Intramolecular 1,3-dipolar cycloaddition of unsaturated nitrones
derived from methyl a-
D
-glucopyranoside
Petra Pa
´
da
´
r,
a
Miklo
´
s Hornya
´
k,
a
Pe
´
ter Forgo
´
,
b
Zolta
´
n Kele,
a
Ga
´
bor Paragi,
c
Nicola M. Howarth
d
and Lajos Kova
´
cs
a,
*
a
Department of Medicinal Chemistry, University of Szeged, Do
´
mte
´
r 8, H-6720 Szeged, Hungary
b
Department of Organic Chemistry, University of Szeged, Do
´
mte
´
r 8, H-6720 Szeged, Hungary
c
Protein Chemistry Research Group, Hungarian Academy of Sciences, University of Szeged, Do
´
mte
´
r 8, H-6720 Szeged, Hungary
d
Chemistry, School of Engineering and Physical Sciences, William H. Perkin Building, Heriot-Watt University, Riccarton,
Edinburgh EH14 4AS, UK
Received 23 December 2004; revised 8 April 2005; accepted 29 April 2005
Abstract—The intramolecular 1,3-dipolar cycloaddition of unsaturated nitrones derived from methyl a-
D
-glucopyranoside with
2-furaldehyde has been studied. This cycloaddition was found to afford three 9-oxa-1-azabicyclo[4.2.1]nonane diastereomers in a 3:1:1
ratio [with the principal isomer possessing a (3S,4R,5S,6S,8S) configuration, determined by NMR spectroscopy]. The effects of different
Lewis acid catalysts (MgCl
2
, ZnCl
2
and BF
3
$OEt
2
) on yields and diastereomeric ratios have been examined in detail. The best result (90%
yield) was achieved when MgCl
2
was present (in toluene, 120 8C bath temperature, 12 h). The stereoselectivity of the 1,3-dipolar
cycloaddition was not significantly altered under the conditions investigated.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
Peptide nucleic acids (PNAs) are nucleic acid mimics
bearing a pseudopeptide backbone (Fig. 1).
1,2
They possess
very favourable hybridisation properties with nucleic acid
targets, display high chemical and biological stabilities and
have the potential to be used as both antisense and antigene
therapeutic agents. Unfortunately, PNA has low lipid
penetration and, consequently, poor cellular uptake. In an
attempt to overcome these undesirable attributes, we have
designed a conformationally restricted oligonucleotide
analogue whose backbone should be positively charged
under physiological conditions. These new chiral nucleo-
side analogues are termed azetidine nucleic acids (ANAs,
Fig. 1). The pivotal step in the synthesis of the ANA
monomers, needed for construction of the oligomers, is a
diastereoselective intramolecular 1,3-dipolar cycloaddition
involving unsaturated nitrones derived from carbohydrate
precursors. Subsequent transformations on the correspond-
ing isoxazolidines obtained should then afford the desired
azetidine derivatives (Fig. 2).
We envisage that it will be possible to control the
stereochemical outcome of the intramolecular 1,3-dipolar
cycloaddition by virtue of steric constraint so that the actual
number of isoxazolidine isomers produced would be
reduced compared to the theoretical. The use of different
Lewis acid catalysts is anticipated to improve both the
stereoselectivity and reactivity of the nitrone. The mechan-
ism of such 1,3-dipolar cycloadditions has been extensively
studied by several authors.
3
Nitrones are nucleophiles which
Tetrahedron 61 (2005) 6816–6823
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.04.066
Figure 1. The structure of PNA and ANA oligomers (B, nucleobase). Only
one diastereoisomer is shown for each ANA structure.
Keywords: 1,3-Dipolar cycloaddition; Isoxazolidines; Bicyclic 1,2-oxaze-
panes; 9-Oxa-1-azabicyclo[4.2.1]nonanes; Asymmetric synthesis.
*
Corresponding author. Tel.: C36 62 545145; fax: C36 62 545141;
e-mail: kovacs@ovrisc.mdche.u-szeged.hu