Alkyne-azide click chemistry mediated carbanucleosides synthesis

Article abstract of DOI:10.1080/15257770701534139

Hitherto unknown 1,4-disubstituted-[1,2,3]-triazolo-4′,4′- dihydroxymethyl-3′-deoxy carbanucleosides were synthesized based on a "click approach." Various alkynes were introduced on a key azido intermediate by the "click" 1,3-dipolar Huisgen cycloaddition

Full text of DOI:10.1080/15257770701534139

Nucleosides, Nucleotides, and Nucleic Acids, 26:1391–1394, 2007
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770701534139
ALKYNE-AZIDE CLICK CHEMISTRY MEDIATED
CARBANUCLEOSIDES SYNTHESIS
Julie Broggi, Nicolas Joubert, Vincent Aucagne, and Sabine Berteina-Raboin
2
Institut de Chimie Organique et Analytique, UMR 6005, Universit e´ d’Orl e´ ans,
Orl e´ ans, France
S. Diez-Gonzalez and Steve Nolan
2
Institute of Chemical Research of Catalonia,
Tarragona, Spain
Dimitri Topalis and Dominique Deville-Bonne
2
Laboratory Enzymology and
Molecular Fonct.–FRE CNRS 2852–University Pierre & Marie Curie, Pairs, France
Jan Balzarini, Johan Neyts, Graciela Andrei, and Robert Snoeck
2
Department of Microbiology & Immunology, Rega Institute for Medicinal Research,
Leuven, Belgium
Luigi A. Agrofoglio
2
Institut de Chimie Organique et Analytique, UMR 6005,
Universit e´ d’Orl e´ ans, Orl e´ ans, France
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Hitherto unknown 1,4-disubstituted-[1,2,3]-triazolo-4 ,4 -dihydroxymethyl-3 -deoxy carba-
nucleosides were synthesized based on a “click approach.” Various alkynes were introduced on a key
azido intermediate by the “click” 1,3-dipolar Huisgen cycloaddition. Their antiviral activities and
cellular toxicities were evaluated on vaccinia virus. None of the synthesized compounds exhibited a
significant antiviral activity.
Keywords Click chemistry; Huisgen cycloaddition; carbanucleosides; alkyne-azide
INTRODUCTION
The recent emergence of life threatening viral diseases such as AIDS,
hepatitis, herpes, smallpox, and so on, has been a living force for the de-
[1]
velopment of small nucleoside libraries. Particularly, analogues of nucle-
osides structurally related to ribavirin have focused much interest as potent
inhibitors of the inosine monophosphate dehydrogenase (IMPDH), which
These studies were supported in part by a grant from Sanofi-Aventis France and Bayer Pharma as
part of a multi-organism call for proposals and in part by an “ANR-05-BLAN-0368-03.”
Address correspondence to Luigi Agrofoglio, Institut de Chimie Organique et Analytique, UMR
6
005, Universit e´ d’Orl e´ ans, Orleans, France. E-mail: luigi.agrofoglio@univ-orleans.fr
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J. Broggi et al.
SCHEME 1
is a requirement for cell replication as this enzyme is involved in de novo
guanine synthesis.[ Thus, as part of our drug discovery group, we demon-
strate herein the efficient microwave assisted synthesis of hitherto unknown
2]
1,2,3-triazolo-carbocyclic nucleosides, an important pharmaceutical class,
through a unique “click” approach. Indeed, the Cu(I)-catalyzed alkyne-azide
[
3–5]
1
,3-dipolar cycloaddition, Huisgen reaction,
recently has emerged as a
powerful and selective reaction to form heteroatom links, and to leads to
[6]
1
,4-disubstituted-1,2,3-triazolo analogues. This transformation has been
described as “click chemistry” as it affords products insensitive to oxygen
and water, in high yields, and without any purification.
RESULTS AND DISCUSSION
The synthetic strategy of the present study is depicted in Scheme 1. The
cyclopent-3-ene diester 1 was obtained from a malonic synthesis starting
with the commercially available methyl malonate and the cis-1,4-dichloro-
2
-butene. After reduction of the diester 1, the diol 2 was acetylated, and the
resulting product 3 was reacted with 3-chloroperoxybenzoic acid to give the
epoxide 4 with good yield. Finally, the azido-carbocycle 5 was obtained af-
ter the nucleophilic ring opening of the strained heterocycle 4 by sodium
azide. This step involves also the deacetylation of the acetylated diols.
Various 1,2,3-triazolo carbanucleosides (6–9) were then synthesized under
the Huisgen conditions. Under a microwave assisted 1,3-dipolar cycloaddi-
tion, various alkynes were reacted with the azido-carbocycle 5 (Table 1). The
mixture copper/copper sulfate Cu(0)/CuSO (II) in situ comproportion-
4
ated was chosen as catalyst in a water and tert-butanol co-solvent. All the
cycloadditions were realized with a rapid complete conversion of the azido-
carbocycle into the desired carbanucleoside.
According to the carbanucleosides, the work-up was slightly different.
The 1,4-disubstituted triazoles obtained from alkynes with a non-polar

Alkyne-Azide Click Chemistry
1393
TABLE 1 Microwave assisted Huisgen 1,3-dipolar cycloaddition
◦
Microwave 125 C
Entry
Alkynes
Products
Time
2 min
1 h
Immediate
2 min
Conversion (%) Yield (%)
1
2
3
4
Phenylacetylene
Heptyne
Propargyl acetate
3–Butyn-1-ol
6
7
8
9
100
100
100
100
98
98
95
95
substituent (phenylacetylene and heptyne (entries 1–2)) were isolated
with very good yields after a simple extraction in ethyl acetate. The
1
,4-disubstituted triazoles obtained from alkynes with a polar substituent
(propargyl acetate and butynol (entries 3–4)) needed a filtration on silica
gel column chromatography to eliminate the salts, since the products had
too much affinity for the aqueous layer.
The regioselectivity of the ligation leading to 1,4-disubstituted-[1,2,3]-
1
13
triazole moiety was confirmed by NMR using H, C long range correlation
spectra (HMBC) (Figure 1). The 50% inhibitory concentration (IC ) of
50
the synthesized compounds was evaluated in Vaccinia virius (VV) cells. The
synthesized products did not show any cytotoxicity nor significant antiviral
activity on VV.
In summary, the first synthesis of hitherto unknown 1,4-disubstituted-
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[
1,2,3]-triazolo-4 ,4 -dihydroxymethyl-3 -deoxycarbanucleosides have been
FIGURE 1 1H,13C long range correlation NMR spectrum (HMBC) of (± ) (8).

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J. Broggi et al.
accomplished using the 1,3-dipolar Huisgen cycloaddition under optimized
click chemistry conditions.
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