Organocatalytic asymmetric Michael addition of aldehydes and ketones to nitroalkenes catalyzed by adamantoyl L-prolinamide

Article abstract of DOI:10.1039/c4ra11214h

A series of adamantoyl l-prolinamides have been synthesized. These compounds have been found to be highly efficient organocatalysts for the Michael addition of aldehydes and ketones to nitroalkenes. Under the optimized reaction conditions, the correspondi

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Organocatalytic Asymmetric Michael Addition of Aldehydes and
Ketones to Nitroalkenes Catalyzed by Adamantoyl L-Prolinamide
Yongchao Wang,‡ Dong Li,‡ Jun Lin∗ and Kun Wei∗
Received (in XXX, XXX) XthXXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
A series of Adamantoyl L-prolinamides have been synthesized. These compounds have been found to be
highly efficient organocatalysts for the Michael addition of aldehydes and ketones to nitroalkenes. Under
the optimized reaction conditions, the corresponding Michael adducts were obtained in good yields (up to
95%), excellent enantioselectivities (up to 99% ee) and moderate diastereoselectivities.
10 Introduction
The organocatalytic asymmetric Michael addition of ketones or
aldehydes to nitroalkenes, as carbon-carbon bond-forming
reactions in organic synthesis, is one of the most powerful and
effective methods for preparation of chiral γ-nitro carbonyl
15 compounds. The nitro group can be easily transformed into
various useful functional groups, such as amines, nitrile oxides,
ketones, and carboxylic acids, etc.1,2 These Michael adducts were
used as important starting materials in the enantioselective
synthesis of chiral biologically active compounds and natural
20 products, such as alkaloids (-)-Rolipram,3 (+)-cryptopleurine,4
(+)-ipalbidine,5
(-)-pancracine,6 and (-)-botryodiplodin.7
The Michael addition can be classified into covalent
(enamine,8 iminium,9 or dienamine activation catalysis10) or
25 noncovalent (hydrogen-bonding and Brønsted acid,11 Brønsted
base and bifunctional activation catalysis,12 or phase-transfer
catalysis13) depending on characteristics of the chemical structure
of the catalyst and the substrate-catalyst interaction. As one of the
most widely used modern organocatalysis based on covalent
30 character, proline and proline derivatives, such as diarylprolinol
silyl ethers, prolinamides, and pyrrolidines, play an important
role in asymmetric catalysis.14 Among a variety of different
catalysts, prolinamide derivatives have been demonstrated as an
excellent reagent in asymmetric enamine organocatalysis.15
35 Although these organocatalysts give good results in the process
of asymmetric Michael addition reactions, discovery of
Figure 1. L-proline adamantoyl L-prolinamide catalysts.
50 Results and discussion
N-Boc-L-proline,
rimantadine,
2-aminoadamantane,
1-
3-
aminoadamantane,
1-amino-3,5-dimethyl-adamantane,
aminoadamantan-1-ol, N-Boc-glycine, N-Boc-L-leucine, N-Boc-
L-phenylalanine are commercially available. With these
55 compounds as starting materials, ten amides (2-11) were easily
prepared in two steps in 84–91% overall yield (Scheme 1 and
Scheme 2, for the general procedure see experimental section).
environment-friendly
nonmetal-catalyzed
asymmetric
organocatalyst in Michael addition reaction is still needed. To the
best of our knowledge, except for several adamantanamine-
40 derived catalysts,16 there is no report to date of adamantoyl L-
prolinamides as organocatalyst used in asymmetric Michael
addition reactions. Thus, adamantanamine-derived catalysts 2–11
(Figure 1) were designed and tested. It was demonstrated that
compound 5 (3,5-dimethyl-1-adamantanamine-prolinamide) had
45 improved effect in catalyzing the asymmetric Michael addition of
aldehydes and ketones to nitroalkenes, and the preliminary
experiment results were reported here.
60
Scheme 1. Synthetic routes to adamantoyl L-prolinamides 2-6.
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enantioselectivity (24% ee, entry 2) was obtained. Among the
organocatalysts surveyed, prolinamides 3 and 4 showed good
catalytic activity with moderate to good enantioselectivity
15 (entries 3 and 4). To our delight, when prolinamide 5 was used,
the best result was observed with an excellent yield (92%) and
enantioselectivity (93% ee, entry 5). In addition, prolinamide 6
was also evaluated (entry 6). Although excellent
enantioselectivity (90% ee) was obtained, the yield (57%) was
20 moderate. To further investigate the role of catalysts, several
adamantanamine-derived chiral catalysts (7-11) were synthesized
and tested in the model Michael reaction. The experiment result
Scheme 2. Synthetic routes to catalysts 7-11.
Initially, the model reaction of propanal (12a) with nitrostyrene
(13a) was carried out in the presence of 10 mol % of catalyst and
10 mol % of benzoic acid as an additive in toluene under room
temperature (Table 1). As shown in Table 1, catalysts 1-11
exhibited significantly different catalytic activity and
enantioselectivity toward the process. L-proline (1) could catalyze
this reaction, but rather poor yield and stereoselectivity were
exhibited
a
moderate performance on both yield and
5
stereoselectivity (entries 7-11). According to the above results,
25 3,5-dimethyl-1-adamantanamine-prolinamide (5) was confirmed
to be the most effective catalyst in terms of both the yield and
enantioselectivity of the reaction.
10 observed (Table1, entry 1). Although prolinamide 2 could
efficiently promote the process with high yields (90%), poor
Table 1. Screening of catalysts and solvents.a
30
entry
catalyst
solvent
time (h)
yieldb(%)
syn/antic
ee(syn)d(%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
1
2
3
4
5
6
7
8
9
10
11
5
5
5
5
5
5
5
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
CH2Cl2
CHCl3
24
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
36
90
94
93
92
57
81
72
77
45
38
86
92
79
77
82
43
59
66:34
65:35
61:39
70:30
62:38
64:36
58:42
60:40
59:41
64:36
66:34
79:21
65:35
68:32
69:31
68:32
70:30
67:33
40
24
63
84
93
90
28
41
53
54
61
88
90
89
82
62
72
72
THF
n-hexane
methanol
acetonitrile
isopropanol
19e
5
toluene
48
79
67:33
91
aAll reactions were carried out with 12a (3.0 mmol), 13a (1.0 mmol), and benzoic acid (10 mol%) in the presence of catalyst (10 mol%) in solvent (2.0
mL) at room temprature. bYield of the isolated product. cDetermined by 1H NMR analysis of the crude products. dDetermined by chiral HPLC, the
absolute configuration was established by comparison with literature data.17, 18, 20 e5 mol% of catalyst 5 was used.
To further optimize the reaction conditions, some reaction
(Table 1, entry 19). Next, the effect of a series of different
35 parameters, including solvents, additives, temperatures, and 50 additives was tested and the results are summarized in Table 2.
amounts of catalyst were examined, and the results are shown in
Tables 1 and 2. A range of typical solvents were first screened in
the presence of benzoic acid (10 mol%) and catalyst 5 (10 mol%)
at room temperature. Some nonpolar and aprotic solvents, such as
Apparently, the reaction proceeded very slowly in the absence of
acid additives and provided poor yield after 48 h (Table 2, entries
1-3). When benzoic acid was used as an acid additive, the best
result was observed with an excellent yield (92%) and
40 hexane, THF, toluene, CHCl3, and CH2Cl2, were investigated for 55 enantioselectivity (93% ee) (Table 2, entry 8). Although the other
this reaction (Table 1, entries 5 and 12-15). The excellent yields
and enantioselectivity (92% yield, and 93% ee) were obtained
when the reaction was carried out in toluene (Table 1, entry 5).
However, some polar solvents, such as methanol, acetonitrile, and
acid additives, such as p-TSA, HCOOH, CH3COOH, CF3COOH,
were also beneficial for this reaction, their yields and
enantioselectivities were slightly lower than the result with
PhCOOH (Table 2, entries 4-7). In addition, three chiral acids,
45 isopropanol, gave moderate enantioselectivities (Table 1, entries 60 tartaric acid, N-Boc-glycine and mandelic acid, were also
16-18), which were unsatisfactory. Moreover, we examined the
influence of catalyst loading on the reaction. When the catalyst 5
was reduced to 5 mol%, the prolonged reaction time was required
employed and gave moderate yield and enantioselectivities
(Table 2, entries 9-11). It was implied that the acid additives only
provide the proton in the Michael addition. The influence of acid
2
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loading on the Michael addition was also examined (Table 2,
significantly except for the increase of diastereoselectivity (82:18
dr) (Table 2, entry 14) at 0 °C by decreasing the reaction
temperature from room temperature to −40 °C. Based on the
overall evaluation, 0 °C was selected to be the optimal reaction
entries 8, 12, and 13). It was observed that 10mol% of PhCOOH
gave the optimal results. We also investigated the effect of
reaction temperature (Table 2, entries 8 and 14–16). The results
5
showed that yields and enantioselectivities have not changed 10 temperature.
Under the above optimized conditions, the scope of the
Table2 Screening of additive and temperature.a
asymmetric Michael addition reaction was investigated by
20 applying different aldehydes and nitroalkenes in the presence of
10 mol % of catalyst 5 and 10 mol% of benzoic acid in toluene at
0 °C. The results are summarized in Table 3. The Michael
addition products were obtained with good yields (81-94%) and
excellent enantioselectivities (92-99% ee). The steric hindrance
25 of the R1 group for aldehydes was beneficial for the increase of
diastereoselectivity to a large degree (entries 1-7). For examples,
the reaction of propanal gave a moderate diastereoselectivity
(64:36 dr) (entry 1), while that of isovaleraldehyde provided an
excellent diastereoselectivity (99:1 dr) (entry 4). Moreover,
30 aromatic nitroalkenes, regardless of electron-donating or electron-
withdrawing substituents on the phenyl ring (entries 8-15),
participated in this process in high yield (81-94%) and excellent
ee values (95-99%). The excellent enantioselectivities (93–97%
ee) was also observed for the Michael addition of aldehydes to
35 nitroalkenes containing heteroaryl groups (entries 16-17).
Additionally, catalyst 5 could be applied for the Michael addition
of alkyl-substituted nitroalkene to aldehydes with high yield
(94%) and excellent enantioselectivities (99%, entriy 18).
Entry Additive
Tem.
(°C)
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
0
Time Yieldb( syn/ant
eed(%
)
(h)
48
48
48
12
12
12
12
12
12
12
12
12
12
12
36
96
%)
<5
<5
<5
48
81
71
88
92
81
47
58
93
73
90
89
91
ic
1
2
None
H2O
nd
nd
nd
nd
nd
nd
71
84
90
91
93
81
79
74
91
78
94
95
96
3
Et3N
4
p-TSA
59:41
60:40
68:32
67:33
62:38
69:31
63:37
66:34
65:35
64:36
82:18
65:35
72:28
5
HCOOH
6
7
8
9
10
11
12e
13f
14
15
16
CH3COOH
CF3COOH
benzoic acid
tartaric acid
N-Boc-glycine
mandelic acid
benzoic acid
benzoic acid
benzoic acid
benzoic acid
benzoic acid
-20
-40
aAll reactions were carried out with 12a (1.0 mmol), 13a (3.0 mmol) and
additive (10 mol%)in the presence of catalyst 5 (10 mol%) in toluene (2.0
b
c
15 mL). Yield of the isolated product. Determined by 1H NMR analysis of
d
e
the crude products. Determined by chiral HPLC. 20 mol% of benzoic
acid was used. f5 mol% of benzoic acid was used.
40 Table 3. Asymmetric Michael Additions of Aldehydes to nitroalkenes catalyzed by 5a.
Entry
1
Product
Yieldb(%)
90
syn:antic
ee(syn)d(%)
Entry
10
Product
Yieldb(%)
91
syn:antic
ee (syn)d(%)
64:36
95
91:9
96
2
3
4
5
86
87
81
89
86:14
89:11
99:1
98
92
98
93
11
12
13
14
82
81
83
93
90:10
90:10
86:14
85:15
95
98
98
97
O
Ph
NO2
H
nPr
77:23
6
7
90
89
81:19
97:3
96
97
15
16
89
83
91:9
98
93
84:16
8
9
94
90
92:8
99
98
17
18
85
94
60:40
95:5
97
98
86:14
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aAll reactions were carried out with nitroalkenes (1.0 mmol) and aldehydes (3.0 mmol) in the presence of catalyst 5 (10 mol%) and benzoic acid (10
b
c
d
mol%) in toluene 2.0 mL) at 0 °C. Yield of the isolated product. Determined by 1H NMR analysis of the crude products. Determined by chiral HPLC,
the absolute configuration was established by comparison with literature data. 17, 18, 20
On the basis of above condition, the catalytic direct
asymmetric Michael addition of ketones to nitroalkenes was also
ee; Table 4, entry 2). The use of cyclopentanone afforded good
diastereoselectivity (70:10 dr) and moderate enantioselectivity
5
investigated, and the results are summarized in Table 4. As 15 (40% ee). Notably, when cyclohexane was employed, the
shown in Table 4, a dramatic lack of selectivity (55:45 dr, and
2% ee) was observed when using aliphatic ketone (Table 4,
entry1). It was found that the ring size of cyclic ketones was a
corresponding adduct was obtained with high yield (89%),
excellent diastereoselectivity (99:1 dr) and excellent
enantioselectivity (99% ee). Additionally, aromatic nitroalkenes
containing electron-donating or electron-withdrawing substituents
10 strong influence on the diastereoselectivity and enantioselectivity.
Reaction of cyclobutanone with 13a proceeded with moderate 20 on the phenyl ring and heteroaryl groups (entries 5-12) gave high
diastereoselectivity (67:33 dr) and poor enantioselectivity (11%
yield (81-89%) and excellent ee values (85-98%).
Table 4. Asymmetric Michael additions of Ketones to nitroalkenes catalyzed by 5a.
Entry
1
Product
Yieldb(%)
95
syn:antic
ee(syn)d(%)
Entry
7
Product
Yieldb(%)
84
syn:antic
ee(syn)d(%)
-
2
93:7
85
2
3
4
92
87
89
67:33
70:10
99:1
11
40
99
8
9
88
83
81
91:9
99:1
98
96
85
10
82:18
5
6
84
86
98:2
99:1
96
90
11
12
87
84
88:12
93:7
97
93
25 aAll reactions were carried out with nitroalkenes(1.0 mmol) andketones (3.0 mmol) in the presence of catalyst 5 (10 mol%) benzoic acid (10 mol%) in
b
c
1
d
toluene (1.0 mL) at 0 °C. Yield of the isolated product. Determined by H NMR analysis of the crude products. Determined by chiral HPLC, the
absolute configuration was established by comparison with literature data. 19
In order to account for the good enantioselectivity of the reaction,
a plausible transition-state model is proposed in Scheme 3. The
30 pyrrolidine functionality activates the aldehydeor ketones through
the formation of an enamine intermediate, and the nitro group of
trans-β-nitrostyrene is directed toward the amide group by the
hydrogen bond between the NH group of the amide and the nitro
group. The enamine formed in situ attacks the Si face of the
35 nitroalkene to finish the Michael adduct. Also, the bulky
aminoadamantane group is considered to be important to the high
catalytic activity and enantioselectivity and diastereoselectivity of
the catalyzed reactions. Our previous research20 and some other
typical literatures21-23 could be taken as a support of the
40 transition-state model.
Scheme 3.Possible transition state of the reaction
45
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N-t-butyloxycarbonyl-rimantadine-L-prolineamide (2a). 95%
Conclusions
20
yield; White solid, m.p. 181–183 °C; [α]D = –48.5 (c 1.0,
In summary, we have developed a new prolinamide catalyst 5 for
the asymmetric conjugate addition reactions of aldehydes or
ketonesto nitroalkenes. This catalyst exhibited rather high
catalytic efficiency and good to excellent stereoselectivity. Since
the catalyst 5 can be easily prepared from commercially available
Boc-L-proline and 1-amino-3,5-dimethyl-adamantane in two
steps, we believe that catalyst 5 is an ideal candidate for
laboratory or large-scale preparations. Further applications of the
1
CHCl3); H NMR (400 MHz, CDCl3, TMS):
δ 7.60 (s, 1H), 4.34
60 –4.24 (m, 1H), 4.00 (m, 1H), 3.49–3.32 (m, 2H), 2.45 (s, 1H),
2.15 (s, 1H), 1.91–1.73 (m, 15H), 1.63 (d, J = 8.0 Hz, 2H), 1.47
5
(s, 9H); 13C NMR (100 MHz, CDCl3, TMS):
δ 170.6, 154.8, 80.3,
61.5, 59.7, 53.0, 47.1, 38.3, 37.1, 37.0, 35.8, 30.9, 28.4, 28.3,
14.4; IR (KBr): 1160, 1385, 1532, 1663, 2901, 3330 cm-1; HRMS
65 (EI) m/z: calcd for C22H36N2O3 [M+Na]+ 399.2618, found
399.2618.
10 catalyst for a wider scope of reactions are being studied in our
laboratory.
Rimantadine-L-prolineamide (2). 96% yield; White solid, m.p.
1
123–126 °C; [α]D20 = –87.7 (c 1.0, CHCl3); H NMR (400 MHz,
CDCl3, TMS):
δ 7.67 (d, J = 9.2 Hz, 1H), 3.75–3.71 (m, 1H),
Experimental section
70 3.65–3.58 (m, 1H), 3.07–3.01 (m, 1H), 2.18–2.08 (m, 2H), 1.98–
1.92 (m, 4H), 1.77–1.46 (m, 16H), 1.02 (d, J = 9.2 Hz, 3H); 13C
General information
NMR (100 MHz, CDCl3, TMS):
δ 174.1, 60.8, 52.1, 47.4, 38.4,
Reagents and Materials were of the highest commercially
15 available (Adamas) grade and used without further purification.
Solvents were purified by standard procedures and distilled
before use. The reactions were monitored by thin layer
37.1, 36.0, 31.1, 28.3, 26.3, 14.1; IR (KBr): 1103, 1511, 1654,
2672, 2844, 2904, 3289 cm-1; HRMS (EI) m/z: calcd for
75 C15H24N2O [M+H]+ 249.1961, found 249.1963.
N-t-butyloxycarbonyl-2-aminoadamantane-L-prolineamide
(3a). The method for the synthesis of 3a was similar to that of 2a.
chromatography (TLC) using silica gel GF254
.
Column
chromatography was performed on silica gel (200–300 mesh).
20 Compounds were visualized by UV and spraying with H2SO4
(10%) in ethanol and followed by heating. The NMR spectra
were recorded on a Bruker DRX400 (1H: 400 MHz, 13C: 100
MHz) or Bruker DRX500 (1H: 500 MHz, 13C: 125 MHz) with
TMS as the internal standard, chemical shifts (δ) are expressed in
25 ppm, and J values are given in Hz, and deuterated CDCl3 and was
used as solvent. IR spectra were recorded on a FT-IR Thermo
Nicolet Avatar 360 using KBr pellet. The mass spectroscopic data
were obtained at the Agilent 1100 LC/MSD Trap LC-mass
spectrometer. HPLC analysis was performed with a Shimadzu
30 LC-10A instrument equipped with Daicel HPLC columns.
General Procedure for Preparation of adamantoyl L-
prolinamide 2-6.
3a is white solid, 93% yield; m.p. 138–141 °C; [α]D20 = –91.4 (c
1
1.0, CHCl3); H NMR (400 MHz, CDCl3, TMS):
δ
7.60 (s, 1H),
80 4.34–4.24 (m, 1H), 4.00 (m, 1H), 3.49–3.32 (m, 2H), 2.45 (s,
1H), 2.15 (s, 1H), 1.91–1.73 (m, 15H), 1.63 (d, J = 8.0 Hz, 2H),
1.47 (s, 9H); 13C NMR (100 MHz, CDCl3, TMS):
80.4, 59.8, 53.2, 47.1, 37.5, 37.1, 37.0, 31.8, 37.8, 28.4, 27.2,
24.6; IR (KBr): 1168, 1380, 1540, 1650, 1712, 2905, 3064, 3289
85 cm-1; HRMS (EI) m/z: calcd for C20H32N2O3 [M+Na]+ 371.2305,
found 371.2305.
2-Aminoadamantane-L-prolineamide (3). The method for the
synthesis of 3 was similar to that of 2. 3 is white solid, 94% yield;
m.p. 108–112 °C; [α]D20 = –37.6 (c 1.0, CHCl3); H NMR (400
δ 170.4, 156.1,
1
90 MHz, CDCl3, TMS):
δ 8.19 (d, J = 5.6 Hz, 1H), 3.99 (d, J = 8.8
Hz, 1H), 3.76–3.73 (m, 1H), 3.07–3.01 (m, 1H), 2.96–2.90 (m,
To a stirred solution of N-t-butyloxycarbonyl-L-proline (1.075g,
5 mmol) in dry dichloromethane (15 mL), was added DMAP
35 (210 mg, 1.5 mmol). The mixture was allowed to stir for 15min
and then cooled to 0 °C and then EDCI (1.22g, 5.5 mmol) was
added. After 20 min, a solution of aminoadamantanes (4 mmol)
in dichloromethane (15 mL) was added to the above reaction
mixture. The resulting solution was stirred at room temperature
40 until complete consumption of nitroalkene (monitored by TLC).
The reaction was quenched with water and extracted with
dichloromethane (3 × 50mL). The combined organic layers were
washed with saturated brine solution (20 mL), followed by drying
over Na2SO4 and evaporating in vacuo. The crude product was
45 purified by column chromatography to give the pure N-t-
butyloxycarbonyl-L-prolineamide (2a).
To a solution of 2a (4 mmol) in CH2Cl2 (10 mL) was added TFA
(3 mL). After stirring at 0 °C for 2.5 hour, the solution was
concentrated under vacuum to leave a glutinous phase. The pH of
50 the mixture was brought into the range of 12 by the addition of
2M NaOH. The aqueous phase was extracted with ethyl acetate.
The ethyl acetate extracts were pooled, washed with brine, dried
over anhydrous Na2SO4, filtered off and the solvent was
evaporated at low pressure to give a crude residue that was
55 purified by column chromatography to give the pure L-
prolineamide (2).
1H), 2.18–2.09 (m, 2H), 1.97–1.70 (m, 16H), 1.68–1.62 (m, 2H);
13C NMR (100 MHz, CDCl3, TMS):
δ 173.9, 60.8, 52.3, 47.3,
37.6, 37.1, 37.0, 32.2, 32.0, 32.0, 30.9, 27.3, 27.1, 26.2; IR (KBr):
95 874, 1095, 1507, 1663, 2660, 2860, 2913, 3309 cm-1; HRMS (EI)
m/z: calcd for C15H24N2O [M+H]+ 249.1961, found 249.1963.
N-t-butyloxycarbonyl-1-aminoadamantane-L-prolineamide
(4a).The method for the synthesis of 4a was similar to that of 2a.
20
4a is amorphous powder, 88% yield; [α]D = –95.3 (c 1.0,
1
100 CHCl3); H NMR (400 MHz, CDCl3, TMS):
δ 7.28 (s, 1H), 5.66
(s, 1H), 4.19–4.07 (m, 1H), 3.43 (m, 2H), 2.33 (s, 1H), 2.13–2.07
(m, 4H), 1.98 (d, J = 3 Hz, 6H), 1.84 (s, 2H), 1.67 (s, 6H), 1.48
(s, J, 9H); 13C NMR (100 MHz, CDCl3, TMS):
δ 171.5, 154.7,
80.3, 61.8, 51.5, 47.0, 41.6, 36.3, 31.1, 29.4, 28.4, 27.6, 23.7; IR
105 (KBr): 1164, 1385, 1646, 1707, 2901, 3321 cm-1; HRMS (EI) m/z:
calcd for C20H32N2O3 [M+Na]+ 371.2311, found 371.2315.
1-Aminoadamantane-L-prolineamide (4). The method for the
synthesis of 4 was similar to that of 2. 4 is white solid, 97% yield;
m.p. 103–106 °C; [α]D20 = –74.4 (c 1.0, CHCl3); H NMR (400
1
110 MHz, CDCl3, TMS):
δ 7.35 (s, 1H), 3.61–3.58 (m, 1H), 3.02–
2.96 (m, 1H), 2.91–2.85 (m, 1H), 2.23 (s, 2H), 2.01 (s, 5H), 2.00
(s, 7H), 1.89–1.83 (m, 1H), 1.68 (s, 10H); 13C NMR (100 MHz,
CDCl3, TMS):
δ 174.1, 61.2, 50.7, 47.2, 41.6, 36.4, 30.8, 29.4,
26.2; IR (KBr): 1102, 1511, 1650, 2668, 2852, 2909, 3285 cm-1;
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DOI: 10.1039/C4RA11214H
HRMS (EI) m/z: calcd for C15H24N2O [M+H]+ 249.1966, found
249.1961.
chromatography to give the pure tert-butyl (2-(((3s,5s,7s)-
60 adamantan-1-yl)amino)-2-oxoethyl)carbamate (7a).
N-t-butyloxycarbonyl-1-amino-3,5-dimethyl-adamantane-L-
prolineamide (5a). The method for the synthesis of 5a was
similar to that of 2a. 5a is white solid, 90% yield; m.p. 168–171
To a solution of 7a (4 mmol) in CH2Cl2 (10 mL) was added TFA
(3 mL). After stirring at 0 °C for 2.5 hour, the solution was
concentrated under vacuum to leave a glutinous phase. The pH of
the mixture was brought into the range of 12 by the addition of
5
1
°C; [α]D20 = –6.8 (c 1.0, CHCl3); H NMR (400 MHz, CDCl3,
TMS):
δ 7.02 (s, 1H), 5.91 (s, 1H), 4.29 (s, 2H), 3.66 (s, 2H), 65 2M NaOH. The aqueous phase was extracted with ethyl acetate.
3.48–3.89 (m, 4H), 2.46 (s, 1H), 2.17 (s, 2H), 1.97–1.90 (m,
The ethyl acetate extracts were pooled, washed with brine, dried
over anhydrous Na2SO4, filtered off and the solvent was
evaporated at low pressure to give a crude residue that was
purified by column chromatography to give the pure L-
10H), 1.71–1.58 (m, 12H), 1.48 (s, 9H), 1.02 (d, J = 6.8 Hz, 6H);
10 13C NMR (100 MHz, CDCl3, TMS):
δ
171.6, 156.0, 80.3, 61.7,
60.0, 53.0, 47.1, 38.3, 37.0, 35.8, 31.2, 28.4, 28.2, 27.3, 24.7,
23.8, 14.4; IR (KBr): 1168, 1389, 1646, 1712, 2931, 3326 cm-1; 70 prolineamide (7).
HRMS (EI) m/z: calcd for C20H32N2O4 [M+Na]+ 399.2618, found
399.2615.
Tert-butyl
(2-(((3S,5S,7S)-adamantan-1-yl)amino)-2-
oxoethyl)carbamate (7a). White solid, 93% yield; m.p. 71–74
20
1
15 1-Amino-3,5-dimethyl-adamantane-L-prolineamide (5). The
°C; [α]D = –1.6 (c 1.0, CHCl3); H NMR (500 MHz, CDCl3,
TMS): 5.84 (s, 1H), 5.33 (s, 1H), 4.14–4.12 (m, 1H), 3.68 (s,
method for the synthesis of 5 was similar to that of 2. 5 is white
δ
20
solid, 95% yield; m.p. 82–85 °C; [α]D = –35.4 (c 1.0, CHCl3); 75 2H), 2.08 (s, 4H), 1.99 (d, J = 2.0 Hz, 1H), 1.68 (s, 6H), 1.46 (s,
1H NMR (400 MHz, CDCl3, TMS):
δ
7.39 (s, 1H), 3.61–3.58 (m,
10H), 1.28–1.26 (m, 1H); 13C NMR (125 MHz, CDCl3, TMS):
δ
1H), 3.02–2.96 (m, 1H), 2.90–2.84 (m, 1H), 2.14–2.04 (m, 4H),
20 1.91–1.81 (m, 4H), 1.78–1.37 (m, 7H), 1.40–1.37 (d, J = 12 Hz,
2H), 1.30–1.27 (d, J = 12 Hz, 2H), 1.19–1.12 (m, 2H), 0.85 (s
168.7, 156.5, 80.4, 60.8, 52.4, 45.4, 42.0, 36.7, 29.8, 28.7, 14.6;
IR (KBr): 576, 1049, 1164, 1487, 1679, 2909, 3322, 3407 cm-1;
HRMS (EI) m/z: calcd for C17H28N2O3 [M+Na]+ 331.1992, found
6H); 13C NMR (100 MHz, CDCl3, TMS):
δ 174.1, 61.2, 52.3, 80 331.1990.
50.7, 47.6, 47.4, 47.2, 42.7, 42.6, 40.0, 32.3, 30.7, 30.1, 26.2; IR
(KBr): 866, 1516, 1642, 2848, 2901, 3281 cm-1; HRMS (EI) m/z:
25 calcd for C17H28N2O [M+H]+ 277.2274, found 277.2274.
N-t-butyloxycarbonyl-3-aminoadamantan-1-ol-L-
N-((3S,5S,7S)-adamantan-1-yl)-2-aminoacetamide (7). White
solid, 97% yield; m.p. 110–112°C; [α]D20 = –8.9 (c 1.0, CHCl3);
1H NMR (500 MHz, CDCl3, TMS):
δ
6.91 (s, 1H), 3.22 (s, 2H),
2.08 (m, 3H), 2.00 (s, 6H), 1.69 (s, 6H), 1.36 (s, 2H); 13C NMR
172.0, 51.6, 45.8, 42.0, 36.8, 29.8;
prolineamide (6a). The method for the synthesis of 6a was 85 (125 MHz, CDCl3, TMS):
δ
similar to that of 2a. 6a is white solid, 91% yield; m.p. 181–183
IR (KBr): 1075, 1383, 1464, 1515, 1649, 1727, 2861, 2931, 3342
cm-1; HRMS (EI) m/z: calcd for C12H20N2O [M+H]+ 209.1648,
found 209.1646.
1
°C; [α]D20 = –86.6 (c 1.0, CHCl3); H NMR (400 MHz, CDCl3,
30 TMS):
δ
7.29 (s, 1H), 5.78 (s, 1H), 4.20–4.07 (m, 1H), 3.44–3.31
(m, 2H), 2.26 (s, 3H), 2.09 (s, 2H), 2.05–1.87 (m, 7H), 1.70 (s,
Tert-butyl (1-(((3S,5S,7S)-adamantan-1-yl)amino)-4-methyl-
2H), 1.56 (s, 2H), 1.47 (s, 9H); 13C NMR (100 MHz, CDCl3, 90 1-oxopentan-2-yl)carbamate (8a).24 The method for the
TMS):
δ
171.2, 154.6, 80.4, 69.0, 61.7, 54.0, 49.0, 47.1, 44.0,
synthesis of 8a was similar to that of 7a. 8a is amorphous
powder, 90% yield; [α]D20 = –10.9 (c 1.0, CHCl3); 1H NMR (500
40.3, 34.9, 31.1, 30.6, 28.4, 23.6; IR (KBr): 1401, 1540, 1671,
35 2921, 3313, 3391 cm-1; HRMS (EI) m/z: calcd for C20H32N2O4
[M+Na]+ 387.2254, found 387.2250.
MHz, CDCl3, TMS):
4.42 (m, 1H), 4.17 (s, 1H), 3.70–3.68 (m, 1H), 1.95 (s, 3H), 1.84–
(6). 95 1.61 (m, 12H), 1.56–1.18 (m, 20H), 0.93–0.89 (m, 6H); 13C NMR
(125 MHz, CDCl3, TMS): 156.8, 153.9, 80.7, 55.1, 52.1, 50.4,
δ 7.70 (s, 1H), 4.96–4.95 (m, 1H), 4.43–
3-Aminoadamantan-1-ol-adamantane-L-prolineamide
The method for the synthesis of 6 was similar to that of 2. 6 is
white solid, 92% yield; m.p. 154–157 °C; [α]D20 = –48.1 (c 1.0,
δ
42.5, 33.0, 32.2, 32.0, 29.6, 28.7, 26.5, 26.4, 25.9, 25.8, 25.0,
23.4, 22.2;IR (KBr) 878, 1098, 1307, 1519, 1646, 2848, 2901,
3289, 3379 cm-1; HRMS (EI) m/z: calcd for C21H36N2O3 [M+H]+
40 CHCl3); 1H NMR (400 MHz, CDCl3, TMS):
δ
7.49 (s, 1H), 3.61–
3.58 (m, 1H), 3.01–2.90 (m, 1H), 2.88–2.84 (m, 1H), 2.43 (s,
2H), 2.25 (s, 2H), 2.14–1.74 (m, 9H), 2.72–1.63 (m, 7H), 1.59– 100 365.2726, found 365.2724.
1.51 (m, 2H); 13C NMR (100 MHz, CDCl3, TMS):
61.0, 53.3, 49.0, 47.2, 44.0, 40.3, 40.3, 34.0, 30.8, 30.6, 26.2;IR
45 (KBr): 1144, 1352, 1552, 1659, 2925, 3252 cm-1; HRMS (EI) m/z:
calcd for C15H24N2O2 [M+H]+ 265.1910, found 265.1913.
δ
174.4, 68.9,
N-((3S,5S,7S)-adamantan-1-yl)-2-amino-4-
methylpentanamide (8).24 The method for the synthesis of 8 was
similar to that of 7. 8 is amorphous powder, 96% yield; [α]D20 = –
1
23.5 (c 1.0, CDCl3); H NMR (500 MHz, CDCl3, TMS):
δ 6.96
General Procedure for Preparation of Catalysts7-11.
105 (s, 1H), 3.25–3.22 (m, 1H), 2.07 (s, 3H), 2.01 (s, 6H), 1.68 (s,
The solution of N-t-butyloxycarbonyl-L-proline (1.052g, 5 mmol)
amantadine (604.5 mg, 4 mmol) in dry dichloromethane (6 mL)
50 was allowed to stir for 15 min and then cooled to 0 °C and then a
dichloromethane (5 mL) solution of dicyclohexylcarbodiimide
9H), 1.44 (s, 2H), 1.32–1.25 (m, 1H), 0.96–0.91 (m, 6H); 13C
NMR (125 MHz, CDCl3, TMS):
δ 175.1, 54.4, 51.4, 44.7, 41.9,
36.8, 34.4, 29.8, 25.3, 23.8, 21.9; IR (KBr): 653, 1095, 1356,
1450, 1523, 1658, 1704, 2852, 2917, 3322 cm-1; HRMS (EI) m/z:
(1.236 g, 6 mmol) was added. After 20 min, the resulting solution 110 calcd for C16H28N2O [M+H]+ 265.2274, found 265.2271.
was stirred at room temperature until complete consumption of
amantadine (monitored by TLC). The reaction was quenched
55 with water and extracted with dichloromethane (3 × 100mL). The
combined organic layers were washed with saturated brine
Tert-butyl
(1-(((3S,5S,7S)-adamantan-1-yl)amino)-1-oxo-3-
phenylpropan-2-yl)carbamate (9a). The method for the
synthesis of 9a was similar to that of 7a. 9a is white solid, 89%
yield; m.p. 83–85°C; [α]D = –15.1 (c 1.0, CHCl3); H NMR
7.31 (t, J = 14.8 Hz, 2H), 7.25 (t, J =
20
1
solution (100 mL), followed by drying over Na2SO4 and 115 (500 MHz, CDCl3, TMS):
δ
evaporating in vacuo. The crude product was purified by column
14.2 Hz, 3H), 5.29 (s, 2H), 4.19 (s, 1H), 3.10–3.08 (m, 1H), 2.95–
6
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2.93 (m, 1H), 2.03 (s, 2H), 1.84 (s, 6H), 1.64 (s, 6H), 1.41 (s,
9H); 13C NMR (125 MHz, CDCl3, TMS):
CDCl3, TMS):
δ
7.33–7.23 (m, 5H), 7.07 (s, 1H), 3.48 (d, J = 3.8
δ
170.2, 155.8, 137.6, 60 Hz, 1H), 3.20 (d, J = 13.6 Hz, 1H), 2.75 (t, J = 22.0 Hz, 1H), 2.28
129.9, 129.0, 127.2, 80.2, 56.9, 52.3, 41.7, 39.6, 36.7, 30.1, 29.7,
28.7; IR (KBr): 1042, 1172, 1258, 1540, 1667, 2856, 2921, 3052,
3318 cm-1; HRMS (EI) m/z: calcd for C24H34N2O3 [M+Na]+
421.2461, found 421.2466.
(s, 2H), 2.03 (s, 2H), 1.95–1.87 (m, 4H), 1.72 (s, 7H), 1.58–1.56
(m, 2H), 1.34 (d, J = 6.2, 1H); 13C NMR (125 MHz, CDCl3,
5
TMS): δ 173.7, 138.4, 129.8, 129.1, 127.2, 69.5, 57.2, 54.0, 49.3,
44.5, 41.4, 40.6, 35.3, 31.0, 22.5;IR (KBr):1049, 1348, 1450,
65 1540, 1650, 2852, 2909, 3064, 3269 cm-1; HRMS (EI) m/z: calcd
for C19H26N2O2 [M+H]+315.2067, found 315.2061.
N-((3S,5S,7S)-adamantan-1-yl)-2-amino-3-
phenylpropanamide (9). The method for the synthesis of 9 was
similar to that of 7. 9 is white solid, 94% yield; m.p. 130–133°C;
General Procedure for the Michael Addition.
10 [α]D20 = –68.3 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3, TMS):
To a stirred solution of corresponding freshly distilled aldehyde
or ketones (3 mmol, 3.0 equiv) in indicated solvent (2 mL) were
δ
7.34–7.29 (m, 2H), 7.27–7.22 (m, 3H), 6.94 (s, 1H), 3.48–3.46
(m, 1H), 3.22–3.19 (m, 1H), 2.75–2.70 (m, 1H), 2.08 (s, 3H), 70 added catalyst and benzoic acid. The mixture was stirred at the
1.99 (s, 7H), 1.69 (s, 7H), 1.29 (s, 3H); 13C NMR (125 MHz,
CDCl3, TMS): 173.5, 138.6, 129.8, 129.0, 127.1, 57.3, 51.5,
15 41.9, 41.6, 36.8, 29.8; IR (KBr): 735, 894, 1111, 1348, 1516,
1662, 2851, 2917, 3309, 3383 cm-1; HRMS (EI) m/z: calcd for
C19H26N2O [M+H]+ 299.2117, found 299.2122.
indicated temperature for 30 min, then corresponding nitroolifen
(1 mmol, 1.0 equiv) was added. The resulting solution was stirred
at the same temperature until complete consumption of
nitroalkene (monitored by TLC). The solvent was quenched with
75 ice water (2 mL), and extracted with ethyl acetate (3 x 10mL).
The combined organic phase was dried over Na2SO4, after
removing the solvent, the crude product was purified by flash
chromatography to afford the corresponding Michael adducts.
Enantiomeric excess was determined by chiral HPLC analysis.
δ
Tert-butyl
((S)-1-(((1R,3R,5R,7S)-3-hydroxyadamantan-1-
yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate (10a). The
20 method for the synthesis of 10a was similar to that of 7a. 10a is
white solid, 91% yield; m.p. 101–103°C; [α]D20 = –30.9 (c 1.0,
1
CHCl3); H NMR (500 MHz, CDCl3, TMS):
δ
6.29 (s, 1H), 5.23 80 (2R,3S)-2-methyl-4-nitro-3-phenylbutanal (14a).20 The title
(s, 1H), 4.00 (d, J = 5.8 Hz, 1H), 2.26 (s, 2H), 2.07–1.89 (m, 7H),
compound 14a was prepared from propanal and nitrostyrene
1.72–1.48 (m, 10H), 1.41 (s, 9H), 0.97–0.88 (m, 8H); 13C NMR
according to the general procedure of Michael addition. 14a is
1
25 (125 MHz, CDCl3, TMS):
δ
172.3, 156.2, 80.3, 69.5, 54.7, 53.9,
pale yellow oil, 90% yield. H NMR (400 MHz, CDCl3 ): δ 9.71
49.3, 44.4, 41.7, 40.6, 40.5, 35.3, 30.9, 28.7, 25.2, 23.3, 22.7; IR
(s, 1H), 9.54 (s, 1H), 7.36–7.27 (m, 5H), 7.22–7.16 (m, 3H),
(KBr): 629, 1042, 1172, 1246, 1360, 1536, 1663, 2353, 2921, 85 4.82–4.78 (m, 2H), 4.71–4.65 (m, 1H), 3.84–3.78 (m, 2H), 2.83–
3322 cm-1; HRMS (EI) m/z: calcd for C21H36N2O4 [M+Na]+
403.2567, found 403.2565.
30 (S)-2-amino-N-((1R,3R,5R,7S)-3-hydroxyadamantan-1-yl)-4-
methylpentanamide (10). The method for the synthesis of 10
2.75 (m, 2H), 1.02 (d, J = 7.2 Hz, 2H), 1.00 (d, J = 7.2 Hz, 3H);
13C NMR (100 MHz, CDCl3 ): δ 202.4, 136.6, 129.4, 129.1,
129.1, 128.2, 128.1, 78.1, 48.7, 48.4, 44.8, 44.0, 12.1, 11.7;
HPLC (Chiralcel OD-H, n-hexane: i-PrOH = 90: 10, flow rate:
was similar to that of 7. 10 is white solid, 95% yield; m.p. 120– 90 1.0 mL/min, λ = 254 nm), Tmajor = 33.6, Tmino r = 25.8, 94% ee.
20
122°C; [α]D = –31.1 (c 1.0, CHCl3); 1H NMR (500 MHz,
(2R,3S)-2-ethyl-4-nitro-3-phenylbutanal (14b).20 The title
compound 14b was prepared from butyraldehyde and
nitrostyrene according to the general procedure of Michael
CDCl3, TMS): 7.07 (m, 1H), 3.12 (d, J = 4.2 Hz, 1H), 2.32 (s,
35 3H), 2.11 (s, 2H), 1.88 (s, 2H), 1.79–1.74 (m, 4H), 1.57–1.40 (m,
8H), 1.21–1.13 (m, 1H), 0.81–0.73 (m, 6H); 13C NMR (125 MHz,
δ
1
addition. 14b is pale yellow oil, 86% yield. H NMR (400 MHz,
CDCl3, TMS):
δ 175.1, 68.9, 60.7, 54.2, 53.8, 49.2, 44.5, 44.3, 95 CDCl3 ): δ 9.72 (s, 1H), 9.48 (s), 7.37–7.29 (m, 4H), 7.18 (d, J =
40.5, 35.3, 30.9, 25.2, 23.7, 22.0; IR (KBr): 563, 911, 959, 1037,
1136, 1217, 1262, 1328, 1548, 1654, 2851, 2917, 3048, 3342 cm-
40 1; HRMS (EI) m/z: calcd for C16H28N2O2 [M+H]+ 281.2223,
found 281.2223.
8.0, 2H), 4.75–4.71 (m, 1H), 4.71–4.60 (m, 1H), 3.83–3.76 (m,
1H), 2.71–2.66 (m, 1H), 1.52–1.49 (m, 2H), 0.99 (t, J = 7.2 Hz,
1H), 0.99 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3 ): δ
203.2, 136.8, 129.1, 128.2, 128.1, 128.0, 78.5, 55.0, 42.7, 20.4,
100 10.7; HPLC (Chiralcel AD-H, n-hexane: i-PrOH = 99:1, flow
rate: 0.8 mL/min, λ = 254 nm), Tmajor = 31.5, Tminor = 40.8, 98%
ee.
Tert-butyl((S)-1-(((1R,3R,5R,7S)-3-hydroxyadamantan-1-
yl)amino)-1-oxo-3-phenylpropan-2-yl)carbamate (11a). The
method for the synthesis of 11a was similar to that of 7a. 11a is
20
45 white solid, 88% yield; m.p. 90–93°C; [α]D = –4.4 (c 1.0,
(R)-2-((S)-2-nitro-1-phenylethyl)pentanal (14c).20 The title
compound 14c was prepared from n-pentanal and nitrostyrene
1
CHCl3); H NMR (500 MHz, CDCl3, TMS):
δ 7.32–7.22 (m,
5H), 5.61 (s, 3H), 5.35 (s, 2H), 4.21 (s, 1H), 3.08–3.04 (m, 1H), 105 according to the general procedure of Michael addition. 14c is
1
2.22 (s, 1H), 1.92–1.66 (m, 14H), 1.51 (s, 2H), 1.42 (s, 6H),
1.38–1.32 (s, 1H); 13C NMR (125 MHz, CDCl3, TMS):
170.6,
50 155.8, 137.4, 129.9, 129.0, 128.8, 127.3, 80.4, 69.4, 56.8, 54.7,
49.1, 48.8, 44.4, 40.4, 40.3, 39.4, 35.2, 34.2, 30.9, 28.7, 25.3,
pale yellow oil, 87% yield. H NMR (400 MHz, CDCl3 ): δ 9.70
(s, 1H), 9.48 (s), 7.37-7.28 (m, 4H), 7.18 (d, J = 7.6, 2H), 4.73-
4.62 (m, 2H), 3.81-3.75 (m, 1H), 2.73-2.68 (m, 1H), 1.51-1.17(m,
5H), 0.94 (t, J = 6.8 Hz, 1H), 0.89 (t, J = 6.8 Hz, 3H); 13C NMR
δ
22.5; IR (KBr): 751, 1037, 1168, 1315, 1372, 1540, 1662, 2917, 110 (100 MHz, CDCl3): δ 203.2, 136.8, 129.1, 128.2, 128.1, 128.0,
3329 cm-1; HRMS (EI) m/z: calcd for C24H34N2O4 [M+Na]+
437.2410, found 437.2408.
55 (S)-2-amino-N-((1R,3R,5R,7S)-3-hydroxyadamantan-1-yl)-3-
phenylpropanamide (11). The method for the synthesis of 11
78.4, 53.8, 43.2, 29.5, 19.8, 13.9; HPLC (Chiralcel OD-H, n-
hexane: i-PrOH = 96:4, flow rate: 1.0 mL/min, λ = 254 nm),
Tmajor = 38.7, Tminor = 31.1, 92% ee.
(2R,3S)-2-isopropyl-4-nitro-3-phenylbutanal (14d).20 The title
was similar to that of 7. 11 is white solid, 96% yield; m.p. 162– 115 compound 14d was prepared from i-pentanal and nitrostyrene
20
165°C; [α]D = –52.8 (c 1.0, CHCl3); 1H NMR (500 MHz,
according to the general procedure of Michael addition. 14d is
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1
pale yellow oil, 81% yield. H NMR (400 MHz, CDCl3): δ 9.93
(s, 1H), 9.71 (s), 7.36–7.27 (m, 3H), 7.19 (d, J = 7.6, 2H), 4.69– 60 MHz, CDCl3): δ 9.71 (s, 1H), 9.49 (s), 7.50–7.45 (t, J = 16.8,
Michael addition. 14i is pale yellow oil, 90% yield. 1H NMR (400
4.65 (m, 1H), 4.60–4.54 (m, 1H), 3.93–3.87 (m, 1H), 2.79–2.76
(m, 1H), 1.72–1.69 (m, 1H), 1.09 (d, J = 7.2 Hz, 3H), 0.88 (d, J =
7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 204.3, 137.1, 129.2,
128.1, 128.0, 79.0, 58.7, 41.9, 27.9, 21.7, 17.0; HPLC (Chiralcel
2H), 7.01 (d, J = 8, 2H), 4.78–4.70 (m, 1H), 4.62–4.57 (m, 1H),
3.81–3.75 (m, 1H), 2.70–2.65 (m, 1H), 1.56–1.46 (m, 2H), 1.00
(t, J = 14.8 Hz, 1H), 0.83 (d, J = 14.8 Hz, 3H); 13C NMR (100
MHz, CDCl3): δ 202.7, 135.9, 132.3, 129.7, 122.2, 78.3, 54.6,
5
AD-H, n-hexane: i-PrOH = 97: 3, flow rate: 0.5 mL/min, λ = 254 65 42.0, 20.3, 10.5; HPLC (Chiralcel AD-H, n-hexane: i-PrOH =
nm), Tmajor = 23.7, Tminor = 28.1, 98% ee.
98.5:1.5, flow rate: 1.0 mL/min, λ = 254 nm), Tmajor = 32.0, Tminor
= 50.4, 98% ee.
(R)-2-((S)-2-nitro-1-phenylethyl)hexanal (14e).20 The title
10 compound 14e was prepared from n-hexaldehyde and
nitrostyrene according to the general procedure of Michael
addition. 14e is pale yellow oil, 89% yield. H NMR (400 MHz, 70 chloro-β-nitrostyreneaccording to the general procedure of
(2R,3S)-3-(4-chlorophenyl)-2-ethyl-4-nitrobutanal (14j).20 The
title compound 14j was prepared from n-butyraldehyde and 4-
1
1
CDCl3): δ 9.70 (s, 1H), 9.47 (s), 7.36–7.27 (m, 3H), 7.17 (d, J =
7.2, 2H), 4.83–4.61 (m, 3H), 3.81–3.75 (m, 1H), 2.72–2.62 (m,
15 1H), 1.50–1.27 (m, 9H), 1.22 (t, J = 10.4 Hz, 1H), 1.17 (d, J =
17.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 203.3, 136.8,
Michael addition. 14j is pale yellow oil, 91% yield. H NMR
(400 MHz, CDCl3): δ 9.71 (s, 1H), 9.49 (s), 7.32–7.45 (t, J =
16.8, 2H), 7.13 (d, J = 7.6, 2H), 4.75–4.71 (m, 1H), 4.63–4.57
(m, 1H), 3.82–3.76 (m, 1H), 2.70–2.65 (m, 1H), 1.56–1.46 (m,
129.1, 128.2, 128.1, 128.0, 78.5, 53.9, 43.1, 28.5, 27.0, 22.5, 75 2H), 1.00 (t, J = 14.4 Hz, 1H), 0.83 (d, J = 15.2 Hz, 3H); 13C
13.7; HPLC (Chiralcel OD-H, n-hexane: i-PrOH = 97: 3, flow
rate: 1.0 mL/min, λ = 254 nm), Tmajor = 40.5, Tminor = 30.4, 93%
NMR (100 MHz, CDCl3): δ 202.7, 135.4, 134.0, 129.6, 129.4,
78.3, 54.7, 42.0, 20.3, 10.5; HPLC (Chiralcel AD-H, n-hexane: i-
20 ee.
PrOH = 98.5:1.5, flow rate: 1.0 mL/min, λ = 254 nm), Tmajor
27.9, Tminor = 42.0, 96% ee.
=
(2R,3S)-2-benzyl-4-nitro-3-phenylbutanal (14f).25 The title
compound 14f was prepared from benzenepropanal 80 (2R,3S)-3-(2-chlorophenyl)-2-ethyl-4-nitrobutanal (14k).20 The
andnitrostyrene according to the general procedure of Michael
addition. 14f is pale yellow oil, 90% yield. H NMR (500 MHz,
25 CDCl3): δ 9.73 (d, J = 2.0, 1H), 9.59 (s), 7.43–7.07 (m, 15H),
title compound 14k was prepared from n-butyraldehyde and 2-
chloro-β-nitrostyreneaccording to the general procedure of
Michael addition. 14k is pale yellow oil, 82% yield. H NMR
1
1
4.89–4.85 (m, 1H), 4.78–4.72 (m, 2H), 3.90–3.85 (m, 1H), 3.15–
(400 MHz, CDCl3): δ 9.74 (s, 1H), 9.52 (s), 7.42–7.28 (m, 1H),
3.02 (m, 1H), 2.84–2.77 (m, 2H); 13C NMR (125 MHz, CDCl3): δ 85 7.26–7.19 (m, 4H), 4.89–4.78 (m, 1H), 4.76–4.67 (m, 1H), 4.50–
203.5, 127.8, 137.7, 129.7, 129.6, 129.3, 129.2, 128.9, 128.8,
128.5, 127.4, 78.5, 55.8, 54.9, 44.9, 43.9, 34.7, 34.0; HPLC
30 (Chiralcel AS-H, n-hexane: i-PrOH = 97:3, flow rate: 0.7
mL/min, λ = 254 nm), Tmajor = 49.0, Tminor = 55.3, 96% ee.
4.45 (m, 1H), 4.38–4.33 (m, 1H), 2.96 (s, 1H), 1.63–1.50 (m,
1H), 0.98 (t, J = 14.8 Hz, 1H), 0.86 (d, J = 14.8 Hz, 3H); 13C
NMR (100 MHz, CDCl3): δ 202.9, 134.5, 134.4, 130.6, 129.3,
127.5, 77.4, 50.1, 39.2, 20.4, 10.7; HPLC (Chiralcel AD-H, n-
90 hexane: i-PrOH = 98.5:1.5, flow rate: 1.0 mL/min, λ = 254 nm),
Tmajor = 16.7, Tminor = 18.7, 95% ee.
(R)-1-(2-nitro-1-phenylethyl)cyclopentane-1-carbaldehyde
(14g). The title compound 14g was prepared from
carboxaldehyde and nitrostyrene according to the general
35 procedure of Michael addition. 14g is pale yellow oil, 89% yield.
1H NMR (500 MHz, CDCl3 ): δ 9.51 (s, 1H), 7.35–7.28 (m, 3H),
(2R,3S)-3-(2,4-dichlorophenyl)-2-ethyl-4-nitrobutanal (14l).20
The title compound 14l was prepared from n-butyraldehyde and
2, 4-dichloro-β-nitrostyreneaccording to the general procedure of
7.24–7.22 (m, 2H), 5.02–4.97 (m, 1H), 4.75–4.71 (m, 1H), 2.10– 95 Michael addition. 14l is pale yellow oil, 81% yield. 1H NMR (400
2.05 (m, 1H), 1.92–1.90 (m, 1H), 1.69–1.55 (m, 7H); 13C NMR
(125 MHz, CDCl3): δ 204.8, 139.5, 137.6, 136.8, 132.6, 129.8,
40 129.6, 129.2, 129.1, 128.9, 128.5, 77.8, 60.7, 49.7, 33.0, 31.9,
31.9, 25.3, 25.1; HPLC (Chiralcel OD-H, n-hexane: i-PrOH =
MHz, CDCl3): δ 9.72 (s, 1H), 9.57 (s), 9.44 (s, 1H), 7.26 (d, J =
8.0 Hz, 1H), 7.17 (d, J = 8.4 Hz, 1H), 4.88–4.76 (m, 1H), 4.71–
4.67 (m, 1H), 4.34–4.28 (m, 1H), 2.94 (d, J = 7.2 Hz, 1H), 1.61–
1.53 (m, 2H), 0.99 (t, J = 14.8 Hz), 0.87 (d, J = 14.8 Hz, 3H); 13
C
95:5, flow rate: 0.5 mL/min, λ = 254 nm), Tmajor = 43.5, Tminor
37.3, 97% ee.
=
100 NMR (100 MHz, CDCl3): δ 202.5, 135.1, 134.5, 133.2, 130.4,
130.0, 127.9, 53.7, 38.6, 20.4, 10.6; HPLC (Chiralcel AD-H, n-
hexane: i-PrOH = 99:1, flow rate: 1.0 mL/min, λ = 254 nm),
Tmajor = 19.2, Tminor = 21.8, 98% ee.
(2R,3S)-2-ethyl-3-(4-fluorophenyl)-4-nitrobutanal (14h).20 The
45 title compound 14h was prepared from n-butyraldehyde and 4-
fluoro-β-nitrostyrene according to the general procedure of
(2R,3S)-2-ethyl-3-(4-methoxyphenyl)-4-nitrobutanal (14m).20
1
Michael addition. 14h is pale yellow oil, 94% yield. H NMR 105 The title compound 14m was prepared from n-butyraldehyde and
(400 MHz, CDCl3): δ 9.72 (d, J = 2.4 Hz), 9.49 (d, J = 2.8 Hz,
1H), 7.19–7.15 (m, 2H), 7.07–6.99 (m, 2H), 4.82–4.70 (m, 2H),
50 3.84–3.79 (m, 2H), 2.61–2.55 (m, 1H), 1.78–1.57 (m, 3H),1.00 (t,
J = 15.2 Hz, 3H), 0.84 (d, J = 15.2 Hz, 1H); 13C NMR (100 MHz,
4-methoxy-β-nitrostyreneaccording to the general procedure of
Michael addition. 14m is pale yellow oil, 83% yield. H NMR
(400 MHz, CDCl3): δ 9.71 (s, 1H), 9.46 (d, J = 2.4), 7.09 (d, J =
8.0, 2H), 6.88–6.84 (m, 2H), 4.71–4.67 (m, 1H), 4.61–4.55 (m,
1
CDCl3): δ 202.8, 163.6, 161.1, 132.1, 129.9, 116.2, 116.0, 78.0, 110 1H), 3.78 (m, J = 5.2, 4H), 2.66–2.61 (m, 1H), 1.70–1.64 (m,
55.0, 43.3, 41.8, 20.6, 11.4; HPLC (Chiralcel AD-H, n-hexane: i-
PrOH = 99:1, flow rate: 1.0 mL/min, λ = 254 nm), Tmajor = 25.0,
55 Tminor = 33.3, 99% ee.
(2R,3S)-3-(4-bromophenyl)-2-ethyl-4-nitrobutanal (14i).20 The
1H), 1.52–1.45 (m, 1H), 0.96 (t, J = 14.8 Hz, 1H), 0.83 (d, J =
14.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 202.4, 159.3,
129.0, 128.5, 114.5, 78.8, 55.2, 42.0, 20.3, 10.7; HPLC (Chiralcel
AD-H, n-hexane: i-PrOH = 96:4, flow rate: 1.0 mL/min, λ = 254
title compound 14i was prepared from n-butyraldehyde and 4- 115 nm), Tmajor = 19.4, Tminor = 16.4, 95% ee.
bromo-β-nitrostyrene according to the general procedure of
(2R,3S)-2-ethyl-4-nitro-3-(p-tolyl)butanal (14n).20 The title
8
|Journal Name, [year], [vol], 00–00
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DOI: 10.1039/C4RA11214H
compound 14n was prepared from n-butyraldehyde and 4-
16a was prepared from acetone and nitrostyrene according to the
methyl-β-nitrostyreneaccording to the general procedure of 60 general procedure of Michael addition. 16a is pale yellow oil,
1
1
Michael addition. 14n is pale yellow oil, 93% yield. H NMR
95% yield. H NMR (500 MHz, CDCl3): δ 7.35 (d, J = 7.2, 1H),
(400 MHz, CDCl3): δ 9.71 (s, 1H), 9.47 (s), 7.15–7.11 (m, 2H),
7.05 (d, J = 0.8, 2H), 4.80–4.69 (m, 1H), 4.67–4.57 (m, 1H),
3.78–3.72 (m, 1H), 2.68–2.63 (m, 1H), 2.31 (d, J = 6.0,
7.30 (t, J = 6.6, 1H), 7.25 (d, J = 7.4, 1H), 4.75–4.71 (m, 1H),
4.65–4.62 (m, 1H), 4.06–4.03 (m, 1H), 2.95 (d, J = 7.0, 1H), 2.16
(s, 3H); 13C NMR (125 MHz, CDCl3): δ 205.8, 139.2, 129.5,
5
3H),1.54–1.47 (m, 2H), 0.98 (t, J = 22 Hz, 1H), 0.82 (d, J = 14.8 65 128.3, 127.8, 79.9, 46.5, 39.5, 30.8; HPLC (Chiralcel AS-H, n-
Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 203.4, 137.9, 133.6,
129.8, 128.1, 127.8, 78.7, 55.1, 42.4, 21.1, 20.4, 10.7; HPLC
10 (Chiralcel OD-H, n-hexane: i-PrOH = 92:8, flow rate: 0.5
mL/min, λ = 254 nm), Tmajor = 43.5, Tminor = 37.3, 97% ee.
hexane: i-PrOH = 92:8, flow rate: 0.5 mL/min, λ = 210 nm),
Tmajor = 33.6, Tminor = 26.4, 2% ee.
(R)-2-((S)-2-nitro-1-phenylethyl)cyclobutan-1-one (16b).27 The
title compound 16b was prepared from cyclobutanone and
70 nitrostyrene according to the general procedure of Michael
(2R,3S)-2-ethyl-4-nitro-3-(4-(trifluoromethyl)phenyl)butanal
(14o).20 The title compound 14o was prepared from n-
butyraldehyde and 4-trifluoromethyl-β-nitrostyreneaccording to
15 the general procedure of Michael addition. 14o is pale yellow oil,
1
addition. 16b is pale yellow oil, 92% yield. H NMR (500 MHz,
CDCl3): δ 7.36 (t, J = 14.5, 4H), 7.32 (t, J = 7.4, 3H), 5.11–5.07
(m, 1H), 4.89–4.86 (m, 1H), 4.69–4.64 (m, 1H), 3.77–3.72 (m,
2H), 3.67–3.62 (m, 1H), 3.14–3.10 (m, 1H), 3.07–3.02 (m, 1H),
1
89% yield. H NMR (400 MHz, CDCl3): δ 9.72 (s, 1H), 9.51 (s),
7.62 (d, J = 8.0, 2H), 7.34 (d, J = 8.0, 2H), 4.83–4.76 (m, 1H), 75 3.00–2.93 (m, 1H), 2.21–2.18 (m, 1H), 2.11–2.03 (m, 1H), 1.78–
4.69–4.63 (m, 1H), 3.93–3.87 (m, 1H), 2.77–2.72 (m, 1H), 1.56–
1.45 (m, 2H), 1.00 (t, J = 8.8 Hz), 0.84 (d, J = 8.8 Hz, 3H); 13C
20 NMR (100 MHz, CDCl3): δ 202.5, 141.4, 128.5, 126.1, 126.0,
78.1, 54.5, 42.2, 21.1, 20.3, 10.4; HPLC (Chiralcel AS-H, n-
1.65 (m, 1H); 13C NMR (125 MHz, CDCl3): δ 208.9, 137.4.
136.9. 129.5. 128.6. 128.5. 128.0. 78.7. 61.9. 61.4. 45.4. 44.9.
44.7. 16.2. 14.7; HPLC (Chiralcel AS-H, n-hexane: i-PrOH =
75:25, flow rate: 0.7 mL/min, λ = 210 nm), Tmajor = 13.7, Tminor
=
hexane: i-PrOH = 93:7, flow rate: 0.5 mL/min, λ = 254 nm), 80 11.2, 11% ee.
T
major = 27.4, Tminor = 30.1, 98% ee.
(R)-2-((S)-2-nitro-1-phenylethyl)cyclopentan-1-one
(16c).27
(2R,3R)-2-ethyl-3-(furan-2-yl)-4-nitrobutanal (14p).20 The title
25 compound 14p was prepared from n-butyraldehyde and 2-(2-
The title compound 16c was prepared from cyclopentanoneand
nitrostyrene according to the general procedure of Michael
1
nitroethenyl)furanaccording to the general procedure of Michael
addition. 14p is pale yellow oil, 83% yield. H NMR (400 MHz, 85 CDCl3): δ 7.34 (t, J = 14.6, 3H), 7.29 (t, J = 13.0, 2H), 7.22–7.19
addition. 16c is pale yellow oil, 90% yield. H NMR (500 MHz,
1
CDCl3 ): δ 9.71 (s, 1H), 9.60 (s), 7.37 (s, 1H), 6.31 (s, 1H), 6.20
(s, 1H), 4.75–4.65 (m, 2H), 4.05–4.00 (m, 1H), 2.79–2.74 (m,
30 1H), 1.57–1.53 (m, 2H), 0.99 (t, J = 8.8 Hz, 1H), 0.89 (d, J = 8.8
Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 202.4, 150.1, 14.7,
(d, J = 7.3, 3H), 5.38–5.35 (m, 1H), 5.04 (d, J = 7.8, 1H), 4.77–
4.72 (m, 1H), 3.79–3.69 (m, 1H), 2.45–2.43 (m, 2H), 2.20–2.11
(m, 1H), 1.97–1.88 (m, 1H), 1.79–1.64 (m, 1H), 1.55–1.46 (m,
1H), 1.35–1.28 (m, 1H); 13C NMR (125 MHz, CDCl3): δ 218.9,
110.5, 110.4, 109.0, 108.8, 76.0, 53.4, 36.5, 20.0, 10.9; HPLC 90 138.2, 78.7, 51.8, 50.9, 48.8, 44.6, 44.4, 42.9, 39.7, 39.1, 28.7,
(Chiralcel AS-H, n-hexane: i-PrOH = 96:4, flow rate: 0.5
mL/min, λ = 254 nm), Tmajor = 41.1, Tminor = 35.8, 93% ee.
27.4, 22.5, 21.0, 20.7; HPLC (Chiralcel AS-H, n-hexane: i-PrOH
= 75:25, flow rate: 0.8 mL/min, λ = 210 nm), Tmajor = 14.7, Tminor
= 10.8, 40% ee.
(R)-2-((S)-2-nitro-1-phenylethyl)cyclohexan-1-one (16d).27 The
35 (2R,3R)-2-ethyl-4-nitro-3-(thiophen-2-yl)butanal (14q).20 The
title compound 14q was prepared from n-butyraldehyde and 1-(2-
thienyl)-2-nitroethene according to the general procedure of 95 title compound 16d was prepared from cyclohexanone and
1
Michael addition. 14q is pale yellow oil, 85% yield. H NMR
(400 MHz, CDCl3 ): δ 9.70 (s, 1H), 9.52 (s), 7.34 (d, J = 4.0 Hz,
40 2H), 7.11 (d, J = 4.8 Hz, 2H), 4.82–4.59 (m, 4H), 4.03–3.96 (m,
2H), 2.69–2.64 (m, 1H), 2.56–2.51 (m, 1H), 1.80–1.75 (m, 1H),
nitrostyrene according to the general procedure of Michael
addition. 16d is white solid, 89% yield. H NMR (500 MHz,
CDCl3): δ 7.34 (t, J = 14.6 Hz, 2H), 7.29 (t, J = 14.4 Hz, 1H),
7.19 (d, J = 7.3 Hz, 2H), 4.99–4.95 (m, 1H), 4.66 (t, J = 22.4 Hz,
1
1.67–1.50 (m, 3H), 1.02 (t, J = 11.2 Hz, 2H), 0.90 (t, J = 11.2 Hz, 100 1H), 3.81–3.77 (m, 1H), 2.74–2.69 (m, 1H), 2.52–2.38 (m, 1H),
3H); 13C NMR (100 MHz, CDCl3): δ 203.4, 203.0, 137.2, 136.6,
127.1, 126.9, 126.9, 126.0, 123.5, 123.3, 78.3, 77.9, 54.9, 54.6,
45 39.4, 38.2, 20.7, 20.3, 11.6, 10.9; HPLC (Chiralcel AD-H, n-
hexane: i-PrOH = 98:2, flow rate: 0.7 mL/min, λ = 254 nm),
Tmajor = 36.2, Tminor = 46.8, 97% ee.
2.12–2.07 (m, 1H), 1.82–1.55 (m, 1H), 1.30–1.22 (m, 1H); 13C
NMR (125 MHz, CDCl3): δ 212.3, 138.2, 129.3, 128.6, 128.2,
79.3, 52.9, 44.4, 43.2, 33.6, 28.9, 25.4; HPLC (Chiralcel AS-H,
n-hexane: i-PrOH = 85:15, flow rate: 0.8 mL/min, λ = 210 nm),
105 Tmajor = 17.6, Tminor = 11.9, 99% ee.
(2R,3R)-2-ethyl-3-(nitromethyl)-5-phenylpentanal (14r).26 The
title compound 14q was prepared from n-butylaldehyde and (4-
50 nitrobut-3-enyl)benzene according to the general procedure of
(R)-2-((S)-1-(4-fluorophenyl)-2-nitroethyl)cyclohexan-1-one
(16e).27 The title compound 16e was prepared from
cyclohexanone and 4-fluoro-β-nitrostyreneaccording to the
1
Michael addition. 14q is pale yellow oil, 94% yield. H NMR
general procedure of Michael addition. 16e is white solid, 84%
1
(500 MHz, CDCl3 ): δ 9.71 (1H, s), 7.35–7.18 (1H, m), 4.58–4.49 110 yield. H NMR (500 MHz, CDCl3): δ 8.14 (d, J = 7.5 Hz, 1H),
(2H, m), 2.74–2.64 (3H, m), 2.51–2.47 (2H, m), 1.86–1.69 (3H,
m), 1.61–1.54 (2H, m); 13C NMR (125 MHz, CDCl3): δ 203.4,
55 140.9, 129.1, 128.7, 126.8, 54.2, 36.6, 33.4, 31.4, 19.1, 12.3;
HPLC (Chiralcel OD-H, n-hexane: i-PrOH = 90:10, flow rate: 0.5
mL/min, λ = 210 nm), Tmajor = 37.4, Tminor = 40.1, 99% ee.
7.63 (t, J = 15.4 Hz, 1H), 7.50 (t, J = 15.4 Hz, 2H), 7.19–7.16 (m,
3H), 7.05–7.02 (m, 3H), 4.97–4.94 (m, IH), 4.65–4.60 (m, 1H),
3.82–3.77 (m, 1H), 2.71–2.65 (m, 1H), 2.52–2.37 (m, 1H), 2.13–
2.09 (m, 1H), 1.84–1.59 (m, 6H), 1.34–1.21 (m, 4H); 13C NMR
115 (125 MHz, CDCl3): δ 212.1, 172.1, 163.6, 161.6, 134.0, 133.9,
130.6, 130.2, 130.1, 128.9, 116.4, 116.2, 79.2, 52.9, 43.7, 43.1,
(S)-5-nitro-4-phenylpentan-2-one (16a).27 The title compound
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DOI: 10.1039/C4RA11214H
1
33.6, 30.1, 28.9, 25.5; HPLC (Chiralcel AD-H, n-hexane: i-PrOH
yield. H NMR (500 MHz, CDCl3): δ 7.10 (d, J = 8.6 Hz, 2H),
60 6.88–6.86 (m, 2H), 4.95–4.92 (m, 1H), 4.63–4.58 (m, 1H), 3.80
(s, 3H), 3.76–3.71 (m, 1H), 2.70–2.64 (m, 1H), 2.50–2.47 (m,
1H), 2.43–2.40 (m, 1H), 2.11–2.08 (m, 1H), 1.82–1.58 (m, 4H),
1.28–1.24 (m, 1H); 13C NMR (125 MHz, CDCl3): δ 212.5, 159.4,
129.9, 129.6, 114.7, 114.5, 79.5, 55.6, 53.1, 43.6, 53.1, 43.6,
= 92:8, flow rate: 0.9 mL/min, λ = 210 nm), Tmajor = 20.8, Tminor
24.2, 96% ee.
(R)-2-((S)-1-(4-chlorophenyl)-2-nitroethyl)cyclohexan-1-one
(16f).27 The title compound 16f was prepared from
=
5
cyclohexanone and 4-chloro-β-nitrostyreneaccording to the
general procedure of Michael addition. 16f is white solid, 86% 65 43.1, 35.5, 28.9, 25.4; HPLC (Chiralcel AS-H, n-hexane: i-PrOH
1
yield. H NMR (500 MHz, CDCl3): δ 7.30 (t, J = 14.0 Hz, 2H),
7.14 (t, J = 8.2 Hz, 2H), 4.98–4.94 (m, 1H), 4.64–4.59 (m, 1H),
= 90:20, flow rate: 0.8 mL/min, λ = 210 nm), Tmajor = 19.7, Tminor
= 20.0, 85% ee.
10 3.81–3.76 (m, 1H), 2.70–2.64 (m, 1H), 2.49–2.47 (m, 1H), 2.41–
2.35 (m, 1H), 2.12–2.09 (m, 1H), 1.82–1.79 (m, 1H), 1.74–1.56
(R)-2-((R)-1-(furan-2-yl)-2-nitroethyl)cyclohexan-1-one
(16k).27 The title compound 16k was prepared from
(m, 3H), 1.28–1.21 (m, 1H); 13C NMR (125 MHz, CDCl3): δ 70 cyclohexanoneand 2-(2-nitroethenyl)furanaccording to the
211.9, 136.8, 134.0, 130.0, 129.5, 79.0, 52.8, 43.8, 43.1, 33.6,
28.8, 25.5; HPLC (Chiralcel AD-H, n-hexane: i-PrOH = 90:10,
15 flow rate: 0.9 mL/min, λ = 210 nm), Tmajor = 27.9, Tminor = 18.8,
90% ee.
general procedure of Michael addition. 16k is white solid, 87%
yield. H NMR (500 MHz, CDCl3): δ 7.33 (d, J = 9.4 Hz, 1H),
1
6.28 (d, J = 2.2 Hz, 1H), 6.19–6.17 (m, 1H), 4.81–4.70 (m, 2H),
4.68–4.65 (m, 1H), 4.00–3.95 (m, 1H), 2.78–2.73 (m, 1H), 2.47–
75 2.45 (m, 1H), 2.40–2.34 (m, 1H), 2.11–2.09 (m, 2H), 1.83–1.38
(m, 5H), 1.27–1.25 (m, 1H); 13C NMR (125 MHz, CDCl3): δ
152.5, 151.4, 142.7, 142.4, 110.9, 110.7, 109.3, 107.9, 77.1, 75.6,
51.4, 51.5, 42.9, 51.5, 42.9, 42.5, 37.9, 37.1, 32.9, 30.4, 28.6,
27.7, 25.5; HPLC (Chiralcel AD-H, n-hexane: i-PrOH = 98:2,
(R)-2-((S)-1-(2-chlorophenyl)-2-nitroethyl)cyclohexan-1-
one(16g).27 The title compound 16g was prepared from
cyclohexanone and 2-chloro-β-nitrostyrene according to the
20 general procedure of Michael addition. 16g is white solid, 84%
1
yield. H NMR (500 MHz, CDCl3): δ 7.39 (d, J = 7.6 Hz, 1H),
7.28–7.21 (m, 3H), 4.95–4.88 (m, 2H), 4.34–4.30 (m, 1H), 2.93 80 flow rate: 1.0 mL/min, λ = 210 nm), Tmajor = 36.7, Tminor = 30.3,
(s, 1H), 2.50–2.47 (m, 1H), 2.44–2.37 (m, 1H), 2.13–2.37 (m,
1H), 2.13–2.10 (m, 1H), 1.84–1.81 (m, 1H), 1.75–1.57 (m, 3H),
25 1.39-1.27 (m, 1H); 13C NMR (125 MHz, CDCl3): δ 212.0, 135.9,
134.9, 130.7, 129.9, 129.3, 127.8, 77.8, 52.2, 43.2, 41.4, 33.4,
97% ee.
(R)-2-((R)-2-nitro-1-(thiophen-2-yl)ethyl)cyclohexan-1-one
(16l).27 The title compound 16l was prepared from
cyclohexanoneand 1-(2-thienyl)-2-nitroethene according to the
28.9, 25.7; HPLC (Chiralcel AS-H, n-hexane: i-PrOH = 90:10, 85 general procedure of Michael addition. 16l is white solid, 84%
flow rate: 0.8 mL/min, λ = 210 nm), Tmajor = 19.7, Tminor = 14.1,
85% ee.
30 (R)-2-((S)-1-(4-bromophenyl)-2-nitroethyl)cyclohexan-1-one
(16h).27 The title compound 16h was prepared from
cyclohexanone and 4-bromo-β-nitrostyreneaccording to the 90 1.35–1.27 (m, 1H); 13C NMR (125 MHz, CDCl3): δ 211.2, 151.4,
yield. 1H NMR (500 MHz, CDCl3): δ 7.37 (d, J = 1.0, 1H), 6.32–
6.31 (m, 1H), 6.21–6.20 (m, 1H), 4.83–4.80 (m, 2H), 4.72–4.68
(m, 1H), 4.02–3.97 (m, 1H), 2.81–2.75 (m, 1H), 2.51–2.36 (m,
1H), 2.15–2.11 (m, 1H), 1.89–1.86 (m, 1H), 1.81–1.63 (m, 4H),
general procedure of Michael addition. 16h is white solid, 88%
yield. H NMR (500 MHz, CDCl3): δ 7.46 (t, J = 16.4 Hz, 2H),
142.7, 110.7, 109.4, 77.7, 51.5, 43.0, 38.0, 32.9, 28.6, 25.5;
HPLC (Chiralcel AS-H, n-hexane: i-PrOH = 80:20, flow rate: 0.8
mL/min, λ = 210 nm), Tmajor = 14.2, Tminor = 12.0, 93% ee.
1
35 7.08 (t, J = 8.2 Hz, 2H), 4.97–4.94 (m, 1H), 4.62–4.60 (m, 1H),
3.80–3.75 (m, 1H), 2.70–2.64 (m, 1H), 2.50–2.47 (m, 1H), 2.42–
2.36 (m, 1H), 2.12–2.08 (m, 1H), 1.83–1.80 (m, 1H), 1.75–1.57
(m, 3H), 1.29–1.21 (m, 1H); 13C NMR (125 MHz, CDCl3): δ
211.9, 137.3, 132.5, 130.4, 122.1, 78.9, 52.8, 43.9, 43.1, 33.6,
40 28.8, 25.5; HPLC (Chiralcel AD-H, n-hexane: i-PrOH = 90:10,
flow rate: 0.7 mL/min, λ = 210 nm), Tmajor = 23.7, Tminor = 28.1,
98% ee.
Acknowledgements
95 This work was supported by Program for Changjiang Scholars
and Innovative Research Team in University (IRT13095),
Training Plan for Young Teachers of Yunnan University and
National Natural Science Foundation of China (No. U1202221),
Scholarship Award for Excellent Doctoral Student of Yunnan
100 Province and Graduate student research innovation project of
Yunnan University (No.YNUY201417).
(R)-2-((S)-2-nitro-1-(p-tolyl)ethyl)cyclohexan-1-one
(16i).27
The title compound 16i was prepared from cyclohexanone and 4-
45 methyl-β-nitrostyreneaccording to the general procedure of
1
Michael addition. 16i is white solid, 83% yield. H NMR (500
Notes and references
MHz, CDCl3): δ 7.14 (d, J = 8.0 Hz, 2H), 7.07 (d, J = 8.0 Hz,
2H), 4.97–4.93 (m, 1H), 4.65–4.60 (m, 1H), 3.77–3.72 (m, 1H),
2.71–2.69 (m, 1H), 2.50–2.47 (m, 1H), 2.44–2.33 (m, 4H), 2.11–
50 2.08 (m, 1H), 1.81–1.57 (m, 4H), 1.28–1.23 (m, 1H); 13C NMR
(125 MHz, CDCl3): δ 212.5, 137.8, 135.1, 130.0, 128.4, 79.5,
52.9, 44.0, 43.1, 33.6, 28.9, 25.4, 21.5; HPLC (Chiralcel AD-H,
n-hexane: i-PrOH = 92:8, flow rate: 0.8 mL/min, λ = 210 nm),
Tmajor = 16.7, Tminor = 18.7, 96% ee.
55 (R)-2-((S)-1-(4-methoxyphenyl)-2-nitroethyl)cyclohexan-1-one
(16j).27 The title compound 16j was prepared from
cyclohexanone and 4-methoxy-β-nitrostyreneaccording to the
general procedure of Michael addition. 16j is white solid, 81% 115
Key Laboratory of Medicinal Chemistry for Natural Resource (Yunnan
University), Ministry of Education, School of Chemical Science and
105 Technology, Yunnan University, Kunming 650091, PR China; Tel: +86
871 5033715; E-mail: kunwei@ynu.edu.cn or linjun@ynu.edu.cn
†Electronic Supplementary Information (ESI) available: 1H and 13C NMR
spectra for compounds 2−11, 2a-11a, 14a-14r, 16a-16n; The spectra of
chiral HPLC for compounds 14a-14r and 16a-16n. This material is
110 available free of charge via the Internet at http://pubs.acs.org.
‡These authors contributed equally to the work.
1 (a) N. Ono. The Nitro Group in Organic Synthesis, Wiley-VCH,
NewYork, 2001; (b) V. V. Perekalin, E. S. Lipina, V. M.
Berestovitskaya, D. A. Efremov. Nitroalkenes: Conjugated Nitro
Compounds, Wiley-VCH, New York, 1994.
10
|Journal Name, [year], [vol], 00–00
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DOI: 10.1039/C4RA11214H
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DOI: 10.1039/C4RA11214H
Organocatalytic Asymmetric Michael Addition of Aldehydes and Ketones to
Nitroalkenes Catalyzed by Adamantoyl L-Prolinamide
Yongchao Wang,‡ Dong Li,‡ Jun Lin∗ and Kun Wei∗
O
NH
NH
H3C
CH3
R3
R3
H
O
Catalyst 5 (10%)
O
+
R1
R2
NO2
NO2
R2
Benzoic acid (10%)
Toluene,0 °C, 24h
n
n=0, 2
R1
n=0, 2
30 examples
up to 95% yield
up to 99:1 dr
up to 99% ee