Highly stereoselective synthesis of 2′-deoxy-β-ribonucleosides via a 3′-(N-acetyl)-glycyl-directing group

Article abstract of DOI:10.1016/j.tetlet.2009.09.006

A facile synthesis of 2′-deoxy-β-ribonucleosides from 3′-O-(N-acetyl)-glycyl-protected 2′-deoxyribofuranose has been developed. The coupling reactions between the protected 2′-deoxyribose and silylated bases exhibited β-selectivity up to 98% presumably vi

Full text of DOI:10.1016/j.tetlet.2009.09.006

Tetrahedron Letters 51 (2010) 240–243
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Tetrahedron Letters
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Highly stereoselective synthesis of 20-deoxy-b-ribonucleosides
via a 30-(N-acetyl)-glycyl-directing group
Zhaogui Liu a,b, Deyao Li a,b, Biaolin Yin c, Jiancun Zhang a,b,
*
a Guangzhou Institute of Biomedicine and Health, CAS, Guangzhou International Business Incubator B-3, Science Park, Guangzhou 510663, PR China
b State Key Laboratory of Respiratory Diseases, Guangzhou Medical College, Guangzhou 510120, PR China
c School of Chemistry and Chemical Engineering, The South China University of Technology, Guangzhou 510640, PR China
a r t i c l e i n f o
a b s t r a c t
A facile synthesis of 20-deoxy-b-ribonucleosides from 30-O-(N-acetyl)-glycyl-protected 20-deoxyribofura-
nose has been developed. The coupling reactions between the protected 20-deoxyribose and silylated
bases exhibited b-selectivity up to 98% presumably via a 10,30-participation mechanism. The 30-directing
group can be introduced and removed easily under mild conditions. This approach provides an efficient
and highly stereoselective entry for the synthesis of 20-deoxy-ribonucleosides.
Article history:
Received 23 April 2009
Revised 26 August 2009
Accepted 1 September 2009
Available online 4 September 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Sugar–modified nucleoside analogs have been shown to exhibit
potent antiviral and antitumor activities,1 and a number of 20-b-
deoxyribonucleoside therapeutics have been in clinical use or un-
der development such as Decitabine, Cladribine, and FUDR.2
(Scheme 1). Ribonucleosides can be synthesized stereoselectively
from acylated ribose and bases, and b-nucleosides are generally
produced in high selectivity due to the participation of a neighbor-
several selective 20-deoxygenation of ribonucleosides in tedious
steps.12 Therefore, a practical synthetic method for the syntheses
of 20-deoxyribonucleosides with high b-selectivity is of great
significance.
Herein, we report a facile and highly b-selective synthesis of 20-
deoxy-b-ribonucleosides through the coupling reaction of 30-O-(N-
acetyl)-glycyl-protected 20-deoxyribofuranoses with silylated
bases.
ing group such as 20-acyloxy group which shields the
a-face from
being attacked by a nucleobase (the Vorbrüggen Reaction).3 How-
ever, in the case of 20-deoxynucleosides, the Vorbrüggen method
Given the fact that an ester group can be easily introduced and
removed under mild conditions, we envisioned that the introduc-
tion of a substituted ester bearing electron donors in the ester
chain as the directing group at C-30 of the 20-deoxy-ribofuranose
generally results in various ratios of b/a anomeric mixtures, which
are often difficult to separate.4
To increase the b-stereoselectivity, a number of methods have
been reported. Lipshultz’s method used a pyrimidine base linked
to the 50 hydroxyl group of a 20-deoxyriboside to improve the b-fa-
cial selectivity, but this method could only be applied to the pyrim-
idine nucleoside analogs.5 Seela and Robins employed 20-deoxy-
NH2
O
N
NH2
N
N
N
N
O
N
HN
30,50-di-O-(p-toluyl)-
a-D-erylthropentofuranosyl chloride as the
N
O
O
N
Cl
O
key intermediate for the synthesis of 20-deoxy-b-ribonucleosides.6
However, the instability of the chloride intermediate,7 the low
yield of the reaction, and the poor solubility of the heterocyclic
base limited its applications.8 Young9 and Mukaiyama10, respec-
O
HO
HO
OH
HO
OH
HO
Telbivudine
Cladribine
Decitabine
tively, adopted a similar strategy aiming to block the a-side of sug-
ars from base attack by different 30-thiocarbamate-directing
groups. These reactions produced b-anomers with high stereose-
lectivities.11 However, these 30-thiocarbamate-directing groups
were difficult to remove under mild conditions. There were also re-
ports that 20-deoxy-b-ribonucleosides could be synthesized via
O
NH2
N
O
F
HN
NH
O
N
N
O
O
N
O
O
O
HO
HO
OH
F
F
OH
Clevudine
Scheme 1. Varieties of 20-b-deoxynucleosides as drugs.
HO
F
HO
* Corresponding author. Tel.: +86 020 32290337; fax: +86 020 32200337/(20)
32290606.
E-mail addresses: liu_zhaogui@gibh.ac.cn (Z. Liu), zhang_jiancun@gibh.ac.cn
(J. Zhang).
Gemcitabine
FUdR
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.09.006

Z. Liu et al. / Tetrahedron Letters 51 (2010) 240–243
241
Nu
favor
Lewis Acid
OMe
Nu
O
O
O
BnO
BnO
BnO
X
n
O
O
O
Nu
unfavor
X
n
X
n
O
O
O
C
A
B
n=0, 1, 2;
X=atoms or groups containing lone-pair electrons;
Scheme 2. The proposed mechanism of glycosylation via a 10,30-participation.
could stabilize the oxonium intermediate, thus leading to high b-
selectivity through a tentative 10, 30-participation mechanism
(Scheme 2) similar to what was proposed by Mukaiyama.11
Table 1 (continued)
Entry
R
Time
8 h
b/
a
Product/yield (%)
To test this proposal,
a
series of 30-directing group was
O
O
O
screened. 50-O-benzyl-10-O-methyl-ribofuranosides were used as
glycosyl donors (1a–p) (Table 1), which can be prepared through
8
P
71/29
86/14
84/16
92/8
3h/59
3i/78
3j/83
3k/88
O
1h
O
Table 1
The glycosylation reactions of silylated pyrimidine with 20-deoxyriboses
OH
O
9
10
11
8 h
8 h
8 h
1i
O
NH
OTMS
N
OMe
BnO
O
TMSOTf
N
O
O
O
BnO
O
+
1,2-DCE, 0ºC-r.t
O
N
OTMS
O
1j
R
R
3a-3p
1a-1p
Entry
R
Time
b/
a
Product/yield (%)
H
N
O
1
2
3
4
5
6
7
8 h
8 h
8 h
8 h
8 h
8 h
8 h
40/60
40/60
80/20
75/25
82/18
80/20
56/44
3a/72
O
1k
1a
O
O
O
H
N
O
OMe
12
13
14
12 h
87/13
73/27
88/12
3l/80
3b/83
3c/61
3d/54
3e/83
3f/43
3g/63
Ph
O
O
O
1l
1b
H
N
O
O
H
OBn
8 h
3m/41
3n/65
N
1m
O
1c
H
N
NHPh
8 h
N(i-Pr)2
1n
O
S
1d
O
O
S
15
16
17
10 h
8 h
83/17
80/20
95/5
3o/73
3p/65
3k/36
NHPh
1o
1e
1f
H
N
Ph
O
SPh
O
O
1p
O
H
N
72 h, ꢀ78 °C
O
1k
SPh
1g
The ratios of b/a
isomers were determined by 1H NMR of crude reaction mixtures.

242
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
Nucleotides as Antitumor and Antiviral Agents; Plenum Press: New York, 1993.
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.
Chem. Lett. 2000, 10, 797; (e) J-Otto, M. Curr. Opin. Pharmacol. 2004, 4, 431.
3. (a) Jung, M. E.; Castro, C. J. Org. Chem. 1993, 58, 807; (b) Sujino, K.; Sugimura, H.
Chem. Lett. 1993, 1187.
4. (a) Javier, G.; Alba, D.; Susana, F.; Vicente, G. J. Org. Chem. 2006, 71, 9765; (b)
Javier, G.; Susana, F.; Vicente, G. Org. Lett. 2004, 6, 3759; (c) Mor´ıs, F.; Gotor, V.
Tetrahedron 1993, 49, 10089.
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.
14. (a) Efange, S. V. S.; Dutta, AK. Nucleosides Nucleotides 1991, 10, 1451; (b)
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

Z. Liu et al. / Tetrahedron Letters 51 (2010) 240–243
243
glycosyl donor (as a
a
and b mixture) (Table 1, entry 11, 135 mg, 0.4 mmol) in
Na2SO4. The solution was filtered and evaporated under reduced pressure to
give 3k (141 mg, 82% yield) as a colorless oil. The ratio of b/ isomers was
and b
1,2-dichloroethane (2.0 mL) under N2 atmosphere, and the mixture was
refluxed for 1 h. The reaction mixture was cooled to 0 °C for 0.5 h, and then a
solution of TMSOTf (277 mg, 1.25 mmol) 1,2-dichloroethane solution (3.0 mL)
was added slowly at 0 °C. The mixture was stirred at rt for 8 h, and then cooled
to 0 °C, and quenched with saturated NaHCO3 aqueous solution and filtered.
The filtrate was extracted with dichloromethane (5 mL) for three times. The
combined organic layer was washed with brine and dried over anhydrous
a
calculated based on the 1H NMR.Selected data for compound 3k (as a
a
mixture): 1H NMR (400 MHz, CDCl3): d 10.01 and 9.93 (2 br s, 1H), 7.58 and
7.50 (2s, 1H), 7.33–7.29 (m, 5H), 6.49 and 6.31 (2 dd, 1H, J = 5.6, 2.4 and 6.0,
2.0 Hz), 5.48 and 5.35 (2 d, 1H, J = 6.4 Hz), 4.63–4.55 (m, 2H), 4.21–4.05 (m,
2H), 3.96–3.84 (m, 1H), 3.60–3.46 (m, 2H), 2.79–2.74 (m, 1H), 2.26–2.19 (m,
1H), 1.94–1.85 (4s, 6H); ESI-MS m/z (432, M+H+), (454, M+Na+).