Revisited 3′-deoxy-3′-C-methyl-β-D-ribonucleoside series

Article abstract of DOI:10.1080/15257770701521730

The synthesis of some 3′-deoxy-3′-C-methylnucleoside analogues bearing naturally occuring nucleic acid bases was achieved from the preparation of a suitable peracylated 3-deoxy-3-C-methyl sugar using a stereoselective pathway. In addition, examples of chemical modifications at the 2′ position are presented. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/15257770701521730

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Revisited 3′-Deoxy-3′-C-Methyl-β-D-
Ribonucleoside Series
Mohamed Aljarah a , Sarah Couturier a , Gilles Gosselin a ,
Christophe Mathé a & Christian Périgaud a
a UMR 5625 CNRS-UM II, Université Montpellier II, Montpellier, France
Published online: 10 Dec 2007.
To cite this article: Mohamed Aljarah , Sarah Couturier , Gilles Gosselin , Christophe Math & Christian
Prigaud (2007) Revisited 3′-Deoxy-3′-C-Methyl-β-D-Ribonucleoside Series, Nucleosides, Nucleotides
and Nucleic Acids, 26:8-9, 1125-1128, DOI: 10.1080/15257770701521730
To link to this article: http://dx.doi.org/10.1080/15257770701521730
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Nucleosides, Nucleotides, and Nucleic Acids, 26:1125–1128, 2007
Copyright ꢀ Taylor & Francis Group, LLC
C
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770701521730
REVISITED 3ꢀ-DEOXY-3ꢀ-C-METHYL-β-D-RIBONUCLEOSIDE SERIES
Mohamed Aljarah, Sarah Couturier, Gilles Gosselin, Christophe Mathe´,
and Christian Pe´rigaud
UMR 5625 CNRS-UM II, Universite´ Montpellier II,
2
Montpellier, France
The synthesis of some 3ꢁ-deoxy-3ꢁ-C-methylnucleoside analogues bearing naturally occuring nu-
2
cleic acid bases was achieved from the preparation of a suitable peracylated 3-deoxy-3-C-methyl sugar
using a stereoselective pathway. In addition, examples of chemical modifications at the 2ꢁ position
are presented.
Keywords Nucleoside; stereoselective synthesis; glycosylation
INTRODUCTION
Nucleoside analogues represent an important class of chemotherapeu-
tic agents.[1] Nowadays, several nucleoside analogues have been approved
for the treatment of various viral infections such as herpes viruses, human
immunodeficiency virus (HIV) and hepatitis B virus. In order to discover
new series of nucleoside analogue able to interfere with cellular and viral
proliferation, different chemical modifications of both the base and/or the
sugar moiety of natural nucleosides may be attempted. In the course of our
ongoing research, we have synthetized hitherto unknown 3ꢁ-C-branched nu-
cleoside analogues from a sugar precursor incorporating a methyl group on
the 3ꢁ position.
SYNTHESIS OF THE SUGAR PRECURSOR
The preparation of the osidic precursor required introduction of a
methyl group on the position 3 of the sugar moiety. In the first synthetic
pathway, this introduction involved reduction of an exocyclic methylene
This work was supported by the European Community (Flavitherapeutics European Contract Num-
ber QLK3-CT-2001-00506). S.C. and M.A. are particularly grateful to the Ministe`re de l’Education
Nationale, de la Recherche et de la Technologie (France) for a doctoral fellowship.
Address correspondence to Christian Pe´rigaud, UMR 5625 CNRS-UM II, Case courrier 008,
Place E. Bataillon, Universite´ Montpellier II, 34095 Montpellier cedex 5, France. E-mail: perigaud@
univ-montp2.fr
1125

1126
M. Aljarah et al.
SCHEME 1
group previously obtained by a Wittig reaction on the keto sugar 4
(Scheme 1). Hydrogenation of the resulting exocyclic double bound in the
presence of Pd/C was not as stereoselective as expected[2,3] and leads to the
formation of two diastereoisomers 6 and 7 with a low diastereoselectivity for
the desired isomer 6.
The influence of pressure, temperature, nature of the solvent and the
catalyst on the stereoselectivity of the hydrogenation reaction have been
investigated. Whatever the conditions used, the two diastereoisomers have
been obtained with a ratio up to 80:20 in favour of the desired compound 6.
Many attempts to separate these two diastereoisomers have been performed
including crystallization, chromatography on silica gel, and reverse phases,
without any success. In a second pathway, the methyl group has been intro-
duced in position 3 by addition of methylmagnesium bromide on the ke-
tosugar 4. This reaction leads only to compound 8,[4] which gives through
radical deoxygenation the diastereoisomer 6 in a stereospecific way. Finally,

3ꢁ-Deoxy-3ꢁ-C-Methyl-β-D-Ribonucleoside
1127
the positions 1 and 2 have been deprotected then acetylated leading to the
expected sugar precursor 9.
SYNTHESIS OF THE NUCLEOSIDE ANALOGUES
The sugar precursor 9 was glycosylated (Scheme 2) with different
heterocyclic bases persilylated with N,O-bis(trimethylsilyl)acetamide
(BSA) according to the Vorbru¨ggen procedure (uracil and
thymine for pyrimidines,[5] N-6-benzoyladenine,[6] and N-2-acetyl-6-O-
diphenylcarbamoyl-guanine[7] for purines).
Cleavage of the different protecting groups of compounds 10–13
give target ribonucleosides 14, 15, 20, and 21. Compounds 16–19 were
obtained after regioselective deacylation and radical reductive process
which upon deprotection provided the corresponding 3ꢁ-C-methyl-2ꢁ,3ꢁ-
dideoxynucleosides 22–25. Conversion of uridine derivatives 12 and 18 to
the cytidine derivatives 26 and 27 was done by conversion of the lactame
function to thioamid followed by aminolysis.[8]
SCHEME 2

1128
M. Aljarah et al.
BIOLOGICAL EVALUATION
Evaluation of the antiviral and antitumoral activities of the 3ꢁ-deoxy-3ꢁ-C-
methyl-nucleosides 14, 15, 20, 21 as well as the 3ꢁ-C-methyl-2ꢁ,3ꢁ-dideoxynu-
cleosides 22–25 is under investigation.
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1. De Clercq, E. Antiviral drugs in current clinical use. J. Clin. Virol. 2004, 30, 115–133.
2. Rosowsky, A.; Lazarus, H.; Yamashita, A. Nucleosides. 12. 9-(3ꢁ-alkyl3ꢁ-deoxy-β-D-ribofuranosyl)
adenines as lipophilic analogues of cordycepin. Synthesis and preliminary biological studies. J. Med.
Chem. 1976, 19, 1265–70.
3. Nair, V.; Mickle, T.; Bera, S. Cyclopropyl and related analogs of the anti-HIV compound iso-
dideoxyadenosine. Nucleosides, Nucleotides Nucleic Acids 2003, 22, 239–247.
4. Nut, R.F.; Dickinson, M.J.; Holly, F.W.; Walton, E. Branched-chain sugar nucleosides. III. 3ꢁ-C-
Methyladenosine. J. Org. Chem. 1968, 33, 1789–1795.
5. Vorbru¨ggen, H.; Bennua, B. Nucleoside syntheses. XXV. A new simplified nucleoside synthesis. Chem.
Ber. 1981 114, 1279–1286.
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unsaturated nucleosides and L-3ꢁ-C-cyano-3ꢁ-deoxyribonucleosides. Tetrahedron 2003, 59, 6423–6431.
7. Robins, M.J.; Zou, R.; Guo, Z.; Wnuk, S.F. Nucleic acid related compounds. 93. A solution for
the historic problem of regioselective sugar-base coupling to produce 9-glycosylguanines or 7-
glycosylguanines. J. Org. Chem. 1996, 61, 9207–9212.
8. Cava, M.P.; Levinson, M.I. Thionation reactions of Lawesson’s reagents. Tetrahedron 1985, 41, 5061–
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