Organocatalytic enantio- and diastereoselective 1,3-dipolar cycloaddition between alanine-derived ketonitrones and E-crotonaldehyde: Efficiency and full stereochemical studies

Article abstract of DOI:10.1016/j.tetasy.2012.11.010

Highly enantio- and exo-selective 1,3-dipolar cycloadditions of alanine-derived ketonitrones to E-crotonaldehyde could be realized in a good yield by the use of a chiral imidazolidinone salt without the addition of water. The origin of the stereoselectivi

Full text of DOI:10.1016/j.tetasy.2012.11.010

Tetrahedron: Asymmetry 23 (2012) 1670–1677
Contents lists available at SciVerse ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Organocatalytic enantio- and diastereoselective 1,3-dipolar cycloaddition
between alanine-derived ketonitrones and E-crotonaldehyde: efficiency
and full stereochemical studies
Khalid B. Selim a,b, Anne Beauchard a, Jérôme Lhoste a, Arnaud Martel a, Mathieu Y. Laurent a,
Gilles Dujardin a,
⇑
a LUNAM Université du Maine, IMMM-UMR 6283 CNRS, Equipe MSO, Faculté des Sciences, 72085 Le Mans, Cedex 9, France
b Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 18 October 2012
Accepted 15 November 2012
Highly enantio- and exo-selective 1,3-dipolar cycloadditions of alanine-derived ketonitrones to E-croton-
aldehyde could be realized in a good yield by the use of a chiral imidazolidinone salt without the addition
of water. The origin of the stereoselectivity in the reaction was discussed and the absolute configuration
of the cycloadduct determined unambiguously.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
ketonitrones display an interesting reactivity with total 3,5-regio-
control and varied degrees of exo-selectivity toward electron-poor
The regio- and stereoselective synthesis of isoxazolidines via
1,3-dipolar cycloaddition (1,3-DC) reactions of nitrones with elec-
tron-poor, or electron-rich, alkenes has been a challenge for asym-
metric catalysis. The isoxazolidines obtained are potential
precursors for biologically important compounds, such as alka-
loids, amino acids, b-lactams, and amino sugars.1,2 Since MacMillan
et al. reported that chiral imidazolidinone organocatalysts acceler-
and electron-rich dipolarophiles under thermal solvent-free
conditions.
In contrast to isomerizable glycine-derived nitrones, these keto-
nitrones, which were almost unexplored dipoles, are geometry-
fixed in a stable E-configuration as a result of minimizing steric
and electrostatic interactions. These stereochemical characteristics
strongly suggest that these ketonitrones could be used as new di-
poles for the asymmetric synthesis of highly functionalized isoxa-
zolidine derivatives, containing up to three contiguous stereogenic
centers and at least one quaternary carbon,12 through organocata-
ated the 1,3-DC of
a,b-unsaturated aldehydes toward nitrones to
achieve both enantio- and endo/exo selectivities,3 a range of chiral
organic catalysts, such as pyrrolidinium salts,4 camphor-derived
hydrazides,5 hybrid diamines,6 and polymer supported imidazolid-
inones,7 have been proposed for the 1,3-DC reaction of a nitrone
lyzed 1,3-DC reactions with
a,b-unsaturated aldehydes.
As part of a program directed toward the enantioselective syn-
with
a
,b-unsaturated aldehydes. The catalytic effect of these
thesis of a,a-disubstituted amino acids (DAA) via ring-opening of
organocatalysts is due to the activation of the alkene moiety of
the aldehyde by lowering the LUMO energy through iminium ion
formation. Most of these reports utilize nitrones derived from aro-
matic aldehydes. However, Jurczak recently reported the 1,3-DC of
glycine-derived nitrones to E-crotonaldehyde catalyzed by hybrid
diamines.8 It is noteworthy that these ester-derived aldonitrones
suffer from E/Z isomerization which leads to a loss of stereoselec-
tivity (Scheme 1).9
isoxazolidines,11b we directed our attention to develop an organo-
catalytic asymmetric version of the 1,3-DC reaction between achi-
ral ketonitrones and a,b-unsaturated aldehydes. It should be noted
that Jurzcak et al. reported on the asymmetric 1,3-DC reaction of
alanine-derived nitrones and E-crotonaldehyde under the effect
of chiral amine organocatalysts.13 However, the data accumulated
in that work did not mention the exo/endo selectivity. Furthermore,
it did not discuss the origin of the enantiofacial selectivity while
the poor yields seemed to suggest that the system is not optimal.
Herein, we offer complete and improved results with a discussion
of some ambiguous aspects developed in the previous report.
Following the seminal work of Winterfeldt et al.,10 our group re-
cently disclosed that a large range of functionalized ketonitrones
could be prepared by condensation between N-benzylhydroxyl-
amine and acetylene dicarboxylates or a-keto esters to form aspar-
tate and alanine-derived nitrones, respectively (Scheme 1).11 These
2. Results and discussion
As shown in Table 1, we investigated the cycloaddition reac-
tions between functionalized ketonitrones 1 and simple electron
⇑
Corresponding author. Tel.: +33 (0)2 4383 3344; fax: +33 (0)2 4383 3902.
E-mail address: gilles.dujardin@univ-lemans.fr (G. Dujardin).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.11.010

K. B. Selim et al. / Tetrahedron: Asymmetry 23 (2012) 1670–1677
1671
glycine-derived nitrones
COOMe
Bn
Bn
N
O
N
O
COOMe
E-isomer
Z-isomer
aspartate-derived nitrones
O
OR
ROOC
BnNHOH
Bn
COOR
Bn
N
OR
RO2C
CO2R
N
O
O
O
substituted alanine-derived nitrones
COOMe
O
OMe
CH2R
O
BnNHOH
Bn
Bn
OMe
N
O
CH2R
N
CH2R
O
O
E-isomer
Z-isomer
Scheme 1. Synthesis and configurational bias of ester-derived nitrones.
deficient dipolarophiles 2 under racemic non-catalyzed thermal
conditions. Acrolein 2a as a monosubstituted dipolarophile reacted
with aspartate-derived nitrone 1a in an exclusively regioselective
manner, to afford oxazolidine 3a as a 3,5-cycloadduct in moderate
yield and with poor diastereoselectivity (52%, exo/endo 53:47, en-
try 1). The origin of the total regiocontrol is steric and favors the
formation of adduct 3a to avoid repulsive interactions between
the formyl group and the aspartate part of the nitrone. Applying
the reaction to microwave conditions enhanced the exo-selectivity
and shortened the reaction time to give 3a as a mixture 68:32 in
95% yield (entry 2). Alanine-derived nitrone 1b was reacted with
2a and gave the same 3,5-regioselectivity in low yield and with
equal diastereomeric ratios (entry 3). Increasing the size of the pro-
tecting group on the nitrogen of the nitrone 1c by using diphenyl-
methyl (DPM) did not increase the selectivity of the exo approach
and afforded 3c as a mixture (62:38, entry 4).
We extended our study to E-crotonaldehyde 2b as a 1,2-disub-
stituted dipolarophile; the thermal cycloaddition reaction of dipole
1a with 2b led to 72% exo-selectivity with 3,4-regiocontrol and 43%
yield of 4a (entry 5). In this case, a normal electron demand reac-
tion can be achieved with the favorable formation of the electron-
ically controlled regioisomer 4a due to the b-substitution of the
alkene which counterbalances the steric effect of the formyl group.
An isomeric adduct was detected in 5–10% in the crude product
which may come from the isomerization of E-crotonaldehyde 2b
to the Z-isomer under the microwave conditions (entries 5–8).
Since the use of aspartic nitrone 1a did not improve the reactivity
or stereoselectivity of the cycloaddition reaction, we envisioned
that the less bulky alanine-derived nitrone 1d could be an alterna-
tive dipole for the reaction. The cycloaddition of 1d and 2b under
microwave conditions was found to proceed smoothly to give the
desired adduct 4b with high exo selectivity in 78% yield (dr
88:12, entry 6). When nitrones 1e and 1f were used in the reaction,
the exo selectivity increased with the size of the N-protecting
group to 95:5 for 1e (R1 = DPM, R3 = Me, entry 7) and to 94:6 for
1f (R1 = DPM, R3 = Et, entry 8) but at the expense of the yield of
the adducts 4c and 4d, respectively. The low yield may be attrib-
uted to the instability of nitrones 1e and 1f under the reaction
temperature.
conditions using hybrid diamine I as a chiral catalyst (Fig. 1) which
has recently been revealed to catalyze the reaction between gly-
cine-derived nitrones and E-crotonaldehyde 2b to afford the isoxa-
zolidine derivatives with high selectivity (up to 91% dr and 90% ee).8
The cycloaddition was conducted in the presence of a catalytic
amount of I (10 mol %), trifluoromethanesulfonic acid (9 mol %) as a
co-catalyst, and water (3 equiv) as shown in Table 2. The reaction
was complete after 72 h at 4 °C, providing cycloadduct 4b in high
yield and with excellent diastereoselectivity (exo/endo 98:2) with
a low enantioselectivity of 52% ee for the exo product (entry 1).
These results suggest that nitrone 1d shows a poor ability to dis-
criminate between the enantiotopic faces of the iminium ion inter-
mediate formed between the primary amine catalyst
I and
aldehyde 2b. With this consideration in mind, the N-Bn group on
the nitrone was replaced by a more sterically demanding N-DPM
group, which was anticipated not to change the electronic property
of the dipole significantly.14 The reaction of 1f proceeded smoothly
and the cycloadduct was obtained with higher enantioselectivity of
63% ee for the exo-4d isomer and 43% ee for the endo-4d isomer in
85% combined yield. Additionally, a similarly preferential formation
of the exo-isomer (95% dr) was observed (entry 2). These results are
better than the ones previously reported.13
Due to the reasonable enhancement in the enantioselectivity
because of the insertion of the N-DPM group, we decided to use
chiral imidazolidinone salt II (Fig. 1) in the cycloaddition reaction
of the nitrone 1f. The major exo product 4d (dr 94:6) was obtained
with 79% ee for the exo isomer and 35% ee for the endo isomer (en-
try 3). This improvement in selectivity of the reaction was accom-
panied by a decrease in the yield of the adduct 4d. Since the low
O
Bn
O
Me
·X
NH
NH2
N
Me
Me
N
H
NH
O
NH2
Bn
Ph
II, X = HCl
III, X = HClO4
On the basis of these encouraging results of the non-catalyzed
thermal conditions, we decided to develop the asymmetric organo-
catalyzed 1,3-dipolar cycloaddition approach under the reported
I
Figure 1. Organocatalysts used in the current work.

1672
K. B. Selim et al. / Tetrahedron: Asymmetry 23 (2012) 1670–1677
Table 1
Non-catalyzed thermal 1,3-DC reactions of nitrones 1aꢀf with acrolein 2a and E-crotonaldehyde 2b
COOR3
R2
COOR3
R2
R1
R1
R4 = H
N
O
N
O
+
COOR3
O
CHO
CHO
R1
MW, 90 °C
3,5-exo-3
3,5-endo-3
N
O
R2
+
1.5 − 6 h
R4
COOR3
R2
COOR3
R2
CHO
R1
R1
1
2
N
O
N
O
CHO
+
R
4 = Me
Me
Me
3,4-endo-4
3,4-exo-4
Entry
1
R1
R2
R3
2, x equiv
R4
Adduct
exo:endoa
Yieldb (%)
1c
2
1a
1a
1b
1c
1a
1d
1e
1f
Bn
Bn
Bn
DPM
Bn
Bn
DPM
DPM
CH2COOMe
CH2COOMe
Me
CH2COOMe
CH2COOMe
Me
Me
Me
Me
Me
Me
Et
2a, 3 equiv
2a, 6 equiv
H
H
H
H
3a
3a
3b
3c
4a
4b
4c
4d
53:47
68:32
50:50
62:38
72:28e
88:12e
95:5e
94:6e
52
95
39
58
43
78
65
43
3d
4
2a, 10 equiv
2a, 10 equiv
2b, 6 equiv
2b, 6 equiv
2b, 6 equiv
2b, 6 equiv
5
6
7
8
Me
Me
Me
Me
Me
Me
Me
Et
a
b
c
Determined by 1H NMR of the crude product.
Isolated combined yield of the exo- and endo-products.
Reaction was performed in toluene (1 mL) at 90 °C for 48 h.
5 mol % of hydroquinone were used.
d
e
6%, 8%, 5%, and 10% of isomeric adduct resulting from the Z-isomer of 2b in entries 1ꢀ4, respectively.
stability of N-DPM nitrone 1f was observed under both thermal
and catalytic 1,3-cycloaddition reactions, we decided to use N-ben-
zyl nitrone 1d in the reaction to afford cycloadduct 4b in 43% yield
with a similar level of exo stereocontrol and with a significant in-
crease in enantioselectivity (94% ee, entry 4).
reaction was performed with only 5 mol % of catalyst, a conversion
of 95% was reached after 7 days without significant changes in dia-
stereoselectivity and the enantioselectivity was improved to 94%
ee (67% yield, 4% recovery of 1d, entry 11). Increasing the catalyst
loading (20 mol %) did not affect the exo/endo ratio or the ee (70%
yield, entry 12). Using catalyst III gave lower enantioselectivity
(77% ee) in comparison to entry 5. Performing the cycloaddition
at ꢀ17 °C gave similar results to those reported in entry 10. Final-
ly, scaling up the reaction to 2 mmol of nitrone, after 5 days, led to
a slight decrease in the enantioselectivity without affecting the
diastereomeric ratio of the cycloadduct 4b in 68% yield along with
10% recovery of the starting material (entry 15). It is noteworthy
that 59% of pure exo-4b can be easily separated after column chro-
matography in the last reaction. In contrast to a previous re-
port,13,15 our newly developed conditions prove the synthetic
utility of using alanine-derived nitrones in catalytic enantioselec-
tive 1,3-DC.
The HClO4-derived catalyst III (Fig. 1) was used to give isoxazol-
idine in 92% ee, 87:13 dr, and 54% yield (entry 5). The superior lev-
els of asymmetric induction and diastereocontrol exhibited by the
HCl salt II encouraged us to select this catalyst for further optimi-
zation of the reaction conditions in order to obtain cycloadduct 4b
in better yields. If the cycloaddition reaction is carried out in an
acidic aqueous medium, hydrolysis of the nitrone over a long reac-
tion time may occur. Contrary to the previous literature which sug-
gested that the presence of water is required for high conversion
and enantioselectivity,3,13 we performed the reaction in the ab-
sence of water and found that the yield of 4b increased from 43%
to 61% without affecting the exo- and enantioselectivities of the
reaction (dr 94:6, 92% ee, entry 6). Replacing water with i-PrOH
as a protic additive afforded 4b in 59% yield, dr 96:4, and 91% ee
(entry 7). When the reaction was carried out in the presence of
2,6-lutidine (10 mol %) to trap the partial excess of HCl, the conver-
sion of the nitrone decreased to 34% and the adduct was isolated in
21% yield (entry 8). The presence of a base strongly decreases the
efficiency of the catalyst. The addition of 4 Å molecular sieves dra-
matically decreased the conversion and the enantioselectivity (10%
conversion, 40% ee, entry 9). This was attributed to removal of the
endogenous water from the reaction medium, which lessens the
turnover of the catalyst and increases the importance of the uncat-
alyzed pathway.
Calculations16 of the iminium ion generated from the imidazo-
lidinone catalyst confirmed the previously collected data on simi-
lar iminiums derived from cinnamaldehyde.17 Similar to what
was reported by Platts et al.17a on the basis of calculations and
NMR data, the favored conformation places the phenyl group to-
ward one methyl group of the imidazolidinone. The two preferred
conformations B and C result from the E-isomer and put the benzyl
group directly above the iminium or the double bond (Fig. 2). This
is evidently responsible for the high facial selectivity observed in
the dipolar cycloaddition. The model of the preferred (E)-iminium
intermediate (Fig. 3) and the position of the benzyl group on the
catalyst framework effectively shield the Re-face (top) of the dipol-
arophile and promote approach of the nitrone to the open Si-face
Encouraged by the results obtained in the absence of water, the
nitrone cycloaddition was carried out at ꢀ10 °C for 5 days to give a
96:4 mixture of 4b adduct with 95% ee of the major exo product in
75% yield with complete conversion of 1d (entry 10). When the
(bottom) of the dipolarophile (Re and Si faces refer to the a-carbon
of the iminium ion). Furthermore, the model shows that cycloaddi-
tion through an exo approach of the nitrone effectively minimizes

K. B. Selim et al. / Tetrahedron: Asymmetry 23 (2012) 1670–1677
1673
Table 2
Organocatalytic enantioselective 1,3-DC reactions of nitrones 1d,f with E-crotonaldehyde 2b
COOEt
Me
COOEt
Me
O
R1
R1
COOEt
Me
N
O
N
O
R1
10 mol% cat.
CHO
+
CHO
N
O
+
MeNO2
conditions
Me
Me
1d,f
Conditions
2b
3,4-exo-4b,d
exo:endoa,b
3,4-endo-4b,d
ee% exo-4c
Entry
1
R1
Adduct
Conversiona (%)
Yieldd (%)
1
2
3
4
5
6
7
8
9
10
11g
12
13
14
15h
1d
1f
1f
Bn
I/TfOH, H2O, 4 °C, 3 days
I/TfOH, H2O, 4 °C, 3 days
II, H2O, 4 °C, 3 days
II, H2O, 4 °C, 3 days
III, H2O, 4 °C, 3 days
II, 4 °C, 3 days
4b
4d
4d
4b
4b
4b
4b
4b
4b
4b
4b
4b
4b
4b
4b
98:2
95:5
94:6
94:6
87:13
94:6
96:4
94:6
95:5
96:4
95:5
95:5
86:14
96:4
96:4
52
63e
79f
94
92
92
91
62
40
95
94
95
77
95
90
100
100
75
89
100
97
95
35
10
99
95
100
97
96
90
92
85
34
43
54
61
59
21
10
75
67
70
68
75
68
DPM
DPM
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
1d
1d
1d
1d
1d
1d
1d
1d
1d
1d
1d
1d
II, i-PrOH, 4 °C, 3 days
II, H2O, 2,6-lutidine, 4 °C, 3 days
II, 4 Å MS, 4 °C, 3 days
II, ꢀ10 °C, 5 days
5 mol % II, ꢀ10 °C, 7 days
20 mol % II, ꢀ10 °C, 5 days
20 mol % III, ꢀ10 °C, 5 days
II, ꢀ17 °C, 5 days
Bn
II, ꢀ17 °C, 4 days
a
b
c
Determined by GC and 1H NMR of the crude product.
Up to 2% isomeric adduct resulting from 3% Z-2b present in E-2b was detected in the crude product by GC and 1H NMR.
Determined by HPLC after reduction to the corresponding alcohol.
Isolated combined yield of exo and endo products.
Ee for endo-4d is 43%.
Ee for endo-4d is 35%.
Performing the reaction for 4 days gave exo/endo 95:5, 94% ee of exo-4b, 57% combined yield, and 20% recovery of 1d.
2 mmol scale of 1d.
d
e
f
g
h
O
Me
O
Me
O
Me
O
Me
O
Me
N
N
N
N
N
Me
Me
Me
Me
Me
Me
Me
Me
N
N
N
N
N
Me
Me
Me
Me
Me
Me
M
e
A
B
C
D
E
ΔH°298:
ΔG°298:
6.1
3.1
2.1
2.3
0.0
0.0
9.3
10.5
6.9
4.5
Figure 2. Relative energies (kJ/mol) of the conformers of the iminium calculated at B3LYP/6-311+G(d,p) level using IEFPCM model with nitromethane as solvent.
the steric interactions between the nitrone ester group and the
geminal dimethyl group on the catalyst scaffold. Therefore, the
N-protecting group (Bn or DPM) plays a minor role on the diaste-
reoselectivity control rather than the enantioselectivity control as
shown in entries 3 and 4.
To assign the absolute stereochemistry of the three new chiral
centers in the isoxazolidine ring created in this 1,3-DC reaction,
the isoxazolidine was converted into a molecule containing a
known configuration of another stereogenic carbon atom
(Scheme 2). Pinnick oxidation of exo-4b (90% ee, entry 15) using
O
O
(R)
COOEt
Me
(S)-(−)-α-methylbenzylamine
NaClO2, NaH2PO4
2-methyl-2-butene
Bn
O
EDC·HCl, HOBt
N
O
N
O
CHO
(S)
DIEA, CH2Cl2
rt, 20 h
t-BuOH/H2O (2:1)
(R) HN
(S)
Me
3,4-exo-4b, 90% ee
5
74% yield (2 steps)
Scheme 2. Synthesis of 5 through oxidation-amide coupling of exo-4b.

1674
K. B. Selim et al. / Tetrahedron: Asymmetry 23 (2012) 1670–1677
Me
O
N
Me
Me
(S)
N
COOEt
Me
COOEt
Me
H
exo-approach
endo-approach
Bn
Bn
(favorable)
(unfavorable)
N
O
N
O
CHO
CHO
O
O
Me
Me
Me
Me
O
O
exo-4b
endo-4b
N
N
Bn
Bn
O
O
Figure 3. Reasonable explanation for the diastereo- and enantioselection in the 1,3-DC reaction catalyzed by imidazolidinone catalyst.
NaClO2 gave the corresponding carboxylic acid, which was sub-
4. Experimental
jected to amide coupling reaction with (ꢀ)-(S)-1-phenylethyl-
amine in the presence of EDC/HOBt to form
5 as a pure
4.1. General methods
diastereomeric compound in 74% yield after column chromatogra-
phy. These reactions indicate that the hindered formyl group can
be easily subjected to several synthetic transformations.18 Crystals
suitable for X-ray crystallography were prepared by slow vapor
diffusion from pentane to Et2O. The X-ray structure of 5 is shown
in Figure 4.19 On the basis of the absolute stereochemistry of
(ꢀ)-(S)-1-phenylethylamine in the X-ray structure 5 (Fig. 4), the
absolute stereochemistry of the stereogenic centers formed in
the isoxazolidine ring of the major enantiomer was assigned as
(3R,4S,5R). The absolute stereochemistry of the isoxazolidine indi-
cates that the nitrone approaches the Si-face of the dipolarophile
when coordinated to the catalyst as previously suggested.
All melting points are uncorrected. Column chromatography
was performed using 40–60 l
m silica gel. NMR (400 MHz for 1H
and 100 MHz for 13C) was measured in CDCl3 unless otherwise
mentioned, and chemical shifts and coupling constants are pre-
sented in parts per million relative to Me4Si and Hertz, respec-
tively. Abbreviations are as follows: s, singlet; d, doublet; t,
triplet; q, quartet, p, pentet, m, multiplet; br, broad. 13C peak mul-
tiplicity assignments were made based on HSQC data. IR spectros-
copy of oil and solid samples was measured neat. The wave
numbers of maximum absorption peaks of IR spectroscopy are pre-
sented in cmꢀ1. MeNO2 was distilled from CaH2 and stored over 4 Å
molecular sieves before use. All reactions were performed under an
argon atmosphere unless otherwise mentioned. Reagents were
purchased from commercial suppliers and used without purifica-
tion. E-Crotonaldehyde was distilled before use. High-resolution
mass spectra were performed on a GCT Premier Micromass. Nitro-
nes 1a11a and 1b11b and catalysts I,20 II,3 and III3 were prepared
according to the reported procedures.
4.2. Procedure for the synthesis of nitrones
4.2.1. 2-(Benzhydrylamino)acetonitrile
To a MeCN (20 mL) solution of benzhydrylamine (0.94 mL,
5.45 mmol) were added i-Pr2NEt (1.9 mL, 10.9 mmol), ClCH2CN
(0.38 mL, 6.00 mmol), and TBAI (3.0 g, 8.175 mmol). After stirring
for 3 days at room temperature, the reaction mixture was concen-
trated in vacuo. The residue was dissolved in CH2Cl2 (20 mL) and
washed with satd NaHCO3 (2 ꢁ 10 mL) and NaCl (2 ꢁ 10 mL). The
organic layer was dried over MgSO4, filtered, and evaporated. Puri-
fication by column chromatography (cyclohexane/EtOAc = 9:1)
gave the title compound (1.05 g, 95%) as a yellow powder, mp
69ꢀ70.6 °C. IR: 3336, 3029, 2924, 2240, 1732, 1701, 1597, 1491,
1452, 1189, 1028. 1H NMR (400 MHz, CDCl3): 1.96 (1H, t,
J = 8.0 Hz, NH), 3.54 (2H, d, J = 8.0 Hz, CH2), 5.07 (1H, s, CH),
7.23–7.46 (10H, m, H-arom). 13C NMR (400 MHz, CDCl3): 35.33,
65.79, 117.66, 127.19, 127.82, 128.89, 141.83. HRMS (EI): m/z
Calcd for C15H14N2: 222.1157 [M+H]+. Found: 222.1172.
Figure 4. Determination of the absolute configuration of 3,4-exo-4b from the X-ray
structure of 5.
3. Conclusion
In conclusion, we have proven that alanine-derived ketonitrone
has significant synthetic value in the asymmetric 1,3-dipolar cyclo-
addition reaction with E-crotonaldehyde catalyzed by imidazolidi-
none catalyst II, which gave rise to the corresponding isoxazolidine
with excellent diastereo- and enantioselectivities in good yield.
Contrary to what was previously reported with this catalyst, the
yield of the cycloadduct was remarkably improved in the absence
of water. The absolute configuration of the three stereogenic cen-
ters of the cycloadduct was determined unambiguously via X-ray
analysis which supports our mechanistic hypothesis. Further stud-
ies are currently in progress to expand upon the scope of this
methodology.
4.2.2. N-Hydroxydiphenylmethanamine oxalic acid salt
At first, m-CPBA (0.97 g, 3.96 mmol) was added in several por-
tions to the above compound (0.44 g, 1.98 mmol) dissolved in
CH2Cl2 (10 mL) at 0 °C. The mixture was stirred for 30 min at room
temperature; then aqueous Na2S2O3 and satd NaHCO3 were added
and the resulting mixture was stirred for an additional 20 min. The
mixture was extracted twice with CHCl3 and the combined extracts
were washed with brine, dried over MgSO4, filtered, and concen-
trated in vacuo to afford the crude product (0.42 g) as a yellow so-

K. B. Selim et al. / Tetrahedron: Asymmetry 23 (2012) 1670–1677
1675
lid. The solid was dissolved in methanol (10 mL), and NH2OHꢂHCl
(0.68 g, 9.9 mmol) was added. After stirring for 4.5 h at 60 °C, the
resulting white suspension was cooled to room temperature, di-
luted with CH2Cl2 (15 mL), and filtered through a pad of CeliteÒ.
The filtrate was concentrated, and the residue was dissolved in
CHCl3 (20 mL) and washed with brine, dried over MgSO4, and fil-
tered. To the filtrate was added a solution of (COOH)2 in MeOH
(0.51 g, 2.97 mmol), and the resulting suspension was concen-
trated to dryness under reduced pressure. The white solid obtained
was triturated with Et2O/hexane (1:1), and collected by filtration to
give the title compound as a white solid (0.39 g, 59%), mp 151.6–
154 °C. IR: 2985, 2861, 1455, 1373, 1204, 1105, 1079. 1H NMR
(400 MHz, CDCl3): 5.27 (1H, s, CH), 7.25 (2H, t, J = 7.2 Hz, Harom),
7.33 (3H, t, J = 7.2 Hz, H-arom), 7.43 (3H, d, J = 7.2 Hz, H-arom),
8.94 (3H, br, COOH). 13C NMR (100 MHz, CDCl3): 69.2 (CH), 127.2
(4-C), 127.7 (2-C), 128.2 (3-C), 140.3 (1-C), 161.9 (COOH). HRMS
(EI): m/z Calcd for C13H14NO:200.1755 [M+H]+. Found: 200.1074.
1H NMR (400 MHz, CDCl3): 1.33 (3H, t, J = 7.1 Hz, ester CH3), 2.30
(3H, s, CH3), 4.28 (2H, q, J = 7.1 Hz, CH2), 7.30–7.39 (10H, m, H-
arom), 8.13 (1H, s, CH). 13C NMR (100 MHz, CDCl3): 12.6 (CH3),
14.2 (CH3), 60.5 (CH2), 75.1 (CH), 126.7, 126.9, 127.6, 136.0
(C ꢁ 3), 161.3 (CO). HRMS (DCI+NH3CH4): m/z Calcd for
C
18H20NO3: 298.1443 [M+H]+. Found: 298.1452.
4.3. General experimental procedure for the preparation of
racemic cycloadducts under thermal conditions
A
mixture of nitrone 1aꢀf (1 equiv) and aldehyde 2a,b
(6ꢀ10 equiv) was heated under microwave irradiation at 90 °C.
After the indicated time, the residue was purified by column chro-
matography to give the racemic adducts 3 and 4.
4.3.1. rac-Methyl 2-benzyl-5-formyl-3-(2-methoxy-2-oxoethyl)-
isoxazolidine-3-carboxylate 3a
Column chromatography (cyclohexane/EtOAc = 9:1) gave 95%
combined yield of exo-3a and endo-3a as a pale yellow oil.
3,5-exo-3a: IR: 2925, 1734, 1436, 1355, 1199, 1088. 1H NMR
4.2.3. (E)-N-(1,4-Dimethoxy-1,4-dioxobutan-2-ylidene)-1,1-diph-
enylmethanamine oxide 1c
To a suspension of the above compound (0.5 g, 1.49 mmol) and
NaOAcꢂ3H2O (0.3 g, 2.23 mmol) in methanol (5 mL), a solution of
dimethylacetylenedicarboxylate (0.21 g, 1.49 mmol) in methanol
(5 mL) was added dropwise at 0 °C and stirred at room temperature
for 20 h. The reaction mixture was evaporated in vacuo and the res-
idue was dissolved in CH2Cl2 (20 mL), washed twice with water,
dried over MgSO4, filtered, and evaporated. Purification by column
chromatography (cyclohexane/EtOAc = 9:1) gave compound 1c as a
white powder (0.38 gm, 75%), mp 97–97.8 °C. IR: 3021, 2949, 2930,
1732, 1702, 1510, 1434, 1313, 1187, 1118. 1H NMR (400 MHz,
CDCl3): 3.68 (3H, s, CH3), 3.79 (2H, s, CH2), 3.84 (3H, s, CH3),
7.31ꢀ7.36 (10H, m, H-arom), 8.30 (1H, s, CH). 13C NMR (100 MHz,
CDCl3): 34.8 (CH2), 52.2 (CH3), 53.0 (CH3), 77.2 (CH), 128.3, 128.4,
129.1, 135.7 (C), 137.0 (C), 162.0 (C=O), 168.5 (CO). HRMS (EI): m/
z Calcd for C19H20NO5:342.1341 [M+H]+. Found: 342.1336.
(400 MHz, CDCl3): 2.62 (1H, dd, J = 13.2, 10.0 Hz, 4a-H), 2.72 (1H,
d, J = 16.4 Hz, H-ester), 3.16 (1H, d, J = 16.4 Hz, H-ester), 3.31 (1H,
dd, J = 13.2, 4.0 Hz, 4b-H), 3.68 (1H, d, J = 13.6 Hz, H-Bn), 3.70
(3H, s, CH3), 3.78 (3H, s, CH3), 3.97 (1H, d, J = 14.0 Hz, H-Bn), 4.27
(1H, dd, J = 10.0, 4.0 Hz, 5b-H), 7.31ꢀ7.34 (5H, m, H-arom), 9.64
(1H, s, CHO). HRMS (EI): m/z Calcd for C16H20NO6: 322.1291
[M+H]+. Found: 322.1279.
3,5-endo-3a: IR: 2953, 2929, 1725, 1436, 1199, 1173, 1074. 1H
NMR (400 MHz, CDCl3): 2.49 (1H, dd, J = 13.2, 3.6 Hz, 4a-H), 2.55
(1H, d, J = 16.4 Hz, H-ester), 3.09 (1H, d, J = 16.4 Hz, H-ester), 3.55
(1H, dd, J = 13.2, 9.6 Hz, 4b-H), 3.64 (1H, d, J = 14.4 Hz, H-Bn),
3.69 (3H, s, CH3), 3.84 (3H, s, CH3), 4.04 (1H, d, J = 14.4 Hz, H-Bn),
4.35 (1H, dd, J = 9.6, 4.0 Hz, 5a-H), 7.33 (5H, t, J = 4.4 Hz, H-arom),
9.51 (1H, s, CHO). 13C NMR (100 MHz, CDCl3): 39.6 (4-C), 40.6 (C,
ester), 52.0 (CH3), 52.5 (CH3), 55.8 (C, Bn), 69.5 (3-C), 79.1 (5-C),
127.6 (Ph), 128.2 (Ph), 128.4 (Ph), 137.1 (Cq, Ph), 170.4 (CO),
170.5 (CO), 203.9 (CHO). HRMS (EI): m/z Calcd for C16H20NO6:
322.1291 [M+H]+. Found: 322.1278.
4.2.4. (E)-N-(1-Ethoxy-1-oxopropan-2-ylidene)-1-phenylmeth-
anamine oxide 1d
A mixture of ethyl pyruvate (1.1 mL, 10 mmol), BnNHOHꢂHCl
(1.76 g, 11 mmol), and NaOAcꢂ3H2O (1.63 g, 12 mmol) in MeOH
(20 mL) was stirred at room temperature for 16 h and then concen-
trated in vacuo. The residue was dissolved in CH2Cl2 (50 mL) and
the organic phase was washed with H2O (3 ꢁ 20 mL), dried over
MgSO4, and concentrated under vacuum to give a crude oil. Purifi-
cation by column chromatography (cyclohexane/EtOAc = 9:1) gave
compound 1d (0.895 g, 40%) as a colorless oil. IR: 3064, 2982, 1709,
1532, 1296, 1133. 1H NMR (400 MHz, CDCl3): 1.33 (3H, t, J = 7.1 Hz,
CH3), 2.26 (3H, s, CH3), 4.28 (2H, q, J = 7.1 Hz, CH2), 5.69 (2H, s,
CH2), 7.34 (3H, dd, J = 5.1, 2.1 Hz, H-arom), 7.50 (2H, dd, J = 5.5,
2.1 Hz, H-arom). 13C NMR (100 MHz, CDCl3): 14.1 (CH3), 15.4
(CH3), 61.9 (CH2), 67.1 (CH2), 128.5, 128.6, 128.9, 134.2 (C), 137.9
(C), 162.5 (CO). HRMS (DCI+NH3CH4): m/z Calcd for C12H16NO3:
222.1130 [M+H]+. Found: 222.1127.
4.3.2. rac-Methyl 2-benzyl-5-formyl-3-methylisoxazolidine-3-
carboxylate 3b
Column chromatography (cyclohexane/EtOAc = 19:1–9:1) gave
39% combined yield of exo-3b and endo-3b as a pale yellow oil.
3,5-exo-3b: 1H NMR (400 MHz, CDCl3): 1.44 (3H, s, 3
a-CH3),
2.28 (1H, dd, J = 12.7, 4.2 Hz, 4
a-H), 3.10 (1H, dd, J = 12.7, 9.5 Hz,
4b-H), 3.74 (1H, d, J = 14.6 Hz, H-Bn), 3.81 (3H, s, CH3), 4.05 (1H,
d, J = 14.6 Hz, H-Bn), 4.30 (1H, dd, J = 9.4, 4.2 Hz, 5b-H),
7.27ꢀ7.39 (5H, m, H-arom), 9.55 (1H, d, J = 0.9 Hz, CHO). 13C
NMR (100 MHz, CDCl3): 20.5 (CH3), 42.2 (CH2), 52.2 (CH3, ester),
55.5 (CH2, Bn), 68.5 (3-C), 79.0 (5-CH), 127.4 (CH, Ph), 128.2
(CH ꢁ 2, Ph), 128.4 (CH ꢁ 2, Ph), 137.7 (Cq, Ph), 172.0 (CO), 204.2
(CHO). HRMS (DCI+NH3CH4): m/z Calcd for C14H18NO4: 264.1236
[M+H]+. Found: 264.1239.
3,5-endo-3b: 1H NMR (400 MHz, CDCl3): 1.50 (3H, s, 3
2.42 (1H, dd, J = 12.9, 10.0 Hz, 4 -H), 2.96 (1H, dd, J = 12.9,
3.5 Hz, 4b-H), 3.74 (3H, s, CH3), 3.77 (1H, d, J = 14.6 Hz, H-Bn),
a-H3),
4.2.5. (E)-N-(1-Methoxy-1-oxopropan-2-ylidene)-1,1-diphenyl-
methanamine oxide 1e
a
1H NMR (400 MHz, CDCl3): 2.30 (3H, s, CH3), 3.83 (3H, s, CH3),
7.30–7.38 (10H, m, H-arom), 8.16 (1H, s, CH). 13C NMR (100 MHz,
CDCl3): 15.6 (CH3), 52.7 (CH3), 76.8 (CH), 128. 2, 128.4, 129.0,
137.5 (C ꢁ 3), 163.2 (CO).
3.81 (1H, d, J = 14.6 Hz, H-Bn), 4.30 (1H, dd, J = 10.0, 3.5 Hz, 5a-
H), 7.27ꢀ7.42 (5H, m, H-arom), 9.60 (1H, s, CHO). 13C NMR
(100 MHz, CDCl3): 18.5 (CH3), 43.4 (CH2), 52.4 (CH3, ester), 55.6
(CH2, Bn), 68.3 (3-C), 79.0 (5-CH), 127.4 (CH, Ph), 128.37 (CH ꢁ 2,
Ph), 128.41 (CH ꢁ 2, Ph), 137.6 (Cq, Ph), 172.3 (CO), 203.4 (CHO).
4.2.6. (E)-N-(1-Ethoxy-1-oxopropan-2-ylidene)-1,1-diphenyl-
methanamine oxide 1f
Following the procedure of 1d. Purification by column chroma-
tography (cyclohexane/EtOAc = 9:1) gave a colorless oil (146 mg,
60%). IR: 3063, 2029, 1703, 1702, 1515, 1495, 1453, 1293, 1137.
4.3.3. rac-Methyl 2-benzhydryl-5-formyl-3-(2-methoxy-2-oxo-
ethyl)isoxazolidine-3-carboxylate 3c
Column chromatography (cyclohexane/EtOAc = 9:1) gave 58%
combined yield of exo-3c and endo-3c as a pale yellow oil. IR:

1676
K. B. Selim et al. / Tetrahedron: Asymmetry 23 (2012) 1670–1677
2952, 1737, 1453, 1242. HRMS (EI): m/z Calcd for C22H24NO6:
398.1605 [M+H]+. Found: 398.1596.
before E-crotonaldehyde 2b (0.08 mL, 1.0 mmol) was added, fol-
lowed by the addition of 2b (4 ꢁ 0.06 ml, 0.75 mmol over 24 h
intervals) over the course of 5 days. The reaction mixture was
passed through a small plug of silica gel, washed with EtOAc, and
concentrated in vacuo to give a crude oil. The conversion and dia-
stereoselectivity were determined by 1H NMR and GC analyses of
the crude to be 99% and dr 96:4, respectively. Purification by col-
umn chromatography (cyclohexane/EtAc = 9:1) gave 4b (54.6 mg,
75% combined yield) with 95% ee for exo-4b as a colorless oil:
3,5-exo-3c: 1H NMR (400 MHz, CDCl3): 2.72 (1H, d, J = 15.8 Hz,
H-ester), 2.88 (1H, d, J = 15.8 Hz, H-ester), 2.93 (1H, dd, J = 13.4,
10.0 Hz, 4a-H), 3.16 (1H, dd, J = 13.6, 4.0 Hz, 4b-H), 3.41 (3H, s,
CH3-ester), 3.64 (3H, s, CH3-ester), 4.27 (1H, ddd, J = 10.0, 4.0,
1.2 Hz, 5b-H), 5.10 (1H, s, H-arom), 7.21ꢀ7.49 (10H, m, H-arom),
9.83 (1H, d, J = 1.2 Hz, a-CHO).
3,5-endo-3c: 1H NMR (400 MHz, CDCl3): 2.25 (1H, d, J = 16.4 Hz,
H-ester), 2.43 (1H, d, J = 16.4 Hz, H-ester), 2.49 (1H, dd, J = 13.2,
½
a 2D0
ꢃ
¼ ꢀ82:8 (c 0.57, CH2Cl2). IR: 2981, 1724, 1642, 1497, 1455,
4.4 Hz, 4
CH3-ester), 3.67 (3H, s, CH3-ester), 4.37 (1H, ddd, J = 9.8, 4.4,
0.8 Hz, 5
a-H), 3.34 (1H, dd, J = 13.2, 9.6 Hz, 4b-H), 3.57 (3H, s,
1380, 1228, 1146. 1H NMR (400 MHz, CDCl3): 1.33 (3H, d,
J = 6.2 Hz, 5b-CH3), 1.35 (3H, t, J = 7.1 Hz, CH3-ester), 1.47 (3H, s,
3a-CH3), 3.48 (1H, dd, J = 6.4, 2.9 Hz, 4b-H), 3.87 (1H, d,
J = 14.9 Hz, H-Bn), 3.97 (1H, d, J = 14.9 Hz, H-Bn), 4.27 (1H, dq,
a
-H), 4.93 (1H, s, H-arom), 7.21ꢀ7.49 (10H, m, H-arom),
9.82 (1H, d, J = 0.8 Hz, b-CHO).
J = 10.8, 7.1 Hz, CH2-ester), 4.29 (1H, dq, J = 10.8, 7.1 Hz, CH2-ester),
4.3.4. rac-Methyl 2-benzyl-4-formyl-3-(2-methoxy-2-oxoethyl)-
5-methylisoxazolidine-3-carboxylate 4a
4.49 (1H, p, J = 6.2 Hz, 5
7.32 (2H, td, J = 7.1, 1.6 Hz, Harom), 7.37 (2H, dd, J = 7.3, 1.6 Hz,
H-arom), 9.82 (1H, d, J = 2.9 Hz,
-CHO). 13C NMR (100 MHz,
CDCl3): 14.3 (CH3, ester), 16.5 (3-CH3), 18.6 (5-CH3), 55.0 (CH2Ph),
61.8 (CH2), 66.4 (4-CH), 72.0 (3-C), 72.2 (5-CH), 127.2, 128.2, 128.3,
137.8 (C), 171.2 (CO), 200.0 (CHO). HRMS (DCI+NH3CH4): m/z Calcd
for C16H22NO4: 292.1549 [M+H]+. Found: 292.1549.
a-H), 7.25 (1H, tt, J = 6.5, 1.6 Hz, H-arom),
Column chromatography (cyclohexane/EtOAc = 9:1) gave 43%
combined yield of exo-4a and endo-4a as a pale yellow oil. IR:
2954, 1731, 1496, 1435, 1221, 1119. HRMS (EI): m/z Calcd for
a
C
17H22NO6: 336.1447 [M+H]+. Found: 336.1440.
3,4-exo-4a: 1H NMR (400 MHz, CDCl3): 1.38 (3H, d, J = 6.2 Hz,
5b-CH3), 2.87 (1H, d, J = 17.4 Hz, H-ester), 3.17 (1H, d, J = 17.4 Hz,
H-ester), 3.63 (1H, d, J = 14.4 Hz, -H-Bn), 3.67 (3H, s, -CH3-ester),
3.83 (1H, dd, J = 5.2, 2.4 Hz, 4b-H), 3.84 (3H, s, b-CH3-ester), 3.97
(1H, d, J = 14.4 Hz, b-H-Bn), 4.34 (1H, td, J = 13.4, 6.2 Hz, 5 -H),
-CHO). 13C
The enantioselectivity was determined by chiral HPLC analysis
after reduction of exo-4b with NaBH4 to the corresponding alcohol,
Chiralpack A-SH, isooctane/i-PrOH = 97:3, 1 mL/min, 254 nm;
retention times (min): 19.0 (minor) and 22.3 (major) for exo-4b.
a
a
a
7.26ꢀ7.33 (5H, m, H-arom), 9.80 (1H, d, J = 2.4 Hz,
a
NMR (100 MHz, CDCl3): 17.8 (5-CH3), 35.9 (CH2, ester), 52.2 (CH3,
ester), 52.6 (CH3, ester), 55.6 (CH2, Bn), 64.6 (4-CH), 73.2 (3-C),
74.0 (5-C), 127.4, 128.1, 128.3, 128.3, 170.1 (CO, ester), 170.8
(CO, ester), 199.4 (CHO).
4.4.2. (3S,4S,5R)-Ethyl 2-benzyl-4-formyl-3,5-dimethylisoxazo-
lidine-3-carboxylate 3,4-endo-4b
1H NMR (400 MHz, CDCl3): 1.29 (3H, t, J = 7.2 Hz, CH3-ester),
1.36 (3H, d, J = 6.4 Hz, 5a-CH3), 1.62 (3H, s, 3a-CH3), 2.73 (1H,
3,4-endo-4a: 1H NMR (400 MHz, CDCl3): 1.33 (3H, d, J = 6.2 Hz,
dd, J = 6.8, 1.7 Hz, 4 -H), 3.84 (1H, d, J = 14.6 Hz, H-Bn), 3.98 (1H,
a
5
a
-CH3), 2.86 (1H, d, J = 16.4 Hz,
1.0 Hz, 4 -H), 3.24 (1H, d, J = 16.4 Hz, b-H- ester), 3.71 (3H, s,
CH3-ester), 3.73 (1H, d, J = 14.4 Hz, -H-Bn), 3.78 (3H, s, CH3-ester),
a
-H-ester), 3.07 (1H, dd, J = 6.4,
d, J = 14.6 Hz, H-Bn), 4.24 (1H, q, J = 7.2 Hz, CH2-ester), 4.47 (1H,
p, J = 6.4 Hz, 5b-H), 7.25 (1H, tt, J = 6.5, 1.6 Hz, H-arom), 7.32 (2H,
td, J = 7.1, 1.6 Hz, H-arom), 7.37 (2H, dd, J = 7.3, 1.6 Hz, H-arom),
9.74 (1H, d, J = 1.7 Hz, b-CHO). 13C NMR (100 MHz, CDCl3): 14.2
(CH3, ester), 19.8 (3-CH3), 21.2 (5-CH3), 55.0 (CH2Ph), 61.7 (CH2),
70.8 (4-CH), 72.7 (3-C), 72.9 (5-CH), 127.1, 128.16, 128.25, 137.8
(C), 170.3 (CO), 197.7 (CHO). HRMS (DCI+NH3CH4): m/z Calcd for
a
a
3.97 (1H, d, J = 14.4 Hz, b-H-Bn), 4.58 (1H, q, J = 6.2 Hz, 5b-H),
7.26ꢀ7.33 (5H, m, H-arom), 9.85 (1H, d, J = 1.2 Hz, b-CHO). 13C
NMR (100 MHz, CDCl3): 21.0 (5-CH3), 38.8 (CH2, ester), 52.3 (CH3,
ester), 52.7 (CH3, ester), 55.2 (CH2, Bn), 69.5 (4-CH), 73.0 (3-C),
73.3 (5-C), 128.1, 128.3, 128.3, 128.4, 168.8 (CO, ester), 171.0
(CO, ester), 197.9 (CHO).
C
16H22NO4: 292.1549 [M+H]+. Found: 292.1549.
4.4.3. (3R,4S,5R)-Ethyl 2-benzhydryl-4-formyl-3,5-dimethylis-
oxazolidine-3-carboxylate 3,4-exo-4d (Table 2, entry 2)
In a 10 mL test tube, catalyst I (14.5 mg, 0.025 mmol), 1f
4.3.5. rac-Methyl 2-benzhydryl-4-formyl-3,5-dimethylisoxazol-
idine-3-carboxylate 4c
Column chromatography (cyclohexane/EtOAc = 9:1) gave 65%
combined yield of exo-4c and endo-4c as a pale yellow oil.
3,4-exo-4c: IR: 2926, 1725, 1453, 1238, 1135. 1H NMR
(400 MHz, CDCl3): 1.24 (3H, s, 3-CH3), 1.35 (3H, d, J = 6.0 Hz, 5b-
CH3), 3.52 (3H, s, CH3-ester), 3.62 (1H, dd, J = 6.0, 2.0 Hz, 4b-H),
(74.3 mg, 0.25 mmol), and water (13 ll, 0.75 mmol) were charged
and suspended in CH3NO2 (1 mL). The mixture was cooled to 4 °C
and stirred for 10 min before the addition of a solution of triflic
acid (2 ll, 0.0225 mmol) in CH3NO2 (0.1 ml). E-Crotonaldehyde
2b (0.08 mL, 1.0 mmol) was then added, followed by the addition
of 2b (2 ꢁ 0.06 ml, 0.75 mmol over 24 h intervals) over the course
of 3 days. The reaction mixture was passed through a small plug of
silica gel, washed with EtOAc, and concentrated in vacuo to give a
crude oil. The conversion and diastereoselectivity were determined
by 1H NMR and GC analyses of the crude to be 100% and dr 95:5,
respectively. Purification by column chromatography (cyclohex-
ane/EtAc = 19:1–9:1) gave 4d (78.6 mg, 85% combined yield) with
63% ee for exo-4d and 43% ee for endo-4d as a pale yellow oil.
4.52 (1H, q, J = 6.0 Hz, 5
J = 6.8, 1.6 Hz, H-arom), 7.22ꢀ7.27 (4H, m, H-arom), 7.44 (4H, td,
J = 7.2, 1.6 Hz, H-arom), 9.75 (1H, d, J = 2.0 Hz,
-CHO). 13C NMR
a-H), 5.08 (1H, s, CH-Ph2), 7.16 (2H, tq,
a
(100 MHz, CDCl3): 16.1 (3-CH3), 19.6 (5-CH3), 52.6 (CH3, ester),
69.3 (4-C), 70.1 (CH-Ph2), 71.7 (5-C), 72.4 (3-Cq), 127.2, 127.4,
127.8, 128.1, 128.3, 140.9, 141.6, 172.1 (CO), 199.1 (CHO). HRMS
(EI): m/z Calcd for C21H24NO4: 354.1705 [M+H]+. Found: 354.1705.
4.4. Typical procedure for the organocatalytic enantioselective
1,3-DC reactions
3,4-exo-4d ½a 2D0
¼ þ2:9 (c 0.85, CH2Cl2). IR: 2980, 2930, 1725,
ꢃ
1493, 1454, 1236, 1028. 1H NMR (400 MHz, CDCl3): 1.20 (3H, s,
3-CH3), 1.23 (3H, t, J = 7.1 Hz, CH3-ester), 1.33 (3H, d, J = 6.1, 5b-
CH3), 3.61 (1H, dd, J = 6.2, 2.4 Hz, 4b-H), 3.91 (1H, dq, J = 10.8,
7.1 Hz, CH2, ester), 3.98 (1H, dq, J = 10.8, 7.1 Hz, CH2, ester), 4.52
4.4.1. (3R,4S,5R)-Ethyl 2-benzyl-4-formyl-3,5-dimethylis-
oxazolidine-3-carboxylate 3,4-exo-4b (Table 2, entry 10)
In a 10 mL test tube, catalyst II (6.4 mg, 0.025 mmol) and 1d
(55.3 mg, 0.25 mmol) were charged and suspended in CH3NO2
(1 mL). The mixture was cooled to ꢀ10 °C and stirred for 10 min
(1H, p, J = 6.1 Hz, 5
1.3 Hz, H-arom), 7.22–7.27 (4H, m, H-arom), 7.45 (4H, td, J = 7.0,
1.4 Hz, H-arom), 9.77 (1H, d, J = 2.4 Hz,
-CHO). 13C NMR
a-H), 5.12 (1H, s, CH-Ph2), 7.16 (2H, tq, J = 6.5,
a

K. B. Selim et al. / Tetrahedron: Asymmetry 23 (2012) 1670–1677
1677
(100 MHz, CDCl3): 13.9 (CH3, ester), 16.4 (3-CH3), 19.3 (5-CH3),
References
61.7 (CH2, ester), 69.0 (4-CH), 70.0 (CH-Ph2), 71.7 (5-CH), 72.5
(3-C), 127.2, 127.3, 127.9, 128.0, 128.21, 128.23, 141.2, 141.5,
171.6 (CO), 199.4 (CHO). HRMS (DCI+NH3CH4): m/z Calcd for
1. For recent reviews, see: (a) Martin, J. N.; Jones, R. C. F. In Synthetic Applications
of 1,3-Dipolar Cycloaddition Chemistry Toward Heterocycles and Natural Products;
Padwa, A., Pearson, W. H., Eds.; Wiley and Sons: Hoboken, NJ, 2003; p 1.
Chapter 1; (b) Gothelf, K. V. In Cycloaddition Reactions in Organic Synthesis;
Kobayashi, S., Jørgensen, K. A., Eds.; Wiley-VCH: Weinheim, Germany, 2002; p
211. Chapter 6; (c) Kanemasa, S. In Cycloaddition Reactions in Organic Synthesis;
Kobayashi, S., Jørgensen, K. A., Eds.; Wiley-VCH: Weinheim, Germany, 2002; p
249. Chapter 7.
2. For selected reviews on asymmetric 1,3-DC reactions, see: (a) Frederickson, M.
Tetrahedron 1997, 53, 403–425; (b) Gothelf, K. V.; Jørgensen, K. A. Chem. Rev.
1998, 98, 863–909; (c) Gothelf, K. V.; Jørgensen, K. A. Chem. Commun. 2000,
1449–1458; (d) Karlsson, S.; Högberg, H.-E. Org. Prep. Proced. Int. 2001, 33, 103–
172; (e) Pellissier, H. Tetrahedron 2007, 63, 3235–3285; (f) Stanley, L. M.; Sibi,
M. P. Chem. Rev. 2008, 108, 2887–2902; (g) Nguyen, T. B.; Martel, A.; Gaulon, C.;
Dhal, R.; Dujardin, G. Org. Prep. Proced. Int. 2010, 42, 387–431; (h) Nájera, C.;
Sansano, J. M.; Yus, M. J. Braz. Chem. Soc. 2010, 21, 377–412; (i) Kissane, M.;
Maguire, A. R. Chem. Soc. Rev. 2010, 39, 845–883; (j) Pellissier, H. Tetrahedron
2012, 68, 2197–2232; (k) Xinga, Y.; Wang, N.-X. Coord. Chem. Rev. 2012, 256,
938–952; (l) Nguyen, T. B.; Martel, A.; Gaulon, C.; Dhal, R.; Dujardin, G. Org.
Prep. Proced. Int. 2012, 44, 1–81.
3. Jen, W. S.; Wiener, J. J. M.; MacMillan, D. W. C. J. Am. Chem. Soc. 2000, 122,
9874–9875.
4. (a) Karlsson, S.; Högberg, H.-E. Tetrahedron: Asymmetry 2002, 13, 923–926; (b)
Karlsson, S.; Högberg, H.-E. Eur. J. Org. Chem. 2003, 15, 2782–2791; (c) Chow, S.
S.; Nevalainen, M.; Evans, C. A.; Johannes, C. W. Tetrahedron Lett. 2007, 48, 277–
280.
5. Lemay, M.; Trant, J.; Ogilvie, W. W. Tetrahedron 2007, 63, 11644–11655.
6. Weselin´ ski, Ł.; Ste˛pniak, P.; Jurczak, J. Synlett 2009, 2261–2264.
7. Puglisi, A.; Benaglia, M.; Cinquini, M.; Cozzi, F.; Celentano, G. Eur. J. Org. Chem.
2004, 3, 567–573.
8. Weselin´ ski, Ł.; Słyk, E.; Jurczak, J. Tetrahedron Lett. 2011, 52, 381–384.
9. (a) Inouye, Y.; Watanabe, Y.; Takahashi, S.; Kakisawa, H. Bull. Chem. Soc. Jpn.
1979, 52, 3763–3764; (b) Inouye, Y.; Hara, J.; Kakisawa, H. Chem. Lett. 1980, 9,
1407–1410.
C
22H26NO4: 368.1862 [M+H]+. Found: 368.1860.
The enantioselectivity was determined by chiral HPLC analysis
after reduction of 4d with NaBH4 to the corresponding alcohol,
Phenomenex Lux 5u cellulose-1, isooctane/i-PrOH = 95:5, 0.5 mL/
min, 254 nm; retention times (min): 23.4 (minor) and 28.0 (major)
for exo-4d and 22.0 (minor) and 26.8 (major) for endo-4d.
4.5. (3R,4S,5R)-Ethyl 2-benzyl-3,5-dimethyl-4-(((S)-1-phenyl-
ethyl)carbamoyl) isoxazolidine-3-carboxylate 5
To a solution of exo-4b (87.4 mg, 0.3 mmol, 90% ee) in a mixture
of t-BuOH (12 mL) and H2O (6 mL) were added NaH2PO4 (144 mg,
1.2 mmol) and 2-methyl-2-butene (12 mL) successively at room
temperature. After stirring at room temperature for 20 min, the
reaction mixture was treated with NaClO2 (163 mg, 1.8 mmol)
and stirred vigorously at room temperature for 1 h. The reaction
mixture was quenched with a saturated NH4Cl solution (15 mL),
and then the aqueous layer was extracted with EtOAc
(3 ꢁ 30 mL). The combined organic layers were washed with H2O
(25 mL) and brine (25 mL), dried over MgSO4, filtered, and concen-
trated in vacuo. The crude carboxylic acid was then dissolved in
THF (5 mL) under nitrogen. (S)-(ꢀ)-a-Methyl benzylamine
(41.5 mg, 0.343 mmol), DIPEA (0.16 mL, 0.9 mmol), EDCꢂHCl
(63.3 mg, 0.33 mmol), and HOBt (45 mg, 0.33 mmol) were then
added. After stirring at room temperature for 20 h, the reaction
mixture was diluted with CH2Cl2 (50 mL), washed with a 1 M HCl
solution (10 mL) and the aqueous layer was extracted with CH2Cl2
(3 ꢁ 20 mL). The combined organic layers were washed with satd
NaHCO3 (10 ml), brine (10 mL), dried over Na2SO4, filtered, and
concentrated in vacuo. The resulting crude was purified by column
chromatography (cyclohexane/EtOAc = 9:1–6:1) to afford com-
10. Winterfeldt, E.; Krohn, W.; Stracke, H. Chem. Ber. 1969, 102, 2346–2361.
11. (a) Nguyen, T. B.; Martel, A.; Dhal, R.; Dujardin, G. Org. Lett. 2008, 10, 4493–
4496; (b) Nguyen, T. B.; Beauseigneur, A.; Martel, A.; Dhal, R.; Laurent, M.;
Dujardin, G. J. Org. Chem. 2010, 75, 611–620.
12. For reviews on the formation of quaternary stereocenters, see: (a) Trost, B. M.;
Jiang, C. Synthesis 2006, 3, 369–396; (b) Christoffers, J.; Baro, A. Adv. Synth.
Catal. 2005, 347, 1473–1482; (c)Quaternary Stereocenters: Challenges and
Solutions for Organic Synthesis; Christoffers, J., Baro, A., Eds.; Wiley-VCH:
Weinheim, Germany, 2005; (d) Douglas, C. J.; Overman, L. E. Proc. Natl. Acad.
Sci. U.S.A. 2004, 101, 5363–5367.
pound 5 (91 mg, 74%) as white solid: mp 82ꢀ83 °C. ½a D20
¼ ꢀ40:3
ꢃ
13. Weselin´ ski, Ł.; Kalinowska, E.; Jurczak, J. Tetrahedron: Asymmetry 2012, 23,
(c 0.53, CH2Cl2). IR: 3286, 2360, 1720, 1638, 1539, 1222, 1122. 1H
NMR (400 MHz, CDCl3): 1.28 (3H, d, J = 6.2 Hz, 5b-CH3), 1.32 (3H,
264–270.
14. Tamura, O.; Kanoh, A.; Yamashita, M.; Ishibashi, H. Tetrahedron 2004, 60, 9997–
10003.
15. In Ref. 13, performing the reaction on a 2 mmol scale afforded the adduct exo-
4b in 18–22% yield with 84% ee.
16. Geometry optimisations on catalyst ammonium ions and iminium ions derived
from the imidazolidinone catalyst and E-crotonaldehyde were performed using
Gaussian 09 at B3LYP/6-311+G(d,p) level using the IEFPCM model for
nitromethane. Thermochemical data were obtained by frequency calculations
performed at the same level.
t, J = 7.1 Hz, CH3-ester), 1.43 (3H, s,
3a-CH3), 1.48 (3H, d,
J = 6.9 Hz, CH3), 3.45 (1H, d, J = 6.9 Hz, 4b-H), 4.00 (1H, d,
J = 14.4 Hz, H-Bn), 4.12 (1H, d, J = 14.4 Hz, H-Bn), 4.22 (1H, dq,
J = 10.8, 7.1 Hz, CH2-ester), 4.26 (1H, dq, J = 10.8, 7.1 Hz, CH2-ester),
4.62 (1H, p, J = 6.2 Hz, 5a-H), 5.14 (1H, p, J = 6.9 Hz, CHPh), 6.60
(1H, d, J = 7.8 Hz, NH), 7.22–7.38 (10H, m, H-arom). 13C NMR
(100 MHz, CDCl3): 14.1 (CH3, ester), 15.9 (3-CH3), 19.4 (5-CH3),
21.8 (CH3), 49.0 (CH), 55.6 (CH2), 61.97 (CH2, ester), 62.03 (4-CH),
72.8 (C), 75.4 (5-CH), 126.2, 127.0, 127.5, 128.2, 128.3, 128.8,
138.2 (C), 142.9 (C), 168.6 (CO, amide), 173.1 (CO, ester). HRMS
(DCI+NH3CH4): m/z Calcd for C24H31N2O4: 411.2284 [M+H]+.
Found: 411.2304.
17. (a) Brazier, J. B.; Evans, G.; Gibbs, T. J. K.; Coles, S. J.; Hursthouse, M. B.; Platts, J.
A.; Tomkinson, N. C. O. Org. Lett. 2009, 11, 133–136; (b) Gordillo, R.; Houk, K. N.
ˆ
J. Am. Chem. Soc. 2006, 128, 3543–3553; (c) Seebach, D.; Gilmour, R.; Groselj, U.;
Deniau, G.; Sparr, C.; Ebert, M.-O.; Beck, A. K.; MacCusker, L. B.; Šišak, D.;
Uchimaru, T. Helv. Chim. Acta 2010, 93, 603–634.
18. In an attempt to obtain a suitable crystal for X-ray studies, reductive amination
was performed using (ꢀ)-(S)-(
a)-phenylethylamine to afford the amine as an
oily product in 91% yield.
19. Crystallographic data for the structure reported herein have been deposited
with the Cambridge Crystallographic Data Center as supplementary
publication no. CCDC 905436. Each cell unit contains a pair of four different
conformers which have the same absolute stereochemistry of the stereogenic
centers. Only one conformer is shown in Figure 4.
Acknowledgment
Financial support of this study by Grants from ANR (BS07-005-
01) is gratefully acknowledged.
20. Kowalczyk, B.; Tarnowska, A.; Weselin´ ski, Ł; Jurczak, J. Synlett 2005, 2373–
2375.