An intramolecular 1,3-dipolar cycloaddition reaction towards the synthesis of chiral azetidine nucleoside analogues: The D-gluco case

Article abstract of DOI:10.1081/NCN-200060056

The diastereoselective intramolecular 1,3-dipolar cycloaddition reaction of unsaturated nitrones, derived from methyl α-D-glucopyranoside with 2-furaldehyde and 2-(benzyloxy)acetaldehyde has been studied. In our pevious studies with 2-furaldehyde, the cyc

Full text of DOI:10.1081/NCN-200060056

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AN INTRAMOLECULAR 1,3-DIPOLAR CYCLOADDITION
REACTION TOWARDS THE SYNTHESIS OF CHIRAL
AZETIDINE NUCLEOSIDE ANALOGUES: THE D-GLUCO
CASE
P. Pádár a , P. Forgó b , Z. Kele a , N. M. Howarth c & L. Kovács a
a Department of Medicinal Chemistry , Heriot-Watt University , Riccarton, Edinburgh, UK
b Department of Organic Chemistry , University of Szeged , Szeged, Hungary
c Department of Chemistry , School of Engineering and Physical Sciences, Heriot-Watt
University , Riccarton, Edinburgh, UK
Published online: 15 Nov 2011.
To cite this article: P. Pádár , P. Forgó , Z. Kele , N. M. Howarth & L. Kovács (2005) AN INTRAMOLECULAR 1,3-DIPOLAR
CYCLOADDITION REACTION TOWARDS THE SYNTHESIS OF CHIRAL AZETIDINE NUCLEOSIDE ANALOGUES: THE D-GLUCO CASE,
Nucleosides, Nucleotides and Nucleic Acids, 24:5-7, 743-745, DOI: 10.1081/NCN-200060056
To link to this article: http://dx.doi.org/10.1081/NCN-200060056
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Nucleosides, Nucleotides, and Nucleic Acids, 24 (5--7):743–745, (2005)
Copyright D Taylor & Francis, Inc.
ISSN: 1525-7770 print/ 1532-2335 online
DOI: 10.1081/NCN-200060056
AN INTRAMOLECULAR 1,3-DIPOLAR CYCLOADDITION REACTION
TOWARDS THE SYNTHESIS OF CHIRAL AZETIDINE NUCLEOSIDE
ANALOGUES: THE D-GLUCO CASE
5
P. P´ad´ar
Department of Medicinal Chemistry, Heriot-Watt University, Riccarton,
Edinburgh, UK
5
P. Forg´o
Department of Organic Chemistry, University of Szeged, Szeged, Hungary
5
Z. Kele
Department of Medicinal Chemistry, Heriot-Watt University, Riccarton,
Edinburgh, UK
5
N. M. Howarth
Department of Chemistry, School of Engineering and Physical Sciences,
Heriot-Watt University, Riccarton, Edinburgh, UK
5
L. Kov´acs
Department of Medicinal Chemistry, Heriot-Watt University, Riccarton,
Edinburgh, UK
5
The diastereoselective intramolecular 1,3-dipolar cycloaddition reaction of unsaturated nitrones,
derived from methyl a-D-glucopyranoside with 2-furaldehyde and 2-(benzyloxy)acetaldehyde has been
studied. In our pevious studies with 2-furaldehyde, the cycloaddition resulted 3 diastereoisomers in a
3:1:1 ratio. In this article, how the number of the possible isomers generated by 1,3-cycloaddition could
be reduced from 4 to 1 when 2-(benzyloxy)acetaldehyde was employed as an aldehyde is shown.
RESULTS AND DISCUSSION
In an attempt to overcome some of the undesirable properties of peptide
nucleic acids (PNAs), we have designed conformationally restricted, chiral
azetidine nucleic acids (ANAs). The key step in the synthesis of the ANA
monomers, which are needed for construction of the oligomers, is a diastereose-
lective intramolecular 1,3-dipolar cycloaddition reaction involving unsaturated
nitrones derived from carbohydrate precursors (Figure 1). The intramolecular 1,3-
The financial support of grants Wellcome Trust 063879/Z/01/Z and EU FP6 TRIoH LSHB-CT-2003-503480 is
gratefully acknowledged.
Address correspondence to L. Kov´acs, Department of Medicinal Chemistry, Heriot-Watt University,
Riccarton, Edinburgh, UK; E-mail: kovacs@ovrisc.mdche.u-szeged.hu
743
Order reprints of this article at www.copyright.rightslink.com

744
P. Pa´da´r et al.
FIGURE 1 a) Zn, sonication[3] or Zn and Co(II)-phthalocyanine,[4] b) NH2OH Á HCl, NaHCO3,[5] c) NaBH3CN,
˚
˚
HCl/dioxane, d) 2-furaldehyde or 2-(benzyloxy)acetaldehyde, toluene, 4 A MS, 50°C, 18 h, e) toluene, 120°C, 4 A
MS, Lewis acid catalysts, 7, 16: 9-oxa-1-azabicyclo[4.2.1]nonane skeleton.
dipolar cycloaddition has the potential to reduce the number of possible resulting
isomers by virtue of steric constraint. Thus, condensation of the hydroxylamines (5
and 12) with different aldehydes 2-furaldehyde (14), 2-(benzyloxy)acetaldehyde
˚
(15), took place successfully at 60--90°C (toluene, 4 A MS) to afford the
corresponding unsaturated nitrones. Subsequent ring closure yielded heterocycles
(7a--d and 16) as diastereomeric mixtures.
The effect of side chain protection on the regio- and diastereoselectivity of the
intramolecular 1,3-cycloaddition has been studied in detail for the D-gluco series.
The reaction involving the benzyl protected nitrone (13) proved to be sluggish
(toluene, reflux, 1 week) and low-yielding; therefore, it was abandoned. All the
cycloaddition products isolated exhibited the same regiochemistry. After 12--48 h,
the benzoyl protected nitrone was found to afford only 9-oxa-1-azabicyclo[4.2.1]-
nonane diastereoisomers 7b--7d (Figure 2). We were unable to isolate the fourth
diastereoisomer (7a) as it was produced in a negligible amount. We assume that the
alternative 8-oxa-1-azabicyclo[4.2.1]nonane derivatives did not form because of
steric hindrance between the furyl chain and oxazepane ring.
FIGURE 2 The structure of diastereoisomers 7a--7d and 16.

P. Pa´da´r et al.
745
The effect of different Lewis acid catalysts (ZnCl2, MgCl2, BF3OEt2), solvents
(toluene, benzene, dioxane) and time (12--48 h) on yields and diastereomeric ratios
have been examined in detail for reactions involving 2-furaldehyde (14). It was
found that 7b was the main isomer in all cases (except when dioxane and ZnCl2
was used). We have ascertained that the best solvent for this reaction is toluene in
presence of MgCl2 as a Lewis acid catalyst (90% yield). The use of a hard Lewis acid
catalyst caused elimination of the benzoyl protecting group and, sometimes,
decomposition and conversion of the furyl group, too (yields: 17--32%). The
stereoselectivity of the reaction did not alter much under the conditions explored.
The cycloaddition was found to afford three 9-oxa-1-azabicyclo[4.2.1]nonane
diastereomers in a 3:1:1 ratio.
Condensation of 2-(benzyloxy)acetaldehyde (15) with benzoyl protected
hydroxylamine (5) resulted in formation of the single cycloaddition product
(16), bearing the 9-oxa-1-azabicyclo[4.2.1]nonane skeleton (Figure 2), and the
expected intermediate unsaturated nitrone was not observed. The reaction took
˚
place at 90°C (toluene, 4 A MS) without the addition of a Lewis acid catalyst. This
surprising result implies that we could potentially reduce the number of the
possible diastereoisomers generated by the intramolecular 1,3-cycloaddition from 4
to 1. The NMR measurements 1H, 13C, HSQC, and HMBC suggest the same trans
arrangement for protons H-6 and H-8 in 16. We have determined both the
configuration of the newly formed chiral centers (C-6, C-8), and the conformation
of the 1,2-oxazepane ring for the all diastereoisomers 7b--7d and 16. Finally, the
results show that the single isomer of 16 has the same configuration and
conformation as the main isomer, 7b. As a conclusion, various isoxazolidine
precursors of chiral azetidine moieties have been successfully synthesised by
employing an intramolecular 1,3-dipolar cycloaddition. Out of the three aldehydes
examined to date, two of them, aldehydes 14 and 15 have been shown to be
suitable candidates for use in this reaction. Our preliminary studies have also found
that, when 15 is employed, one diastereoisomer of 9-oxa-1-azabicyclo[4.2.1]nonane
is formed exclusively, out of a possible four. The configuration and conformation of
the diastereoisomers of the resulting cycloadducts have been examined in detail
using NMR studies. The effect of Lewis acid catalysts and solvents on yield and
diastereomeric ratios have been investigated.
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