Application of chiral cyclic nitrones to the diastereoselective synthesis of bicyclic isoxazolidine nucleoside analogues

Article abstract of DOI:10.1080/15257770701572055

New bicyclic isoxazolidine nucleoside analogues are synthesized through 1,3-dipolar cycloaddition of enantiopure cyclic nitrones to appropriate vinyl nucleobases. The reactions are diastereoselective, giving as the main or the sole product the exo-Re cycloadducts. The diastereoselectivity depends on both the kind of the base and the substitution pattern of the nitrone. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/15257770701572055

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Application of Chiral Cyclic Nitrones
to the Diastereoselective Synthesis
of Bicyclic Isoxazolidine Nucleoside
Analogues
Evdoxia Coutouli-Argyropoulou a , Christos Xatzis a & Nikolaos
Argyropoulos a
a Department of Chemistry, Laboratory of Organic Chemistry,
Aristotle University of Thessaloniki, Thessaloniki, Greece
Version of record first published: 16 Dec 2010.
To cite this article: Evdoxia Coutouli-Argyropoulou , Christos Xatzis & Nikolaos Argyropoulos (2008):
Application of Chiral Cyclic Nitrones to the Diastereoselective Synthesis of Bicyclic Isoxazolidine
Nucleoside Analogues, Nucleosides, Nucleotides and Nucleic Acids, 27:1, 84-100
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Nucleosides, Nucleotides, and Nucleic Acids, 27:84–100, 2008
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770701572055
APPLICATION OF CHIRAL CYCLIC NITRONES TO THE
DIASTEREOSELECTIVE SYNTHESIS OF BICYCLIC ISOXAZOLIDINE
NUCLEOSIDE ANALOGUES
Evdoxia Coutouli-Argyropoulou, Christos Xatzis, and
Nikolaos G. Argyropoulos
Department of Chemistry, Laboratory of Organic Chemistry, Aristotle University of
Thessaloniki, Thessaloniki, Greece
New bicyclic isoxazolidine nucleoside analogues are synthesized through 1,3-dipolar cycloaddi-
2
tion of enantiopure cyclic nitrones to appropriate vinyl nucleobases. The reactions are diastereoselec-
tive, giving as the main or the sole product the exo-Re cycloadducts. The diastereoselectivity depends
on both the kind of the base and the substitution pattern of the nitrone.
Keywords Isoxazolidines; nucleoside analogues; cyclic nitrones; vinyl nucleobases
INTRODUCTION
In the last two decades nucleoside analogues in which the furanose ring
has been replaced by a different carbo- or heterocyclic ring have attracted
special interest by virtue of their biological action as antiviral and anticancer
agents.[1] Among them isoxazolidine nucleosides have emerged as an
important class of nucleoside analogues with potential pharmacological
activity and several approaches for their synthesis have been reported.[2] For
construction of the heterocyclic ring the well-known convenient 1,3-dipolar
cycloaddition approach has been applied in most cases.
Between the several parameters concerning the structure–activity re-
lationship, of immense importance is the conformational behavior of
natural as well as modified nucleosides, since conformational preferences
are observed in the several enzymatic steps. Especially, nucleoside ana-
logues with restricted conformational flexibility induced by a second ring
are target compounds in many cases as potent inhibitors of HIV re-
verse transcriptase.[3] Thus, the incorporation of isoxazolidine rings into
Received 8 January 2007; accepted 29 June 2007.
Address correspondence to Evdoxia Coutouli-Argyropoulou, Department of Chemistry, Laboratory
of Organic Chemistry, Aristotle University of Thessaloniki, Thessaloniki 54124, Greece.
84

Application of Chiral Cyclic Nitrones
85
conformationally restrained nucleoside analogues should be of consider-
able interest. However, to the best of our knowledge only two examples
of bicyclic N ,O-nucleoside analogues have been recently appeared in the
literature.[4] As targeted isoxazolidine analogues we have planned com-
pounds of the general structure A, where the isoxazolidine ring mimics
the sugar moiety and the second five membered ring induces restricted
conformational mobility. Moreover the stereochemical outcome can be
manipulated by the spatial disposition of the functional groups on the
cyclopentane ring. The synthesis of these compounds can be easily achieved
using cyclic nitrones in the 1,3-dipolar cycloaddition approach. Regarding
the attachment of the nucleobase, it may be done either before the for-
mation of the heterocyclic ring, by applying vinyl derivatives of pyrimidine
and purine nucleobases as dipolarophiles, or after the cycloaddition step via
nucleophilic substitution of a suitable preexisting on the starting materials
leaving group by a nucleobase. The application of chiral cyclic nitrones in
the above reaction sequences seems to be of particular importance, since it
allows the creation of multiple stereocenters in a single step with complete
control of their relative configuration.
In connection with our previous studies on the synthesis of modified
nucleosides[5] we report in this paper the synthesis of new bicyclic isoxazo-
lidine nucleoside analogues of the general structure A applying 1,3-dipolar
cycloaddition approach with chiral cyclic nitrones.
RESULTS AND DISCUSSION
For the purposes of our study we have used the previously prepared
chiral polysubstituted nitrones 1 and 2 possessing two different stereo-
chemical patterns of substituents. Nitrone 1 was prepared from d-ribose
and its synthesis and applications to the preparation of pyrrolidine and
pyrrolizidine derivatives have been previously described by us.[6] Nitrone
2 was prepared from d-arabinose and its synthesis and application as
intermediate for the total synthesis of pyrrolizidine alkaloids hyacinthacine

86
E. Coutouli-Argyropoulou et al.
A2 and 7-deoxycasuarine have been previously described by research groups
of Carmona,[7a] Goti,[7b] and Sardine.[7c]
The required vinyl bases 3 were prepared by known alkylation fol-
lowed by elimination procedures.[8] The reactions between nitrone 1 and
vinylbases 3 were carried out by refluxing equimolecular amounts of the
reactants in toluene under an argon atmosphere until the disappearance
of the starting compounds. From the reactions there were obtained the
two diastereoisomers 4 and 5 in high total yields (96–99%) and in ratio
4.5:1 from the reaction with vinyladenine and 2.3:1 from the reactions with
vinylthymine and vinyluracil (Scheme 1).
The structure elucidation of the obtained cycloadducts was mainly based
1
on their spectral data. H NMR assignments, where it was possible, were
confirmed by double-resonance experiments, and selected values, useful
for diagnostic purposes, are given in Table 1. The proposed regiochemistry
is in accordance to the well-established regiochemistry of cycloadditions
SCHEME 1

87

88
E. Coutouli-Argyropoulou et al.
SCHEME 2
of nitrones with monosubstituted alkenes as dipolarophiles where the
formation of 5-substituted isoxazolidines predominates[9] and it is strongly
supported by the chemical shift of the next to isoxazolidine oxygen 7-H
proton, which appears as a doublet of doublets at the higher δ value.
For 5-substituted isoxazolidines there are four possible diastereomers
arising from the exo/endo approach of dipolarophile and also from the Re
and the Si face of the reacting nitrone, as depicted in Scheme 2 for the
nitrone 1. Between these four possible diastereomeric structures the major
products 4 were assigned as exo-Re cycloadducts (Scheme 2, structure I),
whereas the minor products 5 were assigned as exo-Si cycloadducts (structure
III).
The data of Table 1 show that each of the methylene 8-H protons
exhibits, besides their geminal coupling constant (J 1-82 = 13.1–14.3 Hz),
8
a large one (J = 7.0–9.4 Hz) and a small or zero one (J = 0–3.6 Hz). This
shows that each of the 8-H is trans to one of its neighboring 7-H and 8a-H
and cis to the other, which holds only in structures I and III. Futhermore,
in the minor isomer 5 8a-H exhibits two large coupling constants (J =
7.7–7.8 Hz), indicating that, besides to one of the 8-H, it is also cis to
8b-H as it holds in structure III. Therefore, on the basis of the values of
coupling constants, structures I and III were assigned for the major and
minor isomers, respectively. The proposed structure for the major isomer

Application of Chiral Cyclic Nitrones
89
FIGURE 1 NOE enhancements measured on compound 4a.
was further supported by NOE measurements performed on compound 4a
as depicted in Figure 1. The mutual NOE enhancements observed between
8-H2 with both 7-H and 8b-H show that these protons are on the same side
of the plane. Similarly, the significant positive NOE observed between 8a-H
with both 4-H and 8-H1 shows also that these protons are on the same side
above the rings. These spatial arrangements of protons are possible only in
structure I.
The reactions between the nitrone 2 and the vinyl bases 3 were also
performed by refluxing equimolecular amounts of the reactants in toluene
until the disappearance of the starting compounds. The reaction with
vinyladenine gave only isomer 6 in 60% yield, whereas reactions with
vilyluracil and vilylthymine gave the two diastereoisomers 6 and 7 in a ratio
10:1 and 75–80% total yield (Scheme 3).
The structure elucidation of the obtained cycloadducts was based on
their spectral data. 1H NMR assignments, where it was possible, were
confirmed by double-resonance experiments, and selected values, useful for
diagnostic purposes, are given in Table 2.
As in the case of the reactions of nitrone 1, the obtained cycloadducts
were safely assigned as 5-substituted regioisomers on the basis the chemical
shift of the next to isoxazolidine oxygen 2-H proton, which appears as
a doublet of doublets at the higher δ (6.08–6.51). The four possible
diastereomers arising from the exo/endo approach of dipolarophile and
from the Re/Si face of the nitrone 2 are given in Scheme 4. The values of
Table 2 show that the cis to the base more shielded 3-H1 exhibits a small
coupling constant with 2-H (2.2–3.4 Hz) and a larger one (7.3–7.9) with
3a-H indicative that it is trans to 2-H and cis to 3a-H. This arrangement
holds only in structures I and III. Futhermore, in the major isomer 6 the
4-H exhibits two equal rather small coupling constants (J = 4.4–4.6 Hz) with
3a-H and 5-H, indicative that it is trans to both of them. Between structures

90
E. Coutouli-Argyropoulou et al.
SCHEME 3
I and III this arrangement holds only in structure I. In the minor isomer 7
the less protected 3-H2 trans to the base moiety and cis to 2-H exhibits a zero
coupling constant with 3a-H showing their trans arrangement. Therefore,
similarly to the cycloadducts 4 and 5 of nitrone 1, the major products 6 are
assigned as exo-Re cycloadducts (structure I), whereas the minor products 7
are assigned as exo-Si cycloadducts (structure III).
The proposed structures are further supported by NOE measurements
performed on compounds 6c and 7c as depicted in Figures 2 and 3,
respectively. In compound 6c the significant NOE enhancement observed
between the trans to the base 3-H2 and 4-H shows that they are at the same
side. Similarly, in compound 7c the remarkable NOE between the 3-H2
and one of the methylene CH2OBn protons shows that these protons are
on the same side. In accordance with the proposed structure, a significant
positive NOE is also developed on one of CH2OBn upon saturation of 2-H.
However, it should be noted that the more informative for the structure
determination NOE measurements, between 3a-H and its neighboring
protons, were not possible since in all compounds 3a-H appears as multiplet
overlapped with other chemical shifts.
The observed diastereoselectivity of the reactions of nitrones 1 and 2
is in accordance with molecular model predictions. Thus, in all cases the
stereochemically favored exo adducts are formed with predominance of the
exo-Re adduct, which comes from the less sterically hindered transition state.
These findings are also in line with the well-documented behavior of cyclic
nitrones to react via exo transition states[10] and our previous results on
the reactions of nitrone 1 with several dipolarophiles.[6b] Between the two
nitrones studied, nitrone 2 has a more restricted Si phase since besides the
substituent at the 5-position bears also a substituent at the 3-position towards
this phase. Thus, nitrones of this type have been referred to show almost

91

92
E. Coutouli-Argyropoulou et al.
SCHEME 4
perfect discrimination of the two faces affording products only from the
Re-face with the exo-Re as the major or the sole product and the endo-Re as
the minor one.[7a,7b,10d] However, in our experiments with nitrone 2 and
vinyl bases the above described evidence supports structure 7 for the minor
isomer resulting from an exo-Si approach. Nevertheless, the increased steric
hindrance results in a higher diastereoselectivity of nitrone 2 giving rise
exclusively or higher ratios of the major exo-Re adducts. An interesting point
is also the influence of the base on the diastereoselectivity of the reactions.
Thus, the bulkier vinyladenine 3a increases the steric hindrance and induces
higher diastereoselectivity in the reactions with both nitrones 1 and 2. So,
the reaction of the nitrone 1 with 3a gives the major adduct 4 in a higher
ratio (4.5:1 compared to 2.3:1 with 3b and 3c), whereas the reaction of 2
with 3a gives exclusively the major adduct 6.
In conclusion, the cycloaddition reactions of the chiral cyclic nitrones 1
and 2 with vinyl nucleic bases can lead conveniently to asymmetric bicyclic
isoxazolidine nucleoside analogues. All the reactions are diastereoselective
giving the exo-Re cycloadducts as the main or the sole product. The diastere-
oselectivity is dictated by steric factors and it is mainly determined by the
nitrone configuration enhanced further by the magnitude of the nucleic
base in the olefin moiety. These results, together with the possibility to use
sugar-derived cyclic nitrones with known and desirable configuration, allow

Application of Chiral Cyclic Nitrones
93
FIGURE 2 NOE enhancements measured on compound 6c.
access to bicyclic nucleoside analogues, as possible candidates for biological
applications, in a stereocontrolled and predictable manner.
EXPERIMENTAL
Mps are uncorrected and were determined on a Kofler hot-stage micro-
1
scope. IR spectra were recorded on a Perkin-Elmer 297 spectrometer. H
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. 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 analyzer. Column
FIGURE 3 NOE enhancements measured on compound 7c.

94
E. Coutouli-Argyropoulou et al.
chromatography was carried out on Merck Kieselgel (particle size
0.063–0.200 mm) and solvents were distilled before use.
General Procedure for the Cycloaddition Reactions
A solution of the nitrone 1 or 2 (0.5 mmol) and the dipolarophile
3 (0.5 mmol) in toluene (5 mL) was heated to reflux under an argon
atmosphere and the reaction was monitored by TLC until the consumption
of the starting reagents. This took about 2 days for the reactions of nitrone 1
and 8–10 hours for the reactions of nitrone 2. Then the heating was stopped
and after evaporation of the solvent the residue was chromatographed on
a silica gel column with ethyl acetate–methanol 95:5 (for the reaction of 1
with 3a), ethyl acetate (for the reactions of 1 with 3b and 3c and 2 with 3a)
and ethyl acetate–hexane 2:1 (for the reactions of 2 with 3b and 3c) as the
eluents. With the exception of 5a and 7b in all other cases it was possible
to isolate from the column fractions with separated pure isomers. The given
yields are the total yields as they were calculated from the pure fractions and
the estimated consistency of the mixtures by 1H NMR.
9-{(3aS,4S,7R,8aR,8bR)-4-(2-methoxy-2-oxoethyl)-2,2-
dimethylhexahydro [1,3]dioxolo[3,4]pyrrolo[1,2-b]isoxazol-
7-yl}adenine (4a)
This compound was obtained from the reaction of nitrone 1
with 9-vinyadenine (3a) in 81% yield as an solid mp 185–187◦C; Rf
1
(EtOAc/MeOH, 95:5) 0.47; H NMR (CDCl3) δ: 1.36 (s, 3H, CH3), 1.56
(s, 3H, CH3), 2.79 (dd, J = 15.4, 5.8 Hz, 1H, CH2CO2CH3), 2.93 (dd, J =
15.4, 8.9 Hz, 1H, CH2CO2CH3), 3.00 (ddd, J = 13.1, 9.4, 3.2 Hz, 1H, 8-H),
3.16 (ddd, J = 13.1, 7.7, 1.3 Hz, 1H, 8-H), 3.71 (s, 3H, OCH3), 3.80 (br q,
1H, 4-H), 4.03 (br d, 1H, 8a-H), 4.65 (dd, J = 6.4, 3.2 Hz, 1H, 8b-H), 4.81 (t,
J = 6.4 Hz, 1H, 3a-H), 5.89 (br s, 2H, NH2), 6.44 (dd, J = 7.7, 3.2 Hz, 1H,
7-H), 8.17 (s, 1H, Ad-H), 8.33 (s, 1H, Ad-H); 13C NMR (CDCl3) δ: 25.1 and
27.4 (CH3), 34.4 and 42.9 (CH2CO2CH3 and C-8), 51.9 (OCH3), 69.7, 70.2,
81.1, 85.6, and 88.3 (C-3a, C-4, C-7, C-8a, and C-8b), 115.3 (C(CH)3), 119.2,
138.8, 149.3, 152.8, and 155.4 (C-Ad), 171.3 (C=O);MS: m/z (%): 391(32)
[M+H+]. Anal. calcd. for C17H22N6O5 (315.33): C, 52.30; H, 5.68; N, 21.53.
Found: C, 52.56; H, 5.90; N, 21.23.
9-{(3aS,4S,7S,8aS,8bR)-4-(2-methoxy-2-oxoethyl)-2,2-
dimethylhexahydro [1,3]dioxolo[3,4]pyrrolo[1,2-b]isoxazol-
7-yl}adenine (5a)
This compound was obtained from the reaction of nitrone 1 with 9-
vinyladenine (3a) as a mixture with the isomer 4a and it was characterized

Application of Chiral Cyclic Nitrones
95
1
only from its NMR data assigned in the mixture (yield 18%). H NMR
(CDCl3) δ: 1.30 (s, CH3), 1.33 (s, CH3), 2.52 (d, J = 7.0 Hz, CH2CO2CH3),
2.66 (ddd, J = 14.0, 7.9, 2.9 Hz, 8-H), 3.40 (ddd, J = 14.0, 7.7, 1.5 Hz,
8-H), 3.74 (s, OCH3), 3.97–4.05 (m, 4-H superimposed with 8a-H of the 4a
isomer), 4.19 (t, J = 7.8 Hz, 8a-H), 4.73–4.82 (m, 3a-H, 8b-H superimposed
with 3a-H of 4a isomer), 6.30 (br s, NH2), 6.40–6.47 (m, 7-H, superimposed
with 7-H of 4a isomer), 8.17 (s, 1H, Ad-H), 8.33 (s, 1H, Ad-H); 13C NMR
(CDCl3) δ: 24.2 and 26.6 (CH3), 36.7 and 38.1 (CH2CO2CH3 and C-8), 52.0
(OCH3), 67.4, 68.1, 82.3, 82.7, and 87.1 (C-3a, C-4, C-7, C-8a, and C-8b),
113.4 (C(CH)3), 119.4, 138.7, 149.3, 152.9, and 155.4 (C-Ad), 171.3 (C=O).
1-{(3aS,4S,7R,8aR,8bR)-4-(2-methoxy-2-oxoethyl)-2,2-
dimethylhexahydro [1,3]dioxolo[3,4]pyrrolo[1,2-b]isoxazol-
7-yl}uracil (4b)
This compound was obtained from the reaction of nitrone 1 with 1-
1
vinyuracil (3b) in 67% yield as an oil; Rf (EtOAc) 0.47; H NMR (CDCl3)
δ: 1.33 (s, 3H, CH3), 1.53 (s, 3H, CH3), 2.67 (ddd, J = 14.3, 7.7, 3.2 Hz,
1H, 8-H), 2.80 (dd, J = 14.8, 5.8 Hz, 1H, CH2CO2CH3), 2.90 (dd, J = 14.8,
9.6 Hz, 1H, CH2CO2CH3), 3.12 (dd, J = 14.3, 7.0 Hz, 1H, 8-H), 3.67–3.75
(overlapped s and m, 4H, OCH3, and 4-H), 3.88 (dd, J = 7.7, 3.2 Hz, 1H,
8a-H), 4.58 (dd, J = 7.0, 3.2 Hz, 1H, 8b-H), 4.78 (t, J = 7.0 Hz, 1H, 3a-H),
5.69 (d, J = 8.3 Hz, 1H, Ur-H), 6.09 (dd, J = 7.0, 3.2 Hz, 1H, 7-H), 7.73
(d, J = 8.3 Hz, 1H, Ur-H), 9.37 (br s, 1H, NH); 13C NMR (CDCl3) δ: 25.0
and 27.3 (CH3), 34.4 and 43.2 (CH2CO2CH3 and C-8), 51.9 (OCH3), 70.1,
70.5, 83.2, 85.4, and 87.7 (C-3a, C-4, C-7, C-8a and C-8b), 101.9 (C-Ur),
115.4 (C(CH)3), 140.0, 150.4, and 163.4 (C-Ur), 171.3 (C=O); HRESIMS
for C16H21N3O7 (M+Na)+: calcd. 390.1272, found 390.1274. Anal. calcd.
for C16H21N3O7: C, 52.31; H, 5.76; N, 11.44. Found: C, 51.95; H, 5.78; N,
11.28.
1-{(3aS,4S,7S,8aS,8bR)-4-(2-methoxy-2-oxoethyl)-2,2-
dimethylhexahydro [1,3]dioxolo[3,4]pyrrolo[1,2-b]isoxazol-
7-yl}uracil (5b)
This compound was obtained from the reaction of nitrone 1 with 1-
1
vinyuracil (3b) in 29% yield as an oil; Rf (EtOAc) 0.36; H NMR (CDCl3)
δ: 1.30 (s, 3H, CH3), 1.49 (s, 3H, CH3), 2.36–2.48 (m, 2H, 8-H and
CH2CO2CH3), 2.54 (dd, J = 15.4, 7.1 Hz, 1H, CH2CO2CH3), 3.32 (dd, J
= 13.9, 7.1 Hz, 1H, 8-H), 3.71 (s, 3H, OCH3), 3.88 (br q, 1H, 4-H), 4.23 (t,
J = 7.7 Hz, 1H, 8a-H), 4.70–4.77 (m, 2H, 3a-H, and 8b-H), 5.69 (d, J = 8.4
Hz, 1H, Ur-H), 6.09 (dd, J = 7.1, 3.2 Hz, 1H, 7-H), 7.76 (d, J = 8.4 Hz,
1H, Ur-H), 8.66 (br s, 1H, NH); 13C NMR (CDCl3) δ: 24.1 and 26.5 (CH3),
36.4 and 38.8 (CH2CO2CH3 and C-8), 52.1 (OCH3), 67.9, 68.6, 82.6, 85.5,

96
E. Coutouli-Argyropoulou et al.
and 87.1 (C-3a, C-4, C-7, C-8a, and C-8b), 101.9 (C-Ur), 113.4 (C(CH)3),
140.2, 150.3, and 163.3 (C-Ur), 170.7 (C=O). HRESIMS for C16H21N3O7
(M+Na)+: calcd. 390.1272, found 390.1270. Anal. calcd. for C16H21N3O7:
C, 52.31; H, 5.76; N, 11.44. Found: C, 52.18; H, 5.95; N, 11.49.
1-{(3aS,4S,7R,8aR,8bR)-4-(2-methoxy-2-oxoethyl)-2,2-
dimethylhexahydro [1,3]dioxolo[3,4]pyrrolo[1,2-b]isoxazol-
7-yl}thymine (4c)
This compound was obtained from the reaction of nitrone 1 with 1-
vinythymine (3c) in 68% yield as a solid mp 182–184◦C; Rf (EtOAc) 0.52;
1H NMR (CDCl3) δ: 1.34 (s, 3H, CH3), 1.54 (s, 3H, CH3), 1.94 (s, 3H, CH3),
2.67 (ddd, J = 14.1, 7.7, 3.6 Hz, 1H, 8-H), 2.83 (dd, J = 15.3, 5.8 Hz, 1H,
CH2CO2CH3), 2.92 (dd, J = 15.3, 9.5 Hz, 1H, CH2CO2CH3), 3.11 (dd, J
= 14.1, 7.7 Hz, 1H, 8-H), 3.67–3.78 (overlapped s and m, 4H, OCH3, and
4-H), 3.89 (dd, J = 7.7, 3.6 Hz, 1H, 8a-H), 4.60 (dd, J = 6.7, 3.6 Hz, 1H,
8b-H), 4.76 (t, J = 6.7 Hz, 1H, 3a-H), 6.09 (dd, J = 7.7, 3.6 Hz, 1H, 7-H),
7.58 (s, 1H, Thy-H), 9.40 (br s, 1H, NH); 13C NMR (CDCl3) δ: 12.4, 25.0,
and 27.2 (CH3), 34.4 and 43.1 (CH2CO2CH3 and C-8), 51.9 (OCH3), 70.1,
70.5, 83.0, 85.5, and 87.7 (C-3a, C-4, C-7, C-8a, and C-8b), 110.4 (C-Thy),
115.4 (C(CH)3), 135.8, 150.5, and 164.0 (C-Thy), 171.3 (C = O). HRESIMS
for C17H23N3O7 (M+Na)+: calcd. 404.1428, found 404.1430. Anal. calcd.
for C17H23N3O7: C, 53.54; H, 6.08; N, 11.02. Found: C, 53.19; H, 5.94; N,
10.78.
1-{(3aS,4S,7S,8aS,8bR)-4-(2-methoxy-2-oxoethyl)-2,2-
dimethylhexahydro [1,3]dioxolo[3,4]pyrrolo[1,2-b]isoxazol-
7-yl}thymine (5c)
This compound was obtained from the reaction of nitrone 1 with 1-
1
vinythymine (3c) in 30% yield as an oil; Rf (hexane/EtOAc, 3:1) 0.41; H
NMR (CDCl3) δ: 1.31 (s, 3H, CH3), 1.49 (s, 3H, CH3), 1.92 (s, 3H, CH3),
2.30–2.48 (m, 2H, 8-H, and CH2CO2CH3), 2.58 (dd, J = 16.0, 7.1 Hz, 1H,
CH2CO2CH3), 3.29 (dd, J = 13.5, 7.7 Hz, 1H, 8-H), 3.73 (s, 3H, OCH3),
3.85 (br q, 1H, 4-H), 4.22 (t, J = 7.7 Hz, 1H, 8a-H), 4.67–4.78 (m, 2H, 3a-H,
and 8b-H), 6.09 (dd, J = 7.7, 2.6 Hz, 1H, 7-H), 7.57 (s, 1H, Thy-H), 8.68 (br
s, 1H, NH); 13C NMR (CDCl3) δ: 12.6, 24.6, and 26.5 (CH3), 36.6 and 38.8
(CH2CO2CH3 and C-8), 52.0 (OCH3), 67.7, 68.5, 82.6, 84.5, and 87.2 (C-3a,
C-4, C-7, C-8a, and C-8b), 110.2 (C-Thy), 113.4 (C(CH)3), 136.1, 159.3, and
163.9 (C-Thy), 170.7 (C=O). HRESIMS for C17H23N3O7 (M+Na)+: calcd.
404.1428, found 404.1429. Anal. calcd. for C17H23N3O7: C, 53.54; H, 6.08;
N, 11.02. Found: C, 53.41; H, 6.12; N, 10.83.

Application of Chiral Cyclic Nitrones
97
9-{(2R,3aR,4R,5R,6R)-4,5-bis(benzyloxy)-6-
[(benzyloxy)methyl]hexahydro pyrrolo[1,2-b]isoxazol-
2-yl}adenine (6a)
This compound was obtained from the reaction of nitrone 2 with 9-
vinyadenine (3a) in 60% yield as an oil; Rf (EtOAc) 0.12; 1H NMR (CDCl3)
δ: 2.80–2.92 (m, 2H, 3-H), 3.57–3.77 (m, 3H, 6-H, CH2OCH2Ph), 3.92 (m,
1H, 3a-H), 4.14 (t, J = 4.4 Hz, 1H, 4-H) 4.21(t, J = 4.4 Hz, 1H, 5-H),
4.46–4.65 (m, 6H, CH2OCH2Ph), 6.32 (br s, 2H, NH2), 6.51 (dd, J = 5.7,
3.1 Hz, 1H, 2-H), 7.11–7.47 (m, 15H, Ph-H), 8,24 (s, 1H, Ad-H), 8.31 (s,
1H, Ad-H); 13C NMR (CDCl3) δ: 41.4 (C-3), 67.5, 69.7, 71.4, 72.2, 72.4, 73.4,
83.6, 85.5, and 87.9 (C-2, C-3a, C-4, C-5, C-6, and CH2), 119.6 (C-Ad), 127.7,
127.9, 128.0, 128.5, 137.4, 137.8, and 138.1 (C-Ph), 138.9, 149.1, 152.9, and
155.6 (C-Ad); HRESIMS for C33H34N6O4 (M+Na)+: calcd. 601.2534, found
601.2535. Anal. calcd. for C33H34N6O4: C, 68.49; H, 5.92; N, 14.52. Found:
C, 68.55; H, 6.07; N, 14.22.
1-{(2R,3aR,4R,5R,6R)-4,5-bis(benzyloxy)-6-
[(benzyloxy)methyl]hexahydro pyrrolo[1,2-b]isoxazol-
2-yl}uracil (6b)
This compound was obtained from the reaction of nitrone 2 with 9-
1
vinyuracil (3b) in 68% yield as an oil; Rf (hexane/EtOAc, 1:2) 0.40; H
NMR (CDCl3) δ: 2.43 (ddd, J = 13.9, 7.7, 2.2 Hz, 1H, 3-H), 2.81 (dt, J =
13.9, 6.5 Hz, 1H, 3-H), 3.53–3.73 (m, 4H, 3a-H, 6-H, CH2OCH2Ph), 4.07
(t, J = 4.6 Hz, 1H, 4-H), 4.12 (t, J = 4.6 Hz, 1H, 5-H), 4.45–4.60 (m, 6H,
CH2OCH2Ph), 5.68 (d, J = 8.6 Hz, 1H, Ur-H), 6.25 (dd, J = 6.5, 2.2 Hz, 1H,
2-H), 7.19–7.41 (m, 15H, Ph-H), 7.68 (d, J = 8.6 Hz, 1H, Ur-H), 10.00 (s,
1H, NH); 13C NMR (CDCl3) δ: 41.9 (C-3), 67.0, 69.4, 71.3, 72.1, 73.2, 85.1,
85.4, and 87.9 (C-2, C-3a, C-4, C-5, C-6, and CH2), 101.7 (C-Ur), 127.5, 127.6,
127.7, 127.9, 128.3, 128.4, 137.3, 137.6, and 137.8 (C-Ph), 140.1, 150.3, and
163.8 (C-Ur); HRESIMS for C32H33N3O6 (M+Na)+: calcd. 601.2534, found
601.2535. Anal. calcd. for C32H33N3O6: C, 69.17; H, 5.99; N, 7.56. Found: C,
69.18; H, 6.08; N, 7.74.
1-{(2S,3aS,4R,5R,6R)-4,5-bis(benzyloxy)-6-
[(benzyloxy)methyl]hexahydro pyrrolo[1,2-b]isoxazol-
2-yl}uracil (7b)
This compound was obtained from the reaction of nitrone 2 with 9-
vinyuracil (3b) only as a mixture with the isomer 6b and it was characterized
1
only from its NMR data assigned in the mixture (yield 7%). H NMR
(CDCl3) δ: 2.39 (ddd, J = 13.5, 7.9, 3.0 Hz, 1H, 3-H), 3.20 (dd, J = 13.5,
7.1 Hz, 3-H), 3.52–3.62 (m, 6-H), 3.75 (dd, J = 10.0, 4.8 Hz, CH2OCH2Ph),

98
E. Coutouli-Argyropoulou et al.
3.89–4.19 (m, 3a-H, 4-H, 5-H, CH2OCH2Ph), 4.45–4.65 (m, CH2OCH2Ph),
5.62 (d, J = 8.3 Hz. 1H, Ur-H), 6.07 (dd, J = 7.1, 3.0 Hz, 2-H), 7.19–7.41
(m, Ph-H), 7.85 (d, J = 8.3 Hz. 1H, Ur-H), 9.20 (br s, 1H, NH). 13C NMR
(CDCl3) δ: 39.9 (C-3), 66.5, 68.1, 69.0, 72.7, 72.9, 73.3, 84.5, 85.5, and 87.6
(C-2, C-3a, C-4, C-5, C-6, and CH2), 101.6 (C-Ur), 127.7, 127.8, 127.9, 128,
128.4, 128.6, 129.7, 137.2, 137.5, and 137.7 (C-Ph), 140.6, 150.4, and 163.8
(C-Ur).
1-{(2R,3aR,4R,5R,6R)-4,5-bis(benzyloxy)-6-
[(benzyloxy)methyl]hexahydro pyrrolo[1,2-b]isoxazol-
2-yl}thymine (6c)
This compound was obtained from the reaction of nitrone 2 with 9-
vinythymine (3c) in 73% yield as a solid mp 139–141◦C; Rf (hexane/EtOAc,
1
1:2) 0.59; H NMR (CDCl3) δ: 1.91 (s, 3H, CH3), 2.49 (ddd, J = 13.6, 7.5,
2.6 Hz, 1H, 3-H), 2.81 (dt, J = 13.6, 6.6 Hz, 1H, 3-H), 3.57–3.73 (m, 4H,
3a-H, 6-H, CH2OCH2Ph), 4.07 (t, J = 4.4 Hz, 1H, 4-H), 4.15 (t, J = 4.4 Hz,
1H, 5-H), 4.43–4.68 (m, 6H, CH2OCH2Ph), 6.25 (dd, J = 6.6, 2.6 Hz, 1H,
2-H), 7.19–7.41 (m, 15H, Ph-H), 7.48 (s, 1H, Thy-H), 9.22 (s, 1H, NH); 13C
NMR (CDCl3) δ: 12.4 (CH3), 41.6 (C-3), 67.2, 69.5, 71.4, 72.1, 73.2, 84.9,
85.2, and 87.9 (C-2, C-3a, C-4, C-5, C-6, and CH2), 110.4 (C-Thy), 127.5,
127.7, 127.9, 128.2, 128.4, and 128.5 (C-Ph), 135.7 (C-Thy), 137.3, 137.6,
and 137.0 (C-Ph), 150.3 and 164.2 (C-Thy); HRESIMS for C33H35N3O6
(M+H)+: calcd. 570.2599, found 570.2593. Anal. calcd. for C33H35N3O6:
C, 69.58; H, 6.19; N, 7.38. Found: C, 69.59; H, 6.26; N, 7.46.
1-{(2S,3aS,4R,5R,6R)-4,5-bis(benzyloxy)-6-
[(benzyloxy)methyl]hexahydro pyrrolo[1,2-b]isoxazol-
2-yl}thymine (7c)
This compound was obtained from the reaction of nitrone 2 with 9-
1
vinythymine (3c) in 7% yield as an oil; Rf (hexane/EtOAc, 1:2) 0.44; H
NMR (CDCl3) δ: 1.84 (s, 3H, CH3), 2.37 (ddd, J = 13.6, 7.3, 3.4 Hz, 1H,
3-H), 3.18 (dd, J = 13.6, 7.5 Hz, 1H, 3-H), 3.48–3.58 (m, 1H, 6-H), 3.75
(dd, J = 9.5, 4.6 Hz, 1H, CH2OCH2Ph), 3.89–4.16 (m, 4H, 3a-H, 4-H, 5-H,
CH2OCH2Ph), 4.45–4.65 (m, 6H, CH2OCH2Ph), 6.08 (dd, J = 7.5, 3.4 Hz,
1H, 2-H), 7.19–7.41 (m, 15H, Ph-H), 7.67 (s, 1H, Thy-H), 8.38 (s, 1H, NH);
13C NMR (CDCl3) δ: 12.5 (CH3), 38.1 (C-3), 67.0, 68.0, 69.4, 72.8, 73.0, 73.4,
84.4, 85.3, and 87.5 (C-2, C-3a, C-4, C-5, C-6, and CH2), 110.2 (C-Thy), 127.7
127.9, 128.1, 128.5, and 128.6 (C-Ph), 136.2 (C-Thy), 137.3, 137.6, and 137.0
(C-Ph), 150.2 and 163.8 (C-Thy); HRESIMS for C33H35N3O6 (M+Na)+:
calcd. 592.2418, found 592.2419. Anal. calcd. for C33H35N3O6: C, 69.58; H,
6.19; N, 7.38. Found: C, 69.20; H, 6.34; N, 7.17.

Application of Chiral Cyclic Nitrones
99
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