A procedure for facile synthesis of nucleosides using N, O-Bistrimethyl- silylacetamide in the presence of natural phosphate coated with potassium iodide

Article abstract of DOI:10.2174/157017810791112441

Several α-D/L-arabino and β-D/L- xylonucleosides were synthesized in good yields under mild conditions by N-glycosylation of 1-O-acetyl D/L- arabino, and xylofuranose, with silylated nucleobases (uracil, thymine and 6- azauracil) in acetonitrile using natural phosphate (NP) coated with potassium iodide in BSA as catalyst.

Full text of DOI:10.2174/157017810791112441

196
Letters in Organic Chemistry, 2010, 7, 196-199
A Procedure for Facile Synthesis of Nucleosides Using N, O-Bistrimethyl-
silylacetamide in the Presence of Natural Phosphate Coated with
Potassium Iodide
Laila Baddia, Michael Smietanac, Saïd Sebtib, Jean-Jacques Vasseurc and Hassan B. Lazrek*,a
aUnité de Chimie Biomléculaire et Médicinale, Faculté des Sciences Semlalia, Université cadi-Ayyad, 40000
Marrakesh, Morocco
bLaboratoire de chimie Organique Catalyse et Environnement, Faculté des Sciences Ben M’Sik, 20702 Casablanca,
Morocco
cInstitut des Biomolécules Max Mousseron, UMR 5247 CNRS-UMI-UM II, Université de Montpellier II, CC008, Place
E. Bataillon 34095 Montpellier Cedex 5, France
Received September 12, 2009: Revised December 31, 2009: Accepted January 12, 2010
Abstract: Several ꢀ-D/L-arabino and ꢁ-D/L- xylonucleosides were synthesized in good yields under mild conditions by
N-glycosylation of 1-O-acetyl D/L- arabino, and xylofuranose, with silylated nucleobases (uracil, thymine and 6-
azauracil) in acetonitrile using natural phosphate (NP) coated with potassium iodide in BSA as catalyst.
Keywords: N-Glycosylation, D/L nucleosides, natural phosphate, catalyst.
The synthesis and the biological evaluation of nucleoside
analogs with the natural D and unnatural L configuration
have been subjects of some interest, but until recently, the
activities of most nucleosides were associated only with the
D isomers. [1].
chemical transformations [6]. These types of catalysts
represent an important environmentally friendly alternative
to toxic and expensive reagents otherwise required for the
reactions [7].
Recently, we have reported that the reaction of 2, 4-
bis(trimethylsilyloxy)uracil with acetyl-2,3,5-tri-O-benzoyl-
ꢁ-D-ribofuranose in the presence of NP/KI[8] or NP/I2 [9]
selectively gives ꢀ/ꢁ protected uridine in a fair yields. Here
we describe our synthetic efforts to develop a new set of
reaction conditions, using bis- trimethylsilylacetamide
(BSA) and natural phosphate coated with potassium iodide
(NP/KI), under which acetyl-2,3,5-tri-O-benzoyl- D or L-
pentofuranose (Arabinose and Xylose) reacts directly with
persilylated nucleobase (uracil, thymine and 6-azauracil) ,
yielding efficiently in one–pot to the desired nucleosides
(Scheme 1).
Traditional methods of nucleoside analogue synthesis
involve either
a
glycosylation reaction between
a
nitrogenous aromatic base and an activated sugar
intermediate or a derivatization of a preformed nucleoside.
The glycosylation reaction is the most commonly used
approach for the synthesisof nucleosides and has been
applied to the synthesis of diverse nucleosides [2].
Vorbruggen et al. introduced the use of Friedel-Crafts
catalysts to promote the glycosylation reaction [3]. The
typical Vorbruggen reaction requires persilylation of the
nucleobase and then reaction with trimethylsilyl triflate
activated sugar to form the desired acyl protected nucleoside.
The regioselective glycosylation driven by a thermodynamic
equilibrium between the hydrogens of the bases makes this
method particularly attractive [4]. Whereas, the Vorbruggen
[5] reactions frequently conducted as a two-step operation,
our approach was to combine the two steps into a one-pot
reaction with solid phase catalysts. The reactions mediated
by solid phase catalysts are of growing interest because they
offer advantages such as ease of setup, mild conditions, rapid
reactions, increased selectivity and yields of the products,
and low cost. In an effort to develop new practical and
economic catalysts, we and others recently investigated the
use of natural phosphate (NP) alone or doped in various
OBz
OBz
O
AcO
OBz
OBz
O
OBz
BH
B
OBz
Scheme 1. Conditions: BSA/NP/KI/CH3CN, BH= Uracil, Thymine,
6-Azauracil.
The first, set of experiments was carried out using uracil
and acetyl 2,3,5-tri-O-benzoyl-L-arabinofuranose as a model
to evaluate different catalyst and optimize the catalytic
systems (Table 1). Preliminary reactions were carried out in
acetonitrile at 80°C with BSA (1ml, excess) and NP/KI
(0.8eq of KI) as catalyst. We observed that when the amount
of protected L-arabinose was increased from 0.25 eq to 0.75
eq, the yield of nucleoside also improved (Table 1,
*Address correspondence to this author at the Unité de Chimie
Biomléculaire et Médicinale, Faculté des Sciences Semlalia, Université
cadi-Ayyad, 40000 Marrakesh, Morocco; Tel/Fax: 00-212- 524-437408;
Email: hblazrek50@gmail.com
1570-1786/10 $55.00+.00
© 2010 Bentham Science Publishers Ltd.

A Procedure for Facile Synthesis of Nucleosides Using N
Letters in Organic Chemistry, 2010, Vol. 7, No. 3
197
Table 1. Optimisation of N- Glycosylation between Uracil and L-Protected Arabinose
Entry
Sugar
Catalyst
Yield (%)
1
2
3
4
5
4
5
6
7
0.25 eq
0.5eq
NP/KI
43
50
80
45
5
NP/KI
0.75 eq
1eq
NP/KI
NP/KI
0.75 eq
0.75 eq
0.75 eq
0.75 eq
0.75 eq
NP
Al2O3/KI
30
18
12
40
SiO2/KI
C/KI
Montmorillonite K10/KI
Conditions: Uracil(1mmol), BSA, CH3CN, L-protected arabinose, catalyst(0,8eq), reflux 3h.
Table 2. NP/KI/BSA Catalyzed N-Glycosylation of Nucleobases with Protected D/L-Pentofuranose
Sugar
Sugar
Entry
Compounds
Yield
Entry
Compounds
Yield
0.75 eq
0.75 eq
O
BzO
OBz
O
NH
O
N
O
N
1
D-arabinose
D-arabinose
D-arabinose
L-arabinose
74%
7
D-xylose
D-xylose
D-xylose
L-xylose
72%
OBz
OBz
BzO
O
NH
1
O
7
OBz
O
BzO
OBz
O
NH
O
N
O
O
N
2
3
4
64%
60%
80%
8
73%
56%
55%
OBz
OBz
BzO
O
NH
2
8
OBz
O
BzO
OBz
O
NH
N
N
O
O
O
N
9
OBz
N
OBz
BzO
O
NH
3
9
OBz
O
N
OBz
OBz
O
HN
O
O
N
O
10
OBz
OBz
OBz
O
HN
4
10
OBz

198 Letters in Organic Chemistry, 2010, Vol. 7, No. 3
Baddi et al.
(Table 2). Contd…..
Sugar
Sugar
Entry
Compounds
Yield
Entry
Compounds
Yield
0.75 eq
0.75 eq
O
OBz
OBz
O
HN
O
N
O
N
5
L-arabinose
60%
11
L-xylose
57%
OBz
OBz
OBz
O
HN
5
O
11
OBz
O
N
OBz
OBz
O
HN
N
N
O
O
O
6
L-arabinose
60%
12
L-xylose
56%
OBz
N
OBz
OBz
O
HN
6
12
OBz
Conditions: Nucleobase(1mmol), BSA, CH3CN, D/L-protected arabinose and xylose, catalyst(0,8eq), reflux 3h.
entries 1-3). Experiments carried out with other
heterogeneous media impregnated with potassium iodide
such as Al2O3/KI, SiO2/KI, activated charcoal (Norit) C/KI
and Montmorillonite K10/KI revealed that these catalysts, in
general gave lower yields of the nucleosides (Table 1, entries
4-6).
The mechanism of the above N-glycosylation could be
depicted as follows (Fig. 1): Uracil reacts with BSA to give
silylated uracil and the excess of BSA may react with NP/KI
to give (CH3)3Si-I. The later will react with the O-acetyl
2,3,5-tri-O-benzoyl-ꢀ-D-Xylofuranose to afford 1-iodo-
2,3,5-tri-O-benzoyl-ꢀ-D-Xylofuranose A [11]. Then, the
silylated base will react with the compound A to produce the
target ꢀ xylonucleoside B [12].
In order to extend the scope of the present reaction,
several N-glycosylation reactions were performed and the
results are shown in Table 2. In every case, the desired ꢀ or ꢁ
nucleosides were obtained in good yields. Such combination
of high yield and stereoselectivity (ꢁ for D/L-
Arabinonucleosides and ꢀfor D/L-Xylonucleosides) has not
been reported in the N-glycosylation utilizing NP/KI as
catalyst.
CONCLUSION
In summary, we have described an efficient one–pot N-
glycosylation using BSA and NP/KI. This method could be a
nice addition to the existing processes in the nucleoside
synthesis because of its mild reaction condition, simple
work-up procedure, high yields and cheap catalyst.
All of nucleosides Fig. (1) are in agreement with
previously published analysis [10].
O
OTMS
BzO
OBz
NH
O
BSA
N
OAc
CH3CN reflux
OBz
BzO
N
O
H
TMSO
N
O
H
OBz
NP/KI
I
OBz
A
O
NH
BzO
OBz
N
O
+
O
NP/KI
OBz
B
Fig. (1). Possible mechanism of the formation of ꢀ xylofurano-nucleoside.

A Procedure for Facile Synthesis of Nucleosides Using N
Letters in Organic Chemistry, 2010, Vol. 7, No. 3
199
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Natural phosphate (NP) comes from an ore extracted in the region
of Khouribga (it is available in raw form or treated form from
CERPHOS Casablanca, Morocco). Prior to use this material
requires initial treatments such as crushing and washing. For use in
organic synthesis, the NP is treated by techniques involving
attrition, sifting, calcinations (900°C), washing and recalcination.
These treatments lead to a fraction between 100 and 400 lm, which
is rich in phosphate. The structure of NP is similar to that of
fluorapatite [Ca10(PO4)6F2], as shown by X-ray diffraction and
chemical analysis. The surface area of NP was measured at ꢀm2 g-
1 (nitrogen adsorption) and the total pore volume was 0.005 cm3 g-
1.
EXPERIMENTAL SECTION
General Remarks
The NMR spectra were recorded on a Bruker AC 300
MHz spectrometer. Chemical shifts were reported in scale
(ppm) relative to TMS as a standard and the coupling
constants J values are given in Hz. EI mass spectra were
recorded on a Varian MAT 311A spectrometer. TLC was
performed on 60 F254 precoated plastic plates silica gel
(Merck). Column chromatography was performed on silica
gel (Baker, 30-60 ꢀm). All solvents were distilled and dried
before using.
General Experimental Procedure
[7]
A suspension of uracil (112 mg, 0.892 mmol) in
bistrimethylsilylacetamide (BSA) (1 ml), ammonium sulfate
(catalytic amount, 5 mg), and acetonitrile (2.5 ml) was
heated at reflux until a clear solution was obtained (30min).
To this solution was added acetyl 2,3,5-tri-O-benzoyl-L-
Arabinofuranose (0.669 mmol, 0.75eq) and NP/KI (422 mg,
0.8 eq of KI) and the mixture was heated (80°C) for 3h. The
resulting suspension was filtered and the precipitate was
washed with dichloromethane. The filtrate was evaporated
and the residue was purified by column chromatography
(CH2Cl2/MeOH, 98/2) to give the desired nucleoside with
80% yield.
[8]
[9]
Lazrek, H.B.; Rochdi, A.; Redwane, N.; D. Ouzebla, D.; Vasseur
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A one-pot synthesis of D-ribonucleosides using natural
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ACKNOWLEDGEMENTS
This project was supported by the Comite Mixte
Interuniversitaire
Franco-Marocain
Programme
(AI.
MA/06/1430). The authors are indebted to Dr. S. Ananthan
Southern Research Institute in Birmingham, Alabama, USA,
for his helpful discussion and reading the manuscript.
[10]
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