Synthesis of 2′-C-methyl-4′-thio ribonucleosides

Article abstract of DOI:10.1081/NCN-200061823

Starting from 2-C-methyl-ribonolactone, 1,2,3,5-tetra-O-acetyl-2-C-methyl- 4-thioribofuranose was synthesized and condensed with heterocyclic bases to afford 2′-C-methyl-4′-thioribonucleosides. Copyright Taylor & Francis, Inc.

Full text of DOI:10.1081/NCN-200061823

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SYNTHESIS OF 2′-C-METHYL-4′-THIO RIBONUCLEOSIDES
a
a
a
b
a
D. Dukhan , E. Bosc , J. Peyronnet , R. Storer & G. Gosselin
a
Laboratoire Coopératif Idenix—CNRS , Universite Montpellier II , Montpellier Cedex 5,
France
b
Laboratoire de Chimie Médicinale Idenix , Parc Euromedecine, rue Louis Pasteur ,
Montpellier, France
Published online: 15 Nov 2011.
To cite this article: D. Dukhan , E. Bosc , J. Peyronnet , R. Storer & G. Gosselin (2005) SYNTHESIS OF 2′-C-METHYL-4′-THIO
RIBONUCLEOSIDES, Nucleosides, Nucleotides and Nucleic Acids, 24:5-7, 577-580, DOI: 10.1081/NCN-200061823
To link to this article: http://dx.doi.org/10.1081/NCN-200061823
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Nucleosides, Nucleotides, and Nucleic Acids, 24 (5–7):577–580, (2005)
Copyright D Taylor & Francis, Inc.
ISSN: 1525-7770 print/ 1532-2335 online
DOI: 10.1081/NCN-200061823
SYNTHESIS OF 2’-C-METHYL-4’-THIO RIBONUCLEOSIDES
5
D. Dukhan, E. Bosc, and J. Peyronnet
Laboratoire Coop eꢀ ratif Idenix- --- CNRS,
Universit eꢀ Montpellier II, Montpellier Cedex 5, France
5
R. Storer
Laboratoire de Chimie M eꢀ dicinale Idenix, Parc Euromedecine, rue Louis
Pasteur, Montpellier, France
5
G. Gosselin
Laboratoire Coop eꢀ ratif Idenix- --- CNRS, Universit eꢀ Montpellier II, Mont-
pellier Cedex 5, France
5
Starting from 2-C-methyl-ribonolactone, 1,2,3,5-tetra-O-acetyl-2-C-methyl-4-thioribofuranose was
synthesized and condensed with heterocyclic bases to afford 2’-C-methyl-4’-thioribonucleosides.
Keywords 4-Thiosugar, 4’-Thionucleosides, 2’-C-Methyl Branched 4’-Thionucleosides
INTRODUCTION
Recently, several 2’-C-methyl branched ribonucleosides, including 2’-C-
methylcytidine 1 (Scheme 1), were discovered to be potent and selective inhibitors
in cell culture of a number of RNA viruses, like bovine viral diarrhea virus
[1–3]
(
BVDV), yellow fever virus (YFV), and West Nile virus (WNV).
As many key
nucleosides in the field of antiviral and antitumor chemotherapies have been
[4–8]
converted into their 4’-thio derivatives,
we decided to combine these two kinds
of modifications by synthesizing 2’-C-methyl-4’-thio-ribonucleosides in order to
assess their biological activity.
CHEMISTRY
[9]
2
-C-Methyl-D-ribonolactone 3 was converted into its 2,3-O-isopropylidene de-
rivative, and then the 5-hydroxyl group was mesylated to give 4 in quantitative
yield. Subsequent treatment of 4 with aqueous potassium hydroxide yielded the
L-lyxonic acid intermediate, and direct acidification of the reaction mixture afforded
Address correspondence to G. Gosselin, Laboratoire Coop eꢀr atif Idenix—CNRS, Universit eꢀ Montpellier II,
Place Eug `e ne Bataillon, Case Courrier 008, 34095 Montpellier Cedex 5, France; Fax: +33-4-6754-9610; E-mail:
gosselin@univ-montp2.fr
577
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578
D. Dukhan et al.
SCHEME 1 Structures of 2’-C-methylcytidine 1 and its 4’-thio counterpart 2.
[10]
the 2-C-methyl-2,3-O-isopropylidene-L-lyxonolactone 5.
Compound 5 was con-
verted in two steps into the 4,5-epoxide derivative 6. Reaction of 6 with thiourea
resulted in the thiirane 7 formation, with inversion of the C-4 configuration.
[12]
Thiolactonization was accomplished by heating 7 with AcONa in acetic acid.
Reduction of the thiolactone with sodium borohydride, followed by acetylation led
to the protected lactol 8. Finally, removal of the isopropylidene, followed by
peracetylation afforded 1,2,3,5-tetra-O-acetyl-2-C-methyl-4-thio-D-ribofuranose 9
(
Scheme 2).
Both the 1-O-acetyl-2,3-isopropylidene 8 and the peracetylated 9 sugars were
used in glycosylation reactions. When 8 was condensed with silylated uracil, an
inseparable mixture of a and b anomers 10 (50/50) of fully protected 2’-C-methyl-
4’-thiouridine was obtained. After removal of the 5’-acetyl and 2’,3’-isopropylidene
groups, 2’-C-methyl-4’-thiouridine 11 and its corresponding a anomer were
separated and isolated.
Using Vorbr u¨ ggen’s methodology, condensation of the 2-C-methyl-4-thio–
peracetylated sugar 9 with N4-benzoylcytosine, followed by removal of the acetyl
groups under basic conditions, led to the single b anomer 2’-C-methyl-4’-thiocytidine
2. A similar route using 9 and the commercially available 6-chloropurine as starting
material afforded 2’-C-methyl-4’-thioadenosine 12 (Scheme 3).
2 4
SCHEME 2 Synthesis of 1,2,3,5-tetra-O-acetyl-2-C-methyl-4-thio-D-ribofuranose 9. (i): a) Acetone, H SO ;
b) MsCl, pyr/CH
2
Cl
2
; (ii) a) KOH, H
2
O b) HCl/H
2
O; (iii) a) TsCl, pyr/CH
, MeOH, b) Ac O, pyr (vii) AcOH/H
2
Cl
2
; b) NaOMe, MeOH; (iv) Thiourea,
MeOH; (v) Ac O, AcONa, AcOH; (vi) a) NaBH
2
4
2
2
O; c) Ac O, pyr.
2

D. Dukhan et al.
579
SCHEME 3 Synthesis of 2’-C-methyl-4’-thio-uridine 11, -cytidine 2, and -adenosine 12. (A) (i) bis(trimethylsilyl)
acetamide, uracil, TMSOTf, CH CN, reflux; (ii) a) TFA/H O, 4/1 v/v; b) CH ONa, CH OH, room temperature (rt).
B) (i) bis(trimethylsilyl)acetamide, N -benzoylcytosine or 6-chloropurine, TMSOTf, CH CN, reflux; (ii) CH ONa,
3
2
3
3
4
(
3
3
3 3 3
CH OH, room temperature (rt); (iii) NH /CH OH, 100°C.
CONCLUSION
We have developed a convenient approach for the synthesis of 1,2,3,5-tetra-O-
acetyl-2-C-methyl-4-thioribofuranose 9, which enabled us to prepare 2’-C-methyl-4’-
thio-ribonucleosides using Vorbr u¨ ggen’s methodology.
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