Syntheses of acyclo-C-nucleoside analogs from 2,3:4,5-di-O-isopropylidene- D-xylose

Article abstract of DOI:10.1080/07328300500388693

Treatment of 1,2-dideoxy-4,5:6,7-di-O-isopropylidene-D-xylo-hept-1-yn-3- uloses 4a,b with hydrazine hydrate and amidines yielded the 3-(1,2:3,4-di-O- isopropylidene-D-xylo-1,2,3,4-tetrahydroxy-butyl)-5-phenyl-l.1H(2H)-pyrazole 5 and the substituted 4-(1,2

Full text of DOI:10.1080/07328300500388693

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Syntheses of Acyclo‐C‐nucleoside Analogs
from 2,3:4,5‐Di‐O‐isopropylidene‐D‐xylose
Iran Otero a b , Karen Methling a , Holger Feist a , Manfred Michalik c , José
Quincoces d , Helmut Reinke a & Klaus Peseke a
a Institut für Chemie, Universität Rostock, Rostock, Germany
b Facultad de Química y Farmacia, Universidad Central de Las Villas, Santa
Clara, Cuba
c Leibniz‐Institut für Organische Katalyse, Rostock, Germany
d Universidade Bandeirante de Sao Paulo, Rua Maria Candida, Sao Paulo,
Brazil
Published online: 02 Feb 2007.
To cite this article: Iran Otero , Karen Methling , Holger Feist , Manfred Michalik , José
Quincoces , Helmut Reinke & Klaus Peseke (2005) Syntheses of Acyclo‐C‐nucleoside Analogs from
2,3:4,5‐Di‐O‐isopropylidene‐D‐xylose, Journal of Carbohydrate Chemistry, 24:8-9, 809-829, DOI:
10.1080/07328300500388693
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Journal of Carbohydrate Chemistry, 24:809–829, 2005
Copyright # Taylor & Francis LLC
ISSN: 0732-8303 print 1532-2327 online
DOI: 10.1080/07328300500388693
Syntheses of Acyclo-C-
nucleoside Analogs from
2,3:4,5-Di-O-isopropylidene-
D-xylose
Iran Otero
¨
´
Institut fu¨r Chemie, Universitat Rostock, Rostock, Germany and Facultad de Quımica y
Farmacia, Universidad Central de Las Villas, Santa Clara, Cuba
Karen Methling and Holger Feist
¨
Institut fu¨r Chemie, Universitat Rostock, Rostock, Germany
Manfred Michalik
Leibniz-Institut fu¨r Organische Katalyse, Rostock, Germany
´
Jose Quincoces
Universidade Bandeirante de Sao Paulo, Rua Maria Candida, Sao Paulo, Brazil
Helmut Reinke and Klaus Peseke
¨
Institut fu¨r Chemie, Universitat Rostock, Rostock, Germany
Treatment of 1,2-dideoxy-4,5:6,7-di-O-isopropylidene-D-xylo-hept-1-yn-3-uloses 4a,b
with hydrazine hydrate and amidines yielded the 3-(1,2:3,4-di-O-isopropylidene-D-
xylo-1,2,3,4-tetrahydroxy-butyl)-5-phenyl-1H(2H)-pyrazole
4-(1,2:3,4-di-O-isopropylidene-D-xylo-1,2,3,4-tetrahydroxy-butyl)pyrimidines
5
and the substituted
7a–f,
respectively. Reaction of 4a,b with 2-amino-benzimidazol afforded the 2-(1,2:3,4-di-O-
isopropylidene-D-xylo-1,2,3,4-tetrahydroxy-butyl)benzo[4,5]imidazo[1,2-a]pyrimidines
9a,b. Compound 4a and 5-amino-pyrazole-4-carbonic acid derivatives yielded the
Received July 7, 2005; accepted September 20, 2005.
´
´
Dedicated to Professor Dr. Andras Liptak on the occasion of his 70th birthday.
¨
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
809

I. Otero et al.
810
5-(1,2:3,4-di-O-isopropylidene-D-xylo-1,2,3,4-tetrahydroxy-butyl)pyrazolo[1,5-a]pyrimi-
dines 11a – d. Deprotection of pyrazole 5, pyrimidine 7a, and pyrazolo[1,5-a]pyrimidine
11b yielded the acyclo-C-nucleosides 6, 8, and 12, respectively.
Keywords Acyclo-C-nucleoside, Heptynuloses, D-Xylose, Pyrazoles, Pyrimidines,
Beno[4,5]-imidazo[1,2-a]pyrimidines, Pyrazolo[1,5-a]pyrimidines
INTRODUCTION
In recent years the development of strategies for obtaining acyclo-C-nucleoside
analogs has proved to be an active field of research.[1–5] In these analogs of
nucleosides the furanose ring is replaced by a polyhydroxyalkyl chain and
the heterocyclic units appear C,C-linked to these acyclic rests. The interest
in acyclo-C-nucleosides has arisen due to the biologic and toxicologic properties
displayed by many of these compounds. The natural products bengazol A and
(–)-biopterin are representatives of biologically interesting acyclic C-nucleo-
sides.[6,7] Natural as well as synthetic acyclic nucleoside analogs[8–12] have
shown antiviral activities against herpes virus,[13] SIV,[14] and vaccinia.[15]
We chose to generate a reactive group within an acyclic carbohydrate deriva-
tive that would allow efficient construction of a range of heterocycles. Alkynyl
ketones have been used in the formation of a range of heterocyclic systems.
Pyrazoles, pyrimidines, pyridazines, pyridines, triazoles, and isoxazoles have all
been prepared from these intermediates.[16,17] Using this approach, we recently
reported the introduction of an alkynyl ketone functionality into the side chain
of a monosaccharide to synthesize new iso-C-nucleosides.[18] Ethynyl ketones
are valuable synthetic intermediates for the preparation of a wide range of
simple nitrogen-containing heteroaromatic molecules and had been employed
in the synthesis of heterocyclic building blocks, biologically active targets, non-
proteinogenic amino acids, and pyrimidinyl-C-nucleosides.[19,20] In the present
work the ynones 4a,b synthesized from 2,3:4,5-di-O-isopropylidene-D-xylose
represent a versatile class of compounds that can be used as starting materials
for the synthesis of new acyclo-C-nucleosides.
RESULTS AND DISCUSSION
2,3:4,5-Di-O-isopropylidene-D-xylose 2 can be prepared starting from D-xylose
in three reaction steps.[21,22] Treatment of 2 with a solution of ethynylmagne-
sium bromide or lithium phenylacetylide in THF resulted in the formation of
the diastereomeric heptynols 3a,b. The disappearance of the aldehyde
signals and the new resonances for the alkyne carbon atoms in the 13C
NMR spectra clearly demonstrated the formation of the expected alcohols as
(R,S)-mixtures. In the IR spectra absorption bands for the OH group and the
triple bond were present (Scheme 1).

Syntheses of Acyclo-C-nucleoside Analogs
811
Scheme 1
Oxidation of heptynols 3a,b afforded the desired hept-1-yn-3-uloses 4a,b,
which can be used in the facile synthesis of new acyclo-C-nucleosides.
Heptynol 3b was oxidized with PCC (pyridinium chlorochromate) in dichloro-
methane, yielding the ulose 4b as a white solid in 52% yield. However, attempts
to oxidize the heptynol 3a with PCC, MnO2, and other methods were
unsuccessful. The synthesis of the 1,2-dideoxy-4,5:6,7-di-O-isopropylidene-D-
xylo-hept-1-yn-3-ulose 4a could only be achieved by using a mixture of
dimethylsulfoxide and acetic acid anhydride.
Treatment of compound 4b with hydrazine hydrate afforded the 3-(1,2:3,4-
di-O-isopropylidene-D-xylo-1,2,3,4-tetrahydroxy-butyl)-5-phenyl-1H(2H)-pyrazole
5 in 85% yield. The heterocyclization could be confirmed by the absence of the
signals for the carbonyl group and the disappearance of the triple bond in the
13C NMR and the IR spectra. Generally, two tautomeric pyrazole structures
could be formulated for the product. It is assumed that there is an equilibrium
between the two tautomeric forms. Due to the fast NH-proton exchange
process, the atoms C-3 and C-5 were not observable as separate signals in
the 13C NMR spectrum (Scheme 2).
In addition, we examined the deprotection of the synthesized compound. The
cleavage of the isopropylidene groups of compounds 5 was successfully achieved
with aqueous trifluoroacetic acid[23] at 708C and afforded the acyclo-C-nucleoside
analog 6 in 85% yield. In the 1H NMR spectra, 6 signals for the isopropylidene
groups were absent and four signals for OH groups were found instead.
Adamo et al.[16] had reported on the reaction of ynones with amidinium
salts using ethyl acetate/water or acetonitrile as solvent and sodium carbonate
as base to obtain the corresponding pyrimidines. Following this strategy, the

I. Otero et al.
812
Scheme 2
ynones 4a,b were allowed to react with acetamidinium chloride, benzamidi-
nium chloride, S-methyl-isothiouronium sulfate, and O-methyl-isothiouro-
nium hydrogensulfate to synthesize the pyrimidine acyclo-C-nucleosides
7a–f in good yields. Compound 7f was subjected to X-ray analysis at 173 K.
The relevant crystallographic data are given in the experimental part. An
ORTEP drawing of 7f is shown in Figure 1, which gives the numbering
Figure 1: ORTEP drawing of 7f (only one of the two symmetry independent molecules is
shown, the two molecules differ mainly in the position of the phenyl group at C14, dihedral
angle N1-C14-C21-C22: 2 152.278, N3-C44-C51-C52: 163.118).

Syntheses of Acyclo-C-nucleoside Analogs
813
Scheme 3
scheme of the atoms. The deprotection of compound 7a by treatment with
aqueous trifluoroacetic acid afforded the 4-(D-xylo-1,2,3,4-tetrahydroxy-
butyl)-2-methyl-pyrimidine 8 in 80% yield (Scheme 3).
On the other hand, ynones 4a,b were reacted with 2-amino-benzimidazol
in refluxing ethanol to give the 2-(1,2:3,4-di-O-isopropylidene-D-xylo-1,2,3,4-
tetrahydroxy-butyl)benzo[4,5]imidazo[1,2-a]pyrimidines 9a,b in good yields
(Scheme 4). The crystallographic data of 9a were in agreement with the
proposed reaction pathway (Figure 2). The comparison with the spectra of
the similar 2-(methyl 2-O-benzyl-4,6-O-benzylidene-3-deoxy-a-D-altropyrano-
sid-3-yl-methyl)benzo [4,5]imidazo[1,2-a]pyrimidines,[18] whose structures
were analyzed by means of HMBC and NOE experiments, allowed the assign-
ment of all 13C NMR signals. Due to the anisotropy effect of the phenyl ring, the
1
signal of H-6 (d ¼ 6.63) in the H NMR spectrum of 9b is significantly upfield
shifted compared with the H-6 (d ¼ 7.81) signal in the 1H NMR spectrum of 9a.
Scheme 4

I. Otero et al.
814
Figure 2: ORTEP drawing of 9a.
In a similar way the pyrazolo[1,5-a]pyrimidines 11a –d could be obtained
by reaction of terminal ynone 4a with various 5-amino-pyrazole carbonic acid
derivatives. A mixture of ynone 4a and 5-amino-pyrazole carbonic acid deriva-
tives was refluxed in ethanol until the starting material was consumed and the
intermediates 10a–d were formed. The synthesis of the polycyclic compounds
11a –d as white and yellow crystals, respectively, can then be accomplished in
excellent yields after addition of a sodium ethanolate solution to the reaction
mixture at room temperature. The structure of the intermediates 10a–d was
verified by NMR studies. The presence of these intermediates confirmed once
again the postulated reaction pathways. As expected, for the compounds
11a –d no signals of the acetylenic carbon atoms were observed in the 13C
NMR spectra. The structure was proven by the crystallographic data of 11c
(Scheme 5).
We examined the deprotection of compound 11b. The cleavage of the
isopropylidene groups was performed in a mixture of trifluoroacetic acid and
water to afford the 2-amino-N-benzyl-5-(D-xylo-1,2,3,4-tetrahydroxy-butyl)
pyrazolo[1,5-a]pyrimidine-3-carboxamide 12. The polycyclic acyclo-C-nucleoside
12 was obtained as a white solid in 72% yield.

Syntheses of Acyclo-C-nucleoside Analogs
815
Scheme 5
EXPERIMENTAL
¨
Melting points were measured with a Boetius apparatus and are corrected.
Specific rotations were determined with a Polar LmP polarimeter (IBZ
Messtechnik). IR spectra were recorded with a Nicolet 205 FT-IR spectrometer.
1H NMR (500.13, 300.13, and 250.13 MHz) and 13C NMR (125.7, 75.5 MHz, and
62.9 MHz) spectra were recorded on Bruker instruments AVANCE 500, ARX
300, and AC 250, respectively, with CDCl3 as solvent unless otherwise
stated. The calibration of spectra was carried out on CDCl3 (1H, 13C) signals
1
13
(d HCDCl ¼ 7.25; d
C
¼ 77.0). The 13C NMR signals were assigned by
CDCl3
3
DEPT and/or two-dimensional 13C,1H correlation spectra. The mass spectra
were recorded on an AMD 402/3 spectrometer (AMD Intectra GmbH). For
chromatography, Merck silica gel 60 (230–400 mesh) was used. TLC was
performed on silica gel 60 GF254 (Merck) with detection by using UV light

I. Otero et al.
816
Figure 3: ORTEP drawing of 11c.
and charring with sulfuric acid. Elemental analysis was performed on a Leco
CHNS-932 instrument. Solvents were distilled and, if necessary, dried using
standard procedures. The data collections were performed on a Bruker
˚
X8Apex CCD diffractometer system with Mo-Ka radiation (l ¼ 0.71073 A)
and a graphite monochromator with w and v scans after checking the crystal
quality by collecting reflections from 60 frames and determining a reasonable
reduced cell. The structures were 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 276684, 276685, and 276686 contain the supplemen-
tary crystallographic data for compounds 7f, 9a, and 11c, respectively. These
data can be obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.

Syntheses of Acyclo-C-nucleoside Analogs
817
html (or from the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; fax: þ44
1223 336033; e-mail: deposit@ccdc.cam.ac.uk).
1,2-Dideoxy-4,5:6,7-di-O-isopropylidene-D-ido, gulo-hept-1-
ynitol (3a)
Ethynylmagnesium bromide (35 mL, 0.5 M solution in THF) was added
dropwise to a solution of 2,3:4,5-di-O-isopropylidene-D-xylose 2 (2.00 g,
8.7 mmol) in dry THF (50 mL) at 08C. The mixture was stirred for 4 h at
rt, poured into water (20 mL), and extracted with dichloromethane (3 ꢀ 20 mL).
Then the combined organic phases were washed with water (2 ꢀ 20 mL),
dried (Na2SO4), and evaporated under reduced pressure. The residue was
purified by column chromatography (toluene/EtOAc 2 : 1). Compound 3a was
isolated as colorless syrup. Yield: 1.44 g (65%); 2 : 3-mixture of R/S and S/R,
respectively; [a]2D4 þ3.98 (c 1.0, CHCl3); Rf 0.38 (toluene/ethyl acetate, 2 : 1). IR
1
(Film), n (cm–1): 3434 (OH); 3266 ( CH); 2117 (C C). H NMR (250 MHz):
;;
;;
d ¼ 4.53–4.46, 4.45–4.39 (2 ꢀ m, 1H, H-3), 4.33–4.23 (m, 1H, H-4), 4.16–4.09
3
2
(m, 2H, H-5, H-6), 4.05 (dd, 1H, J6,7a ¼ 6.7 Hz, J7a,7b ¼ 8.0 Hz, H-7a), 3.92
3
3
(t, 1H, J6,7b ¼ 8.0 Hz, H-7b), 2.73, 2.67 (2 ꢀ d, 1H, J3,OH ¼ 7.3, 5.2 Hz, OH),
4
2.54, 2.52 (2 ꢀ d, 1H, J1,3 ¼ 1.8, 0.6 Hz, H-1), 1.45, 1.44, 1.42, 1.37 (4 ꢀ s,
12H, 4 ꢀ Me). 13C NMR (125.7 MHz): d ¼ 110.6, 110.3, 109.8, 109.7
(2 ꢀ C(Me)2), 81.6, 81.0 (C-1), 79.5, 78.9 (C-4), 77.1, 76.9 (C-5), 75.3, 75.1
(C-2), 74.9, 74.6 (C-6), 65.8, 65.7 (C-7), 62.6, 62.4 (C-3), 27.3, 27.2, 27.1, 26.1,
25.5, 25.4 (4 ꢀ Me). MS (EI), m/z (%): 257 (3) [MH]þ.
Anal. Calcd for C13H20O5(256.13): C, 60.92; H, 7.87. Found: C, 60.72;
H, 7.81.
1,2-Dideoxy-4,5:6,7-di-O-isopropylidene-1-phenyl-D-ido,
gulo-hept-1-ynitol (3b)
The reaction of 2 (2.00 g, 8.7 mmol) with lithium phenylacetylide (17 mL,
1.0 M solution in THF) was carried out as described above for the preparation
of 3a. The product was purified by column chromatography (toluene/EtOAc
4 : 1). Compound 3b was isolated as colorless syrup. Yield: 1.79 g (62%); 2 : 3-
mixture of R/S and S/R, respectively; [a]2D3 2 9.38 (c 1.0, CHCl3); Rf 0.36
1
(toluene/ethyl acetate, 4 : 1). IR (Film), n (cm21): 3432 (OH); 2231 (C C). H
;;
NMR (250 MHz): d ¼ 7.45–7.39 (m, 2H, Ph), 7.33–7.25 (m, 3H, Ph), 4.75,
3
3
4.67 (2 ꢀ dd, 1H,, J2,3 ¼ 3.7, 4.5 Hz, J3,OH ¼ 5.2, 6.2 Hz, H-3), 4.38–4.26
3
(m, 1H, H-4), 4.25–4.16 (m, 2H, H-5, H-6), 4.05 (dd, 1H, J6,7a ¼ 6.7 Hz,
3
2J7a,7b ¼ 8.0, H-7a), 3.95 (t, 1H, J6,7b ¼ 8.0, H-7b), 2.85, 2.76 (2 ꢀ d, 1H,
OH), 1.47, 1.46, 1.43, 1.36 (4 ꢀ s, 12H, 4 ꢀ Me). 13C NMR (75.5 MHz):
d ¼ 131.7, 128.7, 128.3 (o-, m-, p-Ph), 121.9 (i-Ph), 110.5, 110.2, 109.7, 109.6
(2 ꢀ C(Me)2), 86.8, 86.5, 86.4, 85.9 (C-1, C-2), 79.7, 79.3 (C-4), 76.7 (C-5),

I. Otero et al.
818
75.4, 75.2 (C-6), 65.8, 65.7 (C-7), 63.5, 62.9 (C-3), 27.34, 27.27, 27.13, 26.07,
25.5, 25.4 (4 ꢀ Me). MS (EI), m/z (%): 332 (5) [M]þ.
Anal. Calcd for C19H24O5(332.16): C, 68.66; H, 7.28. Found: C, 68.41; H, 7.14.
1,2-Dideoxy-4,5:6,7-di-O-isopropylidene-D-xylo-hept-1-yn-3-
ulose (4a)
To a solution of compound 3a (0.770 g, 3 mmol) in anhyd. dimethylsulfoxide
(4 mL) was given acetic acid anhydride (1.5 mL) and the mixture was stirred at
228C for 24 h. Then chloroform (30 mL) and cold saturated aqueous NaHCO3
solution were added until neutralization. The mixture was extracted with
chloroform (3 ꢀ 20 mL), the combined organic layers washed with water, and
dried with Na2SO4, and the solvent evaporated. The residue was purified by
column chromatography (toluene/EtOAc 10 : 1). Compound 4a was isolated
as colorless syrup. Yield: 0.365 g (48%); [a]2D1 214.68 (c 1.5, CHCl3); Rf 0.44
(toluene/ethyl acetate, 10 : 1). IR (Film), n (cm21): 3248 (CH); 2094 (C C);
;;
1
3
1684 (CO). H NMR (250 MHz): d ¼ 4.38 (d, 1H, J4,5 ¼ 6.8 Hz, H-4), 4.26 (dt,
3
3
1H, H-6), 4.22 (dd, 1H, J5,6 ¼ 4.6 Hz, H-5), 4.06 (dd, 1H, J6,7a ¼ 6.4 Hz,
3
2J7a,7b ¼ 8.5, H-7a), 3.87 (dd, 1H, J6,7b ¼ 6.4 Hz, H-7b), 3.48 (s, 1H, H-1),
1.50, 1.43, 1.42, 1.37 (4 ꢀ s, 12H, 4 ꢀ Me). 13C NMR (75.5 MHz): d ¼ 186.0
(C-3), 112.3, 110.0 (2 ꢀ C(Me)2), 83.6 (C-1), 82.1 (C-4), 79.4 (C-2), 78.1 (C-5),
75.4 (C-6), 65.5 (C-7), 26.8, 26.1, 26.1, 25.4 (4 ꢀ Me). MS (EI), m/z (%): 255
(5) [MH]þ.
Anal. Calcd for C13H18O5(254.11): C, 61.40; H, 7.14. Found: C, 60.93; H, 6.68.
1,2-Dideoxy-4,5:6,7-di-O-isopropylidene-1-phenyl-D-xylo-
hept-1-yn-3-ulose (4b)
PCC (0.860 g, 4.0 mmol) was added to a solution of 3a (0.660 g, 2.0 mmol) in
dry dichloromethane (40 mL). The mixture was stirred for 12 h, and filtered,
and the residue washed with EtOAc. The solvent was removed under
reduced pressure and the residue was purified by column chromatography
(toluene/EtOAc 10 : 1). Compound 4b was isolated as a white solid. Yield:
0.340 g (52%); mp 73–758C; [a]D22 239.68 (c 1.0, CHCl3); Rf 0.43 (toluene/
1
ethyl acetate, 10 : 1). IR (KBr), n (cm21): 2207 (C C); 1652 (CO). H NMR
;;
3
(250 MHz): d ¼ 7.63–7.35 (m, 5H, Ph), 4.45 (d, 1H, J4,5 ¼ 6.7 Hz, H-4), 4.35–
3
2
4.25 (m, 2H, H-5, H-6), 4.09 (dd, 1H, J6,7a ¼ 6.4 Hz, J7a,7b ¼ 8.5, H-7a), 3.91
(dd, 1H, J6,7b ¼ 6.4 Hz, H-7b), 1.53, 1.51, 1.44, 1.39 (4 ꢀ s, 12H, 4 ꢀ Me). 13C
3
NMR (75.5 MHz): d ¼ 186.3 (C-3), 133.3, 131.3, 128.7 (o-, m-, p-Ph), 119.5
(i-Ph), 112.2, 110.0 (2 ꢀ C(Me)2), 96.2, 86.1 (C-1, C-2), 82.5 (C-4), 78.6 (C-5),
75.8 (C-6), 65.6 (C-7), 26.9, 26.3, 26.2, 25.5 (4 ꢀ Me). MS (EI), m/z (%): 330
(5) [M]þ.
Anal. Calcd for C19H22O5(330.15): C, 69.07; H, 6.71. Found: C, 68.98; H, 6.66.

Syntheses of Acyclo-C-nucleoside Analogs
819
3-(1,2:3,4-Di-O-isopropylidene-D-xylo-1,2,3,4-tetrahydroxy-
butyl)-5-phenyl-1H(2H)pyrazole (5)
A mixture of 4b (0.165 g, 0.5 mmol) and hydrazine hydrate (0.035 mL,
0.75 mmol) in dry ethanol (5 mL) was stirred for 1 h. The solvent was evapo-
rated under reduced pressure and the residue was purified by column chroma-
tography (toluene/EtOAc 1 : 1). Compound 5 was isolated as colorless syrup.
Yield: 0.145 g (85%); [a]2D1 212.68 (c 1.0); Rf 0.22 (toluene/ethyl acetate, 2 : 1).
1H NMR (250 MHz, CDCl3): d ¼ 8.66–7.58 (m, 2H, Ph), 7.43–7.30 (m, 3H,
3
Ph), 6.58 (s, 1H, H-4), 5.00 (d, 1H, J1 ,2 ¼ 8.2 Hz, H-10), 4.24 (ddd, 1H, H-30),
0
0
3
3
4.15 (dd, 1H, J2 ,3 ¼ 5.2 Hz, H-20), 3.98 (dd, 1H, J3 ,
¼ 6.7 Hz,
0
0
0
0
4 a
2
3
J4 a,4 b ¼ 8.5 Hz, H-40a), 3.67 (dd, 1H, J3 ,4 b ¼ 7.3, H-40b), 1.51, 1.50, 1.41,
0
0
0
0
1.36 (4 ꢀ s, 12H, 4 ꢀ Me). 13C NMR (75.5 MHz): d ¼ 130.4 (i-Ph), 128.9,
128.4, 125.6 (o-, m-, p-Ph), 110.3, 109.8 (2 ꢀ C(Me)2), 100.9 (C-4), 81.5 (C-20),
75.1 (C-10), 73.5 (C-30), 65.5 (C-40), 26.84, 26.79, 26.2, 25.4 (4 ꢀ Me); C-3, C-5
are not given due to strong signal broadening. MS (EI), m/z (%): 344 (18) [M]þ.
Anal. Calcd for C19H24N2O4(344.17): C, 66.26; H, 7.02; N, 8.13. Found: C,
66.14; H, 7.32; N, 7.60.
3-(D-xylo-1,2,3,4-Tetrahydroxy-butyl)- 5-phenyl-1H(2H)-
pyrazole (6)
To a stirred solution of compound 5 (0.220 g, 0.5 mmol) in THF (1mL) and
water (2 mL) was given trifluoroacetic acid (0.075 mL, 1.0 mmol) and the
mixture was heated at 658C until the starting material had disappeared
(detected by TLC; approximately 6 h). After filtration through aluminium oxide
(90, active basic, Merck), the residue was washed several times with methanol.
The combined filtrates were evaporated and the remaining residue was
purified by column chromatography (ethyl acetate/methanol, 5 : 1). Compound
6 was isolated as a white foam. Yield: 0.110g (85%); mp 35–378C; [a]2D3 20.78
(c 0.5, MeOH); Rf 0.33 (ethyl acetate/methanol, 5 : 1). 1H NMR (250 MHz,
DMSO-d6): d ¼ 12.72 (bs, NH), 7.84–7.68 (m, 2H, Ph); 7.50–7.21 (m, 3H, Ph),
3
6.56 (s, 1H, H-4), 5.26 (bs, OH-10), 4.74 (t, 1H, J4 ,OH-4 ¼ 5.5 Hz, OH-40), 4.64–
4.33 (m, 3H, H-10, OH-20, OH-30), 3.63 (m, 1H, H-20), 3.49–3.26 (m, 3H, H-30,
H-40). 13C NMR (62.9 MHz, DMSO-d6): d ¼ 128.9, 127.6, 125.2 (o-, m-, p-Ph),
100.4 (C-4), 73.6 (C-20), 71.5 (C-30), 67.8 (C-10), 63.1 (C-40), C-3, C-5, i-Ph-C5 are
not given due to strong signal broadening. MS (EI), m/z (%): 264 (4) [M]þ.
HRMS Calcd for C13H16N2O4: 264.11099. Found: 264.11114.
0
0
4-(1,2:3,4-Di-O-isopropylidene-D-xylo-1,2,3,4-tetrahydroxy-
butyl)-2-methyl-pyrimidine (7a)
A mixture of 4a (0.125 g, 0.5 mmol), acetamidinium chloride (0.061 mg,
0.65 mmol), Na2CO3 (0.138 g, 1.38 mmol), water (0.01 mL), and EtOAc (5 mL)

I. Otero et al.
820
was heated under reflux until the starting material had disappeared (1 h, TLC
control). Then the solution was filtered and evaporated under reduced
pressure. The residue was purified by column chromatography (toluene/
ethyl acetate 1 : 1). Compound 7a was isolated as colorless syrup. Yield:
0.115 g (78%); [a]2D4 þ23.28 (c 1.0, CHCl3); Rf 0.30 (toluene/ethyl acetate 1 : 1).
3
1H NMR (250 MHz): d ¼ 8.61 (d, 1H, J5,6 ¼ 5.2 Hz, H-6), 7.33 (d, 1H, H-5),
3
4.85 (d, 1H, J1 ,2 ¼ 7.6 Hz, H-10), 4.40 (ddd, 1H, H-30), 4.13 (dd, 1H,
0
0
3
2
3
J3 ,4 a ¼ 6.7 Hz, J4 a,4 b ¼ 8.5 Hz, H-40a), 3.99 (dd, 1H, J2 ,3 ¼ 4.9 Hz, H-20),
0
0
0
0
0
0
3
3.89 (dd, 1H, J3 ,4 b ¼ 7.0, H-40b), 2.68 (s, 3H, 2-Me), 1.54, 1.45, 1.43, 1.41
(4 ꢀ s, 12H, 4 ꢀ Me). 13C NMR (75.5 MHz): d ¼ 167.9, 167.7 (C-2, C-4), 157.7
(C-6), 114.3 (C-5), 110.8, 109.8 (2 ꢀ C(Me)2), 81.8 (C-20), 78.7 (C-10), 76.1
(C-30), 66.1 (C-40), 26.9, 26.7, 26.3, 25.9, 25.7 (4 ꢀ Me, 2-Me). MS (CI), m/z
(%): 295 (100) [MH]þ.
0
0
Anal. Calcd for C15H22N2O4(294.16): C, 61.21; H, 7.53; N, 9.52. Found:
C, 61.08; H, 7.58; N, 9.03.
4-(1,2:3,4-Di-O-isopropylidene-D-xylo-1,2,3,4-tetrahydroxy-
butyl)-2-phenyl-pyrimidine (7b)
The reaction of 4a (0.125 g, 0.5 mmol) with benzamidinium chloride
(0.102 g, 0.65 mmol) was carried out as described above for the preparation of
7a. The product was purified by column chromatography (toluene/ethyl
acetate, 10 : 1). Compound 7b was isolated as a white solid. Yield: 0.110 g
(63%); mp 82–848C; [a]2D3 þ18.78 (c 1.0, CHCl3); Rf 0.44 (toluene/ethyl
3
acetate, 10 : 1). 1H NMR (250 MHz): d ¼ 8.80 (d, 1H, J5,6 ¼ 4.9 Hz, H-6),
8.46–8.37 (m, 2H, o-Ph), 7.52–7.45 (m, 3H, m-, p-Ph), 7.44 (d, 1H, H-5), 5.01
3
(d, 1H, J1 ,2 ¼ 7.6 Hz, H-10), 4.52 (ddd, 1H, H-30), 4.20 (dd, 1H,
0
0
3
2
3
J3 ,4 a ¼ 6.4 Hz, J4 a,4 b ¼ 8.5 Hz, H-4 a), 4.13 (dd, 1H, J2 ,3 ¼ 4.9 Hz, H-20),
0
0
0
0
0
0
3.96 (dd, 1H, J3 ,4 b ¼ 7.3, H-40b), 1.58, 1.50, 1.45 (3 ꢀ s, 12H, 4 ꢀ Me). 13C
NMR (75.5 MHz): d ¼ 168.3 (C-4), 163.9 (C-2), 158.0 (C-6), 137.2 (i-Ph), 130.9,
128.6, 128.3, 127.9 (o-, m-, p-Ph), 115.2 (C-5), 110.9, 109.8 (2 ꢀ C(Me)2), 81.8
(C-20), 78.8 (C-10), 76.3 (C-30), 66.1 (C-40), 26.9, 26.8, 26.3, 25.8 (4 ꢀ Me). MS
(FABþ), m/z (%): 357 (100) [MH]þ.
3
0
0
Anal. Calcd for C20H24N2O4 (356.17): C, 67.40; H, 6.79; N, 7.86. Found: C,
66.99; H, 6.80; N, 6.97.
4-(1,2:3,4-Di-O-isopropylidene-D-xylo-1,2,3,4-tetrahydroxy-
butyl)-2-methylthio-pyrimidine (7c)
The reaction of 4a (0.125 g, 0.5 mmol) with S-methyl-isothiouronium
sulfate (0.180 g, 0.65 mmol) was carried out as described above for the
preparation of 7a. The product was purified by column chromatography
(toluene/ethyl acetate, 10 : 1). Compound 7c was isolated as a white solid.

Syntheses of Acyclo-C-nucleoside Analogs
821
Yield: 0.095 g (58%); mp 66–688C; [a]2D1 þ53.58 (c 1.0, CHCl3); Rf 0.38 (toluene/
ethyl acetate, 10 : 1). 1H NMR (250 MHz): d ¼ 8.48 (d, 1H, 3J5,6 ¼ 4.9 Hz, H-6),
3
7.16 (d, 1H, H-5), 4.84 (d, 1H, J1 ,2 ¼ 7.6 Hz, H-10), 4.38 (ddd, 1H, H-30), 4.08
0
0
3
2
J4 a,4 b ¼ 8.5 Hz, H-40a), 4.02 (dd, 1H,
0
0
0
0
(dd, 1H,
J3 ,
¼ 6.4 Hz,
4 a
3
3
J2 ,3 ¼ 4.6 Hz, H-20), 3.89 (dd, 1H, J3 ,4 b ¼ 7.3, H-40b), 2.51 (s, 3H, SMe),
1.51, 1.42, 1.41, 1.38 (4 ꢀ s, 12H, 4 ꢀ Me). 13C NMR (62.9 MHz): d ¼ 172.3
(C-2); 168.3 (C-4), 157.8 (C-6), 112.4 (C-5), 110.9, 109.7 (2 ꢀ C(Me)2); 81.4
(C-20), 78.4 (C-10), 75.9 (C-30), 65.9 (C-40), 26.8, 26.6, 26.2, 25.6 (4 ꢀ Me), 13.9
(SMe). MS (EI), m/z (%): 326 (2) [M]þ.
0
0
0
0
Anal. Calcd for C15H22N2O4S (326.13): C, 55.19; H, 6.79; N, 8.58; S 9.82.
Found: C, 55.45; H, 6.81; N, 8.14; S, 9.89.
4-(1,2:3,4-Di-O-isopropylidene-D-xylo-1,2,3,4-tetrahydroxy-
butyl)-2-methoxy-pyrimidine (7d)
The reaction of 4a (0.125 g, 0.5 mmol) with O-methyl-isothiouronium
sulfate (0.180 g, 0.65 mmol) was carried out as described above for the prep-
aration of 7a. The product was purified by column chromatography (toluene/
ethyl acetate, 3 : 1). Compound 7d was isolated as a white solid. Yield: 0.100 g
(65%); mp 41–438C; [a]2D3 þ28.88 (c 1.0, CHCl3); Rf 0.28 (toluene/ethyl
1
3
acetate, 3 : 1). H NMR (250 MHz): d ¼ 8.49 (d, 1H, J5,6 ¼ 4.9 Hz, H-6), 7.16
3
(d, 1H, H-5), 4.85 (d, 1H, J1 ,2 ¼ 7.6 Hz, H-10), 4.41 (ddd, 1H, H-30), 4.10 (dd,
0
0
3
2
3
1H, J3 , 4 a ¼ 6.7 Hz, J4 a,4 b ¼ 8.5 Hz, H-40a), 4.05 (dd, 1H, J2 ,3 ¼ 4.6 Hz,
0
0
0
0
0
0
3
H-20), 3.97 (s, 3H, OMe); 3.93 (dd, 1H, J3 ,4 b ¼ 7.3, H-40b), 1.52, 1.44, 1.42,
1.38 (4 ꢀ s, 12H, 4 ꢀ Me). 13C NMR (62.9 MHz): d ¼ 170.8, 165.1 (C-2, C-4),
160.0 (C-6), 111.1 (C-5), 110.9, 109.7 (2 ꢀ C(Me)2), 81.5 (C-20), 78.4 (C-10), 75.9
(C-30), 65.9 (C-40), 54.9 (OMe), 26.9, 26.7, 26.2, 25.6 (4 ꢀ Me). MS (EI), m/z
(%): 310 (2) [M]þ.
0
0
Anal. Calcd for C15H22N2O5 (310.35): C, 58.05; H, 7.15; N, 9.03. Found:
C, 57.78; H, 7.07; N, 8.54.
4-(1,2:3,4-Di-O-isopropylidene-D-xylo-1,2,3,4-tetrahydroxy-
butyl)-2-methyl-6-phenyl-pyrimidine (7e)
The reaction of 4b (0.165 g, 0.5 mmol) with acetamidinium chloride
(0.061 mg, 0.65 mmol) was carried out as described above for the preparation
of 7a. The product was purified by column chromatography (toluene/ethyl
acetate, 4 : 1). Compound 7e was isolated as a white solid. Yield: 0.165 g
(90%); mp 70–728C; [a]2D1 22.18 (c 1.0, CHCl3); Rf 0.50 (toluene/ethyl
acetate, 4 : 1). 1H NMR (250 MHz): d ¼ 8.12–8.03 (m, 2H, Ph), 7.73 (s, 1H,
3
H-5), 7.53–7.46 (m, 3H, Ph), 4.92 (d, 1H, J1 ,2 ¼ 7.6 Hz, H-10), 4.46 (ddd, 1H,
0
0
3
2
H-30), 4.17 (dd, 1H, J3 , 4 a ¼ 6.7 Hz, J4 a,4 b ¼ 8.5 Hz, H-40a), 4.06 (dd, 1H,
0
0
0
0
3
3
J2 ,3 ¼ 5.2 Hz, H-20), 3.95 (dd, 1H, J3 ,4 b ¼ 7.3 Hz, H-40b), 2.75 (s, 3H, 2-Me),
0
0
0
0

I. Otero et al.
822
1.58, 1.51, 1.45, 1.43 (4 ꢀ s, 12H, 4 ꢀ Me). 13C NMR (125.7 MHz): d ¼ 168.4,
167.9 (C-4, C-6), 164.9 (C-2), 137.2 (i-Ph), 130.8, 128.9, 127.3 (o-, m-, p-Ph),
109.9 (C-5), 110.8, 109.7 (2 ꢀ C(Me)2), 81.9 (C-20), 78.9 (C-10), 76.2 (C-30), 66.2
(C-40), 26.9, 26.8, 26.3, 26.1, 25.7 (4 ꢀ Me, 2-Me). MS (CI), m/z (%): 371 (100)
[MH]þ.
Anal. Calcd for C21H26N2O4 (370.19): C, 68.09; H, 7.07; N, 7.56. Found:
C, 67.59; H, 6.71; N, 7.39.
4-(1,2:3,4-Di-O-isopropylidene-D-xylo-1,2,3,4-tetrahydroxy-
butyl)-2,6-diphenyl-pyrimidine (7f)
The reaction of 4b (0.165 g, 0.5 mmol) with benzamidinium chloride
(0.102 g, 0.65 mmol) was carried out as described above for the preparation of
7a. Recrystallization from ethyl acetate gave 7f as colorless needles. Yield:
0.205 g (96%); mp 135–1388C; [a]2D3 þ49.28 (c 1.0, CHCl3); Rf 0.63 (toluene/
1
ethyl acetate, 10 : 1). H NMR (250 MHz): d ¼ 8.62–8.54 (m, 2H, Ph), 8.30–
4
0
8.21 (m, 2H, Ph), 7.86 (d, 1H, J1 ,5 ¼ 0.6 Hz, H-5), 7.60–7.47 (m, 6H, Ph),
3
3
5.07 (dd, 1H, J1 ,2 ¼ 7.6 Hz, H-10), 4.58 (ddd, 1H, H-30), 4.24 (dd, 1H, J3 ,
0
0
0
2
3
¼ 6.4 Hz, J4 a,4 b ¼ 8.5 Hz, H-40a), 4.20 (dd, 1H, J2 ,3 ¼ 5.2 Hz, H-20), 4.02
0
0
0
0
0
4 a
(dd, 1H, J3 ,4 b ¼ 7.6, H-40b), 1.63, 1.56, 1.47 (3 ꢀ s, 12H, 4 ꢀ Me). 13C NMR
(75.5 MHz): d ¼ 168.8 (C-4), 164.8, 163.9 (C-2, C-6), 137.5, 137.0 (2 ꢀ i-Ph),
130.9, 130.8, 128.9, 128.5, 128.1, 127.2 (o-, m-, p-Ph), 110.5 (C-5), 110.9, 109.8
(2 ꢀ C(Me)2), 81.8 (C-20), 78.9 (C-10), 76.4 (C-30), 66.2 (C-40), 26.9, 26.8, 26.3,
25.8 (4 ꢀ Me). MS (EI), m/z (%):432 (2) [M]þ.
3
0
0
Anal. Calcd for C26H28N2O4 (432.20): C, 72.20; H, 6.53; N, 6.48. Found:
C, 72.16; H, 6.65; N, 6.20.
X-ray Structure Determination of 7f
Temperature: 173(2) K; crystal system: triclinic; space group: P1; unit cell
˚
˚
˚
dimensions: a ¼ 8.6481(2) A, b ¼ 10.7316(3) A, c ¼ 13.3576(3) A, a ¼
3
˚
71.9460(10)8, b ¼ 84.3760(10)8, g ¼ 74.0510(10)8; volume: 1133.17(5) A ; Z: 2;
density (calculated): 1.268 Mg/m3; absorption coefficient: 0.086 mm21; F(000):
460; crystal size: 0.63 ꢀ 0.29 ꢀ 0.20 mm3; Q range for data collection: 2.95 to
27.508; index ranges: 211 ꢁ h ꢁ 11, 213 ꢁ k ꢁ 13, 217 ꢁ l ꢁ 17; reflections
collected: 48773; independent reflections: 10038 [R(int) ¼ 0.0318]; complete-
ness to Q ¼ 27.508: 97.7%; absorption correction: multiscan (min; max tran-
sitions: 0.9480; 0.9831); data/restraints/parameters: 10038/3/577; goodness-
of-fit on F2: 1.030: final R indices [I . 2s(I)]: R1 ¼ 0.0372, wR2 ¼ 0.0979; R
indices (all data): R1 ¼ 0.0466, wR2 ¼ 0.1072; absolute structure parameter:
20.1(5); largest diff. peak and hole: 0.247 and 20.188 e.A23. The weighting
˚
scheme was calculated according to w21 ¼ s2 (Fo2) þ (0.0633 P)2 þ 0.1228 P
with P ¼ (F2oþ 2 F2c)/3.

Syntheses of Acyclo-C-nucleoside Analogs
823
4-(D-xylo-1,2,3,4-Tetrahydroxy-butyl)-2-methyl-pyrimidine
(8)
The deprotection of compound 7a (0.145 g, 0.5 mmol) was carried out as
described above for the preparation of 6 (reaction time 2 h). The product was
purified by column chromatography (ethyl acetate/methanol, 5 : 1).
Compound 8 was isolated as a colorless syrup. Yield: 0.086 g (80%); [a]D23
þ60.78 (c 1.0, MeOH); Rf 0.21 (ethyl acetate/methanol, 5 : 1). 1H NMR
3
(500 MHz, DMSO-d6): d ¼ 8.62 (d, 1H, J5,6 ¼ 5.1 Hz, H-6), 7.38 (d, 1H, H-5),
3
3
5.45 (d, 1H, J1 ,OH-1 ¼ 5.4 Hz, OH-10), 4.64 (d, 1H, J3 ,OH-3 ¼ 4.7 Hz, OH-30),
0
3
0
0
0
3
4.63 (dd, 1H, J1 ,2 ¼ 3.1 Hz, H-10), 4.59 (t, 1H, J4 ,OH-4 ¼ 5.5 Hz, OH-40),
0
0
0
0
3
3
4.39 (d, 1H, J2 ,OH-2 ¼ 7.0 Hz, OH-20), 3.81 (ddd, 1H, J2 ,3 ¼ 4.5 Hz, H-20),
0
0
0
0
3
3.58 (m, 1H, H-30), 3.51 (m, 1H, J4 a,4 b ¼ 10.9 Hz, H-40a), 3.44 (m, 1H,
H-40b), 2.58 (s, 3H, 2-Me). 13C NMR (62.9 MHz, DMSO-d6): d ¼ 172.1 (C-4),
166.3 (C-2), 157.1 (C-6), 116þ.1 (C-5), 74.0 (C-10), 73.2þ(C-30), 73.1 (C-20), 62.6
(C-40), 25.8 (2-Me). MS (FAB ), m/z (%):215 (50) [MH] .
0
0
HRMS Calcd for C9H14N2O4Na: 237.08458. Found: 237.08525.
2-(1,2:3,4-Di-O-isopropylidene-D-xylo-1,2,3,4-tetrahydroxy-
butyl)benzo[4,5]imidazo[1,2-a]pyrimidine (9a)
A mixture of 4a (0.125 g, 0.5 mmol) and 2-amino-benzimidazol (0.073 g,
0.55 mmol) in ethanol (5 mL) was heated under reflux for 4 h. The solvent
was evaporated under reduced pressure and the residue was purified by
column chromatography (toluene/ethyl acetate, 1 : 1). Recrystallization from
ethyl acetate gave 9a as yellow plates. Yield: 0.145 g (78%); mp 168–1718C;
[a]2D2 þ52.58 (c 1.0, CHCl3); Rf 0.37 (toluene/ethyl acetate, 1 : 1). 1H NMR
(250 MHz): d ¼ 8.74 (d, 1H, 3J3,4 ¼ 7.0 Hz, H-4), 7.96 (dt, 1H,
3
4
5J6,9 ¼ 4J7,9 ¼ 1.0 Hz, J8,9 ¼ 8.0 Hz, H-9), 7.86 (dt, 1H, J6,8 ¼ 1.0 Hz,
3J6,7 ¼ 8.0 Hz, H-6), 7.55 (dt, 1H, J7,8 ¼ 8.0 Hz, H-8), 7.40 (dt, 1H, H-7), 7.23
3
3
(d, 1H, H-3), 5.09 (d, 1H, J1 ,2 ¼ 7.6 Hz, H-10), 4.56 (ddd, 1H, H-30), 4.26 (dd,
0
0
3
3
2
1H, J2 ,3 ¼ 4.3 Hz, H-20), 4.15 (dd, 1H, J3 ,
¼ 6.7 Hz, J4 a,4 b ¼ 8.5 Hz,
0
0
0
0
0
0
4 a
3
H-40a), 3.96 (dd, 1H, J3 ,4 b ¼ 7.3, H-40b), 1.58, 1.48, 1.45, 1.40 (4 ꢀ s, 12H,
4 ꢀ Me). 13C NMR (75.5 MHz): d ¼ 166.5 (C-2), 149.8 (C-10a), 144.4 (C-9a),
133.5 (C-4), 126.7 (C-5a), 126.6 (C-8), 122.1 (C-7), 120.5 (C-9), 110.5 (C-6),
111.0, 109.7 (2 ꢀ C(Me)2), 104.0 (C-3), 81.1 (C-20), 78.9 (C-10), 75.7 (C-30), 66.0
(C-40), 26.8, 26.7, 26.2, 25.7 (4 ꢀ Me). MS (EI), m/z (%): 369 (15) [M]þ.
Anal. Calcd for C20H23N3O4 (369.17): C, 65.03; H, 6.28; N, 11.37. Found: C,
64.64; H, 6.33; N, 11.15.
0
0
X-ray Structure Determination of 9a
temperature: 173(2) K; crystal system: monoclinic; space group: P21; unit
˚
˚
˚
cell dimensions: a ¼ 5.32380(10) A, b ¼ 10.6952(2) A, c ¼ 16.1617(3) A,

I. Otero et al.
824
3
˚
a ¼ 908, b ¼ 93.8530(10)8, g ¼ 908; volume: 918.15(3) A ; Z: 2; density (calcu-
lated): 1.336 Mg/m3; absorption coefficient: 0.094 mm21; F(000): 392; crystal
size: 0.58 ꢀ 0.48 ꢀ 0.18 mm3; Q range for data collection: 3.16 to 29.998;
index ranges: 27 ꢁ h ꢁ 7, 214 ꢁ k ꢁ 14, 222 ꢁ l ꢁ 22; reflections collected:
28155; independent reflections: 5324 [R (int) ¼ 0.0235]; completeness to
Q ¼ 29.998: 99.8%; absorption correction: multiscan (min, max transitions:
0.9473; 0.9832); data/restraints/parameters: 5324/1/248; goodness-of-fit on
F2: 1.033: final R indices [I . 2s(I)]: R1 ¼ 0.0330, wR2 ¼ 0.0866; R indices
(all data): R1 ¼ 0.0349, wR2 ¼ 0.0885; absolute structure parameter :
20.1(5); largest diff. peak and hole: 0.280 and 20.225 e.A23; the weighting
˚
scheme was calculated according to w21 ¼ s2 (Fo2) þ (0.0573 P)2 þ 0.1080 P
with P ¼ (F2oþ 2 F2c)/3.
2-(1,2:3,4-Di-O-isopropylidene-D-xylo-1,2,3,4-tetrahydroxy-
butyl)-4-phenyl-benzo[4,5]imidazo[1,2-a]pyrimidine
(9b)
The reaction of 4b (0.165 g, 0.5 mmol) with 2-amino-benzimidazol (0.073 g,
0.55 mmol) was carried out as described above for the preparation of 9a. The
product was purified by column chromatography (toluene/ethyl acetate 1 : 1).
Recrystallization from ethyl acetate gave 9b as yellow needles. Yield: 0.145 g
(65%); mp 158–1608C; [a]2D3 23.78 (c 1.0, CHCl3); Rf 0.39 (toluene/ethyl
5
acetate, 1 : 1). 1H NMR (250 MHz): d ¼ 7.95 (dt, 1H, J6,9
,
4J7,9 ¼ 1.0 Hz,
3J8,9 ¼ 8.0 Hz, H-9), 7.73–7.55 (m, 5H, Ph), 7.45 (dt, 1H, J7,8 ¼ 8.0 Hz,
3
4J6,8 ¼ 1.0 Hz, H-8), 7.07 (s, 1H, H-3), 7.04 (dt, 1H, J6,7 ¼ 8.0 Hz, H-7), 6.69
3
3
(dt, 1H, H-6), 5.14 (d, 1H, J1 ,2 ¼ 7.6 Hz, H-10), 4.61 (ddd, 1H, H-30), 4.32 (dd,
0
0
3
3
2
1H, J2 ,3 ¼ 4.6 Hz, H-20), 4.20 (dd, 1H, J3 ,
¼ 6.4 Hz, J4 a,4 b ¼ 8.2 Hz,
0
0
0
0
0
0
4 a
3
H-40a), 4.01 (dd, 1H, J3 ,4 b ¼ 7.3, H-40b), 1.57, 1.49, 1.46, 1.43 (4 ꢀ s, 12H,
4 ꢀ Me). 13C NMR (75.5 MHz): d ¼ 165.7 (C-2), 151.1, 150.0 (C-4, C-10a),
145.0 (C-9a), 132.2 (i-Ph), 131.2, 129.4, 128.2, 126.2 (m-, o-, p-Ph), 127.3
(C-5a), 126.6 (C-8), 121.4, 120.4 (C-7, C-9), 114.7 (C-6); 110.9, 109.7
(2 ꢀ C(Me)2), 105.2 (C-3), 81.1 (C-20), 79.0 (C-10), 75.8 (C-30), 66.1 (C-40), 26.8,
26.8, 26.3, 25.7 (4 ꢀ Me). MS (EI), m/z (%): 445 (21) [M]þ.
0
0
Anal. Calcd for C26H27N3O4 (445.20): C, 70.09; H, 6.11; N, 9.43. Found: C,
70.44; H, 6.15; N, 9.05.
2-(p-Anisidino)-5-(1,2:3,4-di-O-isopropylidene-D-xylo-
1,2,3,4-tetrahydroxy-butyl)pyrazolo[1,5-a]pyrimidine-3-
carbonitrile (11a)
A mixture of 4a (0.125 g, 0.5 mmol) and 5-amino-3-(p-anisidino)-1H-
pyrazole-4-carbonitrile (0.115 g, 0.5 mmol) in ethanol (5 mL) was heated
under reflux for 4 h, cooled to 208C, treated with sodium ethanolate

Syntheses of Acyclo-C-nucleoside Analogs
825
(1.5 mmol) in ethanol (5 mL), and stirred for 1 h. After neutralization with
amberlite IR-120 (Fluka-Chemie GmbH), the solvent was removed under
reduced pressure and the residue was purified by column chromatography
(toluene/ethyl acetate, 2 : 1). Compound 11a was isolated as a yellow solid.
Yield: 0.170 g (75%); mp 131–1338C; [a]2D5 þ18.88 (c 0.5, CHCl3); Rf 0.50
1
(toluene/ethyl acetate, 2 : 1). IR (KBr), n (cm21): 3316 (NH); 2218 (CN). H
3
NMR (500 MHz, DMSO-d6): d ¼ 9.35 (s, 1H, NH), 9.06 (d, 1H, J6,7 ¼ 6.9 Hz,
H-7), 7.61–7.57 (m, 2H, Ho-NHC6H4), 7.19 (d, 1H, H-6), 6.92–6.88 (m, 2H,
3
Hm-NHC6H4), 4.95 (d, 1H, J1 ,2 ¼ 7.9 Hz, H-10), 4.31 (dt, 1H, H-30), 4.13 (dd,
0
0
3
3
2
1H, J2 ,3 ¼ 4.5 Hz, H-20), 4.07 (dd, 1H, J3 ,
¼ 6.8 Hz, J4 a,4 b ¼ 8.4 Hz,
0
0
0
0
0
0
4 a
3
H-4a0), 3.76 (dd, 1H, J3 ,4 b ¼ 6.8, H-40b), 3.73 (s, 3H, OMe), 1.47, 1.46, 1.35,
1.33 (4 ꢀ s, 12H, 4 ꢀ Me). 13C NMR (75.5 MHz, DMSO-d6): d ¼ 162.4 (C-5),
157.7 (C-2), 154.7 (Cp-NHC6H4); 150.1 (C-3a), 137.3 (C-7), 133.8 (Ci-
NHC6H4), 120.6 (Co-NHC6H4), 114.1 (Cm-NHC6H4), 113.7 (CN), 110.5, 109.0
(2 ꢀ C(Me)2), 106.8 (C-6), 81.1 (C-20), 78.7 (C-10), 75.0 (C-30), 67.1 (C-3), 65.4
(C-40), 55.4 (OMe), 26.9, 26.8, 26.3, 25.8 (4 ꢀ Me). MS (EI), m/z (%): 465 (100)
[M]þ.
0
0
Anal. Calcd for C24H27N5O5 (465.20): C, 61.92; H, 5.85; N, 15.04. Found: C,
61.84; H, 5.89; N, 14.80.
2-Amino-N-benzyl-5-(1,2:3,4-di-O-isopropylidene-D-xylo-
1,2,3,4-tetrahydroxy-butyl)pyrazolo[1,5-a]pyrimidine-3-
carboxamide (11b)
The reaction of 4a (0.125 g, 0.5 mmol) with 3,5-diamino-N-benzyl-1H-
pyrazole-4-carboxamide (115 mg, 0.5 mmol) was carried out as described
above for the preparation of 11a. The product was purified by column chrom-
atography (toluene/ethyl acetate 1 : 1). Compound 11b was isolated as a
yellow solid. Yield: 0.160 g (68%); mp 58–608C; [a]2D1 þ42.48 (c 1.0, CHCl3); Rf
0.37 (toluene/ethyl acetate, 1 : 1). IR (KBr), n (cm–1): 3429, 3343, 3321 (NH),
3
1655 (CO). 1H NMR (500 MHz): d ¼ 8.42 (d, 1H, J6,7 ¼ 7.0 Hz, H-7), 7.94
(t, 1H, NH), 7.39–7.31 (m, 4H, Ph), 7.28–7.23 (m, 1H, Ph), 7.02 (d, 1H, H-6),
3
3
4.95 (d, 1H, J1 ,2 ¼ 7.5 Hz, H-10), 4.75 (dd, 1H, JNH,CH ¼ 6.5 Hz,
0
0
2
2JCH ¼ 15.0 Hz, NCH2), 4.59 (dd, 1H, JNH,CH ¼ 5.8 Hz, NCH2), 4.21 (dt, 1H,
3
2
2
3
3
H-30), 4.08 (dd, 1H, J2 ,3 ¼ 4.1 Hz, H-20), 3.81 (d, 2H, J3 ,4 ¼ 6.6 Hz, H-40),
1.52, 1.41, 1.37, 1.29 (4 ꢀ s, 12H, 4 ꢀ Me).13C NMR (75.5 MHz): d ¼ 164.1
(CONH), 161.8 (C-5), 160.6 (C-2), 146.3 (C-3a), 139.1 (i-Ph), 134.7 (C-7),
128.6, 127.4, 127.2 (o-, m-, p-Ph), 110.9, 109.8 (2 ꢀ C(Me)2), 104.4 (C-6), 87.7
(C-3), 81.2 (C-20), 78.5 (C-10), 75.2 (C-30), 65.5 (C-40), 42.5 (CH2Ph), 26.8, 26.6,
26.2, 25.4 (4 ꢀ Me). MS (EI), m/z (%): 467 (50) [M]þ.
0
0
0
0
Anal. Calcd for C24H29N5O5 (467.22): C, 61.66; H, 6.25; N, 14.98. Found:
C, 61.20; H, 6.01; N, 14.37.

I. Otero et al.
826
Ethyl 2-(p-Anisidino)-5-(1,2:3,4-di-O-isopropylidene-D-xylo-
1,2,3,4-tetrahydroxy-butyl)pyrazolo[1,5-a]pyrimidine-3-
carboxylate (11c)
The reaction of 4a (0.125 g, 0.5 mmol) with ethyl 5-amino-3-(p-anisidino)-
1H-pyrazole-4-carboxylate (140 mg, 0.5 mmol) was carried out as described
above for the preparation of 11a. The product was purified by column chrom-
atography (toluene/ethyl acetate 4 : 1). Recrystallization from ethyl acetate
gave 11c as yellow needles. Yield: 0.205 g (80%); mp 138–1408C; [a]D22
þ29.28 (c 0.5, CHCl3); Rf 0.46 (toluene/ethyl acetate, 4 : 1). IR (KBr), n
(cm21): 3327 (NH); 1668 (CO). 1H NMR (250 MHz): d ¼ 8.81 (s, 1H, NH),
3
8.52 (d, 1H, J6,7 ¼ 7.0 Hz, H-7), 7.61–7.54 (m, 2H, Ho-NHC6H4), 7.14
3
0
0
(d, 1H, H-6), 6.94–6.87 (m, 2H, Hm-NHC6H4), 4.99 (d, 1H, J1 ,2 ¼ 7.6 Hz,
H-10), 4.58–4.48 (m, 1H, H-30), 4.50–4.31 (m, 2H, OCH2CH3), 4.23 (dd, 1H,
3
2
3
J3 ,4 a ¼ 6.5 Hz, J4 a,4 b ¼ 8.8 Hz, H-40a), 4.14 (dd, 1H, J2 ,3 ¼ 5.5 Hz, H-20),
0
0
0
0
0
0
3
4.10 (dd, 1H, J3 ,4 b ¼ 7.6, H-40b), 3.79 (s, 3H, OMe), 1.58, 1.49,
1.44, 1.43 (4 ꢀ s, 12H, 4 ꢀ Me), 1.45 (t, 3H, 3J ¼ 7.1 Hz, OCH2CH3).
13C NMR (125.7 MHz): d ¼ 165.3 (COOEt), 162.5 (C-5), 159.1 (C-2), 154.9
(Cp-NHC6H4), 147.0 (C-3a), 135.1 (C-7), 133.4 (Ci-NHC6H4), 120.0
(Co-NHC6H4), 114.4 (Cm-NHC6H4), 110.9, 109.7 (2 ꢀ C(Me)2), 104.9 (C-6),
86.1 (C-3), 81.9 (C-20), 78.9 (C-10), 76.6 (C-30), 66.2 (C-40), 60.2 (OCH2CH3),
55.6 (OMe), 26.9, 26.7, 26.3, 25.9 (4 ꢀ Me), 14.6 (OCH2CH3). MS (EI), m/z
(%): 512 (100) [M]þ.
0
0
Anal. Calcd for C26H32N4O7 (512.23): C, 60.93; H, 6.29; N, 10.93. Found:
C, 60.58; H, 6.28; N, 10.66.
X-ray Structure Determination of 11c
Temperature: 173(2) K; crystal system: orthorhombic; space group:
˚
˚
P212121; unit cell dimensions: a ¼ 6.8413(5) A, b ¼ 14.3667(9) A,
3
˚
˚
c ¼ 25.8351(15) A, a ¼ 908, b ¼ 908, g ¼ 908; volume: 2539.3(3) A ; Z: 4;
density (calculated): 1.341 Mg/m3; absorption coefficient: 0.098 mm21; F(000):
1088; crystal size: 0.77 ꢀ 0.14 ꢀ 0.13 mm3; Q range for data collection: 2.94
to 24.008; index ranges: 27 ꢁ h ꢁ 7, 216 ꢁ k ꢁ 16, 227 ꢁ l ꢁ 29; reflections
collected: 17058; independent reflections: 3966 [R(int) ¼ 0.0437]; completeness
to Q ¼ 24.008: 99.1%; absorption correction: multiscan (min, max transitions:
0.9281; 0.9873); data/restraints/parameters: 3966/0/344; goodness-of-fit on
F2: 1.045: final R indices [I . 2s(I)]: R1 ¼ 0.0423, wR2 ¼ 0.1006; R indices
(all data): R1 ¼ 0.0556, wR2 ¼ 0.1079; absolute structure parameter:
-3
˚
20.7(13); largest diff. peak and hole: 0.399 and –0.361 e.A ; the weighting
scheme was calculated according to w–1 ¼ s2 (Fo2) þ (0.0597 P)2 þ 0.5989P
with P ¼ (F2oþ 2 F2c)/3.

Syntheses of Acyclo-C-nucleoside Analogs
827
Ethyl 2-(p-Chloroanilino)-5-(1,2:3,4-di-O-isopropylidene-D-
xylo-1,2,3,4-tetrahydroxy-butyl)pyrazolo[1,5-
a]pyrimidine-3-carboxylate (11d)
The reaction of 4a (0.125 g, 0.5 mmol) with ethyl 5-amino-3-(p-chloroani-
lino)-1H-pyrazole-4-carboxylate (140 mg, 0.5 mmol) was carried out as
described above for the preparation of 11a. The product was purified by
column chromatography (toluene/ethyl acetate 4 : 1). Recrystallization from
ethyl acetate gave 11d as colorless needles. Yield: 0.135 g (53%); mp
158 2 1608C; [a]2D2 þ41.88 (c 1.0, CHCl3); Rf 0.54 (toluene/ethyl acetate, 4 : 1).
IR (KBr), n (cm21): 3438 (NH), 1664 (CO). 1H NMR (250 MHz): d ¼ 9.05
3
(s, 1H, NH), 8.53 (d, 1H, J6,7 ¼ 6.9 Hz, H-7), 7.64–7.57 (m, 2H, Ho-NHC6H4),
7.31–7.22 (m, 2H, Hm-NHC6H4), 7.18 (d, 1H, H-6), 5.00 (d, 1H,
3
J1 ,2 ¼ 7.6 Hz, H-10), 4.58–4.46 (m, 1H, H-30), 4.46–4.32 (m, 2H, OCH2CH3),
0
0
3
2
4.22 (dd, 1H, J3 ,4 a ¼ 6.5 Hz, J4 a,4 b ¼ 8.7 Hz, H-40a), 4.14 (dd, 1H,
0
0
0
0
3
3
J2 ,3 ¼ 5.4 Hz, H-20), 4.10 (dd, 1H, J3 ,4 b ¼ 7.6, H-40b), 1.58, 1.49, 1.45, 1.43
0
0
0
0
(4 ꢀ s, 12H, 4 ꢀ Me), 1.45 (t, 3H, 3J ¼ 7.1 Hz, OCH2CH3). 13C NMR
(75.5 MHz): d ¼ 165.3 (COOEt), 162.9 (C-5); 158.3 (C-2), 146.6 (C-3a), 138.5
(Ci-NHC6H4), 135.2 (C-7), 128.9 (Cm-NHC6H4), 126.5 (Cp-NHC6H4), 119.2
(Co-NHC6H4), 110.9, 109.7 (2 ꢀ C(Me)2), 105.2 (C-6), 86.4 (C-3), 81.8 (C-20),
78.8 (C-10), 76.6 (C-30), 66.2 (C-40), 60.3 (OCH2CH3), 26.9, 26.6, 26.3, 25.8
(4 ꢀ Me), 14.5 (OCH2CH3). MS (EI), m/z (%): 516 (95) [M]þ.
Anal. Calcd for C25H29ClN4O6 (516.18): C, 58.08; H, 5.65; N, 10.84. Found:
C, 58.22; H, 5.66; N, 10.71.
2-Amino-N-benzyl-5-(D-xylo-1,2,3,4-tetrahydroxy-butyl)-
pyrazolo[1,5-a]pyrimidine-3-carboxamide (12)
The deprotection of compound 11b (0.115 g, 0.25 mmol) was carried out as
described above for the preparation of 6 (reaction time 6 h). The product was
purified by column chromatography (ethyl acetate/methanol, 5 : 1).
Compound 12 was isolated as a white solid. Yield: 0.070 g (72%); mp 158–
1
1608C; [a]2D1 þ57.08 (c 0.5, MeOH); Rf 0.21 (ethyl acetate/methanol, 5 : 1). H
3
NMR (250 MHz, DMSO-d6): d ¼ 8.82 (d, 1H, J6,7 ¼ 6.8 Hz, H-7); 8.32 (t, 1H,
NH), 7.44–7.16 (m, 5H, Ph), 7.03 (d, 1H, H-6), 6.44 (s, 2H, NH2), 5.67 (1H,
3
3
J1 ,OH-1 ¼ 6.2 Hz, OH-10), 4.71 (t, 1H, J4 ,OH-4 ¼ 5.3 Hz, OH-40), 4.66–4.44
0
0
0
0
(m, 5H, H-10, OH-20, OH-30, CH2Ph), 3.78 (m, 1H, H-20), 3.59–3.38 (m, 3H,
H-30, H-40). 13C NMR (62.9 MHz, DMSO-d6): d ¼ 164.5 (CONH), 163.9 (C-5),
161.5 (C-2), 145.9 (C-3a), 140.1 (i-Ph), 134.9 (C-7), 128.6, 127.2, 126.8 (o-, m-,
p-Ph), 106.3 (C-6), 86.1 (C-3), 74.4 (C-10), 73.6 (C-30), 72.5 (C-20), 62.7 (C-40),
41.8 (CH2Ph). MS (ESI): 388 [MH]þ.
HRMS Calcd for C18H21N5O5Na: 410.14349, Found: 410.14363.

I. Otero et al.
828
ACKNOWLEDGMENTS
The authors thank the Deutsche Forschungsgemeinschaft and the Fonds der
Chemischen Industrie for financial support. I. O. is grateful to the Deutscher
Akademischer Austauschdienst for a scholarship.
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