Enantioselective Michael Addition of 2-Nitropropane to Substituted Chalcones and Chalcone Analogues Catalyzed by Chiral Crown Ethers Incorporating an α-D-Glucose or an α-D-Mannose Unit

Article abstract of DOI:10.2174/157017810791824865

The chiral monoaza-15-crown-5 lariat ethers annellated to methyl-4,6-O-benzylidene-α-D-glucopyranoside-(1) or -mannopyranoside (2) used as phase transfer catalysts in the Michael addition of 2-nitropropane to substituted chalcones and chalcone analogues resulted in a significant asymmetric induction. The type of substituent on the chalcone molecule was found to have a significant influence on both the chemical yield and the enantioselectivity of the reaction: 24 novel chiral Michael adducts were prepared in 14-68% ee. These ee values were somewhat lower than that experienced in the case of the unsubstituted chalcone (85% ee). In the series of chalcone analogues*The 1-naphthyl Michael adduct was formed in 87% ee. Using glucose-based crown ether 1, Formation of the (+)-enantiomers was preferred, while applying mannose-based 2 as the catalyst, the (-)-enantiomers were in excess.

Full text of DOI:10.2174/157017810791824865

424
Letters in Organic Chemistry, 2010, 7, 424-431
Enantioselective Michael Addition of 2-Nitropropane to Substituted
Chalcones and Chalcone Analogues Catalyzed by Chiral Crown Ethers
Incorporating an ꢀ-D-Glucose or an ꢀ-D-Mannose Unit
Attila Makó1, Zsolt Rapi1, László Drahos2, Áron Szöllꢀsy3, György Keglevich1 and Péter Bakó*,1
1Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, H-1521
Budapest, Hungary
2Chemical Research Institute for Chemistry, Hungarian Academy of Sciences, Pusztaszeri út 59-67, H-1025 Budapest,
Hungary
3Department of Inorganic and Analytical Chemistry, H-1525 Budapest, Hungary
Received November 27, 2009: Revised April 21, 2010: Accepted April 23, 2010
Abstract: The chiral monoaza-15-crown-5 lariat ethers annellated to methyl-4,6-O-benzylidene-ꢁ-D-glucopyranoside- (1)
or –mannopyranoside (2) used as phase transfer catalysts in the Michael addition of 2-nitropropane to substituted
chalcones and chalcone analogues resulted in a significant asymmetric induction. The type of substituent on the chalcone
molecule was found to have a significant influence on both the chemical yield and the enantioselectivity of the reaction:
24 novel chiral Michael adducts were prepared in 14-68% ee. These ee values were somewhat lower than that experienced
in the case of the unsubstituted chalcone (85% ee). In the series of chalcone analogues, the 1-naphthyl Michael adduct was
formed in 87% ee. Using glucose-based crown ether 1, formation of the (+)-enantiomers was preferred, while applying
mannose-based 2 as the catalyst, the (-)-enantiomers were in excess.
Keywords: Chiral crown ether, phase transfer catalysis, asymmetric Michael addition.
1. INTRODUCTION
The hexapyranoside-based 15-crown-5 lariat ethers
described earlier by us possess special complexing ability
due to their flexible side-arm containing a heteroatom at the
end [12]. The overall complexing ability is influenced by the
steric and electronic properties of the N-substituent. A few of
the lariat ethers have been found to be efficient phase
transfer catalysts in certain type of asymmetric reactions
[13]. It came to light that the glucopyranoside- and the
analogous mannopyranoside-based chiral lariat ethers (1 and
2, respectively) are able to induce a significant asymmetric
induction in the Michael addition of 2-nitropropane to
chalcone [14]. Structure of the lariat ethers may be ideal as,
on the one hand, the cavity of the crown entity makes
possible the complexation of the cation (Na+), while on the
other hand, the flexible side-arm (that is the N-substituent)
may bring about an additional coordination of the cation.
The rigid ring system of the carbohydrate moiety annellated
to the acetal ring may also be advantageous from the point of
view of chiral discrimination. Earlier, we described the
reaction of a few substituted chalcones [15], and their
aromatic analogues [16] with 2-nitropropane in the presence
of chiral crown ethers. In this paper, the asymmetric Michael
reaction of additional chalcones and analogues ꢁ,ꢂ-enones
with 2-nitropropane is discussed.
The development of new methodologies for efficient
asymmetric synthesis is of tremendous importance due to the
increasing demand for optically active compounds [1]. One
of the techniques of catalytic asymmetric synthesis currently
attracting considerable interest is phase-transfer catalysis, in
which the enantioselectivity is generated by chiral crown
ether [2]. Crown ethers with carbohydrate moieties form a
special group of optically active macrocycles. Over the past
three decades, numerous macrocycles incorporating one or
more monosaccharide units have been synthesized [3].
Inexpensive natural sugars are “green” and cheap starting
materials in organic syntheses. However, until now, only a
limited number of asymmetric reactions have; however, been
explored in which a sugar-based crown catalyst induced the
enantioselectivity [4]. The Michael reaction is one of the
most important C-C bond-forming reactions, and
stereoselective variants have been extensively investigated in
recent years [5]. High asymmetric induction has been
reported in the Michael addition of methyl phenylacetate to
methyl acrylate catalyzed by carbohydrate-containing chiral
crown ethers [6-10]. Recently, Itoh et al. published the
synthesis of several ꢁ-D-glucose-based chiral macrocycles,
the application of which in a Michael addition led to
relatively high enantioselectivities [11].
2. RESULTS AND DISCUSSION
The addition of 2-nitropropane to substituted chalcones
and chalcone analogues was investigated under phase
transfer catalytic conditions in the presence of azacrown
ethers 1 and 2 (Scheme 1). In earlier studies, these catalysts
*Address correspondence to this author at the Department of Organic
Chemistry and Technology, Budapest University of Technology and
Economics, H-1521 Budapest, Hungary; Tel: +36 1 463 2194;
Fax: +36 1 463 3648; E-mail: pbako@mail.bme.hu
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© 2010 Bentham Science Publishers Ltd.

Enantioselective Michael Addition of 2-Nitropropane to Substituted Chalcones
Letters in Organic Chemistry, 2010, Vol. 7, No. 6
425
gave the best results. The ꢀ,ꢁ-unsaturated ketones were
prepared according to the procedure described in the
literature [17-25].
the electronic factors influencing the acidity of adjacent
protons should be considered. In the case of the dichloro
compounds even lower optical purities (for 14 an ee of 40%,
while for 15 an ee of 23%) were obtained.
OCH3
OCH3
O
O
Then the effect of the substituents in the aromatic ring
(Ar1) next to the carbonyl group was studied provided that
Ar2 = Ph. It is obvious that these products (16-25) were
formed in somewhat better optical yields than compounds 4-
15. The Michael adducts with chloro substituent (16-18),
methyl substituent (19, 20), methoxy substituent (21, 22) and
nitro substituent (23-25) were obtained in 46-68 (entry 14-
16), 55-59 (entry 17-18), 51-58 (entry 19-20) and 41-58 %
ee (21-23), respectively. With one exception (22), the best
optical yields were again obtained in the case of the 3-
substituted derivatives (17, 20, 24 ). It can also be seen that
the results are quite similar, there is no such a significant
difference between the above results (41-68% ee) and those
experienced in the case of compounds 4-15 (14-58% ee).
This must be due to the mere remote position of the
substituent, and the steric effects are not so relevant. These
substituents may influence only the reactivity of the carbonyl
group. Even the presence of sterically more demanding
substituents (as in 26 and 27) did not cause a significant
effect (the ee was 49 and 53%, respectively), only the
chemical yields became lower (30 and 23 %, respectively).
O
O
O
O
O
O
R
S
S
S
N
R
N
R
O
O
O
O
O
O
1
2
R = -CH2CH2CH2OH
The Michael addition was carried out in a solid-liquid
two phase system; using toluene, 35 mol% of sodium tert-
o
butoxide and 7 mol% of the chiral catalyst 1 or 2 at 22 C.
After obtaining the products by preparative TLC, the
asymmetric inductions expressed in terms of enantiomeric
1
excess (ee %) were determined by H NMR spectroscopy in
the presence of the chiral shift reagent (+)-Eu(hfc)3.
First, we wished to study the influence of the substituents
in the aromatic ring of the chalcone on the chemical and
optical yields of the reaction. Table 1 contains the data
obtained with substituted chalcones in the presence of
catalyst 1. As a comparison, the data obtained for the
unsubstituted chalcone (Ar1 = Ph, Ar2 = Ph) are also shown
in the Table (entry 1). In this case, the ee was 85% [4].
It can be concluded that the substituents in the aromatic
ring placed closer to the reaction site (Ar2) have a more
pronounced (decreasing) effect on the optical yields (as
compared with compound 3) than the substituents in the
aromatic ring next to the carbonyl group (Ar1).
It can be seen from Table 1 that the yield and the
enantioselectivity depend strongly on the substituents in the
aromatic ring. Any kind of substituent (Cl, CH3, NO2, OCH3,
F, in different positions) resulted in a decrease in the optical
yield (14-68% ee) as compared to the unsubstituted chalcone
(85% ee). In the first place, the substituents of ꢁ-phenyl ring
(Ar2) were changed, provided that Ar1 = Ph (entry 1-13).
Regarding the position of the chloro substituent, the most
significant enantiomeric excess (ee) was experienced in the
case of the 3-chloro derivative 5 (56%), that was a lower
value in case of the 2-chloro derivative 4 (43%) and much
lower for the 4-chloro species 6 (14%). In case of methyl-,
nitro- and methoxy substituents, the corresponding Michael
adducts were formed in ee-s of 31-35% (7-9), 37-50% (10-
11) and 34-58% (12-13), respectively. Independently of the
nature of the substituents, it seems to be general that the best
optical purity can be achieved in case of the meta position of
the substituent as shown by the example of compounds 5, 8,
11, and 12. This shows that the steric effect is more
considerable in position 2 than in position 3. In position 4,
Regarding the ꢁ-side, the best values were measured with
3-Cl, 3-Me and 3-OMe substituents (with ee values of 56, 55
and 58 %, respectively). The substituents in the Ar1 ring next
to the carbonyl group had a less significant effect on the
optical purity. The best enantioselectivities were obtained in
case of the 3-Cl, 3-Me, 2-OMe and 3-NO2 substituents (with
ee values of 68, 59, 58 and 58%, respectively).
Then the Michael addition was studied with chalcone
analogue ꢀ,ꢁ-enone derivatives (Scheme 2). The results are
summarized in Table 2. Entry 1 represents the results
obtained with the unsubstituted chalcone (Y1 = Y2 = Ph) [4].
In the first place, the effect of different alkyl groups and
naphthyl substituents was studied in place of Y1, keeping the
other substituent Y2 as phenyl. Only a low optical purity
(25% ee) was experienced in the reaction of
benzylideneacetone (Y1 = Me, entry 2), and no product was
t
formed in case of Bu substituent (entry 3). The best optical
yield (87% ee) was achieved with the 1-naphthyl ketone
(entry 4). In the case of the 2-naphthyl product (31), the ee
Ar1
O
O
CH3
NO2
CH3
Ar2
crown cat.
toluene
*
+
H
Ar2
Ar1
NaOBut
CH3
CH3
NO2
3-7
Scheme 1. Michael addition of 2-nitropropane to substituted chalcones, Ar1 and Ar2 listed in Table 1.

426 Letters in Organic Chemistry, 2010, Vol. 7, No. 6
Makó et al.
Table 1. Asymmetric Michael Addition of 2-Nitropropane to Substituted Chalcones Mediated by Chiral Azacrown Ether 1
b
Entry
Product
Ar 1
Ar 2
Time (h)
Yield (%) a
[ꢀ]D
E.e. % c
1
2
3
Ph
Ph
Ph
2-Cl-Ph
3-Cl-Ph
4-Cl-Ph
2-CH3-Ph
3-CH3-Ph
4-CH3-Ph
2-NO2-Ph
3-NO2-Ph
3-CH3O-Ph
4-CH3O-Ph
2,4-di-Cl-Ph
2-Cl-6-F-Ph
Ph
40
17
16
24
48
23
50
20
20
27
52
24
26
21
19
22
24
23
75
27
13
14
13
90
82
55
43
56
60
29
41
58
30
43
47
39
48
18
66
64
60
35
52
35
51
41
45
52
30
23
+ 70,3
+ 66,8
+ 60,0
+ 15,0
+ 24,8
+ 119,9
+ 54,4
+ 107,4
+ 67,6
+ 53,4
+ 39,1
+ 53,1
+ 14,8
+ 16,9
+ 55,7
+ 60,6
+ 22,8
+ 59,8
+ 31,4
+ 54,4
+ 24,3
+ 38,7
+ 39,6
+ 45,4
+ 54,7
85 ( R )d
43 ( R )
56 ( R )
14 ( R )
31
4
3
5
Ph
4
6
Ph
5
7
Ph
6
8
Ph
55
7
9
Ph
49
37 e
50 e
8
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
Ph
9
Ph
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
Ph
58
Ph
34
Ph
40
Ph
23
2-Cl-Ph
3-Cl-Ph
4-Cl-Ph
2-CH3-Ph
3-CH3-Ph
2-CH3O-Ph
3-CH3O-Ph
2-NO2-Ph
3-NO2-Ph
4-NO2-Ph
2-EtOCH2O-Ph
2-iPrO-Ph
52 ( R )
68 ( R )
56 ( R )
55
Ph
Ph
Ph
Ph
59
Ph
58
Ph
51
41 e
58 e
49 e
Ph
Ph
Ph
Ph
49
Ph
53
aBased on substance isolated by preparative TLC; bIn CH2Cl2 at 22 oC; cDetermined by 1H NMR spectroscopy; dLit. [4]; eDetermined by chiral HPLC.
Y1
O
O
CH3
NO2
CH3
Y2
crown cat.
toluene
*
+
H
Y2
Y1
NaOBut
CH3
CH3
NO2
28-36
Scheme 2. Michael addition of 2-nitropropane to ꢀ,ꢁ-enones, Y1 and Y2 listed in Table 2.
Table 2. Asymmetric Michael Addition of 2-Nitropropane to Chalcone Analogues Mediated by Chiral Azacrown Ether 1
b
Entry
Product
Y1
Y2
Time (h)
Yield (%) a
[a]D
E.e. % c
1
2
3
Ph
Me
But
Ph
Ph
28
93
60
27
76
118
60
90
41
60
53
34
-
+68,7
+9,0
-
85 d
25
-
28
29
30
31
32
33
34
35
36
3
Ph
4
1-naphtyl
2-naphtyl
Ph
Ph
35
32
71
-
-8,5
+78,8
-27,8
-
87
38
76
-
32 d
41
-
5
Ph
6
Me
But
7
Ph
8
Ph
1-naphtyl
2-naphtyl
1-naphtyl
51
19
-
+84,1
+65,6
-
9
Ph
But
10
aBased on substance isolated by preparative TLC; bIn CH2Cl2 at 22oC; cDetermined by 1H NMR spectroscopy; dLit. [4].

Enantioselective Michael Addition of 2-Nitropropane to Substituted Chalcones
Letters in Organic Chemistry, 2010, Vol. 7, No. 6
427
Table 3. Asymmetric Michael Addition of 2-Nitropropane to Substituted Chalcones and Chalcone Analogues Catalyzed by
Mannose-Based Crown Ether 2
b
Entry
Product
Ar 1
Ar 2
Time (h)
Yield (%) a
[ꢀ]D
E.e. % c
1
2
3
4
5
6
7
8
3
Ph
Ph
Ph
3-Cl-Ph
3-CH3O-Ph
Ph
52
20
28
22
70
16
32
106
37
52
49
61
39
46
39
68
-74,8
-54,7
-49,3
-53,3
-30,8
-36,0
-8,6
92 ( S ) d
51 ( S )
54
5
12
17
21
24
30
32
Ph
3-Cl-Ph
2-CH3O-Ph
3-NO2-Ph
1-naphtyl
Ph
65 ( S )
Ph
57
54e
Ph
Ph
84
Me
-26,1
71
aBased on substance isolated by preparative TLC; bIn CH2Cl2 at 22 oC; cDetermined by 1H NMR spectroscopy; dLit. [26]; eDetermined by chiral HPLC.
value decreased to 38%. It is worthy to mention that the sign
of the optical rotation was different for the 1- and 2-naphthyl
Michael adducts (30 and 31, respectively). Steric effect may
be responsible for this phenomenon.
Varying the Y2 substituent and keeping the other one
(Y1) as phenyl, we experienced the following. In the case of
Me substituent (entry 6), product 32 was formed in 76 % ee,
while with tBu group there was no reaction at all (entry 7).
Presence of the 1- and 2-naphthyl groups resulted in modest
optical purities (32 % ee for 34 and 41% ee for 35,
respectively). It can be seen that if either Y1 or Y2 was a tBu
substituent (entry 3, 7 and 10 respectively), the Michael
addition was prevented.
The chloro substituent of the aromatic ring may be easily
removed by catalytic hydrogenation in the presence of Pd/C
and sodium acetate to provide unsubstituted 3, whose
antipodes were already characterized [27]. The
hydrogenation of compounds 4, 5, 6, 16, 17, 18, comprising
the (+)-enantiomer in excess led to product 3 with (+)-
optical rotation that is of R configuration. Hence, the
products mentioned above are also of R configuration. The
negative sign of the optical rotation for the compounds (5
and 17) formed in the presence of mannose-based catalyst 2
corresponds to configuration S.
It can be concluded that in the Michael addition studied,
the asymmetric induction depends strongly on the nature of
the Ar1/Y1 and Ar2/Y2 substituents. The Ar1/Y1 substituents
had a more significant impact an the optical yields of the
Michael adducts than the Ar2/Y2 substituents. The steric
effect of the substituents seems to have a larger impact on
the asymmetric induction than the electronic one.
Then the Michael additions were carried out in the
presence of mannose-based crown catalyst 2. The results are
summarized in Table 3, where entry 1 shows the
observations with chalcone as a comparison (the S antipode
was formed in an ee of 92%) [26].
Comparing the data of Table 3 with those shown in
Tables 1 and 2, one can see that in respect of products 5, 12,
17, 21, 24, 30 and 32, the asymmetric induction was
somewhat lower in the presence of mannose-based catalyst
2, as compared to the cases, where glucose-based 1 was
applied. The chemical yields were similar. As an example,
adduct 5 was formed in 56 and 51% ee using catalyst 1 and
2, respectively (Table 1/entry 3 and Table 3/entry 2). A
similar significant decrease was experienced in the case of
the other model compounds. The highest optical putity (84%
ee) was achieved for the formation of product 30 (Ar1 = 1-
naphthyl, Ar2 = Ph). In case of trans-crotonophenone,
product 32 was obtained in a quite good optical yield (71%
ee), but all of the ee values detected remained below the
optical purity of 92% observed for the Michael adduct of the
unsubstituted chalcone.
3. EXPERIMENTAL
3.1. General
Melting points were taken on using a Büchi 510
apparatus and are uncorrected The compounds were
crystallized from ethanol. The specific rotation was
measured with the help of a Perkin-Elmer 241 polarimeter at
°
22 C. NMR spectra were obtained on a Brucker 300 and a
Brucker DRX-500 instrument in CDCl3 with TMS as the
internal standard. Mass spectra were registered from m-
nitrobenzyl alcohol (NOBA) matrix on a Varian MAT312
instrument. Analytical and preparative thin layer
chromatography was performed on silica gel plates (60 GF-
254, Merck), while column chromatography was carried out
using 70-230 mesh silica gel (Merck) using hexane–ethyl
acetate, 10:1 as the eluant. Chemicals and the shift reagent
Eu(hfc)3 were purchased from Aldrich Chem. Co.
Enantoselectivities were determined by 1H NMR
spectroscopy in the presence of chiral shift reagent or by
chiral HPLC analysis (Chiralpak AD-H or Chiralcel OD-H,
detector JASCO UV-1575, pump:PU-1580).
It seems to be general that while the glucose-based
catalyst (1) brings about the prefered formation of the
antipode with positive optical rotation (R), the mannose-
based catalyst (2) promotes the formation of the other
antipode (S). It is worth mentioning that compounds 2 and 1
differ only in the configuration of the C(2) atom of the sugar
moiety. In the glucopyranoside-based 1, position of the C(2)-
O and C(3)-O groups is trans, while that in 2 is cis .
3.2. General Procedure for the Michael Addition of 2-
Nitropropane to ꢀ,ꢁ-enones
The corresponding azacrown ether catalyst (0.10 mmol)
and 0.05 g (0.50 mmol) of sodium tert-butoxide was added
The absolute configurations were proved in the case of
the new chloro-derivatives 4-6, 16-18 by a chemical method.

428 Letters in Organic Chemistry, 2010, Vol. 7, No. 6
Makó et al.

Enantioselective Michael Addition of 2-Nitropropane to Substituted Chalcones
Letters in Organic Chemistry, 2010, Vol. 7, No. 6
429

430 Letters in Organic Chemistry, 2010, Vol. 7, No. 6
Makó et al.
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Tꢂke, L.; Bakó, P.; Keserꢃ, M.G.; Albert, M.; Fenichel, L.
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J.; Novák, T.; Parlagh, Gy.; Tꢂke, L. Enantioselective Michael
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to a solution of 1.44 mmol of ꢀ,ꢁ-enone and 0.3 mL (3.36
mmol) of 2-nitropropane in 3 mL of dry toluene. The mixture
was stirred at room temperature under argon. After a reaction
time of 13 to 106 h, toluene (7 mL) and water (10 mL) were
added and the mixture was stirred for several minutes. The
organic phase was washed with water and dried (Na2SO4).
The crude product obtained after evaporating the solvent was
purified by preparative TLC (silica gel, hexane – ethyl
acetate, 10:1 as the eluant) to give the Michael adducts (4-
32) in a pure form.
[9]
[10]
[11]
[12]
[13]
The reaction times, yields, optical rotation and ee%
values of the new Michael adducts are listed in Tables 1-3,
1
while the melting points and H NMR spectral parameters
are shown in Tables 4-6.
Physical and spectroscopycal data of compounds 3, 9, 13,
18, 28 and 32 are not included in the Tables, as those were
identical with the characteristics described in the literature
(3, [4], 9, 13, 18 [15], 28 [28] and 32 [29]. The optical
rotations measured were included in all case.
3.3. Hydrogenation of Compounds Consisting Chloro-
Substituent
[14]
[15]
A solution of the Michael adduct (4-6, 16-18) (0.9
mmol), sodium acetate (0.1 g, 1.22 mmol) and Pd/C (10%,
100 mg) in methanol (5 mL) was stirred under an
atmosphere of H2 (1 atm) at room temperature for 14 h. The
reaction mixture was filtered and the filtrate was
concentrated. The residue was purified by crystallization to
[16]
o
20
1
give 3 as a solid (0.24 g, 80%); mp 146-148 C; ([ꢀ]D
=
+80.8 (c 1, CH2Cl2) for the pure (+)-(R)-enantiomer). H
NMR (CDCl3) ꢀ ppm:1.54 (s, 3H), 1.63 (s, 3H), 3.70 (dd,
1H, Jgem = 17.6, 3.1 Hz), 4.09 (dd, 1H, Jgem = 17.6, 10.0 Hz)
4.15 (dd, 1H), 7.18-7.32 (m, 5H, CHPhH), 7.42 (t, 2H,
COPhH-m), 7.53 (t, 1H, COPhH-p), 7.85 (d, 2H, COPhH-o);
MS (EI) m/z 298 (M+H)+.
[17]
[18]
[19]
[20]
[21]
[22]
[23]
ACKNOWLEDGEMENT
The above project was supported by the Hungarian
Scientific Research Fund (OTKA K 75098).
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