Reactivity models of 1-N-vinyluracil and synthesis of a new class of potential antiviral agents by the use of 1,3-dipolar cycloaddition reactions

Article abstract of DOI:10.1081/NCN-120022624

By the use of a convergent approach based on 1,3-dipolar cycloaddition reactions between N-protected formylnitrones generated in situ and 1 -N-vinyluracil, a new class of 4′-aza-analogues of 2′,3′ -dideoxynucleosides is synthesized. Competitive reaction for the endocyclic bond of uracil also brings to a new isoxazolidine derivative fused with the pyrimidine nucleus.

Full text of DOI:10.1081/NCN-120022624

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Reactivity Models of 1-N-Vinyluracil and Synthesis of a
New Class of Potential Antiviral Agents by the Use of
1,3-Dipolar Cycloaddition Reactions
E. Colacino a b , G. De Luca a , A. Liguori a , A. Napoli a , C. Siciliano a & G. Sindona a
a Dipartimento di Chimica, Università della Calabria, Arcavacata di Rende, (CS), Italy
b Université de Montpellier II, Labortoire de Chimie Organique Biomoleculaire de Synthèse,
CC008, Place E. Bataillon, F-34095, Montpellier Cedex 5, France
Version of record first published: 31 Aug 2006.
To cite this article: E. Colacino , G. De Luca , A. Liguori , A. Napoli , C. Siciliano & G. Sindona (2003): Reactivity Models of
1-N-Vinyluracil and Synthesis of a New Class of Potential Antiviral Agents by the Use of 1,3-Dipolar Cycloaddition Reactions,
Nucleosides, Nucleotides and Nucleic Acids, 22:5-8, 743-745
To link to this article: http://dx.doi.org/10.1081/NCN-120022624
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS
Vol. 22, Nos. 5–8, pp. 743–745, 2003
Reactivity Models of 1-N-Vinyluracil and Synthesis of a
New Class of Potential Antiviral Agents by the Use of
1,3-Dipolar Cycloaddition Reactions
*
E. Colacino, G. De Luca, A. Liguori, A. Napoli, C. Siciliano,
and G. Sindona
`
Dipartimento di Chimica, Universita della Calabria,
Arcavacata di Rende, (CS), Italy
ABSTRACT
By the use of a convergent approach based on 1,3-dipolar cycloaddition reactions
between N-protected formylnitrones generated in situ and 1-N-vinyluracil, a new
class of 40-aza-analogues of 20,30-dideoxynucleosides is synthesized. Competitive
reaction for the endocyclic bond of uracil also brings to a new isoxazolidine
derivative fused with the pyrimidine nucleus.
By a convergent approach based on 1,3-dipolar cycloaddition reactions between
N-protected formylnitrones 1 generated in situ, starting from the corresponding
hydroxylamines, and 1-N-vinylnucleobases 2 and 3, a new class of 40-aza-20,30-
dideoxynucleosides 4 and 5 was synthesized[1,2] (Sch. 1).
´
*Correspondence: E. Colacino, Universite de Montpellier II, Labortoire de Chimie Organique
Biomoleculaire de Synthese, CC008, Place E. Bataillon, F-34095 Montpellier Cedex 5, France;
`
Fax: þ33 4 6704 2029; E-mail: eveline.colacino@mailcity.com.
743
DOI: 10.1081/NCN-120022624
Copyright # 2003 by Marcel Dekker, Inc.
1525-7770 (Print); 1532-2335 (Online)
www.dekker.com

744
Colacino et al.
Scheme 1.
The tandem mass spectra[3] of these compounds were similar to those of the
wild-type nucleosides but all the protonated isoxazolidinyl nucleosides present a
retrocycloaddition process, which can be considered a ‘marker’ of the chemistry of
this class of compounds. The application of the convertible nucleoside approach
(Sch. 1) was achieved in order to prepare 40-aza-20,30-dideoxynucleosides 9 and 10.
A competitive reaction for the endocyclic bond of 1-N-vinyluracil 3 during 1,3-
dipolar cycloaddition process, characterised by site selectivity affords a new isoxazo-
lidinyl derivative fused with the pyrimidine nucleus (Sch. 1). The regiochemistry of
nitrone attack on double bond C(5)–C(6) was demonstrated by two dimensional
NMR and MS=MS experiments.[4]
On the bases of the above mentioned promising results, some other fused N,O-
heterocycles (Table 1) have been prepared, using as dipolarophiles, modified uracils
on 1-N-position by tetrahydropyranyloxyethyl and 2-benzyloxy-ethoxymethyl moi-
eties. (Sch. 2).
Table 1.
R1
PG
Solvent
Toluene
Toluene
CHCl3
CHCl3
MeOH=CHCl3
MeOH
MeOH=CHCl3
MeOH
Yield (%)
13
14
15
16
17
18
19
20
BnOCH2CH2OCH2-
BnOCH2CH2OCH2-
THPOCH2CH2-
THPOCH2CH2-
BnOCH2CH2OCH2-
HOCH2CH2OCH2-
HOCH2CH2-
THP
Benzyl
THP
Benzyl
20
25
15
19
72
85
70
92
–
–
–
–
THPOCH2CH2-

Reactivity Models of 1-N-Vinyluracil
745
Scheme 2.
The subsequent reductive opening of fused isoxazolidine rings brought to some
new acyclic uridine derivatives functionalised on C(5) by a methylamino group.
REFERENCES
1. Colacino, E.; Sindona, G.; Converso, A.; De Nino, A.; Leggio, A.; Liguori, A.;
Maiuolo, L.; Napoli, A.; Procopio, A.; Siciliano, C. Synthesis of isoxazolidino
analogues of 20,30-dideoxynucleosides. Nucleosides Nucleotides 1999, 18, 581–
583.
2. Colacino, E.; Converso, A.; Liguori, A.; Napoli, A.; Siciliano, C.; Sindona, G.
Simple and efficient routes for the preparation of isoxazolidinyl nucleosides
containing cytosine and 5-methyl-cytosine as new potential anti-HIV drugs.
Tetrahedron 2001, 57, 8551–8557.
3. Colacino, E.; Giorgi, G.; Ligouri, A.; Napoli, A.; Romeo, R.; Salvini, L.;
Siciliano, C.; Sindona, G. Structural characterization of fast atom bombardment
tandem mass spectrometry. J. Mass Spectrom. 2001, 36, 1220–1225.
4. Colacino, E.; De Luca, G.; Liguori, A.; Napoli, A.; Siciliano, C.; Sindona, G.
`
Modelli di Reattivita di 1-N-viniluracile nella Sintesi di Potenziali Antivirali,
XXVI Convegno Nazionale della Divisione di Chimica Organica della Societa
`
Chimica Italiana, Folgaria (TN), Italy, Sep. 7–12, 1999.