Rapid access to 2′-branched-carbocyclic nucleosides and their 4′-epimers from 2-alkyl-cyclopentene-1-ones

Article abstract of DOI:10.1081/NCN-200060271

2-Methyl-2-cyclopentene-1-one was used as starting material in a novel route toward 2′-branched-carbocyclic nucleosides. This methodology was efficiently adapted to the preparation of 4′-epicarbocycles. A series of this new class of molecules was synthesi

Full text of DOI:10.1081/NCN-200060271

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RAPID ACCESS TO 2′-BRANCHED-CARBOCYCLIC
NUCLEOSIDES AND THEIR 4′-EPIMERS FROM 2-ALKYL-
CYCLOPENTENE-1-ONES
J.-C. Meillon a , L. Griffe a , R. Storer b & G. Gosselin a
a Laboratoire Coopératif Idenix—CNRS, Université Montpellier II, Montpellier Cedex 5, France
b Laboratoire de Chimie Médicinale Idenix, Parc Euromedecine, Montpellier, France
Published online: 15 Nov 2011.
To cite this article: J.-C. Meillon , L. Griffe , R. Storer & G. Gosselin (2005) RAPID ACCESS TO 2′-BRANCHED-CARBOCYCLIC
NUCLEOSIDES AND THEIR 4′-EPIMERS FROM 2-ALKYL-CYCLOPENTENE-1-ONES, Nucleosides, Nucleotides and Nucleic Acids,
24:5-7, 695-699, DOI: 10.1081/NCN-200060271
To link to this article: http://dx.doi.org/10.1081/NCN-200060271
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Nucleosides, Nucleotides, and Nucleic Acids, 24 (5–7):695–699, (2005)
Copyright D Taylor & Francis, Inc.
ISSN: 1525-7770 print/ 1532-2335 online
DOI: 10.1081/NCN-200060271
RAPID ACCESS TO 2’-BRANCHED-CARBOCYCLIC NUCLEOSIDES AND
THEIR 4’-EPIMERS FROM 2-ALKYL-CYCLOPENTENE-1-ONES
5
J.-C. Meillon and L. Griffe
Laboratoire Coopeꢀratif Idenix----CNRS, Universiteꢀ
Montpellier II, Montpellier Cedex 5, France
5
R. Storer
Laboratoire de Chimie Meꢀdicinale Idenix, Parc Euromeꢀdecine, Montpellier,
France
5
G. Gosselin
Laboratoire Coopeꢀr a t if Id e nix ----C N RS, Un iv er s i teꢀ Montpellier II,
Montpellier Cedex 5, France
5
2-Methyl-2-cyclopentene-1-one was used as starting material in a novel route toward 2’-branched-
carbocyclic nucleosides. This methodology was efficiently adapted to the preparation of 4’-epi-
carbocycles. A series of this new class of molecules was synthesized as potential antiviral compounds.
Keywords 2’-C-Methyl Branched Nucleosides, Carbocyclic Nucleosides, Cyclopentenones
INTRODUCTION
Modified nucleosides are currently the object of a huge effort in medicinal
chemistry as they remain amongst the most promising molecules for potential
antiviral activity. For instance telbivudine (L-dT), the L enantiomer of natural 2’-
deoxythymidine, is a powerful new drug candidate selective against hepatitis B
virus.[1,2] Furthermore, 2’-C-methyl ribonucleosides were recently shown to possess
very interesting potential for hepatitis C chemotherapy.[3,4] These observations
prompted us to consider the preparation of carbocyclic analogs of 2’-C-branched
ribonucleosides. In general, carbocycles show increased stability in vivo when
compared to nucleosides,[5,6] coupled with biological activity in some examples
Address correspondence to G. Gosselin, Laboratoire Coopeꢀratif Idenix—CNRS, UniversiteꢀMontpellier II,
Place Eug`ene Bataillon, Case Courrier 008, 34095 Montpellier Cedex 5, France; Fax: +33-4-6754-9610; E-mail:
gosselin@univ-montp2.fr
695
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696
J.-C. Meillon et al.
SCHEME 1 Reagents: (a) Lithium diisopropylamide (LDA), benzylbromomethyl ether, THF, À78 to À50°C;
(b) LiAlH4, ether, À78 to À60°C or CeCl3.7 H2O, NaBH4, MeOH, 0°C; (c) 3-chloroperoxybenzoic acid (m-
CPBA), methylene chloride, 0°C; (d) NaH, adenine, DMF, 100°C; (e) palladium hydroxide on charcoal,
cyclohexene, MeOH, reflux.
(e.g., carbovir).[7] Since 2’-branched carbocycles had not been reported when this
*
work was initiated, a need for the design of a new synthetic route giving rapid
access to this class of molecules became obvious.
In this article, we wish to present the shortest synthesis of racemic carbocy-
clic nucleosides reported to date using 2-alkyl-cyclopentenones as versatile
starting materials.
CHEMISTRY
Since both enantiomers of 2’-methyl-branched nucleosides were our initial
targets, the choice of the starting material was oriented toward achiral 5-membered-
rings already bearing a methyl group. The commercially available 2-methyl-
2-cyclopentene-1-one 1 possesses the desired features and was our preferred
starting material.
As they are prone to self-condensation, cyclopentenones are reported as
challenging substrates for a-alkylation reactions.[8,9] Indeed, we encountered some
difficulties in introduction of a hydroxymethyl group on the ketone 1. For instance,
an attempt with gaseous formaldehyde following the procedure of Jernow et al.[10]
gave disappointing results, but, fortunately, 1 could be cleanly alkylated in
acceptable yield using freshly prepared benzylbromomethyl ether[11] (Scheme 1).
Ketone 2 was reduced with LiAlH4 to get an easily separable 2:1 mixture of diols
*
In this poster, numbers are given by analogy with the parent ribonucleosides.

J.-C. Meillon et al.
697
SCHEME 2 Reagents: (a) NaH, 2-amino-6-(methoxyethoxy)-purine, DMF, 120°C; (b) 3N HCl, dioxane, 80°C;
(c) palladium hydroxide on charcoal, cyclohexene, MeOH, reflux.
3a and 3b favoring the trans isomer. The ratio of diols could be dramatically
modified by a simple change of the reducing agent, NaBH4 in presence of CeCl3
giving 3b as the major product in a 3:1 ratio. Both 3a and 3b were epoxidized to
get 4 and 7, which were submitted to the same chemistry: the epoxides were
opened with the sodium salt of adenine, and the carbocycles 5 and 8 were then
deprotected to obtain 2’-methyl-aristeromycin 6 and its 4’-epimer 9 in 5 steps.
SCHEME 3 Reagents: (a) NH3, MeOH, 130°C; (b) N-(chlorocarbonyl)-isocyanate, THF, 0°C; then Et3N, 0°C;
then 14, À40°C; (c) 1N H2SO4, dioxane, 100°C; (d) p-toluenesulfonic acid, 2,2-dimethoxypropane, acetone, RT;
(e) trifluoroacetic anhydride, N-methylpyrrolidine; then p-nitrophenol, MeCN, 0°C; (f) NH3, MeOH, 60°C;
(g) trifluoroacetic acid 90%, 0°C; (h) palladium hydroxide on charcoal, cyclohexene, MeOH, reflux.

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J.-C. Meillon et al.
In a similar fashion, guanosine analogues 11 and 13 were prepared from 4
and 7 respectively using protected guanine.[12] We then focused our attention on
pyrimidine nucleosides. Even though uracil salts were shown to react slowly with
epoxides[13] we found it more advantageous to build the pyrimidine ring starting
from the amine 14. Epoxide 4 was opened with ammonia with perfect regio-and
stereoselective control. Resulting cyclopentylamine 14 was used without
purification in a uracil ring-construction process adapted from previously described
procedures,[14,15] isocyanate 16 being condensed in situ with 14. Compound 17
was then cyclized under acidic conditions to afford carbocycle 18. The latter was
used for the preparation of both cytidine and uridine derivatives 19 and 20.
Compound 19 was synthesized by adaptation of the method of Miah et al.[16]
Again, it was possible to use epoxide 7 in the same route to get the 4’-epimers of 19
and 20 (Schemes 2 and 3).
CONCLUSION
A new synthetic method for the preparation of carbocyclic nucleosides has
been developed from 2-alkyl-cyclopentenones, giving a rapid access to racemic 2’-
branched carbocycles.The versatility of this method allows the preparation of
seldom reported 4’-epi-carbocyclic nucleosides.[17] This method is adaptable to the
synthesis of a large number of potential antiviral targets through the key
intermediates 4 and 7. Furthermore, introduction of various 2’-branching-groups
can be achieved by using the appropriate ketone as a starting material.
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