Investigation of 1,3-dipolar cycloaddition reactions of unsaturated nitrones in ionic liquids

Article abstract of DOI:10.1080/15257770600793851

The effect of the media (achiral and chiral ionic liquids) on the stereochemistry of intramolecular 1,3-dipolar cycloaddition reactions of D-galactose-derived ω-unsaturated nitrones, leading to bicyclic isoxazolidines, has been investigated. Copyright Tay

Full text of DOI:10.1080/15257770600793851

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Investigation of 1,3-Dipolar
Cycloaddition Reactions of Unsaturated
Nitrones in Ionic Liquids
M. Hornyák a , Z. Kele a , L. Kovács a , P. Forgó b & N. M. Howarth c
a Department of Medicinal Chemistry , University of Szeged ,
Szeged, Hungary
b Department of Organic Chemistry , University of Szeged , Szeged,
Hungary
c Department of Chemistry , Heriot-Watt University , Edinburgh,
Riccarton, U.K.
Published online: 16 Feb 2007.
To cite this article: M. Hornyák , Z. Kele , L. Kovács , P. Forgó & N. M. Howarth (2006) Investigation of
1,3-Dipolar Cycloaddition Reactions of Unsaturated Nitrones in Ionic Liquids, Nucleosides, Nucleotides
and Nucleic Acids, 25:8, 867-870, DOI: 10.1080/15257770600793851
To link to this article: http://dx.doi.org/10.1080/15257770600793851
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Nucleosides, Nucleotides, and Nucleic Acids, 25:867–870, 2006
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770600793851
INVESTIGATION OF 1,3-DIPOLAR CYCLOADDITION REACTIONS
OF UNSATURATED NITRONES IN IONIC LIQUIDS
M. Hornya´k, Z. Kele, and L. Kova´cs
Department of Medicinal Chemistry,
2
University of Szeged, Szeged, Hungary
P. F o r g o´
Department of Organic Chemistry, University of Szeged, Szeged, Hungary
2
N. M. Howarth
Department of Chemistry, Heriot-Watt University, Edinburgh,
2
Riccarton, U.K.
The effect of the media (achiral and chiral ionic liquids) on the stereochemistry of intramolecular
2
1,3-dipolar cycloaddition reactions of D-galactose-derived ω-unsaturated nitrones, leading to
bicyclic isoxazolidines, has been investigated.
Keywords 1,3-dipolar cycloaddition; Bicyclic isoxazolidines; Ionic liquids; Nitrone-
alkene cycloaddition; PNA analogues
RESULTS AND DISCUSSION
The recent advancements in the synthesis of peptide nucleic acids
(PNA)[1,2] indicate that conformationally rigid PNAs derived from pyrro-
lidine rings[3,4] have outstanding biological features among the newly
synthesized analogues. This fact prompted us to investigate the synthetic
routes leading to new PNA analogues with azetidine moieties (ANA-1 and
ANA-2, Figure 1)
Our synthetic strategy was based on the preparation of carbohydrate-
based bicyclic isoxazolidines that can further be elaborated into the target
chiral azetidines. Herein we would like to report our preliminary results on
intramolecular 1,3-dipolar cycloaddition reactions for the d-galacto series.
The reaction sequence shown in Scheme 1 was utilized since the simpler
route, which involves iodination at the primary 6-hydroxyl group followed
Received 15 October 2004; accepted 17 April 2006.
Presented at the XVI International Roundtable Conference, September 12–16, 2004.
The financial support of the Wellcome Trust (grant no. 063879/Z/01/Z) and EU FP6 grant (TRIoH
LSHB-CT-2003-503480) is gratefully acknowledged.
Address correspondence to L. Kova´cs, Department of Medicinal Chemistry, University of Szeged,
Szeged, Hungary. E-mail: kovacs@ovrisc.mdche.u-szeged.hu
867

868
M. Hornya´k et al.
FIGURE 1 The structure of azetidine nucleic acid monomers ANA-1 and ANA-2.
by protection of the remaining secondary hydroxyl groups, failed. After
selective protection of 4- and 6-hydroxyl groups of 1 as an acetal, the
remaining free hydroxyl groups of compound 2 were protected either with
benzoyl or benzyl protecting groups (3 and 4). The selective opening of
the 4,6-O-benzylidene ring with N -bromosuccinimide[5] or with the LiAlH4-
AlCl3 reagent[6] provided a series of 6-deoxy-6-halo derivatives with different
protecting group patterns (5–8). The oximes so obtained serve as building
blocks for the synthesis of our target ANA derivatives (Scheme 2).
SCHEME 1

Reactions in Ionic Liquids
869
SCHEME 2
Starting from N -methyl-imidazole and L-alanine, ionic liquids 9[7] and
10[8] were prepared (Figure 2) to investigate the effect of media on the
stereochemical outcome of cycloaddition reaction.
Starting from the bromine derivative 5, nitrone 13 was synthesized in
four steps as depicted in Scheme 2. Nitrone 13 was heated in toluene in
the presence of 9 and 10. The reactions carried out in toluene and in 9
furnished two isomers 14 out of the possible four diastereomers in ratios of
ca. 3:1 and 8:1. In the presence of 10 only one isomer (the main product
of the former two reacions) could be detected. Additionally, the conversion
after 24 h at reflux was about 70% in toluene alone, whereas in the ionic
liquids the starting nitrone 13 completely disappeared (TLC). The detailed
NMR experiments to identify the absolute stereochemistry of the products
formed are in progress.
FIGURE 2 The structure of ionic liquids 9 and 10.

870
M. Hornya´k et al.
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