Asymmetric C-C bond formation via Darzens condensation and Michael addition using monosaccharide-based chiral crown ethers

Article abstract of DOI:10.1016/j.tetlet.2011.01.094

Liquid-liquid phase asymmetric Darzens condensations were promoted by d-glucose- and d-mannose-based crown ethers. The corresponding aromatic and heteroaromatic α,β-epoxyketones were obtained with moderate to high enantioselectivities (up to 96%) as well

Full text of DOI:10.1016/j.tetlet.2011.01.094

Tetrahedron Letters 52 (2011) 1473–1476
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Asymmetric C–C bond formation via Darzens condensation and
Michael addition using monosaccharide-based chiral crown ethers
Péter Bakó a, , Zsolt Rapi a, György Keglevich a, Tamás Szabó a, Péter L. Sóti a, Tamás Vígh a,
⇑
Alajos Grun a,b, Tamás Holczbauer c
}
a Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, PO Box 91, 1521 Budapest, Hungary
b Organic Chemical Technology Research Group of the Hungarian Academy of Sciences, Budapest, Hungary
c Chemical Research Institute for Chemistry, Hungarian Academy of Sciences, H-1525 Budapest, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
Liquid–liquid phase asymmetric Darzens condensations were promoted by
D
-glucose- and
D-mannose-
Received 10 November 2010
Revised 10 January 2011
Accepted 21 January 2011
Available online 1 February 2011
based crown ethers. The corresponding aromatic and heteroaromatic
a,b-epoxyketones were obtained
with moderate to high enantioselectivities (up to 96%) as well as diastereoselectivities (up to 98:2) under
mild reaction conditions. The absolute configurations of several of the epoxyketones were determined by
single crystal X-ray analysis. The Michael additions of diethyl acetylaminomalonate to trans-b-nitroal-
kenes were carried out in a solid–liquid two-phase system in the presence of a
catalyst with up to 99% ee.
D-glucose-based crown
Keywords:
Darzens condensation
Michael addition
Ó 2011 Elsevier Ltd. All rights reserved.
Enantioselectivity
Chiral phase-transfer catalysis
Crown compounds
An attractive approach in catalytic asymmetric synthesis is the
phase-transfer catalytic technique in which the enantioselectivity
is generated by a chiral crown catalyst.1 Optically active crown
ethers in this prominent group contain a carbohydrate moiety as
the source of chirality. However, until now, only a limited number
of asymmetric reactions have been reported, in which the applica-
tion of a monosaccharide-based crown catalyst resulted in a good
enantioselectivity.2 Previously, chiral monoaza-15-crown-5 type
phase system in toluene, employing 30% aq NaOH as the base
and 7 mol % of chiral crown catalyst 1 or 2 at a temperature of
ꢀ5 °C. The products were isolated by preparative TLC and found
to be trans-epoxyketones in all cases. The asymmetric induction
expressed in terms of the enantiomeric excess (ee), was deter-
mined by 1H NMR analysis in the presence of Eu(hfc)3 as the chiral
shift reagent.5a 4-Phenyl-phenacyl chloride (4) was found to be a
promising reagent for the Darzens condensation with benzalde-
hyde (3a Ar = Ph) (Scheme 1).
macrocycles incorporating an a-D-glucopyranoside or an a-D-man-
nopyranoside unit (1 and 2) were synthesized in our laboratory,
and proved to be efficient catalysts in a few asymmetric reactions.3
Herein we report two model reactions, a Darzens condensation
and a Michael addition, in which the monosaccharide-based chiral
macrocycles generated high enantioselectivities in the products.
Chiral epoxides are well-known building blocks in the prepara-
tion of optically pure bioactive compounds and this explains the
current interest in the enantioselective synthesis of chiral epox-
ides. One of the simplest ways to prepare chiral epoxides involves
a Darzens condensation carried out under phase-transfer catalytic
conditions in the presence of optically active catalysts.4
After a 3-h reaction time at rt in the presence of catalyst 1,
trans-epoxyketone 5 was formed in a yield of 50% and de of >98%
as a mixture containing the antipode with negative optical rotation
in 96% ee (100% ee after recrystallization).5b The use of the man-
nose-based crown ether 2 promoted formation of the enantiomer
with positive optical rotation in an ee of 65% (Fig. 1).
On the other hand, the Darzens condensation of heteroaromatic
a-chloroacetyl derivatives 6 and 8 with aromatic aldehydes was
1
crown cat.
toluene
We describe the asymmetric Darzens condensation of aromatic
and heteroaromatic chloromethyl ketones with various aromatic
aldehydes. The reactions were carried out in a liquid–liquid two-
O
+
ArCHO
3a
Cl
Ph
30% NaOH
Ar = Ph
O
O
4
5
96% ee
⇑
Corresponding author.
E-mail address: pbako@mail.bme.hu (P. Bakó).
Scheme 1.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.01.094

1474
P. Bakó et al. / Tetrahedron Letters 52 (2011) 1473–1476
Table 2
OCH3
OCH3
O
O
O
Asymmetric Darzens condensation of 2-chloroacetylthiophene (8) with aromatic
aldehydes in the presence of catalyst 1, at ꢀ5 °C
O
O
O
O
O
O
N
(CH2)3OH
N
(CH2)3OH
Yielda (%)
eec (%)
½ ꢁ
a 2D2
b
Entry
Ar
Time (h)
O
O
O
O
O
1
2
3
4
5
6
7
8
9
Ph
5
4.5
6
20
22
3
5
6
5
9a: 63
9b: 53
9c: 56
9d: 54
9e: 55
9f: 79
9g: 87
9h: 54
9i: 57
ꢀ169.8
ꢀ10.0
71 (84)
51
2-Cl–C6H4
3-Cl–C6H4
4-Cl–C6H4
4-F–C6H4
2-H3C–C6H4
1-Naphthyl
2-Naphthyl
Piperonyl
ꢀ142.1
ꢀ139.0
ꢀ119.7
ꢀ45.7
60 (75)
65 (79)
62 (73)
68 (85)
64 (75)
62
1
2
Figure 1. Crown ethers 1 and 2 incorporating an
mannopyranoside unit.
a-
D
-glucopyranoside and an a-D-
+54.0
ꢀ163.0
ꢀ131.5
86 (100)
a
b
c
Based on isolation by preparative TLC.
O
In CHCl3, c = 1.
Determined by 1H NMR spectroscopy, the ee given in parentheses was obtained
crown cat.
Cl
+
ArCHO
Ar
O
toluene
30% NaOH
after one recrystallization from EtOH.
O
O
O
3
6
7
Scheme 2.
O
crown cat.
Cl
+
ArCHO
Ar
S
toluene
30% NaOH
S
O
O
3
8
9
Scheme 3.
Figure 2. Compound 9f: ORTEP representation at 50% probability level.
Table 1
Asymmetric Darzens condensation of 2-chloroacetylfuran (6) with aromatic
aldehydes in the presence of catalyst 1 at ꢀ5 °C
Yielda (%)
eec (%)
½ ꢁ
a 2D2
b
Entry
Ar
Time (h)
1
2
3
4
5
6
Ph
8
12
5
3
3
7a: 55
7b: 64
7c: 77
7d: 67
7e: 45
7f: 30
ꢀ117.7
ꢀ33.1
54
2-H3C–C6H4
2-Cl–C6H4
4-Cl–C6H4
Piperonyl
2-Naphthyl
57 (72)
70 (91)
62
64
28
ꢀ14.9
ꢀ146.5
ꢀ151.3
ꢀ73.6
1
a
b
c
Based on isolation by preparative TLC.
In CHCl3, c = 1.
Determined by 1H NMR spectroscopy, the ee given in parentheses was obtained
after one recrystallization from EtOH.
Figure 3. Compound 9i: ORTEP representation at 50% probability level.
also studied using the same conditions, but at ꢀ5 °C (Schemes 2
and 3). (There was no asymmetric induction with aliphatic
aldehydes.)
Experimental data for the reactions of 2-chloroacetylfuran (6)
are listed in Table 1.
creased to 85%. It is noteworthy, that the more distant the chloro
atom is situated from the reaction center, the greater the extent
of asymmetric induction, the best ee (65%) being obtained with
p-chlorobenzaldehyde. It is worth mentioning that the use of 1-
naphthaldehyde and 2-naphthaldehyde led to products 9g and
9h with opposite optical rotation, but approximately the same ee
value. The reaction of chloroacetylthiophene with piperonal gave
the best enantioselectivity (86%). Moreover, after completion of
the reaction, about half of epoxyketone 9i precipitated from the
mixture as the pure enantiomer (100% ee).5d
trans-Epoxyketones 7a–f were formed with negative optical
rotation values in yields ranging from 30% to 77%. Reaction of 6
with benzaldehyde gave the 2R,3S-epoxyketone (7a) in an enantio-
meric excess of 54%.6 The use of substituted benzaldehydes led to
increased ee values (57–70%). The maximum selectivity was ob-
tained in the reaction of 2-chlorobenzaldehyde, epoxide 7c being
formed in 70% ee.5c Recrystallization of epoxyketones 7b and 7c
from ethanol resulted in higher ee values of 72% and 91%,
respectively.
A reverse trend was experienced in the phase-transfer Darzens
reaction of 2-chloroacetylthiophene (8), (Scheme 3, Table 2).
In the reaction of 2-chloroacetylthiophene (8) with benzalde-
hyde, product 9a was formed in 71% ee.7 The use of substituted
benzaldehydes led to lower ee values of 51–68% (Table 2, entries
2–8). In the substituted series, 2-methylbenzaldehyde gave the
best optical purity (68% ee). After recrystallization this value in-
To the best of our knowledge, only Arai et al., have reported
high enantioselectivities of up to 86% ee for the reaction of cyclic
a
-chloroketones and aldehydes in the presence of a cinchonine
derivative after reaction times of 80–200 h.8
In the reactions shown in Schemes 2 and 3, the mannose-based
crown ether 2 generated lower enantioselectivities using benzal-
dehyde, products 7a and 9a (both with positive optical rotation)
being obtained in ee’s of 42% and 59%, respectively.
Repeated recrystallization of products 9f and 9i led to pure
enantiomers whose absolute configurations were determined by

P. Bakó et al. / Tetrahedron Letters 52 (2011) 1473–1476
Table 3
1475
O
crown cat. 1
Michael addition of diethyl acetamidomalonate (15) to trans-b-nitroalkenes in the
presence of catalyst 1
Cl
+
ArCHO
Ar
N
R
toluene
30% NaOH
N
R
O
O
Entry
Ar
Time (h)
Yielda (%)
eec (%)
½ ꢁ
a 2D2
b
3
10 R = H
12 R = H, Ar = 1-naphthyl
13
1
2
3
4
5
6
7
Ph
3
3.5
2
4
6
16a: 60
16b: 76
16c: 51
16d: 45
16e: 78
16f: 39
16g: 52
ꢀ42.8
ꢀ11.1
ꢀ25.3
ꢀ35.5
ꢀ11.1
ꢀ6.4
99
67
60
99
97
34
72
2-Cl–C6H4
3-H3CO–C6H4
4-Cl–C6H4
4-O2N–C6H4
4-H3CO–C6H4
Piperonyl
11
R = CH3
R = CH3, Ar = Ph
Scheme 4.
4
7
ꢀ32.5
a
b
c
Based on isolation by preparative TLC.
In CHCl3, c = 1.
Enantioselectivities were determined by chiral HPLC analysis in comparison
with authentic racemic material.
phase comprised the starting materials and the catalyst in a mix-
ture of THF–ether (4:1). Na2CO3, used in twofold excess, formed
the solid phase. The products (16a–g) were obtained by prepara-
tive TLC, while the optical purity was measured by chiral HPLC.
After reaction times of 2–7 h, ee values ranging from 34% to 99%
were obtained in the presence of catalyst 1. The best results were
obtained with b-nitrostyrene 14a and p-chloro-b-nitrostyrene 14d
leading to an ee of 99% in both cases.11b The absolute configuration
of Michael adduct 16a with negative optical rotation was (S).10b It
is noteworthy that the mannose-based catalyst 2 was completely
inefficient but the reason for this is unclear.
Figure 4. Compound 12: ORTEP representation at 50% probability level.
In summary, the a-D-glucopyranoside-based chiral crown ether
1 afforded moderate to good enantioselectivities in the phase-
transfer Darzens condensation of aromatic aldehydes with 2-chlo-
roacetylfuran (up to 70% ee), 2-chloroacetylthiophene (up to 86%
ee), 4-phenyl-phenacyl chloride (96% ee). The reactions of 2-chlo-
roacetylpyrrole and N-methyl-2-chloroacetylpyrrole led to lower
enantioselectivities (up to 51% ee) The addition of diethyl acetam-
idomalonate to trans-b-nitroalkenes resulted in 34–99% ee values
in the presence of catalyst 1.
O
O
O
O
Ar
crown cat. 1
OC2H5
C2H5O
CH3
NO2
NO2
+
Ar
C2H5O
Et2O - THF
Na2CO3
NH
CH3CONH COOC2H5
14
15
16
Scheme 5.
Acknowledgements
single crystal X-ray analysis. In both cases the configuration of the
chiral carbon atoms was found to be 2R,3S (Figs. 2 and 3).5d,9
Analogous reactions between aromatic aldehydes and 2-chloro-
acetylpyrrole (10) or N-methyl-2-chloroacetylpyrrole (11) under
similar conditions took place (Scheme 4) but led to lower enanti-
oselectivities (16–51% ee). The best result was achieved with 1-
naphthaldehyde (51% ee). Compound 12 (Ar = 1-naphthyl) could
be purified by repeated recrystallization and the absolute configu-
ration was found to be 2R,3S after a single crystal X-ray study
(Fig. 4).5e
The Michael reaction of nitroalkanes represents a convenient
access to substituted nitroalkanes which are versatile intermedi-
ates in organic synthesis. The nitro functionality can be easily con-
verted into other groups, giving access to a wide range of
synthetically important compounds. Although catalytic asymmet-
ric versions of this reaction have been developed, most required
metal catalysts or forcing reaction conditions. The addition of
diethyl acetamidomalonate to nitroalkenes has also been studied.
These malonate reactions can be used to prepare pyrrolidinones.
Furthermore, homogeneous catalytic methods have led generally
to moderate to good enantioselctivities.10
Financial support by the Hungarian Scientific Research Fund
(OTKA No. K 75098 and K 81127) is gratefully acknowledged. We
thank Dr. László Párkányi for assistance in the X-ray analysis and
Péter Keglevich for assistance with experiments.
References and notes
1. Asymmetric Phase Transfer Catalysis; Marouka, K., Ed.; Wiley-VCH Verlag GmbH
Co. KgaA: Weinheim, 2008.
2. (a) Jarosz, S.; Listkowski, A. Curr. Org. Chem. 2006, 10, 643; (b) Itoh, T.;
Shirakami, S. Heterocycles 2001, 55, 37; (c) Bakó, P.; Keglevich, G.; Rapi, Z. Lett.
Org. Chem., in press.
}
}
3. (a) Bakó, P.; Szöllosy, Á.; Bombicz, P.; Toke, L. Synlett 1997, 291; (b) Bakó, P.;
}
Czinege, E.; Bakó, T.; Czugler, M.; Toke, L. Tetrahedron: Asymmetry 1999, 10,
4539; (c) Bakó, T.; Bakó, P.; Szöllosy, Á.; Czugler, M.; Keglevich, G.; Toke, L.
}
}
Tetrahedron: Asymmetry 2002, 13, 203; (d) Bakó, P.; Bakó, T.; Mészáros, A.;
}
}
Keglevich, G.; Szöllosy, Á.; Bodor, S.; Makó, A.; Toke, L. Synlett 2004, 643; (e)
Bakó, P.; Makó, A.; Keglevich, G.; Kubinyi, M.; Pál, K. Tetrahedron: Asymmetry
2005, 16, 1861; (f) Jászay, Z.; Pham, T. S.; Németh, G.; Bakó, P.; Petneházy, I.;
}
Toke, L. Synlett 2009, 1429.
4. (a) Arai, S.; Shioiri, T. Tetrahedron Lett. 1998, 39, 2145; (b) Arai, S.; Ishida, T.;
Shioiri, T. Tetrahedron Lett. 1998, 39, 8299; (c) Arai, S.; Shirai, Y.; Ishida, T.;
Shioiri, T. Tetrahedron 1999, 55, 6375; (d) Arai, S.; Shioiri, T. Tetrahedron 2002,
58, 1407.
5. (a) General procedure for the Darzens condensation: A toluene solution (3 mL) of
aromatic 2-chloroketone (1.87 mmol), aromatic aldehyde (2.8 mmol) and the
crown ether (0.14 mmol) was cooled to ꢀ5 °C, and treated with 30% aqueous
NaOH (1 mL). The mixture was stirred at this temperature for 1–22 h. A
mixture of toluene (7 mL) and H2O (3 mL) was added and the solution stirred
for 10 min. The organic phase was washed with cold 10% HCl (3 ꢂ 10 mL) and
H2O (20 mL), dried (Na2CO3) and concentrated. The crude product was purified
on silica gel by preparative TLC with hexane–EtOAc (10:1) as eluent. The
enantioselectivities were determined by 1H NMR spectroscopy in the presence
We report the development of a highly selective conjugate
addition of diethyl acetamidomalonate (15) to nitrostyrene
derivatives 14 under phase-transfer conditions in the presence of
monosaccharide-based crown ether 1 (Scheme 5, Table 3).11a
The Michael addition was carried out in a solid–liquid two-
phase system employing 15 mol % of crown ether 1. The organic

1476
P. Bakó et al. / Tetrahedron Letters 52 (2011) 1473–1476
of Eu(hfc)3 as the chiral shift reagent.; (b) Compound 5: ½a D22
ꢁ
= ꢀ155.2 (c 1,
7. An earlier preparation of 9a via asymmetric epoxidation of an a,b-enone,
CH2Cl2, 96% ee); after crystallization: ½a D22
ꢁ
= ꢀ173.1 (c 1, CH2Cl2, 100% ee). Mp
absolute configuration not determined: Julia, S.; Guixer, J.; Masana, J.; Rocas, J.;
Colonna, S.; Annuziata, R.; Molinari, H. J. Chem. Soc., Perkin Trans. 1 1982, 1317.
8. Arai, S.; Shirai, Y.; Ishida, T.; Shioiri, T. Chem. Commun. 1999, 49.
9. Crystal data for 9f: CCDC 794985 contains the supplementary crystallographic
data for this structure. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
10. (a) Barnes, D. M.; Ji, J.; Fickes, M. G.; Fitzgerald, M. A.; King, S. A.; Morton, H. E.;
Plagge, F. A.; Preskill, M.; Wagaw, S. H.; Wittenberger, S. J.; Zhang, J. J. Am.
Chem. Soc. 2002, 124, 13097; (b) Evans, D. A.; Seidel, D. J. Am. Chem. Soc. 2005,
127, 9958.
130–132 °C; 1H NMR (300 MHz, CDCl3): d (ppm) = 4.11 (d, J = 1.5 Hz, 1H), 4.34
(d, J = 1.5 Hz, 1H), 7.36–7.52 (m, 8H), 7.63 (d, J = 8.4 Hz, 2H), 7.71 (d, J = 8.4 Hz,
2H), 8.10 (d, J = 8.4 Hz, 2H).; (c) Compound 7c: yield: 77%; ½a D22
= ꢀ14.9 (c 1,
ꢁ
CHCl3, 70% ee); after one crystallization: 91% ee. Mp 82–85 °C; 1H NMR
(300 MHz, CDCl3): d (ppm) = 4.03 (s, 1H), 4.48 (s, 1H), 6.61 (d, J = 2 Hz, 1H),
7.28–7.42 (m, 4H), 7.47 (d, 1H), 7.69 (s, 1H).; (d) Compound 9i: yield: 57%;
½
a 2D2
ꢁ
= ꢀ131.5 (c 1, CH2Cl2, 86% ee); after crystallization: ½a D22
ꢁ
= ꢀ268.8 (c 1,
CH2Cl2, 100% ee); Mp: 108–110 °C; 1H NMR (300 MHz, CDCl3, TMS):
d
(ppm) = 4.06 (s, 1H), 4.09 (s, 1H), 5.99 (s, 2H), 6.75–6.89 (m, 3H), 7.18 (s,
1H), 7.74 (d, J = 4.5 Hz, 1H), 8.00 (s, 1H).Crystal data for 9i: CCDC 794986
contains the supplementary crystallographic data for this structure. These data
can be obtained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.; (e) Compound 12: yield:
11. (a) General Procedure for the Michael addition: The trans-b-nitroalkene
(1.01 mmol), diethyl acetamidomalonate (15) (1.47 mmol) and the crown
ether (0.15 mmol) were dissolved in a mixture of anhydrous THF (0.6 mL) and
Et2O (2.4 mL) and dry Na2CO3 (2.08 mmol) was added. The reaction mixture
was stirred at room temperature. After completion of the reaction (2–7 h), the
organic phase was concentrated in vacuo and the residue was dissolved in
toluene (10 mL) and washed with cold 10% HCl (3 ꢂ 10 mL) and water (20 mL),
dried (Na2CO3) and concentrated. The crude product was purified on silica gel
by preparative TLC with hexane–EtOAc (3:1) as eluent. Enantioselectivities
were determined by chiral HPLC analysis using a Chiralpack AD column, (20 °C,
256 nm, 85:15 hexane/i-PrOH, 0.8 mL/min) in comparison with authentic
racemic material; Rt = 17.8 min (major), Rt = 27.7 min (minor).; (b) Data for
32%;
½
a 2D2
ꢁ
= +24.9 (c 1, CHCl3, 51% ee); after repeated crystallization:
½ ꢁ
a 2D2 = +56.5 (c 1, CHCl3, 100% ee); Mp 168 °C (dec) 1H NMR (500 MHz,
CDCl3): d (ppm) = 4.04 (s, 1H); 4.79 (s, 1H); 6.35 (t, J = 3.5 Hz,1H); 7.16–7.20 (m,
2H); 7.48–7.54 (m, 3H); 7.58 (d, J = 7 Hz, 1H); 7.86 (d, J = 8.5 Hz, 1H); 7.91 (t,
J = 4.5 Hz, 1H); 8.01 (t, J = 4.5 Hz, 1H); 9.67 (br s, 1H, NH).Crystal data for 12:
CCDC 794984 contains the supplementary crystallographic data for this
structure. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/
cif.Absolute configuration crystal data: Rigaku R-AXIS Rapid Diffractometer,
CuKa
radiation, k = 1.54187 Å, T = 133(2) K, R = 3.08, Rw = 7.78, N = 2414,
16d: ½a 2D2
ꢁ
= ꢀ35.5 (c 1, CHCl3, 99% ee). Mp 126–128 °C; 1H NMR (300 MHz,
Friedel Pair Coverage = 95%, Flack parameter: 0.1(2), Hooft parameter:
0.09(10).
CDCl3) d 1.23 (t, 3H, J = 7.1 Hz), 1.25 (t, 3H, J = 7.1 Hz), 2.12 (s, 3H), 4.03 (dq, 1H,
J = 10.7, 7.2 Hz), 4.15 (dq, 1H, J = 10.7, 7.2 Hz), 4.24 (dq, 1H, J = 10.7, 7.2 Hz),
4.29 (dq, 1H, J = 10.7, 7.2 Hz), 4.59–4.71 (m, 2H), 5.50 (dd, 1H, J = 21.7, 12.2 Hz),
6.69 (br s, 1H), 7.14 (d, 2H, J = 8.4 Hz), 7.28 (d, 2H, J = 8.7 Hz).
6. An earlier preparation of 7a via asymmetric epoxidation of an
W.-P.; Roberts, S. M. J. Chem. Soc., Perkin Trans. 1 1999, 103.
a,b-enone: Chen,