New pseudonucleosides containing chiral oxazolidin-2-ones and Cyclosulfamides as aglycones: Synthesis and antiviral evaluation

Article abstract of DOI:10.1080/15257770701544492

A series of chiral cyclosulfamides and oxazolidinon-2-ones have been synthesized starting from aminoacids. Regioselective substitution of these pseudopyrimidic heterocyles was carried out under Mitsunobu conditions. Best substitution results were obtained by preliminary deprotection of cyclosulfamides and their condensation with β -D-ribofuranose. Chiral oxazolidin-2-ones were coupled directly with D-ribofuranose. All compounds were tested against HSV-2, VV and SV viruses. Two compounds 6b and 6e showed significant activities against HSV-type 1. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/15257770701544492

Nucleosides, Nucleotides, and Nucleic Acids, 26:1539–1542, 2007
Copyright ꢀ Taylor & Francis Group, LLC
C
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770701544492
NEW PSEUDONUCLEOSIDES CONTAINING CHIRAL
OXAZOLIDIN-2-ONES AND CYCLOSULFAMIDES AS AGLYCONES:
SYNTHESIS AND ANTIVIRAL EVALUATION
Hocine Bouleghlem and Malika Berredjem
Laboratoire de Chimie Organique
2
Applique´e (LCOA), Groupe de Chimie Bioorganique, Faculte´ des Sciences. Universite´
d’Annaba, Annaba, Alge´rie
Marc Lecouvey
7033-CNRS), UFR S.M.B.H. Universite´ Paris 13, Bobigny, France
Laboratoire de Chimie Structurale Biomole´culaire (UMR
2
Nour-Eddine Aouf Laboratoire de Chimie Organique Applique´e (LCOA), Groupe de
2
Chimie Bioorganique, Faculte´ des Sciences. Universite´ d’Annaba, Annaba, Alge´rie
A series of chiral cyclosulfamides and oxazolidinon-2-ones have been synthesized starting from
2
aminoacids. Regioselective substitution of these pseudopyrimidic heterocyles was carried out under
Mitsunobu conditions. Best substitution results were obtained by preliminary deprotection of cyclo-
sulfamides and their condensation with β-D-ribofuranose. Chiral oxazolidin-2-ones were coupled
directly with D-ribofuranose. All compounds were tested against HSV-2, VV and SV viruses. Two
compounds 6b and 6e showed significant activities against HSV-type 1.
Keywords Aminoacids; cyclosulfamides; oxazolidin-2-ones; glycosylation; pseudonucleo-
sides; Mitsunobu reaction
INTRODUCTION
Nucleosides analogues represent interest class of therapeutic agents in
the treatment of cancers and virus infections.[1,2] Most of them, natural
or synthetic have been approved for the treatment of various viral dis-
eases including Herpes Viruses, Human Immunodeficiency Virus (HIV) and
Dedicated to the loving memories of Pr. M. Abdessamad Guellati (1955–2006).
This work is partially supported by: Algerian Ministry of Scientific Research, CNEPRU Project No.
E01120060035, Applied Organic Chemistry Laboratory (FNR 2000), and National Fund of Research.
Fruitful discussions with Ms H. Mesbahi (Faculty of Science) are greatly appreciated.
Address correspondence to Nour-Eddine Aouf, Applied Organic Chemisty Laboratory. Chemistry
Department, Badji Mokhtar University, P.O. Box 12, Annaba, Algeria. E-mail: noureddineaouf@yahoo.fr
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hepatitis B virus infections. In order to discover new nucleotides derivatives
with potent antiviral activity, the modification of heterocyclic aglycone of
natural nucleosides is important for the synthesis of new nucleosides.
In our previous work, we reported the synthesis of new pseudonu-
cleosides containing sulfamylated derivatives of natural amino acids as
aglycone.[3]
CHEMISTRY
The preparation of cyclosulfamides (4a-4e) was performed starting from
N -substituted Gly, Ala, Val, Leu, Phe. Benzoylation of aminoacids, follow-
ing by reduction using LiAlH4, and chlorination with thionyl chloride gave
the 1-substituted N -benzyl 2-chloroethylamine hydrochlorides (substituted
mustards) 3a-3d. Under alkaline conditions the sulfonylation by N -Boc sul-
famoyl chloride (using an excess of triethylamine in dichloromethane),
spontaneously cyclised to give N 5-Boc, N 2-Bn thiadiazolidine 1,1-dioxides
4a-4e.[4] The cyclosulfamides 4a-4e with orthogonal protecting group can
independently be removed under the appropriate conditions. The fusion
method [5] was used for Boc cleavage to give the deprotected chiral cyclosul-
famides 5a-5e in 90–95% yield (Scheme 1).
SCHEME 1 Synthesis of pseudonucleosides containing cyclosulfamide as aglycone (5-deoxy-5-(5-2-
benzyl-3(S)-alkylthiadiazolidinyl)-β-D-ribose.
The regioselective substitution of these pseudopyrimidic heterocycles
was carried out using the Mitsunobu reaction. This reaction has found wide
spread use in many fields because of its high reliability and extensive appli-
cability. In heterocycle structures, the greater nucleophilicity of sulfonyl NH
allowed its selective use by Mitsunobu reaction.[6]

New Pseudonucleosides
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SCHEME 2 Synthesis of pseudonucleosides containing oxazolidin-2-one as aglycone: 5-deoxy-5-((4S)-4
alkyl-2-oxo-1, 3-oxazolidin-3-yl)-β-D-ribose.
The 5ꢁOH substitution of D ribofuranose by the NH of the cyclophos-
phamides using the tandem triphenylphosphine: diisopropylazodicarboxy-
late (DIAD) leaded to the 6a-6e in 35% yield. In the same way, chiral
oxazolidin-2-ones[7] were condensed with a by D-ribofuranose in tetrahy-
drofurane under Mitsunobu conditions. The nucleosides derivatives 2aꢁ-2dꢁ
were obtained in 32% overall yield (Scheme 2).
STRUCTURAL STUDY
The structure of all compounds was unambiguously confirmed by IR,
1H, and 13C NMR, mass spectrometry and element analysis. Cyclosulfamides
3a-3d were characterized by IR spectroscopy based on the presence of char-
acteristic vibration at 1110–1170 cm−1 characteristic sufonyl group and by
intense absorption at 1700–1710 cm−1 characteristic of their carbamate
group. As expected, this latter signal is not present in the spectrum after
1
cleavage. Deprotection was also checked by H NMR based on the disap-
pearance of signal corresponding to the tert-buyl protons. Regiospecific gly-
cosylation in 5ꢁ-postion was confirmed by disappearance of the signal NH
proton and the diastereotopic ribose methylene protons. The β anomeric
configuration of OH in 1ꢁ-position was confirmed by 1H NMR studies: 5.56
ppm (d, Jꢁ1-Jꢁ2 = 7.8 Hz).
The fragmentation in mass spectrometry (FAB) showed the loss of a ben-
zyl group of the pseudonucleosides containing cyclosulfamide.
The condensation (chiral oxazolizolin-2-ones with ribose) was con-
firmed by usual spectroscopic methods. The structural study was completed
by a Cristallographic analysis.
ANTIVIRAL EVALUATION
The antiviral activities of all described pseudonucleosides (6a-6e) and
(2aꢁ-2dꢁ) were tested in vitro against the replication of a number of DNA
viruses (Herpes Simplex Virus type 1 and type 2, Vaccinia virus) and RNA

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H. Bouleghlem et al.
virus (Parainfluenza Virus type III). Except 6a and 6d, none of them showed
an antiviral activity at doses up to 1 mM. The virucide activities of 6a and 6d
only affected only the virions produced by infected cells
CONCLUSION
We described here the synthesis of new pseudonucleosides contain-
ing chiral cyclosulfamides and oxazolidin-2-ones as aglycones. Regiospecific
Mitsunobu reaction was used for the condensation (sugar-modified agly-
cone).The preliminary antiviral results were not encouraging. The antitu-
moral evaluation of the resulting compounds and their incorporation in
biomolecules are currently in progress.
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