Nucleophilic additions of lithiated allylphenylsulfone to nitrones: Experimental and theoretical investigations

Article abstract of DOI:10.1016/j.tet.2005.01.043

The nucleophilic addition of lithiated allylphenylsulfone to nitrones at -80°C proceeds exclusively α to the phenylsulfonyl group affording anti adducts in high yield. At 0°C isoxazolidines are obtained with complete all-trans selectivity. The formation of these compounds involves isomerization of the allylsulphonyl moiety to give a transient vinylsulfone that then undergoes a subsequent intramolecular Michael addition. The addition to several nitrones has been studied and theoretical calculations have been refined to accurately explain the selectivity of the allylation reaction.

Full text of DOI:10.1016/j.tet.2005.01.043

Tetrahedron 61 (2005) 3335–3347
Nucleophilic additions of lithiated allylphenylsulfone to nitrones:
experimental and theoretical investigations
*
Pedro Merino, Vanni Mannucci and Tomas Tejero
´
Departamento de Quimica Organica, Facultad de Ciencias-ICMA, Universidad de Zaragoza, E-50009 Zaragoza, Aragon, Spain
Received 23 September 2004; revised 27 October 2004; accepted 6 January 2005
Available online 1 February 2005
Abstract—The nucleophilic addition of lithiated allylphenylsulfone to nitrones at K80 8C proceeds exclusively a to the phenylsulfonyl
group affording anti adducts in high yield. At 0 8C isoxazolidines are obtained with complete all-trans selectivity. The formation of these
compounds involves isomerization of the allylsulphonyl moiety to give a transient vinylsulfone that then undergoes a subsequent
intramolecular Michael addition. The addition to several nitrones has been studied and theoretical calculations have been refined to
accurately explain the selectivity of the allylation reaction.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
Allylmetalations of imines and related compounds have
proven to be of a great importance for the efficient synthesis
of acyclic and cyclic amine derivatives.1 Although the
reaction of several allylic metals, including allyllithium
derivatives, with imines has been extensively investigated,2
little attention has been directed toward the allylation of
nitrones Wuts and Jung3 have reported the reaction of
allylsilanes and nitrones with trimethylsilyl-triflate as a
catalyst. Similarly, Trombini and co-workers4 found that the
same catalyst served to promote the condensation of
allyltributylstannane with nitrones. The same authors5
Scheme 1.
have also described the reaction of allylic magnesium and
allow the preparation of hydroxyamino-containing subunits
zinc reagents with nitrones to form homoallylic hydro-
3 or 4, depending on the type of addition (a vs g). In
xylamines. More recently, allylation of nitrones in aqueous
particular, a-substituted homoallylic hydroxylamines 3
media have been reported using indium6 and samarium7
should find use as important fundamental building blocks
allylic derivatives.
in many biologically active compounds. In extending our
previous investigations on nucleophilic additions to
To date, no general studies have appeared in the literature
nitrones9 we now focus on the allylsulfonylation of nitrones.
concerning allyllithiation of nitrones 1. A particular
Allylic carbanions formed from the corresponding allyl-
example has been described by Trombini and co-workers
sulfones (XZSO2R) have been widely used in organic
regarding the addition of a substituted lithiated derivative 2
synthesis.10 The presence of the sulfonyl group in 3 strongly
(XZOSiMet2Bu); however, it was reported that low
increases the synthetic potential of these compounds to be
chemical yields were obtained (Scheme 1).8
used as building blocks.11
The introduction of a functional group into the allylic
In this paper, we describe reaction of the lithiated
moiety (leading to functionalized allyllithiums 2) would
allylphenylsulfone 2 (XZSO2Ph) with nitrones 1 and the
dependence of the reaction on the reaction conditions and on
Keywords: Nitrones; Allylation; Hydroxylamines; Isoxazolidines;
the substrate. The nitrones were subjected to several
Allyllithium.
allylsulfonylation conditions with the purpose of finding
reaction conditions suitable for the preparation of allylation
* Corresponding author. Tel.: C34 976 762075; fax: C34 976 762075;
e-mail: pmerino@unizar.es
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.01.043

3336
P. Merino et al. / Tetrahedron 61 (2005) 3335–3347
however, it is possible to explain its formation in terms of a
nucleophilic addition as discussed below. The addition of
pre-complexing agents of the nitrone such as Et2AlCl (entry
2) or BF3$Et2O (entry 3) did not affect the selectivity of the
reaction but lower yields were obtained.
On the other hand, when the reaction was performed in the
presence of a lithium coordinating agent (entries 4 and 5)
the amount of isoxazolidine decreased considerably. Indeed,
in the presence of HMPA the hydroxylamine 5a was the
only product of the reaction. Again, only one diastereo-
isomer could be detected. Interestingly, when the reaction
was carried out at 0 8C only the cyclic compound 7a was
obtained (entries 6 and 7) in a complete regio- and
stereoselective manner. The isoxazolidine 7a was obtained
in almost quantitative chemical yield in the absence of any
additive. Replacement of the N-phenyl group by a tert-butyl
group led to similar results although considerably lower
chemical yields were observed (entries 8 and 9). In the case
of the N-benzyl nitrone 1c only one compound having an
anti configuration was obtained at K80 8C (entry 10); at
0 8C (entry 11) a mixture of three compounds was isolated
from the reaction mixture. Even though the isoxazolidine 7c
was the major product; the anti/syn selectivity was only 3:2.
A similar result was observed with N-methyl nitrone 1d
(entries 12 and 13). Whereas the reaction at low temperature
afforded a 4:1 mixture of hydroxylamines 5d and 6d,
respectively, the reaction at 0 8C gave isoxazolidine 7d
preferentially, the hydroxylamines being obtained in a non-
stereoselective way.
Scheme 2.
products in good regio- and stereoselective ways. Further-
more, we also describe herein a theoretical study of the
possible reaction pathways associated with the addition of
allylic anions to nitrones.
2. Results and discussion
For our initial studies we selected C-phenyl nitrones 1a–d
(Scheme 2) as the substrates and varied both the reaction
conditions and the nature of the N-substituent. Some
pertinent data are collected in Table 1.
In order to establish the range of application of the
allylsulfonylation of nitrones, the addition of lithiated
allylphenylsulfone to other C-substituted nitrones was
investigated (Scheme 3, Table 2). We chose the benzyl
group for N-substitution because it can be easily eliminated
by hydrogenation methods during further elaborations with
synthetic purposes.
As illustrated, the reaction of lithiated allylphenylsulfone 2
with nitrone 1a at K80 8C and in THF as a solvent (entry 1)
afforded a 54:46 mixture of products consisting of the
expected hydroxylamine 5a, coming from a a-addition to
the allylic moiety and the unexpected isoxazolidine 7a.
Each compound was obtained as one stereoisomer
possessing the indicated relative configuration and no traces
of g-addition were detected in the reaction mixture.12
Compound 7 can be seen as the product of a formal [3C2]
cycloaddition between the nitrone and a propenyl sulfone;
As in the case of C-phenyl nitrones 1a–d the reaction at
K80 8C in the presence of HMPA afforded exclusively
hydroxylamines having an anti relative configuration
(entries 1, 3, 5 and 7). With non-aromatic C-substituents
(entries 5 and 7) lower anti/syn selectivity was observed.
Table 1. Addition of lithiated allylphenylsulfone to nitrones 1a–da
Entry
Nitrone
T (8C)
Additiveb
(5C6):7c
5:6c
Yield (%)d
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1b
1b
1c
1c
1d
1d
K80
K80
K80
K80
K80
0
0
K80
0
K80
0
K80
0
None
54:46
40:60
55:45
80:20
100:0
0:100
0:100
100:0
0:100
100:0
30:70
100:0
30:70
O20:1
O20:1
O20:1
O20:1
O20:1
—
—
O20:1
—
80
53
55
63
80
98
70
52
46
88
91
80
91
Et2AlCle
BF3$Et2Oe
TMEDA
HMPA
None
HMPA
HMPA
None
HMPA
None
9
10
11
12
13
O20:1
3:2
4:1
HMPA
None
1:1
a The reaction was performed with 1.2 equiv of lithiated allylphenylsulfone, formed from 1.2 equiv of BuLi and 1.2 equiv of allylphenylsulphone, in THF.
b 1.0 equiv with respect to allylphenylsulfone was added unless otherwise indicated.
c Measured by 1H NMR from the isolated reaction mixture.
d Referred to the isolated reaction mixture.
e 1.0 equiv with respect to the nitrone was added.

P. Merino et al. / Tetrahedron 61 (2005) 3335–3347
3337
in a complete agreement with previous nucleophilic
additions of organometallic reagents to 12.9b
The formation of isoxazolidines 7, 11 and 14 can be
explained in terms of equilibrium between the hydroxy-
amino anion 15, immediately formed after the addition, and
the corresponding vinylsulfone 17 as displayed in Scheme 5.
The isomerization between allyl and vinyl sulfones in a
basic medium is well-known13 and it has been evidenced in
tandem sequences involving intramolecular Michael
additions.14
According to the reaction pathway shown in Scheme 5, at
low temperature (K80 8C) the initially formed adduct 15 is
stable enough to afford the corresponding hydroxylamine
after aqueous work-up. At 0 8C the equilibrium takes place
and the reaction proceeds via the anionic intermediate 17
which ultimately produces 18 through an intramolecular
Michael addition.15 The presence of HMPA is crucial for
avoiding isomerization of 15 even at K80 8C (compare
entries 1 and 5 in Table 1). Presumably, the coordinating
capabilities of HMPA block the equilibration between 15
Scheme 3.
Table 2. Addition of lithiated allylphenylsulfone to nitrones 8a–da
Entry
Nitrone
T (8C)
Additiveb
(9C10):11c
9:10c
Yield (%)d
1
2
3
4
5
6
7
8
8a
8a
8b
8b
8c
8c
8d
8d
K80
0
K80
0
K80
0
K80
0
HMPA
None
HMPA
None
HMPA
None
HMPA
None
100:0
15:85
100:0
20:80
100:0
30:70
100:0
0:100
O20:1
2:1
O20:1
2:1
6:1
2:1
O20:1
—
86
87
80
74
69
73
72
69
a The reaction was performed with 1.2 equiv of lithiated allylphenylsulfone, formed from 1.2 equiv of BuLi and 1.2 equiv of allylphenylsulphone, in THF.
b 1.0 equiv with respect to allylphenylsulfone was added unless otherwise indicated.
1
c Measured by H NMR from the isolated reaction mixture.
d Referred to the isolated reaction mixture.
Following the same trend that nitrones 1a–d, the reaction at
0 8C, in the absence of HMPA, gave rise to isoxazolidines
11 as major products (entries 2, 4, 6 and 8). The modest anti/
syn selectivity observed for hydroxylamines 9 and 10 under
these conditions was probably due to the higher tempera-
ture. Only in the case of nitrone 8d the corresponding
isoxazolidine 11d was obtained as the only product of the
reaction. It is noteworthy that in all cases only one
stereoisomer of isoxazolidines 7 and 11 was obtained thus
showing a complete stereoselectivity in the formation of
such compounds.
Finally, we decided to explore the reactivity of a chiral
substrate. For this purpose nitrone 12, derived from
D-glyceraldehyde and widely used in our laboratory,9b was
chosen. As expected (Scheme 4), the allylsulfonylation of
12 at K80 8C afforded hydroxylamine 13a as the main
product of the reaction. At 0 8C only isoxazolidines 14a and
14b were obtained. The diastereofacial selectivity was also
excellent; the syn adducts (with respect to the dioxolane ring
being obtained with high levels of diastereoselectivity.
Indeed, stereoisomers 13b and 14b were detected in minor
amounts (2–3%).
The diastereofacial selectivity observed in the reaction was
Scheme 4.

3338
P. Merino et al. / Tetrahedron 61 (2005) 3335–3347
Scheme 5.
although some elimination product 19 was obtained. This
product corresponds to the elimination of the N-benzyl
hydroxyamino moiety. An excess of BuLi (entry 4)
dramatically increased the amount of elimination product.
On the other hand, when hydroxylamine 5a was treated with
1.0 equiv of potassium tert-butoxide (entry 5) only a minor
amount of 19 was obtained, the main product of the reaction
Scheme 6.
Table 3. Deprotonation of 5aa
Entry
T (8C)
Base
Equivb
19:7ac
Yield (%)d
e
e
1
2
3
4
5
K80
K80
0
0
0
BuLi
BuLi
1.0
1.5
1.0
1.5
1.0
—
—
—
—
77
90
85
f
f
BuLi
BuLi
8:92
90:10
4:96
tBuOKg
a The reaction was carried out in THF in the presence of 1.0 equiv of HMPA unless otherwise indicated.
b With respect to 5a.
c Measured by 1H NMR from the isolated reaction mixture.
d Referred to the isolated reaction mixture.
e Pure hydroxylamine 5a was recovered.
A mixture of anti and syn hydroxylamines were recovered.
f
g The reaction was conducted without HMPA.
and 17 at low temperature. At 0 8C it has no effect since
formation of isoxazolidine is observed anyway (Table 1,
entry 7). The formation of isoxazolidines through a
concerted cycloaddition reaction between the nitrone and
a propenyl sulfone is not very likely since in a basic medium
the latter is not present but exists as the corresponding
allylic anion.16
being the isoxazolidine 7a. This behavior was also observed
for other hydroxylamines. Under elimination conditions,
compounds 20–23 were preferentially obtained and fully
characterized (Chart 1). The geometry of the alkene group
was established in all cases by NOESY experiments which
showed cross-peaks between the terminal vinyl group
and the vinylic proton of the trisubstituted alkene. In a
similar way to 5a, deprotonation with 1.0 equiv of
either BuLi in the presence of 1.0 equiv of HMPA or
potassium tert-butoxide at 0 8C afforded the corresponding
In order to assess the mechanistic proposal illustrated in
Scheme 5 we decided to study the deprotonation of
hydroxylamine 5a (Scheme 6, Table 3). Treatment of 5a
with 1.0 equiv of BuLi in THF at K80 8C in the presence of
1.0 equiv of HMPA, stirring for 2 h and then aqueous work-
up afforded the starting compound without traces of any
other stereoisomer or isoxazolidine (entry 1). This experi-
ment clearly demonstrates the stability of 5a at low
temperature. The same experiment carried out with
1.5 equiv of BuLi (entry 2) afforded a mixture of anti/syn
diastereomers proving that although a second deprotonation
takes place at the a-phenylsulfonyl carbon atom no
isomerization to 17 is produced. When the reaction was
carried out at 0 8C (entry 3) cyclization to 7a was observed
Chart 1.

P. Merino et al. / Tetrahedron 61 (2005) 3335–3347
Table 4. Selected coupling constants for 5a–d, 6a–d, 9a–c and 10a–c
3339
Entry
R1
R2
anti
syn
3JH,H (anti)
3JH,H (syn)
a
1
2
3
4
5
6
7
Ph
Ph
Ph
Ph
Pyb
Fuc
iPr
Ph
5a
5b
5c
5d
9a
9b
9c
6a
6b
6c
6d
10a
10b
10c
10.0
9.9
9.8
10.0
9.1
10.1
10.0
—
Bn
Me
tBu
Bn
Bn
Bn
9.1
8.5
a
—
9.6
9.1
8.8
a Not obtained.
b 2-Pyridyl.
c 2-Furyl.
i
(Ph, 2-Py, 2-Fu, Pr) for syn adducts indicated the assigned
setereochemistry. In the case of a-alkoxyhydroxylamines
9d, 13a and 13b the observed coupling constants were 4.0,
3.3 and 2.8 Hz, respectively. For these compounds the
assigned relative configurations were deduced from 2D
COSY, NOESY and HMQC experimental data.
Even though these assignments cannot be considered
unambiguous, they are in accordance with earlier reports
by Hassner and co-workers13,19 concerning allylsulfonyl-
ation of imines and are also further supported by theoretical
calculations (see below).
The cis/trans relative configuration of isoxazolidines was
assigned by NOE experiments (Fig. 2). Irradiation of Ha for
all obtained compounds, only produced enhancement of Hc
(5–7%) and irradiation of Hb in the same experiment,
produced enhancement of the methyl group (8–11%).
Irradiation of the methyl group produced enhancements of
Hb (8–10%) and, as expected, of Hc (15–17%). These
relationships were confirmed by 2D NOESY experiments in
which no interesting cross-peaks were detected between Ha
and Hb, and Hb and Hc.
Figure 1. Preferred conformations for compounds 5a–d, 6a–d, 9a–c and
10a–c.
isoxazolidines thus confirming the mechanism outlined in
Scheme 5.
The observed geometry of the newly generated double bond
is in agreement with a stereospecific syn elimination
following a concerted path for the loss of the alkylhydroxy-
amino unit. Such a reaction represents a retro-Michael
addition of a hydroxylamine. Indeed, the corresponding
direct reaction has been demonstrated to be a concerted
process by Ortun˜o and co-workers.17
3. Determination of configuration
The stereochemical assignments of hydroxylamines 5a–d,
6a–d, 9a–c and 10a–c were based on NMR evidence In all
cases the JH,H coupling constants between Ha and Hb
Figure 2. Selected NOE observed for 7a–d, 11a–d and 14 (hobs is given as
percent of hmax).
3
(Table 4, Fig. 1) were in the range of 8.5–10.1 Hz. Those
values are in agreement with the depicted anti and syn
arrangements in which protons Ha and Hb adopt an
antiperiplanar disposition.
The observed pattern for the described NOE is in agreement
with previous observations for substituted isoxazolidines.20
The structures of 7c and 14a were confirmed by single-
crystal
This crystallographic analysis also served to assign
unambiguously the absolute configuration of both 13a and
14a thus confirming the syn diastereofacial preference in the
addition to nitrone 12
X
ray structure determination (Fig. 3).21
Support for that conformation was secured upon cooling to
K40 and K80 8C, no significant changes being observed
for the 1H NMR coupling patterns. This observation
indicated that the solution contained almost exclusively,
one single conformer with respect to the C1–C2 bond.
Indeed, semiempirical calculations18 also supported the
conformational disposition shown in Figure 1 for anti and
syn isomers. These observations, coupled with the 2D
NOESY spectra, which showed strong NOE between the
vinylic protons Hc and groups R2 (Ph, Me, tBu, Bn) for anti
adducts, and between the same proton (Hc) and groups R1
4. Theoretical study
In order to evaluate the importance of electronic and steric

3340
P. Merino et al. / Tetrahedron 61 (2005) 3335–3347
Figure 3. Perspective views (ORTEP) of 7c and 14a. Non-hydrogen atoms are drawn as 50% thermal ellipsoids while hydrogens are drawn at an arbitrary size.
Only the atoms refined with anisotropic thermal parameters are drawn with the principal axes indicated; the isotropic atoms are represented as simple circles.
Some hydrogens have been omitted for clarity.
effects in the outcome of the allylation reactions of nitrones
1 and 8 with lithiated allylphenylsulfone 2, the reaction has
been studied by ab initio molecular orbital calculations We
aimed to clarify what is the preferred attack to the
substituted allylic metal (a vs g) and to rationalize the
experimentally observed differences in anti/syn
selectivities.
reaction proceeds through the initial formation of a starting
complex without energy barrier. The formation of stable
complexes without energy barriers prior to the addition step
has been proposed and demonstrated previously for
nucleophilic additions to nitrones24 and carbonyls.25 After
the formation of the complex, the two possible pathways
illustrated in Scheme 7 and corresponding to a and g attacks
should be considered. Thus, the reaction is expected to
proceed through ‘closed’ transition states in which the
lithium atom is transferred to the nitrone oxygen con-
comitant with C–C bond formation.
Geometry optimizations of the stationery points (reactants,
transition structures and products) were carried out by using
ab initio Hartree–Fock calculations with the 6-31G(d) basis
set.22 All transition structures were found to have only one
negative eigenvalue with the corresponding eigenvector
involving the formation of the newly created C–C bonds.
Vibrational frequencies were calculated (1 atm, 298.15 K)
for all HF/6-31G(d) optimized structures and used unscaled,
to compute ZPVE and activation energies. The transition
states reported were shown to belong to the studied reaction
by intrinsic reaction coordinate (IRC). All calculations were
performed using the Gaussian 03 revision B.05 suite of
programs.23
We found two minima corresponding to the starting
complex C1 and the product P1. Two transition states
TS1 and TS2, corresponding to a and g attacks,
respectively, connecting C1 with P1 were also located.
The calculated free energies for reactants, complex,
transition states and product are collected in Table 5, and
the geometry of TS1 and TS2 is given in Figure 4. As shown
by the energy barrier values (Table 5) the preferred
transition state corresponds to the g attack. Based upon
these simplified calculations it is obvious that the presence
of the sulfonyl group must be considered in order to achieve
valid conclusions.
We began our study by examining the reaction profile for
the nucleophilic addition of unsubstituted allylic lithium to
nitrone 1 (R1ZR2ZMe). In order to simulate the presence
of solvent, water molecules were added when needed. The
Table 5. Calculated free energies (HF/6-31G(d)) and relative free energies
for the stationery points of the allylation of 1
Total energya
Relative energyb
Nitrone
Allyllithium$3H2O
C1
TS1
TS2
P1
K246.812390
K351.913262
K522.722565
K522.693904
K522.707354
K598.793418
K1.43c,d
17.99d,e
9.55d,e
K42.52e
a Hartrees.
b kcal/mol.
c Referred to nitroneCallyllithium$3H2O.
d The energy corresponding to a molecule of water (K76.005368 au) has
been included for comparison of relative energies.
e Referred to complex C1.
Anders and co-workers26 have studied the structure of
sulfur-stabilized allyllithium derivatives, including lithiated
allylphenylsulfone 2. These authors found three possible
structures in the range of 1 kcal/mol as the more stable for 2.
Such structures correspond to the expected h1 Ca–Li A and
Scheme 7.

P. Merino et al. / Tetrahedron 61 (2005) 3335–3347
3341
depicted in Scheme 8. The total and relative free energies
are summarized in Table 6.
The first step corresponds to the formation of a stable
complex C2 (6.97 kcal/mol below the reactants) through the
displacement of a molecule of solvent by the nitrone. This
complex can then evolve in two ways: (i) to give an a
addition affording anti and syn diastereomers P2 and P3,
respectively, and (ii) to give a g addition which, in principle,
could led to E and Z isomers P4 and P5, respectively. The
geometries of the corresponding transition structures TS3,
TS4, TS5 and TS6 are given in Figure 6.
Figure 4. Optimized geometries at HF/6-31G(d) level for the transition
structures TS1 and TS2. Some hydrogen atoms have been omitted for
clarity. Distances of forming bonds are given in angstroms.
Contrary to the obtained data for unsubstituted allyllithium
and in an excellent agreement with experimental results, the
most stable transition structure corresponds to the a attack.
Moreover, calculations correctly predict the preferential
formation of the corresponding anti adduct since TS3
presented the lowest free activation energy (13.01 kcal/
mol). The calculated energy differences between a and g
attacks (TS3 is 5.52 kcal/mol lower in energy than TS5) as
well as the differences between anti and syn approaches
(TS3 is 8.79 kcal/mol lower in energy than TS4) for the a
attack justify the obtention of only one isomer. The final
products are lower in energy than complex C2, indicating an
exothermic transformation.
Figure 5. Energetically stable conformers found for lithiated allylphenyl-
sulfone 2. Relative energies are given in kcal/mol. (Data taken from Ref.
26).
h1Cg–Li B contacted ion pairs (Fig. 5) and, in addition, an
intramolecular OLiO scissor contact ion pair C that is
defined by the authors as a ‘naked’ allyl anion.
The geometries of the transition states are similar regardless
of the approach. It is noteworthy that although we started
from the most stable isomer of lithiated methylsulfone (A,
Fig. 5), all transition states present a geometry (Fig. 6)
nearest to the ‘naked’ anion defined by Anders and co-
workers25 (C, Fig. 5) thus evidencing the crucial role of the
We initially use in our studies structure A as the nucleophile
to be added to 1.27 The calculated reaction paths are
Scheme 8.

3342
P. Merino et al. / Tetrahedron 61 (2005) 3335–3347
Table 6. Calculated free energies and relative free energies (HF/6-31G(d))
for the stationery points of the allylphenylsulfonylation of 1
6. Experimental
Total energya
Relative energyb
6.1. General
Nitrone
A (Me)
C2
TS3
TS4
TS5
TS6
P2
K246.812390
K862.118716
K1032.936849
K1108.921484
K1108.907476
K1108.914279
K1108.911434
K1108.945702
K1108.950959
K1108.954456
K1108.948299
The reaction flasks and other glass equipment were heated
in an oven at 130 8C overnight and assembled in a stream of
Ar. All reactions were monitored by TLC on silica gel 60
F254; the position of the spots were detected with 254 nm
UV light or by spraying with one of the following staining
systems: 50% methanolic sulfuric acid, 5% ethanolic
phosphomolybdic acid and iodine Preparative centrifugally
accelerated radial thin-layer chromatography (radial
chromatography) was performed with a Chromatotronw
Model 7924 T (Harrison Research, Palo Alto, CA, USA)
and with solvents that were distilled prior to use; the rotors
(1 or 2 mm layer thickness) were coated with silica gel
Merck grade type 7749, TLC grade, with binder and
fluorescence indicator (Aldrich 34,644-6) and the eluting
solvents were delivered by the pump at a flow-rate of
K6.97c,d
13.010154d,e
21.800308d,e
17.531360d,e
19.316625d,e
K2.18687e
K5.485688e
K7.680089e
K3.816513e
P3
P4
P5
a Hartrees.
b kcal/mol.
c Referred to nitroneClithiated allylmethylsulfone A$3H2O.
d The energy corresponding to a molecule of water (K76.005368 au) has
been included for comparison of relative energies.
e Referred to complex C2.
Figure 6. Optimized geometries at HF/6-31G(d) level for the transition structures TS3, TS4, TS5 and TS6. Some hydrogen atoms have been omitted for
clarity. Distances of forming bonds are given in angstroms.
phenylsulfonyl group in favoring the a-addition. The bond
lengths of the C–C forming bonds do not change
significantly, whether the approach is a-anti (TS3,
2.13 A), g-E (TS5, 2.16 A), or g-Z (TS6, 2.12 A). Only a
slightly longer forming bond is found for the a-syn approach
˚
(TS4, 2.21 A).
0.5–1.5 mL minK1. Melting points were uncorrected. IR
spectra were recorded on a Perkin–Elmer FT IR instrument
1
in CHCl3. H and 13C NMR spectra were recorded on a
˚
˚
˚
Bruker Avance 400 instrument in CDCl3. Chemical shifts
are reported in ppm (d) relative to CHCl3 (dZ7.26) in
CDCl3. Optical rotations were taken at 25 8C on a Perkin–
Elmer 241 polarimeter. Elemental analysis were performed
on a Perkin–Elmer 240B microanalyzer. Nitrones 1, 8 and
12 were prepared from the corresponding aldehydes as
described.28
5. Conclusions
In conclusion, we have studied in detail the nucleophilic
addition of lithiated allylphenylsulfone 2 to nitrones The
reaction only leads to a-adducts. Thus a-sulfonyl homoallyl
hydroxylamines having an anti relative configuration are
exclusively obtained when the reaction is carried out at
K80 8C and in the presence of HMPA. These products are
stable, but upon treatment with BuLi at 0 8C they cyclized to
isoxazolidines in a process involving isomerization of the
double bond and an intramolecular Michael addition.
Indeed, it is possible to obtain such isoxazolidines by
carrying out the addition of 2 at 0 8C. On the contrary, an
excess of base favors a side reaction consisting of
elimination of the hydroxyamino group, giving rise to
2-phenylsulfonyl dienes. The observed regio- and stereo-
chemical results are well explained by means of compu-
tational methods, which correctly predict both the a-attack
and the preferential anti selectivity.
6.2. General procedure for the allylphenylsulfonylation
of nitrones at K80 8C. Synthesis of homoallyl
hydroxylamines
To a cooled (K80 8C) solution of n-BuLi (1.33 mL of a
1.6 M solution in hexanes, 1.2 mmol) in anhydrous THF
(5 mL) a solution of allylphenylsulfone (0.218 g, 1.2 mmol)
and HMPA (0.215 g, 1.2 mmol) in THF (5 mL) was added
dropwise. After 30 min a solution of nitrone (1 mmol) in
THF (5 mL) was added dropwise. The reaction mixture was
stirred at K80 8C for 2 h at which time the reaction was
quenched by adding saturated aq NH4Cl (1 mL). The
reaction mixture was extracted with EtOAc (3!30 mL).
The combined organic extract was washed with brine, dried
(MgSO4) and concentrated. The crude material was purified
by radial chromatography using 4:1 hexane/ethyl acetate as
an eluent.

P. Merino et al. / Tetrahedron 61 (2005) 3335–3347
3343
6.2.1. (3R*,4S*)-4-Phenyl-4-(N-phenylhydroxyamino)-3-
(phenylsulfonyl)-1-butene 5a. Oil; dH (400 MHz, CDCl3)
4.70 (dd, 1H, JZ9.4, 10.0 Hz), 4.81 (d, 1H, JZ11.0 Hz),
4.89 (d, 1H, JZ17.0 Hz), 5.03 (d, 1H, JZ10.0 Hz), 5.52
(ddd, 1H, JZ9.4, 11.0, 17.0 Hz), 5.90 (bs, 1H, ex. D2O),
6.80 (m, 1H), 6.84 (m, 2H), 7.10 (m, 7H), 7.56 (m, 2H), 7.62
(m, 1H), 7.98 (m, 2H); dC (100 MHz, CDCl3) 69.3, 71.4,
116.8, 121.8 (2C), 125.4, 127.9 (2C), 128.1, 128.4, 128.5
(2C), 128.8 (2C), 129.3 (4C), 133.8, 134.2, 138.3, 149.7. IR
n 1140, 1230, 1300 cmK1. Anal. Calcd for C22H21NO3S
(379.47): C, 69.63; H, 5.58; N, 3.69. Found: C 69.45, H,
5.80, N, 3.70.
6.2.6. (3S*,4S*)-4-(N-Methylhydroxyamino)-4-phenyl-3-
(phenylsulfonyl)-1-butene 6d. Oil; dH (400 MHz, CDCl3)
2.38 (s, 3H), 4.06 (dd, 1H, JZ8.6, 10.1 Hz), 4.31 (d, 1H,
JZ8.6 Hz), 4.84 (d, 1H, JZ17.2 Hz), 5.1 (bs, 1H, ex. D2O),
5.25 (dd, 1H, JZ1.3, 10.1 Hz), 6.07 (dt, 1H, JZ10.1,
17.2 Hz), 7.21 (m, 5H), 7.34 (m, 2H), 7.46 (m, 1H), 7.63 (m,
2H); dC (100 MHz, CDCl3) 45.7, 71.3, 74.4, 124.1, 128.1
(2C), 128.4, 128.6 (2C), 128.9 (2C), 129.4, 129.9 (2C),
133.3, 135.3, 138.8. IR n 1145, 1230, 1290 cmK1. Anal.
Calcd for C17H19NO3S (317.40): C, 64.33; H, 6.03; N, 4.41.
Found: C 64.51, H, 6.23, N, 4.70.
6.2.7. (3R*,4S*)-4-(N-Benzylhydroxyamino)-4-(2-pyri-
dyl)-3-(phenylsulfonyl)-1-butene 9a. Oil; dH (400 MHz,
CDCl3) 3.55, (d, 1H, JZ13.6 Hz), 3.69 (d, 1H, JZ13.6 Hz),
4.48 (d, 1H, JZ9.1 Hz), 4.70 (t, 1H, JZ9.3 Hz), 4.80 (d,
1H, JZ16.9 Hz), 4.89 (dd, 1H, JZ1.1, 10.3 Hz), 5.39 (dt,
1H, JZ10.3, 16.9 Hz), 6.67 (bs, 1H, ex. D2O), 7.30 (m, 7H),
7.51 (m, 2H), 7.60 (m, 1H), 7.83 (m, 2H), 7.90 (m, 1H), 8.45
(m, 1H). dC (100 MHz, CDCl3) 57.4, 69.3, 70.8, 123.1,
123.5, 123.7, 128.2 (2C), 128.5, 128.6 (2C), 129.4 (2C),
129.6 (2C), 133.4, 136.4, 136.5, 137.4, 138.3, 148.6, 156.2.
IR n 1135, 1235, 1285 cmK1. Anal. Calcd for C22H22N2O3S
(359.48): C, 66.98; H, 5.62; N, 7.10. Found: C 66.81, H,
5.44, N, 7.32.
6.2.2.
(3R*,4S*)-4-(N-tert-Butylhydroxyamino)-4-
phenyl-3-(phenylsulfonyl)-1-butene 5b. Oil; dH
(400 MHz, CDCl3) 1.12 (s, 9H), 4.02 (d, 1H, JZ10.0 Hz),
4.52 (t, 1H, JZ9.9 Hz), 4.68 (d, 1H, JZ17.0 Hz), 5.00 (d,
1H, JZ10.1 Hz), 5.20 (bs, 1H, ex. D2O), 5.25 (dt, 1H, JZ
10.0, 17.0 Hz), 7.29 (m, 5H), 7.58 (m, 2H), 7.70 (m, 1H),
7.88 (m, 2H); dC (100 MHz, CDCl3) 25.4, 59.6, 70.5, 71.5,
122.1, 128.2, 128.3 (2C), 128.5 (2C), 129.0 (2C), 128.9,
129.9 (2C), 132.1, 133.0, 139.3. IR n 1135, 1220, 1290 cmK1
Anal. Calcd for C20H25NO3S (359.48): C, 66.82; H, 7.01; N,
3.90. Found: C 66.70, H, 7.16, N, 3.77.
.
6.2.3. (3R*,4S*)-4-(N-Benzylhydroxyamino)-4-phenyl-3-
(phenylsulfonyl)-1-butene 5c. Oil; dH (400 MHz, CDCl3)
3.57 (s, 2H), 4.28 (d, 1H, JZ9.9 Hz), 4.51 (t, 1H, JZ
9.9 Hz), 4.64 (d, 1H, JZ16.9 Hz), 4.83 (d, 1H, JZ10.4 Hz),
5.37 (dt, 1H, JZ9.9, 16.9 Hz), 5.55 (bs, 1H, ex. D2O), 7.30
(m, 10H), 7.45 (m, 2H), 7.59 (m, 1H), 7.84 (m, 2H); dC
(100 MHz, CDCl3) 61.0, 69.5, 71.9, 124.7, 128.1, 128.2
(2C), 128.3 (2C), 128.7 (2C), 128.9, 129.0 (2C), 129.1 (2C),
130.0 (2C), 133.2, 134.8, 137.5, 138.7, 138.9. IR n 1145,
1230, 1310 cmK1. Anal. Calcd for C23H23NO3S (393.50):
C, 70.20; H, 5.89; N, 3.56. Found: C 70.33, H, 5.91, N, 3.38.
6.2.8. (3S*,4S*)-4-(N-Benzylhydroxyamino)-4-(2-pyri-
dyl)-3-(phenylsulfonyl)-1-butene 10a. Oil; dH (400 MHz,
CDCl3) 3.44 (d, 1H, JZ13.4 Hz), 3.75 (d, 1H, JZ13.4 Hz),
4.51 (d, 1H, JZ9.6 Hz), 4.67 (t, 1H, JZ9.9 Hz), 4.94 (d,
1H, JZ17.2 Hz), 5.21 (dd, 1H, JZ1.2, 10.1 Hz), 6.01 (dt,
1H, JZ10.1, 17.2 Hz), 6.70 (bs, 1H, ex. D2O), 7.29 (m, 7H),
7.48 (m, 2H), 7.58 (m, 1H), 7.81 (m, 2H), 7.90 (m, 1H), 8.44
(m, 1H).; dC (100 MHz, CDCl3) 61.0, 66.6, 72.1, 123.2,
123.6, 123.7, 128.2, 128.3 (2C), 128.6 (2C), 128.9 (2C),
129.0 (2C), 133.8, 136.4 (2C), 137.6, 138.2, 148.7, 156.1.
IR n 1145, 1235, 1310 cmK1. Anal. Calcd for C22H22N2O3S
(359.48): C, 66.98; H, 5.62; N, 7.10. Found: C 66.79, H,
5.83, N, 7.25.
6.2.4. (3S*,4S*)-4-(N-Benzylhydroxyamino)-4-phenyl-3-
(phenylsulfonyl)-1-butene 6c. Oil; dH (400 MHz, CDCl3)
3.53 (d, 1H, JZ14.2 Hz), 3.57 (d, 1H, JZ14.2 Hz), 4.13
(dd, 1H, JZ9.1, 10.1 Hz), 4.51 (d, 1H, JZ9.1 Hz), 4.87 (d,
1H, JZ17.0 Hz), 4.90 (bs, 1H, ex. D2O), 5.25 (dd, 1H, JZ
1.3, 10.1 Hz), 6.11 (dt, 1H, JZ10.1, 17.0 Hz), 7.25 (m,
10H), 7.46 (m, 2H), 7.60 (m, 1H), 7.78 (m, 2H); dC
(100 MHz, CDCl3) 61.2, 69.1, 70.5, 123.7, 128.2 (2C),
128.3, 128.4 (2C), 128.5, 128.6 (2C), 128.9, 129.0 (2C),
129.1, 129.7, 129.9, 133.2 (2C), 137.9, 138.5, 138.9. IR n
1145, 1225, 1290 cmK1. Anal. Calcd for C23H23NO3S
(393.50): C, 70.20; H, 5.89; N, 3.56. Found: C 70.45, H,
5.68, N, 3.49.
6.2.9. (3R*,4S*)-4-(N-Benzylhydroxyamino)-4-(2-furyl)-
3-(phenylsulfonyl)-1-butene 9b. Oil; dH (400 MHz,
CDCl3) 3.64 (d, 1H, JZ13.6 Hz), 3.69 (d, 1H, JZ
13.6 Hz), 4.37 (d, 1H, JZ10.1 Hz), 4.50 (t, 1H, JZ
9.8 Hz), 4.81 (d, 1H, JZ17.2 Hz), 4.94 (dd, 1H, JZ0.9,
10.1 Hz), 5.46 (dt, 1H, JZ9.9, 17.2 Hz), 5.50 (bs, 1H, ex.
D2O), 6.27 (dd, 1H, JZ0.8, 3.2 Hz), 6.30 (dd, 1H, JZ1.8,
3.2 Hz), 7.30 (m, 5H), 7.32 (dd, 1H, JZ0.8, 1.8 Hz), 7.40
(m, 2H), 7.51 (m, 1H), 7.79 (m, 2H); dC (100 MHz, CDCl3)
60.9, 63.1, 70.5, 110.2, 111.1, 124.4, 127.3 (2C), 128.3
(2C), 128.4, 128.7 (2C), 129.1 (2C), 129.2, 133.5, 137.1,
138.7, 142.6, 148.8. IR n 1130, 1245, 1310 cmK1. Anal.
Calcd for C21H21NO4S (383.46): C, 65.78; H, 5.52; N, 3.65.
Found: C 65.59, H, 5.78, N, 3.44.
6.2.5. (3R*,4S*)-4-(N-Methylhydroxyamino)-4-phenyl-
3-(phenylsulfonyl)-1-butene 5d. White solid; mp 115–
116 8C; dH (400 MHz, CDCl3) 2.43 (s, 3H), 4.14 (d, 1H, JZ
9.8 Hz), 4.53 (t, 1H, JZ9.8 Hz), 4.75 (d, 1H, JZ16.8 Hz),
4.94 (d, 1H, JZ10.2 Hz), 5.46 (dt, 1H, JZ10.2, 16.8 Hz),
5.83 (bs, 1H, ex. D2O), 7.31 (m, 5H), 7.54 (m, 2H), 7.62 (m,
1H), 7.92 (m, 2H); dC (100 MHz, CDCl3) 44.7, 71.1, 71.8,
123.8, 128.1 (2C), 128.2, 128.6 (2C), 129.2 (2C), 129.9,
6.2.10.
(3S*,4S*)-4-(N-Benzylhydroxyamino)-4-(2-
furyl)-3-(phenylsulfonyl)-1-butene 10b. Oil; dH
(400 MHz, CDCl3) 3.60 (s, 2H), 4.30 (dd, 1H, JZ9.1,
9.9 Hz), 4.56 (d, 1H, JZ9.1 Hz), 4.70 (bs, 1H, ex. D2O),
5.02 (d, 1H, JZ16.8 Hz), 5.27 (dd, 1H, JZ1.1, 10.1 Hz),
6.02 (dt, 1H, JZ10.1, 16.8 Hz), 6.24 (dd, 1H, JZ1.8,
3.2 Hz), 6.26 (dd, 1H, JZ0.8, 3.2 Hz), 7.30 (m, 5H), 7.33
(dd, 1H, JZ0.8, 1.8 Hz), 7.43 (m, 2H), 7.55 (m, 1H), 7.72
130.4 (2C), 133.2, 133.6, 138.7. IR n 1140, 1235, 1310 cmK1
.
Anal. Calcd for C17H19NO3S (317.40): C, 64.33; H, 6.03; N,
4.41. Found: C 64.42, H, 5.87, N, 4.63.

3344
P. Merino et al. / Tetrahedron 61 (2005) 3335–3347
(m, 2H); dC (100 MHz, CDCl3) 61.1, 61.4, 72.3, 110.6,
111.1, 123.7, 127.5 (2C), 128.4 (2C), 128.7 (2C), 129.0,
129.2 (2C), 129.6, 133.4, 137.1, 138.4, 142.4, 148.5. IR n
1125, 1240, 1310 cmK1. Anal. Calcd for C21H21NO4S
(383.46): C, 65.78; H, 5.52; N, 3.65. Found: C 65.84, H,
5.41, N, 3.89.
6.2.15. (2S,3S,4S)-3-(N-Benzylhydroxyamino)-1,2-di-O-
isopropylidene-4-(phenylsulfonyl)-5-hexen-1,2-diol 13b.
Oil; [a]2D0ZK8 (c 0.32, CHCl3); dH (400 MHz, CDCl3) 1.26
(s, 3H), 1.34 (s, 3H), 3.70 (dd, 1H, JZ2.8, 8.4 Hz), 3.89 (d,
1H, JZ13.6 Hz), 3.95 (dd, 1H, JZ6.6, 8.6 Hz), 4.03 (d, 1H,
JZ13.6 Hz), 4.07 (dd, 1H, JZ6.3, 8.6 Hz), 4.32 (m, 2H),
4.65 (bs, 1H, ex. D2O), 5.00 (dd, 1H, JZ1.2, 17.2 Hz), 5.22
(dd, 1H, JZ1.3, 10.1 Hz), 5.97 (dt, 1H, JZ10.1, 17.2 Hz),
7.32 (m, 5H), 7.41 (m, 2H), 7.53 (m, 1H), 7.74 (m, 2H); dC
(100 MHz, CDCl3) 25.5, 26.3, 63.9, 68.2, 69.0, 70.2, 71.3,
109.5, 124.3, 127.4, 128.5 (2C), 128.8 (2C), 129.0 (2C),
129.7 (2C), 133.4, 138.5 (2C), 142.0. IR n 1140, 1210,
1280 cmK1. Anal. Calcd for C22H27NO5S (417.52): C,
63.29; H, 6.52; N, 3.35. Found: C 63.11, H, 6.67, N, 3.52.
6.2.11. (3R*,4S*)-4-(N-Benzylhydroxyamino)-5-methyl-
3-(phenylsulfonyl)-1-hexene 9c. Oil; dH (400 MHz,
CDCl3) 0.98 (d, 6H, JZ7.0 Hz), 1.80 (m, 1H), 3.52 (t,
1H, JZ10.0 Hz), 3.56 (d, 1H, JZ13.4 Hz), 3.61 (d, 1H, JZ
13.4 Hz), 4.30 (t, 1H, JZ9.4 Hz), 4.88 (d, 1H, JZ16.9 Hz),
5.20 (d, 1H, JZ10.1 Hz), 5.40 (bs, 1H, ex. D2O), 5.47 (dt,
1H, JZ10.1, 16.9 Hz), 7.28 (m, 5H), 7.40 (m, 2H), 7.58 (m,
1H), 7.80 (m, 2H); dC (100 MHz, CDCl3) 20.1 (2C), 26.1,
61.4, 63.2, 72.1, 123.6, 127.9, 128.6 (2C), 128.8 (2C), 129.0
(2C), 129.4 (2C), 130.1, 133.6, 133.8, 138.2. IR n 1135,
1240, 1285 cmK1. Anal. Calcd for C20H25NO3S (359.48):
C, 66.82; H, 7.01; N, 3.90. Found: C 66.69, H, 7.17, N, 3.83.
6.3. General procedure for the allylphenylsulfonylation
of nitrones at 0 8C. Synthesis of isoxazolidines
To a cooled (K80 8C) solution of n-BuLi (1.33 mL of a
1.6 M solution in hexanes, 1.2 mmol) in anhydrous THF
(5 mL) a solution of allylphenylsulfone (0.218 g, 1.2 mmol)
in THF (5 mL) was added dropwise. After 30 min the
resulting mixture was warmed to 0 8C and a solution of
nitrone (1 mmol) in THF (5 mL) was added dropwise. The
reaction mixture was stirred at 0 8C for 2 h at which time the
reaction was quenched by adding saturated aq NH4Cl
(1 mL). The reaction mixture was extracted with EtOAc
(3!30 mL). The combined organic extract was washed
with brine, dried (MgSO4) and concentrated. The crude
material was purified by radial chromatography.
6.2.12. (3S*,4S*)-4-(N-Benzylhydroxyamino)-5-methyl-
3-(phenylsulfonyl)-1-hexene 10c. Oil; dH (400 MHz,
CDCl3) 1.00 (d, 6H, JZ6.8 Hz), 1.72 (m, 1H), 3.58 (dd,
1H, JZ8.8, 10.0 Hz), 3.60 (s, 2H), 4.47 (dd, 1H, JZ4.8,
8.8 Hz), 4.92 (d, 1H, JZ17.2 Hz), 5.30 (d, 1H, JZ10.4 Hz),
5.62 (bs, 1H, ex. D2O), 5.94 (dt, 1H, JZ10.4, 17.2 Hz), 7.25
(m, 5H), 7.43 (m, 2H), 7.61 (m, 1H), 7.84 (m, 2H); dC
(100 MHz, CDCl3) 19.8 (2C), 25.2, 61.6, 62.9, 72.4, 123.8,
128.2, 128.4 (2C), 128.7 (2C), 128.9 (2C), 129.3 (2C),
132.4, 133.4, 133.9, 138.4. IR n 1130, 1220, 1320 cmK1
.
Anal. Calcd for C20H25NO3S (359.48): C, 66.82; H, 7.01; N,
3.90. Found: C 66.70, H, 6.88, N, 3.95.
6.3.1. (3S*,4S*,5R*)-2,3-Diphenyl-4-(phenylsulfonyl)-5-
methylisoxazolidine 7a. Oil; dH (400 MHz, CDCl3) 1.34
(d, 3H, JZ6.1 Hz), 3.96 (t, 1H, JZ5.9 Hz), 4.54 (d, 1H, JZ
5.6 Hz), 4.80 (pseudo quintuplet, 1H, JZ6. 5 Hz), 6.94 (m,
3H), 7.29 (m, 5H), 7.50 (m, 4H), 7.61 (m, 1H), 7.82 (m, 2H);
dC (100 MHz, CDCl3) 18.4, 71.0, 75.8, 83.2, 114.3 (2C),
122.1, 126.4 (2C), 127.8, 128.8 (2C), 128.9 (2C), 129.0
(2C), 129.5 (2C), 134.3, 137.4, 140.7, 149.8. IR n 1130,
1240, 1310 cmK1. Anal. Calcd for C22H21NO3S (379.47):
C, 69.63; H, 5.58; N, 3.69. Found: C 69.76, H, 5.72, N, 3.40.
6.2.13. (2S*,3R*)-2-(N-Benzylhydroxyamino)-1-O-(tert-
butyldiphenylsilyl)-3-(phenylsulfonyl)-4-penten-1-ol 9d.
Oil; dH (400 MHz, CDCl3) 1.00 (s, 9H), 3.78 (d, 1H, JZ
13.6 Hz), 3.82 (m, 2H), 3.90 (dd, 1H, JZ4.0, 10.4 Hz), 3.95
(d, 1H, JZ13.6 Hz), 4.12 (dd, 1H, JZ4.3, 9.6 Hz), 4.60 (bs,
1H, ex. D2O), 4.77 (d, 1H, JZ17.2 Hz), 5.17 (dd, 1H, JZ
1.2, 10.1 Hz), 6.02 (dt, 1H, JZ10.1, 17.2 Hz), 7.35 (m,
12H), 7.53 (m, 2H), 7.60 (m, 4H), 7.75 (m, 2H); dC
(100 MHz, CDCl3) 19.2, 26.8 (3C), 59.4, 62.3, 65.3, 71.3,
124.3, 127.6, 127.8 (2C), 127.9 (2C), 128.0, 128.3 (2C),
128.6 (2C), 129.0 (2C), 129.1, 129.9, 130.0, 130.1, 133.4,
135.3, 135.6, 135.7 (4C), 137.8, 138.2. IR n 1145, 1240,
1315 cmK1. Anal. Calcd for C34H39NO4SSi (585.83): C,
69.71; H, 6.71; N, 2.39. Found: C 69.93, H, 6.90, N, 2.51.
6.3.2. (3S*,4S*,5R*)-2-tert-Butyl-3-phenyl-4-(phenyl-
sulfonyl)-5-methylisoxazolidine 7b. Oil; dH (400 MHz,
CDCl3) 1.01 (s, 9H), 1.32 (d, 3H, JZ6.4 Hz), 3.50 (dd, 1H,
JZ5.5, 6.8 Hz), 4.00 (d, 1H, JZ6.8 Hz), 4.10 (dq, 1H, JZ
5.5, 6.4 Hz), 7.33 (m, 5H), 7.55 (m, 2H), 7.62 (m, 1H), 7.81
(m, 2H); dC (100 MHz, CDCl3) 20.4, 26.9 (3C), 59.0, 74.1,
74.8, 82.3, 127.9, 128.2 (2C), 128.5 (2C), 128.8 (2C), 129.1
6.2.14. (2S,3S,4R)-3-(N-Benzylhydroxyamino)-1,2-di-O-
isopropylidene-4-(phenylsulfonyl)-5-hexen-1,2-diol 13a.
Oil; [a]2D0ZC35 (c 0.45, CHCl3); dH (400 MHz, CDCl3)
1.31 (s, 3H), 1.39 (s, 3H), 3.59 (dd, 1H, JZ3.3, 10.1 Hz),
3.70 (dd, 1H, JZ7.3, 8.6 Hz), 3.91 (dd, 1H, JZ6.7, 8.6 Hz),
3.96 (dd, 1H, JZ3.3, 7.1 Hz), 4.04 (d, 1H, JZ13.9 Hz),
4.27 (d, 1H, JZ13.9 Hz), 4.61 (pseudo q, 1H, JZ7.1 Hz),
4.72 (bs, 1H, ex. D2O), 4.82 (d, 1H, JZ16.9 Hz), 5.22 (dd,
1H, JZ1.0, 10.1 Hz), 6.13 (dt, 1H, JZ10.1, 16.9 Hz), 7.29
(m, 3H), 7.34 (m, 2H), 7.41 (m, 2H), 7.53 (m, 1H), 7.74 (m,
2H); dC (100 MHz, CDCl3) 25.3, 26.8, 63.7, 65.2, 66.6,
71.0, 73.2, 109.1, 124.6, 127.3, 128.3 (2C), 128.7 (2C),
129.2 (2C), 129.4 (2C), 133.5, 138.3 (2C), 143.3. IR n 1135,
1240, 1300 cmK1. Anal. Calcd for C22H27NO5S (417.52):
C, 63.29; H, 6.52; N, 3.35. Found: C 63.05, H, 6.36, N, 3.49.
(2C), 135.2, 137.9, 139.5. IR n 1140, 1230, 1305 cmK1
.
Anal. Calcd for C20H25NO3S (359.5): C, 66.82; H, 7.01; N,
3.90. Found: C 66.75, H, 7.24, N, 4.10.
6.3.3. (3S*,4S*,5R*)-2-Benzyl-3-phenyl-4-(phenylsul-
fonyl)-5-methylisoxazolidine 7c. White solid; mp 89–
90 8C; dH (400 MHz, CDCl3) 1.30 (d, 3H, JZ6.4 Hz),
3.74 (t, 1H, JZ5.9 Hz), 4.05 (d, 1H, JZ13.5 Hz), 4.13 (d,
1H, JZ13.5 Hz), 4.44 (d, 1H, JZ5.9 Hz), 4.85 (pseudo
quintuplet, 1H, JZ6.4 Hz), 7.20 (m, 10H), 7.52 (m, 2H),
7.65 (m, 1H), 7.88 (m, 2H); dC (100 MHz, CDCl3) 20.3,
59.1, 70.7, 74.8, 81.9, 127.2 (2C), 127.3, 127.9, 128.3 (4C),
128.5 (2C), 128.7 (2C), 129.5 (2C), 134.2, 137.0, 138.2,
139.1. IR n 1135, 1240, 1310 cmK1. Anal. Calcd for

P. Merino et al. / Tetrahedron 61 (2005) 3335–3347
3345
C23H23NO3S (393.5): C, 70.20; H, 5.89; N, 3.56. Found: C
70.00, H, 5.96, N, 3.39.
75.5, 79.1, 127.5, 127.8 (2C), 128.4 (4C), 129.1 (2C), 129.5
(2C), 129.6 (2C), 129.8 (2C), 133.9, 134.1 (2C), 135.6 (4C),
136.7, 139.2. IR n 1145, 1250, 1310 cmK1. Anal. Calcd for
C34H39NO4SSi (585.8): C, 69.71; H, 6.71; N, 2.39. Found:
C 69.98, H, 6.83, N, 2.12.
6.3.4. (3S*,4S*,5R*)-2,5-Dimethyl-3-phenyl-4-(phenyl-
sulfonyl) isoxazolidine 7d. White solid; mp 68–69 8C; dH
(400 MHz, CDCl3) 1.36 (d, 3H, JZ6.3 Hz), 2.62 (s, 3H),
3.75 (dd, 1H, JZ5.1, 7.0 Hz), 4.02 (d, 1H, JZ7.0 Hz), 4.75
(dq, 1H, JZ5.1, 6.3 Hz), 7.28 (m, 5H), 7.54 (m, 2H), 7.65
(m, 1H), 7.84 (m, 2H); dC (100 MHz, CDCl3) 20.7, 42.8,
73.7, 73.9, 81.6, 127.7, 128.1 (2C), 128.4 (2C), 128.5 (2C),
6.3.9. (3S,4S,5R)-2-Benzyl-3-[(4S)-2,2-dimethyl-1,3-
dioxolan-4-yl]-4-(phenylsulfonyl)-5-methylisoxazolidine
14a. White solid; mp 109–110 8C; [a]2D0ZC10 (c 0.32,
CHCl3); dH (400 MHz, CDCl3) 0.88 (s, 3H), 1.07 (s, 3H),
1.10 (d, 3H, JZ6.1 Hz), 3.15 (m, 1H), 3.42 (dd, 1H, JZ2.8,
8.6 Hz), 3.66 (dd, 1H, JZ2.8, 7.8 Hz), 3.82 (m, 2H), 4.11 (s,
2H), 4.78 (dq, 1H, JZ6.1, 7.8 Hz), 7.28 (m, 3H), 7.33 (m,
2H), 7.54 (m, 2H), 7.61 (m, 1H), 7.86 (m, 2H); dC
(100 MHz, CDCl3) 18.9, 25.1, 26.3, 60.0, 68.4, 69.0, 75.4,
77.0 (2C), 109.9, 128.1, 128.8 (2C), 128.9 (2C), 129.9 (2C),
129.4 (2C), 134.1, 137.7, 138.2. IR n 1125, 1250, 1275 cmK1
.
Anal. Calcd for C17H19NO3S (317.4): C, 64.33; H, 6.03; N,
4.41. Found: C 64.29, H, 6.28, N, 4.22.
6.3.5. (3S*,4S*,5R*)-2-Benzyl-3-(2-pyridyl)-4-(phenyl-
sulfonyl)-5-methylisoxazolidine 11a. Oil; dH (400 MHz,
CDCl3) 1.17 (d, 3H, JZ6.1 Hz), 4.20 (d, 1H, JZ13.5 Hz),
4.33 (d, 1H, JZ13.5 Hz), 4.60 (d, 1H, JZ4.6 Hz), 4.64 (dd,
1H, JZ4.6, 7.1 Hz), 4.90 (dq, 1H, JZ6.1, 7.1 Hz), 6.98 (m,
1H), 7.13 (m, 1H), 7.21 (m, 1H), 7.27 (m, 2H), 7.45 (m, 5H),
7.50 (m, 1H), 7.87 (m, 2H), 8.26 (m, 1H); dC (100 MHz,
CDCl3) 19.12, 59.8, 70.39, 75.2, 77.7, 122.5, 122.7, 127.6,
128.5 (2C), 128.6 (2C), 129.3 (2C), 129.6 (2C), 133.9,
136.5, 138.7, 138.9, 148.8, 157.8. IR n 1145, 1250,
1300 cmK1. Anal. Calcd for C22H22N2O3S (394.5): C,
66.98; H, 5.62; N, 7.10. Found: C 67.12, H, 5.78, N, 6.89.
130.2 (2C), 134.5, 137.1, 139.3. IR n 1130, 1225, 1285 cmK1
.
Anal. Calcd for C22H27NO5S (417.5): C, 63.29; H, 6.52; N,
3.35. Found: C 63.17, H, 6.74, N, 3.49.
6.3.10. (3R,4R,5S)-2-Benzyl-3-[(4S)-2,2-dimethyl-1,3-
dioxolan-4-yl]-4-(phenylsulfonyl)-5-methylisoxazolidine
14b. Oil; [a]2D0ZK22 (c 0.32, CHCl3); dH (400 MHz,
CDCl3) 1.01 (d, 3H, JZ6.1 Hz), 1.05 (s, 3H), 1.09 (s, 3H),
3.41 (dd, 1H, JZ3.8, 8.1 Hz), 3.66 (dd, 1H, JZ5.8, 8.8 Hz),
3.72 (dd, 1H, JZ3.8, 5.8 Hz), 3.79 (dd, 1H, JZ6.8, 8.8 Hz),
3.93 (pseudoq, 1H, JZ5.8 Hz), 4.11 (s, 2H), 4.74 (dq, 1H,
JZ6.1, 8.1 Hz), 7.25 (m, 3H), 7.34 (m, 2H), 7.52 (m, 2H),
7.63 (m, 1H), 7.82 (m, 2H); dC (100 MHz, CDCl3) 16.7,
23.8, 25.1, 59.4, 64.8, 66.3, 74.1, 74.7, 75.5, 108.4, 126.8,
127.6 (2C), 127.9 (2C), 128.8 (2C), 128.9 (2C), 133.5,
136.0, 137.8. IR n 1135, 1225, 1310 cmK1. Anal. Calcd for
C22H27NO5S (417.5): C, 63.29; H, 6.52; N, 3.35. Found: C
63.15, H, 6.39, N, 3.56.
6.3.6. (3S*,4S*,5R*)-2-Benzyl-3-(2-furyl)-4-(phenyl-
sulfonyl)-5-methylisoxazolidine 11b. Oil; dH (400 MHz,
CDCl3) 1.24 (d, 3H, JZ6.1 Hz), 3.62 (dd, 1H, JZ4.9,
6.8 Hz), 4.40 (d, 1H, JZ13.6 Hz), 4.51 (d, 1H, JZ13.6 Hz),
4.77 (d, 1H, JZ4.9 Hz), 4.98 (pseudo quintuplet, 1H, JZ
6.5 Hz), 6.25 (dd, 1H, JZ1.7, 3.2 Hz), 6.28 (dd, 1H, JZ0.9,
3.2 Hz), 7.30 (m, 5H), 7.34 (dd, 1H, JZ0.9, 1.7 Hz), 7.49
(m, 2H), 7.60 (m, 1H), 7.82 (m, 2H); dC (100 MHz, CDCl3)
21.2, 60.2, 63.6, 75.2, 81.4, 110.4, 111.3, 127.2, 127.7 (2C),
128.1 (2C), 128.9 (2C), 129.1 (2C), 133.2, 137.3, 138.5,
140.3, 149.0. IR n 1140, 1240, 1275 cmK1. Anal. Calcd for
C21H21NO4S (383.5): C, 65.78; H, 5.52; N, 3.65. Found: C
65.62, H, 5.36, N, 3.81.
6.4. General procedure for the conversion of hydroxyl-
amines into isoxazolidines
To a cooled (0 8C) solution hydroxylamine (0.5 mmol) in
THF (5 mL) n-BuLi (0.8 mL of a 1.6 M solution in hexanes,
0.5 mmol) was added dropwise. After 1 h the reaction was
quenched by adding saturated aq NH4Cl (1 mL). The
reaction mixture was extracted with EtOAc (3!15 mL).
The combined organic extract was washed with brine, dried
6.3.7. (3S*,4S*,5R*)-2-Benzyl-3-(isopropyl)-4-(phenyl-
sulfonyl)-5-methylisoxazolidine 11c. Oil; dH (400 MHz,
CDCl3) 0.55 (d, 3H, JZ6.8 Hz), 0.70 (d, 3H, JZ6.6 Hz),
0.95 (d, 3H, JZ6.1 Hz), 2.70 (m, 1H), 3.28 (dd, 1H, JZ3.8,
7.8 Hz), 3.36 (dd, 1H, JZ3.8, 6.4 Hz), 4.10 (d, 1H, JZ
13.2 Hz), 4.15 (d, 1H, JZ13.2 Hz), 4.70 (dq, 1H, JZ6.1,
7.8 Hz), 7.32 (m, 5H), 7.55 (m, 2H), 7.64 (m, 1H), 7.80 (m,
2H); dC (100 MHz, CDCl3) 19.8 (2C), 20.5, 27.3, 59.6, 61.7,
75.8, 80.9, 127.4, 127.5 (2C), 128.3 (2C), 128.5 (2C), 129.2
1
(MgSO4), concentrated and examined by H NMR. The
crude material was purified by radial chromatography.
To obtain elimination products preferentially the reaction
was repeated using 1.5 equiv of BuLi (0.47 mL of a 1.6 M
solution in hexanes, 0.75 mmol).
(2C), 134.1, 138.1, 138.6. IR n 1160, 1240, 1305 cmK1
.
Anal. Calcd for C20H25NO3S (359.48): C, 66.82; H, 7.01; N,
3.90. Found: C 66.65, H, 7.25, N, 4.11.
6.4.1. (Z)-4-Phenyl-3-(phenylsulfonyl)-1,3-butadiene 19.
Oil; dH (400 MHz, CDCl3) 5.40 (dt, 1H, JZ1.2, 11.0 Hz),
5.83 (dd, 1H, JZ1.2, 17.8 Hz), 6.31 (ddd, 1H, JZ1.2, 11.0,
17.8 Hz), 7.32 (m, 3H), 7.44 (m, 4H), 7.51 (m, 1H), 7.82 (m,
3H), 7.81 (s, 1H); dC (100 MHz, CDCl3) 123.9, 126.5, 128.1
(2C), 128.7 (2C), 129.0 (2C), 130.0 (2C), 130.5 (2C), 133.2,
133.4, 138.2, 138.7. IR n 1125, 1210, 1270 cmK1. Anal.
Calcd for C16H14O2S (270.4): C, 71.08; H, 5.22. Found: C
71.17, H, 5.40.
6.3.8. (3S*,4S*,5R*)-2-Benzyl-3-(tert-butyldiphenyl-
siloxymethyl)-4-(phenylsulfonyl)-5-methylisoxazolidine
11d. Oil; dH (400 MHz, CDCl3) 0.93 (s, 9H), 0.95 (d, 3H,
JZ6.2 Hz), 3.36 (dd, 1H, JZ6.1, 10.6 Hz), 3.52 (dd, 1H,
JZ6.2, 10.6 Hz), 3.55 (dd, 1H, JZ4.3, 7.4 Hz), 3.70 (dt,
1H, JZ4.3, 6.1 Hz), 3.99 (d, 1H, JZ13.2 Hz), 4.12 (d, 1H,
JZ13.2 Hz), 4.66 (dq, 1H, JZ6.2, 7.4 Hz), 7.25 (m, 7H),
7.33 (m, 4H), 7.45 (m, 6H), 7.59 (m, 1H), 7.80 (m, 2H); dC
(100 MHz, CDCl3) 18.7, 26.9 (3C), 29.7, 64.8, 67.5, 74.3,
6.4.2. (Z)-4-(2-Pyridyl)-3-(phenylsulfonyl)-1,3-butadiene
20. Oil; dH (400 MHz, CDCl3) 5.36 (dt, 1H, JZ1.1,

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(c) Merino, P.; Delso, J. I.; Mannucci, V. Curr. Org. Synth.
2005, in press.
11.6 Hz), 5.71 (dd, 1H, JZ1.0, 17.4 Hz), 6.50 (ddd, 1H, JZ
1.1, 11.6, 17.4 Hz), 7.40 (m, 3H), 7.54 (m, 1H), 7.80 (m,
3H), 8.3 (s, 1H), 8.6 (m, 1H); dC (100 MHz, CDCl3) 123.8,
124.5, 128.6 (2C), 129.4 (2C), 130.0, 130.6, 132.9, 133.1,
133.3, 138.5, 139.1, 148.3, 150.2. IR n 1115, 1200,
1275 cmK1. Anal. Calcd for C15H13NO2S (271.33): C,
66.40; H, 4.83; N, 5.16. Found: C, 66.72; H, 4.56; N, 5.37.
2. For recent and representative examples see (a) Andrews, P. C.;
Peatt, A. C.; Raston, C. L. Tetrahedron Lett. 2004, 45,
243–248. (b) Ollevier, T.; Ba, T. Tetrahedron Lett. 2003, 44,
9003–9005. (c) Gastner, T.; Ishitani, H.; Akiyama, R.;
Kobatashi, S. Angew. Chem., Int. Ed. Engl. 2001, 40,
1896–1898. (d) Sebellius, S.; Wallner, O. A.; Szabo, K. J.
Org. Lett. 2003, 5, 3065–3068. (e) Cainelli, G.; Giacomini, D.;
Galetti, P.; Quintavalla, A. Eur. J. Org. Chem. 2002,
3153–3161. (f) Hirabayashi, R.; Ogawa, C.; Sugiura, M.;
Kobayashi, S. J. Am. Chem. Soc. 2001, 123, 9493–9499. (g)
Ogawa, C.; Sugiura, M.; Kobayashi, S. J. Org. Chem. 2002,
67, 5359–5364. (h) Yamasaki, J.; Fujii, K.; Wada, R.; Kanai,
M.; Shibasaki, M. J. Am. Chem. Soc. 2002, 124, 6536–6537. (i)
Wipf, P.; Kendall, C. Org. Lett. 2001, 3, 2773–2776. (j)
Sugiura, M.; Robvieux, F.; Kobayashi, S. Synlett 2003,
1749–1751. (k) Yanada, R.; Okaniwa, M.; Kaieda, A.;
Ibuka, T.; Takemoto, Y. J. Org. Chem. 2001, 66, 1283–1286.
3. Wuts, P. G. M.; Jung, Y.-W. J. Org. Chem. 1988, 53,
1957–1965.
6.4.3. (Z)-4-(2-Furyl)-3-(phenylsulfonyl)-1,3-butadiene
21. Oil; dH (400 MHz, CDCl3) 5.40 (dt, 1H, JZ1.0,
12.1 Hz), 5.90 (dd, 1H, JZ1.0, 17.9 Hz), 6.46 (dd, 1H,
JZ2.0, 3.5 Hz), 6.74 (bd, 1H, JZ3.5 Hz), 6.83 (ddd, 1H,
JZ1.2, 12.1, 17.9 Hz), 7.41 (m, 3H), 7.53 (m, 1H), 7.80 (m,
2H), 8.08 (s, 1H); dC (100 MHz, CDCl3) 110.1, 122.9,
123.6, 128.5 (2C), 129.6 (2C), 130.2, 131.9, 134.3, 137.9,
139.6, 139.7, 143.0. IR n 1135, 1225, 1250 cmK1. Anal.
Calcd for C14H12O3S (260.31): C, 64.60; H, 4.65. Found: C
64.71, H, 4.80.
6.4.4. (Z)-5-Methyl-3-(phenylsulfonyl)-1,3-hexadiene 22.
Oil; dH (400 MHz, CDCl3) 1.03 (d, 6H, JZ6.6 Hz), 2.70
(dh, 1H, JZ6.6, 10.1 Hz), 5.32 (dt, 1H, JZ1.0, 11.6 Hz),
5.45 (dd, 1H, JZ1.0, 17.9 Hz), 6.18 (ddd, 1H, JZ1.0, 11.6,
17.9 Hz), 6.80 (d, 1H, JZ10.1 Hz), 7.43 (m, 2H), 7.51 (m,
1H), 7.76 (m, 2H); dC (100 MHz, CDCl3) 22.0 (2C), 28.1,
123.1, 125.5, 127.8 (2C), 128.9 (2C), 129.0, 133.1, 140.0,
149.4. IR n 1110, 1220, 1260 cmK1. Anal. Calcd for
C13H16O2S (236.33): C, 66.07; H, 6.82. Found: C 65.84, H,
6.99.
4. Gianotti, M.; Lombardo, M.; Trombini, M. Tetrahedron Lett.
1998, 39, 1643–1646.
5. Fiumana, A.; Lombardo, M.; Trombini, M. J. Org. Chem.
1997, 62, 5623–5626.
6. Kumar, H. M. S.; Anjaneyulu, S.; Reddy, E. J.; Yadav, J. S.
Tetrahedron Lett. 2000, 41, 9311–9314.
7. Laskar, D. D.; Prajapati, D.; Sandhu, J. S. Tetrahedron Lett.
2001, 42, 7883–7886.
8. Lombardo, M.; Spada, S.; Trombini, C. Eur. J. Org. Chem.
1998, 2361–2364.
6.4.5. (Z)-4-[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]-3-
(phenylsulfonyl)-1,3-butadiene 23. Oil; [a]2D0ZC28 (c
0.26, CHCl3); dH (400 MHz, CDCl3) 1.41 (s, 3H), 1.50 (s,
3H), 3.78 (dd, 1H, JZ6.9, 8.4 Hz), 4.16 (dd, 1H, JZ6.4,
8.4 Hz), 4.83 (td, 1H, JZ6.6, 8.3 Hz), 5.50 (m, 2H), 6.28
(dd, 1H, JZ11.1, 17.9 Hz), 6.96 (d, 1H, JZ8.3 Hz), 7.50
(m, 2H), 7.63 (m, 1H), 7.86 (m, 2H); dC (100 MHz, CDCl3)
25.7, 26.6, 69.1, 72.1, 110.6, 125.1, 125.4, 128.2 (2C), 129.1
(2C), 133.4, 138.7, 139.2, 143.2. IR n 1130, 1235,
1280 cmK1. Anal. Calcd for C15H18O4S (294.4): C, 61.20;
H, 6.16. Found: C 61.08, H, 6.30.
9. (a) Merino, P. In Padwa, A., Ed.; Science of Synthesis;
Thieme: Stuttgart, 2004; Vol. 27, pp 511–580. (b) Merino, P.;
Franco, S.; Merchan, F. L.; Tejero, T. Synlett 2000, 442–454.
10. (a) Hassner, A.; Ghera, E.; Yechezkel, T.; Kleiman, V.;
Balasubramanian, T.; Ostercamp, D. Pure Appl. Chem. 2000,
72, 1671–1683. (b) Alonso, D. A.; Najera, C.; Sansano, J. M.
Tetrahedron 1994, 50, 6603–6620.
11. For reviews and treatises on the synthetic potential of the
sulfonyl group see (a) Biellman, J. F.; Ducep, J.-B. Org. React.
1982, 27, 1–344. (b) Uchida, Y. In The Chemistry of Sulfones
and Sulfoxides; Patai, S., Rappoport, Z., Stirling, C. J. M.,
Eds.; Wiley: New York, 1988; pp 583–664. (c) Simpkins, N. S.
Sulphones in Organic Synthesis; Pergamon: Oxford, 1993. (d)
Najera, C.; Yus, M. Tetrahedron 1999, 55, 10547–10658.
12. It is known that carbanions derived from allylic sulphones
undergo a- rather than g-alkylation. See Ref. 11c.
13. Kumareswaran, A.; Hassner, A. Tetrahedron: Asymmetry
2001, 12, 3409–3415.
Acknowledgements
This work was supported by the Spanish Ministry of Science
and Technology (MCYT) and FEDER Program (Project
BQU2001-2428), and the Government of Aragon in Spain
(Project P116-2001 and Consolidated Research Groups
Program). One of us (V. M.) thanks the Spanish Ministry of
Education for a grant (F.P.U. program). We also thank Mr.
Vincent Terrasson and Mrs. Carole Cabrol for technical
assistance and Prof. Fernando Lahoz (ICMA, University of
Zaragoza-CSIC) for collecting X-ray data.
14. Dong, Z.; Pyne, S. G.; Skelton, B. W.; White, A. H. Synlett
1997, 103–104.
15. The corresponding protonated 17 was not detected in any case
because of the rapidity of the Michael addition.
16. We have also performed parallel studies that demonstrate the
lack of reactivity between nitrone 1 and propenyl sulfone at
0 8C during 1 h. In addition, theoretical calculations show that
a concerted process between a nitrone and an allylic anion is
clearly disfavored.
References and notes
17. Moglioni, A. G.; Muray, E.; Castillo, J. A.; Alvarez-Larena,
A.; Moltrasio, G. V.; Branchadell, V.; Ortun˜o, R. M. J. Org.
Chem. 2002, 67, 2402–2410.
1. (a) Yamamoto, Y.; Asoa, N. Chem. Rev. 1993, 93, 2207–2293.
(b) Masse, C. E.; Panek, J. S. Chem. Rev. 1995, 95, 1293–1316.
18. We generate 73 different conformations by stepwise rotation

P. Merino et al. / Tetrahedron 61 (2005) 3335–3347
3347
of 58 around the C1–C2 bond, and they were optimized. The
heat of formation (DHf) was calculated (PM3, MOPAC2000)
for all these conformations and the relative and absolute
minima were reoptimized. The minimum energy structure
obtained in each case was essentially identical to those
depicted in Figure 1.
R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao,
O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.;
Cross, J. B.; Adamo, C.; Jaramillo, J.; Gomperts, R.;
Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.;
Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.;
Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V.
G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas, O.;
Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J.
B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.;
Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.;
Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.;
Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challa-
combe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M.
W.; Gonzalez, C.; Pople, J. A. Gaussian, Inc., Pittsburgh PA,
2003.
19. (a) Hassner, A.; Kumareswaran, R. Tetrahedron: Asymmetry
2001, 12, 269–2276. (b) Kumareswaran, R.; Balasubramanian,
T.; Hassner, A. Tetrahedron Lett. 2000, 41, 8157–8162.
20. Merino, P.; Franco, S.; Merchan, F. L.; Romero, P.; Tejero, T.;
Uriel, S. Tetrahedron: Asymmetry 2003, 14, 3731–3743.
21. The authors have deposited the atomic coordinates for these
structures with the Cambridge Crystallographic Data Centre.
CCDC 250314 and CCDC 250315 contain the supplementary
crystallographic data for compounds 7c and 14a, respectively.
These data can be obtained free of charge via www.ccdc.cam.
ac.uk/data_request/cif, by emailing data_request@ccdc.cam.
ac.uk, or by contacting The Cambridge Crystallographic Data
Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax: C44
1223 336033. The graphic views shown in Figure 3 were made
with ORTEP3 software. Copyright by Farrugia, L. J.,
University of Glasgow, 1997–2000.
24. (a) Merino, P.; Tejero, T. Tetrahedron 2001, 57, 8125–8128.
(b) Merino, P.; Tejero, T.; Revuelta, J.; Romero, P.; Cicchi, S.;
Mannucci, V.; Brandi, A.; Goti, A. Tetrahedron: Asymmetry
2003, 14, 367–379.
25. (a) Safont, V. S.; Moliner, V.; Oliva, M.; Castillo, R.; Andres,
J.; Gonzalez, F.; Carda, M. J. Org. Chem. 1996, 61,
3467–3475. (b) Murga, J.; Falomir, E.; Carda, M.; Marco,
J. A. Tetrahedron 2000, 57, 6239–6247.
22. Structures were first optimized through step by step calcu-
lations using semiempirical methods (PM3) and then fully
optimized at the HF/6-31G(d) level of theory.
26. Piffl, M.; Weston, J.; Gu¨nter, W.; Anders, E. J. Org. Chem.
2000, 65, 5942–5950.
23. Gaussian 03, revision B.05. Frisch, M. J.; Trucks, G. W.;
Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J.
R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K. N.; Burant, J.
C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.;
Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson,
G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda,
27. In order to simplify the calculations the phenyl group was
replaced by a methyl group and the solvent was modelized by
water molecules.
28. Dondoni, A.; Franco, S.; Merchan, F. L.; Merino, P.; Tejero, T.
Synth. Commun. 1994, 22, 2200–2224.