1,3-Dipolar cycloaddition approach to isoxazole, isoxazoline and isoxazolidine analogues of C-nucleosides related to pseudouridine

Article abstract of DOI:10.1016/j.tet.2005.11.019

Isoxazole, isoxazoline and isoxazolidine analogues of C-nucleosides related to pseudouridine have been synthesized by 1,3-dipolar cycloaddition reactions of nitrile oxides and nitrones derived from mono and disubstituted uracil-5-carbaldehydes and 2,4-dim

Full text of DOI:10.1016/j.tet.2005.11.019

Tetrahedron 62 (2006) 1494–1501
1,3-Dipolar cycloaddition approach to isoxazole, isoxazoline and
isoxazolidine analogues of C-nucleosides related to pseudouridine
a
a
Evdoxia Coutouli-Argyropoulou,a, Pygmalion Lianis, Marigoula Mitakou,
*
Anestis Giannoulisa and Joanna Nowakb
aDepartment of chemistry, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
bErasmus student from A. Mickiewicz University, Poznan, Poland
Received 2 August 2005; accepted 10 November 2005
Available online 5 December 2005
Abstract—Isoxazole, isoxazoline and isoxazolidine analogues of C-nucleosides related to pseudouridine have been synthesized by
1,3-dipolar cycloaddition reactions of nitrile oxides and nitrones derived from mono and disubstituted uracil-5-carbaldehydes and
2,4-dimethoxypyrimidine-5-carbaldehyde. The dimethoxy derivatives have been easily deprotected to the corresponding uracils bearing the
heterocyclic ring instead of a sugar moiety. The regio and stereoselectivity of the reactions are discussed.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
and has attracted the interest of organic chemists and
biochemists since its discovery in 1957.4 The occurrence of
pseudouridine in highly conserved regions of RNA indicates
that certain physicochemical properties of pseudouridine are
critical to the biological function of RNA molecules.
Since the latter part of the 1980s unnatural nucleoside
analogues have played an important role as anticancer and
antiviral agents.1 Consequently, several variations have
been made to both the heterocyclic base and the sugar
moiety in the search for effective and selective derivatives.
Due to the need for the base moiety to preserve the base-
pairing functionalities, only minor modifications of the base
are usually found in biologically active nucleosides
analogues. The C-5 position is usually the position of
choice for the introduction of substituents in pyrimidine
nucleosides since it is not involved in the Watson–Crick
base-pairing.2 On the contrary, a lot of variations have been
made in the sugar part replacing it by acyclic moieties or
carbo or other heterocyclic rings. Among them, isoxazoline
and isoxazolidine nucleosides have emerged as an important
class of nucleoside analogues and several approaches
for their synthesis have been reported.3
Thus the biological significance of pseudouridine has
resulted in studies aimed at the incorporation of synthetic
pseudouridine analogues with modified sugar moieties.5
Recently, the synthesis of isoxazoline analogues of
pseudouridine by 1,3-dipolar cycloaddition reactions of
5-uracil nitrones has been described.6
During recent years and in connection with our interests to
induce nucleoside modifications,7 we have also attempted to
apply the convenience and diversity of 1,3-dipolar
cycloaddition reactions to the synthesis of pseudouridine
analogues. However, our initial attempts to isolate
cycloaddition products via the in situ formation of nitrile
oxides from 5-uracilcarbaldehyde oxime or 1-monosubsti-
tuted 5-uracilcarbaldehyde oximes were unsuccessful even
in the presence of very active dipolarophiles such as methyl
acrylate. On the contrary these oximes gave mixtures of
isoxazolidines from the reaction of intermediate nitrones.8a
Nitrone generation from oximes via a 1,2-prototropic
process or an 1,3-azaprotiocyclotransfer is a well known
reaction established by Grigg,8b,c and it has been also
described by us for other oximes.8d The last findings
indicated that nitrone cycloaddition can work with uracil
nitrones barrying free NH bonds. This has been also shown
recently by the work of Chiacchio et al.6
Besides the variations in the sugar and base moieties a
crucial modification results from varying their connection,
as in the C-nucleosides, which have a carbon–carbon
linkage instead of an hydrolyzable carbon–nitrogen bond
between the sugar and the aglycon. The most abundant
natural C-nucleoside is pseudouridine a C-5 linked uridine.
Pseudouridine is the first C-nucleoside found in nature
Keywords: Pyrimidine; Pseudouridine; Cycloaddition.
*
Corresponding author. Tel.: C30 2310 997733; fax: C30 2310 997679;
e-mail: evd@chem.auth.gr
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.11.019

E. Coutouli-Argyropoulou et al. / Tetrahedron 62 (2006) 1494–1501
1495
However, nucleoside analogues with restricted confor-
mational flexibility induced by a second ring or by
unsaturation are the target compounds in many cases,
since they are potent inhibitors of HIV-1 reverse tran-
scriptase.3k,o,9 Thus, in order to expand the use of 5-uracil
dipoles for the formation of both saturated and unsaturated
rings, we report in this paper, the application of
cycloaddition reactions of both nitrile oxides and nitrone
uracil dipoles by applying monosubsituted, disubstituted
and protected uracil derivatives.
Nitrile oxide 3b was generated in situ from the correspon-
ding oxime in the presence of the dipolarophile in a biphasic
methylene chloride/aqueous bleach system. Generation of
nitrile oxide 3a following the same procedure was
unsuccessful. As we have already mentioned, in our initial
attempts we failed to isolate nitrile oxide cycloaddition
products from 1-substituted uracil aldoximes. Thus, as well
as the above standard procedure for the generation of the
nitrile oxide 3a from the oxime 2a, several other alternative
procedures using N-chlorosuccinimide, and several vari-
ations in the reaction time, temperatures and work up were
also tested without success. Nitrile oxide 3b reacted with
both allylic benzoate (5) and propargylic benzoate (6) to
give the isoxazoline 7b and the isoxazole 8b, respectively,
in good yields (70–80%). The reactions were regioselective
and only 5-substituted cycloadducts were isolated. The
reactions of nitrones 4 with the alkene 5 took place under
reflux in xylene to give isoxazolidines 9 as the main
products in satisfactory yields (70–72%). The reactions
were regio and stereoselective. In both cases only
5-substituted derivatives with a cis arrangement of the 30
and 50 substituents (structure 9) were isolated, although in
the crude reaction mixture, traces of compounds with
2. Results and discussion
As starting materials for the formation of the dipoles we
have chosen the mono and disubstituted aldehydes 1a and
1b and the dimethoxy-5-formyl pyrimidine 11 (Schemes 1
and 2). The octyl derivatives 1a and 1b have been chosen for
purposes of higher solubility and enhanced hydrophobicity,
whereas aldehyde 11 is a protected form of 5-formyluracil.
The above aldehydes were prepared according to the
procedures we have previously described.10 The oximes
2a, 2b, 12 as well as the nitrones 4a, 4b and 14 were
prepared from the corresponding aldehydes applying
conventional procedures. As dipolarophiles, we have used
allylic or propargylic alcohol derivatives in order to ensure
the presence of a 50-hydroxymethyl group in the final
product, which potentially allows enzymatic phosphor-
ylation for antiviral expression or incorporation into
automatic solid phase synthesis.
1
structure 10 were also detected on the basis of some H
NMR chemical shifts (Table 1).
Dimethoxypyridine dipoles 13 and 14 showed analogous
behaviour. Nitrile oxide 13 generated in situ from the oxime
12 reacted regioselectively with 5 to give the isoxazoline
derivative 15. The reaction of 13 with the alkyne derivative
Scheme 1. Reagents and conditions: (i) NH2OH$HCl, Na2CO3, EtOH/H2O, 20 8C, 24 h; (ii) NaOCl, CH2Cl2/H2O, 0–20 8C, 24 h; (iii) CH3NHOH$HCl,
Na2CO3, EtOH/H2O, 20 8C, 24 h; (iv) Xylene, reflux, 48 h.

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E. Coutouli-Argyropoulou et al. / Tetrahedron 62 (2006) 1494–1501
Scheme 2. Reagents and conditions: (i) NH2OH$HCl, Na2CO3, EtOH/H2O, 20 8C, 24 h; (ii) NaOCl, CH2Cl2/H2O, 0–20 8C, 24 h; (iii) CH3NHOH$HCl,
Na2CO3, EtOH/H2O, 20 8C, 24 h; (iv) Xylene, reflux, 48 h; (v) CH3COOH, NaI, 90 8C, 1 h.
Table 1. Selected values for proton chemical shifts and coupling constants of compounds 9, 10, 19, 20
40-Ha
40-Hb
30-H
4.03 (dd, J3 ,4 aZ5.1 Hz, J3 ,4 bZ7.3 Hz)
Compound
0
0
0
0
0
0
0
0
0
0
9a
9b
19
20
2.10 (dt, J4 a,4 bZ12.2 Hz,
3.02 (ddd, J4 a,4 bZ12.2 Hz, J3 ,4 bZ7.3 Hz,
0
0
0
0
0
0
J3 ,4 aZJ4 a,5 Z5.1 Hz)
J4 b,5 Z8.4 Hz)
0
0
0
0
0
0
0 0 0 0
3.99 (dd, J3 ,4 aZ5.1 Hz, J3 ,4 bZ7.8 Hz)
2.05 (dt, J4 a,4 bZ13.6 Hz,
3.02 (ddd, J4 a,4 bZ13.6 Hz, J3 ,4 bZ7.8 Hz,
0
0
0
0
0
0
J3 ,4 aZJ4 a,5 Z5.1 Hz)
J4 b,5 Z8.4 Hz)
0
0
0
0
0
0
0 0 0 0
3.85 (dd, J3 ,4 aZ6.4 Hz, J3 ,4 bZ8.4 Hz)
2.05 (dt, J4 a,4 bZ12.8 Hz,
2.89 (ddd, J4 a,4 bZ12.8 Hz, J3 ,4 bZ8.4 Hz,
0
0
0
0
0
0
J3 ,4 aZJ4 a,5 Z6.4 Hz)
J4 b,5 Z7.7 Hz)
0
0
0
0
0
0
0 0 0 0
4.24 (dd, J3 ,4 aZ5.7 Hz, J3 ,4 bZ3.9 Hz)
2.41 (ddd, J4 a,4 bZ14.2 Hz,
2.55 (ddd, J4 a,4 bZ14.2 Hz, J3 ,4 bZ3.9 Hz,
0
0
0
0
0
0
J3 ,4 aZ5.7 Hz, J4 a,5 Z7.7 Hz)
2.29–2.37 (m)
2.25–2.35 (m)
J4 b,5 Z8.9 Hz)
2.60–2.69 (m)
2.60–2.69 (m)
0 0 0 0
4.22 (dd, J3 ,4 aZ6.0 Hz, J3 ,4 bZ4.1 Hz)
4.22 (dd, J3 ,4 aZ5.2 Hz, J3 ,4 bZ3.8 Hz)
10a
10b
0
0
0
0
6 was also regioselective affording the 50-substituted isomer
17. The reaction of the nitrone 14 with the alkene 5 was also
regioselective, but less stereospecific than that of nitrones 4
resulting in the formation of the two 50-substituted
stereoisomes 19 and 20 in a ratio 1.5:1.
of diagnostic value for compounds 9, 10, 19 and 20 are
given in Table 1.
In 9a, 9b, and 19, the one of 40-H (4a0-H) appears at a higher
field, and exhibits smaller coupling constants with both 30-H
and 50-H than the other 40-H (4b0-H), indicating a trans
topological relationship with both of them. On the contrary,
in compound 20 each of the 40-H exhibits one large and one
small coupling constant indicative that is trans to one and cis
The structure elucidation of the obtained cycloadducts was
made on the basis of their elemental analysis and their
spectral data. All the compounds give molecular ion peaks
in the mass spectra and the expected chemical shifts in the
1H and 13C NMR spectra. The differentiation between
stereoisomers 9 and 10 and between 19 and 20 was less
obvious and was based on observed coupling constants and
NOE measurements carried out on compound 9b. The
protons assignment was confirmed by decoupling experi-
ments and selected chemical shifts and coupling constants
1
to the other. An interesting feature also in the H NMR
spectra is the difference in the chemical shifts of the two
40-H protons, which is remarkably larger in the stereo-
isomers 9a, 9b, and 19 with a cis arrangement of the 30 and
50 substituents than in 20 with a trans arrangement probably
as a result of the shielding effect of both substituents to the
same proton. Also, the chemical shift of 30-H is higher in

E. Coutouli-Argyropoulou et al. / Tetrahedron 62 (2006) 1494–1501
1497
the trans isomer than in the cis. Thus the presence of
1
multipets in the H NMR of the crude reaction mixtures at
the regions 2.25–2.37 and 2.60–269 as well as a dd at d 4.22
are indicative for isomers 10a and 10b.
The proposed stereochemistry for the isolated cycloadducts
was further supported by NOE measurements carried out on
compound 9b. As depicted in Figure 1, the mutual large
NOE enhancements observed upon saturation of 30-H, 50-H
and 4b0-H are in accordance with their cis arrangement.
Scheme 3. Reagents and conditions: (i) KOH, MeOH/H2O, 20 8C, 24 h.
bearing isoxazole, isoxazoline or isoxazolidine rings instead
of a sugar unit. The case of dimethoxy pyrimidine
derivatives is significant in the sense that they could be
deprotected without affecting the heterocyclic ring moiety.
The presence of substituents differentiates the stereoselec-
tivity of the reactions favoring those more close related to
the natural products (cis cycloadducts) as a result of
enhanced secondary interactions.
Figure 1.
3. Experimental
3.1. General
It should be mentioned that the stereoselectivity of the
reactions leading0 preferentially to cycloadducts with a cis
arrangement of 3 and 50 substituents is favorable, since cis
cycloaaducts match more the natural analogues. On the
contrary, trans cycloadducts were referred as the main
products of the reactions of unsubstituted uracil nitrones.6
The observed stereoselectivity of the reactions can be
explained via an endo approach of the dipolarophile
assuming Z-configuration of the nitrone as it has been
proved for aldonitrones.6,11 Secondary interactions that
favor an endo approach obviously prevail in the reactions of
octyl and dioctyl substituted nitrones 4, leading almost
exclusively to the formation of cis cycloadducts 9. In the
reaction of the dimethoxy nitrone 14, competition between
steric factors and secondary interactions leads to the
formation of a substantial amount of the minor trans isomer
20 as a product of the exo approach of the dipolarophile.
Mps are uncorrected and were determined on a Kofler
hot-stage microscope. IR spectra were recorded on a Perkin-
Elmer 297 spectrometer. 1H NMR spectra were recorded at
300 MHz on a Bruker 300 AM spectrometer and 13C NMR
spectra at 75.5 MHz on the same spectrometer, and are
quoted relative to tetramethylsilane as internal reference, in
deuteriochloroform solutions, unless otherwise stated. Mass
spectra (EI) were performed on a VG-250 spectrometer with
ionization energy maintained at 70 eV. High resolution
mass spectra (HRESI) were obtained with a 7 T APEX II
spectrometer. Microanalyses were performed on a Perkin-
Elmer 2400-II element analyser. Column chromatography
was carried out on Merck Kieselgel (particle size
0.063–0.200 mm) and solvents were distilled before use.
The preparation of the aldehydes 1 and 11 was made
according to previously described procedures.10
The dimethoxy derivatives 15, 17 and 19 were readily
transformed to uracil derivatives 16, 18 and 21, respec-
tively, in satisfactory yields (67–72%) and without loss of
the heterocyclic ring moiety, by heating in acetic acid in the
presence of sodium iodide. The obtained uracils, besides the
disappearance of the methoxy chemical shifts and the
presence of NH resonances, exhibits in their NMR almost
the same characteristics with their precursors.
3.2. Synthesis of oximes 2 and 12
General procedure. An aqueous solution (2.5 ml) of
hydroxylamine hydrochloride (2.25 mmol) and sodium
carbonate (1.5 mmol) were added to an ethanolic solution
(5 ml) of the aldehyde 1 or 11 (1 mmol) and the reaction
mixture was stirred at room temperature for 24 h. After that
the ethanol was evaporated, water was added and the
mixture was extracted with methylene chloride. The organic
layer was dried over sodium sulfate and after evaporation of
the solvent the oximes were obtained as white solids and
they were used without further purification.
The removal of the benzoyl group from the obtained
cycloadducts can be also done easily by alkaline hydrolysis.
In a representative experiment compounds 9a and 9b were
transformed quantitatively to the corresponding hydroxy
derivatives 22a and 22b with potassium hydroxide in
aqueous methanol solution (Scheme 3).
3.2.1. 1-Octyl-5-uracilcarbaldehyde oxime (2a). This
compound was obtained in 90% yield as a white solid, mp
173–176 8C; IR (Nujol): nmax 3300, 3150, 3040, 1680,
1600 cmK1; 1H NMR (DMSO-d6CCDCl3)): d 0.87 (t, JZ
7.2 Hz, 3H, CH3), 1.27–1.31 (m, 10H, CH2CH2(CH2)5CH3),
1.68 (br t, 2H, CH2CH2(CH2)5CH3), 3.74 (t, JZ7.2 Hz, 2H,
In conclusion, cycloaddition reactions of nitrones or nitrile
oxides derived from suitably substituted uracils or
dimethoxy pyrimidines can be used as versatile procedures
for the synthesis of modified pseudouridine analogues

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E. Coutouli-Argyropoulou et al. / Tetrahedron 62 (2006) 1494–1501
CH2CH2(CH2)5CH3), 7.82 and 7.95 (two s, 2H, CH]N and
6-H), 10.79 and 11.45 (two br s, 2H, NH and OH); 13C NMR
(DMSO-d6CCDCl3): d 12.9 (CH3), 21.2, 25.0, 27.7, 27.8
and 30.3 (CH2(CH2)6CH3), 47.6 (CH2(CH2)6CH3), 105.8
(C-5), 139.6 and 140.1 (C]N and C-6), 149.3 (C-2), 161.2
(C-4); MS (EI): m/z (%) 267 (MC, 84). Anal. Calcd for
C13H21N3O3: C, 58.41; H, 7.92; N, 15.72. Found: C, 58.41;
H, 7.86; N, 15.35.
solid, mp 70–72 8C; IR (Nujol): nmax 3070, 3030, 1695,
1
1630, 1590 cmK1; H NMR: d 0.85–0.89 (m, 6H, CH3),
1.26–1.32 (m, 20H, CH2CH2(CH2)5CH3), 1.58–1.67
(m, 4H, CH2CH2(CH2)5CH3), 3.79 (t, JZ7.3 Hz, 2H,
CH2CH2(CH2)5CH3), 3.81 (s, 3H, N–CH3), 3.96 (t, JZ
7.4 Hz, 2H, CH2CH2(CH2)5CH3), 7.62 (s, 1H, 6-H), 9.83 (s,
1H, CH]N(O)); 13C NMR: d 14.0 (CH3), 22.5, 26.4, 26.9,
27.5, 29.0, 29.1, 29.2, 31.7 and 31.8 (CH2(CH2)6CH3), 41.8,
50.6 and 53.5 (CH2(CH2)6CH3 and N–CH3), 105.6 (C-5),
128.5 (CH]N(O)), 142.5 (C-6), 150.1 (C-2), 161.4 (C-4);
MS (EI): m/z (%) 393 (MC, 26). Anal. Calcd for
C22H39N3O3: C, 67.14; H, 9.99; N, 10.68. Found: C,
67.50; H, 9.58; N, 10.53.
3.2.2. 1,3-Dioctyl-5-uracilcarbaldehyde oxime (2b). This
compound was obtained in 87% yield as a white solid, mp
128–130 8C; IR (Nujol): nmax 3290, 3040, 1685, 1620,
1590 cmK1; 1H NMR: d 0.83–0.87 (m, 6H, CH3), 1.27–1.32
(m, 20H, CH2CH2(CH2)5CH3), 1.62–1.71 (m, 4H,
CH2CH2(CH2)5CH3), 3.78 (t, JZ7.3 Hz, 2H, CH2CH2-
(CH2)5CH3), 3.95 (t, JZ7.1 Hz, 2H, CH2CH2(CH2)5CH3),
7.66 and 8.13 (two s, 2H, CH]N and 6-H), 8.80 (br s, 1H,
OH); 13C NMR: d 14.0 (CH3), 22.6, 26.4, 26.9, 27.5, 29.0,
29.2, 31.7 and 31.8 (CH2(CH2)6CH3), 41.8 and 50.4
(CH2(CH2)6CH3), 106.1 (C-5), 139.6 (C]N), 143.8 (C-6),
150.7 (C-2), 161.2 (C-4); MS (EI): m/z (%) 379 (MC, 11).
Anal. Calcd for C21H37N3O3: C, 66.46; H, 9.83; N, 11.07.
Found: C, 66.45; H, 9.42; N, 10.79.
3.3.3. N-Methyl-C-(1,3-dimethoxy-5-pyrimidine) nitrone
(14). This compound was obtained in 75% yield as a white
solid, mp 168–170 8C; IR (Nujol): nmax 3040, 1585, 1570,
1
1540 cmK1; H NMR: d 4.04, 4.05 and 4.12 (three s, 9H,
OCH3 and N–CH3), 7.57 (s, 1H, 6-H), 10.19 (s, 1H,
CH]N(O)); 13C NMR: d 53.9, 54.2 and 54.9 (OCH3 and
N–CH3), 107.2 (C-5), 126.4 (CH]N(O)), 157.5 (C-6),
164.8 and 167.6 (C-2 and C-4); MS (EI): m/z (%) 197 (MC,
100). Anal. Calcd for C8H11N3O3: C, 48.73; H, 5.62; N,
21.31. Found: C, 48.62; H, 5.53; N, 21.71.
3.2.3. 2,4-Dimethoxy-5-pyrimidinecarbaldehyde oxime
(12). This compound was obtained in 87% yield as a white
solid, mp 150–154 8C; IR (Nujol): nmax 3200, 3010, 1580,
3.4. Formation of nitrile oxides 3 and 13 and reactions
with the dipolarophiles 5 and 6
1
1550 cmK1; H NMR: d 4.04 (s, 3H, OCH3), 4.06 (s, 3H,
OCH3), 8.19 and 8.56 (two s, 2H, 6-H and CH]N), 8.85 (br
s, 1H, OH); 13C NMR: d 54.3 and 55.1 (OCH3), 107.7 (C-5),
143.2 (C]N), 156.9 (C-6), 161.7 and 168.3 (C-2 and C-4);
HRESIMS for C7H9N3O3 (MCNa)C: calcd 206.0536,
found 206.0536.
General procedure. A solution of the aldoxime 2 or 12
(0.5 mmol) and the dipolarophile 5 or 6 (1 mmol) in
methylene chloride (5 ml) was cooled to 0 8C and
commercial bleach (4 ml) was added. The reaction mixture
was warmed to room temperature and allowed to react
overnight with stirring. The reaction mixture was extracted
with methylene chloride and the organic layer was dried
over sodium sulfate. After evaporation of the solvent the
residue was chromatographed on a silica gel column with
hexane–ethyl acetate (3/1 for the reactions of 2b, 2/1 for
reactions of 12) as the eluent.
3.3. Synthesis of nitrones 4 and 14
General procedure. An aqueous solution (2.5 ml) of
methylhydroxylamine hydrochloride (2 mmol) and sodium
carbonate (1.5 mmol) were added to an ethanolic solution
(5 ml) of the aldehyde 1 or 11 (1 mmol) and the reaction
mixture was stirred at room temperature for 24 h. After that
the ethanol was evaporated, water was added and the
mixture was extracted with methylene chloride. After
drying and evaporation of the solvent from the organic
layer the residue nitrones were used without further
purification.
3.4.1. 5-(50-Benzoyloxymethyl-isoxazolin-30-yl)-1,3-
dioctyluracil (7b). This compound was obtained in 70%
yield as an oil; IR (liquid film): nmax 3060, 1710–1640,
1
1595, 1575 cmK1; H NMR: d 0.87–0.89 (m, 6H, CH3),
1.26–1.31 (m, 20H, CH2CH2(CH2)5CH3), 1.61–1.70 (m,
4H, CH2CH2(CH2)5CH3), 3.44 (dd, JZ18.0, 7.1 Hz, 1H,
40-H), 3.65 (dd, JZ18.0, 10.9 Hz, 1H, 40-H), 3.78 (t, JZ
7.4 Hz, 2H, CH2CH2(CH2)5CH3), 3.93 (t, JZ7.4 Hz, 2H,
CH2CH2(CH2)5CH3), 4.38–4.49 (m, 2H, CH2OCOPh),
4.98–5.10 (m, 1H, 50-H), 7.42 (t, JZ7.6 Hz, 2H, Ph-H),
7.56 (t, JZ7.6 Hz, 1H, Ph-H), 7.88 (s, 1H, 6-H), 8.04 (d, JZ
7.6 Hz, 2H, Ph-H); 13C NMR: d 14.1 (CH3), 22.7,
26.5, 26.9, 27.1, 27.2, 27.3, 27.5, 29.1, 29.2, 29.3, 31.7
and 31.8 (CH2(CH2)6CH3), 39.0 (C-40), 41.9 and 50.5
(CH2(CH2)6CH3), 65.4 (CH2OCOPh), 78.5 (C-50), 103.5
(C-5), 128.4, 129.7, 129.8 and 133.2 (C-Ph), 141.7 (C-6),
150.6 and 152.8 (C-2 and C]N), 161.0 (C-4), 166.3 (C]O);
MS (EI): m/z (%) 539 (MC, 8). Anal. Calcd for C31H45N3O5:
C, 68.99; H, 8.40; N, 7.79. Found: C, 69.27; H, 8.57; N, 7.99.
3.3.1. N-Methyl-C-(1-octyl-5-uracil) nitrone (4a). This
compound was obtained in 84% yield as a white solid,
mp 190–193 8C; IR (Nujol): nmax 3180, 3110, 3040,
1
1670, 1590 cmK1; H NMR (45 8C): d 0.89 (br, 3H, CH3),
1.29–1.34 (m, 10H, CH2CH2(CH2)5CH3), 1.75 (br t, 2H,
CH2CH2(CH2)5CH3), 3.76–3.80 (m, 5H, CH2CH2(CH2)5CH3
and N–CH3), 7.56 (s, 1H, 6-H), 8.81 (br s, 1H, NH), 9.90 (s,
1H, CH]N(O)); 13C NMR (45 8C): d 13.8 (CH3), 22.5, 26.5,
29.0 and 31.7 (CH2(CH2)6CH3), 47.6 (CH2 (CH2)6CH3), 53.5
(N–CH3), 106.5 (C-5), 127.6 (CH]N(O)), 144.3 (C-6),
149.8 (C-2), 161.8 (C-4); MS (EI): m/z (%) 281 (MC, 86).
Anal. Calcd for C14H23N3O3: C, 59.77; H, 8.24; N, 14.93.
Found: C, 59.87; H, 8.07; N, 14.89.
3.4.2. 5-(50-Benzoyloxymethyl-isoxazol-30-yl)-1,3-diocty-
luracil (8b). This compound was obtained in 80% yield as
a white solid, mp 47–49 8C; IR (Nujol): nmax 3050, 1710,
3.3.2. N-Methyl-C-(1,3-dioctyl-5-uracil) nitrone (4b).
This compound was obtained in 87% yield as a white

E. Coutouli-Argyropoulou et al. / Tetrahedron 62 (2006) 1494–1501
1499
1650, 1595 cmK1
;
1H NMR: d 0.85–0.89 (m, 6H,
5.1 Hz, 1H, 40-H), 2.73 (s, 3H, N–CH3), 3.02 (ddd,
JZ12.2, 8.4, 7.3 Hz, 1H, 40-H), 3.48–3.76 (m, 2H,
CH2CH2(CH2)5CH3), 4.03 (dd, JZ7.3, 5.1 Hz, 1H, 30-H),
4.31 (dd, JZ12.0, 6.0 Hz, 1H, CH2OCOPh), 4.47 (dd, JZ
12.0, 3.3 Hz, 1H, CH2OCOPh), 4.67 (dddd, JZ8.4, 6.0, 5.1,
3.3 Hz, 1H, 50-H), 7.41 (t, JZ7.4 Hz, 2H, Ph-H), 7.43 (s,
1H, 6-H) 7.55 (t, JZ7.4 Hz, 1H, Ph-H), 7.98 (d, JZ7.4 Hz,
2H, Ph-H), 9.81 (s, 1H, NH); 13C NMR: d 13.9 (CH3), 22.5,
26.3, 28.9, 29.0 and 31.6 (CH2(CH2)6CH3), 37.5 (C-40),
44.1 and 48.7 (CH2(CH2)6CH3 and N–CH3), 63.1 and 64.9
(C-30 and CH2OCOPh), 74.6 (C-50), 113.6 (C-5), 128.3,
129.4, 129.6 and 133.1 (C-Ph), 141.7 (C-6), 150.5 (C-2),
163.5 (C-4), 166.1 (C]O); MS (EI): m/z (%) 443 (MC, 10).
Anal. Calcd for C24H33N3O5: C, 64.99; H, 7.50; N, 9.57.
Found: C, 65.11; H, 7.50; N, 9.24.
CH3), 1.26–1.32 (m, 20H, CH2CH2(CH2)5CH3),
1.62–1.78 (m, 4H, CH2CH2(CH2)5CH3), 3.83 (t, JZ
7.4 Hz, 2H, CH2CH2(CH2)5CH3), 3.99 (t, JZ7.4 Hz, 2H,
CH2CH2(CH2)5CH3), 5.46 (s, 2H, CH2OCOPh), 7.13 (s, 1H,
40-H), 7.46 (t, JZ7.4 Hz, 2H, Ph-H), 7.60 (t, JZ7.4 Hz, 1H,
Ph-H), 8.05 (s, 1H, 6-H), 8.07 (d, JZ7.4 Hz, 2H, Ph-H); 13C
NMR: d 14.0 (CH3), 22.5, 26.4, 26.8, 26.9, 27.5, 29.0,
29.1, 29.2, 31.7 and 31.8 (CH2(CH2)6CH3), 41.9 and 50.5
(CH2(CH2)6CH3), 56.9 (CH2OCOPh), 102.4 (C-5), 104.5
(C-40), 128.4, 129.1, 129.9 and 133.5 (C-Ph), 141.6 (C-6),
150.6 (C-2), 156.8 (C]N), 161.9 (C-4), 165.7 and 166.3
(C]O and C-50); HRESIMS for C31H43N3O5 (MCNa)C:
calcd 560.3095, found 560.3098.
3.4.3. 5-(50-Benzoyloxymethyl-isoxazolin-30-yl)-2,4-
dimethoxypyrimidine (15). This compound was obtained
in 65% yield as a white solid, mp 132–133 8C; IR (Nujol):
3.5.2. (30RS,50SR)-5-(50-Benzoyloxymethyl-isoxazolidin-
30-yl)-1,3-dioctyluracil (9b). This compound was obtained
in 70% yield as an oil; IR (liquid film): nmax 3060,
1720–1690, 1660–1630, 1590 cmK1; 1H NMR: d 0.85–0.92
(m, 6H, CH3), 1.15–1.40 (m, 20H, CH2CH2(CH2)5CH3),
1.50–1.70 (m, 4H, CH2CH2(CH2)5CH3), 2.05 (dt,
JZ13.6, 5.1 Hz, 1H, 40-H), 2.73 (s, 3H, N–CH3),
3.02 (ddd, JZ13.6, 8.4, 7.8 Hz, 1H, 40-H), 3.49–3.75
(m, 2H, CH2CH2(CH2)5CH3), 3.90 (t, JZ9.3 Hz, 2H,
CH2CH2(CH2)5CH3), 3.99 (dd, JZ7.8, 5.1 Hz, 1H, 30-H),
4.32 (dd, JZ11.9, 6.1 Hz, 1H, CH2OCOPh), 4.43 (dd, JZ
11.9, 3.1 Hz, 1H, CH2OCOPh), 4.67 (dddd, JZ8.4, 6.1, 5.1,
3.1 Hz, 1H, 50-H), 7.37 (s, 1H, 6-H), 7.41 (t, JZ7.6 Hz, 2H,
Ph-H), 7.56 (t, JZ7.6 Hz, 1H, Ph-H), 7.97 (d, JZ7.6 Hz,
2H, Ph-H); 13C NMR: d 14.0 (CH3), 22.5, 26.4, 26.9,
27.5, 28.9, 29.0, 29.1, 31.6 and 31.7 (CH2(CH2)6CH3), 37.7
(C-40), 41.4, 44.2 and 49.7 (CH2(CH2)6CH3 and N–CH3),
63.7 and 65.1 (C-30 and CH2OCOPh), 74.5 (C-50), 112.9
(C-5), 128.3, 129.5, 129.7 and 133.1 (C-Ph), 139.3 (C-6),
150.8 (C-2), 162.6 (C-4), 166.2 (C]O); MS (EI): m/z (%)
555 (MC, 16). Anal. Calcd for C32H49N3O5: C, 69.16; H,
8.89; N, 7.56. Found: C, 69.46; H, 8.81; N, 7.25.
nmax 3030, 1710, 1595, 1535 cmK1; H NMR: d 3.32 (dd,
1
JZ17.4, 6.8 Hz, 1H, 40-H), 3.57 (dd, JZ17.4, 10.9 Hz, 1H,
40-H), 4.01 (s, 3H, OCH3), 4.04 (s, 3H, OCH3), 4.43–4.56
(m, 2H, CH2OCOPh), 5.08–5.17 (m, 1H, 50-H), 7.41 (t, JZ
7.6 Hz, 2H, Ph-H), 7.55 (t, JZ7.6 Hz, 1H, Ph-H), 8.02 (d,
JZ7.6 Hz, 2H, Ph-H), 8.65 (s, 1H, 6-H); 13C NMR: d 39.0
(C-40), 54.2 and 54.4 (OCH3), 65.4 (CH2OCOPh), 78.0
(C-50), 105.2 (C-5), 128.3, 129.4, 129.5 and 133.1 (C-Ph),
151.5 (C]N), 158.1 (C-6), 165.7, 166.1 and 167.9 (C-2,
C-4 and C]O); MS (EI): m/z (%) 343 (MC, 9%). Anal.
Calcd for C17H17N3O5: C, 59.47; H, 4.99; N, 12.44. Found:
C, 59.34; H, 4.89; N, 12.39.
3.4.4.
5-(50-Benzoyloxymethyl-isoxazol-30-yl)-2,4-
dimethoxypyrimidine (17). This compound was obtained
in 90% yield as a white solid, mp 98–100 8C; IR (Nujol):
nmax 3050, 1715, 1590, 1550 cmK1; 1H NMR: d 4.07 (s, 3H,
OCH3), 4.11 (s, 3H, OCH3), 5.48 (s, 2H, CH2OCOPh), 6.82
(s, 1H, 40-H), 7.47 (t, JZ7.4 Hz, 2H, Ph-H), 7.58 (t, JZ
7.4 Hz, 1H, Ph-H), 8.09 (d, JZ7.4 Hz, 2H, Ph-H), 8.85 (s,
1H, 6-H); 13C NMR: d 54.4 and 55.2 (OCH3), 56.7
(CH2OCOPh), 104.7 (C-5), 104.9 (C-40), 128.5, 129.5,
129.9 and 133.6 (C-Ph), 156.6 (C]N), 158.1 (C-6), 163.5,
165.8, 166.7 and 168.1 (C-2, C-4, C-50 and C]O); MS (EI):
m/z (%) 341 (MC, 23). Anal. Calcd for C17H15N3O5: C,
59.82; H, 4.43; N, 12.31. Found: C, 59.60; H, 4.53; N, 12.51.
3.5.3. (30RS,50SR)-5-(50-Benzoyloxymethyl-isoxazolidin-
30-yl)-2,4-dimethoxypyrimidine (19). This compound was
obtained in 52% yield as an oil; IR (liquid film): nmax 3060,
1
1715, 1595, 1565 cmK1; H NMR: d 2.05 (dt, JZ12.8,
6.4 Hz, 1H, 40-H), 2.68 (s, 3H, N–CH3), 2.89 (ddd, JZ12.8,
8.4, 7.7 Hz, 1H, 40-H), 3.85 (dd, JZ8.4, 6.4 Hz, 1H, 30-H),
3.97 (s, 3H, OCH3), 4.00 (s, 3H, OCH3), 4.37 (dd, JZ11.5,
3.9 Hz, 1H, CH2OCOPh), 4.45 (dd, JZ11.5, 7.1 Hz, 1H,
CH2OCOPh), 4.61 (dddd, JZ7.7, 7.1, 6.4, 3.9 Hz, 1H,
50-H), 7.37 (s, 1H, 6-H), 7.42 (t, JZ7.6 Hz, 2H, Ph-H), 7.54
(t, JZ7.6 Hz, 1H, Ph-H), 8.01 (d, JZ7.6 Hz, 2H, Ph-H);
13C NMR: d 38.9 (C-40), 43.5 (N–CH3), 53.9 (OCH3), 54.7
(OCH3), 64.1 and 66.0 (C-30 and CH2OCOPh), 74.3 (C-50),
113.1 (C-5), 128.2, 129.6, 129.8 and 132.9 (C-Ph), 156.4
(C-6), 164.6, 166.4 and 168.7 (C-2, C-4 and C]O); MS
(EI): m/z (%) 359 (MC, 17). Anal. Calcd for C18H21N3O5:
C, 60.16; H, 5.89; N, 11.69. Found: C, 60.28; H, 6.10;
N, 11.39.
3.5. Reactions of nitrones 4 and 14 with the dipolarophile 5
General procedure. A solution of the nitrone 4 or 14
(0.5 mmol) and the dipolarophile 5 (1 mmol) in xylene
(5 ml) was heated to reflux and the reaction was monitored
by TLC until the consumption of the nitrone. After 2 days
only traces of the nitrone were detected in the TLC. The
heating was stopped and after evaporation of the solvent the
residue was chromatographed on a silica gel column with
hexane–ethyl acetate (1/1 for the reaction of 4a, 3/1 for the
reaction of 4b, 2/1 for the reaction of 14) as the eluent.
3.5.1. (30RS,50SR)-5-(50-Benzoyloxymethyl-isoxazolidin-
30-yl)-1-octyluracil (9a). This compound was obtained
in 72% yield as an oil; IR (liquid film): nmax 3190, 3060,
3.5.4. (30RR,50SS)-5-(50-Benzoyloxymethyl-isoxazolidin-
30-yl)-2,4-dimethoxy-pyrimidine (20). This compound
was obtained in 26% yield as an oil; IR (liquid film): nmax
3060, 1710, 1660, 1600–1560 cmK1; 1H NMR: d 2.41 (ddd,
JZ14.2, 7.7, 5.7 Hz, 1H, 40-H), 2.55 (ddd, JZ14.2, 8.9,
1715–1650, 1595, 1575 cmK1; H NMR: d 0.87 (t, JZ
1
8.5 Hz, 3H, CH3), 1.15–1.40 (m, 10H, CH2CH2(CH2)5CH3),
1.50–1.65 (m, 2H, CH2CH2(CH2)5CH3), 2.10 (dt, JZ12.2,

1500
E. Coutouli-Argyropoulou et al. / Tetrahedron 62 (2006) 1494–1501
3.9 Hz, 1H, 40-H), 2.69 (s, 3H, N–CH3), 4.00 (s, 3H, OCH3),
4.02 (s, 3H, OCH3), 4.24 (dd, JZ5.7, 3.9 Hz, 1H, 30-H),
4.41 (dd, JZ12.2, 6.4 Hz, 1H, CH2OCOPh), 4.50–4.61 (m,
2H, CH2OCOPh and 50-H), 7.47 (t, JZ7.4 Hz, 2H, Ph-H),
7.57 (t, JZ7.4 Hz, 1H, Ph-H), 8.11 (d, JZ7.4 Hz, 2H,
74.6 (C-50), 113.0 (C-5), 128.3, 129.5 and 133.2 (C-Ph),
138.2 (C-6), 151.6 (C-2), 163.9 (C-4), 166.5 (C]O); MS:
m/z (%) 331 (MC, 10). Anal. Calcd for C16H17N3O5: C,
58.00; H, 5.17; N, 12.68. Found: C, 57.98; H, 5.01; N, 12.82.
13
Ph-H), 8.35 (s, 1H, 6-H); C NMR: d 38.7 (C-40), 43.8
3.7. Hydrolysis of compounds 9
(N–CH3), 54.0 (OCH3), 54.7 (OCH3), 64.0 and 65.4 (C-30
and CH2OCOPh), 74.8 (C-50), 112.6 (C-5), 128.3, 129.6,
129.9 and 133.0 (C-Ph), 156.6 (C-6), 164.6, 167.6 and 169.3
(C-2, C-4 and C]O); MS (EI): m/z (%) 359 (MC, 14). Anal.
Calcd for C18H21N3O5: C, 60.16; H, 5.89; N, 11.69. Found:
C, 60.26; H, 5.99; N, 11.30.
General procedure. An aqueous solution (1 ml) of KOH
(10%) was added to a methanolic solution (5 ml) of the
compound 9a or 9b (0.1 mmol) and the reaction mixture was
stirred at room temperature for 24 h. After that the methanol
was evaporated, water was added, neutralized with
ammonium chloride and the mixture was extracted with
methylene chloride. The organic layer was dried over
sodium sulfate and after evaporation of the solvent
compounds 22 were obtained quantitatively as oils. For
analytical purposes, they were further purified by column
chromatography on a silica gel column with ethyl acetate as
the eluent.
3.6. Demethylation of compounds 15, 17 and 19
General procedure. The dimethoxy derivative 15 or 17 or
19 (0.2 mmol) was heated with sodium iodide (0.1 g) in
glacial acetic acid (3 ml) at 90 8C for 1 h. The solvent was
removed under reduced pressure and the residue was
chromatographed on a silica gel column with 3% methanol
in methylene chloride as the eluent.
3.7.1. (30RS,50SR)-5-(50-Hydroxymethyl-isoxazolidin-
30-yl)-1-octyluracil (22a). This compound was obtained
in 100% yield as an oil; IR (liquid film): nmax 3400, 3180,
3050, 1690–1640 cmK1; 1H NMR: d 0.87 (t, JZ6.6 Hz, 3H,
CH3), 1.19–1.40 (m, 10H, CH2CH2(CH2)5CH3), 1.59–1.73
(m, 2H, CH2CH2(CH2)5CH3), 2.01 (dt, JZ12.9, 5.9 Hz, 1H,
40-H), 2.50 (br s, 1H, OH), 2.69 (s, 3H, N–CH3), 2.91
(dt, JZ12.9, 7.9 Hz, 1H, 40-H), 3.59 (dd, JZ12.8, 5.3 Hz, 1H,
CH2OH), 3.64–3.79 (m, 3H, CH2CH2(CH2)5CH3 and
CH2OH), 3.90 (dd, JZ7.9, 5.9 Hz, 1H, 30-H), 4.36–4.46 (m,
1H, 50-H), 7.48 (s, 1H, 6-H), 9.62 (br s, 1H, NH); 13C NMR: d
14.0 (CH3), 22.5, 26.4, 29.1, 29.7 and 31.6 (CH2(CH2)6CH3),
37.7 (C-40), 44.0 and 49.1 (CH2(CH2)6CH3 and N–CH3), 63.6
and 64.5 (C-30 and CH2OH), 76.6 (C-50), 112.9 (C-5), 141.7
(C-6), 150.5 (C-2), 163.5 (C-4); MS (EI): m/z (%) 339 (MC,
8). Anal. Calcd for C17H29N3O4: C, 60.15; H, 8.61; N,12.38.
Found: C, 60.01; H, 8.90; N, 12.14.
3.6.1. 5-(50-Benzoyloxymethyl-isoxazolin-30-yl)-uracil
(16). This compound was obtained in 72% yield as a
white solid, mp 253–257 8C; IR (Nujol): nmax 3210, 3080,
3040, 1710, 1640 cmK1 1H NMR (CDCl3/DMSO-d6):
;
d 3.35 (dd, JZ17.8, 6.9 Hz, 1H, 40-H), 3.52 (dd, JZ
17.8, 11.0 Hz, 1H, 40-H), 4.33 (dd, JZ12.3, 5.5 Hz, 1H,
CH2OCOPh), 4.42 (dd, JZ12.3, 3.5 Hz, 1H, CH2OCOPh),
4.96 (dddd, JZ11.0, 6.9, 5.5, 3.5 Hz, 1H, 50-H), 7.48 (t, JZ
7.7 Hz, 2H, Ph-H), 7.63 (t, JZ7.7 Hz, 1H, Ph-H), 7.77 (s,
1H, 6-H), 7.96 (d, JZ7.7 Hz, 2H, Ph-H), 10.12 (br s, 2H,
13
NH); C NMR (CDCl3/DMSO-d6): d 36.5 (C-40), 63.7
(CH2OCOPh), 75.5 (C-50), 101.1 (C-5), 126.7, 127.4, 127.7
and 131.4 (C-Ph), 139.6 (C-6), 148.9 (C-2), 150.4 (C]N),
160.1 (C-4), 163.4 (C]O); HRESIMS for C15H13N3O5
(MCNa)C: calcd 338.0747, found 338.0748.
3.6.2. 5-(50-Benzoyloxymethyl-isoxazol-30-yl)-uracil (18).
This compound was obtained in 67% yield as a white solid,
mp 217–220 8C; IR (Nujol): nmax 3210, 3080, 3050, 1715,
3.7.2. (30RS,50SR)-5-(50-Hydroxymethyl-isoxazolidin-
30-yl)-1,3-dioctyluracil (22b). This compound was obtained
in 100% yield as an oil; IR (liquid film): nmax 3400, 3060,
1690, 1660–1630 cmK1; 1H NMR: d 0.85–0.92 (m, 6H, CH3),
1.14–1.41 (m, 20H, CH2CH2(CH2)5CH3), 1.50–1.75 (m, 4H,
CH2CH2(CH2)5CH3), 1.97 (dt, JZ12.6, 6.4 Hz, 1H, 40-H),
2.30 (br s, 1H, OH), 2.68 (s, 3H, N–CH3), 2.87 (dt, JZ12.6,
8.3 Hz, 1H, 40-H), 3.59 (dd, JZ11.9, 5.2 Hz, 1H, CH2OH),
3.69–3.80 (m, 3H, CH2CH2(CH2)5CH3 and CH2OH),
3.85–3.96 (m, 3H, CH2CH2(CH2)5CH3 and 30-H),
4.34–4.43 (m, 1H, 50-H), 7.35 (s, 1H, 6-H); 13C NMR: d
14.0 (CH3), 22.6, 26.5, 27.0, 27.5, 29.1, 29.2, 29.7, 31.7 and
31.8 (CH2(CH2)6CH3), 38.0 (C-40), 41.6, 44.0 and 50.0
(CH2(CH2)6CH3 and N–CH3), 64.1 and 64.9 (C-30 and
CH2OH), 76.9 (C-50), 112.1 (C-5), 139.2 (C-6), 150.8 (C-2),
162.7 (C-4); MS (EI): m/z (%) 451 (MC, 9). Anal. Calcd for
C25H45N3O4: C, 66.48; H, 10.04; N, 9.30. Found: C, 66.26; H,
10.21; N, 9.25.
1
1590 cmK1; H NMR (CDCl3/DMSO-d6): d 5.47 (s, 2H,
CH2OCOPh), 7.02 (s, 1H, 40-H), 7.51 (t, JZ7.4 Hz, 2H,
Ph-H), 7.64 (t, JZ7.4 Hz, 1H, Ph-H), 8.01–8.07 (over-
lapped d and s, 3H, Ph-H and 6-H), 11.34–11.52
(overlapped br s, 2H, NH); 13C NMR (CDCl3/DMSO-d6):
d 55.1 (CH2OCOPh), 100.0 (C-5), 102.7 (C-40), 126.9,
127.7, 128.0 and 131.9 (C-Ph), 139.5 (C-6), 149.3, 155.1,
160.6 163.5 and 164.6 (C-2, C-4, C]N C-50and C]O);
HRESIMS for C15H11N3O5 (MCNa)C: calcd 336.0591,
found 336.0591.
3.6.3. (30RS,50SR)-5-(50-Benzoyloxymethyl-isoxazolidin-
30-yl)-uracil (21). This compound was obtained in 76%
yield as a white solid, mp 210–212 8C; IR (Nujol): nmax 3190,
1
3150, 3060, 1710, 1660 cmK1; H NMR (CDCl3/CD3OD):
d 2.03 (dt, JZ12.9, 6.1 Hz, 1H, 40-H), 2.72 (s, 3H, N–CH3),
2.98 (ddd, JZ12.9, 9.2, 7.4 Hz, 1H, 40-H), 3.85 (dd, JZ7.4,
6.1 Hz, 1H, 30-H), 4.33–4.42 (m, 2H, CH2OCOPh),
4.61–4.70 (m, 1H, 50-H), 7.42 (s, 1H, 6-H), 7.43 (t, JZ
7.4 Hz, 2H, Ph-H), 7.56 (t, JZ7.4 Hz, 1H, Ph-H), 8.00 (d,
JZ7.4 Hz, 2H, Ph-H); 13C NMR (CDCl3/CD3OD): d 37.7
(C-40), 43.9 (N–CH3), 63.2 and 65.3 (C-30 and CH2OCOPh),
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