1,3-Dipolar cycloaddition of nitrones with phenylvinyl sulfone. An experimental and theoretical study

Article abstract of DOI:10.1016/j.tetasy.2012.01.006

The addition of three nitrones to phenylvinylsulfone, 1, has been studied. The stereochemistry previously established by two-dimensional NMR techniques was confirmed by X-ray crystal structure determination. Theoretical studies made us propose that this r

Full text of DOI:10.1016/j.tetasy.2012.01.006

Tetrahedron: Asymmetry 23 (2012) 76–85
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1,3-Dipolar cycloaddition of nitrones with phenylvinyl sulfone.
An experimental and theoretical study
MariFe Flores a, Pilar García a, Narciso M. Garrido a, Carlos T. Nieto a, Pilar Basabe a, Isidro S. Marcos a,
Francisca Sanz-González b, Jonathan M. Goodman c, David Díez a,
⇑
a Departamento de Química Orgánica, Facultad de Ciencias Químicas, Universidad de Salamanca, Plaza de los Caídos 1-5, 37008 Salamanca, Spain
b Servicio General de Rayos X, Universidad de Salamanca, Universidad de Salamanca, Spain
c Department of Chemistry, Lensfield Road, Cambridge, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
The addition of three nitrones to phenylvinylsulfone, 1, has been studied. The stereochemistry previously
established by two-dimensional NMR techniques was confirmed by X-ray crystal structure determina-
tion. Theoretical studies made us propose that this reaction is not purely regioselective, but by controlling
the substituents of nitrone and temperature the regioselectivity increases.
Received 13 December 2011
Accepted 5 January 2012
Available online 8 February 2012
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
O
O
BnO
OBn
The 1,3-dipolar cycloaddition is one of the most useful reactions
in organic synthesis.1 Many dipoles and dipolarophiles have been
employed to obtain either carbocycles or heterocycles. It is worth
mentioning that nitrones have been successfully employed to pro-
duce aza-heterocycles such as isoxazolidines in a simple manner.2
The 1,3-dipolar cycloaddition of nitrones derived from pyrrolidine
compounds to different dipolarophiles has been an essential trans-
formation in the synthesis of pyrrolidines, pyrrolizidines, and ind-
olizidines because of the important role of these ring systems in
many natural products with physiological activity.3 Although the
intermolecular cycloaddition of nitrones with alkenes has been
extensively studied, the corresponding reaction of nitrones with
phenylvinylsulfones has received little attention.4
Recently, there has been a renewed interest in the crystallogra-
phy of sulfones,5 thus we decided to study the cycloaddition of sev-
eral nitrones with a commercially available sulfone. Herein the
behavior of three nitrones (Fig. 1), which has been previously stud-
ied in cycloaddition reactions to obtain biologically active com-
pounds3 with phenylvinylsulfone 1 is disclosed. This sulfone has
been employed to obtain isoxazolidines, but always with open
chain nitrones.6
N
O
N
O
N
O
4
2
3
Figure 1. Nitrones employed in the study.
2. Results and discussion
Our study began with the 1,3-dipolar cycloaddition reaction of
chiral nitrone 3 with phenylvinylsulfone in different solvents and
under conditions as shown in Table 2. We selected nitrone 3 be-
cause it has been used extensively by others for the synthesis of
many biologically active compounds,3b,c,g and the possibility that
the resulting isoxazolidines would be crystalline. As a conse-
quence, it was possible to easily establish unequivocally the ste-
reochemistry of the final adducts. When 3 was reacted with
phenylvinylsulfone 1 in toluene, the four isoxazolidines 5a–5d
were obtained (Scheme 1).
The structure of these compounds was established by one and
two-dimensional NMR experiments. The assignments of all the
hydrogens and carbons are included in the Experimental. The
hydrogen coupling constants, especially H3 and H3a (Table 1),
were essential for the determination of the stereochemistry. Com-
pounds 5a–5d were all crystalline and it was possible to confirm
their structures unequivocally by single crystal X-ray diffraction
(Fig. 2).9
Nitrone, 2, has been obtained as described by Brandi and Cor-
dero et al.7 Chiral nitrone 3, has been synthesized according to
the procedure of Goti et al.3c Finally nitrone 4, was obtained start-
ing from diethyl tartrate according to the procedure of Brandi
et al.8
⇑
Corresponding author. Tel.: +34 923 294474; fax: +34 923 294574.
E-mail address: ddm@usal.es (D. Díez).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2012.01.006

MariFe Flores et al. / Tetrahedron: Asymmetry 23 (2012) 76–85
77
O
O
O
O
O
O
O
O
O
O
H
H
H
H
4
Ph
O
6
a
SO2Ph
SO2Ph
N
N
S
3a
N
O
+
N
N
3
O
O
O
1 O
O
SO2Ph
SO2Ph
3
1
5a
5b
5c
5d
Scheme 1. Reaction of nitrone 3 with phenyl vinyl sulfone 1. See Table 2.
tio. In order to investigate the possibility of a retrocycloaddition we
submitted separately compounds 5a–5d into the same cycloaddi-
tion conditions. We only observed a conversion in quantitative
yield of 5b into 5a; all the rest were recovered without change.
(Scheme 2).
Table 1
Coupling constants for isoxazolidines 5a–5d
J (Hz) 5a 5b
H2 –H3 7.6 8.7
5c
5d
a
—
—
—
—
—
—
H2b–H3
H2 –H2 b
H2–H3
H2–H3b
H3 –H3b
H3–H3a
H3 –H3a
H3b–H3a
H3a–H4
H4–H5
5.6
7.6
—
—
—
5.6
—
—
1.8
6.2
6.2
3.0
8.7
8.7
a
O
O
O
O
a
—
—
—
8.8
7.4
3.8
13.6
—
5.8
7.6
2.6
6.2
5.6
3.6
13.8
7.4
13.6
—
7.4
7.4
1.8
6.6
5.6
2.6
13.2
H
H
a
Toluene, 110 ºC
100%
SO2Ph
SO2Ph
8.7
N
N
a
—
—
O
O
2.6
6.6
5.6
5b
5a
H5–H6
H5–H6b
H6 –H6b
a
Scheme 2. Conversion of 5b into 5a.
3.0
a
13.2
13.2
Having obtained the best yields with toluene at 25 °C, we chose
these conditions to study the 1,3-dipolar cycloaddition with the
other nitrones. Our results are shown in Scheme 3 and Table 3.
It was observed (Table 3, entry 1) that nitrone 2 reacts with
phenylvinylsulfone with no regio- or stereoselectivity. In the case
of nitrone 4, entry 2, the same facial selectivity as nitrone 3 is ob-
served: the addition is anti to the benzyl group in the 3-position of
nitrone. Nitrone 4 is less regioselective and shows the opposite
preference to nitrone 3 (Table 2, entry 5). Under the same condi-
tions, the proportion 5a + 5b is bigger than 7c + 7d for nitrone 3
than for nitrone 4.
See numbering of compounds in Scheme 1.
Table 2
Solvent and temperature conditions effect in the reaction of nitrone 3, with
phenylvinylsulfone 1
Entry
Solvent
Tª (°C)
t (h)
Yield
Additive
Ratio%
5a
5b
5c
5d
1
2
3
4
5
6
7
8
THF
THF
DCM
DCM
Toluene
Toluene
Toluene
Toluene
25
16
7
4
6
6
24
7
12
76
27
77
30
98
80
26
89
35
27
33
32
38
23
24
23
32
26
33
32
38
27
23
47
19
16
11
11
13
31
13
17
14
31
24
26
13
19
41
12
ꢀ78
25
In order to explain the experimental results, including the reg-
iochemistry, diastereoselectivity, and kinetic control, we under-
took a theoretical study of these dipolar cycloadditions. Although
there is a considerable background of theoretical studies about
1,3-dipolar cycloadditions in which nitrones are involved as di-
poles,10 and a wide variety of dipolarophiles have been checked,
surprisingly there are only a few examples of computational inves-
ꢀ78
25
25
HMPA
ꢀ78
85
tigations with a
,b-unsaturated sulfones.11
Mechanistic details such as regiochemistry, synchronicity, and
endo/exo ratios for this type of cycloaddition with nitrones have
been long discussed.11b Regiochemistry depends on the nature of
the dipolarophile; the endo/exo adducts ratio is related to the size
of both reactants, and the synchronicity is the result of several sys-
tem and environmental factors. Because of the nature of the envi-
ronment of the reactions (solvents rather apolar and aprotic), a
concerted cycloaddition mechanism was assumed.
3. Computational details
All the calculations were performed in Jaguar v. 7.6.12 Molecular
minimizations of reactants, products, and transition states were
carried out with Density Functional Theory (DFT) using Becke’s13
three-parameter hybrid exchange (B3) with the Lee-Yang-Parr’s14
(LYP) correlation functional (B3LYP). Although the use of B3LYP
for transition states has been shown to be rather effective, there
are some cases where the results are not reliable.15 Particularly
in the light of recent papers by Houk, showing that B3LYP may
not be the functional of choice for 4+2 cycloadditions,16 we’ve also
Figure 2. X-ray crystal structures for compounds 5a–5d.
As can be seen from Table 2, the stereochemistry of the addition
occurs anti with respect to the acetonide group. Isoxazolidines are
mainly obtained with the sulfonyl group in the 3-position and
there is no special endo/exo selectivity. When the reaction is
performed in the presence of a coordinating agent (entry 6) the
regioselectivity of the reaction changes though not the endo/exo ra-

78
MariFe Flores et al. / Tetrahedron: Asymmetry 23 (2012) 76–85
R
R
R
R
R
R
R
R
R
R
5a
H
H
H
H
Ph
O
a
SO2Ph
SO2Ph
N
N
S
N
O
+
N
N
O
O
O
O
O
SO2Ph
SO2Ph
1
R
H
R
R
R
H
R
H
2
4
H
6a
H
6b
6c
6d
OBn
OBn 7a
OBn 7b
OBn 7c
OBn 7d
Scheme 3. Reaction of nitrones 1 and 4 with phenylvinyl sulfone.
Table 3
Isoxazolidines obtained from reaction of nitrones 2 and 4 with phenylvinyl sulfone 1
Entry
Nitrone
Tª (°C)
t (h)
Yield
Isoxazolidines
a
b
c
d
1
2
2
4
25
25
6
6
38
45
1.1
1.2
1.3
1.0
1.0
2.5
1.1
Not observed
performed single point calculations with M05-2X17 over B3LYP
optimized geometries with ultrafine grid (UF), which has been
18
demonstrated to be a more realistic method.15 6-31G⁄ basis set
has been chosen to perform the calculations because it provides
good correlation with experimental data.19 Transition state search
was performed through Linear Synchronous Transit (LST), after
those geometry optimizations using the same theory level was
achieved. As the best yields of the reactions were obtained in tol-
uene, additional environmental effects were taken into account
through PBF20 solvent model, using toluene’s dielectric constant
Figure 3. Frontier molecular orbitals from sulfone 1 and nitrones 2 and 3.
at 298 K,
e = 2.34. Posterior vibrational normal mode analysis was
carried out to verify that reactants and products were stationary
points (zero imaginary frequencies) and transition structures had
one and only one imaginary frequency. Quick reaction coordinate
(QRC)21 was used for each transition structure to check that they
were on the pathway from reactants to products, rather than sug-
gesting a different mechanism. Thermodynamic data were ex-
tracted from vibration analysis and scaling factors were not
applied.
Table 4
HOMO/LUMO energies, electronic chemical potential, chemical hardness and global
electrophilicity index of reactants (in a.u.)
Molecule
HOMO
LUMO
l
g
x
1
2
3
ꢀ0.270
ꢀ0.228
ꢀ0.212
ꢀ0.051
ꢀ0.024
ꢀ0.008
ꢀ0.160
ꢀ0.126
ꢀ0.110
0.219
0.204
0.204
0.058
0.038
0.029
3.1. Computational analysis of reactants
Structures of phenylvinylsulfone 1 and nitrones 2, 3 were min-
imized according with the parameters described. After that, fron-
tier molecular orbital (FMO) analysis and global/local reactivity
indexes were used to predict regioselectivity. Figure 3 shows
FMO interactions of phenylvinylsulfone 1 with nitrones 2 and 3.
It is clear that the electron density transfer takes place from the
HOMO orbitals of nitrones to LUMO orbital of phenylvinylsulfone,
as a result of the small energy gap (normal electron demand char-
acter). This is supported with the global reactivity indexes summa-
rized in Table 4. Electronic chemical potential is defined as the
After evaluating the global nucleophilic/electrophilic character,
a local analysis was carried out through Fukui indices calculation.
Fukui functions are defined as f+
=
q
k(N + 1) ꢀ
k(N ꢀ 1), for LUMO/HOMO electron density varia-
tion. Thus, electrophilicity local indices are calculated from Fukui
parameters xk f . As we can see in Table 5, the preferred two
qk(N) and
k
fꢀ
=
qk(N) ꢀ
q
k
=
x
center interactions take place between centers O1–C1 and C2–C3,
leading to a 3-phenylsulfonyl isoxazolidine regiochemistry.
In summary, preliminary analysis of the reactants lead to two
ideas: (i) Nitrones act as nucleophiles and sulfones 1 as electro-
philes, (ii) the most favorable attack takes places from the O1 of
nitrones to C1 of sulfone, leading to a 3-phenylvinyl isoxazolidine
as the major regioisomer.
mean value of HOMO and LUMO energies [l = (eHOMO + eLUMO)/2]
and is a relative measure of the molecular capacity to donate elec-
tron density, while the global electrophilicity index is the ratio
x
g
=
l
2/(2
g
), which measures the total ability to attract electrons.
is the chemical hardness, and is the difference between the
= (eLUMO HOMO)].
3.2. Computational analysis of the reactions
HOMO and LUMO energies [
g
ꢀ
e
Dipoles 2–3 have an electronic chemical potential higher than
sulfone, which means that the electronic flow is again from the nit-
rone type dipoles to sulfone 1 as dipolarophile. Although the chem-
ical hardness of the three species involved are almost the same,
phenylvinylsulfone possesses a high electrophilicity, so it has more
potential to experience nucleophilic attacks than its dipole
counterparts.
The theoretical study of the reactants lead to an explanation for
the regiochemistry. Transition states and reaction pathways were
investigated next. Tables 6 and 7 and Figures 5 and 6 summarized
the energy and geometric and thermodynamic parameters to-
gether with energy profiles of the reaction between 1 and 3.
Figure 5 shows relative free energy profiles of the different path-
ways toward isoxazolidine products, differentiating regiochemical

MariFe Flores et al. / Tetrahedron: Asymmetry 23 (2012) 76–85
79
Table 5
where kB is Boltzmann’s constant; h is Planck’s constant; R is the
ideal gas constant; T is the temperature (25 °C), and,
Gà is the rel-
Fukui functions and local electrophilicity indexes for the centers of the species
involved in the 1,3-dipolar cycloaddition
D
ative Gibbs energy of the transition state structures. It is interesting
to note that the activation enthalpies for TS-5a and TS-5b are
slightly lower than other intermediates with B3LYP functional,
but the TS-5b enthalpy according to M05-2X theory is much lower
almost 6 kcal/mol. Moreover, the activation entropies in both theo-
ries are similar, with no special differences between channels. This
results in a small Gibbs activation energy of the 3-phenylsulphonyl
isoxazolidine pathway 5b, as a consequence of the minimum entro-
py effect on different channels and a dominance of the enthalpy
term, which are plotted in Figure 5.
2
Ph
1
3
S
O
O
O2
2 N
1
O
1
3
2
2 N
1
O
3
Sulfone 1
Nitrone 2
Nitrone 3
C1
C2
O1
C3
O1
C3
Rate constants were calculated to compare experimental and
theoretical results, suggesting that the major product should be
5b, with the other isomers forming to a much lesser extent. One
reason of this discrepancy between theoretical and experimental
results might be the type of functional used; therefore single point
calculations on each of the gas phase optimized structures with the
M05-2X functional under an ultrafine grid (UF), together with the
PBF solvation model, was envisaged as has been described previ-
ously. The results show no new differences, keeping the 5b channel
as the only product. However, the corresponding energies of the
products are lower than the B3LYP model, showing that a possible
backward process would be energetically more demanding than
the direct cycloaddition.
From these results, we conclude that the theoretical behaviors
are far from the experimental results, which imply that there is a
competition between kinetic and thermodynamic effects and Eyr-
ing theory does not completely cover the study. The reaction en-
ergy studies compared with the experimental data suggest that
at lower temperatures the reaction is not a pure cycloaddition
and could take place in two steps: Michael addition and then
cyclization.
f+
0.229
0.014
0.014
0.001
0.124
0.010
0.007
0.001
0.164
0.521
0.006
0.020
0.449
0.344
0.018
0.013
0.180
0.500
0.005
0.015
0.405
0.366
0.012
0.011
fꢀ
x+
xꢀ
routes employing B3LYP/6-31G⁄ theory and M05-2X(UF)/6-31G⁄//
B3LYP/6-31G⁄. According to the B3LYP/6-31G⁄ results, 5b pathway
is the most favorable line of reaction both in the gas phase and
surrounded by a toluene Poisson-Boltzmann Finite (PBF) type envi-
ronment, with a difference of 2 kcal/mol in solvent with respect to
the next transition level (Table 6). Furthermore, comparing the
molecular gas phase and solution energies is remarkable that in
gas phase the second favorable pathway is to 5d, while in a solvated
system, 5a is as favorable as 5d. This observation suggests that in the
gas phase the endo approach is more important than regiochemistry,
as a consequence of secondary orbital interaction between HOMO
and LUMO, which is comparable to solvation effects forward. In 5b,
this interaction takes place between H of nitrone 3 and O of sulfone
1, while in 5d, the interaction is localized as a lateral interaction be-
tween HOMO and LUMO, as a result of the extension of the latter
along the sulfone group (Fig. 4).
Another interesting feature is that when the four cycloaddition
products were heated in toluene separately only 5b turns into 5a
(Scheme 2); the rest did not exhibit any transformation. This fact
is consistent with the idea that these reactions are thermally
irreversible, as a consequence of the greater activation energy (be-
tween 23 and 28 kcal/mol for B3LYP, 32–41 kcal/mol for M05-2X)
Table 6 presents thermodynamic data for the structures stud-
ied. Rate constants were calculated according with the Eyring tran-
sition state theory:
DGz
TkB
h
ꢀ
ð
RT Þ
k ¼
e
ð1Þ
Table 6
Relative enthalpies (kcal/mol), entropies (cal/K/mol) and Gibbs energies (kcal/mol) in solution at 298 K
Reaction
Species
(PBF)B3LYP/6-31G⁄
(PBF)M05-2X(UF)/6-31G⁄//B3LYP/6-31G⁄
a
a
a
a
a
a
D
H
D
S
D
G
k(25)
krel
30
%
D
H
D
S
D
G
k(25)
krel
%
1 + 3
TS-5a
TS-5b
TS-5c
TS-5d
5a
13.59
11.03
14.10
14.13
ꢀ17.45
ꢀ16.32
ꢀ20.75
ꢀ18.63
ꢀ42.35
ꢀ42.94
ꢀ47.36
ꢀ43.13
ꢀ52.60
ꢀ52.94
ꢀ56.97
ꢀ37.83
26.21
23.83
28.22
26.98
ꢀ1.78
ꢀ0.54
ꢀ3.77
ꢀ7.36
3.72 ꢁ 10ꢀ7
1.90 ꢁ 10ꢀ5
9.03 ꢁ 10ꢀ8
1.11 ꢁ 10ꢀ8
2
98
0
8.91
1.20
7.86
7.31
ꢀ32.95
ꢀ31.77
ꢀ31.23
ꢀ35.25
ꢀ50.38
ꢀ51.01
ꢀ49.71
ꢀ50.29
ꢀ52.47
ꢀ53.24
ꢀ51.71
ꢀ52.19
23.94
16.41
22.68
22.31
ꢀ17.30
ꢀ15.90
ꢀ15.81
ꢀ19.69
1.74 ꢁ 10ꢀ5
5.76
1
0
1700
331693
100
0
1
8
1.44 ꢁ 10ꢀ4
8
16
0
2.72 ꢁ 10ꢀ4
0
5b
5c
5d
Transition structures are listed with theoretical rate constants (in sꢀ1) and relative ratio to 5c. PBF-B3LYP/6-31G(d) and M05-2X (UF)/6-31G⁄//B3LYP/6-31G⁄ theories.
Table 7
Bond distances, bond differences and bond final distance average (in Ångstrom) of the minimized structures
Reaction
Species
d(O1–C1)
d(C2–C3)
D
d(O1–C1)
D
d(C2–C3)
%
1 + 3
TS-5a
TS-5b
TS-5c
TS-5d
5a
5b
5c
5d
2.021
1.841
2.074
2.199
1.444
1.420
1.385
1.396
2.239
2.326
2.188
2.090
1.554
1.540
1.541
1.531
0.577
0.421
0.689
0.803
0.685
0.786
0.647
0.559
40
30
50
58
44
51
42
37

80
MariFe Flores et al. / Tetrahedron: Asymmetry 23 (2012) 76–85
HOMO
HOMO
LUMO
LUMO
5b
5d
Figure 4. Detail of secondary orbital interaction for intermediates 5b and 5d.
O
N
O
N
O
O
H
H
5a,
SO2Ph (
)
5b,
SO2Ph (
)
O
O
5c
SO2Ph (
,
)
O
O
5d
SO2Ph (
,
)
Figure 5. Free energy reaction profiles of the 1,3-dipolar cycloadditions of nitrone 3 with phenylvinylsulfone 1 using B3LYP/6-31G(d) theory (left) and M05-2X (UF)/6-31G⁄//
B3LYP/6-31G⁄ theory (right), both with a PBF solvation model.
for the possible cycloreversion reactions. If these barriers were
lower, a mixture of the four products would be obtained. For this
reason, the mechanism of the interconversion is in agreement with
an epimerization type reaction through the betaine intermediate I
(Scheme 4). This outcome would explain a theoretical increase in
5a, due to the involvement of this epimerization after the
cycloaddition.
Figure 6 shows geometrical parameters of the bonds of the five
centers involved in the isoxazolidine ring formation.
Table 7 shows bond lengths of the transition structures and sta-
tionary points, and difference between each state. To check the
synchronicity of the reactions, average difference between transi-
tion bond structures and products were calculated.
formation is more advanced, while in pathways c/d it is more
delayed. This is reflected by the Fukui indices: in the first case
(a most favorable interaction) and a small repulsive interaction
between oxygen of the nitrone and oxygen of the sulfone group
in the latter. Local reactivity indexes also explain that the least
synchronous transition state 5b led also to the lowest activation
barrier, as a result of the most favorable interactions. The lower
synchronicity of the reaction, the further from a cyclic electron
density flow and, consequently, electron density is more local-
ized and a weaker stabilization is seen in non-polar solvents
such as toluene. This could be the reason why the transition
structure 5b has the weakest solvent stabilization and 5a has
the strongest.
As can be seen, these 1,3 dipolar cycloadditions are slightly
asynchronous, due to the small difference between both dis-
tances. It is interesting that in pathways a/b the O1–C1 bond
The following reaction profiles between phenylvinylsulfone 1
and nitrone 2 was realized. Results are summarized in Tables 8
and 9 and Figures 7 and 8.

MariFe Flores et al. / Tetrahedron: Asymmetry 23 (2012) 76–85
81
1.352
1.275
1.331
C3
1.337
C3
1.307
O1
C3
2.239
C2
1.293
O1
2.188
2.074
O1
2.021
2.326
1.348
1.388
C2
1.841
1.278
O1
C2
C1
C1
C3
2.199
C1
1.391
1.407
2.090
C1
C2
1.388
TS-5c
TS-5d
TS-5a
TS-5b
Figure 6. Transition structures of the dipolar cycloaddition reaction between sulfone 1 and nitrone 3. Bond lengths of selected bonds are in Ångstrom.
O
O
O
O
H
H
SO2Ph
SO2Ph
N
N
O
O
5b
5a
reasonably
stable
much
less
much
less
O
O
O
O
O
O
stable
stable
H
SO2Ph
N
N
N
O
O
O
SO2Ph
SO2Ph
I
II
Scheme 4. Probable betaine intermediates in the conversion of 5b to 5a.
III
Table 8
Relative enthalpies, Gibbs energies (both in kcal/mol) and entropies (cal/mol) in solution at 298 K
Reaction
Species
(PBF)B3LYP/6-31G⁄
(PBF)M05-2X(UF)/6-31G⁄//B3LYP/6-31G⁄
a
a
a
a
a
a
D
H
D
S
D
G
k(25)
krel
25
123
1
%
D
H
D
S
D
G
k(25)
krel
%
1 + 2
TS-6a
TS-6b
TS-6c
TS-6d
6a
12.10
11.08
14.39
13.55
ꢀ46.25
ꢀ46.48
ꢀ45.73
ꢀ47.77
ꢀ48.20
ꢀ49.79
ꢀ48.80
ꢀ55.88
25.89
24.94
28.02
27.79
3.99
6.52
4.71
4.28
6.41 ꢁ 10ꢀ7
3.21 ꢁ 10ꢀ6
1.75 ꢁ 10ꢀ8
2.61 ꢁ 10ꢀ8
16
82
0
3.18
1.68
7.83
6.99
ꢀ24.66
ꢀ23.18
ꢀ23.11
ꢀ25.22
ꢀ48.86
ꢀ49.29
ꢀ48.56
ꢀ49.21
ꢀ50.82
ꢀ51.36
ꢀ51.07
ꢀ50.87
17.75
16.38
22.31
21.67
0.6
4182
42,292
9
91
0
6.07
2.70 ꢁ 10ꢀ4
2
6
1
1
8.02 ꢁ 10ꢀ4
0
ꢀ10.37
ꢀ9.51
6b
6c
6d
ꢀ8.32
ꢀ7.87
ꢀ9.84
ꢀ7.88
ꢀ12.37
ꢀ10.05
Transition structures are listed together with negative imaginaries frequencies and theoretical rate constants (in sꢀ1).
Once again, according to the B3LYP functional used, the 6b
route is the most favorable reaction pathway, both in the gas phase
and solution. However, the difference between this route and the
next one, 6a, is smaller than the previous case. Another interesting
aspect is the preference toward 6a/6b pathways and no great endo
approach selectivity. This is significant, because the dioxolane
group has a weak second order interaction between HOMO and
LUMO and this interaction is not present for unsubstituted 2.
Table 8 and Figure 7 show thermodynamic data for the four
routes and the relative energy profile of the 1 + 2 dipolar cycload-
dition. Channels 6a/6b show as well a low activation enthalpy
compared with the rest, and activation entropies of these channels
are slightly less negative (B3LYP). Differences between Gibbs acti-
vation energies are smaller than the previous case (about 1 kcal/
mol between energy levels). Rate constant calculations show again
that 6b is the more favorable product. As far as M05-2X

82
MariFe Flores et al. / Tetrahedron: Asymmetry 23 (2012) 76–85
Table 9
Bond distances, bond differences and bond final distance average (in Ångstrom) of the minimized structures
Reaction
Species
d(O1–C1)
d(C2–C3)
D
d(O1–C1)
D
d(C2–C3)
%
1 + 2
TS-6a
TS-6b
TS-6c
TS-6d
6a
6b
6c
6d
1.879
1.797
2.167
2.201
1.433
1.431
1.416
1.417
2.313
2.366
2.073
2.056
1.530
1.540
1.523
1.525
0.446
0.366
0.751
0.784
0.783
0.826
0.550
0.531
31
26
53
55
51
54
36
35
H
H
6a,
SO2Ph (
)
6b,
SO2Ph (
)
N
N
O
6c
SO2Ph (
,
)
O
O
SO2Ph (6d,
)
O
Figure 7. Free energy reaction profiles of the 1,3-dipolar cycloadditions of nitrone 2 with phenylvinylsulfone 1 using B3LYP/6-31G(d) theory (left) and M05-2X (UF)/6-31G⁄//
B3LYP/6-31G⁄ theory (right), both with PBF solvation model.
1.333
C3
1.352
C3
1.279
1.352
1.275
1.328
2.366
1.307
O1
O1
1.314
C3
O1
2.167
2.073
2.201
2.056
2.313
O1
1.879
1.388
C1
1.797
C2
C2
1.391
C1 1.401
1.411
C2
C1
C1
TS-6a
TS-6b
TS-6c
TS-6d
Figure 8. Transition structures of the dipolar cycloaddition reaction between sulfone 1 and nitrone 2. Bond lengths of selected bonds are in Ångstrom.
calculations are concerned, 6b is again the dominant reaction path-
way, due to the enthalpy value. And besides, the relative Gibbs en-
ergy of the products is now negative, diminishing the previously
B3LYP values in a similar fashion to the backward reaction. This
is more realistic since the reaction at room temperature is sponta-
neous: M05-2X predicts endergonic reactions, while B3LYP sup-
ports exergonic processes.
Figure 8 and Table 9 show geometrical parameters of the bonds
of the five atoms involved in the cycloaddition between 1 and 2, to-
gether with the synchronicity parameters of the reactions.
The data reveal similar conclusions to the initial cycloaddition
study of 1+3, although this cycloaddition is less synchronous.
In summary, reaction of nitrones 2 and 3 with phenylvinylsulf-
one 1 in toluene as solvent results in a mixture of diastereoisomers,
in which the major product is from the endo approach which leads
to a 3-phenylsulfonylisoxazolidines 5b and 6b, followed by the
other diastereoisomers 5a and 6a. However, the transition state
results suggest that the selectivity should be much higher than
that observed experimentally. This may be indicative of additional
processes that were not considered by the calculations, such as
alternative pathways or a different spin state. The conversion be-
tween 5b to 5a shows a very interesting behavior of this system,
and might compensate the large difference between epimers due
to a consecutive reaction. Alternatively, it may be an indication

MariFe Flores et al. / Tetrahedron: Asymmetry 23 (2012) 76–85
83
that the level of theory used (PBF-B3LYP/6-31G(d)) is insufficiently
accurate to compare the competing reactions in these cases. Single
point M05-2X calculations led to the same conclusions, but
improving the endergonic character of the reactions, correspond-
ing with the experimental behavior of these systems at 25 °C.
organic layers were washed with brine, dried (Na2SO4), filtered,
and concentrated. The resulting crude residue was purified by flash
chromatography (silica gel, hexane/EtOAc 6:4) to obtain isoxazoli-
dines 5a, 5b, 5c, and 5d in 77% combined yield.
Table 2, entry 4: Phenyl vinyl sulfone 1 (72.6 mg, 0.43 mmol) was
added to a solution of nitrone 3 (56.5 mg, 0.35 mmol) in DCM
(1.2 mL) at ꢀ78 °C. The resulting mixture was stirred for 6 h, then
it was quenched with saturated aqueous solution of NH4Cl and the
product was extracted with EtOAc (3 ꢁ 15 mL). The combined or-
ganic layers were washed with brine, dried (Na2SO4), filtered, and
concentrated. The resulting crude residue was purified by flash chro-
matography (silica gel, hexane/EtOAc 6:4) to obtain isoxazolidines
5a, 5b, 5c, and 5d in 30% combined yield.
Table 2, entry 5: Phenyl vinyl sulfone 1 (536 mg, 3.18 mmol)
was added to a solution of nitrone 3 (400 mg, 2.54 mmol) in tolu-
ene (8.5 mL) at rt. The resulting mixture was stirred for 6 h, then it
was quenched with saturated aqueous solution of NH4Cl and the
product was extracted with EtOAc (3 ꢁ 15 mL). The combined or-
ganic layers were washed with brine, dried (Na2SO4), filtered,
and concentrated. The resulting crude residue was purified by flash
chromatography (silica gel, hexane/EtOAc 6:4) to obtain isoxazoli-
dines 5a, 5b, 5c, and 5d in 98% combined yield. Ratio Table 2.
Table 2, entry 6: 1.0 equiv HMPA with respect to phenylvinyl-
sulfone 1 was added.
Table 2, entry 7: Phenyl vinyl sulfone 1 (62.4 mg, 0.37 mmol)
was added to a solution of nitrone 3 (46.6 mg, 0.29 mmol) in tolu-
ene (1 mL) at ꢀ78 °C. The resulting mixture was stirred for 7 h,
then it was quenched with saturated aqueous solution of NH4Cl
and the product was extracted with EtOAc (3 ꢁ 15 mL). The com-
bined organic layers were washed with brine, dried (Na2SO4), fil-
tered, and concentrated. The resulting crude residue was purified
by flash chromatography (silica gel, hexane/EtOAc 6:4) to obtain
isoxazolidines 5a, 5b, 5c, and 5d in 26% combined yield.
4. Conclusions
The 1,3-dipolar cycloadditions of phenylvinylsulfone and sev-
eral nitrones have been studied both experimentally and theoreti-
cally, showing that this reaction is not perfectly regioselective, but,
by controlling the substituents of nitrone and temperature, the
regioselectivity can be biased toward the 3-phenylisoxazolidine
products. X-ray structures and the coupling constants are given
for several isoxazolidines that will help in the structural determi-
nation of analogue compounds.
5. Experimental section
5.1. General
Unless otherwise stated, all chemicals were purchased as the
highest purity commercially available and were used without fur-
ther purification. IR spectra were recorded on a BOMEM 100 FT-IR
or an AVATAR 370 FT-IR Thermo Nicolet spectrophotometers. 1H
and 13C NMR spectra were performed in CDCl3 and referenced to
the residual peak of CHCl3 at d 7.26 ppm and d 77.0 ppm, for 1H
and 13C, respectively, using Varian 200 VX and Bruker DRX 400
instruments. Chemical shifts are reported in d ppm and coupling
constants (J) are given in Hertz. MS were performed at a VG-TS
250 spectrometer at 70 eV ionizing voltage. Mass spectra are pre-
sented as m/z (% rel int.). HRMS were recorded on a VG Platform
(Fisons) spectrometer using chemical ionization (ammonia as
gas) or Fast Atom Bombardment (FAB) technique. For some of
the samples, QSTAR XL spectrometer was employed for electro-
spray ionization (ESI). Optical rotations were determined on a Per-
kin-Elmer 241 polarimeter in 1 dm cells. THF were distilled from
sodium, and dichloromethane was distilled from calcium hydride
under argon atmosphere.
Table 2, entry 8: To a stirred solution of nitrone 3 (125 mg,
0.78 mmol) in toluene (4 mL), phenyl vinyl sulfone 1 (160 mg,
0.94 mmol) was added and the mixture was heated at 85 °C. After
12 h the reaction was quenched with saturated aqueous solution of
NH4Cl and the product was extracted with EtOAc (3 ꢁ 15 mL). The
combined organic layers were washed with brine, dried (Na2SO4),
filtered, and concentrated. The resulting crude residue was purified
by flash chromatography (silica gel, hexane/EtOAc 6:4) to obtain
isoxazolidines 5a, 5b, 5c and 5d in 89% combined yield.
5.2. Cycloaddition of nitrone 3 to phenyl vinyl sulfone 1
Table 2, entry 1: Phenyl vinyl sulfone 1 (64 mg, 0.39 mmol) was
added to a solution of nitrone 3 (40 mg, 0.26 mmol) in THF (1 mL)
at rt. The resulting mixture was stirred for 16 h, then it was
quenched with saturated aqueous solution of NH4Cl and the prod-
uct was extracted with EtOAc (3 ꢁ 15 mL). The combined organic
layers were washed with brine, dried (Na2SO4), filtered, and con-
centrated. The resulting crude residue was purified by flash chro-
matography (silica gel, hexane/EtOAc 6:4) to obtain
isoxazolidines 5a, 5b, 5c, and 5d in 76% combined yield.
Table 2, entry 2: Phenyl vinyl sulfone 1 (58.6 mg, 0.35 mmol)
was added to a solution of nitrone 3 (45.6 mg, 0.29 mmol) in THF
(1 mL) at ꢀ78 °C. The resulting mixture was stirred for 7 h, then
it was quenched with saturated aqueous solution of NH4Cl and
the product was extracted with EtOAc (3 ꢁ 15 mL). The combined
organic layers were washed with brine, dried (Na2SO4), filtered,
and concentrated. The resulting crude residue was purified by flash
chromatography (silica gel, hexane/EtOAc 6:4) to obtain isoxazoli-
dines 5a, 5b, 5c, and 5d in 27% combined yield.
5.2.1. (3R,3aR,4S,5R)-3-Phenylsulfonyl-4,5-isopropylidenedioxy-
hexahydropyrrolo[1,2-b]isoxazole 5a
½
a 2D0
ꢂ
¼ þ11:2 (c 0.7, CHCl3); IR (film)
m ;
: 3440, 2983, 2925 cmꢀ1
1H NMR (400 MHz, CDCl3, 25°, TMS): d = 7.96 (d, 3J (H,H) = 8.0 Hz,
2H), 7.71 (t, 3J (H,H) = 7.4 Hz, 1H), 7.63 (t, 3J (H,H) = 7.2 Hz, 2H),
4.84 (dt, 3J (H,H) = 2.8, 6.2 Hz, 1H), 4.50 (dd, 3J (H,H) = 1.8, 6.2 Hz,
1H), 4.20 (d, 3J (H,H) = 7.6 Hz, 1H), 4.05 (dd, 3J (H,H) = 1.8, 5.6 Hz,
1H), 3.91 (dd, 3J (H,H) = 5.6, 7.6 Hz, 1H), 3.33 (dd, 3J (H,H) = 2.8,
13.2 Hz, 1H), 3.17 (dd, 3J (H,H) = 6.2, 13.2 Hz, 1H), 1.47 (s, 3H),
1.25 ppm (s, 3H); 13C NMR (100 MHz, CDCl3, 25°, TMS): d = 137.5,
134.4, 129.6, 128.7, 113.1, 83.5, 79.6, 72.6, 70.3, 66.1, 59.2, 26.4,
24.8 ppm; HRMS (EI) C15H19NO5S requires (M+Na) 348. 0876;
found 348.0868.
5.2.2. (3S,3aR,4S,5R)-3-Phenylsulfonyl-4,5-isopropylidenedioxy-
hexahydropyrrolo[1,2-b]isoxazole 5b
½
a 2D0
ꢂ
¼ þ22:5 (c 1.4, CHCl3); IR (film)
m: 3457, 2987, 2921, 1315,
1156 cmꢀ1
;
1H NMR (400 MHz, CDCl3, 25°, TMS): d = 7.96 (d, 3J
(H,H) = 8.2 Hz, 2H), 7.70 (t, 3J (H,H) = 7.6 Hz, 1H), 7.60 (t, 3J
(H,H) = 7.4 Hz, 2H), 5.64 (dd, 3J (H,H) = 2.6, 6.6 Hz, 1H), 5.02 (ddd,
3J (H,H) = 3.0, 5.6, 6.6 Hz, 1H), 4.29 (t, 3J (H,H) = 8.7 Hz, 1H), 4.21
(t, 3J (H,H) = 8.7 Hz, 1H), 3.91 (dd, 3J (H,H) = 2.6, 8.7 Hz, 1H), 3.89
(t, 3J (H,H) = 8.7 Hz, 1H), 3.44 (dd, 3J (H,H) = 5.6, 13.2 Hz, 1H),
Table 2, entry 3: Phenyl vinyl sulfone 1 (25.4 mg, 0.15 mmol)
was added to a solution of nitrone 3 (18.4 mg, 0.12 mmol) in
DCM (0.5 mL) at rt. The resulting mixture was stirred for 4 h, then
it was quenched with saturated aqueous solution of NH4Cl and the
product was extracted with EtOAc (3 ꢁ 15 mL). The combined

84
MariFe Flores et al. / Tetrahedron: Asymmetry 23 (2012) 76–85
3.30 (dd, 3J (H,H) = 3.0, 13.2 Hz, 1H), 1.50 (s, 3H), 1.37 ppm (s, 3H);
13C NMR (100 MHz, CDCl3, 25°, TMS): d = 139.5, 134.3, 129.6, 128.0,
112.7, 80.2, 79.0, 72.9, 68.4, 65.9, 58.7, 26.7, 24.8 ppm; HRMS (EI)
(H,H) = 6.7 Hz, 2H), 4.16–4.11 (m, 2H), 4.05 (ddd, 3J (H,H) = 4.6,
8.8, 12.7 Hz, 1H), 3.76 (ddd, 3J (H,H) = 4.6, 7.3, 7.3 Hz, 1H), 3.20
(ddd, 3J (H,H) = 3.4, 7.9, 13.0 Hz, 1H), 2.99 (dt, 3J (H,H) = 13.0,
7.9 Hz, 1H), 2.05–1.94 (m, 1H), 1.94–1.86 (m, 1H), 1.78–1.69 (m,
1H), 1.65–1.60 ppm (m, 1H); 13C NMR (100 MHz, CDCl3, 25°,
TMS): d = 137.9, 134.2, 129.5, 128.6, 74.2, 66.2, 55.8, 31,
23.6 ppm; HRMS (EI) C12H15NO3S requires (M+Na) 276.0665;
found 276.0669.
C15H19NO5S requires (M+Na) 348. 0876; found 348.0868.
5.2.3. (2R,3aS,4S,5R)-2-Phenylsulfonyl-4,5-isopropylidenedioxy-
hexahydropyrrolo[1,2-b]isoxazole 5c
½
a 2D0
ꢂ
¼ þ155:0 (c 0.9, CHCl3); IR (film)
m: 3379, 2987, 2905,
1438, 1389, 1299 cmꢀ1 1H NMR (400 MHz, CDCl3, 25°, TMS):
;
d = 7.97 (d, 3J (H,H) = 7.6 Hz, 2H), 7.64 (t, 3J (H,H) = 7.8 Hz, 1H),
7.62 (t, 3J (H,H) = 7.4 Hz, 2H), 5.02 (dd, 3J (H,H) = 3.8, 8.8 Hz, 1H),
4.86 (m, H-5, 1H), 4.55 (dd, 3J (H,H) = 2.6, 6.2 Hz, 1H), 3.85 (ddd,
3J (H,H) = 2.6, 5.8, 8.0 Hz, 1H), 3.38 (dd, 3J (H,H) = 3.6, 13.8 Hz,
1H), 3.31 (dd, 3J (H,H) = 5.6, 13.8 Hz, 1H), 3.22 (ddd, 3J (H,H) = 3.8,
7.6, 13.6 Hz, 1H), 2.60 (ddd, 3J (H,H) = 5.8, 8.8, 13.6 Hz, 1H), 1.48
(s, 3H), 1.28 ppm (s, 3H); 13C NMR (100 MHz, CDCl3, 25°, TMS):
d = 136.0, 134.2, 129.1, 129.0, 113.4, 92.0, 83.9, 80.3, 70.9, 61.5,
33.6, 26.7, 24.8 ppm; HRMS (EI) C15H19NO5S requires (M+Na)
348. 0876; found 348.0868.
5.3.3. (2R⁄,3aR⁄)-2-Phenylsulfonyl-hexahydropyrrolo[1,2-b]isox-
azole 6c
IR (film)
m
: 3436, 3068, 2946, 2868, 1442, 1377, 1307, 1148,
1074 cmꢀ1
;
1H NMR (400 MHz, CDCl3, 25°, TMS): d = 7.99 (d, 3J
(H,H) = 8.0 Hz, 2H), 7.70 (t, 3J (H,H) = 7.9 Hz, 1H), 7.58 (t, 3J
(H,H) = 8.0 Hz, 2H), 5.04 (dd, 3J (H,H) = 4.0, 8.4 Hz, 1H), 3.85–3.81
(m, 1H), 3.36–3.31 (m, 1H), 3.23 (ddd, 3J (H,H) = 4.0, 7.0, 12.4 Hz,
1H), 3.05 (dt, 3J (H,H) = 8.3, 13.8 Hz, 1H), 2.50 (ddd, 3J (H,H) = 4.0,
8.4, 12.4 Hz, 1H), 2.04–1.93 (m, 2H), 1.76–1.74 (m, 1H), 1.60–
1.57 ppm (m, 1H); 13C NMR (100 MHz, CDCl3, 25°, TMS): d = 136.7,
133.9, 129.5, 128.9, 92.5, 65.5, 57.3, 36.8, 30.8, 23.8 ppm; HRMS
(EI) C12H15NO3S requires (M+Na) 276.0665; found 276.0682.
5.2.4. (2S,3aS,4S,5R)-2-Phenylsulfonyl-4,5-isopropylidenedioxy-
hexahydropyrrolo[1,2-b]isoxazole 5d
½
a 2D0
ꢂ
¼ ꢀ130:5 (c 1.6, CHCl3); IR (film)
m
: 3475. 2935. 1310.
5.3.4. (2S⁄,3aR⁄)-2-Phenylsulfonyl-hexahydropyrrolo[1,2-b]isox-
azole 6d
1149. 1067 cmꢀ1 1H NMR (400 MHz, CDCl3, 25°, TMS): d = 7.97
;
(d, 3J (H,H) = 7.4 Hz, 2H), 7.64 (t, 3J (H,H) = 7.8 Hz, 1H), 7.62 (t, 3J
(H,H) = 7.4 Hz, 2H), 4.99 (ddd, 3J (H,H) = 2.6, 5.6, 6.6 Hz, 1H), 4.95
(d, 3J (H,H) = 7.4 Hz, 1H), 4.74 (dd, 3J (H,H) = 1.8, 6.6 Hz, 1H), 3.92
(dt, 3J (H,H) = 7.4, 1.8 Hz, 1H), 3.70 (dd, 3J (H,H) = 5.6, 13.2 Hz,
1H), 3.45 (dd, 3J (H,H) = 2.6, 13.2 Hz, 1H), 2.88 (ddd, 3J (H,H) = 7.9,
8.0, 15 Hz, 1H), 2.80 (dt, 3J (H,H) = 13.6, 7.4 Hz, 1H), 1.48 (s, 3H),
1.28 ppm (s, 3H); 13C NMR (100 MHz, CDCl3, 25°, TMS): d = 136.8,
134.3, 129.2, 129.1, 112.5, 94.0, 81.9, 79.7, 71.5, 61.1, 39.9, 26.5,
24.9 ppm; HRMS (EI) C15H19NO5S requires (M+Na) 348. 0876;
found 348.0865.
IR (film)
m
:
3395, 3056 2942, 2872, 1454, 1332, 1136,
1091 cmꢀ1
;
1H NMR (400 MHz, CDCl3, 25°, TMS): d = 7.91 (d, 3J
(H,H) = 8.0 Hz, 2H), 7.66 (t, 3J (H,H) = 8.0 Hz, 1H), 7.56 (t, 3J
(H,H) = 8.0 Hz, 2H), 4.94 (t, 3J (H,H) = 8.2 Hz, 1H), 3.80 (m, 1H),
3.46 (dt, 3J (H,H) = 5.4, 12.7 Hz, 1H), 3.06 (dd, 3J (H,H) = 7.3,
12.7 Hz, 1H), 2.88 (dt, 3J (H,H) = 8.2, 13.5 Hz, 1H), 2.73 (ddd, 3J
(H,H) = 7.9, 8.2, 13.5 Hz, 1H), 2.11–2.05 (m, 1H), 1.95–1.92 (m,
1H), 1.89–1.85 (m, 1H), 1.77–1.75 ppm (m, 1H); 13C NMR
(100 MHz, CDCl3, 25°, TMS): d = 137, 134, 129.5, 129, 93.3, 65.5,
56.5, 36.6, 28.3, 23.3 ppm; HRMS (EI)
C12H15NO3S requires
(M+Na) 276.0665; found 276.0655.
5.3. Cycloaddition of nitrone 2 to phenyl vinyl sulfone 1
5.4. Cycloaddition of nitrone 4 to phenyl vinyl sulfone 1
Table 3, entry 1: Phenyl vinyl sulfone 1 (5 g, 29.4 mmol) was
added to a solution of nitrone 2 (2 g, 23.5 mmol) in toluene
(75 mL) at rt. The resulting mixture was stirred for 6 h, then it
was quenched with saturated aqueous solution of NH4Cl and the
product was extracted with EtOAc (3 ꢁ 15 mL). The combined or-
ganic layers were washed with brine, dried (Na2SO4), filtered,
and concentrated. The resulting crude residue was purified by flash
chromatography (silica gel, hexane/EtOAc 6:4) to obtain isoxazoli-
dines 6a, 6b, 6c, and 6d in a 38% yield. Ratio Table 3.
Table 3, entry 2: Phenyl vinyl sulfone 1 (710 mg, 4.23 mmol)
was added to a solution of nitrone 4 (1.01 g, 3.38 mmol) in toluene
(11.5 mL) at rt. The resulting mixture was stirred for 6 h, then it
was quenched with saturated aqueous solution of NH4Cl and the
product was extracted with EtOAc (3 ꢁ 15 mL). The combined or-
ganic layers were washed with brine, dried (Na2SO4), filtered,
and concentrated. The resulting crude residue was purified by flash
chromatography (silica gel, hexane/EtOAc 6:4) to obtain isoxazoli-
dines 7a, 7b, 7c, and 7d in 45% combined yield. Ratio Table 3.
5.3.1. (3R⁄,3aR⁄)-3-Phenylsulfonyl–hexahydropyrrolo[1,2-b]-
isoxazole 6a
5.4.1. (3R,3aR,4S,5S)-4,5-Bis(benzyloxy)-3-phenylsulfonyl-hexa-
hydropyrrolo[1,2-b]isoxazole 7a
IR (film)
m:
3379, 2942, 2868, 1442, 1377, 1295, 1131,
1091 cmꢀ1
;
1H NMR (400 MHz, CDCl3, 25°, TMS): d = 7.93 (d, 3J
½
a 2D0
ꢂ
¼ þ84:3 (c 0.9, CHCl3); IR (film)
m: 3064, 3027, 2929, 2856,
(H,H) = 8.0 Hz, 2H), 7.69 (t, 3J (H,H) = 7.6 Hz, 1H), 7.61 (t, 3J
(H,H) = 6.8 Hz, 2H), 4.32 (q, 3J (H,H) = 7.6 Hz, 1H), 4.27 (t, 3J
(H,H) = 7.6 Hz, 1H), 3.94 (t, 3J (H,H) = 7.6 Hz, 1H), 3.81 (q, 3J
(H,H) = 7.6 Hz,1H), 3.29 (dt, 3J (H,H) = 6.9, 7.7 Hz, 1H), 3.10 (dt, 3J
(H,H) = 6.9, 7.7 Hz, 1H), 2.63–2.60 (m, 1H), 2.20–2.10 (m, 1H),
1.98–1.95 (m, 1H), 1.93–1.83 ppm (m, 1H); 13C NMR (100 MHz,
CDCl3, 25°, TMS): d = 140.1, 133.9, 129.3, 127.8, 69.5, 66.8, 65.5,
55.6, 25 ppm; HRMS (EI) C12H15NO3S requires (M+Na) 276.0665;
found 276.0649.
1577, 1450, 1307, 1140 cmꢀ1; 1H NMR (400 MHz, CDCl3, 25°, TMS):
d = 7.90 (d, 3J (H,H) = 8.2 Hz, 2H), 7.69 (t, 3J (H,H) = 7.6 Hz, 1H), 7.59
(t, 3J (H,H) = 7.6 Hz, 2H), 7.36–7.22 (m, 10H), 4.53 (d, 3J
(H,H) = 11.6 Hz, 1H), 4.50 (d, 3J (H,H) = 11.7 Hz, 2H), 4.40 (d, 3J
(H,H) = 11.6 Hz, 1H), 4.21–4.13 (m, 3H), 4.04–3.97 (m, 3H), 3.51
(dd, 3J (H,H) = 5.2, 14.0 Hz, 1H), 3.19 ppm (dd, 3J (H,H) = 1.8,
14 Hz, 1H); 13C NMR (100 MHz, CDCl3, 25°, TMS): d = 137.5,
137.3, 137.2, 134.3, 129.5, 128.8, 128.6, 128.5, 128.0, 127.9,
127.7, 86.3, 82.8, 71.7, 71.6, 70.9, 66.3, 59.1 ppm; HRMS (EI)
C26H27NO5S requires (M+Na) 488.1502; found 488.1484.
5.3.2. (3S⁄,3aR⁄)-3-Phenylsulfonyl-hexahydropyrrolo[1,2-b]isox-
azole 6b
5.4.2. (3S,3aR,4S,5S)-4,5-Bis(benzyloxy)-3-phenylsulfonyl-hexa-
hydropyrrolo[1,2-b]isoxazole 7b
IR (film)
1078 cmꢀ1
(H,H) = 7.0 Hz, 2H), 7.70 (t, 3J (H,H) = 7.5 Hz, 2H), 7.62 (t, 3J
m:
3436, 2958, 2860, 1442, 1393, 1299, 1144,
;
1H NMR (400 MHz, CDCl3, 25°, TMS): d = 7.93 (d, 3J
½
a 2D0
ꢂ
¼ þ58:0 (c 0.3, CHCl3); IR (film)
m: 3399, 3064, 3027, 2933,
2856, 1462, 1377, 1315, 1144 cmꢀ1; 1H NMR (400 MHz, CDCl3, 25°,

MariFe Flores et al. / Tetrahedron: Asymmetry 23 (2012) 76–85
85
TMS): d = 7.94 (d, 3J (H,H) = 8.0 Hz, 2H), 7.65 (t, 3J (H,H) = 7.8 Hz,
1H), 7.49 (t, 3J (H,H) = 7.8 Hz, 2H), 7.37–7.25 (m, 10H), 5.14 (d, 3J
(H,H) = 2.7 Hz, 1H), 4.76 (m, 2H), 4.63 (m, 2H), 4.42 (m, 1H), 4.32
(m, 1H), 4.16 (dd, 3J (H,H) = 2.7, 5.2 Hz, 1H), 3.95 (m, 1H), 3.86 (t,
3J (H,H) = 5 Hz, 1H), 3.44–3.36 ppm (m, 2H); 13C NMR (100 MHz,
CDCl3, 25°, TMS): d = 138.9, 137.8, 137.7, 134.1, 129.5, 129.2,
128.9, 128.5, 128.3, 128, 127.8, 84.6, 84.0, 72.7, 71.8, 65.3, 68.3,
59.1 ppm; HRMS (EI) C26H27NO5S requires (M+Na) 488.1502;
found 488.1510.
Guarna, F.; Merino, P.; Tejero, T. Org. Lett. 2003, 5, 4235–4238; (g) Closa, M.;
Wightman, R. H. Synth. Commun. 1998, 28, 3443–3450; (h) Liautard, V.;
Desvergnes, V.; Martin, O. R. Tetrahedron: Asymmetry 2008, 19, 1999–2002; (i)
Desvergnes, S.; Vallee, Y.; Py, S. Org. Lett. 2008, 10, 2967–2970; (j) Desvergnes,
S.; Desvergnes, V.; Martin, O. R.; Itoh, K.; Liu, H.; Py, S. Bioorg. Med. Chem. 2007,
15, 6443–6449; (k) Schleiss, J.; Rollin, P.; Tatibouet, A. Angew. Chem, Int. Ed.
2010, 49, 577–580; (l) Palmer, A. M.; Jager, V. Eur. J. Org. Chem. 2001, 1293–
1308; (m) Kaliappan, K. P.; Das, P. Synlett 2008, 841–844; (n) Cardona, F.;
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Roberts, S.; Davies, G. J.; Rose, D. R.; Goti, A. Chem. Eur. J. 2009, 15, 1627–1636;
See also: (o) Alcaide, B.; Almendros, P.; Alonso, J. M.; Aly, M. F.; Pardo, C.; Saez,
E.; Torres, M. R. J. Org. Chem. 2002, 67, 7004–7013; (p) Busqué, F.; de March, P.;
Figueredo, M.; Font, J.; Gallagher, T.; Milan, S. Tetrahedron: Asymmetry 2002, 13,
437–445; (q) Cordero, F. M.; Pisaneschi, F.; Gensini, M.; Goti, A.; Brandi, A. Eur.
J. Org. Chem. 2002, 1941–1951; (r) Richichi, B.; Cicchi, S.; Chiacchio, U.; Romeo,
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C.; Cordero, F. M.; Brandi, A. Tetrahedron Lett. 2002, 43, 5711–5714; (t)
Nagasawa, K.; Georgieva, A.; Koshino, H.; Nakata, T.; Kita, T.; Hashimoto, Y. Org.
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5.4.3. (2R,3aS,4S,5S)-4,5-Bis(benzyloxy)-2-phenylsulfonyl-hexa-
hydropyrrolo[1,2-b]isoxazole 7c
½
a 2D0
ꢂ
¼ þ90:5 (c 0.2, CHCl3); IR (film)
m: 3412, 3052 3023, 2925,
2860, 1442, 1307, 1066, 1144 cmꢀ1 1H NMR (400 MHz, CDCl3,
;
25°, TMS): d = 7.96 (d, J = 8.1 Hz, 2H), 7.58 (t, 3J (H,H) = 7.6 Hz, 1H),
7.55 (t, 3J (H,H) = 7.8 Hz, 2H), 7.34–7.22 (m, 10H), 5.07 (dd, 3J
(H,H) = 3.4, 8.2 Hz, 1H), 4.52 (d, 3J (H,H) = 11.7 Hz, 2H), 4.48 (d, 3J
(H,H) = 11.7 Hz, 1H), 4.43 (d, 3J (H,H) = 11.7 Hz, 1H), 4.09 (dd, 3J
(H,H) = 3.0, 5.4 Hz, 1H), 3.95–3.90 (m, 2H), 3.48 (dd, 3J (H,H) = 5.4,
14.4 Hz, 1H), 3.39 (dd, 3J (H,H) = 3.0, 14.4 Hz, 1H), 3.21 (ddd, 3J
(H,H) = 3.4, 8.2, 14.0 Hz,, 1H), 2.72 ppm (ddd, 3J (H,H) = 5.6, 8.2,
14.0 Hz, 1H); 13C NMR (100 MHz, CDCl3, 25°, TMS): d = 138.5,
137.4, 137.3, 134.0, 129.5, 129.3, 129.0, 128.5, 128.0, 127.9, 127.7,
92.7, 87.9, 84.3, 71.9, 71.6, 69.8, 60.1, 34.9 ppm; HRMS (EI)
4. (a) Croce, P. D.; Rosa, C.; Stradi, R.; Ballabio, M. J. Heterocycl. Chem. 1983, 20,
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Org. Lett. 2003, 5, 2489–2492.
C26H27NO5S requires (M+Na) 488.1502; found 488.1482.
5.5. Conversion of 5b into 5a
A stirred solution of isoxazolidine 5b (34.5 mg, 0.22 mmol) in
toluene (0.5 mL) was heated at 110 °C. After 72 h the reaction
was quenched with saturated aqueous solution of NH4Cl and the
product was extracted with EtOAc (3 ꢁ 15 mL). The combined or-
ganic layers were washed with brine, dried (Na2SO4), filtered,
and concentrated, obtaining isoxazolidine 5a in a 100% yield.
5. (a) Kaduk, J. A.; Cahill, P. J.; Venkateshwaran, L. N. J. Appl. Crystallogr. 1999, 32,
15–20; (b) Rudolph, F. A. M.; Fuller, A. L.; Slawin, A. M. Z.; Bühl, M.; Aitken, R.
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´
(d) Heaney, F.; Fenlon, J.; OMahony, C.; McArdle, P.; Cunningham, D. Org.
Acknowledgements
´
Biomol. Chem. 2003, 1, 4302–4316; (e) Heaney, F.; OMahony, C.; McArdle, P.;
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The authors would like to thank the F.S.E., MICINN (CTQ2009-
11172) and Junta de Castilla y León for the financial support
(GR178 and SA001A09) and for the doctoral fellowships awarded
to M.F.F. and C.T.N. Drs. A. M. Lithgow and C. Raposo are acknowl-
edged for the NMR and Mass Spectra, respectively.
7. (a) Cordero, F. M.; Machetti, F.; De Sarlo, F.; Brandi, A. Gazz. Chim. Ital. 1997, 127,
25–27; See also: (b) Murahashi, S. I.; Shiota, T. Tetrahedron Lett. 1987, 28, 2383–
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Tetrahedron Lett. 2005, 46, 1287–1290; (d) Merino, P.; Delso, I.; Tejero, T.;
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