), 127.7,
128.1, 128.4 (Ph), 136.4 (i-Ph), 139.2 (C-5), 146.8 (C-3); MS(EI), m/z (%):
341 [M]þ.
0
0
Anal. Calcd for C18H19N3O4(341.361): C, 63.33; H, 5.61; N, 12.31; Found: C,
63.51; H, 5.46; N, 12.01.
3-(3-O-Benzyl-1,2-O-isopropylidene-a-D-xylo-tetrofuranos-4-yl)-1-(2-
hydroxyethyl)-1H-pyrazole-4-carbonitrile (5a) and 5-(3-O-Benzyl-1,2-
O-isopropylidene-a-D-xylo-tetrofuranos-4-yl)-1-(2-hydroxyethyl)-1H-
pyrazole-4-carbonitrile (5b). To a solution of 2 (122 mg, 0.323 mmol) in
MeOH (2 mL) was added 2-hydrazinoethanol (0.065 mL, 0.97 mmol) at rt.
The resulting mixture was stirred for 1 h. After completion of the reaction
(monitored by TLC) the solvent was evaporated in vacuo and the residue
purified by column chromatography (toluene/EtOAc 9 : 1) gave the isomeric
products 5a and 5b.
Compound 5a: Yield: 44 mg (35%, colorless syrup); Rf 0.51 (ethyl acetate);
1
[a]2D4 –49 (c ¼ 1.0, CHCl3); IR (capillary), n (cm21): 3463 (OH), 2235 (CN); H
NMR (250.1 MHz, CDCl3): d 1.35, 1.53 (2s, 6H, CMe2), 2.76 (br, 1H, OH), 3.92
(“t”, 2H, H-200), 4.16 (d, 1H, J3 ,4 ¼ 3.5 Hz, H-30), 4.20 (“t”, 2H, H-100), 4.34
(d, 1H, JCH(a),CH(b) ¼ 12.5 Hz, CHHPh), 4.50 (d, 1H, CHHPh), 4.72 (d, 1H,
0
0
J1 ,2 ¼ 3.8 Hz, H-20), 5.43 (d, 1H, H-40), 6.16 (d, 1H, H-10), 7.08–7.10 (m, 2H,
o-Ph), 7.22–7.28 (m, 3H, m-, p-Ph), 7.86 (s, 1H, H-5); 13C NMR (62.9 MHz,
CDCl3): d 26.3, 26.9 (CMe2), 54.8 (C-100), 60.8 (C-200), 72.1 (CH2Ph), 77.3
(C-40), 82.9, 83.1 (C-20, C-30), 92.3 (C-4), 105.2 (C-10), 112.2 (CMe2), 113.3
(CN), 127.2, 127.7, 128.2 (Ph), 136.6 (C-5), 137.2 (i-Ph), 151.0 (C-3); MS(EI),
m/z (%): 385 [M]þ.
0
0

“Reversed” Pyrazole-C-nucleoside Precursors
29
Anal. Calcd for C20H23N3O5(385.417): C, 62.33; H, 6.01; N, 10.90; Found: C,
62.01; H, 5.91; N, 11.01.
Compound 5b: Yield: 44 mg (35%, colorless syrup); Rf 0.53 (ethyl acetate);
1
IR (capillary), n (cm21): 3353 (OH), 2186 (CN); H NMR (250.1 MHz, CDCl3):
d 1.37, 1.55 (2s, 6H, CMe2), 2.90 (br, 1H, OH), 3.85 (t, 2H, J ¼ 4.5 Hz, H-200),
4.18 (d, 1H, J3 ,4 ¼ 3.3 Hz, H-30), 4.22–4.40 (m, 3H, H-100, CHHPh), 4.53
0
0
(d, 1H, JCH(a),CH(b) ¼ 11.6 Hz, CHHPh), 4.74 (d, 1H, J1 ,2 ¼ 3.6 Hz, H-20), 5.54
(d, 1H, H-40), 6.11 (d, 1H, H-10), 6.94–7.01 (m, 2H, o-Ph), 7.24–7.30 (m, 3H,
m-, p-Ph), 7.79 (s, 1H, H-3); 13C NMR (62.9 MHz, CDCl3): d 26.2, 26.9 (CMe2),
53.8 (C-100), 61.4 (C-200), 72.5 (CH2Ph), 75.4 (C-40), 82.4, 82.8 (C-20, C-30), 92.5
(C-4), 105.0 (C-10), 112.8 (CMe2), 112.9 (CN), 127.8, 128.4, 128.6 (Ph), 136.2
(i-Ph), 141.6 (C-3), 142.7 (C-5); MS(EI), m/z (%): 385 [M]þ.
0
0
3-O-Benzyl-6-deoxy-1,2-O-isopropylidene-6-[bis(methylsulfanyl)methy-
lene]-a-D-xylo-hept-5-ulofuranurononitrile (6). Sodium hydride (60%,
0.3 g, 6.6 mmol) was stirred for 10min in heptane (3 mL). The solvent was
decanted after the sodium hydride had settled. Then toluene (3mL) was added
and stirring continued for another 5 min. A solution of 1 (1g, 3.18 mmol),
carbon disulphide (0.41 mL, 6.6 mmol), and methyl iodide (0.81 mL, 13 mmol)
in dimethylformamide (10 mL) was added. The mixture was stirred for 1 h,
then poured into ice water and extracted with chloroform. The residue was
purified by column chromatography (toluene/ethyl acetate 8 : 2) to obtain 6 as
a yellow syrup. Yield: 690 mg (52%, yellow syrup); Rf 0.54 (toluene/ethyl
acetate 8 : 2); [a]2D2 þ10 (c ¼ 1.0, CHCl3); IR (capillary), n (cm21): 1683 (C55O),
1
2201 (CN); H NMR (250.1 MHz, CDCl3): d 1.35, 1.51 (2s, 6H, CMe2), 2.46,
2.62 (2s, 6H, 2 ꢀ SMe), 4.47 (d, 1H, JCH(a),CH(b) ¼ 12.0 Hz, CHHPh), 4.67
(m, 2H, H-2, H-3), 4.68 (d, 1H, CHHPh), 5.33 (d, 1H, J3,4 ¼ 4.5 Hz, H-4), 6.17
(d, 1H, J1,2 ¼ 3.5 Hz, H-1), 7.16–7.31 (m, 5H, Ph); 13C NMR (75.5 MHz,
CDCl3): d 19.7, 20.8 (2 ꢀ SMe), 26.6, 27.2 (CMe2), 72.3 (CH2Ph), 82.7, 83.4,
83.9 (C-2,3,4), 102.6 (C-6), 105.6 (C-1), 112.6 (CMe2), 117.1 (CN), 127.7, 127.9,
128.3 (Ph), 136.8 (i-Ph), 183.7 (C-10), 186.3 (CO); MS(EI), m/z (%): 421 [M]þ.
HRMS Calcd for C20H23NO5S2: 421.10178. Found: 421.10121.
3-(3-O-Benzyl-1,2-O-isopropylidene-a-D-xylo-tetrofuranos-4-yl)-1-(5-
methylsulfanyl)-1H-pyrazole-4-carbonitrile (7). To a solution of 6
(100 mg, 0.23 mmol) in EtOH (2 mL) was added hydrazine hydrate (0.03 mL,
0.62 mmol) at rt. The resulting mixture was stirred for 15 min. After completion
of the reaction (monitored by TLC) the solvent was evaporated in vacuo and the
residue purified by column chromatography (toluene/EtOAc 8 : 2) to obtain 7 as
a yellow syrup. Yield: 80 mg (87%, yellow syrup); Rf 0.51 (toluene/EtOAc 7 : 3);
[a]2D2 2101 (c ¼ 0.8, CHCl3); IR (capillary), n (cm21): 3248 (NH), 2230 (CN); 1H
NMR (250.1 MHz, CDCl3): d 1.33, 1.53 (2s, 6H, CMe2), 2.58 (s, 3H, SMe), 4.22
(d, 1H, J3 ,4 ¼ 3.2 Hz, H-30), 4.35 (d, 1H, JCH(a),CH(b) ¼ 11.6 Hz, CHHPh), 4.52
0
0

I. A. Hashmi et al.
30
(d, 1H, CHHPh), 4.69 (d, 1H, J1 ,2 ¼ 3.7 Hz, H-20), 5.38 (d, 1H, H-40), 6.01 (d, 1H,
H-10), 7.02–7.05 (m, 2H, o-Ph), 7.26–7.30 (m, 3H, m-, p-Ph), 10.83 (br, 1H, NH);
13C NMR (62.9 MHz, CDCl3): d 14.2 (SMe), 25.1, 25.8 (CMe2), 71.8 (CH2Ph),
73.5 (C-40), 81.1, 81.6 (C-20, C-30), 89.7 (C-4), 103.9 (C-10), 111.8 (CMe2), 111.2
(CN), 126.8, 127.4, 127.6 (Ph), 135.0 (i-Ph), 144.9 (C-3), 150.1 (C-5); MS(EI),
m/z (%): 387 [M]þ.
0
0
HRMS Calcd for C19H21N3O4S: 387.12527. Found: 387.12949.
3-(3-O-Benzyl-1,2-O-isopropylidene-a-D-xylo-tetrofuranos-4-yl)-1-(2-
hydroxyethyl)-5-methylsulfanyl-1H-pyrazole-4-carbonitrile (8). To a
solution of 6 (100 mg, 0.23 mmol) in EtOH (2 mL) was added 2-hydrazinoetha-
nol (0.047 mL, 0.71 mmol) at rt. The resulting mixture was stirred for 20 min.
After completion of the reaction (monitored by TLC) the solvent was evapor-
ated in vacuo and the residue purified by column chromatography (toluene/
EtOAc 8 : 2) to obtain 8 as a colorless syrup. Yield: 75 mg (73.5%, colorless
syrup); Rf 0.58 (toluene/EtOAc 7 : 3); [a]2D5 –28 (c ¼ 1.0, CHCl3); IR (capillary),
n (cm21): 3480 (OH), 2150 (CN); 1H NMR (250.1 MHz, CDCl3): d 1.34, 1.51 (2s,
6H, CMe2), 2.48 (s, 3H, SMe), 2.59 (br s, 1H, OH), 3.94 (br m, 2H, H-200), 4.14
(d, 1H, J3 ,4 ¼ 3.5 Hz, H-30), 4.21–4.39 (m, 3H, H-100, CHHPh), 4.53 (d, 1H,
0
0
JCH(a),CH(b) ¼ 12.3 Hz, CHHPh), 4.72 (d, 1H, J1 ,2 ¼ 3.7 Hz, H-20), 5.38 (d, 1H,
H-40), 6.14 (d, 1H, H-10), 7.05–7.10 (m, 2H, o-Ph), 7.20–7.26 (m, 3H, m-,
p-Ph); 13C NMR (75.5 MHz, CDCl3): d 18.4 (SMe), 26.3, 26.9 (CMe2), 51.6
(C-100), 61.0 (C-200), 72.1 (CH2Ph), 77.4 (C-40), 82.8, 83.1 (C-20, C-30), 97.2 (C-4),
105.3 (C-10), 112.2 (CMe2), 113.1 (CN), 127.2, 127.7, 128.2 (Ph), 137.1 (i-Ph),
144.0 (C-3), 151.0 (C-5); MS(EI), m/z (%): 431 [M]þ.
0
0
HRMS Calcd for C21H25N3O5S: 431.15149. Found: 431.15298.
3-(3-O-Benzyl-1,2-O-isopropylidene-a-D-xylo-tetrofuranos-4-yl)-1-methyl-
5-methylsulfanyl-1H-pyrazole-4-carbonitrile (9). To a solution of 6
(100 mg, 0.23 mmol) in EtOH (2 mL) was added methylhydrazine (0.04 mL,
0.71 mmol) at rt. The resulting mixture was stirred for 15 min. After completion
of the reaction (monitored by TLC) the solvent was evaporated in vacuo and the
residue purified by column chromatography (toluene/EtOAc 8 : 2) to obtain 9 as
a yellow syrup. Yield: 70 mg (74%, yellow syrup); Rf 0.58 (toluene/EtOAc 8 : 2);
[a]2D2 229 (c ¼ 1.0, CHCl3); IR (capillary), n (cm21): 2233 (CN); 1H NMR
(250.1 MHz, CDCl3): d 1.34, 1.51 (2s, 6H, CMe2), 2.49 (s, 3H, SMe), 3.86
(NMe), 4.14 (d, 1H, J3 ,4 ¼ 3.5 Hz, H-30), 4.32 (d, 1H, JCH(a),CH(b) ¼ 12.2 Hz,
0
0
CHHPh), 4.53 (d, 1H, CHHPh), 4.70 (d, 1H, J1 ,2 ¼ 3.6 Hz, H-20), 5.36 (d, 1H,
H-40), 6.14 (d, 1H, H-10), 7.06–7.11 (m, 2H, o-Ph), 7.20–7.26 (m, 3H, m-,
p-Ph); 13C NMR (75.5 MHz, CDCl3): d 18.0 (SMe), 26.3, 27.0 (CMe2), 37.2
(NMe), 72.2 (CH2Ph), 77.5 (C-40), 83.0, 83.4 (C-20, C-30), 96.9 (C-4), 105.3
(C-10), 112.1 (CMe2), 113.1 (CN), 127.3, 127.6, 128.2 (Ph), 137.3 (i-Ph), 143.0
(C-3), 150.6 (C-5); MS(EI), m/z (%): 401 [M]þ.
0
0

“Reversed” Pyrazole-C-nucleoside Precursors
HRMS Calcd for C20H23N3O4S: 401.14093. Found: 401.14177.
31
3-(3-O-Benzyl-a,b-D-xylo-tetrofuranos-4-yl)-1H-pyrazole-4-carbonitrile
(10). To a solution of 4 (100 mg, 0.29 mmol) in AcOH (2 mL)/H2O (0.5 mL) was
added a few drops of trifloroacetic acid at 08C. The resulting mixture was
stirred for 8 h at rt. After completion of the reaction (monitored by TLC) the
solvent was evaporated in vacuo and the residue purified by column chromato-
graphy (toluene/EtOAc 6 : 4) to obtain 10 as a colorless syrup. Yield 60 mg
(68%, colorless syrup); Rf 0.45 (toluene/EtOAc 6 : 4); [a]2D2 2120 (c ¼ 1.0,
CHCl3); IR (capillary), n (cm21): 3347 (NH, OH), 2230 (CN); 1H NMR
3
3
0
0
0
0
(500.1 MHz, acetone-d6): d 3.90 (dd, 1H, J2 ,3 ¼ 8.0 Hz, J3 ,4 ¼ 6.5 Hz,
3
3
H-3(0b)), 4.12 (dd, 1H, J2 ,3 ¼ 9.5 Hz, J3 ,4 ¼ 6.5 Hz, H-3(a)), 4.16 (dd, 1H,
0
0
0
0
0
3
3
3
3
0
0
0
0
0
0
0
J1 ,2 ¼ 3.5 Hz,
J2 ,3 ¼ 9.5 Hz, H-2(a)), 4.18 (dd, 1H,
J1 ,2 ¼ 5.5 Hz,
0
0
0
0
J2 ,3 ¼ 8.0 Hz, H-2(b)), 4.75 (d, 1H, OH(2 a)), 4.91–5.00 (m, 2H(CH2), 1H(a)
,
3
0
0
0
0
0
CH2, H-4(a)), 5.08 (d, 1H, J3 ,4 ¼ 6.5 Hz, H-4(b)), 5.25 (br, 1H, OH(2 b)), 5.55
3
3
0
0
0
0
0
0
(d, 1H, J1 ,2 ¼ 5.5 Hz, H-1(b)), 5.79 (d, 1H, J1 ,2 ¼ 3.5 Hz, H-1(a)), 6.20
0
0
(d, 1H, OH(1 b)), 6.50 (br, 1H, OH(1 a)), 7.26–7.31 (m, 1H, p-Ph), 7.33–7.37
(m, 2H, m-Ph), 7.45–7.48 (m, 2H, o-Ph), 7.93 (s, 1H, H-5(a)), 7.94 (s, 1H,
13
H-5(b)); C NMR (125.8 MHz, acetone-d6): d 67.0 (C-4(0b)), 68.1 (C-4(0a)), 70.9
(C-2(0a)), 73.4 (C-2(0b)), 74.6 (CH2(b)), 74.9 (CH2(a)), 80.4 (C-3(0a)), 81.7 (C-3(0b)),
81.7 (C-1(0a)), 85.3 (C-1(0b)), 91.4 (C-4(b)), 91.8 (C-4(a)), 113.8 (CN(a)), 113.9
(CN(b)), 128.2 (p-Ph(a)), 128.2 (p-Ph(b)), 128.7, 128.9 (o-Ph(b), m-Ph(b)), 128.6,
129.0 (o-Ph(a), m-Ph(a)), 139.4 (i-Ph(b)), 139.9 (i-Ph(a)), 144.0 (C-5(b)), 144.2
(C-5(a)), 146.9 (C-3(b)), 147.8 (C-3(a)); MS(EI), m/z (%): 301 [M]þ.
Anal. Calcd for C15H15N3O4(301.30): C, 59.80; H, 5.02; N, 13.95. Found: C,
60.21; H, 4.96; N, 13.71.
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