The highly enantioselective 1,3-dipolar cycloaddition of alkyl glyoxylate-derived nitrones to E-crotonaldehyde catalyzed by hybrid diamines

Article abstract of DOI:10.1016/j.tetlet.2010.11.015

1,3-Dipolar cycloaddition of alkyl glyoxylate-derived nitrones to E-crotonaldehyde can be catalyzed by hybrid diamines, obtained from (S)-BINAM and l-α-amino acids. The hybrid of (S)-BINAM and l-Phe was found to be the best organocatalyst. Products were o

Full text of DOI:10.1016/j.tetlet.2010.11.015

Tetrahedron Letters 52 (2011) 381–384
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Tetrahedron Letters
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The highly enantioselective 1,3-dipolar cycloaddition of alkyl glyoxylate-derived
nitrones to E-crotonaldehyde catalyzed by hybrid diamines
a
⇑
Łukasz Weselinski , Edyta Słyk a,b, Janusz Jurczak a,b,
´
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 29 July 2010
Revised 19 October 2010
Accepted 5 November 2010
Available online 18 November 2010
1,3-Dipolar cycloaddition of alkyl glyoxylate-derived nitrones to E-crotonaldehyde can be catalyzed by
hybrid diamines, obtained from (S)-BINAM and L-a-amino acids. The hybrid of (S)-BINAM and L-Phe
was found to be the best organocatalyst. Products were obtained in good yield and diastereoselectivity
as well as high enantioselectivity (82–91% ee). Subsequent transformations into functionalized pyrrolid-
inones have been demonstrated.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Amino acids
Asymmetric organocatalysis
Binaphthyl derivatives
1,3-Dipolar cycloaddition
Nitrones
1,3-Dipolar cycloaddition (1,3-DC) of nitrones to alkenes pro-
vides isoxazolidines,1 which are useful precursors for interesting
heterocyclic products. The general utility of an asymmetric variant
of this reaction has been demonstrated by syntheses of many opti-
cally active products.2 Enantioselective protocols for 1,3-DC involv-
ing the use of metal complexes have been widely explored with
limited levels of success.3
nitrones to vinyl ethers catalyzed by a chiral bisoxazoline–copper
complex, however, only two examples of high enantioselectivity
were observed.
Herein we reportthe first highlyenantioselective organocatalytic
1,3-DC of glyoxylate-derived nitrones 1a–j to E-crotonaldehyde (2)
(Scheme 1). We initially investigated the reaction of 2 with N-
benzyl-a-ethoxycarbonylmethanimine N-oxide (1b) as a model
The use of chiral secondary amines as organocatalysts for this
process to test our catalysts: commercially available MacMillan’s
imidazolidinone C1,4a and three hybrid diamines C2–C4 obtained
by us.8 In the presence of C1, a nearly equimolar mixture of diaste-
reomeric products 3b9 + 4b was obtained in low yield (Table 1, entry
1). After reduction, the corresponding 3,4-trans-alcohol10 was
isolated with 58% ee. Since catalyst C1 was inefficient in this case,
we investigated the chiral salts of amines C2–C4 (entries 2–4).
These salts were recently developed by us and used as efficient
type of 1,3-DC reaction with
a,b-unsaturated aldehydes is one of
the most promising synthetic strategies to have emerged recently.4
However, most reports concerning such organocatalyzed 1,3-DC,
including our earlier paper,5 describe reactions of aromatic nitro-
nes, especially benzaldehyde or naphthaldehyde derivatives.
Therefore, in this study, we focused our attention on asymmetric
1,3-DC of alkyl glyoxylate-derived nitrones to E-crotonaldehyde.
The possibility of ester group introduction into the isoxazolidine
product allows further synthetic manipulations. Thus, glyoxylate
nitrones were successfully applied as substrates for the diastereose-
lective synthesis of, for example, alkaloids, amino acids, and amino-
sugars.2 To our knowledge, only two examples of enantioselective
protocols for such substrates have been described.6,7 The reaction
of t-butyl glyoxylate nitrone (1e) with allyl alcohol catalyzed by a
chiral zinc complex, leading to an isoxazolidine product (68%, 92%
ee), was reported by Inomata’s group.6 Jørgensen and co-workers7
reported the first inverse electron demand 1,3-DC of glyoxylate
catalysts for the 1,3-DC of aromatic nitrones to
a,b-unsaturated
aldehydes.5 We envisioned that the increased rigidity and bulkiness
of our catalysts might lead to improved stereocontrol of the reac-
tion. Among the salts tested, C2*TfOH gave the best results in terms
of yield and stereoselectivity. Under optimized conditions,5 the mix-
ture of products 3b + 4b was obtained in 80% yield, in a 3.8:1 ratio,
and 90% ee of the major diastereomer 3b (entry 2). Next, we inves-
tigated the scope of the 1,3-DC reaction with nitrones of type 1. As
shown in Table 2, this reaction worked especially well for primary
ester derived nitrones (entries 1, 2, and 4). Usually, enantiocontrol
over 85% ee was observed. The best results were obtained for ben-
zylic glyoxylate-derived nitrones (entries 7–10).
The presence of a substituent on the benzyl ring affected neither
the stereoselectivity nor the yield of the reaction. The results
⇑
Corresponding author. Tel.: +48 22 632 05 78; fax: +48 22 632 66 81.
E-mail address: jurczak@icho.edu.pl (J. Jurczak).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.11.015

´
382
Łukasz Weselinski et al. / Tetrahedron Letters 52 (2011) 381–384
R1
R1
O
R1
N+
O-
N
O
N
O
2
R2OOC
R2OOC
R2OOC
C1 C2-C4
or
/*TfOH
O
O
º
MeNO2, 4 C
1a-j
3a-j
4a-j
1
2
1
2
1
2
1
2
1
2
a
b
c
d
e
: R =Bn, R =Me, : R =Bn, R =Et, : R =Bn, R =i-Pr, : R =Bn, R =n-Bu, : R =Bn, R =t-Bu,
f: R1=Bn, R2=Cy, g: R1=Bn, R2=Bn, h: R1=Bn, R2=PMB, i: R1=Bn, R2=4-NO2Bn, j: R1=Me, R2=Bn
Scheme 1.
Table 1
for the smallest methyl ester 1a (entry 1). We believe that some
of the lower yields may be explained by ester group lability under
the acidic conditions of the reaction. In all examples, after
reduction of the carbonyl group, the major diastereomer of the
corresponding alcohol could be isolated in pure form via
chromatography.
The configurations of products 3, being 3,4-trans, 4,5-trans were
deduced from their 1H NMR spectra and confirmed by X-ray crys-
tallographic analysis of compounds 3b and 3g, performed on their
N-tosylhydrazones. From the same X-ray analyses, we determined
the absolute configurations of these two compounds as (3R,4S,5R).
The ORTEP projection of the N-tosylhydrazone of 3b is shown in
Figure 1.
Screening of the catalysts in the model 1,3-DC reaction of 1b with 2a
R3
O
NH2
O
NH
N
HCl
Bn
NH
N
H
NH2
O
R3
C2, R3=Bn
C3, R3=Me
C1
C4, R3=i-Bu
Our earlier experiments on the influence of the acid additive
suggest an iminium ion as a catalytic intermediate.5 Moreover,
the 1H NMR spectra of catalyst C2, recorded in the presence of
increasing amounts of TfOH, show an upfield shift of the amide
Entrya
Catalystb
Yieldc (%)
3b:4bd
ee (%) of 3e
1
2
3
4
C1
C2
C3
C4
20
80
82
79
1.5:1
3.8:1
1:1
58
90
60
45
proton (
D
ꢀ0.2 ppm, 0.5 equiv TfOH), indicating an internal hydro-
gen-bonding interaction between the amide and trifluoromethane-
sulfonic acid. Analogously, the amine proton was shifted downfield
1:1
a
(D
ꢀ0.5 ppm, 0.5 equiv TfOH), being consistent with ammonium
The reactions were carried out on 0.25 mmol scale for 72 h.
Except for C1 (20 mol %), 10 mol % of the catalysts C2–C4 in the presence of
b
salt formation. When the C2*TfOH salt solution in nitromethane
was treated with crotonaldehyde 2, the mixture turned dark-red
within a few minutes. This observation is also consistent with
the possibility of the formation of a conjugated iminium ion.
As we did not succeed in growing crystals of catalyst C2 or its
salt that were suitable for X-ray crystallographic analysis, we per-
formed other experiments to assess further the influence of the
stereogenic elements of the catalyst on its activity. We have shown
that only the S configuration of the binaphthyl moiety, combined
9 mol % of TfOH were applied.
c
Isolated combined yield of 3b and 4b.
d
Determined after 1H NMR analysis of the crude reaction mixture.
e
Determined after reduction of the carbonyl group to the corresponding alcohol
and HPLC analysis using chiral columns.
Table 2
Scope of glyoxylate nitrones 1 in the 1,3-DC reaction with 2 catalyzed by 10 mol % of
with an
L
-amino acid, led to enhanced stereoselectivity.5 To
C2 in the presence of 9 mol % of TfOHa
Entrya
Product
Yieldb (%)
Ratio of 3:4c
ee (%) of 3d
1
2
3
4
5
6
7
8
9
3a/4a
3b/4b
3c/4c
3d/4d
3e/4e
3f/4f
3g/4g
3h/4h
3i/4i
49
80
64
75
70
69
77
79
90
58e
2.5:1
3.8:1
1:1
4.6:1
7:1
5.6:1
8.5:1
9.5:1
9.9:1
6.6:1
82
90
91
87
87
86
90
89
90
88
10
3j/4j
a
b
c
The reactions were carried out on 0.25 mmol scale for 72 h.
Isolated combined yield of 3 and 4.
Determined after 1H NMR analysis of the crude reaction mixture.
d
Determined after reduction of the carbonyl group to the corresponding alcohol
and HPLC analysis using chiral columns.
e
Isolated as the corresponding 3,4-trans-alcohol.
obtained with t-butyl nitrone 1e were promising, but purification
of the product by chromatography on silica gel was difficult. Only
in the case of i-propyl glyoxylate nitrone 1c were the results signif-
icantly worse in terms of diastereocontrol and yield (entry 3),
although a drop in yield and enantioselectivity was also observed
Figure 1. ORTEP projection of the N-tosylhydrazone of 3b.

´
383
Łukasz Weselinski et al. / Tetrahedron Letters 52 (2011) 381–384
compare the influence of both axial chirality and the stereogenic
center, we reinvestigated the reaction of aromatic nitrone 5 with
E-crotonaldehyde (2), performed in the presence of two non-hy-
brid analogs of C2: (S)-BINAM glycine diamide C6 and biphenyl
axially chiral binaphthyl moiety, leads to increased diastero- and
enantiocontrol.
Cycloadduct 3b was chosen for further studies toward synthetic
applications of the obtained isoxazolidines. We envisioned that
changing the carbonyl group at C-4 to an amine functionality and
subsequent cleavage of the N–O bond of the starting isoxazolidine
L-Phe diamide C7 (Table 3, entries 2 and 3). We also performed
the same reaction in the presence of -Phe methyl ester hydrochlo-
L
ride C5 (entry 1). The selectivity for both C5 and C6 was low, indi-
cating that none of the different stereogenic elements themselves
were responsible for the high level of asymmetric induction. How-
ever, the biphenyl diamide produced the endo adduct 6a in good
yield and stereoselectivity: 84% yield, 3.8:1 dr, and 81% ee. This re-
sult confirms that the presence of both amino acid units is impor-
tant for high asymmetric induction but, when combined with the
might lead to the formation of a new c-lactam ring 2-pyrrolidinone
derivative. Such cleavage is known to be facile, for example, by cat-
alytic hydrogenation. A similar strategy for lactam formation was
applied by Brandi et al.11 for the synthesis of alkaloids.
The 2-pyrrolidinone moiety is present in many natural prod-
ucts,12 compounds of medicinal interest,13 and peptidomimetic
building blocks.14 Stereoselective synthesis of these compounds of-
ten requires multi-step procedures. Thus, development of new effi-
cient methods for their enantioselective synthesis represents an
attractive target.15
Table 3
Comparison of the catalysts C5–C7 and C2 in the 1,3-DC reaction of 5 with 2
First, to demonstrate the preparative utility of our methodology,
we performed the reaction of 1b with 2 (Scheme 1), using a lower
loading (5 mol %) of catalyst C2 (with 4.5 mol % of TfOH). Diaste-
reomerically pure 3b was isolated in 65% yield and 87% ee. Thus,
the enantioselectivity was only slightly affected by reducing the
catalyst amount. Next, we converted 3b into the corresponding
amine by reductive amination with NH4OAc and subjected it to
catalytic hydrogenation. However, after consumption of the start-
ing material, analysis of the reaction mixture showed only decom-
position products.
O
cat. 10 mol%
Bn
TfOH 9 mol%
N O
2
Ph
MeNO2,
*
O-
N+
Bn
º
4 C
O
Ph
6a: (3R)
6b: (3S)
5
R3
O
NH2
Bn
CO2Me
NH
NH2*HCl
G
NH
NH2
C5
O
R3
C6, G=(S)-1,1-binaphth-2,2'-yl,
R3=H
C7, G=1,1'-biphen-2,2'-yl, R3=Bn
Entrya
Catalystb
Yieldc (%)
6a:6bd
ee (%) of 6ae
1
2
3
4
C5
C6
C7
C2
78
59
84
75
1:1.3
1:2
3.8:1
7:1
23
5
81
925
a
The reactions were carried out on 0.25 mmol scale for 72 h.
Except for C5 (10 mol %), 10 mol % of the catalysts C2, C6, and C7 in the presence
b
of 9 mol % of TfOH were used.
c
Isolated combined yield of 6a and 6b.
d
Determined after 1H NMR analysis of the crude reaction mixture.
e
Determined after reduction of the carbonyl group to the corresponding alcohol
and HPLC analysis using chiral columns.
Figure 2. ORTEP projection of N-Me pyrrolidinone 8a.
OH
Bn
H
BocHN
O
Pd(OH)2/C
N O
Bn
MeNH2/EtOH
MeOH, 72 h
EtO2C
N O
N
Me
then Et3N, Boc2O
80-90%
NaBH3CN, 2 h
55%
EtO2C
NHMe
7
8a
O
3b
OH
Bn
Pd(OH)2/C
H
N O
5 mmol scale
5 mol% C2
65%, 87% ee
BocHN
O
NH2OH*HCl
MeOH, 72 h
EtO2C
then Et3N, Boc2O
35%
THF/H2O
80%
N
H
OH
N
9
8b 86% ee
Scheme 2.

´
384
Łukasz Weselinski et al. / Tetrahedron Letters 52 (2011) 381–384
3H, CO2CH2CH3). 13C NMR (50 MHz, CDCl3): d = 198.1, 170.1, 136.2, 129.3,
128.6, 127.8, 74.2, 66.8, 65.3, 62.0, 61.2, 19.4, 14.2.
Since the intermediate amine seemed to be unstable, we
decided instead to subject the corresponding oxime 9 to catalytic
hydrogenation. This time, the N-Boc protected 2-pyrrolidinone
8b16 was isolated in 28% yield over three-steps (Scheme 2).
Next, we wanted to test the strategy with other substituted
amines. When we subjected N-Me amine 7 to catalytic hydrogena-
10. (3R,4R,5R)-2-Benzyl-3-ethoxycarbonyl-4-hydroxymethyl-5-methylisoxazolidine:
colorless crystals after recrystallization (>99% ee), mp 62.5–63.5 °C (hexane/2-
propanol), [a]
D = +85.7 (c = 1.25, CHCl3). 1H NMR (200 MHz, CDCl3): d = 7.42–
7.22 (m, 5H, Har), 4.23–4.06 (m, 3H, overlapped CH2Ph and CHCH3), 4.14 (q,
J = 7, 2H, CO2CH2CH3), 3.77 (d, J = 5.6, 2H, CH2OH), 3.54 (d, J = 7, 1H, CHCO2Et),
2.64–2.57 (m, 1H, CHCH2OH), 2.10 (br s, 1H, OH), 1.34 (d, J = 6.2, 3H, CHCH3),
1.22 (t, J = 7, 3H, CO2CH2CH3). 13C NMR (50 MHz, CDCl3): d = 171.7, 136.7,
129.4, 128.5, 127.7, 75.4, 70.1, 62.0, 61.9, 61.6, 56.9, 18.7, 14.3. LR ESI-MS: m/z:
302.1 for [M+Na]+. HR ESI-MS: m/z: calcd for [C15H21NO4+Na]+: 302.1368,
found: 302.1376. HPLC conditions: DAICEL CHIRALPAKÒ AD-H, 2-propanol/
hexane 5%, 1 ml/min, 35 °C, UV 215 nm, t1 = 16.2 min (major enantiomer:
3R,4R,5R), t2 = 19.3 min.
tion, the yield of the crucial
c-lactam formation step was in the
range of 80–90%, and pyrrolidinone 8a17 was isolated in 50% yield
over three-steps, as shown in Scheme 2. After recrystallization,
compound 8a was analyzed by X-ray crystallographic analysis
and its relative configuration was confirmed (Fig. 2).
11. Brandi, A.; Cardona, F.; Cicchi, S.; Cordero, F. M.; Goti, A. Chem. Eur. J. 2009, 15,
7808–7821.
In conclusion, we have developed the first organocatalytic
enantioselective reaction of alkyl glyoxylate-derived nitrones with
E-crotonaldehyde.18 The reaction is effective with organocatalyst
loadings as low as 5 mol %. Enantioselectivities of up to 91% ee
were observed. We also demonstrated the application of the ob-
tained cycloadduct 3b in short and simple syntheses of functional-
ized 2-pyrrolidinones.
12. For recent selected examples, see: (a) Xu, W.; Kong, A.; Lu, X. J. Org. Chem. 2006,
71, 3854–3858; (b) Jang, D. S.; Lee, G. Y.; Lee, Y. M.; Kim, Y. S.; Sun, H.; Kim, D.-
H.; Kim, J. S. Chem. Pharm. Bull. 2009, 57, 397–400; (c) Ling, T.; Potts, B. C.;
Macherla, V. R. J. Org. Chem. 2010, 75, 3882–3885; See also references cited in:
(d) Pelletier, S. M.-C.; Ray, P. C.; Dixon, D. J. Org. Lett. 2009, 11, 4512–4515.
13. For selected examples, see: (a) Hwang, D. J.; Kim, S. N.; Choi, J. H.; Lee, Y. S.
Bioorg. Med. Chem. 2001, 9, 1429–1437; (b) Xiao, Y.; Araldi, G. L.; Zhao, Z.;
Reddy, A.; Karra, S.; Brugger, N.; Fischer, D.; Palmer, E.; Bao, B.; Mckenna, S. D.
Bioorg. Med. Chem. Lett. 2008, 18, 821–824; (c) Anwar, M.; Cowley, A. R.;
Moloney, M. G. Tetrahedron: Asymmetry 2010, 21, 1758–1770.
Acknowledgment
14. Crucianelli, E.; Galeazzi, R.; Martelli, G.; Orena, M.; Rinaldi, S.; Sabatino, P.
Tetrahedron 2010, 66, 400–405. and references cited therein..
Financial support from the Polish Ministry of Science and Higher
Education (Grant PBZ-KBN-126/T09/06) is gratefully acknowledged.
Crystallographic data (excluding structure factors) for the struc-
tures in this paper: N-tosylhydrazones of 3b (CCDC 796643) and 3g
(CCDC 796644) and compound 8a (CCDC 796645) have been
deposited with the Cambridge Crystallographic Data Centre. Copies
of the data can be obtained, free of charge, on application to CCDC,
12 Union Road, Cambridge CB2 1EZ, UK [fax: +44 (0) 1223 336033
or email: deposit@ccdc.cam.ac.uk].
15. For selected examples, see: (a) Anada, M.; Hashimoto, S. Tetrahedron Lett. 1998,
39, 79–82; (b) Overman, L. E.; Remarchuk, T. P. J. Am. Chem. Soc. 2002, 124, 12–
13; (c) Johnson, T. A.; Jang, D. O.; Slafer, B. W.; Curtis, M. D.; Beak, P. J. Am.
Chem. Soc. 2002, 124, 11689–11698; (d) Nichols, P. J.; DeMattei, J. A.; Barnett, B.
R.; LeFur, N. A.; Chuang, T.-H.; Piscopio, A.-D.; Koch, K. Org. Lett. 2006, 8, 1495–
1498; (e) Kotkar, S. P.; Chavan, V. B.; Sudalai, A. Org. Lett. 2007, 9, 1001–1004.
16. tert-Butyl
(8b): colorless solid, recrystallization from CH2Cl2/hexane, mp 129–130 °C.
D = +24.0 (c = 0.7, MeOH). 1H NMR (200 MHz, CD3CN): d = 6.33 (br s, 1H,
(3R,4S,10R)-[4-(1-hydroxyethyl)-2-oxo-pyrrolidin-3-yl]-carbamate
[a]
NH), 5.70 (br s, 1H, NHBoc), 4.09–4.00 (m, 1H, CHNHBoc), 3.82–3.74 (m, 1H,
CHOH), 3.55 (br s, 1H, CH2), 3.30–3.20 (m, 1H, CH), 3.00–2.91 (m, 1H, CH2), 1.41
(s, 9H, t-Bu), 1.10 (d, J = 6.4, 3H, CHCH3). 13C NMR (50 MHz, CD3CN): d = 80.7,
69.2, 55.0, 50.7, 42.0, 28.9, 21.4. LR ESI-MS: m/z: 267.1 for [M+Na]+, 511.3 for
[2M+Na]+. HR ESI-MS: m/z: calcd for [C11H20N2O4+Na]+: 267.1321, found:
267.1313. Optical purity (86% ee) was determined by HPLC analysis of its
dibenzylic derivative.
References and notes
1. Grigor’ev, I. A. Nitrile Oxides, Nitrones, and Nitronates in Organic Synthesis In
Feuer, H., Ed., 2nd ed.; John Wiley and Sons: Hoboken, New Jersey, 2008; pp
129–434.
2. For reviews in this area, see: (a) Tufariello, J. J. Acc. Chem. Res. 1979, 12, 396–
403; (b) Frederickson, M. Tetrahedron 1997, 53, 403–425.
3. For recent reviews, see: (a) Gothelf, K. V.; Jørgensen, K. A. Chem. Rev. 1998, 98,
863–910; (b) Gothelf, K. V.; Jørgensen, K. A. Chem. Commun. 2000, 1449–1458;
(c) Pellissier, H. Tetrahedron 2007, 63, 3235–3285; (d) Stanley, L. M.; Sibi, M. P.
Chem. Rev. 2008, 108, 2887–2902.
4. (a) Jen, W. S.; Wiener, J. J. M.; MacMillan, D. W. C. J. Am. Chem. Soc. 2000, 122,
9874–9875; (b) Puglisi, A.; Benaglia, M.; Cinquini, M.; Cozzi, F.; Celentano, G.
Eur. J. Org. Chem. 2004, 567–573; (c) Karlsson, S.; Högberg, H.-E. Tetrahedron:
Asymmetry 2002, 13, 923–926; (d) Karlsson, S.; Högberg, H.-E. Eur. J. Org. Chem.
2003, 2782–2791; (e) Chow, S. S.; Nevalainen, M.; Evans, C. A.; Johannes, C. W.
Tetrahedron Lett. 2007, 48, 277–280; (f) Lemay, M.; Trant, J.; Ogilvie, W. W.
17. tert-Butyl
(3R,4S,10R)-[4-(1-hydroxyethyl)-1-methyl-2-oxo-pyrrolidin-3-yl]-
carbamate (8a): colorless solid, recrystallization from CH2Cl2/hexane afforded
crystals (mp 125–128 °C), suitable for single crystal X-ray diffraction.
[
a
]
D = ꢁ42.7 (c = 0.45, CHCl3). 1H NMR (200 MHz, CDCl3): d = 5.35 (br s, 1H,
NH), 4.10 (dd, J1 = 6.4, J2 = 9.2, 1H, CHNHBoc), 3.91–3.77 (m, 1H, CHOH), 3.34–
3.24 (m, 1H, CH2), 3.04–2.99 (m, 1H, CH2), 2.89 (s, 3H, N-Me), 2.13 (quin, J = 9,
1H, CH), 1.46 (s, 9H, t-Bu), 1.18 (d, J = 6.4, 3H, CHCH3). 13C NMR (50 MHz,
CDCl3): d = 171.6, 158.2, 81.4, 69.4, 56.7, 50.7, 48.9, 30.4, 28.4, 20.7. LR ESI-MS:
m/z: 281.1 for [M+Na]+, 539.3 for [2M+Na]+. HR ESI-MS: m/z: calcd for
[C12H22N2O4+Na]+: 281.1477, found: 281.1472.
18. General procedure for the 1,3-dipolar cycloaddition (1,3-DC):
A solution of
nitrone 1 (0.25 mmol, 1 equiv) in MeNO2 (1 mL) was placed in a vial, and H2O
(13
(20
l
l
l, 0.75 mmol, 3 equiv), the catalyst (0.025 mmol, 0.1 equiv), and TfOH
l of a 10% v/v solution in MeNO2, 0.0225 mmol, 0.09 equiv) were added
and the resulting mixture was cooled to 4 °C. Next, freshly distilled (E)-
Tetrahedron 2007, 63, 11644–11655; For
a
comparison between
crotonaldehyde (2) was added [82 l, 1 mmol, 4 equiv, followed by 3 equiv at
l
organocatalysed and Lewis acid catalysed 1,3-dipolar cycloadditions, see
24 h intervals (two portions)] and the mixture was left to stir for 72 h, then 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
diastereoselectivity (based on integration relative to the carbonyl peaks). After
flash chromatography on silica gel (hexane–EtOAc), product 3 was isolated as
an oil in 49–90% yield.
Nájera, C.; Sansano, J. M.; Yus, M. J. Braz. Chem. Soc. 2010, 21, 377–412.
´
5. Weselinski, Ł.; Ste˛pniak, P.; Jurczak, J. Synlett 2009, 2261–2264.
6. Ukaji, Y.; Taniguchi, K.; Sada, K.; Inomata, K. Chem. Lett. 1997, 547–548.
7. Jensen, K. B.; Hazell, R. G.; Jørgensen, K. A. J. Org. Chem. 1999, 64, 2353–2360.
´
8. Kowalczyk, B.; Tarnowska, A.; Weselinski, Ł.; Jurczak, J. Synlett 2005, 2372–
2375.
General procedure for reduction of the 1,3-DC products 3: Product 3 was reduced
to the corresponding alcohol with 1 equiv of NaBH4 in MeOH at 0 °C for 30 min.
After aqueous work-up, the diastereomerically pure 3,4-trans-alcohol was
purified by flash chromatography on silica gel (hexane–EtOAc) and isolated in
60–70% yield. The ee values of the alcohols were determined by chiral HPLC.
All new compounds obtained here had correct analytical and spectral data.
9. (3R,4S,5R)-2-Benzyl-3-ethoxycarbonyl-4-formyl-5-methylisoxazolidine
colorless oil,
D = +50.1 (c = 0.75, CHCl3). 1H NMR (200 MHz, CDCl3):
d = 9.83 (d, J = 1.4, 1H, CHO), 7.38–7.26 (m, 5H, ar.), 4.57 (dq, J1 = 6.1,
(3b):
[a]
H
J2 = 12.2, 1H, CHCH3), 4.18 (q, J = 7, 2H, CO2CH2CH3), 4.12 (d, J = 13.2, 1H,
CH2Ph), 4.06 (d, J = 5.2, 1H, CHCO2Et), 4.00 (d, J = 13.2, 1H, CH2Ph), 3.55 (ddd,
J1 = 1.4, J2 = 5.2, J3 = 6.4, 1H, CHCHO), 1.47 (d, J = 6.2, 3H, CHCH3), 1.26 (t, J = 7,