The asymmetric organocatalytic 1,3-dipolar cycloaddition of alkyl pyruvate-derived nitrones and α,β-unsaturated aldehydes

Article abstract of DOI:10.1016/j.tetasy.2012.02.003

The catalytic asymmetric 1,3-dipolar cycloaddition of pyruvate-derived nitrones to α,β-unsaturated aldehydes was investigated in the presence of various chiral amines. Highly functionalized isoxazolidines containing a quaternary stereocenter were obtained in moderate yields with up to 92% ee. To the best of our knowledge, this is the first example of an enantioselective 1,3-dipolar cycloaddition of ketonitrones. The model product was subsequently transformed into a 2-pyrrolidinone derivative in two steps.

Full text of DOI:10.1016/j.tetasy.2012.02.003

Tetrahedron: Asymmetry 23 (2012) 264–270
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Tetrahedron: Asymmetry
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The asymmetric organocatalytic 1,3-dipolar cycloaddition of alkyl
pyruvate-derived nitrones and
a,b-unsaturated aldehydes
a
b
a,b,
⇑
´
Łukasz Weselinski , Eleonora Kalinowska , Janusz Jurczak
a Department of Chemistry, University of Warsaw, Pasteura 1, 02–093 Warsaw, Poland
b 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 19 January 2012
Accepted 3 February 2012
The catalytic asymmetric 1,3-dipolar cycloaddition of pyruvate-derived nitrones to a,b-unsaturated alde-
hydes was investigated in the presence of various chiral amines. Highly functionalized isoxazolidines
containing a quaternary stereocenter were obtained in moderate yields with up to 92% ee. To the best
of our knowledge, this is the first example of an enantioselective 1,3-dipolar cycloaddition of ketonitro-
nes. The model product was subsequently transformed into a 2-pyrrolidinone derivative in two steps.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
according to a literature procedure, in diastereomerically pure
E-form (as established by NMR data).8 At the beginning, we inves-
The 1,3-dipolar cycloaddition of nitrones remains a powerful
method for the construction of nitrogen-containing heterocyclic
products.1 Among existing asymmetric variants of this reaction,2
the use of chiral amines as organocatalysts for the activation of
tigated its reaction with (E)-crotonaldehyde 2b under standard
conditions used by us5 in the presence of hybrid diamine salt
C1ꢀTfOH (Scheme 1, Chart 1). The results are presented in Table 1.
We obtained isoxazolidine 3a in a 75% yield as the sole product;
the relative configuration was determined by a NOESY experiment.
After its reduction with NaBH4, the corresponding alcohol 4a was
isolated with a moderate 47% ee value (Table 1, entry 1). We also
investigated the reaction of other pyruvate-derived nitrones 1b-d
with (E)-crotonaldehyde 2b, since the stereoselective formation of
quaternary stereogenic centers is often strongly substrate-depen-
dent.6 However, in all cases the ee’s were in the range of 35–53%
ee (entries 2–4), with the highest value obtained for nitrone 1b
a
,b-unsaturated aldehydes as dipolarophiles is one of the latest
developments in this area.3 In our laboratory, we have developed
a new family of organocatalysts, known as hybrid diamines,4 and
showed that their efficiency in the reaction of aromatic nitrones
with
a,b-unsaturated aldehydes was comparable to the efficiency
of the catalysts reported by other groups.3g Recently, we have also
reported the first highly enantioselective 1,3-dipolar cycloaddition
of alkyl glyoxylate-derived nitrones to (E)-crotonaldehyde,
catalyzed by hybrid diamines and demonstrated the application
of the cycloadducts obtained in the synthesis of functionalized
2-pyrrolidinones.5 In continuation of our efforts to expand upon
the utility of hybrid diamines as organocatalysts, we became inter-
ested in the 1,3-dipolar cycloaddition reaction of pyruvate-derived
nitrones. These substrates would lead to isoxazolidines possessing
a quaternary stereogenic center, the stereocontrolled formation of
which is often a challenging task.6 According to a literature search,
this task has not been realized by means of enantioselective
catalysis with ketonitrones as dipoles. Some examples of non-
asymmetric 1,3-dipolar cycloaddition of pyruvate-derived nitrones
have been previously reported.7,8
(entry 2). The nitrones with a larger alkyl group at the
a-position
(e.g., i-Pr nitrone, see Experimental section) were not reactive.
The use of other hybrid diamines C2 and C3 (Chart 1) as organocat-
alysts led to similar results, indicating the small influence of the
side chain of the amino acid part of the catalyst on the stereochem-
ical outcome of the reaction (entries 5 and 6). Similarly, a low ee
was obtained with the non-hybrid biphenyl analogue of the phen-
ylalanine catalyst (33% ee).5 Attempts at the modification of previ-
ously established experimental conditions were also unsuccessful,
for example, reactions conducted in toluene and acetonitrile led to
the product 3a in 30% and 41% ee, respectively. The combination of
nitromethane as the solvent and trifluoromethanesulfonic (triflic)
acid as the co-catalyst was found to be crucial for the highest level
of enantioselectivity, which was still not synthetically useful.
Subsequently, we investigated the reaction of nitrone 1b with var-
2. Results and discussion
ious a,b-unsaturated aldehydes (Scheme 1). Using 20 mol % of the
We obtained the model compound (E)-N-(1-methoxy-1-oxo-
propan-2-ylidene)(phenyl)methanamine oxide 1a in a good yield
hybrid catalyst C1⁄TfOH in the reaction with (E)-pentenal 2c led
after 168 h at 4 °C to a single diastereomer of isoxazolidine 3f in
a 60% yield and with low enantioselectivity (17% ee, Table 1,
entry 7). The reaction with acrolein 2a under similar conditions
⇑
Corresponding author. Tel.: +48 22 632 05 78; fax: +48 22 632 66 81.
E-mail address: jurczak@icho.edu.pl (J. Jurczak).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2012.02.003

´
265
Łukasz Weselinski et al. / Tetrahedron: Asymmetry 23 (2012) 264–270
Z
Z
Z
Z
O-
R2
Z
N
O
N
O
N
O
N
O
N+
i
ii
+
R1O2C
R2
R1O2C
R2
R1O2C
+
R2
R1O2C
R2
+
R1O2C
O
O
O
HO
HO
1
2
3
4
ent-4
ent-3
1a: Z=Bn, R1=Me; b: Z=Bn, R1=Et, c: Z=R1=Bn, d: Z=R1=Me
2
: R =H; : R2=Me; c: R2=Et
2a
b
3a: Z=Bn, R1=R2=Me; b: Z=Bn, R1=Et, R2=Me; c: Z=Bn, R1=Bn, R2=Me; d: Z=R1=R2=Me; e: Z=Bn, R1=Et, R2=H; f: Z=Bn, R1=R2=Et
Z=Bn, R =R =Me; Z=Bn, R =Et, R =Me; : Z=Bn, R =Bn, R =Me; d: Z=R =R =Me; e: Z=Bn, R =Et, R =H; f: Z=Bn, R =R =Et
1
2
1
2
1
2
1
2
1
2
1
2
4a:
b:
c
Scheme 1. Reagents: (i) catalyst (10–20 mol %), MeNO2; (ii) NaBH4, MeOH.
R
O
O
NH2
Ph
Ph
OR
N
C1: R=Bn
C2: R=Me
C3: R=i-Bu
N
N
R1
R2
NH
NH
CO2Me
N
H
N
H
N
H
Bn
N
H
N
O
H
C4: R=TMS
C5: R=TBDMS
C9: R1=R2=Me
C10: R1=H, R2=t-Bu
C6
C7
C8
NH2
O
R
Chart 1.
Table 1
We replaced the TMS moiety with a larger and less sensitive
TBDMS group of the organocatalyst C5.11 However, this catalyst
was also unstable under our conditions, when strong acid cocata-
lysts (TfOH or p-TsOH) were used. However, when we conducted
the reaction at room temperature for 3 days in the presence of
10 mol % of TFA salt of C5, we were able to isolate 33% of 3b, with
81% ee. Other pyrrolidine derivatives C6–C8 were less successful,
and we obtained products 3b in only moderate ee (28% ee for both
C6 and C7 and 40% ee for C8).
The results of the reaction of nitrones 1a–d with (E)-crotonaldehydes 2a–c, catalyzed
by hybrid diamines C1–C3a
Entry Catalyst
Nitrone Aldehyde Time (h) Yield of 3b (%) eec (%)
1
2
3
4
5
6
7
8
C1*TfOH 1a
2b
2b
2b
2b
2b
2b
2c
2a
72
72
75 47
81 53d
81 35
52 41
44 45
36 47
C1*TfOH 1b
C1*TfOH 1c
C1*TfOH 1d
C2*TfOH 1b
C3*TfOH 1b
C1*TfOH 1b
C1*TfOH 1b
72
72
72
72
168
80
Previously, we have shown that the imidazolidinone hydrochlo-
ride salt C9⁄HCl was not an efficient catalyst for the reaction of gly-
oxylate-derived nitrones.5 When we applied this catalyst for the
model reaction of nitrone 1b with (E)-crotonaldehyde 2b, we found
that after 22 h the isolated yield of 3b was 43%, while the enanti-
oselectivity was high even at 20 °C (43%, 89% ee, respectively).
Other experiments revealed that among the salts tested, similar
results could be obtained with some other salts (H2SO4, Table 2,
entry 4 or with p-TsOH, entry 8). The results of the experiments
with the use of different salts of C9 are summarized in Table 2.
Analysis of the crude reaction mixtures revealed the presence of
large amounts of ethyl pyruvate, as an outcome of the hydrolysis of
nitrone, in addition to other side-products, which resulted in a
decrease in the yield of isoxazolidine 3b. It is noteworthy that only
small amounts of these side-products were detected when the
hybrid primary diamines C1–C3 were used as catalysts. We
decided to continue our experiments with the commercially avail-
able catalyst C9ꢀHCl. The results are summarized in Table 3.
The highest yields and ee’s were determined for nitrone 1b
(43%, 89% ee, Table 2, entry 1). For nitrones 1a and 1c, 60–70% con-
versions were obtained after 24 h at 20 °C, and the ee values were
determined to be 86% and 82%, respectively. The optimal value of
the catalyst was 10 mol % (entries 1–3). We found that decreasing
the temperature led to slightly enhanced enantioselectivities with
similar yields, albeit with prolonged reaction times (entry 2). The
presence of water is required for high conversions and enantiose-
lectivities (entries 1, 2 as compared with entries 4,5). We also ob-
served a decrease in the enantioselectivity, when the reaction was
performed in the absence of water for a prolonged time (entry 5).
This may be attributed to the reversibility of the 1,3-dipolar cyclo-
addition reaction in the presence of the imidazolidinone catalyst,
as shown recently by Tomkinson for the same catalysis of the
Diels–Alder reaction.12 Experiments with other solvents (CH2Cl2,
60 17
e
—
45
a
Reaction conditions: 1 (0.25 mmol), 2 (1 mmol, then 0.75 mmol after every
24 h), catalyst [0.025 mmol for (E)-crotonaldehyde, 0.05 for other dipolarophiles],
acid co-catalyst [0.0225 mmol, for (E)-crotonaldehyde, 0.045 for other dipolaro-
philes], MeNO2 (1 ml), H2O (0.75 mmol), 4 °C.
b
Isolated yield after flash chromatography.
Determined by chiral HPLC analysis of the corresponding alcohol 4.
42% ee with p-TsOH as the co-catalyst.
An inseparable mixture of products was obtained.
c
d
e
(80 h, 4 °C) led to a mixture of products, among which the 3,4-
trans-isoxazolidine 3e was identified after reduction to the corre-
sponding alcohol 4e, and its enantioselectivity estimated by HPLC
as being up to 45% ee (Table 1, entry 8). Among the other dipolaro-
philes, cinnamaldehyde or methyl oxobutenoate were not reactive.
Although good yields of the single diastereomeric products
were obtained, our catalysts were not efficient enough in the case
of ketonitrones as dipoles. Therefore, we decided to investigate the
reaction with other catalysts, that were successfully applied for the
1,3-dipolar cycloaddition of nitrones with acyclic dipolarophiles.
Among the most efficient and readily available are the diphenyl
prolinol silyl ether C4 triflic acid salt, developed by Nevalainen3e
and MacMillan’s imidazolidinones of type C6 and C7 (Chart 1).9
We obtained the
L-prolinol-derivative C4ꢀTfOH according to the
described procedure.3e When we performed the reaction of ethyl
pyruvate-derived nitrone 1b with (E)-crotonaldehyde 2b in toluene
or wet nitromethane at 20 °C, only trace amounts of product for-
mation were observed. In wet nitromethane at 4 °C, the conversion
of the nitrone levelled up to 40%, and the enantioselectivity of the
corresponding alcohol 4b was determined to be 85% ee. However,
this result was not reproducible, which may be attributed to cata-
lyst deactivation by the silyl ether hydrolysis under the conditions
used.10 Therefore, we turned our attention to more stable catalysts.

´
Łukasz Weselinski et al. / Tetrahedron: Asymmetry 23 (2012) 264–270
266
Table 2
The results of the reaction of nitrone 1b with (E)-crotonaldehyde 2b, catalyzed by the different salts of C9a
Entry
Acid co-catalyst
Conversion of 1bb (%)
Isolated yield of 3bc (%)
eed (%)
1
2
3
4
5
6
7
8
9
HCl
TfOH
HClO4
H2SO4
CH2ClCO2H
CHCl2CO2H
CCl3CO2H
p-TsOH
HBr
>90
>60
>70
>90
>40
>70
>40
>70
>60
43
—
—
34
—
—
—
—
—
89
58
56
91
67
89
86
86e
64
a
Reaction conditions: 1 (0.25 mmol), 2b (1 mmol, then 0.75 mmol after every 24 h), catalyst salt (0.025 mmol), MeNO2 (1 ml), H2O (0.75 mmol), 22 h,
20 °C.
b
Determined after 1H NMR integration.
Isolated yield after flash chromatography. Due to the similar Rf values of product 3b with nitrone 1b, which led to difficulties in its purification, the
c
yield was determined for conversions higher than 90%.
d
Determined by chiral HPLC analysis of the alcohol 4b.
44% yield and 83% ee for the reaction conducted at 4 °C for 68 h in the presence of 20 mol % of the catalyst.
e
Table 3
The results of the reaction of nitrone 1b with (E)-crotonaldehyde 2b, catalyzed by the hydrochloride salt of C9a
Entry
Time (h)
Temp (°C)
Conversion of 1bb (%)
Isolated yield of 3bc (%)
eed (%)
1
2
3
4
5
22
69
48
22
94
20
4
20
20
20
>90
>90
60
60
50
43
45
—
—
—
89
92
79e
79f
69f
a
Reaction conditions: 1 (0.25 mmol), 2b (1 mmol, then 0.75 mmol after every 24 h), C9ꢀHCl (0.025 mmol), acid cocatalyst (0.0225 mmol), MeNO2 (1 ml),
H2O (0.75 mmol).
b
Determined after 1H NMR integration.
Isolated yield after flash chromatography. Due to the similar Rf values of product 3b with nitrone 1b, which led to difficulties in its purification, the
c
yield was determined for conversions higher than 90%.
d
Determined by chiral HPLC analysis of the alcohol 4b.
Reaction conducted in the presence of 5 mol % catalyst.
Reaction conducted in anhydrous solvent.
e
f
THF, CH3CN, EtOAc and DMF) instead of nitromethane were
unsuccessful.
sponding tosylohydrazones and also confirmed by similar analysis
of the derived lactam 6 (Scheme 2).5 These compounds differ from
3 only at the stereogenic center at C-3, but the relative configura-
tion of all centers, 3,4-trans,4,5-trans, is retained. In case of prod-
ucts 3, we were unable to prepare their crystalline derivatives,
suitable for similar analysis. However, the functionalized 2-pyrro-
lidinone ent-8 was prepared according to our described procedure5
from the obtained cycloadduct ent-3b (84% ee) (Scheme 3). The
relative configuration of compound ent-8 was confirmed by X-ray
crystallographic analysis (Fig. 1).13 As described previously in the
synthesis of 6,5 no change in the stereochemistry was observed
during this transformation. Therefore, we assumed that the config-
uration of the products of type 3 was also (3R,4S,5R).
Next, we performed several experiments with the second gen-
eration MacMillan’s imidazolidinone C10, which was previously
shown to be more efficient for many reactions of enals, especially
those involving sterically encumbered substrates, by an increased
formation rate of the iminium ion intermediate.9 In our case, we
obtained both lower conversions and ee’s (both values in the range
of 50–60%). The C10 trans-isomer did not promote the reaction, but
instead the nearly quantitative hydrolysis of nitrone 1b was ob-
served. With an increased amount of catalyst C10 (20 mol %), high
conversion was achieved at 20 °C after 24 h, and the product was
isolated in a 50% yield with a moderate enantiomeric excess of
54%. Therefore, we did not investigate this catalyst further.
For synthetic purposes, we performed experiments with nitrone
1b and (E)-crotonaldehyde 2b on a larger (2 mmol) scale with imi-
dazolidinone C9 hydrochloride salt as the catalyst. However, we
found that scaling up the reaction resulted in a further decrease
of the yield, with product 3b being isolated in 18–22% yield. A de-
crease in the ee was also observed (84% ee as compared with 89%
ee for 0.25 mmol scale, see Table 3, entry 1). This is also due to the
sensitivity of nitrone, since the use of such substrates often influ-
ences the reaction progress, when performed on a preparative
scale.
OH
Bn
BocHN
O
H
N
O
EtO2C
N
O
Me
6
5
Scheme 2. Transformation of the glyoxylate-derived cycloadduct 5 into 6.5
As mentioned earlier, we previously described the preparation
of cycloadducts of type 5 (Scheme 2), from the reaction of glyoxy-
late-derived nitrones with E-crotonaldehyde, catalyzed by hybrid
diamine C1.5 Their (3R,4S,5R) configuration was unambiguously
determined from X-ray crystallographic analysis of the corre-
3. Conclusion
We have reported the first enantioselective organocatalytic
1,3-dipolar cycloaddition of ketonitrones to
hydes, leading to products containing a quaternary stereocenter.
a,b-unsaturated alde-

´
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Łukasz Weselinski et al. / Tetrahedron: Asymmetry 23 (2012) 264–270
OH
OH
Bn
Bn
Bn
Bn
BocHN
O
H
BocHN
O
H
N
O
N
O
N
O
N
O
i
ii
+
EtO2C
+
EtO2C
EtO2C
+
EtO2C
N
N
O
O
MeHN
MeHN
Me
Me
7
8
ent-
3b
ent-
7
ent-3b
8
Scheme 3. Reagents and conditions: (i) MeNH2/EtOH, NaBH3CN, AcOH, MeOH, 2 h, rt, 50%; H2, Pd/C, Pd(OH)2/C, MeOH, 120 h, rt, then Boc2O, Et3N, 24 h, rt, 29%.
1H and 13C NMR spectra were recorded in CDCl3 using a Varian
Unity plus spectrometer (200 MHz and 50 MHz, respectively).
Chemical shifts of the 1H NMR and 13C NMR are reported as d val-
ues relative to TMS as the internal standards. The following abbre-
viations are used to indicate the multiplicity: s—singlet; d—
doublet; t—triplet; q—quartet; m—multiplet; b—broad signal. Mass
spectra (LRMS and HRMS) were recorded on a Quattro LC Micro-
mass instrument using the ESI technique. Enantiomeric ratios of
the products were determined using an HPLC method. HPLC anal-
ysis was performed on a Knauer Smartline series HPLC fitted with
the diode-array detector (DAD) and ChiracelÒ AS-H (250 ꢁ 4.6 mm,
5
l
m) column eluted with 2-propanol (3–5%) in hexane.
4.2. General procedure for synthesis of catalysts C1–C3
To the solution of N-Cbz or N-Boc protected -amino acid
a
Figure 1. ORTEP projection of the N–Me pyrrolidinone ent-8.
(7.74 mmol, 2.2 equiv) in dry THF (40 ml), Et3N (1.08 ml,
7.74 mmol; 2.2 equiv) was added and the mixture was cooled to
0 °C. A solution of ethyl chloroformate (0.74 ml, 7.74 mmol, 2.2
equiv) in dry THF (5 ml) was added over 15 min and the mixture
was stirred for 30 min at the same temperature. Then a solution
of (S)-BINAM (1 g; 3.52 mmol; 1 equiv) in dry THF (50 ml) was
added over 15 min at 0 °C and the mixture was stirred overnight
with warming up. The reaction mixture was subsequently refluxed
for 3 h and after cooling, the precipitate of Et3NꢀHCl was filtered off
and washed with THF. The filtrate was concentrated under reduced
pressure and the residue was purified by column chromatography
on silica gel to afford the catalyst precursor in 60% (from
N-Cbz-Phe-OH), 80% (from N-Boc-Ala-OH), and 42% (from
N-Boc-Leu-OH) yields. Cbz protecting group was removed by cata-
lytic hydrogenation (balloon) in MeOH over 48 h in the presence of
Pd/C. After filtration of the catalyst and evaporation of the solvent,
pure C1 was obtained in a 92% yield as a colorless foam. The Boc
protecting group was removed by stirring the compounds in a
1:1 mixture of CH2Cl2/TFA (20–30 equiv) for several hours. After
dilution with water and extraction of the impurities with an organ-
ic solvent, which was discarded, the remaining mixture was alkal-
ized with 20% NaOH and extracted three times with CH2Cl2. The
combined extracts were dried over MgSO4. After evaporation of
the solvent, pure products C2–C3 were obtained in 74–85% yield
as colorless foams.
Although it is possible to obtain high level of asymmetric induction
with commercially available organocatalysts (up to 92% ee), the
reaction yields are not satisfactory. Hybrid catalysts, developed
by us, led only to products with low to moderate enantioselectiv-
ity, but the nitrones were stable in their presence, which resulted
in good yields of the products. These results show that the solution
of the problem possibly lies in the careful optimization of the cat-
alyst’s structure which paves the way for further investigation of
this reaction. Although the nitrone scope as demonstrated is lim-
ited to pyruvic acid derivatives, examples of the reaction with
three various dipolarophiles were shown. Moreover, the possibility
of transformation of the obtained cycloadduct into a functionalized
c-lactam, containing a quaternary stereogenic center was success-
fully demonstrated.
4. Experimental section
4.1. General information
Commercially available chemicals were used as received, unless
otherwise indicated. THF was dried over sodium in the presence of
benzophenone and nitromethane was distilled over CaH2.
Crotonaldehyde, acrolein, and pentenal were freshly distilled
before use. (S)-1,10-Binaphthyl-2,20-diamine [(S)-BINAM],14
N-benzylhydroxylamine hydrochloride,15 benzyl pyruvate,16 ethyl
3-methyl-2-oxobutyrate,17 and methyl oxobutenoate18 were
prepared according to the literature procedures. Nitrones were
4.2.1. (2S,20S)-N,N0-((S)-1,10-Binaphthyl-2,20-diyl)bis(2-amino-3-
phenylpropanamide) C1
Colorless foam. [
a
]
D = ꢂ129 (c 0.7, CH2Cl2). 1H NMR (200 MHz,
prepared from the corresponding
a-ketoesters and N-alkylhydr-
CDCl3): d = 9.24 (br s, 2H, ArNH), 8.42–7.93 (m, 6H, ArH), 7.50–
7.02 (m, 16H, ArH), 3.51–3.49 (AB/2, J = 3.6, 2H, CH2), 3.46–3.44
(AB/2, J = 3.6, 2H, CH2), 3.20–3.18 (AB/2, J = 3.6, 2H, CH2), 3.13–
oxylamines according to the described procedure.8 Catalysts
C4ꢀTfOH,3e C5,11 C6ꢀHCl,19 C7, and C8ꢀ2HCl20 were prepared
according to the literature procedures. Analytical TLC was carried
out on commercial 0.25 mm plates coated with 0.25 mm of Merck
Kieselgel 60 F254. Preparative flash silica chromatography was
performed using Merck Kieselgel 60 (230–400 mesh). Optical rota-
tions were measured on a Perkin-Elmer 241 polarimeter at 20 °C.
All melting points were measured on a Köfler Boëtius apparatus.
3.11 (AB/2, J = 3.6, 2H, CH2), 2.37–2.25 (m, 2H, C H), 1.18 (b, 4H,
a
NH2). 13C NMR (50 MHz, CDCl3): d = 173.7, 137.6, 134.9, 132.8,
131.4, 129.6, 129.2, 128.8, 128.5, 127.1, 127.0, 125.8, 125.4,
122.1, 121.4, 57.0, 40.5. LR ESI-MS: m/z: 579.3 for [M+H]+, 601.3
for [M+Na]+. HR ESI-MS: m/z: calcd for [C38H34N4O2+H]+:
579.2760, found: 579.2758.

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Łukasz Weselinski et al. / Tetrahedron: Asymmetry 23 (2012) 264–270
268
4.2.2. (2S,20S)-N,N0-((S)-1,10-Binaphthyl-2,20-diyl)bis(2-aminopro-
panamide) C2
4.4.5. (E)-N-(1-Ethoxy-3-methyl-1-oxobutan-2-ylidene)(phenyl)-
methanamine oxide (i-Pr nitrone)
Colorless powder, mp 166–168 °C (CH2Cl2). [
a]
D = ꢂ39.0 (c 0.7,
CH2Cl2). 1H NMR (200 MHz, CDCl3): d = 9.22 (br s, 2H, ArNH),
8.44–7.92 (m, 6H, ArH), 7.48–7.15 (m, 6H, ArH), 3.38–3.28 (q,
Bn
O-
N+
J = 7, 2H, C H), 1.14–1.10 (d, J = 7, 10H, overlapped CH3 and NH2).
a
EtO2C
13C NMR (50 MHz, CDCl3): d = 175.0, 135.0, 132.8, 131.3, 129.6,
128.5, 127.0, 125.8, 125.4, 122.0, 121.2, 51.3, 21.3. LR ESI-MS: m/
z: 427.2 for [M+H]+, 449.2 for [M+H]+. HR ESI-MS: m/z: calcd for
[C26H26N4O2+H]+: 427.2134, found: 427.2134; calcd for
[C26H26N4O2+Na]+: 449.1953, found: 449.1960.
On a 5 mmol scale from ethyl 3-methyl-2-oxobutyrate and N-
benzylhydroxylamine hydrochloride, after purification by flash
chromatography (AcOEt/hexane 10%), a colorless oil was obtained
(0.4 g, 32%). 1H NMR (200 MHz, CDCl3): d = 7.43–7.32 (m, 5H, ArH),
5.24 (s, 2H, NCH2), 4.35–4.24 (q, J = 7, 2H, OCH2CH3), 3.61–3.48
(septet, J = 7, 1H, CH), 1.35–1.28 (t, J = 7, 3H, OCH2CH3), 1.18–1.14
(d, J = 7, 6H, CH(CH3)2). 13C NMR (50 MHz, CDCl3): d = 163.7
(C@O), 133.8 (Cq), 128.8 (CH), 128.7 (CH), 67.3 (NCH2), 62.2
(OCH2), 28.1 (CH), 17.9 (2xCH3), 14.2 (CH3).
4.2.3. (2S,20S)-N,N0-((S)-1,10-Binaphthyl-2,20-diyl)bis(2-amino-4-
methylpentanamide) C3
Colorless foam. [
CDCl3): d = 9.26 (br s, 2H, ArNH), 8.43–7.92 (m, 6H, ArH), 7.48–7.15
a
]
D = ꢂ23.0 (c 0.7, CH2Cl2). 1H NMR (200 MHz,
(m, 6H, ArH), 3.30–3.28 (AB/2, J = 3.8, 2H, C H), 3.25–3.23 (AB/2,
a
J = 3.8, 2H, C H), 1.52–1.50 (AB/2, J = 3.4, 2H, CH2), 1.48–1.46 (AB/
a
4.5. General procedure for the 1,3-dipolar cycloaddition
2, J = 3.4, 2H, CH2), 1.14–1.09 (m, 2H, CH(CH3)2), 0.86–0.84 (d,
J = 6, 6H, CH3), 0.83–0.81 (d, J = 6, 6H, CH3). 13C NMR (50 MHz,
CDCl3): d = 175.0, 135.0, 132.9, 131.3, 129.5, 128.5, 127.0, 125.8,
125.3, 122.1, 121.2, 54.1, 43.8, 25.0, 23.5, 21.5. LR ESI-MS: m/z:
511.3 for [M+H]+, 533.3 for [M+Na]+. HR ESI-MS: m/z: calcd for
[C32H38N4O2+H]+: 511.3073, found: 511.3072; calcd for
[C32H38N4O2+Na]+: 533.2892, found: 533.2892.
A solution of nitrone 1 (0.25 mmol, 1 equiv) in nitromethane
(1 mL) was placed in a vial, water (13 ll, 0.75 mmol, 3 equiv) and
the catalyst (0.025 mmol, 0.1 equiv) were added and the resulting
mixture stirred at the indicated temperature for few minutes. Next,
freshly distilled dipolarophile was added (1 mmol, 4 equiv, fol-
lowed by 3 equiv after every 24 h) and the mixture was left to stir
for the indicated time, after which it was filtered through a silica
gel plug rinsing with EtOAc, and concentrated. The crude mixture
was subjected to 1H NMR analysis for determination of the conver-
sion of nitrone. After flash chromatography on silica gel (15–30%
EtOAc-hexane), product 3 was isolated as an oil in 34–81% yield.
4.3. Nitrones 1a–d
4.4.1. (E)-N-(1-Methoxy-1-oxopropan-2-ylidene)(phenyl)meth-
anamine oxide 1a
On a 10 mmol scale from methyl pyruvate and N-benzylhydr-
oxylamine hydrochloride, after purification by flash chromatogra-
phy (AcOEt/hexane 15%), a colorless oil was obtained (1.5 g, 77%).
The spectroscopic data were identical to the literature.8
4.5.1. (3R,4S,5R)-2-Benzyl-4-formyl-3-methoxycarbonyl-3,5-
dimethylisoxazolidine 3a
Colorless oil, [
a]
D = ꢂ42.1 (c 1, CH2Cl2) for 47% ee. 1H NMR
(200 MHz, CDCl3): d = 9.84–9.82 (d, J = 3, 1H, CHO), 7.36–7.32 (m,
5H, ArH), 4.56–4.44 (dq, J1 = 6.2, J2 = 12.4, 1H, NOCHCH3), 4.00–
3.93 (d, J = 14.4, 1H, NCH2Ph), 3.86–3.77 (d, J = 14.4, 1H, NCH2Ph),
3.82 (s, 3H, OCH3), 3.51–3.47 (dd, J1 = 3, J2 = 6.4, 1H, CHCHO),
1.48 (s, 3H, OCH3), 1.35–1.32 (d, J = 6, 3H, NOCHCH3). 13C NMR
(50 MHz, CDCl3): d = 200.1 (CHO), 172.0 (C@O), 137.8 (Cq), 128.5
(CH), 128.4 (CH), 127.4 (CH), 72.42 (NOCH), 72.36 (Cq), 66.6
(CHCHO), 55.2 (NCH2Ph), 52.8 (OCH3), 18.7 (CH3), 16.8 (CH3). LR
ESI-MS: m/z: 300.1 for [M+Na]+, 332.1 for [M+MeOH+Na]+. HR
ESI-MS: m/z: calcd for [C16H23NO5+Na]+: 332.1474, found:
332.1438.
4.4.2. (E)-N-(1-Ethoxy-1-oxopropan-2-ylidene)(phenyl)meth-
anamine oxide 1b
On a 6 mmol scale from ethyl pyruvate and N-benzylhydroxyl-
amine hydrochloride, after purification by flash chromatography
(AcOEt/hexane 15%), a colorless oil was obtained (1.25 g, 87%). 1H
NMR (200 MHz, CDCl3): d = 7.52–7.48 (m, 2H, ArH), 7.35–7.32 (m,
3H, ArH), 5.69 (s, 2H, NCH2Ph), 4.33–4.23 (q, J = 7, 2H, OCH2CH3),
2.25 (s, 3H, CH3), 1.36–1.29 (t, J = 7, 3H, OCH2CH3). 13C NMR
(50 MHz, CDCl3): d = 162.7 (C@O), 134.3 (Cq), 129.1 (CH), 128.7
(CH), 128.6 (CH), 67.3 (NCH2), 62.1 (OCH2), 15.5 (CH3), 14.3 (CH3).
4.4.3. (E)-N-(1-Benzyloxy-1-oxopropan-2-ylidene)(phenyl)meth-
anamine oxide 1c
On a 10 mmol scale from benzyl pyruvate and N-benzylhydr-
oxylamine hydrochloride, after purification by flash chromatogra-
4.5.2. (3R,4S,5R)-2-Benzyl-3-ethoxycarbonyl-4-formyl-3,5-
dimethylisoxazolidine 3b
Colorless oil, [
a]
D = ꢂ48.9 (c 1, CH2Cl2) for 53% ee. 1H NMR
(200 MHz, CDCl3): d = 9.83–9.81 (d, J = 3, 1H, CHO), 7.39–7.24 (m,
5H, ArH), 4.56–4.44 (dq, J1 = 6.2, J2 = 12.4, 1H, NOCHCH3), 4.34–
4.23 (q, J = 7, 2H, OCH2CH3), 4.02–3.94 (d, J = 14.4, 1H, NCH2Ph),
3.89–3.82 (d, J = 14.4, 1H, NCH2Ph), 3.51–3.47 (dd, J1 = 3, J2 = 6.4,
1H, CHCHO), 1.48 (s, 3H, CH3), 1.38–1.32 (m, 6H, overlapped
NOCHCH3 and OCH2CH3). 13C NMR (50 MHz, CDCl3): d = 200.2
(CHO), 171.4 (C@O), 137.9 (Cq), 128.5 (CH), 128.4 (CH), 127.4
(CH), 72.4 (NOCH), 72.2 (Cq), 66.6 (CHCHO), 62.0 (OCH2), 55.2
(NCH2Ph), 18.7 (CH3), 16.7 (CH3), 14.7 (OCH2CH3). LR ESI-MS: m/
z: 346.2 for [M+MeOH+Na]+. HR ESI-MS: m/z: calcd for
[C17H25NO5+Na]+: 346.1630, found: 346.1596.
phy (AcOEt/hexane 15%),
a colorless oil was obtained, that
solidified upon standing in the refrigerator (1.6 g, 60%). 1H NMR
(200 MHz, CDCl3): d = 7.49–7.44 (m, 2H, ArH), 7.38–7.30 (m, 8H,
ArH), 5.69 (s, 2H, NCH2Ph), 5.25 (s, 2H, OCH2), 2.26 (s, 3H, CH3).
13C NMR (50 MHz, CDCl3): d = 162.5 (C@O), 135.2 (Cq), 134.2
(Cq), 129.2 (CH), 128.9 (CH), 128.84 (CH), 128.76 (CH), 128.7
(CH), 128.5 (CH), 67.7 (CH2), 67.4 (CH2), 15.6 (CH3).
4.4.4. (E)-N-(1-Methoxy-1-oxopropan-2-ylidene)methanamine
oxide 1d
On 7 mmol scale methyl pyruvate and N-methylhydroxylamine
hydrochloride, after purification by flash chromatography (AcOEt/
hexane 15%) colorless oil was obtained (0.5 g, 53%). 1H NMR
(200 MHz, CDCl3): d = 4.19 (s, 2H, NCH3), 3.84 (s, 3H, OCH3), 2.25
(s, 3H, CH3). 13C NMR (50 MHz, CDCl3): d = 163.2 (C@O), 53.5
(CH3), 52.8 (CH3), 15.1 (CH3).
4.5.3. (3R,4S,5R)-2-Benzyl-3-benzyloxycarbonyl-4-formyl-3,5-
dimethylisoxazolidine 3c
Colorless oil, [
a
]
D = ꢂ33.4 (c 1, CH2Cl2) for 35% ee. 1H NMR
(200 MHz, CDCl3): d = 9.80–9.79 (d, J = 3, 1H, CHO), 7.38–7.25 (m,

´
269
Łukasz Weselinski et al. / Tetrahedron: Asymmetry 23 (2012) 264–270
10H, ArH), 5.25 (s, 2H, OCH2Ph), 4.54–4.42 (dq, J1 = 6.2, J2 = 12.4,
1H, NOCHCH3), 3.98–3.91 (d, J = 14.4, 1H, NCH2Ph), 3.83–3.76 (d,
J = 14.4, 1H, NCH2Ph), 3.50–3.45 (dd, J1 = 3, J2 = 6.4, 1H, CHCHO),
1.48 (s, 3H, CH3), 1.31–1.28 (d, J = 6, 3H, NOCHCH3). 13C NMR
(50 MHz, CDCl3): d = 200.1 (CHO), 171.3 (C@O), 137.9 (Cq), 135.4
(Cq), 128.9 (CH), 128.8 (CH), 128.6 (CH), 128.5 (CH), 128.4 (CH),
127.4 (CH), 72.4 (NOCH), 72.3 (Cq), 67.7 (OCH2Ph), 66.5 (CHCHO),
55.2 (NCH2Ph), 18.6 (CH3), 16.8 (CH3). LR ESI-MS: m/z: 408.2 for
[M+MeOH+Na]+. HR ESI-MS: m/z: calcd for [C22H27NO5+Na]+:
408.1787, found: 408.1798.
CDCl3): d = 7.39–7.23 (m, 5H, ArH), 4.29–4.18 (q, J = 7, 2H,
OCH2CH3), 3.94 (s, 2H, NCH2Ph), 3.90–3.83 (m, 1H, NOCHCH3),
3.80–3.67 (m, 2H, CH2OH), 2.87–2.77 (dt, J1 = 6.6, J2 = 13.2, 1H,
CHCH2OH), 2.4 (br s, 1H, OH), 1.43 (s, 3H, CH3), 1.35–1.28 (m, 6H,
overlapped NOCHCH3 and OCH2CH3). 13C NMR (50 MHz, CDCl3):
d = 173.2 (C@O), 138.5 (Cq), 128.4 (CH), 127.2 (CH), 76.1 (NOCH),
71.6 (Cq), 61.8 (CH2), 61.6 (CH2), 56.9 (CHCH2OH), 55.4 (NCH2Ph),
19.6 (CH3), 15.0 (CH3), 14.4 (CH3). HPLC conditions: DAICEL CHIR-
ALPAKÒ AS-H, 2-propanol/hexane 3%, 1 ml/min., 35 °C, UV
215 nm, tminor = 12.0 min., tmajor = 15.4 min. (major for C1–C5 and
C8–C10).
4.5.4. (3R,4S,5R)-4-Formyl-3-methoxycarbonyl-2,3,5-trimethyl-
isoxazolidine 3d
4.6.3. (3R,4R,5R)-2-Benzyl-3-benzyloxycarbonyl-4-hydroxy-
Colorless oil, [
a
]
D = ꢂ36.0 (c 1.5, CH2Cl2) for 41% ee. 1H NMR
methyl-3,5-dimethylisoxazolidine 4c
Colorless oil, [
a]
D = ꢂ30.7 (c 1.35, CH2Cl2) for 35% ee. 1H NMR
(200 MHz, CDCl3): d = 9.82–9.81 (d, J = 3, 1H, CHO), 4.67–4.54 (dq,
J1 = 6.2, J2 = 12.4, 1H, NOCHCH3), 3.82 (s, 3H, OCH3), 3.57–3.53
(dd, J1 = 2.4, J2 = 6.6, 1H, CHCHO), 2.63 (s, 3H, NCH3), 1.42 (s, 3H,
CH3), 1.37–1.32 (d, J = 6.2, 3H, NOCHCH3). 13C NMR (50 MHz,
CDCl3): d = 200.0 (CHO), 172.3 (C@O), 72.6 (NOCH), 66.1 (CHCHO),
53.0 (OCH3), 38.8 (NCH3), 18.8 (CH3), 16.4 (CH3).
(200 MHz, CDCl3): d = 7.38–7.24 (m, 10H, ArH), 5.21 (s, OCH2Ph),
3.98–3.91 (d, J = 14.6, 1H, NCH2Ph), 3.92–3.80 (m, 1H, NOCHCH3),
3.89–3.82 (d, J = 14.6, 1H, NCH2Ph), 3.80–3.67 (m, 2H, CH2OH),
2.88–2.78 (dt, J1 = 6.2, J2 = 12.4, 1H, CHCH2OH), 2.2 (br s, 1H, OH),
1.44 (s, 3H, CH3), 1.32–1.29 (d, 3H, NOCHCH3). 13C NMR (50 MHz,
CDCl3): d = 172.9 (C@O), 138.4 (Cq), 135.7 (Cq), 128.8 (CH), 128.6
(CH), 128.5 (CH), 128.4 (CH), 127.2 (CH), 76.2 (NOCH), 71.7 (Cq),
67.2 (OCH2Ph), 61.8 (CH2OH), 57.0 (CHCH2OH), 55.3 (NCH2Ph),
19.5 (CH3), 15.0 (CH3). HPLC conditions: DAICEL CHIRALPAKÒ AS-
H, 2-propanol/hexane 3%, 1 ml/min., 35 °C, UV 215 nm, tmi-
nor = 17.5 min., tmajor = 23.6 min. (major for C1 and C9).
4.5.5. (3R,4S,5R)-2-Benzyl-3-ethoxycarbonyl-5-ethyl-4-formyl-
3-methylisoxazolidine 3f
Colorless oil, [a]
D = +7.9 (c = 1.1, CH2Cl2) for 17% ee. 1H NMR
(200 MHz, CDCl3): d = 9.83–9.82 (d, J = 2.6, 1H, CHO), 7.39–7.24
(m, 5H, ArH), 4.35–4.22 (m, 3H, overlapped OCH2CH3 and
NOCHCH2CH3), 3.94 (s, 2H, NCH2Ph), 3.56–3.52 (dd, J1 = 3, J2 = 6.2,
1H, CHCHO), 1.80–1.54 (m, 2H, NOCHCH2CH3), 1.46 (s, 3H, CH3),
1.37–1.30 (t, J = 7, 3H, OCH2CH3), 0.92–0.84 (t, J = 7.4, 3H, NOCH-
CH2CH3). 13C NMR (50 MHz, CDCl3): d = 200.2 (CHO), 171.5
(C@O), 138.0 (Cq), 128.5 (CH), 128.4 (CH), 127.3 (CH), 77.5 (NOCH),
72.1 (Cq), 65.2 (CHCHO), 62.0 (OCH2), 55.2 (NCH2Ph), 26.6
(NOCHCH2CH3), 16.3 (CH3), 14.4 (CH3), 10.3 (CH3).
4.6.4. (3R,4R,5R)-2-Benzyl-3-methoxycarbonyl-3,5-dimethyl-4-
tosyloxymethylisoxazolidine 4d-tosylate
Colorless oil, [
a]
D = ꢂ27.0 (c 0.3, CH2Cl2) for 41% ee. 1H NMR
(200 MHz, CDCl3): d = 7.81–7.77 (d, J = 8.2, 2H, ArH), 7.39–7.35 (d,
J = 8.2, 2H, ArH), 4.20–4.12 (d, J1 = 7, J2 = 9.8, 1H, CH2OTs), 4.03–
3.94 (d, J1 = 7.6, J2 = 9.8, 1H, CH2OTs), 3.77–3.71 (m, 1H, CHCH3),
3.73 (s, 3H, OCH3), 2.99–2.88 (dt, J1 = 7.2, J2 = 14.4, 1H, CHCH2OTs),
2.56 (s, 3H, PhCH3), 2.46 (s, 3H, NCH3), 2.2 (br s, 1H, OH), 1.34–1.30
(d, J = 6.2, 3H, CHCH3), 1.19 (s, 3H, CH3). 13C NMR (50 MHz, CDCl3):
d = 172.0 (C@O), 145.4 (Cq), 132.7 (Cq), 130.2 (CH), 128.1 (CH), 76.5
(NOCH), 71.6 (Cq), 68.8 (CH2OTs), 53.6 (CHCH2OTs), 52.4 (OCH3),
38.3 (NCH3), 21.9 (CH3), 18.8 (CH3). HPLC conditions: DAICEL CHI-
RAL-PAKÒ AS-H, 2-propanol/hexane 5%, 1 ml/min., 35 °C, UV
215 nm, tmajor = 19.2 min. (major for C1), tminor = 21.8 min.
4.6. General procedure for reduction of the 1,3-dipolar cyclo-
addition products
Products 3 were reduced to the corresponding alcohols 4 with
1 equiv of NaBH4 in MeOH at 0 °C for 30 min. After aqueous
work-up, alcohols 4 were purified by flash chromatography on sil-
ica gel (30–40% EtOAc–hexane) and isolated in 60–70% yield. The
ee values of the alcohols were determined by chiral HPLC. In the
case of product 3d, the ee was determined from the corresponding
4d-tosylate, after reduction to alcohol 4d and its subsequent tosy-
lation (TsCl, Et3N, CH2Cl2, rt, overnight, then purification by chro-
matography on silica gel).
4.6.5. (3R,4R)-2-Benzyl-3-ethoxycarbonyl-4-hydroxymethyl-3-
methylisoxazolidine 4e
Colorless oil, could not be purified, 45% ee. 1H NMR (200 MHz,
CDCl3): d = 7.34–7.26 (m, 5H, ArH), 4.30–4.19 (q, J = 7.2, 2H,
OCH2CH3), 4.20–4.12 (dd, J1 = 7.6, J2 = 9, 1H, NOCH2), 4.00–3.93
(d, J = 14.4, 1H, NCH2Ph), 3.91–3.84 (d, J = 14.4, 1H, NCH2Ph),
3.78–3.75 (d, J = 6.2, 2H, CH2OH), 3.71–3.65 (dd, J1 = 5.8, J2 = 7.6,
1H, NOCH2), 3.29–3.16 (m, 1H, CHCH2OH), 2.7 (br s, 1H, OH),
1.48 (s, 3H, CH3), 1.36–1.29 (t, J = 7, 3H, OCH2CH3). 13C NMR
(50 MHz, CDCl3): d = 172.5 (C@O), 138.1 (Cq), 128.7 (CH), 128.5
(CH), 127.4 (CH), 71.0 (Cq), 68.5 (NOCH2), 62.0 (CH2), 61.8 (CH2),
55.6 (NCH2Ph), 50.1 (CHCH2OH), 14.6 (CH3), 14.4 (CH3). LR ESI-
MS: m/z: 302.1 for [M+ Na]+, 581.3 for [2 M+ Na]+. HR ESI-MS: m/
z: calcd for [C15H21NO4+Na]+: 302.1368, found: 330.1381. HPLC
conditions: DAICEL CHIRALPAKÒ AS-H, 2-propanol/hexane 3%,
1 ml/min., 35 °C, UV 215 nm, tminor = 20.7 min., tmajor = 24.4 min.
(major for C1).
4.6.1. (3R,4R,5R)-2-Benzyl-4-hydroxymethyl-3-methoxycarbonyl-
3,5-dimethylisoxazolidine 4a
Colorless oil, [
a
]
D = ꢂ42.6 (c 1, CH2Cl2) for 47% ee. 1H NMR
(200 MHz, CDCl3): d = 7.39–7.23 (m, 5H, ArH), 3.93–3.91 (d,
J = 3.8, 2H, CH2OH), 3.87–3.84 (m, 1H, NOCHCH3), 3.77 (br s, 5H,
overlapped NCH2Ph and OCH3), 2.68–2.55 (dt, J1 = 6.4, J2 = 12.8,
1H, CHCH2OH), 2.2 (br s, 1H, OH), 1.44 (s, 3H, CH3), 1.36–1.33 (d,
J = 6.2, 3H, NOCHCH3). 13C NMR (50 MHz, CDCl3): d = 174.0
(C@O), 138.4 (Cq), 128.4 (CH), 127.2 (CH), 76.1 (NOCH), 71.7
(Cq), 61.8 (CH2OH), 57.1 (CHCH2OH), 55.4 (NCH2Ph), 52.4 (OCH3),
19.6 (CH3), 15.0 (OCH3). HPLC conditions: DAICEL CHIRALPAKÒ
AS-H, 2-propanol/hexane 3%, 1 ml/min., 35 °C, UV 215 nm,
tminor = 15.4 min., tmajor = 18.1 min. (major for C1 and C9).
4.6.2. (3R,4R,5R)-2-Benzyl-3-ethoxycarbonyl-4-hydroxymethyl-
4.6.6. (3R,4R,5R)-2-Benzyl-3-ethoxycarbonyl-5-ethyl-4-hydroxy-
3,5-dimethylisoxazolidine 4b
methyl-3-methylisoxazolidine 4f
Colorless oil, [
(200 MHz, CDCl3): d = 7.36–7.25 (m, 5H, ArH), 4.28–4.17 (q, J = 7,
Colorless oil,
[
a]
D = ꢂ46.9 (c 1.05, CH2Cl2) for 47% ee,
a]
D = +4.5 (c 2.15, CH2Cl2) for 17% ee. 1H NMR
[
a]
D = ꢂ59.1° (c = 0.85, CHCl3) for 88% ee. 1H NMR (200 MHz,

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Łukasz Weselinski et al. / Tetrahedron: Asymmetry 23 (2012) 264–270
270
2H, OCH2CH3), 4.07–4.00 (d, J = 14.4, 1H, NCH2Ph), 3.96–3.88 (d,
J = 14.4, 1H, NCH2Ph), 3.80–3.58 (m, 3H, overlapped NOCHCH2CH3
and CH2OH), 2.93–2.84 (m, 1H, CHCH2OH), 2.4 (br s, 1H, OH), 1.78–
1.55 (m, 2H, NOCHCH2CH3), 1.46 (s, 3H, CH3), 1.35–1.28 (t, J = 7, 3H,
OCH2CH3), 0.95–0.87 (t, J = 7.4, 3H, NOCHCH2CH3). 13C NMR
(50 MHz, CDCl3): d = 173.4 (C@O), 138.5 (Cq), 128.5 (CH), 128.4
(CH), 127.1 (CH), 80.8 (NOCH), 71.7 (Cq), 61.9 (CH2), 61.7 (CH2),
55.6 (CHCH2OH), 55.2 (NCH2Ph), 27.6 (NOCHCH2CH3), 14.36
(CH3), 14.32 (CH3), 10.7 (CH3). LR ESI-MS: m/z: 330.2 for [M+
Na]+, 637.4 for [2 M+ Na]+. HR ESI-MS: m/z: calcd for [C17H25NO4+-
Na]+: 330.1681, found: 330.1670. HPLC conditions: DAICEL CHIR-
ALPAKÒ AS-H, 2-propanol/hexane 3%, 1 ml/min., 35 °C, UV
215 nm, tmajor = 9.6 min. (major for C1), tminor = 10.8 min.
Acknowledgment
Financial support from the Polish Ministry of Science and Higher
Education (Grant PBZ-KBN-126/T09/06) is gratefully acknowledged.
References
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312–331; For selected recent examples of natural product synthesis, see: (h)
Höck, S.; Borschberg, H.-J. Helv. Chim. Acta 2006, 89, 542–557; (i) Sánchez-
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G.; Metz, P. Angew. Chem., Int. Ed. 2011, 50, 3892–3894.
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M. Tetrahedron 1997, 53, 403–425; (d) Gothelf, K. V.; Jørgensen, K. A. Chem. Rev.
1998, 98, 863–910; (e) Gothelf, K. V.; Jørgensen, K. A. Chem. Commun. 2000,
1449–1458; (f) Karlsson, S.; Högberg, H.-E. Org. Prep. Proced. Int. 2001, 33, 103–
172; (g) Pellissier, H. Tetrahedron 2007, 63, 3235–3285; (h) Stanley, L. M.; Sibi,
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9874–9875; (b) Karlsson, S.; Högberg, H.-E. Tetrahedron: Asymmetry 2002, 13,
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Puglisi, A.; Benaglia, M.; Cinquini, M.; Cozzi, F.; Celentano, G. Eur. J. Org. Chem.
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Lewis acid catalysed 1,3-dipolar cycloadditions, see: (h) Nájera, C.; Sansano, J.
4.6.7. (3S,4R,5S)-4-(Aminomethyl)methyl-2-benzyl-3-ethoxy-
carbonyl-3-methylisoxazolidine ent-7
To a solution of aldehyde ent-3b (84% ee, obtained with
10 mol % of ent-C9ꢀHCl) (0.13 g, 0.45 mmol, 1 equiv) in 20 ml
MeOH, an 8.0 M solution of MeNH2/EtOH (1 ml, 15 equiv) was
added, followed by 1.64 ml of AcOH, until the pH was acidic. Then
NaBH3CN (28 mg, 1 equiv) was added in one portion and the solu-
tion was stirred for 2 h at rt. The mixture was then concentrated,
poured into 30 ml aq. NaHCO3 and the whole was extracted with
6x30 ml CH2Cl2; the combined extracts were dried over Na2SO4,
the solids were filtered off, and the solvent was removed. The
residual oil was purified by flash chromatography (MeOH/CH2Cl2
2–5%), to yield 70 mg (50%) of amine ent-7 as a slightly yellow
oil of satisfactory purity. 1H NMR (200 MHz, CDCl3): d = 7.40–
7.22 (m, 5H, ArH), 4.26–4.15 (q, J = 7.2, 2H, OCH2CH3), 3.97–3.90
(d, J = 14.6, 1H, NCH2Ph), 3.88–3.81 (d, J = 14.6, 1H, NCH2Ph),
3.84–3.78 (m, 1H, NOCHCH3), 2.79–2.76 (d, J = 6.4, 2H, CH2NHCH3),
2.73–2.63 (m, 1H, CHCH2NHCH3), 2.45 (s, 3H, NHCH3), 1.37 (s, 3H,
CH3), 1.37–1.34 (d, J = 6.2, 3H, NOCHCH3), 1.34–1.27 (t, J = 7.2, 3H,
OCH2CH3). 13C NMR (50 MHz, CDCl3): d = 172.9 (C@O), 138.6 (Cq),
128.4 (CH), 128.3 (CH), 127.1 (CH), 77.9 (NOCH), 71.7 (Cq), 61.3
(OCH2), 55.4 (NCH2Ph), 55.2 (CHCH2NHCH3), 51.9 (CHCH2NHCH3),
36.8 (NHCH3), 20.0 (CH3), 14.6 (CH3), 14.4 (CH3).
M.; Yus, M. J. Braz. Chem. Soc. 2010, 21, 377–412; For
organocatalytic cyclizations and cycloadditions, see: (i) Moyano, A.; Rios, R.
Chem. Rev. 2010, 111, 4703–4832.
a review on
´
4. Kowalczyk, B.; Tarnowska, A.; Weselinski, Ł.; Jurczak, J. Synlett 2005, 2372–
2375.
´
5. Weselinski, Ł.; Słyk, E.; Jurczak, J. Tetrahedron Lett. 2011, 52, 381–384.
6. (a)Quaternary Stereocenters: Challenges and Solutions for Organic Synthesis;
Christoffers, J., Baro, A., Eds.; Wiley-VCH: Weinheim, 2005; For selected
reviews, see: (b) Douglas, C. J.; Overman, L. E. Proc. Natl. Acad. Sci. U.S.A. 2004,
101, 5363–5367; (c) Trost, B. M.; Jiang, C. Synthesis 2006, 3, 369–396; (d) Cozzi,
P. G.; Hilgraf, R.; Zimmermann, N. Eur. J. Org. Chem. 2007, 5969–5994; (e) Bella,
M.; Gasperi, T. Synthesis 2009, 10, 1583–1614; (f) Hawner, C.; Alexakis, A. Chem.
Commun. 2010, 46, 7295–7306; (g) Das, J. P.; Marek, I. Chem. Commun. 2011, 47,
4593–4623.
7. Chiacchio, U.; Piperno, A.; Rescifina, A.; Romeo, G.; Uccella, N. Tetrahedron
1998, 54, 5695–5708.
8. Nguyen, T. B.; Beauseigneur, A.; Martel, A.; Dhal, R.; Laurent, M.; Dujardin, G. J.
Org. Chem. 2010, 75, 611–620.
9. For a review on the application of the imidazolidinone catalysts, see: Lelais, G.;
MacMillan, D. W. C. Aldrichim. Acta 2006, 39, 79–87.
10. No reaction was observed under the same conditions in the presence of the
salts of (S)-diphenyl-2-pyrrolidinemethanol as organocatalysts.
11. Hayashi, Y.; Gotoh, H.; Hayashi, T.; Shoji, M. Angew. Chem., Int. Ed. 2005, 44,
4212–4215.
4.6.8. tert-Butyl (3S,4R,10S)-[4-(1-hydroxyethyl)-1,3-dimethyl-2-
oxopyrrolidin-3-yl]-carbamate ent-8
Amine ent-7 (70 mg, 0.23 mmol, 1 equiv) was dissolved in
10 ml of MeOH, Pd/C and Pd(OH)2/C were added under an argon
atmosphere and the whole was stirred in an atmosphere of
hydrogen (balloon) for 120 h at rt. The catalysts were filtered
off, washed with methanol, and the filtrate was evaporated. The
oil obtained was redissolved in MeOH (3 ml), after which Boc2O
(61 mg, 0.27 mmol, 1.2 equiv) and Et3N (42 ll, 0.29 mmol,
1.3 equiv) were added and the whole mixture was stirred for
24 h at rt. The volatiles were then evaporated and the residue
was purified by flash chromatography (MeOH/CH2Cl2 3%),
12. Brazier, J. B.; Jones, K. M.; Platts, J. A.; Tomkinson, N. C. O. Angew. Chem., Int. Ed.
2011, 50, 1613–1616.
yielding 18 mg (29%) of
c-lactam ent-8 as a colorless solid.
13. CCDC-832691 contains the supplementary crystallographic data for compound
ent-8. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
14. Miyano, S.; Nawa, M.; Mori, A.; Hashimoto, H. Bull. Chem. Soc. Jpn. 1984, 57,
2171–2176.
15. Nguyen, T. B.; Martel, A.; Dhal, R.; Dujardin, G. Synthesis 2009, 18, 3174–3176.
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3902.
18. Satoh, T.; Hanaki, N.; Kuramochi, Y.; Inoue, Y.; Hosoya, K.; Sakai, K. Tetrahedron
2002, 58, 2533–2549.
Recrystallization from CH2Cl2/n-hexane afforded crystals (m.p.
173–175 °C), suitable for single crystal X-ray diffraction.
[a]
D = +24.0 (c 0.85, CHCl3). 1H NMR (200 MHz, CDCl3): d = 5.41
(br s, 1H, NH), 5.00 (br s, 1H, OH), 3.98–3.84 (m, 1H, CHOH),
3.30–3.21 (m, 1H, CH2), 2.89 (s, 3H, NCH3, overlapped with m,
1H, CH2, 2.89–2.80), 2.60–2.46 (m, 1H, CH), 1.43 (s, 9H,
C(CH3)3), 1.42 (S, 3H, CH3), 1.19–1.16 (d, J = 6, 3H, CHCH3). 13C
NMR (50 MHz, CDCl3): d = 175.2 (C@O), 156.6 (NHC@O), 80.9
(Cq (t-Bu)), 65.5 (CHOH), 60.0 (Cq), 51.8 (CHCH2), 48.8 (CH2),
30.4 (NCH3), 28.5 (C(CH3)3), 21.4 (CH3), 16.6 (CH3). LR ESI-MS:
m/z: 295.2 for [M+Na]+, 567.3 for [2 M+Na]+. HR ESI-MS: m/z:
calcd for [C13H24N2O4+Na]+: 295.1634, found: 295.1643.
19. Sparr, C.; Tanzer, E.-M.; Bachmann, J.; Gilmour, R. Synthesis 2010, 8, 1394–
1397.
20. De Costa, B. R.; Dominguez, C.; He, X.-s.; Williams, W.; Radesca, L.; Bowen, W. J.
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