Stereoselective synthesis of 1-deoxy-1-ethynyl-β-d-ribofuranose as a versatile scaffold

Article abstract of DOI:10.1016/j.tetlet.2012.10.053

We have developed an efficient stereoselective synthesis of 1-deoxy-1-ethynyl-β-d-ribofuranose (R^E), via the β-selective cyanation of the anomeric position of 1-O-acetyl-2,3,5-tri-O- benzoyl-β-d-ribofuranose. Under conditions for copper(I)-cata

Full text of DOI:10.1016/j.tetlet.2012.10.053

Tetrahedron Letters 53 (2012) 6987–6989
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Stereoselective synthesis of 1-deoxy-1-ethynyl-b-D-ribofuranose
as a versatile scaffold
Yoshiaki Kitamura a, Kana Edayoshi a, Yukio Kitade a,b,
⇑
a Department of Biomolecular Science, Faculty of Engineering, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan
b United Graduate School of Durg Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan
a r t i c l e i n f o
a b s t r a c t
-ribofuranose (RE), via
-ribofuranose.
Under conditions for copper(I)-catalyzed alkyne–azide 1,3-dipolar cycloaddition, the cycloaddition of
E with 4-fluorobenzylazide was accomplished within 5 min, to afford the corresponding triazole ribonu-
cleoside in quantitative yield.
Article history:
We have developed an efficient stereoselective synthesis of 1-deoxy-1-ethynyl-b-
the b-selective cyanation of the anomeric position of 1-O-acetyl-2,3,5-tri-O-benzoyl-b-
D
Received 7 September 2012
Revised 9 October 2012
Accepted 12 October 2012
Available online 23 October 2012
D
R
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
C-Nucleoside
Alkynes
Stereoselective synthesis
Huisgen cycloaddition
Click chemistry
C-Nucleosides have attracted considerable interest in medicinal
chemistry and chemical biology for their biological properties,
which include anticancer and antiviral activities.1 In particular, b-
C-nucleosides functionalized at the 1-position of ribose are useful
chiral building blocks for constructing natural products and
pharmaceuticals.
Here we report the stereoselective synthesis of RE (1) using 1-O-
acetyl-2,3,5-tri-O-benzoyl-b-D-ribofuranose (2) as starting mate-
rial. Moreover, RE rapidly reacted with 4-fluorobenzylazide5 to
produce the corresponding triazole ribonucleoside, under condi-
tions for Cu(I)-catalyzed alkyne-azide 1,3-dipolar cycloaddition
(CuAAC).
In the course of this study, several types of nucleoside analogues
The synthesis of 1 was achieved as shown in Scheme 1. First, 36
was prepared by anchimeric assisted stereoselective nucleophilic
addition of cyanide via TMSCN to the oxocarbenium ion intermedi-
ate generated in situ from commercially available 2. Treatment of 3
with sodium methoxide and subsequent hydrolysis of the resulting
imidate in situ with HCl gave the fully deprotected methyl ester in
70% yield. After selective introduction of a TBDPS group at the 5-
OH, the secondary hydroxyl groups of 4 were subjected to isopro-
pylidenation. Fully protected methyl ester 5 was advanced to the
corresponding ethynyl riboside 6 by a one-pot protocol using DI-
BAL-H and Bestmann-Ohira reagent.7 Finally, removal of the TBDPS
and isopropylidene groups by acidic hydrolysis afforded 1 in 79%
yield. The structures and stereochemistry of compounds 1 and 3–
6 were determined by spectroscopic analysis, including the exten-
sive use of 2D NMR techniques.
bearing one or more ethynyl groups have been developed (Fig. 1).2
1-Deoxy-1-ethynyl-b-D
-ribofuranose 1 (RE, Fig. 2) is the simplest
acetylenic b-C-nucleoside, yet an efficient synthetic method for RE
has not been reported. Buchanan and co-workers have reported
nonstereoselective syntheses of RE utilizing 2,3,5-tri-O-benzyl-
D
-ri-
bose or
D
-ribose diethyl dithioacetal as a key intermediate.2a,c The
direct attachment of a trimethylsilyl (TMS)-alkynyl group, which
can be easily converted into an ethynyl group by desilylation, has
been achieved at the anomeric position of ribose. Lubin-Germain
and Uziel et al. used an alkynylindium reagent, which was gener-
ated in situ from indium(0) and TMS-alkynyl iodide, to introduce
the TMS-alkynyl group to 1-O-acetyl-2,3,5-tri-O-benzyl-
nose.3 Botta and co-workers demonstrated that 1-O-acetyl-2,3,5-
tri-O-benzoyl- -ribofuranose reacted with trimethylsilylacetylene
in the presence of EtAlCl2 to afford 1-deoxy-1-trimethylsilylalky-
nyl-
-ribofuranose.4 However, both protocols gave the correspond-
D-ribofura-
D
We next examined the application of 1 in positron emission
tomography (PET) labeling using rapid CuAAC. We have recently
reported a rapid ligand-free CuAAC protocol for PET labeling of
RNA oligomers.8 Under the reaction conditions [copper sulfate
pentahydrate (100 equiv) and sodium ascorbate (100 equiv) in
0.1 M phosphate buffer (pH 7.0)/DMSO/MeCN at rt], RE (1)
smoothly reacted with 10 equiv of 4-fluorobenzylazide within
D
ing C-ribonucleosides as anomeric mixtures, which can be difficult
to separate.
⇑
Corresponding author. Tel./fax: +81 58 293 2640.
E-mail address: ykkitade@gifu-u.ac.jp (Y. Kitade).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.10.053

6988
Y. Kitamura et al. / Tetrahedron Letters 53 (2012) 6987–6989
Figure 1. Nucleoside analogues bearing one or more ethynyl groups.
5 min to give the desired triazole ribonucleoside 7 in quantitative
yield (Scheme 2).
In conclusion, the efficient stereoselective synthesis of RE was
developed. Furthermore, we demonstrated that RE rapidly reacted
with azide compounds to give the corresponding C-triazole ribonu-
cleosides. These results will contribute to the design of molecular
imaging tools for developing nucleic acid drugs.
Figure 2. 1-Deoxy-1-ethynyl-b-D
-ribofuranose (RE; 1).
Scheme 1. Synthesis of 1. Reagents and conditions: (a) TMSCN, TMSOTf, CH2Cl2, rt, quant; (b) (i) NaOMe, MeOH, rt; (ii) HCl, rt, 70%; (c) TBDPSCl, pyridine, rt, 79%; (d) 2,2-
dimethoxypropane, p-TsOH, acetone, 94%; (e) (i) DIBAL-H, CH2Cl2, À78 °C; (ii) Bestmann-Ohira reagent, K2CO3, MeOH, rt, 67%; (f) CF3CO2H, H2O, rt, 79%.
Scheme 2. CuAAC reaction of RE (1) with 4-fluorobenzylazide.

Y. Kitamura et al. / Tetrahedron Letters 53 (2012) 6987–6989
6989
80.9, 74.4, 71.8, 69.4, 63.1; MS (DRAT) m/z 472 [M+H]+, HRMS (DART) Calcd for
27H22NO7 [M+H]+: 472.1396. Found: 472.1360.
Acknowledgments
C
1-deoxy-1-methoxycarbonyl-5-O-tert-butyldiphenylsilyl-b-d-ribofuranose 4:
colorless oil; 1H NMR (400 MHz, CDCl3) d = 7.72–7.66 (m, 4H, H-Ph), 7.45–
7.36 (m, 6H, H-Ph), 4.42–4.38 (m, 2H, H-1, H-2), 4.27 (t, J = 4.0 Hz, 1H, H-3), 4.08
(q, J = 4.0 Hz, 1H, H-4), 3.82 (d, J = 4.0 Hz, 2H, H-5), 3.75 (s, 3H, CO2CH3), 1.05 (s,
9H, C(CH3)3); 13C NMR (100 MHz, CDCl3) d = 171.5, 135.6, 135.5, 133.0, 132.8,
129.8, 129.8, 127.8, 127.7, 84.8, 81.1, 74.2, 72.7, 64.1, 52.3, 26.7, 19.1; MS
(DRAT) m/z 431 [M+H]+, HRMS (DART) Calcd for C23H31O6Si [M+H]+: 431.1890.
Found: 431.1890; Anal. Calcd for C23H30O6SiÁ1/3H2O: C, 64.16; H, 7.02. Found: C,
63.28; H, 7.08.
This work was supported by Grants-in-Aid for Scientific Re-
search from the Japan Society for the Promotion of Science (JSPS).
References and notes
1. For a review on synthetic strategies and biological applications of C-nucleosides,
see: Stambasky, J.; Hocek, M.; Kocovsky, P. Chem. Rev. 2009, 109, 6729–6764.
2. Many nucleoside analogues bearing one or more ethynyl groups have been
reported. For examples, see (a) Buchanan, J. G.; Edgar, A. R.; Power, M. J.;
Williams, G. C. Carbohydr. Res. 1975, 45, 312–316; (b) Sharma, R. A.; Bobek, M. J.
Org. Chem. 1978, 43, 367–369; (c) Aslani-Shotorbani, G.; Buchanan, J. G.; Edgar,
A. R.; Shahidi, P. K. Carbohydr. Res. 1985, 136, 37–52; (d) Parry, R. J.; Muscate, A.;
Askonas, L. J. Biochemistry 1991, 30, 9988–9997; (e) Matsuda, A.; Takenuki, K.;
Tanaka, M.; Sasaki, T.; Ueda, T. J. Med. Chem. 1991, 34, 812–819; (f) Matsuda, A.;
Shinozaki, M.; Yamaguchi, T.; Homma, H.; Nomoto, R.; Miyasaka, T.; Watanabe,
Y.; Abiru, T. J. Med. Chem. 1992, 35, 241–252; (g) Amin, M. A.; Stoeckli-Evans, H.;
Gossauer, A. Helv. Chim. Acta 1995, 78, 1879–1886; (h) Hattori, H.; Tanaka, M.;
Fukushima, M.; Sasaki, T.; Matsuda, A. J. Med. Chem. 1996, 39, 5005–5011; (i)
Harry-O’kuru, R. E.; Smith, J. M.; Wolfe, M. S. J. Org. Chem. 1997, 62, 1754–1759;
(j) Hattori, H.; Nozawa, E.; Iino, T.; Yoshimura, Y.; Shuto, S.; Shimamoto, Y.;
Nomura, M.; Fukushima, M.; Tanaka, M.; Sasaki, T.; Matsuda, A. J. Med. Chem.
1998, 41, 2892–2902; (k) Nomura, M.; Shuto, S.; Tanaka, M.; Sasaki, T.; Mori, S.;
Shigeta, S.; Matsuda, A. J. Med. Chem. 1999, 42, 2901–2908; (l) Sukeda, M.;
Ichikawa, S.; Matsuda, A.; Shuto, S. J. Org. Chem. 2003, 68, 3465–3475; (m)
Heinrich, D.; Wagner, T.; Diederichsen, U. Org. Lett. 2007, 9, 5311–5314; (n)
Nakahara, M.; Kuboyama, T.; Izawa, A.; Hari, Y.; Imanishi, T.; Obika, S. Bioorg.
Med. Chem. Lett. 2009, 19, 3316–3319.
1-deoxy-1-methoxycarbonyl-5-O-tert-butyldiphenylsilyl-2,3-O-isopropyridene-
b-d-ribofuranose 5: colorless oil; 1H NMR (400 MHz, CDCl3) d = 7.69–7.66 (m,
4H, H-Ph), 7.45–7.39 (m, 6H, H-Ph), 4.93 (dd, J = 6.2 Hz, 3.9 Hz, 1H, H-2), 4.75
(dd, J = 6.2 Hz, 2.0 Hz, 1H, H-3), 4.51(d, J = 3.9 Hz, 1H, H-1), 4.28 (dd, J = 4.6 Hz,
2.0 Hz, 1H, H-4), 3.76–3.74 (m, 2H, H-5), 3.70 (s, 3H, CO2CH3), 1.56 (s, 3H, CH3 of
isopropylidene), 1.37 (s, 3H, CH3 of isopropylidene), 1.06 (s, 9H, C(CH3)3); 13C
NMR (100 MHz, CDCl3) d = 170.8, 135.6 135.6, 132.9, 132.9, 129.8, 129.7, 127.8,
127.7, 113.7, 85.7, 84.0, 83.4, 82.3, 64.1, 52.2, 27.2, 26.8, 25.3, 19.1; MS (DRAT)
m/z 471 [M+H]+, HRMS (DART) Calcd for C26H35O6Si [M+H]+: 471.2203. Found:
471.2154; Anal. Calcd for C26H34O6Si: C, 66.35; H, 7.28. Found: C, 66.08; H, 7.24.
1-deoxy-1-ethynyl-5-O-tert-butyldiphenylsilyl-2,3-O-isopropyridene-b-d-ribo-
furanose 6: colorless oil; 1H NMR (400 MHz, CDCl3): d = 7.73–7.68 (m, 4H, H-Ph),
7.46–7.37 (m, 6H, H-Ph), 4.81 (dd, J = 6.2 Hz, 2.0 Hz, 1H, H-3), 4.76 (dd, J = 6.2 Hz,
2.9 Hz, 1H, H-2), 4.63 (dd, J = 2.9 Hz, 2.4 Hz, 1H, H-1), 4.22 (dt, J = 5.8 Hz, 2.0 Hz,
1H, H-4), 3.86–3.78 (m, 2H, H-5), 2.42 (d, J = 2.4 Hz, 1H, CꢀCH), 1.53 (s, 3H, CH3
of isopropylidene), 1.35 (s, 3H, CH3 of isopropylidene), 1.09 (s, 9H, C(CH3)3); 13
C
NMR (100 MHz, CDCl3): d = 135.7, 135.6, 133.2, 133.2, 129.7, 129.7, 127.7, 127.7,
113.6, 86.2, 86.0, 82.7, 81.6, 74.9, 74.4, 63.6, 27.0, 26.9, 25.3, 19.2; MS (DRAT) m/
z 437 [M+H]+, HRMS (DART) Calcd for C26H33O4Si [M+H]+: 437.2148. Found:
437.2187; Anal. Calcd for C26H32O4Si: C, 71.52; H, 7.39. Found: C, 71.34; H, 7.39.
:
1-deoxy-1-ethynyl-b-d-ribofuranose 12a colorless oil; 1H NMR (400 MHz,
3. Youcef, R. A.; Santos, M. D.; Roussel, S.; Baltaze, J.-P.; Lubin-Germain, N.; Uziel, J.
J. Org. Chem. 2009, 74, 4318–4323.
acetone-d6) d = 4.32 (dd, J = 5.2 Hz, 2.1 Hz, 1H, H-1), 4.11 (q, J = 5.2 Hz, 1H,
H-3), 4.08 (q, J = 5.2 Hz, 1H, H-2), 3.83–3.79 (m, 1H, H-4), 3.78–3.58 (m, 2H, H-5),
3.00 (d, J = 2.1 Hz, 1H, CꢀCH); 13C NMR (100 MHz, acetone-d6): d = 85.8, 82.9,
77.5, 75.5, 73.3, 72.3, 63.1; MS (DRAT) m/z 159 [M+H]+, HRMS (DART) Calcd for
C7H11O4 [M+H]+: 159.0657. Found: 159.0663.
4. Castagnolo, D.; Botta, L.; Botta, M. Tetrahedron Lett. 2009, 50, 1526–1528.
5. The preparation of 4-[18F]-fluorobenzylazide has been established. See: Thonon,
D.; Kech, C.; Paris, J.; Lemaire, C.; Luxen, A. Bioconj. Chem. 2009, 20, 817–823.
6. Morelli, C. F.; Manferdini, M.; Veronese, A. C. Tetrahedron 1999, 55, 10803–
10814.
7. Dickson, H. D.; Smith, S. C.; Hinkle, K. W. Tetrahedron Lett. 2004, 45, 5597–5599.
8. Shiraishi, T.; Kitamura, Y.; Ueno, Y.; Kitade, Y. Chem. Commun. 2011, 47, 2691–
2693
1-[1-(4-fluorobenzyl)-1H-1,2,3-triazol-4-yl]-1-deoxy-b-d-ribofuranose
7:
colorless oil; 1H NMR (400 MHz, acetone-d6) d = 7.99 (s, 1H, CH of triazole),
7.44 (dd, J = 8.8 Hz, 5.3 Hz, 2H, CH of 4-F-Ph), 7.15 (t, J = 8.8 Hz, 2H, CH of 4-F-
Ph), 5.62 (s, 1H, NCH2(4-F-Ph)), 4.88 (d, J = 5.1 Hz, 1H, H-1), 4.25 (q, J = 5.1 Hz,
1H, H-2), 4.19 (q, J = 5.1 Hz, 1H, H-3), 3.93 (dd, J = 8.2 Hz, 3.8 Hz, 1H, H-4), 3.73
Physical and spectral data of synthetic compounds.1-deoxy-1-cyano-2,3,5-tri-O-
benzoyl-b-d-ribofuranose 36: colorless solid; 1H NMR (400 MHz, CDCl3) d =
8.15–8.12 (m, 2H, H-Ph), 7.98–7.92 (m, 4H, H-Ph), 7.61–7.54 (m, 3H, H-Ph),
7.47–7.36 (m, 6H, H-Ph), 6.01 (dd, J = 5.3 Hz, 4.4 Hz, 1H, H-2), 5.86 (t, J = 5.3 Hz,
(dd, J = 11.9 Hz, 8.2 Hz, 1H, H-5 ), 3.60 (dd, J = 11.9 Hz, 3.8 Hz, 1H, H-5b); 13C
a
NMR (100 MHz, acetone-d6): d = 163.4 (d, J = 244.1 Hz), 148.8, 133.1, 131.2 (d, J =
8.6 Hz), 123.3, 116.4 (d, J = 21.9 Hz), 85.8, 78.6, 77.2, 72.4, 63.2, 53.4; MS (DRAT)
m/z 310 [M+H]+, HRMS (DART) Calcd for C14H17FN3O4 [M+H]+: 310.1203. Found:
310.1188; Anal. Calcd for C14H16FN3O4Á7/6H2O: C, 50.91; H, 5.59; N, 12.72.
Found: C, 50.95; H, 5.39; N, 12.53.
1H, H-3), 4.99 (d, J = 4.4 Hz, 1H, H-1), 4.75–4.71 (m, 2H, H-4, H-5 ), 4.62 (dd, J =
a
13.2 Hz, 4.9 Hz, 1H, H-5b); 13C NMR (100 MHz, CDCl3) d = 166.1, 165.0, 164.8,
134.0, 133.8, 133.4, 129.8, 129.8, 129.7, 129.2, 128.6, 128.5, 128.4, 128.1, 115.7,