Synthesis of certain 2′-Deoxy-3′,5′-di-O-benzyl-4′- thio-nucleosides using natural phosphate doped with trifluoromethanesulfonic acid as catalyst

Article abstract of DOI:10.1080/10426500802077671

A series of 2′-deoxy-4′-thionucleosides are synthesized by coupling 1-O-acetyl-2-deoxy-3,5-di-O-benzyl-4-thio-D-erythro-pentufuranose to trimethylsilylated nucleobases using natural phosphate doped with trifluoromethanesulfonic acid as catalyst. The detai

Full text of DOI:10.1080/10426500802077671

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Synthesis of Certain 2′-
Deoxy-3′,5′-di- O -benzyl-4′-
thio-nucleosides Using Natural
Phosphate Doped with
Trifluoromethanesulfonic Acid
as Catalyst
O. Moukha-Chafiq a , J. A. Secrist III a & H. B. Lazrek
b
a Drug Discovery Division , Southern Research
Institute , Birmingham , Alabama , USA
b Unité de Chimie des Biomolécules et Médicinale,
Faculty of Science Semlalia , Marrakech , Morocco
Published online: 19 Dec 2008.
To cite this article: O. Moukha-Chafiq , J. A. Secrist III & H. B. Lazrek (2008)
Synthesis of Certain 2′-Deoxy-3′,5′-di- O -benzyl-4′-thio-nucleosides Using Natural
Phosphate Doped with Trifluoromethanesulfonic Acid as Catalyst, Phosphorus, Sulfur,
and Silicon and the Related Elements, 184:1, 76-81, DOI: 10.1080/10426500802077671
To link to this article: http://dx.doi.org/10.1080/10426500802077671
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Phosphorus, Sulfur, and Silicon, 184:76–81, 2009
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500802077671
Synthesis of Certain 2ꢀ-Deoxy-3ꢀ,5ꢀ-di-O-benzyl-4ꢀ-thio-
nucleosides Using Natural Phosphate Doped with
Trifluoromethanesulfonic Acid as Catalyst
O. Moukha-Chafiq,1 J. A. Secrist III,1 and H. B. Lazrek2
1Drug Discovery Division, Southern Research Institute, Birmingham,
Alabama, USA
2Unite´ de Chimie des Biomole´cules et Me´dicinale, Faculty of Science
Semlalia, Marrakech, Morocco
A series of 2ꢀ-deoxy-4ꢀ-thionucleosides are synthesized by coupling 1-O-acetyl-2-
deoxy-3,5-di-O-benzyl-4-thio-D-erythro-pentufuranose to trimethylsilylated nucle-
obases using natural phosphate doped with trifluoromethanesulfonic acid as cat-
alyst. The detail of this one-pot method and the comparison between the percent-
age of α and β-2ꢀ-deoxy-4ꢀ-thionucleosides with those described previously are also
reported.
Keywords 2ꢀ-Deoxy-3ꢀ,5ꢀ-di-O-benzyl-4ꢀ-thionucleosides; natural phosphate; trifluo-
romethanesulfonic acid
INTRODUCTION
Recently, the use of solid acids such as clays, zeolites, and ion-exchange
resins has achieved importance in organic chemistry.1 Heterogeneous
solid acids are advantageous over conventional homogeneous acid cata-
lysts because they can be easily recovered from the reaction mixture by
filtration and can be reused after activation or without activation, thus
making the processes economically viable.2 Of the many possible het-
erogeneous catalysts, natural phosphate (NP)3 is especially attractive
because of its low cost, reusability, flexibility in acid strength, ease of
Received 3 January 2008; accepted 11 February 2008.
This investigation was supported by University Cadi Ayyad Marrakesh, Morocco;
CNRST (Rabat Morocco); and by National Institute of Health (P01-CA34200). H.B.L.
thanks all colleagues in the Drug Discovery Division (SRI) for their help. The authors
are indebted to Dr. James M. Riordan, Mr. Mark Richardson, Ms. J. Truss, and Ms. Joan
Bearden for spectral data and MS.
Address correspondence to Jack Secrist III, Drug Discovery Division, Southern Re-
search Institute, P.O. Box 55305, Birmingham, AL 35255-5305, USA. E-mail: secrist@
sri.org
76

Synthesis of Certain 2ꢀ-Deoxy-3ꢀ,5ꢀ-di-O-benzyl-4ꢀ-thio-nucleosides
77
handling, environmental compatibility, non-toxicity, and experimental
simplicity.4
4ꢀ-Thionucleoside analogs, in which the furanose ring oxygen is re-
placed by a sulfur atom, increasingly have become of interest ow-
ing to their demonstrated resistance toward phosphorolytic cleavage
and their broad range of biological activity.5 Since the first report
by Reist et al.,6 the synthesis of 4ꢀ-thionucleosides has mostly been
carried out using the Vorbruggen-type condensation between an ap-
propriate 4-thiopentofuranose and a silylated nucleobase.7 Groups
have reported the synthesis of 2ꢀ-deoxy-4ꢀ-thioribonucleosides from
the corresponding 4ꢀ-thioribonucleosides. For instance, Haraguchi
et al.8 have recently reported the stereoselective synthesis of 2ꢀ-
deoxy-4ꢀ-thioribonucleosides based on electropholic glycosidation of
4- thiofuranoid glycols. Moreover, Inouie et al.9 developed a practi-
cal synthesis of 2ꢀ-deoxy-4ꢀ-thioribonucleosides using a radical reac-
tion of the corresponding 2ꢀ-alpha- bromo derivatives. Although the
Pummerer-type thioglycosidation10 is also available as an alterna-
tive, a serious drawback commonly seen in these methods is the
lack of the desired β–stereoselectivity. For example, in the synthe-
sis of 2ꢀ-deoxy-4ꢀ-thionucleosides, the α-anomer was obtained as the
major product in many cases. Surprisingly, even in the synthesis of
4ꢀ-thioribonucleosides, where neighboring group participation by the
2-O-acyl group can be expected, the β-anomer is formed only in a slight
excess. This stereochemical outcome limits the accessibility to a vari-
ety of 4ꢀ-thionucleosides that are necessary for the efficient study of
structure–activity relationship in medicinal chemistry.11
Vorbruggen et al.12 described a one-pot nucleoside synthesis com-
bining three steps in one: (a) silylation of the hetrocyclic base, (b)
silylation of the triflate or nonaflate salts to form trimethylsilyl triflate
(TMSOTf), and (c) nucleoside synthesis with 1-O-acyl in the presence
of a Friedel–Crafts catalyst. Reagents used to perform this reaction
are mixture of trimethylsilyl chloride (TMSCl), hexamethyldisilazane
(HMDS), and trifluoromethane sulfonic acid (TfOH) in an effort to
produce TMSOTf in situ.
With all these considerations in mind, we have recently reported
a new one-pot reaction using the inexpensive NP doped with potas-
sium iodide or iodine as a catalyst instead of TMSOTf, TMSClO4,
or iodotrimethylsilane to perform the glycosylation reaction. We
showed that the β-ribonucleoside was obtained as a major isomer
and in good yield.11 These results led us to extend this new short
and efficient method to the synthesis of a number of 2ꢀ-deoxy-4ꢀ-
thionucleosides (Scheme 1) using a moisture-insensitive catalyst sys-
tem (HMDS/NP/CF3SO3H) instead of TMSOTf.

78
O. Moukha-Chafiq et al.
SCHEME 1
EXPERIMENTAL
Natural Phosphate Characteristics and Preparation
of the Catalyst
NP comes from an ore extracted in the region of Khouribga, Morocco (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 1m2 g−1
(nitrogen adsorption), and the total pore volume was 0.005 cm3 g−1
.
Preparation of the Catalyst
To 3g of NP in 10 mL of CH2Cl2 was added 1 mL of CF3SO3H. The
flask was stopped tightly, and the mixture was stirred for 10 min, and
then evaporated to dryness.
Typical Procedure: Preparation of the Nucleoside
A suspension of the nucleobase (1 mmol) in hexamethyldisilazane
(4 mL) and ammonium sulfate (catalytic amount) was heated at reflux
until a clear solution was obtained. To this solution was added a solution
of the sugar (0.9 mmol) in acetonitrile (5 mL), NP/CF3SO3H (500 mg),
and the mixture was heated (80◦C) overnight. The resulting suspension
was filtered, and the precipitate was washed with dichloromethane.
The filtrate was evaporated, and the residue was purified by column
chromatography.

Synthesis of Certain 2ꢀ-Deoxy-3ꢀ,5ꢀ-di-O-benzyl-4ꢀ-thio-nucleosides
79
TABLE I Synthesis of 2ꢀ-Deoxy-3ꢀ,5ꢀdi-O-benzyl-4ꢀ-thio-α/β-
D-thionucleosides
Nucleobase
(1 mmol)
Sugar 1
(0.9 eq)
Entry
NP/CF3SO3H mg/mg
Yield∗
%
α:β
1
2
3
4
5
6
7
8
Uracil
Uracil
Uracil
354 mg
354 mg
354 mg
354 mg
354 mg
354 mg
354 mg
354 mg
0/150
350/0
<5
<10
53
35
56
50
44
44
–
50/50
55/45
66/34
50/50
50/50
50/50
50/50
350/150
350/150
350/150
350/150
350/150
350/150
Thymine
Acetyl cytosine
Adenine
Acetyl guanine
5-Azacytosine
∗The yield was calculated after purification on chromatography column.
RESULTS AND DISCUSSION
To this end, we have first synthesized the 1-O-acetyl-2-deoxy-3,5-di-
O-benzyl-4-thio-D-erythro-pentufuranose (1) following the same proce-
dure reported by Walker.13 Then, to assess the influence of NP doped
with different catalysts on the coupling reaction to find the most ef-
fective conditions, several experiments were carried out. From these
studies, it was noted that the desired 2ꢀ-deoxy-4ꢀ-thionucleosides were
obtained in modest yields by using NP and trifluoromethansulfonic as
catalyst at 80◦C in acetonitrile overnight.
As depicted in Table I, when either NP and CF3SO3H were used
alone, the coupling reaction of 4-thiosugar 1 to bis-(trimethylsilyl)uracil
gave the 2ꢀ-deoxy-4ꢀ-thionucleoside mixtures in less than 5% and 10%
yields, respectively. As can be seen in the subsequent examples, the
yield increased significantly when NP doped with CF3SO3H was used.
We have also noted that the percentages of α- and β-anomers are
mostly the same. This result represents a significant improvement
in the production of the β-anomer previously reported procedures in
which the α-anomers are major products (α:β ratio changes from 9:1 to
∼2.8:1).10b,15−18
This finding encouraged us to examine the use of other “inexpen-
sive” catalysts in order to improve the yield of these coupling reactions.
Thus, when potassium iodide was used instead of trifluoromethanesul-
fonic acid, the yield was dramatically decreased with a slight excess of
α-anomers. Also, we did not observe any improvements in the results
by using tin (IV) chloride, titanium chloride, or trifluoroacetic acid.
1
All 2ꢀ-deoxy-4ꢀ-thionucleosides were characterized by H NMR and
by comparison with literature data.15−18

80
O. Moukha-Chafiq et al.
CONCLUSION
We have developed a practical and novel natural phosphate-catalyzed
glycosylation reaction. We showed that NP doped with trifluo-
romethanesulfonic acid is a mild and inexpensive catalyst for the
preparation of 2ꢀ-deoxy-3ꢀ,5ꢀdi-O-benzyl-4ꢀ-thio- α/β-D-thionucleosides
with modest stereoselectivity towards β-isomer. The advantages of this
method are the easy workup and applicability in synthetic nucleosides
chemistry.
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