Highly Enantioselective Michael Addition of Aromatic Ketones to Nitrodienes and the Application to the Synthesis of Chiral γ-Aminobutyric Acid

Article abstract of DOI:10.1055/s-0036-1588604

A highly enantioselective Michael addition of aromatic ketones to α,β,γ,δ-unsaturated nitro compounds is described. In the presence of a chiral primary amine-thiourea based on dehydroabietic amine, γ-nitro ketones were obtained in excellent enantioselecti

Full text of DOI:10.1055/s-0036-1588604

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–J
paper
A
X.-T. Guo et al.
Paper
Synthesis
Highly Enantioselective Michael Addition of Aromatic Ketones to
Nitrodienes and the Application to the Synthesis of Chiral γ-Ami-
nobutyric Acid
Xing-Tao Guo
Feng Sha
NO2
catalyst (30 mol%)
S
O
NO2
4-MeC6H4CO2H (30 mol%)
O
R
+
N
H
N
R1
Xin-Yan Wu*
CH2Cl2, 25 °C, 7 d
H
R1
R2
NH2
R2
25 examples
up to 95% yield
up to 95% ee
Key Laboratory for Advanced Materials and Institute of Fine
Chemicals, School of Chemistry & Molecular Engineering,
East China University of Science and Technology, Shanghai
200237, P. R. of China
R1 = Ar, Me
R =
H
NH3+Cl–
NO2
O
O
catalyst
xinyanwu@ecust.edu.cn
4 steps
HO
Ph
Ph
Ph
anticonvulsant
82% total yield
Received: 15.07.2016
Accepted after revision: 02.09.2016
Published online: 26.09.2016
tones7 as Michael acceptors. These reports encourage us to
examine such primary amine-thioureas for the Michael ad-
dition between aromatic ketones and nitrodienes. Herein,
we report our results on the asymmetric Michael reaction
and the application of the resulting chiral γ-nitro ketone in
the synthesis of another functional molecule.
DOI: 10.1055/s-0036-1588604; Art ID: ss-2016-h0499-op
Abstract A highly enantioselective Michael addition of aromatic ke-
tones to α,β,γ,δ-unsaturated nitro compounds is described. In the pres-
ence of a chiral primary amine-thiourea based on dehydroabietic
amine, γ-nitro ketones were obtained in excellent enantioselectivities
(up to 95% ee) with up to 95% yield. In addition, this methodology has
been successfully applied in the asymmetric synthesis of chiral 3-(ami-
nomethyl)-5-phenylpentanoic acid.
Initially, the Michael addition of acetophenone (2a) to
nitrodiene 3a was selected as a model reaction to screen
the primary amine-thioureas derived from the chiral di-
aminocyclohexane (DACH) backbone (Figure 1). According
to previous work,5 this Michael reaction proceeds through
enamine catalysis. It was well documented that the enam-
ine forms more easily in the presence of an acid, which
could promote the reaction rate and the chemical yield.8
Therefore, the reactions were carried out with 15 mol% chi-
ral organocatalyst together with 15 mol% benzoic acid. As
illustrated in Table 1, both enantiomers of the Michael
product were obtained in 48% yield with 95% ee by using
dehydroabietic amine-based chiral organocatalysts 1a and
1b. Catalyst 1c containing a racemic DACH backbone afford-
ed racemic γ-nitro ketone with a retained yield. These re-
sults revealed that the stereoselectivity and the absolute
configuration of the desired product were dependent on
the chiral DACH scaffold, and the dehydroabietic amine
moiety matched well with both chiral DACH with opposite
configuration. This observation is in agreement with previ-
ous reports using dehydroabietic amine-based organocata-
lysts.6,9 (1R,2R)-DACH-derived thioureas 1d–h without a
rosin scaffold were also examined, and the desired products
were afforded in lower yields, despite the high enantio-
selectivities obtained (entries 4–8 vs 1–3). Unlike the dehy-
droabietic amine, the chiral phenylethyl thiourea scaffold
had an impact on both the enantioselectivity and yield (en-
try 4 vs 5). The results also indicated that the organocata-
lysts bearing an aliphatic thiourea motif showed higher cat-
alytic activities than those with an aromatic motif, proba-
Key words chiral primary amine-thiourea, enantioselective catalysis,
ketone, Michael addition, nitrodiene
Chiral γ-nitro ketones are synthetic precursors for a
number of bioactive molecules, and they have received
growing attention in organic synthesis.1 Among the pub-
lished methodologies, the asymmetric Michael addition of
ketones to nitroalkenes is one of the most straightforward
approaches to provide chiral γ-nitro ketones.2 Besides the
well-known β-nitrostyrenes, nitrodienes are another class
of effective Michael acceptors for the reaction.3 In the past
decade, much attention has been paid to the organocatalyt-
ic asymmetric Michael reaction of ketones to nitrodienes.
However, successful examples are limited to aliphatic ke-
tones as Michael donors.4 Conversely, there are only a few
chiral organocatalysts that are determined to be effective
for the enantioselective conjugate addition between aro-
matic ketones and nitrodienes.5 As a consequence, explora-
tion of highly efficient catalytic systems for the enantiose-
lective Michael reaction between aromatic ketones and ni-
trodienes is still in demand.
As reported in the literature, chiral primary amine-
thioureas which are based on a dehydroabietic amine have
shown high efficiency for the enantioselective conjugate
addition with β-nitrostyrenes6 and α,β-unsaturated ke-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

B
X.-T. Guo et al.
Paper
Synthesis
S
S
N
N
H
NH
NH
1b
H
H
H
NH2
NH2
1a
S
S
S
Ph
N
N
H
Ph
N
H
N
N
NH
H
H
H
H
NH2
NH2
NH2
trans
1c
1d
1e
CF3
S
S
S
Bn
Ph
N
N
N
N
F3C
N
N
H
H
H
H
H
H
NH2
NH2
NH2
1f
1g
1h
Figure 1 Structure of chiral bifunctional organocatalysts 1a–h
bly mainly because of the electronic effect. It should be
noted that the low yield of all examples could be a result of
a poor conversion of reaction.
except dimethyl sulfoxide (entries 3–7). The solvent screen
suggests that dichloromethane is optimal for this Michael
reaction.
The solvent survey was then conducted in the presence
of 15 mol% of 1a together with 15 mol% benzoic acid (Table
2). All the solvent systems tested gave a slow conversion of
the reactions. When chloroform was used as solvent, the
Michael product was obtained with 45% yield and excellent
enantioselectivity (95% ee). In contrast, other solvents in-
cluding toluene, tetrahydrofuran, ethyl acetate, acetonitrile,
and dimethyl sulfoxide led to a much lower yield, though
good enantioselectivities were observed in these solvents
Table 2 Solvent Effect in the Enantioselective Michael Reaction of 2a
and 3aa
Ph
15 mol% 1a
15 mol% PhCO2H
O
O
Ph
+
NO2
NO2
Ph
solvent, 25 °C, 7 d
Ph
2a
3a
4a
Entry
Solvent
Yield (%)b
ee (%)c
1
2
3
4
5
6
7
CH2Cl2
CHCl3
toluene
THF
48
45
30
26
27
20
8
95
95
90
90
89
95
10
Table 1 Screening of Chiral Organocatalysts for the Enantioselective
Michael Reaction of 2a and 3aa
Ph
15 mol% catalyst
15 mol% PhCO2H
O
O
Ph
EtOAc
MeCN
DMSO
+
NO2
NO2
Ph
Ph
CH2Cl2, 25 °C, 7 d
2a
3a
4a
Entry
Catalyst
Yield (%)b
ee (%)c
a Reaction conditions: nitrodiene 3a (0.2 mmol), acetophenone (2a, 2.0
mmol), organocatalyst 1a (0.03 mmol), benzoic acid (0.03 mmol), solvent
(2 mL), 25 °C, 7 d.
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
48
48
48
38
32
32
15
20
95
–95
0
b Isolated yield.
c The ee values were determined by chiral HPLC analysis.
Next, diverse additives were screened (Table 3). A slow
reaction rate was consistently observed in all the examples
tested. When the reaction was carried out without additive,
product 4a was obtained in 40% yield with retained enantio-
selectivity. By using carboxylic acids, the enantioselectivity
was maintained but the yields varied, probably due to the
different acidities of compounds (entries 2–11). For exam-
ple, 4-nitrobenzoic acid resulted in a much lower reaction
rate (entry 5), while 4-methylbenzoic acid gave the desired
product with 52% yield. The desired product was obtained
97
94
96
92
87
1g
1h
a Reaction conditions: nitrodiene 3a (0.2 mmol), acetophenone (2a, 2.0
mmol), chiral organocatalyst (0.03 mmol), benzoic acid (0.03 mmol),
CH2Cl2 (2 mL), 25 °C, 7 d.
b Isolated yield.
c The ee values were determined by chiral HPLC analysis.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

C
X.-T. Guo et al.
Paper
Synthesis
with 48% yield when acetic acid, 4-methoxybenzoic acid, or
benzoic acid was employed as additive. On the other hand,
carboxylic acids including formic acid, propionic acid, 4-
fluorobenzoic acid, 4-chlorobenzoic acid, and 4-bromoben-
zoic acid afforded γ-nitro ketone with a lower yield than 4-
methylbenzoic acid (entries 2, 4, 6–8 vs 10). Moreover, the
reaction did not proceed by using a stronger acid such as 4-
toluenesulfonic acid as additive (entry 12). The additive
survey indicated that a proper acidity of additive was criti-
cal for the reaction rate, and 4-methylbenzoic acid was se-
lected as the additive for further experiments.
was observed when the reaction was carried out at 40 °C,
the yield decreased largely and byproducts appeared (entry
8 vs 7). On the basis of the above results, the optimal reac-
tion conditions were established to be 0.2 mol/L nitrodiene
3 in CH2Cl2 with 10 equivalents ketone 2, 30 mol% catalyst
loading and 30 mol% 4-methylbenzoic acid at 25 °C.
Table 4 Further Optimization of Reaction Conditions for the Enantio-
selective Michael Reactiona
Ph
O
O
1a/4-MeC6H4CO2H
Ph
+
NO2
NO2
Ph
Table 3 The Effect of Additives for the Enantioselective Michael Reac-
tion of 2a and 3aa
CH2Cl2, 25 °C, 7 d
Ph
2a
3a
4a
Ph
Entry
1a
(mol%)
Acid
(mol%)
2a
(equiv)
3a
(mol/L)
Yield
(%)b
ee
(%)c
15 mol% 1a
15 mol% additive
O
O
Ph
+
NO2
NO2
1
2
3
4
5
6
7
8d
15
15
15
15
15
20
30
30
15
15
15
15
15
20
30
30
10
10
10
5
0.1
0.2
0.3
0.2
0.2
0.2
0.2
0.2
52
57
54
45
49
63
73
35
95
95
94
95
95
94
95
93
Ph
Ph
CH2Cl2, 25 °C, 7 d
2a
3a
4a
Entry
Additive
pKa
Yield (%)b
ee (%)c
1
2
–
–
40
45
48
45
29
45
45
46
48
52
48
trace
95
95
95
95
96
96
96
96
95
95
95
15
10
10
10
HCO2H
AcOH
EtCO2H
3.75
4.76
4.87
3.42
4.14
3.97
3.97
4.20
4.38
4.47
–6.62
3
4
5
4-O2NC6H4CO2H
4-FC6H4CO2H
4-ClC6H4CO2H
4-BrC6H4CO2H
PhCO2H
a Reaction conditions: acetophenone (2a), nitrodiene 3a, organocatalyst
1a, 4-methylbenzoic acid, CH2Cl2 (2 mL), 25 °C, 7 d.
b Isolated yield.
6
c The ee values were determined by chiral HPLC analysis.
d Temperature: 40 °C, time: 3.5 d.
7
8
9
With the optimal reaction conditions in hand, the sub-
strate scope of ketones was then examined using nitrodiene
3a as Michael acceptor (Table 5, entries 1–12). When ace-
tophenones were used as donors, the Michael reaction was
achieved with 65–85% yield along with 89–95% ee (entries
1–9). The catalytic activity was sensitive to the electronic
effect of substituents on the phenyl group, and acetophe-
nones with electron-withdrawing groups were more reac-
tive than those without substituents or with electron-do-
nating groups (entries 2–7 vs entries 1, 8 and 9). However,
substrates 2 bearing ortho-substituted phenyl group such
as 2-chlorophenyl and 2-bromophenyl could not react with
nitrodiene 3a under the typical reaction condition, proba-
bly due to an ortho-effect. 2-Acetonaphthone afforded the
desired product 4j with 65% yield and 89% ee (entry 10).
Ketones bearing heteroaromatic rings were also tolerated
(entries 11 and 12). To our disappointment, an alkyl aryl
ketone, propiophenone, was unreactive as a nucleophile
under the typical reaction conditions.
10
11
12
4-MeC6H4CO2H
4-MeOC6H4CO2H
p-TsOH
d
–
a Reaction conditions: nitrodiene 3a (0.2 mmol), acetophenone (2a, 2.0
mmol), organocatalyst 1a (0.03 mmol), additive (0.03 mmol), CH2Cl2 (2
mL), 25 °C, 7 d.
b Isolated yield.
c The ee values were determined by chiral HPLC analysis.
d Not determined.
To obtain an even higher yield and enantioselectivity,
reaction conditions including substrate concentration, the
ratio of ketone to nitrodiene, catalyst loading and reaction
temperature were also investigated (Table 4). The desired
product was obtained in higher yield with an unchanged
enantioselectivity when the concentration of nitrodiene 3a
was increased from 0.1 M to 0.2 M, but further increase of
substrate concentration to 0.3 M did not improve the yield
(entries 2 and 3). Product 4a was afforded with a reduced
yield when the acetophenone amount relative to nitrodiene
3a was decreased to 5 equivalents or increased to 15 equiv-
alents (entries 4 and 5 vs 2). Enhancement of the chiral cat-
alyst loading resulted in the production of higher yields
(entries 6 and 7 vs 2). Although the shortest reaction time
A further exploration of the substrate scope was cen-
tered on nitrodienes bearing various aryl group by using 1-
(4-chlorophenyl)ethanone as the Michael donor (Table 5,
entries 13–22). All the nitrodienes gave the corresponding
γ-nitro ketones with excellent enantioselectivities (91–94%
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

D
X.-T. Guo et al.
Paper
Synthesis
ee) and good yields (74–95%). Substrates 3 bearing elec-
tron-withdrawing substituents on the phenyl group were
more reactive than those without substituents or with elec-
tron-donating substituents (entries 13–19 vs entries 4, 20
and 21). In addition, nitrodienes containing heteroaromatic
group such as the furyl group promoted the reaction well to
afford product 4v with 89% yield and 92% ee. Besides
(1E,3E)-4-aryl-1-nitrobuta-1,3-dienes, Michael acceptors
such as ethyl (2E,4E)-5-nitropenta-2,4-dienoate (entry 23)
and (E)-(4-nitrobut-3-en-1-yn-1-yl)benzene (Equation 1)
also appeared to be tolerant under the typical reaction con-
ditions. However, δ-alkyl α,β,γ,δ-unsaturated nitro com-
pounds, such as (1E,3E)-1-nitrohepta-1,3-diene and
[(1E,3E)-4-nitrobuta-1,3-dien-1-yl]cyclohexane, were un-
reactive electrophiles under the typical reaction condition.
Ph
O
30 mol% 1a
NO2 30 mol% 4-MeC6H4CO2H
O
NO2
+
Ph
CH2Cl2, 25 °C, 7 d
Ph
Ph
2a
3m
4x
81% yield, 93% ee
Equation 1
As expected, acetone is more reactive than acetophe-
none under the typical reaction condition (Equation 2).
When the catalyst loading was 10 mol%, the Michael reac-
tion was accomplished in a shorter time with 85% yield and
87% ee. According to the optical rotation values reported in
the literature,5a,c the absolute configurations of all products
4a–y were assigned as the S-configuration.
Table 5 Substrate Scope of the Enantioselective Michael Addition be-
tween Aromatic Ketones and Nitrodienesa
Ar
30 mol% 1a
30 mol% 4-MeC6H4CO2H
O
O
R
+
NO2
NO2
Ar
R
CH2Cl2, 25 °C, 7 d
2
3
4
10 mol% 1a
10 mol% 4-MeC6H4CO2H
O
O
Entry
Ar
Ph
R
Yield (%)b
ee (%)c
Ph
+
NO2
NO2
Ph
CH2Cl2, 25 °C, 4 d
1
2
Ph
73 (4a)
80 (4b)
83 (4c)
83 (4d)
82 (4e)
85 (4f)
85 (4g)
70 (4h)
65 (4i)
65 (4j)
78 (4k)
80 (4l)
95 (4m)
90 (4n)
91 (4o)
90 (4p)
88 (4q)
87 (4r)
89 (4s)
79 (4t)
74 (4u)
89 (4v)
82 (4w)
95
90
92
93
92
89
92
93
92
89
90
90
93
92
93
91
93
92
92
92
94
92
94
2m
3a
4y
85% yield, 87% ee
4-O2NC6H4
4-FC6H4
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
3
Equation 2
4
4-ClC6H4
3-ClC6H4
4-BrC6H4
3-BrC6H4
4-MeC6H4
4-MeOC6H4
2-naphthyl
2-thienyl
2-furyl
5
An important synthetic application of this methodology
is the transformation of the Michael products 4 into the
corresponding optically active γ-aminobutyric acid (GABA)
analogues, such as chiral 3-(aminomethyl)-5-phenylpenta-
noic acid with good anticonvulsive biological activity.10 To
the best of our knowledge, the asymmetric synthesis of chi-
ral 3-(aminomethyl)-5-phenylpentanoic acid has not previ-
ously been achieved.
We began our total synthesis by the condensation of γ-
nitro ketone 4a with hydroxylamine hydrochloride to give
the corresponding oxime 5 in 96% yield. The Beckman rear-
rangement of oxime 5 afforded the corresponding amide 6
with 94% yield. It should be noted that the transformation
of carbonyl group had no impact on the enantioselectivity
(Scheme 1). Subsequently, reduction of both nitro group
and carbon–carbon double bond gave the corresponding
amine 7 with excellent yield. Finally, the hydrochloride salt
of (R)-3-(aminomethyl)-5-phenylpentanoic acid was ob-
tained in 92% yield after the hydrolysis of compound 7.
In summary, a highly enantioselective Michael addition
of aromatic ketones to nitrodienes was developed by using
dehydroabietic amine-based chiral primary amine-
thiourea. A wide range of aromatic ketones and nitrodienes
could be used for the reaction, and the resulting chiral γ-ni-
tro ketones were obtained in excellent enantioselectivities
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
Ph
4-O2NC6H4
3-O2NC6H4
2-O2NC6H4
4-NCC6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
4-MeC6H4
4-MeOC6H4
2-furyl
CO2Et
a Reaction conditions: nitrodiene 3 (0.3 mmol), ketone 2 (3.0 mmol), or-
ganocatalyst 1a (0.09 mmol), 4-methylbenzoic acid (0.09 mmol), CH2Cl2
(1.5 mL), 25 °C, 7 d.
b Isolated yield.
c The ee values were determined by chiral HPLC analysis.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

E
X.-T. Guo et al.
Paper
Synthesis
(S,E)-3-(Nitromethyl)-1,5-diphenylpent-4-en-1-one (4a)5a
NO2
OH NO2
O
NH2OH.HCl, pyridine
N
25
White solid; yield: 64.7 mg (73%, 95% ee); mp 103.9–104.2 °C; [α]D
+11.8 (c 1.05, CHCl3).
EtOH, reflux, 1 h
Ph
Ph
Ph
5, 96% yield, 95% ee
Ph
HPLC [Daicel Chiralpak AD-H, λ = 254 nm, eluent: i-PrOH/hexane
(10:90), flow rate: 0.9 mL/min]: tR = 19.3 (major), 22.3 min (minor).
4a, 95% ee
TsCl, MeCN
reflux, 4 h
1H NMR (400 MHz, CDCl3): δ = 7.98 (d, J = 7.6 Hz, 2 H), 7.62 (t, J = 7.6
Hz, 1 H), 7.51 (t, J = 7.6 Hz, 2 H), 7.37–7.30 (m, 5 H), 6.60 (d, J = 15.6
Hz, 1 H), 6.19 (dd, J = 15.6, 8.8 Hz, 1 H), 4.75 (dd, J = 12.0, 6.0 Hz, 1 H),
4.64 (dd, J = 12.0, 6.0 Hz, 1 H), 3.82–3.74 (m, 1 H), 3.33 (d, J = 6.8 Hz, 2
H).
NO2
NH2
Pd(OH)2/C, H2
O
O
MeOH, 40 °C, 4 h
PhNH
6, 94% yield, 95% ee
Ph
PhNH
Ph
7, 99% yield
(S,E)-3-(Nitromethyl)-1-(4-nitrophenyl)-5-phenylpent-4-en-1-one
(4b)5a
concd HCl
110 °C, 18 h
Pale yellow solid; yield: 81.7 mg (80%, 90% ee); mp 142.1–143.0 °C;
[α]D25 +10.5 (c 0.82, CHCl3).
HPLC [Daicel Chiralpak AS-H, λ = 254 nm, eluent: i-PrOH/hexane
(30:70), flow rate: 0.9 mL/min]: tR = 42.2 (major), 49.5 min (minor).
1H NMR (400 MHz, CDCl3): δ = 8.33 (d, J = 8.4 Hz, 2 H), 8.11 (d, J = 8.8
Hz, 2 H), 7.34–7.26 (m, 5 H), 6.60 (d, J = 16.0 Hz, 1 H), 6.15 (dd, J =
16.0, 8.4 Hz, 1 H), 4.74–4.62 (m, 2 H), 3.81–3.72 (m, 1 H), 3.42–3.30
(m, 2 H).
NH3+Cl–
Ph
O
HO
8, 92% yield
Scheme 1 Asymmetric synthesis of (R)-3-(aminomethyl)-5-phenyl-
pentanoic acid
(S,E)-1-(4-Fluorophenyl)-3-(nitromethyl)-5-phenylpent-4-en-1-
one (4c)5a
25
White solid; yield: 78.0 mg (83%, 92% ee); mp 66.7–67.8 °C; [α]D
+8.4 (c 0.78, CHCl3).
(up to 95% ee) with up to 95% yield. Moreover, this method-
ology established was successfully applied to the asymmet-
ric synthesis of chiral 3-(aminomethyl)-5-phenylpentanoic
acid.
HPLC [Daicel Chiralpak AD-H, λ = 254 nm, eluent: i-PrOH/hexane
(10:90), flow rate: 0.9 mL/min]: tR = 23.1 (major), 26.8 min (minor).
1H NMR (400 MHz, CDCl3): δ = 8.03–8.00 (m, 2 H), 7.37–7.27 (m, 5 H),
7.18 (t, J = 8.4 Hz, 2 H), 6.60 (d, J = 16.0 Hz, 1 H), 6.18 (dd, J = 16.0, 8.4
Hz, 1 H), 4.73 (dd, J = 12.0, 6.0 Hz, 1 H), 4.64 (dd, J = 12.0, 7.2 Hz, 1 H),
3.81–3.72 (m, 1 H), 3.54–3.24 (m, 2 H).
1H and 13C NMR spectra were recorded on Varian 300 or Bruker 400
spectrometers relative to TMS (δ = 0.00) using CDCl3 or CD3OD as sol-
vent (1H), and or to solvent carbon (δ = 77.0 for CDCl3 or δ = 49.0 for
CD3OD) (13C). IR spectra were recorded on a Nicolet Magna-I 550
spectrophotometer. HRMS were recorded on Waters Micromass GCT
Premier spectrometer with EI or ESI resource. Melting points were
measured on WRS-1B digital melting point apparatus and are uncor-
rected. Optical rotations were measured on a WZZ-2A digital po-
larimeter at the wavelength of the Na D-line (589 nm). TLC was per-
formed on 10–40 μm silica gel plates. Column chromatography was
carried out with silica gel (300–400 mesh) using mixtures of EtOAc
and petroleum ether as eluent. HPLC analysis was performed on Wa-
ters equipment using Daicel Chiralpak AS-H or AD-H columns or a
Daicel Chiralcel OJ column.
(S,E)-1-(4-Chlorophenyl)-3-(nitromethyl)-5-phenylpent-4-en-1-
one (4d)5a
25
White solid; yield: 82.1 mg (83%, 93% ee); mp 126.1–127.8 °C; [α]D
–6.8 (c 0.82, CHCl3).
HPLC [Daicel Chiralpak AD-H, λ = 254 nm, eluent: i-PrOH/hexane
(10:90), flow rate: 0.9 mL/min]: tR = 26.3 (major), 31.4 min (minor).
1H NMR (400 MHz, CDCl3): δ = 7.92 (d, J = 8.4 Hz, 2 H), 7.48 (d, J = 8.8
Hz, 2 H), 7.36–7.27 (m, 5 H), 6.60 (d, J = 15.6 Hz, 1 H), 6.18 (dd, J =
15.6, 8.4 Hz, 1 H), 4.73 (dd, J = 12.0, 6.0 Hz, 1 H), 4.64 (dd, J = 12.0, 7.2
Hz, 1 H), 3.80–3.72 (m, 1 H), 3.35–3.24 (m, 2 H).
CH2Cl2, CHCl3, EtOAc, MeCN, and DMSO were distilled from CaH2. THF
and toluene were distilled from Na/benzophenone. All ketones were
commercially available of analytical grade and used without purifica-
tion. Nitrodienes were prepared according to the literature.11
(S,E)-1-(3-Chlorophenyl)-3-(nitromethyl)-5-phenylpent-4-en-1-
one (4e)
25
Pale yellow oil; yield: 81.1 mg (82%, 92% ee); [α]D –13.7 (c 0.81,
CHCl3).
HPLC [Daicel Chiralpak AD-H, λ = 254 nm, eluent: i-PrOH/hexane
(10:90), flow rate: 0.9 mL/min]: tR = 19.4 (major), 21.6 min (minor).
1-Aryl-3-(nitromethyl)alk-4-en-1-ones 4; General Procedure
To a solution of catalyst 1a (0.09 mmol), 4-methylbenzoic acid (0.09
mmol), and ketone 2 (3.0 mmol) in CH2Cl2 (1.5 mL) was added nitro-
diene 3 (0.3 mmol) at 25 °C, and the resulting mixture was stirred at
25 °C until the reaction was complete (monitored by TLC). The solvent
was removed under reduced pressure and the residue was purified by
flash chromatography to afford product 4.
IR (KBr, film): 2963, 2924, 2853, 1679, 1588, 1541, 1449, 1419, 1372,
1256, 1217, 965, 758, 693 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.95 (s, 1 H), 7.85 (d, J = 8.0 Hz, 1 H),
7.59 (d, J = 8.0 Hz, 1 H), 7.45 (d, J = 8.0 Hz, 1 H), 7.37–7.27 (m, 5 H),
6.62 (d, J = 16.0 Hz, 1 H), 6.17 (dd, J = 16.0, 8.4 Hz, 1 H), 4.73 (dd, J =
12.0, 6.0 Hz, 1 H), 4.64 (dd, J = 12.0, 7.2 Hz, 1 H), 3.81–3.73 (m, 1 H),
3.36–3.25 (m, 2 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

F
X.-T. Guo et al.
Paper
Synthesis
13C NMR (100 MHz, CDCl3): δ = 195.7, 137.9, 136.0, 135.1, 133.6,
133.4, 130.1, 128.6, 128.1, 128.0, 126.4, 126.2, 126.1, 78.6, 40.4, 37.1.
1H NMR (400 MHz, CDCl3): δ = 8.48 (s, 1 H), 8.00 (dd, J = 8.8, 1.6 Hz, 1
H), 7.97 (d, J = 8.0 Hz, 1 H), 7.90 (t, J = 9.2 Hz, 2 H), 7.64–7.55 (m, 2 H),
7.35–7.21 (m, 5 H), 6.61 (d, J = 16.0 Hz, 1 H), 6.21 (dd, J = 16.0, 8.8 Hz,
1 H), 4.76 (dd, J = 12.0, 6.0 Hz, 1 H), 4.66 (dd, J = 12.0, 7.2 Hz, 1 H),
3.86–3.77 (m, 1 H), 3.50–3.39 (m, 2 H).
HRMS (EI): m/z [M – NO2] calcd for C18H16ClO: 283.0890; found:
283.0899.
(S,E)-1-(4-Bromophenyl)-3-(nitromethyl)-5-phenylpent-4-en-1-
(S,E)-3-(Nitromethyl)-5-phenyl-1-(thiophen-2-yl)pent-4-en-1-one
one (4f)5a
(4k)5c
Pale yellow solid; yield: 95.4 mg (85%, 89% ee); mp 98.5–99.3 °C;
25
Pale yellow oil; yield: 70.5 mg (78%, 90% ee); [α]D +9.9 (c 0.70,
[α]D25 –3.6 (c 0.95, CHCl3).
CHCl3).
HPLC [Daicel Chiralpak AD-H, λ = 254 nm, eluent: i-PrOH/hexane
(10:90), flow rate: 0.9 mL/min]: tR = 29.3 (major), 35.2 min (minor).
1H NMR (400 MHz, CDCl3): δ = 7.84 (d, J = 8.8 Hz, 2 H), 7.65 (d, J = 8.4
Hz, 2 H), 7.36–7.27 (m, 5 H), 6.60 (d, J = 16.0 Hz, 1 H), 6.17 (dd, J =
16.0, 8.4 Hz, 1 H), 4.73 (dd, J = 12.4, 6.0 Hz, 1 H), 4.64 (dd, J = 12.0, 7.2
Hz, 1 H), 3.80–3.72 (m, 1 H), 3.35–3.23 (m, 2 H).
HPLC [Daicel Chiralpak AD-H, λ = 254 nm, eluent: i-PrOH/hexane
(10:90), flow rate: 0.9 mL/min]: tR = 24.3 (major), 28.7 min (minor).
1H NMR (400 MHz, CDCl3): δ = 7.60 (s, 1 H), 7.36–7.27 (m, 5 H), 7.24–
7.23 (m, 1 H), 6.59–6.55 (m, 2 H), 6.13 (dd, J = 16.0, 8.8 Hz, 1 H), 4.69
(dd, J = 12.0, 6.0 Hz, 1 H), 4.60 (dd, J = 12.0, 7.6 Hz, 1 H), 3.76–3.67 (m,
1 H), 3.21–3.10 (m, 2 H).
(S,E)-1-(3-Bromophenyl)-3-(nitromethyl)-5-phenylpent-4-en-1-
(S,E)-1-(Furan-2-yl)-3-(nitromethyl)-5-phenylpent-4-en-1-one
one (4g)5a
(4l)5c
25
Pale yellow oil; yield: 95.5 mg (85%, 92% ee); [α]D +6.7 (c 0.96,
25
Pale yellow oil; yield: 68.5 mg (80%, 90% ee); [α]D +12.3 (c 0.65,
CHCl3).
CHCl3).
HPLC [Daicel Chiralpak AS-H, λ = 254 nm, eluent: i-PrOH/hexane
(10:90), flow rate: 0.9 mL/min]: tR = 22.8 (major), 28.3 min (minor).
1H NMR (400 MHz, CDCl3): δ = 8.11 (s, 1 H), 7.90 (d, J = 8.0 Hz, 1 H),
7.74 (d, J = 8.0 Hz, 1 H), 7.41–7.27 (m, 6 H), 6.60 (d, J = 15.6 Hz, 1 H),
6.17 (dd, J = 15.6, 8.8 Hz, 1 H), 4.72 (dd, J = 12.0, 6.0 Hz, 1 H), 4.64 (dd,
J = 12.0, 7.2 Hz, 1 H), 3.81–3.72 (m, 1 H), 3.36–3.25 (m, 2 H).
HPLC [Daicel Chiralpak AD-H, λ = 254 nm, eluent: i-PrOH/hexane
(10:90), flow rate: 0.9 mL/min]: tR = 25.4 (major), 28.2 min (minor).
1H NMR (400 MHz, CDCl3): δ = 7.60 (s, 1 H), 7.32–7.24 (m, 6 H), 6.59–
6.55 (m, 2 H), 6.12 (dd, J = 16.0, 8.8 Hz, 1 H), 4.68 (dd, J = 12.0, 6.0 Hz,
1 H), 4.59 (dd, J = 12.0, 7.6 Hz, 1 H), 3.76–3.67 (m, 1 H), 3.21–3.09 (m,
2 H).
(S,E)-3-(Nitromethyl)-5-phenyl-1-(4-tolyl)pent-4-en-1-one (4h)5a
(S,E)-1-(4-Chlorophenyl)-3-(nitromethyl)-5-(4-nitrophenyl)pent-
4-en-1-one (4m)
25
White solid; yield: 65.0 mg (70%, 93% ee); mp 112.5–113.6 °C; [α]D
+5.9 (c 0.65, CHCl3).
25
Yellow solid; yield: 106.8 mg (95%, 93% ee); mp 126.8–128.3 °C; [α]D
HPLC [Daicel Chiralpak AD-H, λ = 254 nm, eluent: i-PrOH/hexane
(10:90), flow rate: 0.9 mL/min]: tR = 20.4 (major), 26.6 min (minor).
1H NMR (400 MHz, CDCl3): δ = 7.85 (d, J = 8.4 Hz, 2 H), 7.34–7.23 (m, 7
H), 6.57 (d, J = 16.0 Hz, 1 H), 6.16 (dd, J = 16.0, 8.4 Hz, 1 H), 4.71 (dd,
J = 12.0, 8.4 Hz, 1 H), 4.61 (dd, J = 12.0, 8.8 Hz, 1 H), 3.78–3.70 (m, 1
H), 3.26 (d, J = 6.4 Hz, 2 H), 2.42 (s, 3 H).
+35.6 (c 0.71, CHCl3).
HPLC [Daicel Chiralpak AD-H, λ = 254 nm, eluent: i-PrOH/hexane
(10:90), flow rate: 0.9 mL/min]: tR = 35.7 (major), 47.9 min (minor).
IR (KBr, film): 2913, 2851, 1685, 1591, 1551, 1514, 1342, 1217, 1092,
972, 818 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 8.10 (d, J = 8.4 Hz, 2 H), 7.87 (d, J = 8.4
Hz, 2 H), 7.42 (d, J = 8.1 Hz, 4 H), 6.63 (d, J = 15.9 Hz, 1 H), 6.35 (dd, J =
15.9, 8.7 Hz, 1 H), 4.72 (dd, J = 12.3, 5.7 Hz, 1 H), 4.64 (dd, J = 12.0, 7.5
Hz, 1 H), 3.83–3.72 (m, 1 H), 3.29 (d, J = 6.3 Hz, 2 H).
(S,E)-1-(4-Methoxyphenyl)-3-(nitromethyl)-5-phenylpent-4-en-1-
one (4i)5a
25
White solid; yield: 63.4 mg (65%, 92% ee); mp 116.9–117.2 °C; [α]D
13C NMR (75 MHz, CDCl3): δ = 195.4, 147.0, 142.5, 140.2, 134.5, 131.5
–11.9 (c 0.63, CHCl3).
(2), 129.4, 129.1, 127.0, 123.9, 78.3, 39.9, 37.1.
HPLC [Daicel Chiralpak AD-H, λ = 254 nm, eluent: i-PrOH/hexane
(10:90), flow rate: 0.9 mL/min]: tR = 36.3 (major), 50.4 min (minor).
HRMS (EI): m/z [M – NO2] calcd for C18H15ClNO3: 328.0740; found:
328.0748.
1H NMR (400 MHz, CDCl3): δ = 7.94 (d, J = 8.8 Hz, 2 H), 7.34–7.22 (m, 5
H), 6.95 (d, J = 8.8 Hz, 2 H), 6.57 (d, J = 16.0 Hz, 1 H), 6.17 (dd, J = 16.0,
8.8 Hz, 1 H), 4.72 (dd, J = 12.0, 6.0 Hz, 1 H), 4.61 (dd, J = 12.0, 7.8 Hz, 1
H), 3.88 (s, 3 H), 3.78–3.69 (m, 1 H), 3.23 (d, J = 6.4 Hz, 2 H).
(S,E)-1-(4-Chlorophenyl)-3-(nitromethyl)-5-(3-nitrophenyl)pent-
4-en-1-one (4n)
Pale yellow solid; yield: 101.2 mg (90%, 92% ee); mp 126.1–128.2 °C;
[α]D25 +17.4 (c 0.67, CHCl3).
(S,E)-1-(Naphthalen-2-yl)-3-(nitromethyl)-5-phenylpent-4-en-1-
one (4j)5a
HPLC [Daicel Chiralpak AD-H, λ = 254 nm, eluent: i-PrOH/hexane
(30:70), flow rate: 0.9 mL/min]: tR = 25.9 (major), 34.3 min (minor).
25
White solid; yield: 67.4 mg (65%, 89% ee); mp 131.9–132.6 °C; [α]D
–19.9 (c 0.67, CHCl3).
IR (KBr, film): 2917, 2847, 1685, 1551, 1526, 1351, 1217, 1092, 972,
819, 733 cm–1
.
HPLC [Daicel Chiralpak AD-H, λ = 254 nm, eluent: i-PrOH/hexane
(10:90), flow rate: 0.9 mL/min]: tR = 29.9 (major), 45.8 min (minor).
1H NMR (300 MHz, CDCl3): δ = 8.06 (s, 1 H), 7.96 (d, J = 8.1 Hz, 1 H),
7.80 (d, J = 8.1 Hz, 2 H), 7.51 (d, J = 7.5 Hz, 1 H), 7.30–7.34 (m, 3 H),
6.54 (d, J = 15.9 Hz, 1 H), 6.22 (dd, J = 15.9, 5.7 Hz, 1 H), 4.67–4.51 (m,
2 H), 3.75–3.66 (m, 1 H), 3.21 (d, J = 6.0 Hz, 2 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

G
X.-T. Guo et al.
Paper
Synthesis
13C NMR (75 MHz, CDCl3): δ = 195.7, 148.7, 140.5, 138.1, 134.8, 132.7,
19F NMR (279 MHz, CDCl3): δ = –114.0.
131.6, 130.1, 129.8, 129.7, 129.4, 122.8, 121.1, 78.7, 40.2, 37.3.
HRMS (EI): m/z [M] calcd for
C18H15ClFNO3: 347.0724; found:
HRMS (EI): m/z [M – NO2] calcd for C18H15ClNO3: 328.0740; found:
347.0722.
328.0747.
(S,E)-1,5-Bis(4-chlorophenyl)-3-(nitromethyl)pent-4-en-1-one
(S,E)-1-(4-Chlorophenyl)-3-(nitromethyl)-5-(2-nitrophenyl)pent-
(4r)
4-en-1-one (4o)
Pale yellow solid; yield: 95.1 mg (87%, 92% ee); mp 81.7–82.8 °C;
Pale yellow solid; yield: 102.3 mg (91%, 93% ee); mp 132.5–134.3 °C;
[α]D25 +42.1 (c 0.63, CHCl3).
[α]D25 –25.9 (c 0.68, CHCl3).
HPLC [Daicel Chiralpak AD-H, λ = 254 nm, eluent: i-PrOH/hexane
(10:90), flow rate: 0.9 mL/min]: tR = 35.6 (major), 40.3 min (minor).
HPLC [Daicel Chiralpak AD-H, λ = 254 nm, eluent: i-PrOH/hexane
(30:70), flow rate: 0.9 mL/min]: tR = 20.6 (major), 27.6 min (minor).
IR (KBr, film): 2921, 2847, 1685, 1589, 1550, 1490, 1401, 1377, 1217,
IR (KBr, film): 2921, 2851, 1685, 1550, 1521, 1342, 1091, 966, 818,
1091, 1012, 969, 810 cm–1
.
740 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.87 (d, J = 8.7 Hz, 2 H), 7.43 (d, J = 8.4
Hz, 2 H), 7.28–7.20 (m, 4 H), 6.51 (d, J = 15.9 Hz, 1 H), 6.11 (dd, J =
15.9, 8.4 Hz, 1 H), 4.68 (dd, J = 12.0, 6.0 Hz, 1 H), 4.59 (dd, J = 12.0, 7.2
Hz, 1 H), 3.77–3.66 (m, 1 H), 3.24 (d, J = 6.6 Hz, 2 H).
13C NMR (75 MHz, CDCl3): δ = 195.7, 140.1, 134.6, 134.5, 133.6, 132.3,
129.4, 129.1, 128.7, 127.6, 127.0, 78.6, 40.1, 37.1.
1H NMR (300 MHz, CDCl3): δ = 7.85 (d, J = 8.1 Hz, 1 H), 7.80 (d, J = 8.7
Hz, 2 H), 7.49–7.29 (m, 5 H), 6.95 (d, J = 15.9 Hz, 1 H), 6.08 (dd, J =
15.9, 8.1 Hz, 1 H), 4.68–4.55 (m, 2 H), 3.74–3.63 (m, 1 H), 3.30–3.16
(m, 2 H).
13C NMR (75 MHz, CDCl3): δ = 195.9, 147.7, 140.5, 134.8, 133.6, 132.5,
132.1, 129.7, 129.5, 129.4, 128.8, 124.9, 108.9, 78.6, 40.2, 37.1.
HRMS (EI): m/z [M – NO2] calcd for C18H15Cl2O: 317.0500; found:
HRMS (EI): m/z [M – NO2] calcd for C18H15ClNO3: 328.0740; found:
317.0492.
328.0746.
(S,E)-5-(4-Bromophenyl)-1-(4-chlorophenyl)-3-(nitrometh-
(S,E)-4-[5-(4-Chlorophenyl)-3-(nitromethyl)-5-oxopent-1-en-1-
yl)pent-4-en-1-one (4s)
yl]benzonitrile (4p)
Pale yellow solid; yield: 109.1 mg (89%, 92% ee); mp 102.4–103.2 °C;
25
White solid; yield: 95.8 mg (90%, 91% ee); mp 105.2–106.7 °C; [α]D
[α]D25 +59.8 (c 0.72, CHCl3).
+37.8 (c 0.64, CHCl3).
HPLC [Daicel Chiralpak AD-H, λ = 254 nm, eluent: i-PrOH/hexane
(10:90), flow rate: 0.9 mL/min]: tR = 38.5 (major), 43.8 min (minor).
HPLC [Daicel Chiralpak AD-H, λ = 254 nm, eluent: i-PrOH/hexane
(20:80), flow rate: 0.9 mL/min]: tR = 43.5 (major), 47.8 min (minor).
IR (KBr, film): 2917, 2847, 1685, 1588, 1550, 1487, 1400, 1377, 1217,
IR (KBr, film): 2921, 2847, 2229, 1685, 1550, 1378, 1221, 1092, 972,
1092, 1072, 1008, 968, 817 cm–1
.
818 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.87 (d, J = 8.7 Hz, 2 H), 7.43 (d, J = 8.9
Hz, 2 H), 7.39 (d, J = 8.4 Hz, 2 H), 7.18 (d, J = 8.1 Hz, 2 H), 6.50 (d, J =
15.6 Hz, 1 H), 6.13 (dd, J = 15.6, 8.4 Hz, 1 H), 4.69 (dd, J = 12.0, 6.0 Hz,
1 H), 4.59 (dd, J = 12.0, 7.2 Hz, 1 H), 3.77–3.65 (m, 1 H), 3.25 (d, J = 6.3
Hz, 2 H).
13C NMR (75 MHz, CDCl3): δ = 195.6, 140.1, 135.0, 134.6, 132.4, 131.6,
129.4, 129.1, 127.9, 127.1, 121.8, 78.5, 40.1, 37.1.
1H NMR (300 MHz, CDCl3): δ = 7.79 (d, J = 8.4 Hz, 2 H), 7.47 (d, J = 8.1
Hz, 2 H), 7.35 (d, J = 8.4 Hz, 2 H), 7.30 (d, J = 8.4 Hz, 2 H), 6.50 (d, J =
15.9 Hz, 1 H), 6.21 (dd, J = 15.9, 8.4 Hz, 1 H), 4.62 (dd, J = 12.3, 5.7 Hz,
1 H), 4.54 (dd, J = 12.0, 7.2 Hz, 1 H), 3.73–3.62 (m, 1 H), 3.19 (d, J = 6.6
Hz, 2 H).
13C NMR (75 MHz, CDCl3): δ = 195.7, 140.8, 140.5, 134.8, 132.6, 132.3,
130.8, 129.7, 129.4, 127.2, 119.0, 111.5, 78.6, 40.2, 37.4.
HRMS (EI): m/z [M – NO2] calcd for C18H15BrClO: 360.9995; found:
HRMS (EI): m/z [M] calcd for
C19H15ClN2O3: 354.0771; found:
360.9986.
354.0779.
(S,E)-1-(4-Chlorophenyl)-3-(nitromethyl)-5-(p-tolyl)pent-4-en-1-
(S,E)-1-(4-Chlorophenyl)-5-(4-fluorophenyl)-3-(nitrometh-
one (4t)
25
yl)pent-4-en-1-one (4q)
White solid; yield: 81.5 mg (79%, 92% ee); mp 88.8–90.2 °C; [α]D
+7.9 (c 0.54, CHCl3).
25
White solid; yield: 91.8 mg (88%, 93% ee); mp 92.2–94.5 °C; [α]D
+13.8 (c 0.61, CHCl3).
HPLC [Daicel Chiralpak AD-H, λ = 254 nm, eluent: i-PrOH/hexane
(10:90), flow rate: 0.9 mL/min]: tR = 23.4 (major), 26.3 min (minor).
HPLC [Daicel Chiralpak AD-H, λ = 254 nm, eluent: i-PrOH/hexane
(10:90), flow rate: 0.9 mL/min]: tR = 31.6 (major), 36.3 min (minor).
IR (KBr, film): 2913, 2842, 1685, 1589, 1550, 1400, 1378, 1216, 1092,
IR (KBr, film): 2917, 2847, 1685, 1589, 1551, 1508, 1378, 1227, 1093,
969, 818, 803 cm–1
.
968, 818 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.88 (d, J = 8.7 Hz, 2 H), 7.44 (d, J = 8.7
Hz, 2 H), 7.22 (d, J = 8.7 Hz, 2 H), 7.10 (d, J = 8.7 Hz, 2 H), 6.52 (d, J =
15.6 Hz, 1 H), 6.10 (dd, J = 15.6, 8.4 Hz, 1 H), 4.69 (dd, J = 12.0, 6.0 Hz,
1 H), 4.59 (dd, J = 12.0, 7.2 Hz, 1 H), 3.77–3.65 (m, 1 H), 3.25 (d, J = 6.3
Hz, 2 H), 2.32 (s, 3 H).
1H NMR (300 MHz, CDCl3): δ = 7.87 (d, J = 8.4 Hz, 2 H), 7.43 (d, J = 8.4
Hz, 2 H), 7.30–7.25 (m, 2 H), 6.97 (d, J = 8.4 Hz, 2 H), 6.53 (d, J = 15.9
Hz, 1 H), 6.05 (dd, J = 15.9, 8.1 Hz, 1 H), 4.69 (dd, J = 12.0, 8.1 Hz, 1 H),
4.59 (dd, J = 12.0, 7.5 Hz, 1 H), 3.78–3.65 (m, 1 H), 3.25 (d, J = 6.6 Hz, 2
H).
13C NMR (75 MHz, CDCl3): δ = 195.7, 164.0 (d, JC-F = 246.1 Hz), 140.1,
134.6, 132.3, 132.2 (d, JC-F = 3.2 Hz), 129.4, 129.0, 128.0 (d, JC-F = 8.0
Hz), 126.0, 115.6 (d, JC-F = 21.5 Hz), 78.7, 40.2, 37.2.
13C NMR (75 MHz, CDCl3): δ = 195.9, 140.0, 137.9, 134.7, 133.4, 133.2,
129.4, 129.3, 129.0, 126.3, 125.1, 78.7, 40.3, 37.2, 21.2.
HRMS (EI): m/z [M – NO2] calcd for C19H18ClO: 297.1046; found:
297.1039.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

H
X.-T. Guo et al.
Paper
Synthesis
(S,E)-1-(4-Chlorophenyl)-5-(4-methoxyphenyl)-3-(nitrometh-
yl)pent-4-en-1-one (4u)
1H NMR (400 MHz, CDCl3): δ = 7.98 (d, J = 7.6 Hz, 2 H), 7.60 (t, J = 7.2
Hz, 1 H), 7.48 (d, J = 7.6 Hz, 2 H), 7.35 (d, J = 7.2 Hz, 2 H), 7.27 (d, J = 7.6
Hz, 3 H), 4.76 (dd, J = 12.4, 4.2 Hz, 1 H), 4.65 (dd, J = 12.4, 6.8 Hz, 1 H),
4.11–4.05 (m, 1 H), 3.46 (d, J = 6.8 Hz, 2 H).
Pale yellow solid; yield: 79.9 mg (74%, 94% ee); mp 87.8–93.0 °C;
[α]D25 +63.2 (c 0.53, CHCl3).
(S,E)-4-(Nitromethyl)-6-phenylhex-5-en-2-one (4y)5c
HPLC [Daicel Chiralpak AS-H, λ = 254 nm, eluent: i-PrOH/hexane
(10:90), flow rate: 0.9 mL/min]: tR = 34.2 (minor), 70.8 min (major).
25
White solid; yield: 59.5 mg (85%, 87% ee); mp 98.8–99.7 °C; [α]D
+15.9 (c 0.59, CHCl3).
IR (KBr, film): 2917, 2834, 1685, 1589, 1550, 1511, 1400, 1378, 1249,
1175, 1092, 1032, 964, 818 cm–1
.
HPLC [Daicel Chiralpak AD-H, λ = 254 nm, eluent: i-PrOH/hexane
(10:90), flow rate: 0.9 mL/min]: tR = 26.2 (major), 30.8 min (minor).
1H NMR (400 MHz, CDCl3): δ = 7.36–7.27 (m, 5 H), 6.55 (d, J = 15.6 Hz,
1 H), 6.10 (dd, J = 15.6, 8.4 Hz, 1 H), 4.62 (dd, J = 12.0, 6.0 Hz, 1 H), 4.55
(dd, J = 12.0, 8.0 Hz, 1 H), 3.60–3.51 (m, 1 H), 2.77 (d, J = 6.8 Hz, 2 H),
2.21 (s, 3 H).
1H NMR (300 MHz, CDCl3): δ = 7.88 (d, J = 8.7 Hz, 2 H), 7.44 (d, J = 8.4
Hz, 2 H), 7.25 (d, J = 8.4 Hz, 2 H), 6.82 (d, J = 8.7 Hz, 2 H), 6.50 (d, J =
15.6 Hz, 1 H), 6.00 (dd, J = 15.6, 8.4 Hz, 1 H), 4.68 (dd, J = 12.0, 6.0 Hz,
1 H), 4.58 (dd, J = 12.0, 7.2 Hz, 1 H), 3.78 (s, 3 H), 3.75–3.65 (m, 1 H),
3.23 (d, J = 6.3 Hz, 2 H).
13C NMR (75 MHz, CDCl3): δ = 195.9, 159.4, 140.0, 134.7, 132.9, 129.4,
129.0, 128.8, 127.6, 123.9, 113.9, 78.8, 55.2, 40.3, 37.3.
(S,E)-3-(Nitromethyl)-1,5-diphenylpent-4-en-1-one Oxime (5)
To a solution of γ-nitro ketone 4a (1477.1 mg, 5 mmol) and hydroxyl-
amine hydrochloride (521.5 mg, 7.5 mmol) in EtOH (25 mL) was add-
ed pyridine (594.1 mg, 7.5 mmol), and the resulting mixture was
stirred at reflux for 1 h. The reaction was cooled to r.t., EtOH was re-
moved under reduced pressure, and the residue was purified by flash
chromatography to afford oxime 5 (1489.6 mg, 96%; 95% ee) as a pale-
yellow solid; mp 109.3–110.8 °C; [α]D25 –17.6 (c 3.76, CHCl3).
HRMS (EI): m/z [M] calcd for
359.0931.
C19H18ClNO4: 359.0924; found:
(S,E)-1-(4-Chlorophenyl)-5-(furan-2-yl)-3-(nitromethyl)pent-4-
en-1-one (4v)
Pale yellow solid; yield: 85.4 mg (89%, 92% ee); mp 85.2–86.8 °C;
[α]D25 +20.1 (c 0.57, CHCl3).
HPLC [Daicel Chiralcel OJ, λ = 254 nm, eluent: i-PrOH/hexane (50:50),
flow rate: 0.9 mL/min]: tR = 18.2 (minor), 25.1 min (major).
HPLC [Daicel Chiralpak AD-H, λ = 254 nm, eluent: i-PrOH/hexane
(10:90), flow rate: 0.9 mL/min]: tR = 31.6 (major), 36.0 min (minor).
IR (KBr, film): 3244, 3052, 3022, 2923, 2850, 1548, 1494, 1445, 1378,
IR (KBr, film): 2917, 2851, 1685, 1589, 1550, 1482, 1400, 1377, 1216,
966, 939, 751, 692 cm–1
.
1092, 1012, 962, 819, 739 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 9.48 (s, 1 H), 7.58–7.53 (m, 2 H), 7.42–
7.39 (m, 3 H), 7.26–7.18 (m, 5 H), 6.38 (d, J = 15.6 Hz, 1 H), 5.95 (dd,
J = 15.6, 8.8 Hz, 1 H), 4.48–4.38 (m, 2 H), 3.45–3.36 (m, 1 H), 3.11–3.02
(m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 156.6, 136.2, 134.8, 133.4, 129.8,
128.9, 128.5, 127.8, 126.5, 126.4 (2), 79.1, 39.8, 28.5.
1H NMR (300 MHz, CDCl3): δ = 7.88 (d, J = 8.7 Hz, 2 H), 7.44 (d, J = 8.4
Hz, 2 H), 7.31 (s, 1 H), 6.40–6.33 (m, 2 H), 6.21 (d, J = 3.0 Hz, 1 H), 6.05
(dd, J = 15.9, 8.7 Hz, 1 H), 4.67 (dd, J = 12.0, 6.0 Hz, 1 H), 4.56 (dd, J =
12.0, 7.2 Hz, 1 H), 3.76–3.64 (m, 1 H), 3.23 (d, J = 6.6 Hz, 2 H).
13C NMR (75 MHz, CDCl3): δ = 195.6, 151.5, 142.2, 140.1, 134.6, 129.4,
129.0, 124.6, 121.8, 111.3, 108.8, 78.6, 40.2, 36.9.
HRMS (EI): m/z [M] calcd for C18H18N2O3: 310.1317; found: 310.1316.
HRMS (EI): m/z [M] calcd for
C16H14ClNO4: 319.0611; found:
319.0613.
(S,E)-3-(Nitromethyl)-N,5-diphenylpent-4-enamide (6)
To a solution of oxime 5 (596.3 mg, 1.92 mmol) in MeCN (4 mL) was
added TsCl (366.2 mg, 1.92 mmol), and the resulting mixture was
stirred at reflux for 4 h. The mixture was cooled to r.t., MeCN was re-
moved under reduced pressure, and the residue was purified by flash
chromatography to afford amide 6 (561.0 mg, 94%; 95% ee) as a pale-
yellow solid; mp 127.1–129.3 °C; [α]D25 –29.1 (c 5.61, CHCl3).
Ethyl (S,E)-4-(Nitromethyl)-6-oxo-6-phenylhex-2-enoate (4w)
Colorless oil; yield: 71.7 mg (82%, 94% ee); [α]D25 +21.9 (c 0.48, CHCl3).
HPLC [Daicel Chiralpak AD-H, λ = 254 nm, eluent: i-PrOH/hexane
(10:90), flow rate: 0.9 mL/min]: tR = 27.0 (major), 32.2 min (minor).
IR (KBr, film): 2962, 2923, 2856, 1681, 1545, 1451, 1408, 1377, 1366,
1270, 1219, 968, 759, 693 cm–1
.
HPLC [Daicel Chiralpak AD-H, λ = 254 nm, eluent: i-PrOH/hexane
(10:90), flow rate: 0.9 mL/min]: tR = 34.4 (major), 47.0 min (minor).
1H NMR (400 MHz, CDCl3): δ = 7.94 (d, J = 7.2 Hz, 2 H), 7.61 (t, J = 7.2
Hz, 1 H), 7.49 (t, J = 7.6 Hz, 2 H), 6.91 (q, J = 8.0 Hz, 1 H), 5.99 (d, J = 8.0
Hz, 1 H), 4.72–4.58 (m, 2 H), 4.18 (q, J = 7.2 Hz, 2 H), 3.82–3.74 (m, 1
H), 3.28 (d, J = 6.4 Hz, 2 H), 1.28 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 196.1, 165.6, 144.4, 136.1, 133.8,
128.8, 128.0, 124.3, 77.4, 60.7, 39.2, 35.7, 14.1.
IR (KBr, film): 3297, 3131, 3055, 3052, 2919, 2853, 2368, 1660, 1600,
1548, 1496, 1440, 1375, 1310, 1246, 965, 754, 694 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.47 (d, J = 8.0 Hz, 2 H), 7.44 (s, 1 H),
7.33–7.22 (m, 7 H), 7.12 (t, J = 7.2 Hz, 1 H), 6.58 (d, J = 16.0 Hz, 1 H),
6.13 (dd, J = 16.0, 8.4 Hz, 1 H), 4.70 (dd, J = 12.4, 6.0 Hz, 1 H), 4.61 (dd,
J = 12.0, 7.2 Hz, 1 H), 3.64–3.55 (m, 1 H), 2.64 (d, J = 6.4 Hz, 2 H).
HRMS (EI): m/z [M – NO2] calcd for C15H17NO5: 245.1178; found:
13C NMR (100 MHz, CDCl3): δ = 168.4, 137.3, 136.0, 133.6, 128.9,
245.1174.
128.5, 128.0, 126.4, 125.9, 124.7, 120.3, 78.7, 39.1, 38.4.
(S)-3-(Nitromethyl)-1,5-diphenylpent-4-yn-1-one (4x)5c
HRMS (EI): m/z [M] calcd for C18H18N2O3: 310.1317; found: 310.1318.
Pale yellow solid; yield: 71.3 mg (81%, 93% ee); mp 75.2–76.8 °C;
[α]D25 –5.9 (c 0.48, CHCl3).
(R)-3-(Aminomethyl)-N,5-diphenylpentanamide (7)
HPLC [Daicel Chiralpak AD-H, λ = 254 nm, eluent: i-PrOH/hexane
(5:95), flow rate: 0.9 mL/min]: tR = 47.4 (major), 56.3 min (minor).
To a solution of amide 6 (560.5 mg, 1.81 mmol) in MeOH (20 mL) was
added 20% Pd(OH)2 on activated charcoal (380.1 mg, containing 0.54
mmol palladium), and the resulting mixture was stirred under a bal-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

I
X.-T. Guo et al.
Paper
Synthesis
loon H2 pressure at 40 °C for 4 h. After cooling to r.t., the mixture was
filtered through a bed of Celite and MeOH was removed under re-
duced pressure, and then the residue was purified by flash chroma-
Commun. 2008, 2975. (e) Ballini, R.; Petrini, M. ARKIVOC 2009,
(ix), 195. (f) Ballini, R.; Gabrielli, S.; Palmieri, A.; Petrini, M. Curr.
Org. Chem. 2011, 15, 1482.
25
tography to afford amine 7 (509.3 mg, 99%) as a pale-yellow oil; [α]D
(2) For selected reviews, see: (a) Perlmutter, P. Conjugate Addition
Reactions in Organic Synthesis; Pergamon: Oxford, 1992. (b) Gil,
M.; Roman, E.; Serrano, J. A. Trends Org. Chem. 2001, 9, 17.
(c) Berner, O. M.; Tedeschi, L.; Enders, D. Eur. J. Org. Chem. 2002,
1877. (d) Christoffers, J.; Baro, A. Angew. Chem. Int. Ed. 2003, 42,
1688. (e) Notz, W.; Tanaka, F.; Barbas, C. F. III. Acc. Chem. Res.
2004, 37, 580. (f) Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007,
107, 5713. (h) Almasi, D.; Alonso, D. A.; Nájera, C. Tetrahedron:
Asymmetry 2007, 18, 299. (i) Tsogoeva, S. B. Eur. J. Org. Chem.
2007, 1701. (j) Vicario, J. L.; Badia, D.; Carrillo, L. Synthesis 2007,
2065. (k) Córdova, A. Catalytic Asymmetric Conjugate Reactions;
Wiley-VCH: Weinheim, 2010. (l) Roca-Lopez, D.; Sadaba, D.;
Delso, I.; Herrera, R. P.; Tejero, T.; Merino, P. Tetrahedron:
Assymetry 2010, 21, 2561. (m) Ji, J.-X.; Chan, A. S. C. Catalytic
Asymmetric Synthesis; Wiley-VCH: Weinheim, 2010, 479.
(n) Zhang, Y.; Wang, W. Catal. Sci. Technol. 2012, 2, 42.
(o) Serdyuk, O. V.; Heckel, C. M.; Tsogoeva, S. B. Org. Biomol.
Chem. 2013, 11, 7051. (p) Vicario, J. L.; Reyes, E.; Carrillo, L.;
Uria, U. Comprehensive Organic Synthesis; Vol. 4; Pergamon:
Oxford, 2014, 119.
–7.5 (c 5.09, CHCl3).
IR (KBr, film): 3244, 3063, 3024, 2925, 2856, 1660, 1599, 1545, 1499,
1442, 1311, 1254, 1032, 754, 697 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 9.42 (s, 1 H), 7.53 (d, J = 8.0 Hz, 2 H),
7.14–6.92 (m, 10 H), 3.02–2.98 (m, 1 H), 2.86–2.77 (m, 2 H), 2.53–2.31
(m, 4 H), 1.60–1.52 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 170.9, 141.1, 137.8, 128.9, 128.4,
128.3, 126.0, 124.6, 120.4, 42.9, 39.2, 34.1, 33.4, 32.6.
HRMS (EI): m/z [M] calcd for C18H22N2O: 282.1732; found: 282.1734.
(R)-3-(Aminomethyl)-5-phenylpentanoic Acid Hydrochloride (8)
Amine 7 (508.6 mg, 1.80 mmol) was added to concd HCl (10 mL), and
the resulting mixture was stirred at 110 °C for 18 h. The mixture was
cooled to r.t., and the aqueous layer was basified with sat. aq Na2CO3
until ca. pH 9, followed by washing with EtOAc (2 × 25 mL), then acid-
ified with 6 M aq HCl until ca. pH 3. The solvent was removed under
reduced pressure, then the residue was added to EtOH (50 mL) and
the resulting suspension was stirred vigorously for 30 min. After fil-
tration, the filtrate was concentrated in vacuum to afford γ-amino
acid hydrochloride 8 (403.5 mg, 92%) as a pale-yellow solid; mp
158.2–160.3 °C; [α]D25 +48.2 (c 4.02, MeOH).
(3) For reviews, see: (a) Ballini, R.; Araújo, N.; Gil, M. V.; Román, E.;
Serrano, J. A. Chem. Rev. 2013, 113, 3493. (b) Tsakos, M.;
Kokotos, C. G. Tetrahedron 2013, 69, 10199.
(4) For the organocatalytic asymmetric Michael addition of ali-
phatic ketones to nitrodienes, see: (a) List, B.; Pojarliev, P.;
Martin, H. J. Org. Lett. 2001, 3, 2423. (b) Chua, P. J.; Tan, B.; Zeng,
X.; Zhong, G. Bioorg. Med. Chem. Lett. 2009, 19, 3915. (c) Lu, A.;
Gao, P.; Wu, Y.; Wang, Y.; Zhou, Z.; Tang, C. Org. Biomol. Chem.
2009, 7, 3141. (d) Zeng, X.; Zhong, G. Synthesis 2009, 1545.
(e) Belot, S.; Quintard, A.; Krause, N.; Alexakis, A. Adv. Synth.
Catal. 2010, 352, 667. (f) Lu, A.; Liu, T.; Wu, R.; Wang, Y.; Zhou,
Z.; Wu, P.; Fang, J.; Tang, C. Eur. J. Org. Chem. 2010, 5777. (g) Li,
Z.-B.; Luo, S.-P.; Guo, Y.; Xia, A.-B.; Xu, D.-Q. Org. Biomol. Chem.
2010, 8, 2505. (h) Chen, J.-R.; Fu, L.; Zou, Y.-Q.; Chang, N.-J.;
Rong, J.; Xiao, W.-J. Org. Biomol. Chem. 2011, 9, 5280.
(i) Quintard, A.; Langlois, J. B.; Emery, D.; Mareda, J.; Guénée, L.;
Alexakis, A. Chem. Eur. J. 2011, 17, 13433. (j) Lu, A.; Wu, R.;
Wang, Y.; Zhou, Z.; Wu, P.; Fang, J.; Tang, C. Eur. J. Org. Chem.
2011, 122. (k) Lu, A.; Liu, T.; Wu, R.; Wang, Y.; Wu, P.; Zhou, Z.;
Fang, J.; Tang, C. J. Org. Chem. 2011, 76, 3872. (l) He, T.; Wu, X.-Y.
Synth. Commun. 2012, 42, 667. (m) Tsakos, M.; Trifonidou, M.;
Kokotos, C. G. Tetrahedron 2012, 68, 8630. (n) Singh, S.; Chimni,
S. S. Tetrahedron: Asymmetry 2012, 23, 1068. (o) Tsakos, M.;
Elsegood, M. R. J.; Kokotos, C. G. Chem. Commun. 2013, 49, 2219.
(p) Xia, A.-B.; Wu, C.; Xu, D.-Q.; Wang, Y.-F.; Du, X.-H.; Li, Z.-B.;
Xu, Z.-Y. J. Org. Chem. 2013, 78, 1254. (q) Wang, Y.; Jiang, M.; Liu,
J.-T. Tetrahedron: Asymmetry 2014, 25, 212. (r) Xia, A.-B.; Zhao,
L.; Wang, T.; Zhang, Y.-P.; Zhang, A.-G.; Xu, D.-Q.; Xu, Z.-Y. New J.
Chem. 2015, 39, 355. (s) Kaplaneris, N.; Koutoulogenis, G.;
Raftopoulou, M.; Kokotos, C. G. J. Org. Chem. 2015, 80, 5464.
(5) For the organocatalytic asymmetric Michael addition of aro-
matic ketones to nitrodienes, see: (a) He, T.; Qian, J.-Y.; Song, H.-
L.; Wu, X.-Y. Synlett 2009, 3195. (b) Li, B.-L.; Wang, Y.-F.; Luo, S.-
P.; Zhong, A.-G.; Li, Z.-B.; Du, X.-H.; Xu, D.-Q. Eur. J. Org. Chem.
2010, 656. (c) Ma, H.; Liu, K.; Zhang, F.-G.; Zhu, C.-L.; Nie, J.; Ma,
J.-A. J. Org. Chem. 2010, 75, 1402. (d) Tsakos, M.; Kokotos, C. G.
Eur. J. Org. Chem. 2012, 576.
IR (KBr, film): 3418, 3177, 3086, 3023, 2936, 2854, 2580, 2233, 1721,
1571, 1529, 1491, 1454, 1407, 1304, 1257, 1201, 1055, 1008, 971,
938, 845, 798, 755, 727, 699, 661, 605 cm–1
.
1H NMR (400 MHz, CD3OD): δ = 7.19–7.11 (m, 4 H), 7.06 (t, J = 7.2 Hz,
1 H), 2.92 (d, J = 6.8 Hz, 2 H), 2.67–2.53 (m, 2 H), 2.49–2.36 (m, 2 H),
2.12–2.03 (m, 1 H), 1.73–1.55 (m, 2 H).
13C NMR (100 MHz, CD3OD): δ = 175.9, 142.7, 129.5, 129.4, 127.1,
44.2, 37.0, 34.6 (2), 33.6.
HRMS (ESI): m/z [M – Cl]+ calcd for C12H18NO2: 208.1332; found:
208.1302.
Acknowledgment
We are grateful for the financial support from National Natural Sci-
ence Foundation of China (Nos. 21242007, 21102043), Science and
Technology
Commission
of
Shanghai
Municipality
(Nos.
15ZR1409200), and the Fundamental Research Funds for the Central
Universities.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588604.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
ortioInfgrmoaitn
References
(1) For selected reviews, see: (a) Ballini, R. Stud. Nat. Prod. Chem.
1996, 19, 117. (b) Sulzer-Mosse, S.; Alexakis, A. Chem. Commun.
2007, 3123. (c) Ballini, R.; Palmieria, A.; Righib, P. Tetrahedron
2007, 63, 12099. (d) Ballini, R.; Palmieri, A.; Barboni, L. Chem.
(6) (a) Jiang, X.; Zhang, Y.; Chan, A. S. C.; Wang, R. Org. Lett. 2009,
11, 153. (b) Guo, X.-T.; Sha, F.; Wu, X.-Y. Res. Chem. Intermed.
2016, 42, 6373.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

J
X.-T. Guo et al.
Paper
Synthesis
(7) Guo, X.-T.; Shen, J.; Sha, F.; Wu, X.-Y. Synthesis 2015, 47, 2063.
(8) (a) Saito, S.; Nakadai, M.; Yamamoto, H. Synlett 2001, 1245.
(b) Mase, N.; Tanaka, F.; Barbas, C. F. III. Org. Lett. 2003, 5, 4369.
(c) Mangion, I. K.; Northrup, A. B.; MacMillan, D. W. C. Angew.
Chem. Int. Ed. 2004, 43, 6722. (d) Gryko, D.; Zimnicka, M.;
Lipinski, R. J. Org. Chem. 2007, 72, 964.
(9) (a) Jiang, X.; Zhang, Y.; Liu, X.; Zhang, G.; Lai, L.; Wu, L.; Zhang,
J.; Wang, R. J. Org. Chem. 2009, 74, 5562. (b) Jiang, X.; Zhang, Y.;
Wu, L.; Zhang, G.; Liu, X.; Zhang, H.; Fu, D.; Wang, R. Adv. Synth.
Catal. 2009, 351, 2096. (c) Jiang, X.; Zhang, G.; Fu, D.; Cao, Y.;
Shen, F.; Wang, R. Org. Lett. 2010, 12, 1544. (d) Jiang, X.; Wang,
Y.; Zhang, G.; Fu, D.; Zhang, F.; Kai, M.; Wang, R. Adv. Synth.
Catal. 2011, 353, 1787. (e) Cao, Y.; Jiang, X.; Liu, L.; Shen, F.;
Zhang, F.; Wang, R. Angew. Chem. Int. Ed. 2011, 50, 9124.
(f) Zhang, G.; Zhang, Y.; Yan, J.; Chen, R.; Wang, S.; Ma, Y.; Wang,
R. J. Org. Chem. 2012, 77, 878. (g) Wu, X.-Y.; Shen, J.; Zhao, X.;
Sha, F. CN103421044, 2013. (h) Shi, X.-M.; Dong, W.-P.; Zhu, L.-
P.; Jiang, X.-X.; Wang, R. Adv. Synth. Catal. 2013, 355, 3119.
(i) Wang, L.; Shi, X.-M.; Dong, W.-P.; Zhu, L.-P.; Wang, R. Chem.
Commun. 2013, 49, 3458. (j) Jiang, X.; Zhu, H.; Shi, X.; Zhong, Y.;
Li, Y.; Wang, R. ChemCatChem 2013, 5, 2187. (k) Zhao, X.; Kang,
T.; Shen, J.; Sha, F.; Wu, X.-Y. Chin. J. Chem. 2015, 32, 1333.
(10) Bryans, J. S.; Horwell, D. C.; Kneen, C. O.; Wustrow, D. J.; Thorpe,
A. J. WO 9817627, 1998.
(11) (a) Belot, S.; Massaro, A.; Tenti, A.; Mordini, A.; Alexakis, A. Org.
Lett. 2008, 10, 4557. (b) Dockendorff, C.; Sahli, S.; Olsen, M.;
Milhau, L.; Lautens, M. J. Am. Chem. Soc. 2005, 127, 15028.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J