Thermal and Sc(OTf)3 catalyzed 1,3-dipolar cycloaddition of open-chain nitrones to α,β-unsaturated lactones: Combined experimental and computational studies

Article abstract of DOI:10.1016/j.tetasy.2012.12.006

The stereoselectivity of 1,3-dipolar cycloaddition reactions of C-phenyl open-chain nitrones and α,β-unsaturated γ- and δ-lactones was investigated under thermal and catalytic conditions. It was found that under thermal conditions, the endo approach of th

Full text of DOI:10.1016/j.tetasy.2012.12.006

Tetrahedron: Asymmetry 24 (2013) 89–103
Contents lists available at SciVerse ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Thermal and Sc(OTf)3 catalyzed 1,3-dipolar cycloaddition of open-chain
nitrones to
a,b-unsaturated lactones: combined experimental
and computational studies
⇑
´
_
´
Marcin Sniezek, Sebastian Stecko , Irma Panfil, Bartłomiej Furman, Zofia Urbanczyk-Lipkowska,
Marek Chmielewski
Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 25 October 2012
Accepted 14 December 2012
The stereoselectivity of 1,3-dipolar cycloaddition reactions of C-phenyl open-chain nitrones and
unsaturated c- and d-lactones was investigated under thermal and catalytic conditions. It was found that
a,b-
under thermal conditions, the endo approach of the reactants was preferred leading to the thermody-
namic product. In the presence of Sc(OTf)3 the exo adduct was obtained in high yield and selectivity.
The energies of the cycloaddition reactions were investigated by means of molecular orbital calculations
at the B3LYP/6-31+G(d,p) and MP3/6-31+G(d,p) theory level. Different reaction channels and reactant
approaches, fitting the individual regio- and stereochemical preferences, are discussed. The computa-
tional results were compared with the corresponding experimental data and found to be in good
agreement.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
last 25 years, they have also been found to exhibit a variety of
interesting activities against some non-bacterial diseases.1
Since discovery of penicillin, b-lactam antibiotics represent one
of the most powerful tools against bacterial infections. Over the
In 1979 Tufariello et al.2 reported a simple and attractive entry
to the basic skeleton of thienamycin based on the 1,3-dipolar
MeOOC
1,3-DCA
COOMe
+
N
N
O
O
hydrogenolysis
OH
O
HO
NH2
H
H
MeOOC
intramolecular
N-acylation
S
HN
N
N
O
OH
COOH
thienamycin
Scheme 1.
⇑
Corresponding author. Tel.: +48 22 343 2137; fax: +48 22 632 6681.
E-mail address: sebastian.stecko@icho.edu.pl (S. Stecko).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.12.006

´
_
M. Sniezek et al. / Tetrahedron: Asymmetry 24 (2013) 89–103
90
cycloaddition (1,3-DCA) of a five-membered cyclic nitrone and
methyl crotonate. The general strategy of synthesis, which was
such as 1–8, however, one prerequisite must be fulfilled, the key
cycloaddition step must proceed with high stereoselectivity.
Cl
OCH3
OH
OMe
OH
N
F
O
N
N
O
O
OCH3
F
1
3
(-)-SCH 48461
Ezetimibe
(+)-SCH 54016 2
cholesterol inhibitor
cholesterol acyl
cholesterol inhibitor
transferase inhibitor
HO
O
OH
O
O
OH
OH
Cl
O
COOH
F
O
N
O
N
O
Cl
F
4
5, antifungal
, hypocholesterolemic
R2
O
HN
OH
R1
AcO
N
H
N
N
O
N
O
O
R
O
N
R3
6, analgestic
7, anticancer
8, selective estrogen
receptor modulator
(SERM)
based on the formation of an isoxazolidine adduct, followed by hy-
drogenolysis of the N,O-bond to give a b-amino acid and its subse-
quent cyclization leading to the b-lactam ring (Scheme 1), has been
exploited in a variety of target oriented syntheses3.
Tufariello’s strategy also offers a particularly attractive entry to
N,4-diaryl substituted b-lactams. Compounds, which belong to this
group, for instance 1–8, exhibit a wide range of interesting biologi-
cal activities such as cholesterol absorption inhibition (compounds
1–4),4 antifungal (compound 5),5 and analgesic activity (compound
6)6 or anticancer properties (compounds 7–8).7
Previously we had demonstrated that cyclic dipolarophiles,
such as sugar-derived d-lactone 9, are attractive reagents for the
thermally induced 1,3-DCA furnishing adducts, which in turn can
be transformed into the corresponding 2-azetidinones. For exam-
ple, the adduct of lactone 9 with C-anisyl-N-phenyl nitrone 10
was converted into 1,4-diaryl b-lactam 11 with a polyol side chain
at the C-3 carbon atom.8
Independently, we have demonstrated the stereocontrolled
transformation of adducts of simple five-membered cyclic nitrones
(e.g. 17 and its chiral substituted derivatives) and c- and d-lactones
It is important to note that the biological properties of b-lactam
compounds 1–8 are directly related to the configuration of the ste-
reogenic centers in the 2-azetidinone ring. The presence of trans-
or cis-substitution pattern at the ring is important for the bioactiv-
ity of these compounds.
12, 14, and 15 into selected iminosugars.9 These syntheses9,10
prompted us to investigate, in greater detail, factors responsible
for the stereoselectivity of the 1,3-dipolar cycloaddition process.
Our experimental studies were combined with quantum mechanic
computations, studying in detail the reaction mechanism, its exo/
endo- and facial selectivity,11 as well as the chiraloopical properties
of the cycloadducts.12
As mentioned, the Tufariello strategy is a useful tool for the syn-
thesis of the central structural fragment of bioactive monobactams

´
_
M. Sniezek et al. / Tetrahedron: Asymmetry 24 (2013) 89–103
91
OCH3
OMe
OH
AcO
AcO
H
H
N
TBSO
O
O
O
N
Ph
O
O
9
10
11
BnO
BnO
O
O
O
O
O
O
O
O
O
BnO
RO
11
12
13
14
15
Ph
16
R: H
R: Bn
R
O
N
N
N
O
18
19
Bn
R: H
O
Ph
R: Me
20 R: Ph
17
21
We have recently reported on the application of diaryl nitrones
in a formal synthesis of Ezetimibe 1,13 and related compounds14
via Cu(I)-mediated Kinugasa cycloaddition/rearrangement cascade
2. Results and discussion
2.1. Thermal 1,3-dipolar cycloaddition of nitrones to
unsaturated lactones
reactions between terminal acetylenes15 derived from
L-glyceral-
dehyde acetonide and suitable C,N-diarylnitrones.
Finally, bearing in mind that the 4-aryl and N,4-diaryl azetidi-
nones exhibit particularly interesting biological properties,4–7 we
have revisited our previous work on the cycloaddition reactions
of nitrones, but focused our attention on 1,3-dipolar cycloadditions
Herein we selected lactones 11–16 and the nitrones 18–21. All
sugar-derived lactones were obtained following known methods.16
The nitrones were synthesized using common methods by reacting
the corresponding aldehydes with phenyl- or benzylhydroxyl-
amine.17 Thermal cycloaddition reactions were performed follow-
ing standard procedures,8 by reacting the nitrone and
dipolarophile in toluene solution at reflux; at room temperature,
the formation of products was not observed, even after extension
of the reaction time for up to 1 week.
involving diaryl nitrone 21 with a,b-unsaturated c- and d-lactones
11–16. Herein our aim was to find a way to achieve stereochemical
control of the configuration of the newly formed stereogenic cen-
ters. We focused our attention on the exo/endo selectivity as a func-
tion of the reaction time, as well as the thermal and catalytic
conditions of the cycloaddition reaction.
AcO
BnO
BnO
O
O
4
O
O
O
N
6
O
AcO
O
7
O
BnO
O
6
6a
4
BnO
O
HO
7a
H
H
H
H
H
H
H
H
H
H
3a
3
3a
O 1
3
O 1
O
O
O
N
N
N
N
Ph
Bn
22
Bn
Ph
25
Ph
23
24
26
AcO
AcO
O
O
lactone 10
PhMe, Δ
H
H
N
O
O
Bn
N
Bn
19
27
O
O
HO
12
lactone
H
H
N
PhMe, Δ
O
O
Bn
N
Ph
19
28
Scheme 2.

´
_
M. Sniezek et al. / Tetrahedron: Asymmetry 24 (2013) 89–103
92
In the case of
L
-erythro lactones, such as 16, due to the anti sub-
MgI2, MgBr2ꢀEt2O, Zn(OTf)2, Cu(OTf)2, InCl3, In(OTf)3, FeCl3, and
Yb(OTf)3, revealed that only the ytterbium salt provided promising
results. Following the Kobayashi protocol,23 in the presence of a
ytterbium salt, the corresponding cycloadducts were obtained with
poor yield (<10%) but with high stereoselectivity providing almost
exclusively the exo isomers. Better results were obtained when
Sc(OTf)3 was used instead of Yb(OTf)3. The best results for Sc(OTf)3
were observed when the reaction was performed in toluene at
room temperature. The replacement of toluene with CH2Cl2 led
to a decrease in the yield, but the stereoselectivity remained at
the same level. In the case of MeCN, as reported by Komatsu
et al.25 the formation of a product was not observed.
With preliminary studies in hand, we directed our attention to
the unsubstituted lactones 11 and 14, and protected lactones 10,
13, and 15 (Table 1). Since a catalytic reaction could not be per-
formed if the lactone had a free hydroxyl group (we did not ob-
serve formation of any product), the cycloaddition to lactone 12
was not investigated further. The influence of the catalyst was
demonstrated by the cycloaddition of 10 and nitrone 21. Under
the thermal conditions a mixture of adducts 29 and 30 was formed
in 54% yield and with a ratio of approximately 77:23, respectively.
In the presence of the catalyst, the ratio of adducts was 96:4,
respectively, and the yield was 60%. It should be noted that this
cycloaddition reaction was found to be reversible. Heating of the
kinetic product 29 caused its isomerization to 30 in 21% after
24 h. Further extension of reflux time in toluene increased the
amount of isomer 30 to 41% after 72 h, and 49% after 96 h
(Fig. 1). This observation demonstrated the reversibility of the
cycloaddition and the preference of the phenyl substituent at C3
to occupy the convex-side of the bicyclic skeleton.
stitution of a six-membered ring, even the simple nitrone 18 pro-
vided a mixture of adducts 22 and 23 in a ratio of approximately
2.5:1, respectively, as a result of the addition to both sides of the lac-
tone ring (Scheme 5).18 These reactions, therefore, were not investi-
gated further since their usefulness in context of our goal, that is,
target-oriented syntheses, appeared to be limited. In other cases ex-
plored, the nitrone molecule approached the double bond
exclusively anti to the substituent or both substituents in the lac-
tone (10, 12, and 15). Thus, the simple nitrone 18 with lactones
10, 12, and 15 gave adducts 24, 25, and 26, respectively (Scheme 2).8
Due to the disfavored interaction of the methyl group with the
lactone carbonyl group, N-benzyl-C-methyl nitrone 19 approaches
lactones 10 and 12 in the endo mode to provide the corresponding
adducts 27 and 28 (56%), which are the thermodynamic products;
in these cases the formation of the corresponding exo isomers was
not observed (Scheme 2).8
From a synthetic point of view, the C,N-disubsitituted nitrones
20 and 21 represent suitable substrates for the synthesis of bioac-
tive N,4-diaryl-2-azetidinones. However, our previous studies
showed that the reaction of nitrones 20 and 21 with lactones 10–
15 furnish, under thermal conditions, the corresponding mixtures
of exo and endo adducts. Moreover, the ratio of the resulting adducts
is difficult to predict, while at the same time the ratio plays a critical
role in controlling the configuration at C-4 of the azetidinone ring,
which cannot be epimerized at a later stage of the synthesis.
2.2. Catalytic 1,3-dipolar cycloaddition of nitrones to
unsaturated lactones
The insufficient exo/endo selectivity of the reactions investi-
gated, which limits their practical application in target-oriented
synthesis, prompted us to focus our attention on the catalytic var-
iant of the investigated reactions.
Beginning in the early 1980s, Lewis acid-catalyzed 1,3-dipolar
cycloadditions started to play an important role in this field of re-
search.17,19 The efficiency of the catalysts relies not only on their
capability to enhance the reaction rate and yield but also on their
ability to affect the stereochemical course of the process by influ-
encing the reaction regiochemistry, as well as its exo/endo-, diaste-
reo-, and enantioselectivity.
Compounds, such as MgBr2ꢀEt2O, ZnI2, and titanium-based Le-
wis acids such as TiCl4 and Ti(Oi-Pr)2Cl2 have been explored as po-
tential catalysts for 1,3-dipolar cycloadditions. In pioneering
works, Kanemasa et al. showed that certain Lewis acids such as
ZnCl2 and Ti(Oi-Pr)2Cl2 can catalyze 1,3-dipolar cycloadditions that
result in endo-derived isoxazolidines with respect to the substi-
tuted olefin, while metal catalysts such as MgBr2ꢀEt2O and ZnBr2,
promote the formation of exo-derived isoxazolidines.20 Tamura
et al. further extended this line of research by using MgBr2ꢀEt2O
as a Lewis acid catalyst in cycloaddition reactions with a chiral nit-
rone and allylic alcohols.21 A few other groups have also reported
that BF3ꢀEt2O can be used as an efficient promoter for Lewis acid-
assisted stereocontrolled cycloadditions with nitrones.22 In 1997,
Kobayashi et al.23 reported the Yb(OTf)3 catalyzed reactions of
diarylnitrones with electron-poor olefins. They reported that the
reaction yield strongly depended on the solvent; non-polar sol-
vents such as hexane, benzene, or toluene were the most appropri-
ate to provide the endo cycloadducts predominantly. The same
preference was also observed by Jørgensen et al.24 A year later,
Komatsu et al.25 demonstrated that for the same reaction the
change of solvent from toluene to MeCN allowed to control the
diasteroselectivity of the reaction to be controlled.
The catalytic effect of Sc(OTf)3 was also demonstrated for other
reactions (Table 1). Benzyl protected lactone 15 gave a mixture of
31 and 32; under thermal conditions, adducts were formed in 43%
yield in a ratio of 67:33, whereas in the presence of the catalyst, the
yield was 51% and the ratio was 96:4, respectively. The same re-
sults were obtained when nitrone 9, obtained from anisaldehyde,
was used. Under the thermal conditions, a mixture of 33 and 34
was obtained in a 41% yield and a ratio of approximately 63:37,
respectively, whereas in the presence of the catalyst a mixture of
the same adducts, in a ratio of 96:4, was obtained in 51% yield.
Under thermal conditions, unsubstituted lactone 14 yielded a
mixture of 35 and 36 in 56% yield and in a ratio of 73:27, whereas
in the presence of a catalyst on adducts, a mixture was formed in
60% yield and a ratio of 96:4, respectively. Heating the kinetic
product 35 showed the following: after 3 days 22% of 36, after
10 days 42% of 36, and after 38 days 62% of 36. Due to the instabil-
ity of nitrones, a further extension of the heating resulted in a de-
crease of the reaction yield.
Five-membered lactones 11 and 13 reacted under thermal con-
ditions with diphenyl nitrone 21 to give mixtures of exo and endo
adducts 37/38 and 39/40 with similar yields and ratios of the prod-
ucts. Under the thermal conditions compounds 37 and 38 were ob-
tained in 56% yield and in a ratio of approximately 6:4, whereas 39
and 40 were obtained in 60% yield and a ratio of 73:27, respec-
tively. In the presence of the acid catalyst, exo adducts 37 and 39
dominated in a ratio: 96:4 and 98:2, respectively, however, the
reaction yield was significantly lower (29–33%). Recently, we have
shown that the 5-substituted c-lactones underwent racemization
via a hydroxyl-furan tautomer.10b It could be postulated that the
hydroxyl-furan tautomer of 11 and 13 is also responsible for the
lower stability of the substrate in the presence of an acid catalyst.
Analogous reactions performed with lactones 13 and 15 using
N-benzyl-nitrone 20 resulted in the formation, in each case, of
mostly the kinetic exo products 41 and 43, respectively, under both
thermal and catalytic conditions, but in a much lower yield com-
pared to that recorded for diphenyl nitrone 21.
Based on these reports, we started to test the influence of Lewis
acid additives on the stereochemical outcome of the investigated
reactions. Initial screening of various Lewis acids, for instance

´
_
M. Sniezek et al. / Tetrahedron: Asymmetry 24 (2013) 89–103
93
Table 1
Thermal and Sc(OTf)3-catalyzed reaction of nitrones 9, 20, and 21 with sugar-derived lactones
Entry
Nitrone
Lactone
Products
Thermal conditionsa
Catalytic conditionsb
Yield (%)
dr
Yield (%)
dr
AcO
AcO
AcO
O
O
AcO
H
O
O
H
H
H
1
21
10
54
77:23
60
96:4
O
O
Ph
Ph
N
N
Ph
Ph
30
29
BnO
BnO
BnO
BnO
O
O
O
O
H
H
H
H
2
21
15
43
67:33
51
96:4
O
O
Ph
Ph
N
N
Ph
Ph
33
34
BnO
BnO
BnO
BnO
O
O
O
O
H
H
H
H
3
9
15
41
63:37
51
96:4
O
O
PMP
PMP
N
N
Ph
Ph
34
33
O
O
O
O
H
O
H
H
H
O
4
21
14
56
73:27
60
96:4
Ph
Ph
N
N
Ph
Ph
35
36
O
O
O
O
H
O
H
H
H
O
5
21
11
56
60:40
33
96:4
Ph
Ph
N
N
Ph
Ph
37
38
O
O
O
H
O
BnO
BnO
H
H
H
O
O
6
21
13
60
73:27
29
96:4
Ph
Ph
N
N
Ph
Ph
39
40
BnO
BnO
BnO
BnO
O
O
O
O
H
H
H
H
7
20
13
28
75:35
17
96:4
O
O
Ph
Ph
N
N
Bn
44
Bn
43
(continued on next page)

´
_
M. Sniezek et al. / Tetrahedron: Asymmetry 24 (2013) 89–103
94
Table 1 (continued)
Entry
Nitrone
Lactone
Products
Thermal conditionsa
Catalytic conditionsb
Yield (%)
dr
Yield (%)
dr
O
O
O
O
BnO
BnO
H
H
H
H
O
O
8
20
15
38
68:32
19
96:4
Ph
Ph
N
N
Bn
Bn
41
42
a
Reaction conditions: nitrone (1.5 mmol), lactone (1 mmol) in PhMe at 115 °C.
Reaction conditions: nitrone (1.5 mmol), lactone (1 mmol), Sc(OTf)3 (0.1 mmol), MS 4 Å (400 mg) in PhMe at 30 °C; PMP: p-methoxyphenyl.
b
respectively. The electronic structures of the stationary points
and bond orders (Wiberg indexes)35 were analyzed by the natural
bond orbital method (NBO).36 The intrinsic reaction coordinates
(IRC)37 were also calculated to analyze the mechanism in detail
for all of the transition structures obtained. The solvent effect
was treated by the single-point calculation for gas-phase station-
ary points using the self-consistent reaction field (SCRF)38 based
on the polarizable continuum model (PCM) reported by Tomasi
et al.39
The electronic chemical potential
values were approximated in terms of the one-electron energies of
l
40 and chemical hardness g41
the frontier molecular orbitals HOMO and LUMO (EHOMO, ELUMO
)
using Eqs. (1) and (2), respectively:
eHOMO
þ
eLUMO
l
g
¼
¼
ð1Þ
ð2Þ
2
Figure 1. Change of the 29/30 ratio during elongated heating of adduct 29 obtained
under kinetic control conditions (in the presence of Sc(OTf)3). Isomerization was
performed in boiling toluene.
eLUMO
l2
ꢁ
eHOMO
ꢀ
x
¼
ð3Þ
ð4Þ
2
g
1
S ¼
2.3. Theoretical studies on thermal and LA-catalyzed 1,3-dipolar
cycloadditions of diarylnitrones and unsaturated lactones
2g
at the ground state of molecules. The global electrophilicity power
x
was evaluated using Eq. (3) whereas global softness S is given
The enhancement of the reaction of nitrones 18–21 with sugar-
derived unsaturated lactones 11–16 encouraged us to further
study this process by the application of computational methods.
There are several examples of computational studies on 1,3-DCA
reactions involving nitrones26 including studies on the Lewis acid
effect.27
by Eq. (4).42
2.3.2. Study on the thermal 1,3-DC between diphenylnitrone 21
and unsaturated valerolactone 14
As a computational model, we investigated the theoretical out-
come of the reaction between C,N-diphenylnitrone 21 and six-
membered lactone 14 (Scheme 3). For the sake of clarity, nitrone
21 is assigned as N and lactone 14 as L. As shown in Table 1, the
reaction between these to reagents provides two bicyclic isoxazoli-
dines 35 and 36 in a ratio of 73:27, under thermal conditions, or in
a ratio of 96:4 in the presence of a scandium salt catalyst. For the
sake of clarity, these compounds are marked as P-1 and P-2,
respectively.
For the model reaction, the two distinct regioisomeric approach
modes of the oxygen atom of N relative to the b-conjugated posi-
tion of lactone L, named meta and ortho, are possible. These two ap-
proaches led to regioisomeric isoxazolidines P-1/P-2 and P-10/P-20
(Scheme 3).
The 1,3-DCA reaction investigated has been analyzed using glo-
bal reactivity indices defined in the context of conceptual DFT43
which is a useful and powerful tool to understand the behavior
of cycloadditions.41,44 The frontier molecular orbital energies and
the global properties are provided in Table 2.
The HOMO/LUMO energy gaps (LUMO2/HOMO1 4.118 eV and
LUMO1/HOMO2 5.543 eV) between reactants N and L indicate that
the LUMO2/HOMO1 interaction is predominant, which is typical for
normal electron-demand cycloaddition reactions (Table 2, Fig. 2).
Recently, we have also investigated 1,3-dipolar cycloadditions
of five-membered nitrone 17 with
a,b-unsaturated c- and d-lac-
tones 11 and 14 through molecular orbital calculations at the
B3LYP/6-31+G(d) level theory to find a good agreement with the
experimental data.11 These successful studies prompted us to use
similar calculations to characterize the 1,3-dipolar cycloadditions
between lactones 11 and 14 and diphenyl nitrone 21 and compare
them with experimental results in order to explain the stereo-
chemical pathway involving substituted congeners 13 and 15.
2.3.1. Computational methods
The initial geometry optimization and conformational search of
reactants and products were carried out using the HyperChem
v.7.51 suite of applications.28 For all molecular modeling calcula-
tions the MM+ force field29 was used. The final geometry optimiza-
tion of the stationary points was carried out using DFT methods at
the B3LYP30 and MP331 level theory with 6-31+G(d,p) basis set
implemented with GAUSSIAN 03 suite of software.32 The optimiza-
tions were carried out using a Berny analytical gradient method33
or QST3 method.34 The stationary points were characterized by the
frequency calculations in order to verify that the minima and tran-
sition structures (TSs) had zero and one imaginary frequency,

´
_
M. Sniezek et al. / Tetrahedron: Asymmetry 24 (2013) 89–103
95
O
O
O
O
H
H
H
H
H
H
meta
O
O
N
N
Ph
Ph
Ph
Ph
Ph
O
H
O
P-1 (35)
P-2 (36)
O
+
N
Ph
O
O
O
O
L
N
ortho
H
H
H
H
H
H
O
O
N
N
Ph
Ph
Ph
Ph
P-1'
P-2'
Scheme 3.
Table 2
DFT/6-31+G(d,p) calculated frontier orbital energies and static global reactivity indices
Molecule
EHOMO (a.u.)
ELUMO (a.u.)
l
(a.u.)
g
(a.u.)
x
(eV)
S (a.u.)
N
ꢁ0.21554
ꢁ0.27270
ꢁ0.27904
ꢁ0.28279
ꢁ0.07525
ꢁ0.12266
ꢁ0.06413
ꢁ0.12905
ꢁ0.14540
ꢁ0.19768
ꢁ0.17159
ꢁ0.20592
0.14029
0.15004
0.21491
0.15374
2.05
3.54
1.86
3.75
3.564046
3.332445
2.326555
3.252244
Sc–N complex
L
Sc–L complex
Cl3Sc
O
O
Ph
0.14
Ph
0.17
0.26
0.54
α
β
O
α
β
O
N
O
0.88
0.25
-
ω+
ω+k
fk
k
Figure 3. Nucleophilic Fukui function values (fkꢁ
electrophilicity values (
)
at nitrone N and the local
-
þk ) of free lactone L and its complex with ScCl3.
rone carbon atom (0.14 eV). As one should expect, the Cb position of
lactone L has a more electrophilic center of the molecule according
to the analysis of local electrophilicity indices. Consequently, the
preferred mode of nucleophilic attack of the nitrone N at the Cb
position of lactone L should favor the formation type P-1/P-2
regioisomers (meta channel); this was observed experimentally.
According to the above presented computational results and the
experimental evidence, the formation of isoxazolidines P-10 and
P-20 is omitted from further discussion and only the exo/endo selec-
tivity of the reaction of N and L through a meta reactivity channel is
considered.
Figure 2. Energy diagram of HOMO and LUMO orbitals of nitrone N, lactone L, and
their complexes with ScCl3.
The electronic chemical potential
l of nitrone N is higher than that
calculated for lactone L, which indicates that the net charge trans-
fer will take place from dipole N to dipolarophile L. This result is in
agreement with the FMO energy predictions as well as the charge
transfer analysis of TSs (vide infra). The electrophilicity powers of
nitrone N and lactone L are 2.05 and 1.86 eV, respectively, which
classify both of them as strong electrophiles. The low value of
As in our previous computational studies,11 the search of sta-
tionary points was preceded by conformation analysis. The confor-
mational search (in a range of 5 kcal/mol) using an MM+ force field
led to identification of two conformers for P-1 and two conformers
for structure P-2, respectively. The re-calculation of the molecular
geometries using DFT methods in the gas phase provided the opti-
mized minimized geometries which are given in Figure 4. The rel-
ative energies for the conformers are also provided in Figure 4. As
reported in Table 3, isoxazolidine P-2 is thermodynamically more
stable than adduct P-1 by 1.2 kcal/mol.
D
x for the reaction of N and L (0.19 eV) indicates that the cycload-
dition reaction will have a low polar character (vide infra).
þ
An investigation of the local electrophilicity indices
-
45 at the
k
46
electrophilic reagent and the nucleophilic Fukui functions fkꢁ at
nucleophilic one can be useful for the prediction of the regioselectiv-
ity of a given reaction. Both calculated parameters,
-
þ for lactone L
An investigation of the potential energy surface (PES) made it
possible to localize the stationary points for the endo and exo ap-
proach (Table 3, Fig. 5). Their analysis indicated a concerted me-
chanism for the cycloaddition in both cases.
k
and fkꢁ for nitrone N, respectively, are summarized in Figure 3.
The nitrone oxygen atom is a more reactive site for nucleophilic
attack due to the larger value of fkꢁ (0.25 eV) with respect to the nit-

´
_
M. Sniezek et al. / Tetrahedron: Asymmetry 24 (2013) 89–103
96
Figure 4. B3LYP/6-31+G(d,p) structures of conformational isomers of P-1 and P-2. The relative energies are given in relation to the lowest energy conformer of exo and endo-
adducts, respectively.
Table 3
Total/free (E and G in a.u.) and relative (
D
E,
D
G in kcal/mol) energies at 25 °C, for all stationary points of the reaction between nitrone N and lactone L in the gas phase and in
Reverse rxnb
toluene (DFT B3LYP/6-31+G(d,p))a
Geometry
Direct reaction in gas phase
Direct reaction in toluene
E
D
E
G
D
G
D
E
D
G
E
D
E
N
L
ꢁ631.7507702
ꢁ344.4969027
—
—
ꢁ631.790127
ꢁ344.526469
—
—
—
—
—
—
ꢁ631.7510941
ꢁ344.5026753
—
—
MC-1
TS-1b
P-1b
ꢁ976.2523342
ꢁ976.2173843
ꢁ976.2612332
ꢁ976.2545373
ꢁ976.2126910
ꢁ976.2631089
ꢁ2.9
19.0
–8.5
ꢁ976.308699
ꢁ976.264040
ꢁ976.307439
ꢁ976.307758
ꢁ976.260276
ꢁ976.310526
5.0
33.0
5.7
27.5
29.9
27.2
30.1
ꢁ976.2613536
ꢁ976.2251513
ꢁ976.2679945
ꢁ976.2615609
ꢁ976.2206596
ꢁ976.2695633
ꢁ4.8
18.0
ꢁ8.9
ꢁ4.9
20.8
ꢁ9.9
MC-2
TS-2b
P-2b
–4.3
22.0
–9.7
5.5
35.3
3.8
a
All energies are referred to the energy of N + L; energies include ZPE correction.
The lowest energy conformer.
b
tion, were found. MC-1 and MC-2 are located at 2.9 and 4.3 kcal/
mol, respectively, below the reagents N and L.
The activation energies associated with the exo and endo ap-
proach of the reactants in the 1,3-DC reaction are 21.9 (TS-1) and
26.3 kcal/mol (TS-2), respectively. The formation of the cycload-
ducts P-1 and P-2 is exothermic by ꢁ8.5 and ꢁ9.7 kcal/mol,
respectively.
The geometries, including conformers, of the TSs are given in
Figure 6. The lengths of the forming O–C and C–C bonds for TS-1
are 1.967 and 2.296 Å, respectively, and for TS-2 1.995 and
2.207 Å, respectively. These results confirm the concerted mecha-
nism of the cycloaddition. However, due to the electron-deficient
nature of the dipolarophile, the process is asynchronous in what
can be seen, that is, the Oꢀ ꢀ ꢀC distance is shorter than the Cꢀ ꢀ ꢀC
one. The same conclusion can be drawn when the bond order is ta-
ken into consideration. To follow the nature of the formation pro-
cess for the C–O and C–C bonds, the Wiberg bond indexes were
also computed using the NBO population analysis as implemented
in GAUSSIAN 03 and the results are shown in Table 4. In both cases,
the formation of the O–C bond is more advanced than the corre-
sponding C–C bond, which also confirms the asynchronicity of
the reaction. The lower energy exo transition state is slightly more
advanced and more asynchronous than endo one.
The charge transfer (qCT) values, taken from the natural popula-
tion analysis (NPA),34,36,47 are 0.02e for TS-1, and 0.01e for TS-2.
These low values indicate that the TSs have a low polar character,
which is in agreement with the low value of Dx computed for this
cycloaddition reaction. Moreover, the positive value of qCT indi-
cates the charge transfer from the nitrone to the lactone, which
is also in clear agreement with the lower electronic potential
l
of the lactone L compared to that of the nitrone N (see Table 1),
and with the highly electrophilic character of the lactone.
Table 3 contains data of the single-point calculation of the gas-
phase geometries using the PCM model. In toluene, all structures
are stabilized in the range of 3–6 kcal/mol. The inclusion of a sol-
vent decreased the energy difference between the activation bar-
Figure 5. Energy profiles, in gas-phase and in toluene (in parenthesis) in kcal/mol,
for the uncatalyzed 1,3-DC reaction between N and L.
For both reactive channels, two molecular complexes, MC-1 and
MC-2, respectively, associated with a very early step of the reac-

´
_
M. Sniezek et al. / Tetrahedron: Asymmetry 24 (2013) 89–103
97
Figure 6. Transition states for reaction of the nitrone N with the lactone L (for clarity some hydrogen atoms are omitted).
Table 4
Distances for the forming bonds, Wiberg bond orders, and charge transfer (in terms of residual charge of the nitrone fragment in the transition state) for transition structures
Structurea
Atoms’ distance (Å)
Bond order
NPA qCT (e)
O–C bond
C–C bond
O–C bond
C–C bond
TS-1
TS-2
1.967
1.995
2.296
2.207
0.42
0.41
0.33
0.37
0.02
0.01
a
The lowest energy conformer.
rier of the formation of P-1 and P-2 from 4.4 to 3.0 kcal/mol
(Fig. 5), but the relationships within the energy profile presented
in Figure 5 remained the same. This is due to the better solvation
of MC-1 compared to MC-2 [this is in agreement with larger dipole
moment of the former one (8.8 debye) than MC-2 2.6 debye].
The estimated high activation barrier of the exo and endo cyc-
loadditions remains in agreement with the experimental evidence.
As mentioned in a previous section, there was no formation of the
desired product(s) when the reaction was carried out in toluene at
room temperature (kinetic control conditions), thus, an increase of
the temperature was required to perform the reaction between N
and L. In this case the composition of the post-reaction mixture
is influenced by the thermodynamic stability of the products. The
comparison of the data from Table 3 indicates that under thermo-
dynamic control, the P-1/P-2 mixture in a ratio of ca. 7:1 should be
Finally, the outcome of the reaction of N with lactone L can also
be affected by the fact that nitrones have limited thermal stability
(for instance they can undergo a deoxygenation process leading to
the corresponding imines which are commonly observed in the
post-reaction mixture). Such decomposition seriously perturbs
the cycloaddition reaction and, as a consequence, together with
other factors, hinders the predictability of the composition of the
post-reaction mixture.
2.3.3. Study on the 1,3-DC between diphenylnitrone 21 and
unsaturated valerolactone 14 catalyzed by a scandium salt
As demonstrated earlier, the addition of a catalytic amount of
Sc(OTf)3 enhanced the cycloaddition between nitrones 9, 20, and
21 and the sugar-derived lactones to provide almost exclusively
the corresponding exo adducts. The most important fact is that
the presence of a scandium salt makes it possible to carry out
the investigated 1,3-DC reactions at room temperature.
expected (DE 1.2 kcal/mol) according to Boltzmann distribution
analysis. A more accurate ratio is obtained when a solvent effect
is included; in toluene, the estimated ratio is ca. 5:1 (
mol) which is close to the data presented in Table 1.
D
E 1.0 kcal/
These results encouraged us to broaden our analysis of the cat-
alytic variant of the cycloaddition through quantum mechanics
methods. To simplify the computational model, the reaction of nit-
rone N with lactone L in the presence of ScCl3 instead of Sc(OTf)3
was investigated.
The catalytic effect of the Lewis acid (LA) can be achieved by the
coordination of the scandium salt either by the nitrone or the lac-
tone. According to the visualization in Figure 1 and the numerical
data in Table 1, the coordination of the nitrone by the LA decreases
the energy of its HOMO orbital but, at the same time, increases the
HOMOnitrone/LUMOlactone gap (from 4.1 to 5.7 eV). On the other
hand, the lactone activation decreases its LUMO energy value
resulting in a smaller frontier orbital’s gap (from 4.1 to 2.4 eV)
and a predominance of such an interaction.
The differences between the calculated and experimental re-
sults may be caused by several factors. Although the elevated tem-
perature is used to accelerate the cycloaddition, it is difficult to
confirm that the reaction proceeds under real thermodynamic con-
trol conditions. As a result, the composition of the reaction mixture
cannot be estimated directly based on the relative stability of prod-
ucts. Of course, a solution could be to repeat the experiment in a
higher boiling solvent and compare the results. However, that is
not the case. The problem is the reversibility of the cycloaddition
reaction and the stability of the nitrone, which resulted in a dra-
matic decrease of the reaction yield.
The computation study for the model process indicates that the
activation barrier for retro-processes is only 1.3 to 1.4-fold higher
than those for the forward reactions. This means that when the
reaction of N with lactone L is conducted in refluxing toluene,
the retro-cycloaddition process cannot be neglected. This is even
more possible in a higher boiling solvent. It should be noted that
the decomposition of the P-1 product should be easier than that
of the endo-isomer P-2 due to its lower thermal stability and lower
activation barrier (compare retro-TS-1 and retro-TS-2). As demon-
strated earlier, the reversibility of the cycloaddition can be easily
demonstrated by extended heating of the exo product; after a per-
iod of time, the endo isomer along with starting lactone can be de-
tected in the crude reaction mixture.
The coordination of the LA to the lactone L changes its elec-
tronic chemical potential
l (Table 1), but it is still lower than the
value for the nitrone indicating that the direction of the net charge
transfer through the reaction remains the same. The activation of
the lactone by the LA increases the lactone electrophilicity from
1.86 to 3.75 eV for the corresponding complex. Moreover, the large
D
x value for nitrone N and lactone ScCl3–L complex (1.7 eV) indi-
cates the large polar character of the catalyzed 1,3-DC reaction,
which is in the agreement with further CT analysis (vide infra).
As presented in Figure 2, the coordination of ScCl3 to lactone L in-
creases the local electrophilicity at the b-carbon atom of the corre-
sponding complex to ca. 0.88 eV.

´
_
M. Sniezek et al. / Tetrahedron: Asymmetry 24 (2013) 89–103
98
The search for stationary points for the catalyzed reaction be-
addition has mostly a concerted character with only one transition
state.
tween nitrone N and lactone L was preceded by an investigation
of the structure of the lactone L/ScCl3 complex. The PES analysis
of the lactone ScCl3–L complex resulted in generation of the two
structures presented in Figure 7. The Sc-L-cf2 structure, with the
Lewis acid coordinated in an anti-relationship to the ring oxygen
atom, is the lowest energy conformer, although the energy differ-
ence is quite small. Additionally, further calculations also con-
firmed that the anti-location of the LA with respect to the ring
oxygen atom is also more preferred for other stationary points.
Consequently, the Sc-L-cf2 conformation of lactone L/ScCl3 com-
plex Sc–L was taken into consideration throughout further studies.
Similar to the uncatalyzed process described in Section 2.1, the
effect of the Lewis acid was studied only for one reactivity channel,
that is, the meta channel. As before, both the exo and endo ap-
proaches of the 1,3-dipole to the dipolarophile were analyzed.
The analysis of the potential energy surface revealed that the LA
has a different effect depending on the exo or endo approach.
Whereas the exo approach has a stepwise mechanism, with two
transition states and one intermediate, the alternative endo cyclo-
As for the non-catalyzed process, during the PES analysis for the
scandium-catalyzed cycloaddition, two distinct molecular com-
plexes MC-3 and MC-4, were found (Table 5). MC-3 and MC-4
are located at 6.1–8.5 kcal/mol, respectively, below the reagents
N and Sc–L. Along the exo-cycloaddition, the TS-3-I is located at
9.2 kcal/mol above MC-3. Highly confusing is the location of IN,
which was found at 2 kcal/mol above the corresponding transition
state TS-3-I. The second transition state TS-3-II, which corresponds
to the C–C bond formation, is located at 1.2 kcal/mol above the
intermediate. Along the endo approach, the TS-4 is located at
16.7 kcal/mol above MC-4. The formation of cycloadducts P-3 (ad-
duct P-1/ScCl3 complex) and P-4 (adduct P-2/ScCl3 complex) is
exothermic by ꢁ12.9 and ꢁ11.4 kcal/mol, respectively (Table 5).
Initially, it was suspected that the deviation of energy values for
polar species IN, as well as TS-3-II, resulted from the calculation
that did not consider the presence of the solvent, that is in the
gas phase. However, the single-point calculation involving the sol-
vent effect did not resolve the problem (Table 5). The energy gap
between TS-3-I and IN was smaller but the latter one (IN) was still
higher in energy.
As reported previously for studies on Diels–Alder reactions, the
HF calculations overestimate the activation barrier energy, whereas
the MP2 calculations underestimate that energy.48 Thus, during
studies on the AlCl3-catalyzed 1,3-DCA Domingo et al.27c,47,49
reported that MP3 calculations are a more suitable method for pro-
viding reasonable activation energies. Therefore, the single-point
calculations at MP3 level were carried out for all stationary points
optimized by the DFT method. The comparison of the relative ener-
gies calculated at both levels can be found in Table 6.
ScCl3
O
O
O
O
ScCl3
Sc-L-cf1
Sc-L-cf2
ΔE 0.5 kcal/mol
ΔE 0.0 kcal/mol
Figure 7. Two ScCl3/lactone L complexes.
Table 5
B3LYP/6-31+G(d,p) total (E, in a.u.) and relativea
approaches of the 1,3-DCA of nitrone N and lactone L in the presence of ScCl3
(DE, kcal/mol) energies, in gas phase, dichloromethane and toluene, of the stationary points involved in the exo and endo
Geometry
In gas phase
In dichloromethane
In toluene
E
D
E
E
D
E
E
D
E
Sc–L
N
ꢁ2486.181265
ꢁ631.9588851
—
—
ꢁ2486.211260
ꢁ631.9677013
—
—
ꢁ2486.197459
ꢁ631.9634539
—
—
MC-3
TS-3-I
IN
TS-3-II
P-3
ꢁ3118.149802
ꢁ3118.135294
ꢁ3118.132008
ꢁ3118.130099
ꢁ3118.160658
ꢁ6.1
3.1
5.1
6.3
ꢁ12.9
ꢁ3118.180386
ꢁ3118.164657
ꢁ3118.163671
ꢁ3118.159213
ꢁ3118.187831
ꢁ0.9
9.0
9.6
12.3
ꢁ5.6
ꢁ3118.167216
ꢁ3118.150916
ꢁ3118.148886
ꢁ3118.145616
ꢁ3118.174727
ꢁ3.7
6.3
7.6
9.6
ꢁ18.3
MC-4
TS-4
p-4
ꢁ3118.153635
ꢁ3118.126987
ꢁ3118.158305
ꢁ8.5
ꢁ3118.181538
ꢁ3118.153925
ꢁ3118.186170
ꢁ1.6
15.7
ꢁ4.5
ꢁ3118.168235
ꢁ3118.141197
ꢁ3118.172547
ꢁ4.6
12.4
ꢁ7.3
8.3
ꢁ11.4
a
Relative to reactants, ZPE correction was not included.
Table 6
MP3/6-31+G(d,p) total (E, a.u.) and relative energies (D
E, kcal/mol),a in gas phase and toluene and dichloromethane, of the stationary points involved in the exo approach of the
1,3-DCA of nitrone N and lactone Sc–L complex in the presence of ScCl3
Geometry
Gas phase
MP3/6-31+G(d,p)
Toluene
Dichloromethane
N
Sc–L
ꢁ630.0804285
ꢁ2482.614343
—
—
ꢁ630.0853176
ꢁ2482.622384
—
—
ꢁ630.0898512
ꢁ2482.638102
—
—
MC-3
TS-3-I
IN
TS-3-II
P-3
ꢁ3112.716699
ꢁ3112.700048
ꢁ3112.707531
ꢁ3112.698003
ꢁ3112.750014
ꢁ13.8
ꢁ3.3
ꢁ3112.732754
ꢁ3112.717370
ꢁ3112.726368
ꢁ3112.715418
ꢁ3112.765908
ꢁ15.7
ꢁ6.1
ꢁ3112.747861
ꢁ3112.732855
ꢁ3112.743026
ꢁ3112.730834
ꢁ3112.780983
ꢁ12.5
ꢁ3.1
ꢁ8.0
ꢁ11.7
ꢁ4.8
ꢁ9.5
ꢁ2.0
ꢁ1.8
ꢁ34.7
ꢁ36.5
ꢁ33.3
MC-4
TS-4
P-4
ꢁ3112.715851
ꢁ3112.694891
ꢁ3112.747251
ꢁ13.2
ꢁ0.1
ꢁ3112.732105
ꢁ3112.712741
ꢁ3112.763409
ꢁ15.3
ꢁ3.2
ꢁ3112.747246
ꢁ3112.727152
ꢁ3112.779104
ꢁ12.1
0.5
ꢁ32.9
ꢁ35.0
ꢁ32.1
a
Relative to reactants, ZPE correction was not included.

´
_
M. Sniezek et al. / Tetrahedron: Asymmetry 24 (2013) 89–103
99
The MP3 calculations predict the higher stabilization of MC-3
and MC-4 with respect to B3LYP ones. The same trend is observed
for the energies of products coordinated to ScCl3 (P-3 and P-4)
(Table 6, Fig. 8). Although the MP3 calculations give higher stabil-
ization of MC-3, the first activation barrier of the stepwise exo cyc-
loadditions calculated at both theory levels is similar and equals
9.2 kcal/mol (B3LYP) and 10.5 kcal/mol, respectively. A large diver-
gence was found for the relative energies of IN and TS-3-II, which
may result from the overestimation of the energy of the highly po-
lar IN species by B3LYP calculations. Now, the intermediate IN is
located at 4.7 kcal/mol below the transition state TS-3-I, as one
should expect. As a result, the activation energy of the second step,
that is, C–C bond formation, increases from 1.2 (B3LYP) to 6.0 kcal/
mol.
Analogous to the concerted process leading to the endo adduct
P-4, the MP3 calculated activation barrier is lower by 3.5 kcal/
mol than the value obtained with B3LYP. However, the MP3 meth-
od still gives the correct exo/endo selectivity with the exo approach
being the preferred process over the endo one. The activation en-
ergy difference is 2.8 kcal/mol.
The geometries of the transition states and the intermediate in-
volved in the two aforementioned stereochemical approaches are
shown in Figure 9 and the numerical data associated with bond
lengths and orders are given in Table 7. In the case of the exo ap-
proach, the first step is the nucleophilic attack of the oxygen atom
of N at the b-position of the Sc–L complex, which proceeds through
the TS-3-I transition state. The length of the forming Oꢀ ꢀ ꢀC bond is
1.860 Å, while the distance between the corresponding carbon
Table 7
Distances for the forming bonds, Wiberg bond orders, and charge transfer (in terms of
residual charge of the nitrone fragment in the stationary points) for the transition
structures and the intermediate in Lewis acid catalyzed cycloaddition of nitrone N to
the Sc–L complex
Structure
Atoms’ distance (Å)
Bond order
O–C bond C–C bond
NPA qCT (e)
O–C bond
C–C bond
TS-3-I
IN
TS-3-II
1.860
1.581
1.564
3.387
3.142
2.535
0.40
0.67
0.64
0.03
0.03
0.20
0.28
0.49
0.26
Figure 8. Energy profile [MP3/6-31+(d,p)], in gas-phase, for the ScCl3-catalyzed 1,3-
DC reactions between nitrone N and lactone L.
TS-4
1.909
2.338
0.51
0.29
0.21
Figure 9. Structures of the TSs and the intermediate involved in the ScCl3-catalyzed 1,3-DC reactions between nitrone N and lactone L.

´
_
M. Sniezek et al. / Tetrahedron: Asymmetry 24 (2013) 89–103
100
atoms at nitrone and lactone becomes 3.387 Å. The Oꢀ ꢀ ꢀC bond or-
der for TS-3-I is 0.40, whereas for Cꢀ ꢀ ꢀC it is only 0.03. The O–C
bond length of the corresponding intermediate IN is 1.581 Å while
the C/C distance remains 3.142 Å. The O–C bond order for IN is
0.67. In the transition state associated with C–C bond formation
TS-3-II, the distance of both carbon atoms comes to 2.535 Å and
the bond order is 0.2. The Oꢀ ꢀ ꢀC and Cꢀ ꢀ ꢀC distances at TS-4, leading
to the endo adduct P-4, are 1.909 and 2.338 Å, respectively. The
bond orders are 0.51 and 0.29. Such a large difference between
the length and order of both forming bonds indicates the asynchro-
nicity of the cycloaddition.
derived lactones. Under the catalytic variant, the cycloadditions
proceed under mild conditions at room temperature to provide al-
most exclusively exo adducts with high stereoselectivity.
The mechanism of the 1,3-dipolar cycloaddition of C,N-diphe-
nylnitrone with unsaturated valerolactone under thermal and Le-
wis acid-mediated conditions has been studied using DFT and
MP3 methods. Computational results indicated that in the absence
of a Lewis acid, the reaction takes place through an asynchronous
concerted mechanism with a low polar character and provides the
exo cycloadduct as a major product in full agreement with the
experimentally observed trends.
The values of the charge transfer (CT) along with exo and endo
cycloaddition are reported in Table 7. In the LA-catalyzed reaction
of nitrone N to the Sc–L complex, the charge flows from the 1,3-di-
pole to the dipolarophilic species for both stereochemical ap-
proaches. The CT of the nucleophilic attack of N to the Sc–L
complex along the stepwise process is: 0.13e at MC-3 and 0.28e
at TS-3-I. In the endo process, CT values are 0.12e at MC-4 and
0.21e for TS-4. The large CT values obtained for MC-3 and MC-4
indicate the large electronic interaction between both reactants
and justify the large stabilization energy during the formation of
these molecular complexes. At the stepwise process going from
TS-3-I to IN, the CT values increase from 0.28e to 0.49e, which indi-
cates the highly Zwitterionic character of these species. The large
polar character of the investigated cycloaddition with respect to
the non-catalyzed process is in full agreement with the large in-
crease of the electrophilicity of lactone L as a result of coordination
with the LA. Consequently, such coordination leads to an increase
The coordination of a scandium salt to the lactonic dipolaro-
phile results in significant changes of the cycloaddition reaction
investigated, resulting in a large enhancement of the electrophilic-
ity of the ScCl3/lactone complex. However, the addition of a Lewis
acid has a different effect on the reaction mechanism depending on
the trajectory of the approach of the reactant. As demonstrated, in
the formation of the exo product, the reaction mechanism is chan-
ged from concerted into stepwise proceeding through an Zwitter-
ionic intermediate. The intermediate is formed by nucleophilic
attack of the nitrone oxygen atom at the highly electrophilic b-con-
jugated position of the Sc/lactone complex. This Michael-type
addition is the rate-determining step. The product is formed
through subsequent intramolecular ring closure. In the endo ap-
proach, the reaction mechanism is mostly concerted, although it
appears to be highly asynchronous. The computed activation en-
ergy barriers confirm the high diastereoselectivity observed
experimentally.
of
Dx for the catalyzed cycloaddition after which it becomes a
As demonstrated, the influence of Lewis acid on the outcome of
the cycloaddition reaction investigated, particularly its regioselec-
tivity, can also be correctly explained by analysis of the global and
local reactivity indices.
more polar process.
Bearing in mind the large polar character of the transition states
and the intermediate involved in the Lewis acid catalyzed 1,3-DCA
reaction, it should be expected that the solvent effect has a large
influence on the energies. The results of the single-point calcula-
tions of the gas-phase geometries (MP3 method) using PCM model
are presented in Table 6. In toluene as well as in dichloromethane,
the solvent effects stabilize all the species in the range of 5–
22 kcal/mol. With the inclusion of the solvent effect, the TS-3-I
activation barrier is equal to 9.7 (toluene) and 9.4 kcal/mol (dichlo-
romethane). Due to the Zwitterionic character of IN, it can be sta-
bilized by a solvent, which results in an increase of the activation
energy barrier for TS-3-II (from 6.0 to 6.9 kcal/mol, in toluene,
and to 7.7 kcal/mol in more polar dichloromethane). Nevertheless,
the first step is still the rate-determining step. The MP3/PCM calcu-
lations provide somewhat confusing data for the activation energy
4. Experimental
4.1. General
1H and 13C NMR spectra were recorded on a Varian VN MRS
Spectrometer at 600 and 150 MHz, respectively, in CDCl3 or C7D8.
TMS was used as the internal standard. Chemical shifts are re-
ported as d values in ppm, and coupling constants are in Hertz.
The proton assignment was carried out based on COSY experi-
ments. Infrared spectra were recorded on a FT-IR-1600 Perkin–El-
mer spectrophotometer. CD spectra were recorded on a Jasco J-815
spectropolarimeter. Optical rotations were recorded on a Jasco P-
2000 polarimeter. High-resolution mass spectra were recorded
on an ESI-TOF Mariner Spectrometer (Perspective Biosystem) or a
Synapt G2-S Waters Spectrometer for electrospray ionization. Thin
layer chromatography was performed on Merck aluminum sheet
Silica Gel 60 F254. Column chromatography was carried out using
Merck silica gel (230–400 mesh). Diastereoisomers’ ratios of the
reactions investigated were assigned by 1H NMR or/and HPLC
analysis.
barrier for the formation of endo adduct P-4 (TS-4
D
Eà 13.2 kcal/
mol in gas-phase vs 12.2 and 12.6 kcal/mol for toluene and dichlo-
romethane, respectively). An expected trend can be found for the
data obtained by B3LYP/PCM calculations; now, after inclusion of
the solvent, the activation energy changes from 16.7 up to
17.3 kcal/mol due to the slightly larger solvent stabilization of
the molecular complex than the transition state.
Solvent effect calculations confirm that the coordination of Le-
wis acid to the dipolarophile significantly accelerates the cycload-
dition reaction by a strong reduction of the activation energies.
These calculations also confirm that the higher acceleration of
the formation of the exo adduct compared to the endo adduct is
what makes the scandium salt catalyzed 1,3-dipolar cycloaddition
highly diastereoselective.
Nitrones 9 and 20–2150 and unsaturated lactones 10, 13, 15, and
1616 were obtained following the literature procedures. Lactones
12 and 14 were purchased from Aldrich. Lactone 11 was obtained
from furfural according to the literature procedure.51
4.2. Thermal 1,3-dipolar cycloaddition—general procedure
3. Conclusions
Lactone (1 mmol) and nitrone (1.5 mmol) were dissolved in tol-
uene (10 ml) and refluxed for 24 h, after which the solvent was re-
moved under reduced pressure and the residue was
chromatographed on silica gel.
We have reported the Sc(OTf)3-catalyzed 1,3-dipolar cycloaddi-
tion reactions between acyclic nitrones and six-membered sugar-

´
_
M. Sniezek et al. / Tetrahedron: Asymmetry 24 (2013) 89–103
101
4.3. Catalytic 1,3-dipolar cycloaddition—general procedure
(1H, dd, J 9.4, 4.4 Hz), 4.46 (1H, d, J 12.0 Hz), 4.34 (1H, d, J
12.0 Hz), 4.24–4.18 (1H, m), 4.05 (1H, d, J 11.8 Hz), 3.96 (1H, d, J
11.8 Hz), 3.87 (1H, dd, J 4.1, 3.1 Hz), 3.66 (1H, t, J 9.0 Hz), 3.40
(1H, dd, J 9.6, 3.7 Hz), 3.35 (1H, dd, J 9.8, 6.2 Hz); 13C NMR
(150 MHz, C7D8, signals for Ph carbon atoms are omitted) d:
165.8, 76.5, 75.7, 72.4, 72.1, 71.6, 70.7, 66.9, 54.2, 52.6; IR (film)
The mixture of Sc(OTf)3 (0.1 mmol) and MS 4 Å (400 mg) in dry
PhMe (10 ml) was stirred for 30 min at room temperature. Next, the
lactone (1 mmol) and nitrone (1.5 mmol) were added and reaction
mixture was kept at 30 °C for 72 h, after which the molecular sieves
were filtered off and residue was chromatographed on silica gel.
m
: 1747 cmꢁ1; HRMS (ESI) m/z calcd for C34H33NO6Na [M+Na]+
574.2206; found 574.2202.
4.4. (3R,3aR,6R,7S,7aS)-7-(Acetoxy)-6-(acetoxymethyl)-2,3-diph-
enyltetrahydro-2H-pyrano[3,4-d]isoxazol-4(6H)-one 29
4.9. (3S,3aR,6R,7S,7aS)-7-(Benzyloxy)-6-(benzyloxymethyl)-3-
(4-methoxyphenyl)-2-phenyltetrahydro-2H-pyrano[3,4-d]
isoxazol-4(6H)-one 34
Oil; ½a 2D0
ꢂ
¼ ꢁ57 (c 1.2, CHCl3); 1H NMR (600 MHz, CDCl3, signals
for Ph hydrogen atoms are omitted) d: 5.45 (1H, d, J 9.0 Hz), 5.27
(1H, dd, J 1.9, 1.4 Hz), 4.59 (1H, dd, J 4.8, 2.1 Hz), 4.40–4.38 (1H,
m), 4.11 (1H, dd, J 11.6, 5.4 Hz), 3.96 (1H, t, J 9.1 Hz), 3.90 (1H,
dd, J 11.7, 10.4 Hz), 2.07 (3H, s), 1.98 (3H, s); 13C NMR (150 MHz,
CDCl3, signal of Ph carbon atoms are omitted) d: 170.1, 169.4,
166.2, 75.8, 73.8, 73.6, 71.4, 65.4, 61.5, 52,2, 20.6; HRMS (ESI) m/
z calcd for [M+Na]+ C23H23NO7Na 448.1366; found 448.1388; IR
½
a 2D0
ꢂ
¼ þ27 (c 1, CHCl3); 1H NMR (600 MHz, C7D8, signals for
Ph hydrogen atoms are omitted) d: 4.79 (1H, dd, J 8.2, 4.6 Hz),
4.63 (1H, d,
11.9 Hz) 4.28 (1H, d, J 11.9 Hz), 4.10 (1H, d, J 11.8 Hz), 4.09
(1H, d, 11.8 Hz), 3.88–3.85 (1H, m), 3.74 (1H, dd, 8.2,
J 6.0 Hz), 4.56–4.52 (1H, m), 4.47 (1H, d, J
J
J
6.1 Hz), 3.57 (1H, dd, J 9.8, 4.2 Hz), 3.47 (1H, dd, J 9.7, 5.6 Hz),
(film) m .
: 1747 cmꢁ1
3.26 (3H, s); 13C NMR (150 MHz, C7D8) d: 168.0, 75.7, 75.4,
73.1, 72.2, 72.4, 71.6, 67.6, 56.2, 54.2; IR (film)
HRMS (ESI) m/z calcd for
found 574.2204.
m ;
: 1747 cmꢁ1
C
34H33NO6Na [M+Na]+ 574.2206;
4.5. (3S,3aR,6R,7S,7aS)-7-(Acetoxy)-6-(acetoxymethyl)-2,3-diph-
enyltetrahydro-2H-pyrano[3,4-d]isoxazol-4(6H)-one 30
Oil; ½a 2D0
ꢂ
¼ þ76 (c 1.3, CHCl3); 1H NMR (600 MHz, CDCl3, signals
4.10. (3R⁄,3aR⁄,7aR⁄)-2,3-Diphenyltetrahydro-2H-pyrano[3,4-
d]isoxazol-4(6H)-one 35
for Ph hydrogen atoms are omitted) d: 5.40 (1H, dd, J 3.1, 1.5 Hz),
5.10–5.08 (1H, m), 4.71 (1H, dd, J 7.5, 3.1 Hz), 4.59 (1H, d, J
2.1 Hz), 4.29 (1H, dd, J 11.8, 5.6 Hz), 4.24 (1H, dd, J 11.8, 7.0 Hz),
3.65 (1H, dd, J 7.4, 6,1 Hz), 2.11 (3H, s), 2.09 (3H, s); 13C NMR
(150 MHz, CDCl3) d: 170.3, 169.3, 167.8, 73.8, 73.2, 73.1, 71.4,
64.2, 61.9, 54.9, 20,7; HRMS (ESI) m/z calcd for [M+Na]+ C23H23NO7-
Oil; 1H NMR (600 MHz, CDCl3, signals for Ph hydrogen atoms
are omitted) d: 5.49 (1H, d, J 9.3 Hz), 4.76 (1H, dt, J 9.2, 3.1 Hz),
3.97 (2H, dd, J 7.2, 3.8 Hz), 3.90 (1H, t, J 9.0 Hz), 2.08–2.04 (2H,
m); 13C NMR (150 MHz, CDCl3) d: 167.9, 149.2, 137.0, 129.3,
128.5, 128.1, 127.5, 122.8, 114.4, 73.5, 71.2, 64.3, 53.4; 26.3; IR
Na 448.1366; found 448.1388; found; IR (film) m .
: 1747 cmꢁ1
(film)
m
: 1743 cmꢁ1; HRMS (EI) m/z calcd for C18H17NO3 [M]
4.6. (3R,3aR,6R,7S,7aS)-7-(Benzyloxy)-6-(benzyloxymethyl)-2,3-
diphenyltetrahydro-2H-pyrano[3,4-d]isoxazol-4(6H)-one 31
295.1208; found 295.1205.
4.11. (3S⁄,3aR⁄,7aR⁄)-2,3-Diphenyltetrahydro-2H-pyrano[3,4-
d]isoxazol-4(6H)-one 36
Oil; ½a 2D0
ꢂ
¼ ꢁ62:4 (c 1.12, CHCl3); 1H NMR (600 MHz, C7D8, sig-
nals for Ph hydrogen atoms are omitted) d: 5.15 (1H, d, J 8.7 Hz),
4.66 (1H, dd, J 9.4, 4.4 Hz), 4.43 (1H, d, J 12.0 Hz), 4.32 (1H, d, J
12.0 Hz), 4.16–4.13 (1H, m), 4.02 (1H, d, J 11.4 Hz), 3.95 (1H, d, J
11.4 Hz), 3.86 (1H, dd, J 4.3, 3.2 Hz), 3.67 (1H, t, J 9.1 Hz), 3.37 (1H,
dd, J 9.6, 3.6 Hz), 3.33 (1H, dd, J 10.2, 6.6 Hz); 13C NMR (150 MHz,
C7D8, signals for Ph carbon atoms are omitted) d: 165.9, 76.4, 75.3,
72.8, 72.3, 71.7, 70.6, 66.9, 52.6; HRMS (ESI) m/z calcd for [M+Na]+
Oil; 1H NMR (600 MHz, C7H8, signals for Ph hydrogen atoms are
omitted) d: 4.75 (d, J 3.0 Hz, 1H), 4.14 (dd, J 6.2, 4.7 Hz, 1H), 3.94 (d,
J 10.9 Hz, 1H), 3.46 (dd, J 10.9, 4.6 Hz, 1H), 2.54 (dd, J 6.4, 3.1 Hz,
1H); IR (film) m
: 1743 cmꢁ1; HRMS (EI) m/z calcd for C18H17NO3
[M] 295.1208; found 295.1205.
544.2099; found 544.2105; IR (film) m .
: 1741 cmꢁ1
4.12. (3R⁄,3aR⁄,6aS⁄)-2,3-Diphenyltetrahydrofuro[3,4-d]isox-
azol-4(2H)-one 37
4.7. (3S,3aR,6R,7S,7aS)-7-(Benzyloxy)-6-(benzyloxymethyl)-2,3-
diphenyltetrahydro-2H-pyrano[3,4-d]isoxazol-4(6H)-one 32
Oil; 1H NMR (600 MHz, C7D8, signals for Ph hydrogen atoms are
omitted) d: 4.43 (1H, d, J 9.0 Hz), 4.25–4.23 (1H, ddd, J 8.1, 6.5,
2.9 Hz), 4.00 (1H, dd, J 10.3, 2.9 Hz), 3.62 (1H, dd, J 10.2, 6.5 Hz),
2.88 (1H, dd, J 9.0, 8.1 Hz); 13C NMR (150 MHz, C7D8, signals for
Ph carbon atoms are omitted) d:171.4, 77.3, 72.1, 70.3, 53.8; IR
Oil; ½a 2D0
ꢂ
¼ þ46:1 (c 1.1, CHCl3); 1H NMR (600 MHz, C7D8, signals
for Ph carbon atoms are omitted) d: 4.77 (1H, dd, J 8.3, 4.7 Hz), 4.64
(1H, d, J 6.2, Hz), 4.56–4.53 (1H, m), 4.47 (1H, d, J 11.9 Hz) 4.28 (1H,
d, J 11.9 Hz), 4.10 (1H, d, J 11.8 Hz), 4.09 (1H, d, J 11.8 Hz), 3.88–3.86
(1H, m), 3.73 (1H, dd, J 8.3, 6.2 Hz), 3.58 (1H, dd, J 9.9, 4.2 Hz), 3.49
(1H, dd, J 9.9, 5.7 Hz); 13C NMR (150 MHz, C7D8, signals for Ph car-
bon atoms are omitted) d: 168.0, 75.7, 75.5, 73.2, 72.3, 72.2, 71.7,
67.5, 54.1; HRMS (ESI) m/z calcd for [M+Na]+ 544.2099; found
(film)
m
: 1741 cmꢁ1; HRMS (EI) m/z calcd for C17H15NO3 [M]
281.1052; found 281.1050.
4.13. (3S⁄,3aR⁄,6aS⁄)-2,3-Diphenyltetrahydrofuro[3,4-d]isox-
azol-4(2H)-one 38
544.2102; IR (film) m .
: 1742 cmꢁ1
Oil; 1H NMR (600 MHz, C7D8) d: 4.76 (1H, d, J 3.0 Hz), 4.15 (1H,
dd, J 6.4, 4.5 Hz), 3.94 (1H, d, J 10.9 Hz), 3.46 (1H, dd, J 10.9, 4.5 Hz),
2.54 (1H, dd, J 6.4, 3.0 Hz); 13C NMR (150 MHz, C7D8, signals for Ph
carbon atoms are omitted) d: 174.7, 77.7, 71.6, 69.8, 56.9; IR (film)
4.8. (3R,3aR,6R,7S,7aS)-7-(Benzyloxy)-6-(benzyloxymethyl)-3-
(4-methoxyphenyl)-2-phenyltetrahydro-2H-pyrano[3,4-d]
isoxazol-4(6H)-one 33
m
: 1742 cmꢁ1; HRMS (EI) m/z calcd for C17H15NO3 [M] 281.1052;
Oil; ½a 2D0
ꢂ
¼ ꢁ69 (c 1.1, CHCl3); 1H NMR (600 MHz, C7D8, signals
found 281.1049.
for Ph hydrogen atoms are omitted) d: 5.12 (1H, d, J 8.6 Hz), 4.66

´
_
M. Sniezek et al. / Tetrahedron: Asymmetry 24 (2013) 89–103
102
4.14. (3R,3aR,6R,6aS)-6-(Benzyloxymethyl)-2,3-diphenyl-
tetrahydrofuro[3,4-d]isoxazol-4(2H)-one 39
4.19. (3S,3aR,6R,7S,7aS)-2-Benzyl-7-(benzyloxy)-6-(benzyloxy-
methyl)-3-phenyltetrahydro-2H-pyrano[3,4-d]isoxazol-4(6H)-
one 44
Oil; ½a 2D0
ꢂ
¼ ꢁ61 (c 1.1, CHCl3); 1H NMR (600 MHz, C7D8, sig-
nals for Ph hydrogen atoms are omitted) d: 4.76 (1H, dd, J 7.5,
2.1 Hz), 4.47 (1H, d, J 9.0 Hz), 4.41 (1H, dd, J 4.9, 2.5 Hz), 4.15
(1H, d, J, 12.0 Hz), 4.08 (1H, d, J, 12.0 Hz), 3.30 (1H, dd, J 9.0,
7.5 Hz), 3.19 (1H, dd, J 10.7, 3.0 Hz), 3.10 (dd, J 10.7, 2.6 Hz);
13C NMR (150 MHz, C7D8, signals for Ph carbon atoms are omit-
ted) d: 171.2, 81.1, 79.9, 73.3, 72.2, 69.5, 55.4 HRMS (EI) m/z
Oil; ½a 2D0
ꢂ
¼ þ117:5 (c 1.3, CHCl3); 1H NMR (600 MHz, C7D8, sig-
nals for Ph hydrogen atoms are omitted) d: 4.35 (1H, br s), 4.16 (1H,
br s), 3.98 (1H, d, J 11.9 Hz), 3.93 (1H, d, J 12.3 Hz), 3.81 (1H, d, J
12.3 Hz), 3.79 (1H, d, J 12.5 Hz), 3.49 (1H, br s), 3.40 (1H, br s),
3.21 (2H, m), 3.25 (1H, br s), 3.21–3.17 (1H, m), 3.12 (1H, d, J
14.5 Hz); 13C NMR (150 MHz, C7D8, signals for Ph carbon atoms
are omitted) d: 167.3, 75.6, 74.8, 74.3, 73.2, 71.8, 71.4, 67.9, 55.2;
calcd for C25H24NO4 [M] 402.1705; found 402.1701; IR (film)
m:
1781 cmꢁ1
.
HRMS (EI) m/z calcd for
C
34H33NO5 [M] 536.2437; found
.
536.2441; IR (film)
m
: 1741, cmꢁ1
4.15. (3S,3aR,6R,6aS)-6-(Benzyloxymethyl)-2,3-diphenyl-
tetrahydrofuro[3,4-d]isoxazol-4(2H)-one 40
Acknowledgment
Oil; ½a 2D0
ꢂ
¼ þ94 (c 1.1, CHCl3); 1H NMR (600 MHz, C7D8, signals
Authors are grateful to the European Union within European
Regional Development Fund (Project POIG.01.01.02.-14-102/09)
for financial support of research.
for Ph hydrogen atoms are omitted) d: 4.90 (1H, d, J 3.1 Hz), 4.68
(1H, d, J 6.4 Hz), 4.30 (1H, t, J 2.5 Hz), 4.02 (1H, d, J 12.2 Hz), 3.97
(1H, d, J 12.2 Hz), 3.48 (1H, dd, J 6.4, 3.2 Hz), 3.11 (1H, dd, J 10.6,
3.0 Hz), 3.10 (dd, J 10.6, 2.3 Hz); 13C NMR (150 MHz, C7D8, signals
for Ph carbon atoms are omitted) d: 174.9, 80.9, 79.5, 73.1, 71.7,
69.0, 58.6 HRMS (EI) m/z calcd for C25H24NO4 [M] 402.1705; found
References
1. Veinberg, G.; Vorona, M.; Shestakova, I.; Kanepe, I.; Lukevics, E. Curr. Med.
Chem. 2003, 10, 1744–1758.
2. (a) Tufariello, J. J. Acc. Chem. Res. 1979, 12, 396–403; (b) Tufariello, J. J.; Tette, J.
P. J. Org. Chem. 1975, 40, 3866–3869.
402.1700; IR (film) m .
: 1777 cmꢁ1
4.16. (3R,3aR,6R,6aS)-N-Benzyl-6-(benzyloxymethyl)-3-phenyl-
tetrahydrofuro[3,4-d]isoxazol-4(2H)-one 41
3. (a) Denmark, S. E.; Cottell, J. J. J. Org. Chem. 2001, 66, 4276–4284; (b) Denmark,
S. E.; Hurd, A. R. J. Org. Chem. 2000, 65, 2875–2886; (c) Denmark, S. E.;
Thorarensen, A. J. Am. Chem. Soc. 1997, 119, 125–137; (d) DeShong, P.; Dicken,
C. M.; Leginus, J. M.; Whittle, R. R. J. Am. Chem. Soc. 1984, 106, 5598–5602; (e)
DeShong, P.; Leginus, J. M. J. Am. Chem. Soc. 1983, 105, 1686–1688; (f) Funk, R.
L.; Bolton, G. L.; Daggett, J. U.; Hansen, M. M.; Horcher, L. H. M. Tetrahedron
1985, 41, 3479–3495; (g) Goti, A.; Cardona, F.; Brandi, A. Synlett 1996, 761–763;
(h) Goti, A.; Cicchi, S.; Cacciarini, M.; Cardona, F.; Fedi, V.; Brandi, A. Eur. J. Org.
Chem. 2000, 3633–3645; (i) Goti, A.; Cicchi, S.; Fedi, V.; Nannelli, L.; Brandi, A. J.
Org. Chem. 1997, 62, 3119–3125; (j) Goti, A.; Fedi, V.; Nannelli, L.; De Sarlo, F.;
Brandi, A. Synlett 1997, 577–579; (k) Holmes, A. B.; Bourdin, B.; Collins, I.;
Davison, E. C.; Rudge, A. J.; Stork, T. C.; Warner, J. Pure Appl. Chem. 1997, 69,
531–536; (l) Kliegel, W. Pharmazie 1977, 32, 411–416; (m) McCaig, A. E.;
Meldrum, K. P.; Wightman, R. H. Tetrahedron 1998, 54, 9429–9446; (n)
Schwartz, M. A.; Swanson, G. C. J. Org. Chem. 1979, 44, 953–958; (o)
Tufariello, J. J.; Meckler, H.; Senaratne, K. P. A. Tetrahedron 1985, 41, 3447–3453.
4. (a) Bays, H. E.; Moore, P. B.; Drehobl, M. A.; Rosenblatt, S.; Toth, P. D.; Dujovne,
C. A.; Knopp, R. H.; Lipka, L. J.; LeBeaut, A. P.; Yang, B.; Mellars, L. E.; Cuffie-
Jackson, C.; Veltri, E. P. Clin. Ther. 2001, 23, 1209–1230; (b) Burnett, D. A.;
Caplen, M. A.; Davis, H. R.; Burrier, R. E.; Clader, J. W. J. Med. Chem. 1994, 37,
1733–1736; (c) Chen, L.-Y.; Zaks, A.; Chackalamannil, S.; Dugar, S. J. Org. Chem.
1996, 61, 8341–8343; (d) Clader, J. W. J. Med. Chem. 2003, 47, 1–9; (e) Dugar, S.;
Clader, J. W.; Chan, T.-M.; Davis, H. J. Med. Chem. 1995, 38, 4875–4877; (f)
Ghosal, A.; Zbaida, S.; Chowdhury, S. K.; Iannucci, R. M.; Feng, W.; Alton, K. B.;
Patrick, J. E.; Davis, H. R. Pat. Appl. 2002.; (g) Knopp, R. H.; Gitter, H.; Truitt, T.;
Bays, H.; Manion, C. V.; Lipka, L. J.; LeBeaut, A. P.; Suresh, R.; Yang, B.; Veltri, E.
P. Eur. Heart J. 2003, 24, 729–741.
Oil; ½a 2D0
ꢂ
¼ ꢁ59 (c 1.0, CHCl3); 1H NMR (600 MHz, C7D8, signals
for Ph hydrogen atoms are omitted) d: 4.57 (1H, dd, J 7.9, 2.0 Hz),
4.34 (1H, d, J 2.4 Hz), 4.12 (1H, dd, J 12.0 Hz), 4.02 (1H, dd, J
12.0 Hz), 3.85 (1H, d, J 14.4 Hz), 3.55 (1H, d, J 8.0 Hz), 3.36 (1H, d,
J 14.4 Hz), 3.13 (1H, dd, J 10.7, 2.5 Hz), 3.04 (1H, t, J 7.9 Hz), 2.95
(1H, dd, J 10.7, 2.5 Hz); 13C NMR (150 MHz, C7D8, signals for Ph car-
bon atoms are omitted) d: 171.8, 83.6, 78.2, 73.2, 73.1, 69.7, 59.0,
54.1; HRMS (EI) m/z calcd for C26H26NO4 [M] 416.1862; found
416.1856; IR (film) m .
: 1775 cmꢁ1
4.17. (3S,3aR,6R,6aS)-N-Benzyl-6-(benzyloxymethyl)-3-phenyl-
tetrahydrofuro[3,4-d]isoxazol-4(2H)-one 42
Oil; ½a 2D0
ꢂ
¼ þ78 (c 1.0, CHCl3); 1H NMR (600 MHz, C7D8, sig-
nals of Ph hydrogen atoms are omitted) d: 4.52 (1H, d,
J
6.2 Hz), 4.14 (1H, br s), 4.06 (1H, d, J 12.2 Hz), 4.04–3.98 (1H,
m), 3.97 (1H, d, J 12.2 Hz), 3.78–3.65 (1H, m), 3.54 (1H, d, J
14.3 Hz), 3.42 (1H, dt), 3.06 (1H, d, J 9.2 Hz), 2.81 (1H, d, J
9.2 Hz); 13C NMR (150 MHz, C7D8, signals for Ph carbon atoms
omitted) d: 175.5, 80.4, 79.9, 74.0, 73.2, 69.3, 59.3 58.2; HRMS
(EI) m/z calcd for C26H26NO4 [M] 416.1862; found 416.1859; IR
5. Keri, R. S.; Hosamani, K. M.; Reddy, H. S.; Shingalapur, R. V. Arch. Pharm. 2010,
343, 237–247.
6. Aslanian, R. G.; Bennett, C. E.; Burnett, D. A.; Chan, T. -Y.; Kiselgof, E. Y.;
Knutson, C. E.; Harris, J. M.; McKittrick, B. A.; Palani, A.; Smith, E. M.; Vaccaro, H.
M.; Xiao, D.; Kim, H. M., Pat. Appl. WO 2008/033464A2, 2008.
7. (a) Banik, I.; Becker, F. F.; Banik, B. K. J. Med. Chem. 2002, 46, 12–15; (b) Meegan,
M. J.; Carr, M.; Knox, A. J. S.; Zisterer, D. M.; Lloyd, D. G. J. Enzyme Inhib. Med.
Chem. 2008, 23, 668–685.
(film) m .
: 1778 cmꢁ1
4.18. (3R,3aR,6R,7S,7aS)-2-Benzyl-7-(benzyloxy)-6-(benzyloxy-
methyl)-3-phenyltetrahydro-2H-pyrano[3,4-d]isoxazol-4(6H)-
one 43
8. (a) Panfil, I.; Chmielewski, M. Tetrahedron 1985, 41, 4713–4716; (b) Panfil, I.;
_
Chmielewski, M.; Bełzecki, C. Heterocycles 1986, 24, 1609–1617; (c) Panfil, I.;
_
Bełzecki, C.; Chmielewski, M. J. Carbohydr. Chem. 1987, 6, 463–470; (d) Panfil, I.;
_
Bełzecki, C.; Urbanczyk-Lipkowska, Z.; Chmielewski, M. Tetrahedron 1991, 47,
Oil; ½a 2D0
ꢂ
¼ ꢁ61 (c 1.1, CHCl3); 1H NMR (600 MHz, C7D8, signals
10087–10094.
9. (a) Socha, D.; Jurczak, M.; Chmielewski, M. Carbohydr. Res. 2001, 336, 315–318;
for Ph hydrogen atoms are omitted) d: 4.96 (1H, br s), 4.35 (1H, dd,
J 5.8, 3.8 Hz), 4.26 (1H, d, J 12.0 Hz), 4.15 (2H, m), 4.07 (1H, d, J
12.0 Hz), 3.85 (1H, d, J 8.7 Hz), 3.80–3.74 (2H, m), 3.59 (1H, t, J
8.7 Hz), 3.54 (1H, dd, J 9.5, 4.6 Hz), 3.51–3.43 (2H, m); 13C NMR
(150 MHz, C7D8, signals for Ph carbon atoms are omitted) d:
166.0, 75.8, 75.0, 72.9, 72.8, 72.7, 72.3, 67.6, 59.5, 53.1; HRMS
(b) Panfil, I.; Solecka, J.; Chmielewski, M. J. Carbohydr. Chem. 2006, 25, 673–684;
´
(c) Pasniczek, K.; Socha, D.; Jurczak, M.; Solecka, J.; Chmielewski, M. Can. J.
Chem. 2006, 84, 534–539; (d) Socha, D.; Pas´niczek, K.; Jurczak, M.; Solecka, J.;
Chmielewski, M. Carbohydr. Res. 2006, 341, 2005–2011; (e) Stecko, S.; Jurczak,
M.; Urban´ czyk-Lipkowska, Z.; Solecka, J.; Chmielewski, M. Carbohydr. Res. 2008,
343, 2215–2220; (f) Stecko, S.; Jurczak, M.; Staszewska-Krajewska, O.; Solecka,
J.; Chmielewski, M. Tetrahedron 2009, 65, 7056–7063; (g) Stecko, S.; Pas´niczek,
K.; Jurczak, M.; Solecka, J.; Chmielewski, M. Pol. J. Chem. 2009, 83, 237–243; (h)
Stecko, S.; Solecka, J.; Chmielewski, M. Carbohydr. Res. 2009, 344, 167–176.
(ESI) m/z calcd for
558.2266; IR (film)
C
34H33NO5Na [M+Na]+ 558.2256; found
m
: 1742 cmꢁ1
.

´
_
M. Sniezek et al. / Tetrahedron: Asymmetry 24 (2013) 89–103
103
10. (a) Stecko, S.; Pas´niczek, K.; Jurczak, M.; Urban´ czyk-Lipkowska, Z.;
Chmielewski, M. Tetrahedron: Asymmetry 2006, 17, 68–78; (b) Stecko, S.;
Pas´niczek, K.; Jurczak, M.; Urban´ czyk-Lipkowska, Z.; Chmielewski, M.
Tetrahedron: Asymmetry 2007, 18, 1085–1093.
11. (a) Stecko, S.; Pas´niczek, K.; Michel, C.; Milet, A.; Perez, S.; Chmielewski, M.
Tetrahedron: Asymmetry 2008, 19, 2140–2148; (b) Stecko, S.; Pas´niczek, K.;
Michel, C.; Milet, A.; Pérez, S.; Chmielewski, M. Tetrahedron: Asymmetry 2008,
19, 1660–1669.
28. HyperChem™ Professional 7.51, H., Inc., 1115 NW 4th Street, Gainesville, FL
32601, USA.
29. Hocquet, A.; Langgård, M. J. Mol. Model. 1998, 4, 94–112.
30. (a) Becke, A. D. Phys. Rev. A 1988, 38, 3098–3100; (b) Becke, A. D. J. Chem. Phys.
1993, 98, 5648–5652; (c) Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B 1988, 37,
785–789.
31. (a) Pople, J. A.; Binkley, J. S.; Seeger, R. Int. J. Quantum Chem. 1976, 10, 1–19; (b)
Pople, J. A.; Seeger, R.; Krishnan, R. Int. J. Quantum Chem. 1977, 11, 149–163.
32. GAUSSIAN 09, Revision A.02; Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria,
G. E.; Robb, M. A.; Cheeseman, J. R.; Montgomery, J. A.; 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, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda,
Y.; Kitao, O.; Nakai, H.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.; Challacombe,
M.; Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A.;
GAUSSIAN, Inc.: Pittsburgh, PA, 2003.
12. Stecko, S.; Frelek, J.; Chmielewski, M. Tetrahedron: Asymmetry 2009, 20, 1778–
1790.
13. Michalak, M.; Stodulski, M.; Stecko, S.; Mames, A.; Panfil, I.; Soluch, M.;
Furman, B.; Chmielewski, M. J. Org. Chem. 2011, 76, 6931–6936.
14. Michalak, M.; Stodulski, M.; Stecko, S.; Woz´nica, M.; Staszewska-Krajewska, O.;
Kalicki, P.; Furman, B.; Frelek, J.; Chmielewski, M. Tetrahedron 2012, 68, 10806–
10817.
15. Stecko, S.; Michalak, M.; Stodulski, M.; Mucha, Ł.; Parda, K.; Furman, B.;
Chmielewski, M. Synthesis 2012, 44, 2695–2698.
16. (a) Descotes, G.; Martin, J.-C. Carbohydr. Res. 1977, 56, 168–172; (b) Qiu, D.;
Schmidt, R. R. Synthesis 1990, 875–877; (c) Fazio, F.; Schneider, M. P.
Tetrahedron: Asymmetry 2000, 11, 1869–1876; (d) Takhi, M.; Abdel-Rahman,
A. A. H.; Schmidt, R. R. Synlett 2001, 427–429.
17. Grigor’ev, I. A. Nitrile Oxides, Nitrones, and Nitronates in Organic Synthesis; John
Wiley & Sons, Inc., 2007. pp 129–434.
´
18. Panfil, I.; Urbanczyk-Lipkowska, Z.; Chmielewski, M. Pol. J. Chem. 2005, 79,
33. (a) Schlegel, H. B. J. Comput. Chem. 1982, 3, 214–220; (b) Schlegel, H. B. In
Modern Electronic Structure Theory; Yarkony, D. R., Ed.; World Scientific:
Singapore, 1994.
34. (a) Peng, C.; Schlegel, H. B. Israel J. Chem. 1993, 33, 449–454; (b) Peng, C.; Ayala,
P. Y.; Schlegel, H. B.; Frisch, M. J. J. Comput. Chem. 1996, 17, 49–56.
35. Wiberg, K. B. Tetrahedron 1968, 24, 1083–1096.
239–249.
19. (a) Gothelf, K. V.; Jørgensen, K. A. Chem. Rev. 1998, 98, 863–910; (b) Gothelf, K.
V.; Jorgensen, K. A. Chem. Commun. 2000, 1449–1458; (c) Kanemasa, S. Synlett
2002, 1371–1387; (d) Pellissier, H. Tetrahedron 2007, 63, 3235–3285; (e)
Stanley, L. M.; Sibi, M. P. Chem. Rev. 2008, 108, 2887–2902.
20. (a) Kanemasa, S.; Uemura, T.; Wada, E. Tetrahedron Lett. 1992, 33, 7889–7892;
(b) Kanemasa, S.; Tsuruoka, T.; Wada, E. Tetrahedron Lett. 1993, 34, 87–90; (c)
Kanemasa, S.; Tsuruoka, T. Chem. Lett. 1995, 24, 49–50.
36. Reed, A. E.; Weinstock, R. B.; Weinhold, F. J. Chem. Phys. 1985, 83, 735–746.
37. (a) Fukui, K. Acc. Chem. Res. 1981, 14, 363–368; (b) Head-Gordon, M.; Pople, J. A.
J. Chem. Phys. 1988, 89, 5777–5786.
21. Tamura, O.; Shiro, T.; Ogasawara, M.; Toyao, A.; Ishibashi, H. J. Org. Chem. 2005,
70, 4569–4577.
22. (a) Frank, É.; Wölfling, J.; Aukszi, B.; König, V.; Schneider, T. R.; Schneider, G.
Tetrahedron 2002, 58, 6843–6849; (b) Li, X.; Takahashi, H.; Ohtake, H.; Ikegami,
S. Heterocycles 2003, 59, 547–571.
23. Kobayashi, S.; Akiyama, R.; Kawamura, M.; Ishitani, H. Chem. Lett. 1997, 1039–
1040.
24. Sanchez-Blanco, A. I.; Gothelf, K. V.; Jørgensen, K. A. Tetrahedron Lett. 1997, 38,
7923–7926.
38. (a) Tomasi, J.; Persico, M. Chem. Rev. 1994, 94, 2027–2094; (b) Simkin, B. Y.;
Sheikhet, I. Quantum Chemical and Statistical Theory of Solutions—A
Computational Approach; Ellis Horwood: London, 1995.
39. (a) Cossi, M.; Barone, V.; Cammi, R.; Tomasi, J. Chem. Phys. Lett. 1996, 255, 327–
335; (b) Cances, E.; Mennucci, B.; Tomasi, J. J. Chem. Phys. 1997, 107, 3032–
3041; (c) Barone, V.; Cossi, M.; Tomasi, J. J. Comput. Chem. 1998, 19, 404–417.
40. (a) Parr, R. G.; Pearson, R. G. J. Am. Chem. Soc. 1983, 105, 7512–7516; (b) Parr, R.
G.; Szentpály, L. v.; Liu, S. J. Am. Chem. Soc. 1999, 121, 1922–1924.
41. Domingo, L. R.; Aurell, M. J.; Pérez, P.; Contreras, R. Tetrahedron 2002, 58, 4417–
4423.
42. Chattaraj, P. K.; Sarkar, U.; Roy, D. R. Chem. Rev. 2006, 106, 2065–2091.
43. (a) Geerlings, P.; De Proft, F.; Langenaeker, W. Chem. Rev. 2003, 103, 1793–
1874; (b) Ess, D. H.; Jones, G. O.; Houk, K. N. Adv. Synth. Catal. 2006, 348, 2337–
2361.
44. Pérez, P.; Domingo, L. R.; José Aurell, M.; Contreras, R. Tetrahedron 2003, 59,
3117–3125.
25. Minakata, S.; Ezoe, T.; Nakamura, K.; Ryu, I.; Komatsu, M. Tetrahedron Lett.
1998, 39, 5205–5208.
26. (a) Sustmann, R.; Sicking, W.; Huisgen, R. J. Am. Chem. Soc. 1995, 117, 9679–
9685; (b) Liu, J.; Niwayama, S.; You, Y.; Houk, K. N. J. Org. Chem. 1998, 63, 1064–
1073; (c) Cossío, F. P.; Morao, I.; Jiao, H.; Schleyer, P. v. R. J. Am. Chem. Soc. 1999,
121, 6737–6746; (d) Carda, M.; Portolés, R.; Murga, J.; Uriel, S.; Marco, J. A.;
Domingo, L. R.; Zaragozá, R. J.; Röper, H. J. Org. Chem. 2000, 65, 7000–7009; (e)
Di Valentin, C.; Freccero, M.; Gandolfi, R.; Rastelli, A. J. Org. Chem. 2000, 65,
6112–6120; (f) Herrera, R.; Nagarajan, A.; Morales, M. A.; Méndez, F.; Jiménez-
Vázquez, H. A.; Zepeda, L. G.; Tamariz, J. J. Org. Chem. 2001, 66, 1252–1263; (g)
Kavitha, K.; Venuvanalingam, P. J. Chem. Soc., Perkin Trans. 2 2002, 2130–2139;
(h) Merino, P.; Mates, J. A.; Revuelta, J.; Tejero, T.; Chiacchio, U.; Romeo, G.;
Iannazzo, D.; Romeo, R. Tetrahedron: Asymmetry 2002, 13, 173–190; (i) Merino,
P.; Revuelta, J.; Tejero, T.; Chiacchio, U.; Rescifina, A.; Romeo, G. Tetrahedron
2003, 59, 3581–3592; (j) Aurell, M. J.; Domingo, L. R.; Pérez, P.; Contreras, R.
Tetrahedron 2004, 60, 11503–11509; (k) Ess, D. H.; Houk, K. N. J. Phys. Chem. A
2005, 109, 9542–9553; (l) Grimme, S.; Mück-Lichtenfeld, C.; Würthwein, E.-U.;
Ehlers, A. W.; Goumans, T. P. M.; Lammertsma, K. J. Phys. Chem. A 2006, 110,
2583–2586; (m) Merino, P.; Tejero, T.; Chiacchio, U.; Romeo, G.; Rescifina, A.
Tetrahedron 2007, 63, 1448–1458; (n) Acharjee, N.; Banerji, A. Comput. Theory
Chem. 2011, 967, 50–58.
45. Domingo, L. R.; Aurell, M. J.; Pérez, P.; Contreras, R. J. Phys. Chem. A 2002, 106,
6871–6875.
46. Parr, R. G.; Yang, W. J. Am. Chem. Soc. 1984, 106, 4049–4050.
47. Reed, A. E.; Curtiss, L. A.; Weinhold, F. Chem. Rev. 1988, 88, 899–926.
48. (a) Bach, R. D.; McDouall, J. J. W.; Schlegel, H. B.; Wolber, G. J. J. Org. Chem. 1989,
54, 2931–2935; (b) Bachrach, S. M.; Liu, M. J. Org. Chem. 1992, 57, 6736–6744;
(c) Li, Y.; Houk, K. N. J. Am. Chem. Soc. 1993, 115, 7478–7485; (d) Bachrach, S. M.
J. Org. Chem. 1994, 59, 5027–5033.
49. Domingo, L. R.; Arnó, M.; Andrés, J. J. Am. Chem. Soc. 1998, 120, 1617–1618.
50. Brüning, I.; Grashey, R.; Hauck, H.; Huisgen, R.; Seidl, H. Org. Synth. 1966, 46,
127–130.
51. Näsman, J. H. Org. Synth. 1990, 68, 162–167.
27. (a) Domingo; Luis, R. Eur. J. Org. Chem. 2000, 2265–2272; (b) Tanaka, J.;
Kanemasa, S. Tetrahedron 2001, 57, 899–905; (c) Domingo, L. R.; Benchouk, W.;
Mekelleche, S. M. Tetrahedron 2007, 63, 4464–4471.