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Z. Liu et al. / Tetrahedron Letters 51 (2010) 240–243
esterification of the 20-deoxyribose and various carboxylic acids. A
number of solvents and catalysts were tested, and best result was
obtained with 1,2-dichloroethane as the solvent13 and TMSOTf as
the catalyst.14 The coupling reactions between a series of 30-acyl-
50-benzyl-10-O-methyl ribofuranosides (Table 1, entries 1–17,
groups were screened. When the directing group was N-acetyl-gly-
cinate, the b-selectivity and yield were significantly improved
(Table 1, entry 11). Other N-protected groups (Table 1, entries
12–16) led to lower b-selectivities. These poor selectivities (Table
1, entries 7 and 8 and entries 14–16) may be due to the misalign-
ment of the lone pair electrons and the oxonium ion intermediate.
Based on the above results, we believed that 30-O-N-acetyl-
glycinate was a suitable directing group for the nucleo-glycosyl-
ation of 20-deoxyribofuranses. Further study was conducted to
investigate the influence of temperature. When 1k was coupled
with silylated thymidine, 72 h was needed for the reaction to
be completed at ꢀ78 °C in a low yield (Table 1, entry 17). Then
50-O-Benzyl-10-O-acetyl-ribofuranose 4 was used for the coupling
reaction because AcO is a better C-10-leaving group at ꢀ78 °C,
b/
a
= 50/50ꢁ20/80) and silylated thymidine were studied at 0 °C.
These coupling reactions gave b/
a
anomeric selectivities ranging
from 60/40 to 95/5 (Table 1, entries 1–17).
Similar to the literature reports,7,8 we obtained low b-selectivity
(b/a = 40/60) when R was acetyl or benzoyl, which was rational-
ized by the lack of stabilizing effect of the oxonium ion by the acet-
yl or benzoyl group (Scheme 1). Two oxalic acid derivatives were
prepared as the directing group and the b-selectivities were im-
proved but still moderate (Table 1, entries 3 and 4). The moderate
selectivity may be due to the rigidity of the oxalyl side chains
which could increase conformation restrain when forming the oxo-
nium bridge. Further efforts were made to use more flexible chains
as the directing groups. It was also found that chains containing S
or P atom lead to low yields and low b-selectivities (Table 1, entries
5–8). We also prepared the xanthate analogs9,10 (Table 1, entry 5),
and the b-selectivity was improved remarkably (b/a = 98/2, Table
2, entry 1). It is worth noting that the reaction could be com-
pleted within 2 h.9 To further investigate the scope of this meth-
od, we examined the reactions with different heterocyclic bases
including N4-benzoylcytosine, N6-benzoyladenine, and N2-ben-
zoyl-guanine. All the coupling reactions provided high b-selectiv-
ities and good yields (Table 2).
and the selectivity was modest. When the side chains were
droxy acetyl and -methoxy acetyl (Table 1, entries 9 and 10),
the b-selectivities and yields were improved significantly. Finally,
a-hy-
a
These 30-protected 20-deoxynucleosides were readily hydrolyzed
to give the corresponding nucleosides in excellent yields (5a–d,
Table 2) upon treatment with a 1.0 M NaOH solution (Table 2).
In summary, a facile and efficient method for highly diastereo-
selective preparation of 20-deoxy-b-ribonucleosides has been
developed using the 30-O-(N-acetyl)-glycinate as the protecting
and directing group of the 20-deoxyribofuranose. This method pro-
vides a highly selective and high-yielding glycosylation entry for
the synthesis of 2-deoxy-b-nucleosides and its analogs.
a series of substituted a-amine or a-amide esters as the directing
Table 2
glycosylation reaction with different heterocyclic bases
Base
O
OAc
O
O
BnO
Base(TMS)n
TMSOTf
BnO
O
O
-78ºC, 2h
O
Acknowledgments
N
N
H
H
O
O
This work was supported by Knowledge Innovation Project of
The Chinese Academy of Sciences (grant number: KSCX1-YW-10)
and Guangzhou Science and Technology Plan Item (item number:
2006Z2-E5011).
a
4
5a-5d Yield
Base
O
BnO
1.0M NaOH
HO
b
References and notes
THF/H2O=1/1
1. (a) De Clercq, E. J. Clin. Virol. 2004, 30, 115; (b) Chu, C. K.; Baker, D. C. Nucleosides
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2. (a) Genu-Dellac, C.; Gosselin, G.; Imbach, J. L. Tetrahedron Lett. 1991, 32, 79; (b)
Zhong, Minghong; Ireneusz, N.; Morris, J. R. J. Org. Chem. 2006, 71, 7773; (c)
Ding, Y. Chem. Lett. 2006, 35, 952; (d) Hu, L.; Liu, B.; Hacking, D. R. Bioorg. Med.
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Chem. Lett. 1993, 1187.
4. (a) Javier, G.; Alba, D.; Susana, F.; Vicente, G. J. Org. Chem. 2006, 71, 9765; (b)
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5. Lipshultz, B. H.; Hayakawa, H.; Kato, K. Synthesis 1994, 1476.
6. (a) Hoffer, M. Chem. Ber. 1960, 93, 2777; (b) Seela, F.; Chen, F.; Bindig, U. Helv.
Chim. Acta. 1994, 77, 194.
Yield
Entry
Base
b/
a
Product/
Product/
yielda (%)
yieldb (%)
O
HN
O
1
2
98/2
96/4
5a/82
6a/95
6b/90
N
H
NHBz
7. (a) Bardos, T. J.; Kotick, M. P.; Szantay, C. Tetrahedron Lett. 1966, 16, 1759; (b)
Wendell, W.; Harvey, I. S. Carbohydr. Res. 1981, 90, 41.
N
O
5b/71
8. Kotik, M. P.; Szantay, C.; Bardos, T. J. J. Org. Chem. 1969, 34, 3806.
9. Young, R. J.; Shaw-Ponter, S.; Hardy, G. W.; Mills, G. Tetrahedron Lett. 1994, 35,
8687.
N
H
10. (a) Mukaiyama, T.; Hirano, N.; Nishida, M.; Uchiro, H. Chem. Lett. 1996, 99; (b)
Christine Chapeau, M.; Marnett, Lawrence J. J. Org. Chem. 1993, 58, 7258.
11. Sugimura, H.; Osumi, K.; Kodaka, Y.; Sujino, K. J. Org. Chem. 1994, 59, 7653.
12. (a) Aoyama, H. Bull. Chem. Soc. Jpn. 1987, 60, 2073.
NHBz
N
N
N
3
4
95/5
92/8
5c/83
5d/73
6c/87
6d/90
13. (a) Kawana, M.; Kuzuhara, H. Carbohydr. Res. 1989, 189, 87; (b) Pankeiwicz, K.
W.; Krzeminski, J.; Watanbe, K. A. J. Org. Chem. 1995, 60, 7902; (c) Rao, Avr;
Gurjar, M. K.; Lalitha, S. J. Chem. Soc., Perkin Trans. 1 1994, 2051.
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Vorbruggen, H.; Krolikiewicz, K. Angew. Chem., Int. Engl. 1975, 14, 421.
15. Typical procedure for the preparation of 3k is as follows:Typical procedure for the
preparation of 3k is as follows: (1): Preparation of trimethylsilylated thymine 2
in situ: To a solution of (NH4)2SO4 (6 mg, 0.05 mmol) in 1,2-dichloroethane
(2.0 mL) were added thymine (63 mg, 0.5 mmol) and HMDS (201 mg,
1.25 mmol) under N2 atmosphere, and the mixture was refluxed for 2 h.(2):
N
H
O
N
NH
N
H
N
NHBz
Yielda, see Ref. 15.
Yieldb, isolated yields.
To the solution of trimethylsilylated thymine
2 was added a solution of