A short and efficient synthesis of 2′-deoxybenzo- and pyridoimidazole C-nucleosides

Article abstract of DOI:10.1016/S0040-4039(03)01401-1

A short route to a series of 2′-deoxy-C-nucleosides featuring substituted nucleobases has been developed. The key step is the formation of the cyclized products following Mukaiyama's type amide coupling and a simple dehydration, starting from readily accessible synthons. The epimerization of the C1′-stereogenic center was avoided under mild and controlled conditions.

Full text of DOI:10.1016/S0040-4039(03)01401-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 5807–5810
A short and efficient synthesis of 2%-deoxybenzo- and
pyridoimidazole C-nucleosides
Mohamed Jazouli,a Dominique Guianvarc’h,† Mohamed Soufiaoui,a,* Khalid Bougrin,a
Pierre Vierlingb and Rachid Benhidab,*
aLaboratoire de Chimie des Plantes et de Synthe`se Organique et Bioorganique, Universite´ Mohamed V-Agdal,
Faculte´ des Sciences, Avenue Ibn Batouta, BP 1014, Rabat, Morocco
bLaboratoire de Chimie Bioorganique UMR-CNRS 6001, Universite´ de Nice-Sophia Antipolis, Parc Valrose,
06108 Nice cedex 2, France
Received 3 June 2003; accepted 5 June 2003
Abstract—A short route to a series of 2%-deoxy-C-nucleosides featuring substituted nucleobases has been developed. The key step
is the formation of the cyclized products following Mukaiyama’s type amide coupling and a simple dehydration, starting from
readily accessible synthons. The epimerization of the C1%-stereogenic center was avoided under mild and controlled conditions.
© 2003 Elsevier Ltd. All rights reserved.
C-Nucleosides are important targets in organic synthe-
sis due to their potential value as therapeutic agents
and biochemical probes. They have been also found in
a number of natural and synthetic products (such as
thiazofurin, showdomycin, pyrazomycin, etc...) with
potent antiviral or antitumor activities.1 Recently, sev-
eral synthetic C-nucleosides have been studied as
chemotherapeutic agents,1,2 as potential universal
bases,3 or as building blocks in artificial DNA and
RNA syntheses4 for the control of gene expression.
Their properties were also investigated in a number of
other biochemical applications.5 Another attractive fea-
ture of C-nucleosides arises from the presence of the
CꢀC glycosidic bond which confers to these analogs a
greater resistance towards chemical and enzymatic
hydrolysis than to the N-nucleosides. Therefore, a large
number of synthetic approaches to C-ribofuranosyl
nucleosides have recently been explored.6 However, less
attention has been focused on their 2%-deoxy analogs.7
One of the most well known strategy is the conversion
of the C-nucleosides to their 2%-deoxy derivatives by
using the radical 2%-deoxygenation process (Barton–
McCombie reaction) which, however, requires addi-
tional steps and, thus, decreases the overall yield.8 The
standard nucleophilic substitution of an appropriate
halogenated sugar has also been largely used but was in
some cases low yielding.9
In the continuation of our studies aimed at overcoming
the chemical limitations of triple helix formation by
using modified synthetic oligonucleotides,10 we report
herein a short synthesis (three key steps) of 2%-deoxy-C-
nucleosides 6 featuring a heterocyclic nucleobase, start-
ing from the readily accessible O-Tol protected
2%-deoxyribonic acid 3 with a given a or b anomeric
configuration (Scheme 1). These three steps consist into
(i) a Mukaiyama’s type coupling between 2%-deoxyri-
bonic acid 3 and ortho-aryl disubstituted diamines (a–d)
to give the conjugates 4 followed by sequential (ii) acid
catalyzed ring-closure, and (iii) O-Tol deprotection to
afford the target 2%-deoxybenzimidazole or pyridoimi-
dazole C-nucleosides 6.
The starting known 2%-deoxyribonic acids 3a and 3b
were best obtained in two steps from the O-Tol pro-
tected a-chlorosugar 1 by using TMSCN and BF3Et2O
as catalyst (Scheme 1), followed by the hydrolysis of the
resulting cyano-derivative 2a and 2b, respectively
(ꢀ90% overall yields). The cyano-derivative 2 was
obtained as a mixture of a/b diastereomers (a/b molar
ratio=1/3) which were easily separated by standard
silica gel column chromatography. It should be noted
that, when we performed the Cl/CN substitution as
* Corresponding authors. Tel.: +33-(0)4-9207-6153; fax: +33-(0)4-
9207-6151; e-mail: benhida@unice.fr
† Present address: Laboratoire de Biophysique, UR 565 INSERM,
UMR 8646 CNRS, Muse´um National d’Histoire Naturelle, 43 rue
Cuvier 75231 Paris Cedex 05, France.
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01401-1

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M. Jazouli et al. / Tetrahedron Letters 44 (2003) 5807–5810
AcOH, yielding the protected 2%-deoxy-C-nucleoside
derivatives 5b (Table 1, entries 1, 3 and 5), providing
however that the temperature was kept at 40–45°C.
Indeed, epimerization at the C1%-stereocenter occurred
when this reaction was performed in AcOH at 95–
110°C (see Table 1, entries 2 and 4).14 This epimeriza-
tion likely took place before or during cyclization. That
it did not occur from the cyclized 5b anomer (b“a) is
strongly supported by the fact that no epimerization
was observed when the pure b-anomers (and also the
a-anomers) of 5a or 5b were heated in AcOH, the
starting materials remaining unchanged (although par-
tial degradation was detected). These results are further
in line with our recent findings in the ribo-series with
similar analogs15 and outline that the epimerization
process in C-nucleosides is highly dependent on the
nature of the aglycone part.9,16 In the case of the
pyridine analog 4db, the cyclization was very slow at
40°C and gave a much lower yield of the desired
compound 5db (25%), the starting material being
mainly recovered (70%). Conversion of 4db into 5db
could be improved by heating at higher temperature
(110°C) or by using additional TFA (1 equiv.) (entries 7
and 8, respectively). However, partial epimerization was
observed under these more drastic conditions.
Scheme 1. Synthetic strategy to the 2%-deoxy-C-nucleosides
6b.
The O-Tol-deprotection in 5a–db was performed with
MeONa in MeOH and afforded quantitatively the
target 2%-deoxy-C-nucleosides 6a–db (Scheme 1).
described in literature, i.e. by using NaCN in different
solvents11 or Et2AlCN in toluene,12 we isolated 2 in
much lower yields (below 45%) and with a non-con-
trolled a/b anomeric ratio. These lower yields were due
in part to the observed 3%- and 5%-toluoyl cleavage side
reaction.
Where the synthesis sequence of the a anomers was
concerned, the coupling step 3(a–d)a“4(a–d)a was
accomplished in a similar way as for their b-analogs,
but required longer reaction times. Unfortunately,
when 4(a–d)a were heated in AcOH, we observed not
only the cyclization into their respective derivatives
5(a–d)a but also the intramolecular migration of the
toluoyl group from the 3%-position to the ortho-NH2
group. Indeed, and as shown in Scheme 2, derivative
7ba together with the expected 5ba (in nearly 1/1 molar
ratio) was also isolated after AcOH treatment of 4ba.
The coupling of 3b with the ortho-diamines (a–d) using
Mukaiyama’s
reagent
(chloromethylpyridinium
iodide)13 in CH2Cl2 afforded the corresponding b-con-
jugates 4a–db in good yields (75–92%). These com-
pounds, apart from the pyridine analog 4db (vide
infra), were then cleanly cyclized by simple heating in
Table 1.
Entry
ortho-Diamine (a–d)
Temp. (°C)/time (h)
5 a/b ratio (yield %)a
0/100 (60)
1
2
3
4
5
6
7
8
X=C, R=Ac
X=C, R=Ac
X=C, R=NO2
X=C, R=NO2
X=C, R=H
X=N, R=H
X=N, R=H
X=N, R=H
40/12
95/16
40/12
95/16
45/12
45/12
110/14
50/14
5a
5a
5b
5b
5c
5d
5d
5d
50/50 (67)
0/100 (61)
45/55 (50)
0/100 (55)
0/100 (25)
25/75 (51)
20/80 (50)b
a Yield of pure isolated products (two steps).
b 1 equiv. of TFA was added.

M. Jazouli et al. / Tetrahedron Letters 44 (2003) 5807–5810
5809
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B., Ed.; Plenum Press: New York, 1994; Vol. 3, 421–535;
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2. For recent articles, see: (a) Franchetti, P.; Marchetti, S.;
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6. (a) Wichai, U.; Woski, S. A. Org. Lett. 1999, 1, 1173–
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Martini, C.; Costa, B.; Varani, K.; Borea, P. A.; Grifan-
tini, M. Bioorg. Med. Chem. 2000, 8, 2367–2373; (c)
Ramasamy, K. S.; Bandaru, R.; Averett, D. J. Org.
Chem. 2000, 65, 5849–5851; (d) Franchetti, P.; Marchetti,
S.; Cappellaci, L.; Yalowitz, J. A.; Jayaram, H. N.;
Goldstein, B. M.; Grifantini, M. Bioorg. Med. Chem.
Lett. 2001, 11, 67–69; (e) Chun, B. K.; Song, G. Y.; Chu,
C. K. J. Org. Chem. 2001, 66, 4852–4858; (f) Manferdini,
M.; Morelli, C. F.; Veronese, A. C. Tetrahedron 2002, 58,
1005–1010.
7. (a) Calter, M. A.; Zhu, C. J. Org. Chem. 1999, 64,
1415–1419; (b) Chen, D.-W.; Beuscher, A. E., IV;
Stevens, R. C.; Wirsching, P.; Lerner, R. A.; Janda, K.
D. J. Org. Chem. 2001, 66, 1725–1732; (c) Griesang, N.;
Richert, C. Tetrahedron Lett. 2002, 43, 8755–8758; (d)
Takase, M.; Morikawa, T.; Abe, H.; Inouye, M. Org.
Lett. 2003, 5, 625–628.
8. For recent examples, see: (a) Tanaka, K.; Shionoya, M.
J. Org. Chem. 1999, 64, 5002–5003; (b) Seela, F.; Debe-
lak, H. J. Org. Chem. 2001, 66, 3303–3312.
Scheme 2. Cyclization/cleavage steps of the a-derivative.
The O- to N-toluoyl migration, which was not detected
in the case of the b-anomers, is probably favored in the
case of a-analogs by (i) the close cis relationship of the
two substituents in 1%- and 3%-positions (Scheme 2) and
(ii) the known 2%-endo sugar conformation of such
analogs. This migration could be avoided by reversing
the order of the reaction sequence. Thus, when 4ba was
first submitted to MeONa/MeOH (deprotection) and
then cyclized (AcOH/40°C), the desired product 6ba
was obtained in 87% overall yield.17
In summary, we have developed a short and straight-
forward synthesis of 2%-deoxy-C-nucleosides featuring
substituted benzimidazole or pyridoimidazole nucle-
obases. The sequential coupling–cyclization steps could
be performed in one operation making the methodol-
ogy more attractive. Furthermore, this process is highly
flexible and does not require the protection of the
heterocycles and allows conventional post-synthetic
transformations.
Acknowledgements
We are grateful to the CNRS and the Universite´ de
Nice-Sophia Antipolis for financial support (Conven-
tion CNRS-CNR 11492).
9. See for example: Aketani, S.; Tanaka, K.; Yamamoto,
K.; Ishihama, A.; Cao, H.; Tengeiji, A.; Hiraoka, S.;
Shiro, M.; Shionoya, M. J. Med. Chem. 2002, 45, 5594–
5603 and also Refs. 7b and 7c.
10. (a) Guianvarc’h, D.; Benhida, R.; Fourrey, J.-L.;
Maurisse, R.; Sun, J. S. J. Chem. Soc., Chem. Commun.
2001, 1814–1815; (b) Guianvarc’h, D.; Fourrey, J.-L.;
Maurisse, R.; Sun, J. S.; Benhida, R. Org. Lett. 2002, 4,
4209–4212; (c) Guianvarc’h, D.; Fourrey, J.-L.; Maurisse,
R.; Sun, J. S.; Benhida, R. Bioorg. Med. Chem. 2003, 11,
2751–2759.
References
1. For reviews on the chemistry and biochemistry of C-
nucleoside analogs, see: (a) Hacksell, U.; Daves, G. D.,
Jr. Prog. Med. Chem. 1985, 22, 1–65; (b) Postema, M. H.
D. Tetrahedron 1992, 48, 8545–8599; (c) Watanabe, K. A.

5810
M. Jazouli et al. / Tetrahedron Letters 44 (2003) 5807–5810
11. Kolb, A.; Huynh Dinh, T.; Igolen, J. Bull. Soc. Chim. Fr.
1973, 3447.
12. Iyer, R. P.; Phillips, L. R.; Egan, W. Synth. Commun.
2H, J=8.2 Hz), 8.40 (s, 1H). 13C NMR (CDCl3, 50
MHz) l 21.97, 22.02, 26.27, 36.09, 64.40, 76.04, 79.28,
84.54, 116.98, 122.07, 126.58, 126.94, 127.01, 128.59,
129.51, 129.64, 130.03, 130.11, 144.56, 144.78, 146.22,
166.21, 166.55, 171.69. MS (ES+) m/z=531 [M+H]+, 553
[M+Na]+.
1991, 21, 2053.
13. Mukaiyama, T.; Usui, M.; Shimada, E.; Saigo, K. Chem.
Lett. 1975, 1045–1048.
1
14. The anomeric configuration at the C1%-stereocenter of
5aa. H NMR (CDCl3, 200 MHz) l (ppm) 2.25 (s, 3H),
1
purified products was assigned on the basis of H NMR
2.41 (s, 3H), 2.67 (s, 3H), 2.92–3.13 (m, 2H), 4.53 (m,
2H), 4.68 (m, 1H), 5.62 (m, 1H), 5.76 (dd, 1H, J=6.5 and
4.4 Hz), 6.83 (d, 2H, J=8.0 Hz), 7.10–7.40 (m, 6H), 7.59
(d, 1H, J=8.5 Hz), 7.95 (d, 2H, J=8.0 Hz), 8.23 (br s,
1H). 13C NMR (CDCl3, 50 MHz) l 21.84, 21.97, 27.07,
37.96, 64.43, 76.10, 76.35, 83.93, 123.38, 126.50, 126.91,
129.22, 129.58, 129.63, 129.95, 132.39, 144.58, 144.54,
158.69, 166.06, 166.73. MS (ES+) m/z=513 [M+H]+.
6aa. 1H NMR (CD3OD, 200 MHz) l (ppm) 2.30 (ddd,
1H, J=12.9, 5.0 and 4.7 Hz), 2.64 (s, 3H), 2.78 (ddd, 1H,
J=13.3, 6.3 and 8.2 Hz), 3.65 (dd, 1H, J=12.6 and 5.0
Hz), 3.74 (dd, 1H, J=12.6 and 4.0 Hz), 4.17 (dd, 1H,
J=8.3 and 4.1 Hz), 4.42 (m, 1H), 5.40 (dd, 1H, J=8.3
and 5.0 Hz), 7.57 (d, 1H, J=8.6 Hz), 7.90 (dd, 1H,
J=8.6 and 1.5 Hz), 8.19 (d, 1H, J=1.5 Hz). 13C NMR
(CD3OD, 50 MHz) l 27.28, 42.12, 63.83, 73.93, 76.22,
89.32, 124.52, 133.53. MS (ES−) m/z=275 [M−H]−.
(2D COSY-NOESY experiments).
15. (a) Guianvarc’h, D.; Benhida, R.; Fourrey, J.-L. Tetra-
hedron Lett. 2001, 42, 647–650; (b) Guianvarc’h, D.;
Fourrey, J.-L.; Tran Huu Dau, M.-E.; Gue´rineau, V.;
Benhida, R. J. Org. Chem. 2002, 67, 3724–3732.
16. For the conversion of a to b anomer, see: (a) Chaudhuri,
N. C.; Ren, R. X.-F.; Kool, E. T. Synlett 1997, 341–347;
(b) Jiang, Y. L.; Stivers, J. T. Tetrahedron Lett. 2003, 44,
85–88.
17. Spectral data of selected compounds.
4ab. Mp (AcOEt)=181–183°C. 1H NMR (CDCl3, 200
MHz) l (ppm) 2.28–2.41 (m, 1H), 2.37 (s, 3H), 2.43 (s,
3H), 2.46 (s, 3H), 2.71–2.86 (m, 1H), 4.20 (br s, 2H),
4.55–4.93 (m, 4H), 5.56 (d, 1H, J=4.8 Hz), 6.75 (d, 1H,
J=8.5 Hz), 7.18 (d, 2H, J=7.9 Hz), 7.28 (d, 2H, J=7.9
Hz), 7.71 (dd, 1H, J=2.0 and 8.5 Hz), 7.85 (d, 1H,
J=2.0 Hz), 7.87 (d, 2H, J=8.2 Hz), 7.95 (d, 2H, J=8.2
Hz), 8.53 (br s, 1H). 13C NMR (CDCl3, 50 MHz) l 21.98,
26.43, 37.83, 64.60, 76.24, 79.38, 85.48, 116.83, 126.93,
128.58, 129.62, 129.68, 130.07, 144.83, 145.92, 166.6,
167.40, 170.47. MS (ES+) m/z=531 [M+H]+, 553 [M+
Na]+, 569 [M+K]+.
1
4ba. H NMR (CDCl3, 200 MHz) l (ppm) 2.33 (s, 3H),
2.41 (s, 3H), 2.80 (dd, 2H, J=5.7 and 2.9 Hz), 4.49 (d,
2H, J=4.6 Hz), 4.68 (br s, 2H), 4.77 (t, 1H, J=4.6 Hz),
4.89 (t, 1H, J=6.0 Hz), 5.54 (t, 1H, J=2.9 Hz), 6.70 (d,
1H, J=8.8 Hz), 7.10 (d, 2H, J=8.1 Hz), 7.25 (d, 2H,
J=8.2 Hz), 7.80 (d, 2H, J=8.2 Hz), 7.92 (dd, 1H, J=8.8
and 2.5 Hz), 7.93 (d, 2H, J=8.1 Hz), 8.01 (d, 1H, J=2.4
Hz), 8.56 (s, 1H). 13C NMR (50 MHz, CDCl3) l (ppm)
21.64; 21.69, 35.81, 64.27, 75.93, 79.03, 84.19, 111.71,
115.31, 120.77, 120.86, 122.87, 124.00, 126.22, 126.66,
129.75, 129.78, 138.11, 144.59, 144.86, 148.48, 166.36,
166.78, 172.39.
5ab. Mp (AcOEt)=129–131°C. 1H NMR (CDCl3, 200
MHz) l (ppm) 2.30–2.50 (m, 1H), 2.37 (s, 3H), 2.44 (s,
3H), 2.68 (s, 3H), 2.88 (ddd, 1H, J=13.9, 5.8 and 1.2
Hz), 4.59–4.88 (m, 3H), 5.59 (m, 1H), 5.68 (dd, 1H,
J=10.1 and 5.8 Hz), 7.18 (d, 2H, J=7.9 Hz), 7.29 (d, 2H,
J=7.9 Hz), 7.61 (d, 1H, J=8.5 Hz), 7.74 (br s, 1H), 7.91
(d, 2H, J=8.5 Hz), 7.93 (dd, 1H, J=8.5 and 1.6 Hz),
7.97 (d, 2H, J=8.5 Hz), 8.24 (d, 1H, J=1.6 Hz). 13C
NMR (CDCl3, 50 MHz) l 21.69, 21.75, 26.79, 39.15,
64.77, 76.03, 76.15, 84.58, 114.69, 123.29, 126.35, 126.47,
128.28, 129.68, 132.34, 144.54, 144.70, 156.79, 166.25,
167.84. MS (IC) m/z=513 [M+H]+, 119 [Tol]+.
6ba. 1H NMR (CD3OD, 200 MHz) l (ppm) 2.34 (ddd,
1H, J=13.0, 8.2 and 4.9 Hz), 2.80 (ddd, 1H, J=13.0, 6.2
and 5.0 Hz), 3.70 (m, 2H), 4.19 (dd, 1H, J=4.3 and 8.2
Hz), 4.38–4.50 (m, 1H), 5.42 (dd, 1H, J=5.0 and 8.2 Hz),
7.60 (d, 1H, J=8.9 Hz), 8.11 (dd, 1H, J=8.9 and 2.0
Hz), 8.39 (d, 1H, J=2.0 Hz). 13C NMR (50 MHz,
CD3OD) l (ppm) 42.08, 63.86, 73.95, 76.23, 89.84,
119.52, 145.18, 163.52. MS (ES−) m/z 278 [M−H]−.
1
6ab. H NMR (CDCl3, 200 MHz) l (ppm) 2.30 (m, 1H),
2.43 (m, 1H), 2.65 (s, 3H), 3.65–3.85 (2dd, 2H, J=12.0,
6.4 and 4.8 Hz), 4.05 (m, 1H), 4.32 (m, 1H), 5.40 (dd, 1H,
J=9.6 and 6.3 Hz), 7.59 (d, 1H, J=8.5 Hz), 7.92 (dd,
1H, J=8.5 and 1.5 Hz), 8.21 (d, 1H, J=1.5 Hz). 13C
NMR (CD3OD, 50 MHz) l 26.95, 42.81, 63.63, 73.68,
75.90, 89.80, 128.85, 130.12, 130.23, 130.65, 133.44,
159.87. MS (ES−) m/z=275 [M−H]−.
1
8ba. H NMR (DMSO-d6, 200 MHz) l (ppm) 2.08 (dt,
1H, J=12.8 and 3.1 Hz), 2.40 (ddd, 1H, J=13.3, 9.0 and
5.4 Hz), 2.50 (s, 3H), 3.70 (s, 2H), 3.90–3.99 (m, 1H),
4.05–4.17 (m, 1H), 4.54 (dd, 1H, J=9.0 and 3.7 Hz), 4.96
(br s, 1H), 6.39 (t, 1H, J=6.8 Hz), 7.01 (d, 1H, J=8.9
Hz), 7.17 (d, 1H, J=8.9 Hz), 7.45 (m, 1H), 7.86 (dd, 1H,
J=2.8 and 8.9 Hz), 7.94 (d, 1H, J=5.7 Hz), 9.20 (d, 1H,
J=3.0 Hz), 10.08 (s, 1H). 13C NMR (50 MHz, DMSO-
d6) l 26.70, 41.11, 62.08, 71.26, 78.31, 88.84, 107.92,
112.38, 112.90, 117.12, 120.07, 131.24, 131.32, 139.46,
139.71, 141.63, 146.64, 154.23, 171.85, 171.92. MS (ES−)
m/z=414 [M−H]−.
1
4aa. H NMR (CDCl3, 200 MHz) l (ppm) 2.24 (s, 3H),
2.26 (s, 3H), 2.34 (s, 3H), 2.73 (m, 2H), 4.29 (br s, 2H),
4.44 (d, 2H, J=4.6 Hz), 4.70 (t, 1H, J=4.6 Hz), 4.83 (t,
1H, J=6.5 Hz), 5.49 (br t, 1H, J=3.2 Hz), 6.67 (d, 1H,
J=8.5 Hz), 6.99 (d, 2H, J=7.9 Hz), 7.19 (d, 2H, J=7.9
Hz), 7.60–7.67 (m, 2H), 7.74 (d, 2H, J=8.2 Hz), 7.88 (d,