Synthesis of conformationally locked C-nucleosides having a 2,5- dioxabicyclo [2.2.1] heptane ring system

Article abstract of DOI:10.1016/S0040-4039(99)01998-X

Some novel C-nucleosides having a 2,5-dioxabicyclo[2.2.1]heptane ring system were successfully synthesized via the coupling reaction of tetrahydrofurancarbaldehyde 1 with the lithium and the magnesium derivatives of aromatic heterocycles.

Full text of DOI:10.1016/S0040-4039(99)01998-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 215–219
Synthesis of conformationally locked C-nucleosides having a
2,5-dioxabicyclo[2.2.1]heptane ring system
Satoshi Obika, Yoshiyuki Hari, Ken-ichiro Morio and Takeshi Imanishi ∗
Graduate School of Pharmaceutical Sciences, Osaka University, 1–6 Yamadaoka, Suita, Osaka 565-0871, Japan
Received 8 September 1999; revised 12 October 1999; accepted 18 October 1999
Abstract
Some novel C-nucleosides having a 2,5-dioxabicyclo[2.2.1]heptane ring system were successfully synthesized
via the coupling reaction of tetrahydrofurancarbaldehyde 1 with the lithium and the magnesium derivatives of
aromatic heterocycles. © 1999 Elsevier Science Ltd. All rights reserved.
Keywords: nucleic acid analogues; bicyclic heterocyclic compounds; nitrogen heterocycles; Mitsunobu reactions.
Conformationally locked nucleosides constitute a class of molecules for antisense and antigene ap-
plications, which have been the focus of extensive work.1 We have recently accomplished the first syn-
thesis of 20-O,40-C-methyleneribonucleosides having a fixed N-form sugar conformation,2 which were
found to have potent RNA recognition ability when they were introduced into oligonucleotides.3–7 On the
other hand, natural and unnatural C-nucleosides have received a great deal of attention because of their
potent biological activities, such as antiviral and antitumor activities.8–10 Despite their importance, there
is limited information available on the relationship between the conformation of C-nucleosides and their
biological activities. Furthermore, C-nucleosides, unlike the natural nucleosides, can possess a great va-
riety of heterocycles; therefore, the C-nucleoside analogues with fixed N-conformation are also of interest
for antisense and antigene applications, along with their biological activities. Herein we report the first
convenient synthesis of conformationally locked C-nucleosides having a 2,5-dioxabicyclo[2.2.1]heptane
ring system.
The aldehyde 1 is used as a key building block for the synthesis of the bicyclic C-nucleosides. The
synthetic route to 1 is shown in Scheme 1. Its synthesis started from 4-hydroxymethyl derivative 2,11
which was monosilylated by a tert-butyldiphenylsilyl group to afford 3 (70%).† Toluene-p-sulfonylation
of 3 gave 4 (98%) and then acidic hydrolysis of 4 afforded diol 5 (77%). Because the reaction of
diol 5 under the alkaline conditions was found to give the oxetane product 6 (43%) along with the
desired product 7 (35%),12 the C3-hydroxy group was selectively protected according to the previously
∗
†
Corresponding author. Fax: +81 6-6879-8204; e-mail: imanishi@phs.osaka-u.ac.jp (T. Imanishi)
The stereochemistry of 3, 8 and 14 was confirmed by 1H NMR and NOE measurements.
0040-4039/00/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)01998-X
tetl 15926

216
reported procedure.2 The diol 5 was initially treated with benzaldehyde and zinc chloride to give 2,3-O-
benzylidene derivative 8 (100%) as the sole diastereoisomer.† In the presence of titanium tetrachloride,
2,3-O-benzylidene 8 was treated with sodium cyanoborohydride in acetonitrile to afford 3-O-benzyl
derivative 9 (67%) along with a 2-O-benzyl derivative (27%). Upon exposure of 9 to sodium hexame-
thyldisilazide in tetrahydrofuran, bicyclic methyl ribofuranoside 10 was obtained (95%). Deprotection at
the 5-hydroxy group in 10 (10→11, 100%) followed by substitution by a benzyl group gave 12 (11→12,
92%), which was treated with 10% HCl to give the desired compound 1 successively (100%).‡ From
1
analysis of the H NMR spectrum, 1 was found to exist in an aldehyde form (not a hemiacetal form)
because of the ring strain derived from the 2-O,4-C-methylene bridge.
Scheme 1. Reagents and conditions: (i) TBDPSCl (2.2 equiv.), Et3N, CH2Cl2, rt; (ii) TsCl, Et3N, DMAP, CH2Cl2, rt; (iii)
CF3COOH:THF:H2O (14:8:3), rt; (iv) (Me3Si)2NNa (10 equiv.), THF:benzene (5:2), rt; (v) PhCHO, ZnCl2, rt; (vi) NaBH3CN
(5 equiv.), TiCl4 (5 equiv.), MeCN, rt; (vii) (Me3Si)2NNa, THF, rt; (viii) TBAF, THF, rt; (ix) BnBr, NaH, DMF, rt; (x) 10% HCl,
THF, rt
Next, the aldehyde 1 was coupled with the magnesium and the lithium derivatives of some aromatic
heterocycles as shown in Table 1. The magnesium derivative of 2-phenyl-5-oxazole gave the S-epimer
of compound 13a as a main product, while those of 2-pyridine, N-triisopropylsilyl-3-pyrrole and 2-tert-
butyldiphenylsilyl-1-N,N-dimethylsulfamoyl-5-imidazole afforded the R-epimer of 13b, 13c and 13d,
respectively.§ This stereoselectivity may be explained by the re-face attack of nucleophiles on the
carbonyl group of the chelation model,¶ as illustrated in Fig. 1. On the other hand, the lithium salts
of heterocycles also gave the corresponding products; however, significant stereoselectivities were not
observed.
After separation of the R- and S-epimers of 13a–c by silica gel column chromatography, these
compounds were cyclized under typical Mitsunobu conditions.15–17 As shown in Table 2, S-13a and
R-13b, which were obtained as major products in the coupling reaction of 1 with magnesium salts,
were treated with diethyl azodicarobxylate (DEAD) and triphenylphosphine (TPP) in tetrahydrofuran
‡
Recently, the aldehyde 1 was alternatively prepared by Wengel et al.13,14
§
The stereochemistry of 13 was determined from the structure of their cyclization products 14.
¶
A similar chelation model for 2,3,5-tri-O-benzyl-D-ribofuranose was reported by Yokoyama et al.15

217
Table 1
Coupling reaction of 1 with some aromatic heterocycles
Fig. 1. Proposed chelation model
to give only bicyclic β-C-nucleosides 14a,b in good yields,k while S-13c gave the anomeric mixtures
of 14c (α:β=29:71). This is probably due to the partial SN1-type reaction caused by the electron-
donating feature of the N-silylated pyrrole ring. A mixture of R- and S-13d (R:S=90:10) was also
employed for this ring-closure reaction by treatment with 1,10-azobis(N,N-dimethylformamide) (TMAD)
and tributylphosphine (TBP) in benzene to afford the desired product 14d (α:β=10:90). α-Anomeric C-
nucleosides were also obtained by using R-13a, S-13b and S-13c as shown in Table 3.†
Thus, we have successfully achieved the synthesis of conformationally locked C-nucleoside analogues
k
1
0
0
0
In the H NMR spectra, β-14 showed all singlet signals for C1 -, C2 - and C3 -protons, which clearly indicate that the
conformation of β-14 is locked in N-form.2 β-14a: 1H NMR (CDCl3) δ: 3.86 (2H, s), 4.12, 4.16 (2H, ABq, J=8 Hz), 4.35 (1H,
s), 4.41 (1H, s), 4.62, 4.71 (2H, ABq, J=12 Hz), 4.62 (2H, s), 5.13 (1H, s), 7.02 (1H, s), 7.31–7.32 (10H, m), 7.43–7.46 (3H,
m), 7.86 (2H, d, J=7 Hz). β-14b: H NMR (CDCl3) δ: 3.85 (2H, s), 4.02 (1H, s), 4.12, 4.13 (2H, ABq, J=8 Hz), 4.43, 4.58
1
(2H, ABq, J=12 Hz), 4.61 (1H, s), 4.66 (2H, s), 5.18 (1H, s), 7.14–7.36 (11H, m), 7.51 (1H, d, J=8 Hz), 7.65 (1H, ddd, J=2, 8,
8 Hz) 8.54 (1H, d, J=5 Hz).

218
Table 2
Synthesis of β-anomeric C-nucleosides
Table 3
Synthesis of α-anomeric C-nucleosides
14 through the coupling reaction of aldehyde 1 with the lithium and the magnesium derivatives of
some aromatic heterocycles, and the subsequent Mitsunobu-type ring-closure reaction. Work on further
chemical modification and some application of bicyclic C-nucleosides 14 is now in progress.
Acknowledgements
Part of this work was supported by a grant-in-aid for Scientific Research (B), no. 09557201, from Japan
Society for the Promotion of Science. We are also grateful to Takeda Science Foundation for financial
support.
References
1. Herdewijn, P. Liebigs Ann. Chem. 1996, 1337–1348.
2. Obika, S.; Nanbu, D.; Hari, Y.; Morio, K.; In, Y.; Ishida, T.; Imanishi, T. Tetrahedron Lett. 1997, 38, 8735–8738.

219
3. Obika, S.; Nanbu, D.; Hari, Y.; Andoh, J.; Morio, K.; Doi, T.; Imanishi, T. Tetrahedron Lett. 1998, 39, 5401–5404.
4. Singh, S. K.; Nielsen, P.; Koshkin, A. A.; Wengel, J. Chem. Commun. 1998, 455–456.
5. Koshkin, A. A.; Singh, S. K.; Nielsen, P.; Rajwanshi, V. K.; Kumar, R.; Meldgaard, M.; Olsen, C. E.; Wengel, J. Tetrahedron
1998, 54, 3607–3630.
6. Singh, S. K.; Wengel, J. Chem. Commun 1998, 1247–1248.
7. Koshkin, A. A.; Nielsen, P.; Meldgaard, M.; Rajwanshi, V. K.; Singh, S. K.; Wengel, J. J. Am. Chem. Soc. 1998, 120,
13252–13253.
8. Postema, M. H. D. Tetrahedron 1992, 48, 8545–8599.
9. Postema, M. H. D. C-Glycoside Synthesis; CRC Press: London, 1995.
10. Levy, D. E.; Tang, C. The Chemistry of C-Glycosides; Elsevier Science: Oxford, 1995.
11. Jones, G. H.; Taniguchi, M.; Tegg, D.; Moffatt, J. G. J. Org. Chem. 1979, 44, 1309–1317.
12. Obika, S.; Morio, K.; Nanbu, D.; Imanishi, T. Chem. Commun. 1997, 1643–1644.
13. Nielsen, P.; Wengel, J. Chem. Commun. 1998, 2645–2646.
14. Kværnø, L.; Wengel, J. Chem. Commun. 1999, 657–658.
15. Yokoyama, M.; Toyoshima, H.; Shimizu, M.; Togo, H. J. Chem. Soc., Perkin Trans. 1 1997, 29–33.
16. Mitsunobu, O. Synthesis 1981, 1–28.
17. Tsunoda, T.; Otsuka, J.; Yamamiya, Y.; Ito, S. Chem. Lett. 1994, 539–542.