Enantioselective Michael addition of cyclic ketones to nitroolefins catalyzed by a novel fluorine-insertion organocatalyst

Article abstract of DOI:10.1016/j.tetasy.2013.12.015

A novel fluorine-insertion organocatalyst, which was designed based on the fluorine-ammonium ion gauche effect, was synthesized and used successfully to catalyze the asymmetric Michael addition of cyclic ketones to nitroolefins. High yields and excellent diastereo- and enantioselectivities were achieved under mild conditions. A possible stereochemical model is also proposed.

Full text of DOI:10.1016/j.tetasy.2013.12.015

Tetrahedron: Asymmetry 25 (2014) 212–218
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Enantioselective Michael addition of cyclic ketones to nitroolefins
catalyzed by a novel fluorine-insertion organocatalyst
⇑
Yanan Wang, Min Jiang, Jin-Tao Liu
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 16 October 2013
Accepted 12 December 2013
A novel fluorine-insertion organocatalyst, which was designed based on the fluorine–ammonium ion
gauche effect, was synthesized and used successfully to catalyze the asymmetric Michael addition of
cyclic ketones to nitroolefins. High yields and excellent diastereo- and enantioselectivities were achieved
under mild conditions. A possible stereochemical model is also proposed.
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
a C–H bond. Furthermore, the polarized nature of Cd+–Fdꢀ bond
evokes the gauche effect (Fig. 2).8,9 Therefore, a single C–F bond
Fluorine is an important atom in organic chemistry. The C–F
bond is dramatically different from a C–H bond due to the high
electronegativity of fluorine.1,2 The properties of organic com-
pounds, such as the conformations of molecules, can often be
altered by the introduction of a fluorine atom. For instance, the
proline molecule has two conformations for the pyrrolidine ring,
can establish a conformational rigidity and tip the balance between
multiple conformers to favor a single species.
σ∗C-F
F
F
c
c
C -exo and C -endo (Fig. 1).3 When R1 = H and R2 = OH, N3, or F,
X
H
H
H
H
H
H
c
C -endo is the favored conformation. When R2 = H and R1 = OH, F,
H
c
C -exo is the favored one. Therefore, the different substituent has
X
H
σC-H
a dramatic impact on the conformation of the pyrrolidine ring. Fur-
thermore, the electronegativity of the substituent can alter the rel-
ative energies of the conformers and make a single conformer
more popular.4–7
gauche
X=F, OCOR, NHCOR etc.
anti
Figure 2. The fluorine gauche effect.
R1
R2
N
Recently, some fluorine-insertion catalysts were reported
which utilize the unique properties of fluorine. Marson et al. syn-
thesized a C2-symmetric, enantiopure vicinal difluoropyrrolidine
catalyst.10 A few years later, List et al. reported on the trans-4-flu-
oroproline catalyzed transannular aldolization of cyclic diketones,
which were used as a key step in a short synthesis of (+)-hirsuten-
e.11 Recently, Gilmour et al. showcased a series of novel fluorinated
organocatalysts and investigated their potential uses in organic
synthesis.12 Alexakis et al. also designed a novel fluorine stabilized
catalyst.13
R2
R1
N
O
O
Cγ-endo
Cγ-exo
Figure 1. The conformation of 4-substituted proline derivatives.
When a fluorine atom is incorporated into a pyrrolidine ring,
the main factors for controlling the molecular topology are
charge–dipole interactions. Due to the high electronegativity of
fluorine, the C–F bond is highly polarized and has a vacant low-en-
Although N-(2-pyrrolidinylmethyl)pyrrolidine
1 is an ideal
organocatalyst,14 poor results were obtained in some asymmetric
reactions, such as the Michael addition of cyclohexanone and
nitrostyrene. We envisioned that introducing a fluorine atom at
the 4-position of the pyrrolidine may result in an efficient fluori-
nated organocatalyst 1-F, which is conformationally stable
(Fig. 3). Alexakis has already confirmed that this conformational
ergy r⁄C–F orbital that can interact with adjacent
r bonds, such as
⇑
Corresponding author. Tel.: +86 21 54925188.
E-mail address: jtliu@sioc.ac.cn (J.-T. Liu).
0957-4166/$ - see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.12.015

Y. Wang et al. / Tetrahedron: Asymmetry 25 (2014) 212–218
213
F
solvent-free conditions for this transformation because of it being
environmentally friendly. The effect of an additive was also exam-
ined. In the presence of 10 mol % trifluoroacetic acid, the reaction
proceeded well to afford 4a in 93% yield with 16:1 dr and 98% ee
in 20 h. Other additives such as 2,4-dinitro-benzenesulfonic acid
and benzoic acid, gave 4a with high ee (up to 99%), but the yield
decreased slightly. As a control experiment, the reaction catalyzed
by 1 was also examined and a notable loss in enantioselectivity
(86% ee) was observed (entry 15).17
insertion of fluorine
N
H
N
N
H
N
1
1-F
Figure 3. New fluorinated aminocatalyst.
change does not lead to any extra steric hindrance, because the
atomic radius of fluorine is close to that of a hydrogen atom.13
Herein we report the synthesis and application of this new fluori-
nated pyrrolidine-based catalyst.
Next, we studied the Michael addition reaction between cyclo-
hexanone 3a and a variety of nitroolefins and the results are sum-
marized in Table 2. It was found that better stereoselectivities were
obtained in the absence of an additive for electron-rich b-nitrosty-
renes 2b and 2c (entries 2 and 3). However, the reactions of elec-
tron-deficient b-nitrostyrenes 2d–2g with substituents at the
para- or ortho-position occurred smoothly in the presence of TFA
to give the corresponding products 4d–4g with high enantioselec-
tivities, ranging from 91% to 99%, and relatively lower yields and
enantioselectivities were afforded without TFA (entries 5–9).
Therefore, TFA might contribute in activating the substrate and
make the preferred conformation of the transition state more
favored by the coordination effect of the proton in these reactions.
The reactions of a naphthyl nitroolefin (entry 10) and a heteroaryl
nitroolefin (entry 11) also proceeded well and afforded adducts 4h
and 4i with 98% and 98% ee, respectively, when an additive was
added. However, the results were unsatisfactory for b-cyclohexyl
nitroolefin 2j, and adduct 4j was obtained in low yield with mod-
erate stereoselectivities after 6.5 days along with the recovery of
some starting material (entry 12); similar results were obtained
with n-butyl substituted nitroolefin 2k, probably due to the less
reactive nature of the alkyl nitroolefin (entry 13).
The Michael addition of different ketones with trans-nitrosty-
rene was also investigated (Table 3). When heterocyclic ketone
3b was used as the Michael donor, better results were obtained
in the presence of CF3COOH and the desired product 4l was iso-
lated in 92% yield with 39:1 dr and 95% ee (Table 3, entry 2). The
reaction of cyclopentanone afforded product 4m with lower dia-
stereoselectivity and moderate enatioselectivity, with or without
TFA as the additive (entry 3). Both cycloheptanone 3d and acetone
3e showed low activity, which might be attributed to a less favored
coordination. By prolonging the reaction time to 14 days, their
reactions with 2a in the absence of an additive afforded the corre-
sponding adducts 4n and 4o with 80% and 49% ee, respectively (en-
tries 4 and 5). Unfortunately, the reaction of aromatic ketone 3f
was unsuccessful and no adduct was formed under any conditions
(entry 6).
2. Results and discussion
Our first goal was the synthesis of fluorinated pyrrolidine 1-F.
According to the literature,15 the esterification of (2S,4R)-4-
hydroxypyrrolidine-2-carboxylic acid 1-A and subsequent N-pro-
tection afforded compound 1-B in high yield. The fluorination of
the hydroxyl group with diethylaminosulfurtrifluoride (DAST) took
place smoothly and 1-B was converted into (2S,4S)-4-fluoro-
substituted pyrrolidine 1-C stereoselectively. The reduction of the
ester group in 1-C with DIBAL-H afforded aldehyde 1-D, which pro-
duced 1-E via condensation with pyrrolidine and the following
reduction of the imine. The target compound 1-F was obtained
via the N-deprotection of 1-E (Scheme 1).
In order to test the catalytic potential of this new fluorine-inser-
tion organocatalyst, the Michael addition of ketones to nitroolefins
was selected as a model reaction.16 In a preliminary experiment,
trans-nitrostyrene 2a was treated with cyclohexanone 3a
(5.0 equiv) and catalyst 1-F (10 mol %) at room temperature under
solvent free conditions. The corresponding adduct 4a was obtained
in 97% yield with 51:1 dr and 96% ee after 23 h. The relative and
absolute configuration of 4a was determined by comparison of
its 1H NMR spectra and specific rotation with those in the literature
as shown in Table 1.16
Encouraged by the results, we further screened a range of reac-
tion parameters for the selective formation of syn-4a and the key
results are shown in Table 1. Decreasing the amount of cyclohexa-
none (3.0 equiv) or catalyst (5 mol %) lowered the yield and diaste-
reoselectivity (entries 2 and 3). Examination of the solvents
revealed that acetonitrile, methanol, and dimethyl sulfoxide
(DMSO) gave much lower yields (entries 4–6). Excellent diastere-
oselectivity or enantioselectivity was achieved with a decrease of
the yield in hexane, tetrahydrofuran (THF), or dichloromethane
(entries 7–9). Although toluene was a suitable solvent, affording
adduct 4a in 93% yield with 57:1 dr and 96% ee, we chose the
We further examined the Michael addition of (E,E)-(4-nitro-1,3-
butadienyl) benzene 2k with cyclohexanone 3a. The corresponding
i) SOCl2 (1.5 equiv)
MeOH, rt→45 °C, 6 h
F
HO
HO
DAST (2.0 equiv)
COOMe
COOH
COOMe
CH2Cl2, -78 °C
16 h, 76%
ii) Boc2O (1.5 equiv)
rt, 16 h, 95%
N
N
H
N
Boc
Boc
1-C
1-A
1-B
DIBAL-H (2.0 equiv)
CH2Cl2, -78 °C
6 h, 68%
F
F
F
pyrrolidine (1.2 equiv)
NaBH3CN (0.7 equiv)
i) HCl.Et2O
CHO
N
rt, overnight
N
N
N
H
Boc
N
ii) 1M NaOH
rt, 2 h, 90%
4Å MS
Boc
MeOH, 0 °C, 12 h, 54%
1-F
1-E
1-D
Scheme 1. Synthesis of fluorinated pyrrolidine 1-F.

214
Y. Wang et al. / Tetrahedron: Asymmetry 25 (2014) 212–218
Table 1
Optimization of the 1-F catalyzed asymmetric Michael addition reaction of cyclohexanone and trans-nitrostyrene
O
O
Ph
1-F (10 mol%)
NO2
NO2
additive (10 mol%)
+
Ph
solvent, rt, 23 h
2a
3a, 5.0 equiv
4a
Entrya
Solvent
Additive
Yieldb (4a, %)
drc
eed (%)
1
Neat
Neat
Neat
—
—
—
—
—
—
—
—
——
—
97
84
80
67
50
24
81
88
84
93
93
86
90
90
73
51:1
27:1
33:1
21:1
21:1
16:1
99:1
99:1
65:1
57:1
16:1
58:1
85:1
16:1
35:1
96
94
98
>99
99
88
76
98
98
96
98
99
95
99
86
2e
3f
4
5
6
7
8
9
10
11g
12
13
14
15h
Acetonitrile
Methanol
DMSO
Hexane
THF
CH2Cl2
Toluene
Neat
Neat
Neat
Neat
Neat
Trifluoroacetic acid
2,4-Dinitro-benzenesulfonic acid
3,5-Dinitrobenzoic acid
Benzoic acid
Trifluoroacetic acid
a
Reactions were performed with trans-nitrostyrene (0.47 mmol), cyclohexanone (2.35 mmol, 5.0 equiv), additive (0 or 10 mol %), and 1-F (10 mol %) for 23 h at room
temperature.
b
Yield of isolated product.
c
d
e
f
Determined by 1H NMR spectroscopy.
Determined by chiral HPLC analysis (Chiralpak PC, hexane-i-PrOH, 95:5).
5 mol % catalyst was used and the reaction time was 35 h.
3.0 equiv of cyclohexanone was used and the reaction time was 25 h.
The reaction time was 20 h.
g
h
1 was used as the catalyst.
product 4q was isolated in 84% yield with 14:1 dr and 99% ee in the
absence of an additive. Good yield and excellent enantioselectivity
were also obtained while using 10 mol% TFA as the additive
(Scheme 2).
Table 2
Michael addition of cyclohexanone with various nitroolefins
O
O
R
1-F (10 mol%)
CF3COOH (X mol%)
NO2
Based on the above experimental results, a stereochemical
model was proposed to account for the high enantio- and diastere-
oselectivity of the Michael addition reaction of six-membered
ketones and nitroolefins. The pyrrolidine derivative reacted with
carbonyl compounds to form the favored (E)-trans-enamine. As
NO2
+
R
neat, rt, 20-23 h
2
3a, 5.0 equiv
4
Entrya
1
X (mol %)
2, R
4
Yieldb (%)
drc
eed (%)
c
shown in Figure 4, (E)-trans-C -endo is the favored conformation.
0
10
0
10
0
10
0
10
0
10
0
10
0
10
0
10
0
10
0
10
0
10
2a, C6H5
4a
97
93
91
85
80
43
78
92
80
86
83
92
77
94
76
77
89
90
30
16
58
43
51:1
16:1
99:1
28:1
30:1
18:1
60:1
33:1
50:1
49:1
99:1
99:1
26:1
99:1
66:1
99:1
21:1
21:1
11:1
15:1
8:1
96
98
93
87
88
86
92
91
90
98
87
76
97
99
95
98
94
98
78
84
91
96
When a fluorine atom was introduced at the 4-position of the pyr-
c
rolidine ring, the stabilization of the C -exo conformer decreased
2
2b, 4-MeOC6H4
2c, 4-tBuC6H4
4b
4c
4d
4e
4f
due to the gauche effect.13 The lower enatioselectivity (86% vs
98% ee), which was obtained by unfluorinated catalyst 1 (Table 1,
entry 15), confirmed the conformational stabilization for catalyst
1-F and intermediate A.
3
4
2d, 4-ClC6H4
2e, 4-BrC6H4
2f, 2-BrC6H4
2g, 2,4-Cl2C6H3
2h, 1-Naphthyl
2i, 2-Furyl
5
3. Conclusion
6
In conclusion, we have designed and synthesized a novel fluo-
rine-insertion organocatalyst, which was successfully applied in
the Michael addition reaction of six-membered ketones to nitro-
olefins. The gauche effect plays an important role in the transfor-
7
4g
4h
4i
8
9
mation and results in
enatioselectivity.
a
high diastereoselectivity and
10e
11f
2j, Cyclohexyl
2k, nBu
4j
4k
4. Experimental
4.1. General
20:1
a
Conditions: 2 (0.47 mmol), 3a (2.35 mmol, 5.0 equiv), catalyst 1-F (10 mol %),
CF3COOH (X mol %), neat, rt, 20–23 h.
b
1H NMR spectra were recorded in CDCl3 on a Bruker AM-400
spectrometer (400 MHz) with TMS as an internal standard. 19F
NMR spectra were taken on a Bruker AM-400 (376 MHz) spectrom-
eter using CFCl3 as an external standard. 13C NMR spectra were
Yield of isolated product.
c
Determined by 1H NMR spectroscopy.
d
Determined by chiral HPLC analysis.
The reaction time was 6.5 d.
The reaction time was 5.5 d.
e
f

Y. Wang et al. / Tetrahedron: Asymmetry 25 (2014) 212–218
215
Table 3
Michael addition of various Michael donors 3 with trans-nitrostyrene
1-F
(10 mol%)
CF3COOH (X mol%)
neat, rt, time
NO2
3
+
4
Ph
5.0 equiv
2a
Entrya
1
X (mol %)
3
Time
4
Yieldb (%)
drc
eed (%)
O
O
Ph
0
10
23 h
20 h
97
93
51:1
16:1
96
98
NO2
NO2
3a
O
4a
Ph
O
O
2
0
10
25 h
23 h
98
92
13:1
39:1
78
95
O
3b
4l
O
Ph
3
4
0
10
25 h
24 h
71
84
4:1
2:1
84
88
O
NO2
3c
O
4m
O
Ph
0
10
14 d
14 d
69
46
17:1
18:1
80
69
NO2
3d
4n
O
O
Ph
5
0
10
14 d
14 d
56
58
—
—
49
37
NO2
NO2
3e
O
4o
Ph
6e
0
10
23 h
23 h
NR
NR
—
—
—
—
O
Ph
Ph
4p
3f
a
b
c
Conditions: 2a (0.47 mmol), 3 (2.35 mmol, 5.0 equiv), catalyst 1-F (10 mol %), CF3COOH (X mol %), neat, rt.
Yield of isolated product.
Determined by 1H NMR spectroscopy.
Determined by chiral HPLC analysis.
NR = no reaction.
d
e
Ph
F
N
O
O
(H+)
1-F (10 mol%)
NO2
CF3COOH (X mol%)
NO2
+
Ph
neat, rt, 23 h
O2N
N
2k
3a, 5.0 equiv
4q
Ar
X = 0: 84% yield, 14:1 dr, 99% ee
X = 10: 90% yield, 26:1 dr, 99% ee
(E)-trans-Cγ-endo
A
Scheme 2. Michael addition of diene 2k and ketone 3a.
Figure 4. Proposed stereochemical model.
recorded in CDCl3 on a Bruker AM-400 spectrometer (100 MHz)
with TMS as internal standard. NMR data are reported as follows:
chemical shift, multiplicity (s = singlet, d = doublet, t = triplet,
m = multiplet), coupling constants (Hz). IR spectra were obtained
with a Nicolet AV-360 spectrophotometer. Melting points were
measured on a melt-Temp apparatus and are uncorrected. Mass
spectra were obtained on a Finnigan GC–MS 4021. HRMS data were
obtained on a high-resolution mass spectrometer. Enantiomeric
excesses were determined by chiral HPLC using a Waters instru-
ment. All reactions were monitored by TLC with Huanghai GF254
silica gel coated plates. Flash column chromatography was carried
out using 300–400 mesh silica gels. Unless otherwise mentioned,
solvents and reagents were purchased from commercial sources
and used as received. CH2Cl2 was freshly distilled by standard pro-
cedure prior to use.

216
Y. Wang et al. / Tetrahedron: Asymmetry 25 (2014) 212–218
4.2. Synthesis of 1-F
4.2.1. N-Boc-trans-4-hydroxy-
minor), 28.1, 23.2. HRMS (EI) calcd for C14H25FN2O2 (M+)
272.1900, found 272.1905. IR (KBr, cmꢀ1): 2972, 2934, 2824,
2798, 2769, 1693, 1455, 1408, 1365, 1243, 1182, 1116, 1084,
883.
L
-proline methyl ester 1-B15a
This is
a known compound; a white solid, 95% yield;
½
a 2D0
ꢁ
¼ ꢀ65:8 (c 0.5, CHCl3, 589 nm). 1H NMR (400 MHz, CDCl3): d
4.32–4.41 (m, 2H), 3.68 (s, 3H), 3.50–3.55 (m, 2H), 2.19–2.28 (m,
4.2.5. (S,S)-2-((Pyrrolidin-1-yl)methyl)-4-fluoro-pyrrolidine 1-F
Compound 1-E (435.5 mg, 1.60 mmol) was treated with
HClꢂEt2O solution (3 mL), and the mixture was stirred overnight
at room temperature. The solvent was then evaporated in vacuo,
and the residue was dissolved in a 1 M NaOH solution. The reac-
tion mixture was stirred for 2 h at room temperature, and then
extracted with ethyl acetate. The combined organic extract was
dried over Na2SO4, and the solvent was evaporated in vacuo to
1H), 1.99–2.02 (m, 1H), 1.40 (s, 3H), 1.35 (s, 6H) ppm.
4.2.2. N-Boc-cis-4-fluoro-L
-proline methyl ester 1-C15b
This is a known compound; pale yellow solid, 76% yield;
½
a 2D0
ꢁ
¼ ꢀ59:6 (c 0.7, CHCl3, 589 nm). 1H NMR (400 MHz, CDCl3): d
5.21 (d, J = 53.6 Hz, 1H), 4.46 (dd, J = 31.8, 10 Hz, 1H), 3.46–3.80
(m, 2H), 3.65 (s, 3H), 2.14–2.44 (m, 2H), 1.39 (s, 4H), 1.34 (s, 5H)
ppm. 19F NMR (376 MHz, CDCl3): d ꢀ173.5 (m, 1F) ppm.
give 1-F as a pale yellow oil, 275.4 mg, 90% yield. ½a D20
¼ þ13:5
ꢁ
(c 1.0, CHCl3, 589 nm). 1H NMR (400 MHz, MeOH-d4): d 5.23 (dt,
J = 55.1, 4.2, 1H), 3.16–3.25 (m, 2H), 2.85 (ddd, J = 35.4, 13.0,
3.8 Hz, 1H), 2.52–2.68 (m, 6H), 2.19–2.34 (m, 1H), 1.65–1.80 (m,
5H) ppm. 19F NMR (376 MHz, MeOH-d4): d ꢀ170.94 (m, 1F)
ppm. 13C NMR (100 MHz, CDCl3): d 94.8 (JC–F = 173.0 Hz), 61.6,
57.0, 54.5, 53.7 (JC–F = 23.0 Hz), 38.0 (JC–F = 20.0 Hz), 23.5. HRMS
(ESI) calcd for C9H18FN2 (M+H+) 173.1454, found 173.1449. IR
(KBr, cmꢀ1): 3338 (br), 2928, 2855, 2798, 1456, 1406, 1378,
1304, 1156, 861.
4.2.3. N-Boc-cis-4-fluoro-L
-prolinal 1-D15c
At first, DIBAL-H (1.5 M in toluene, 2.9 mL, 4.36 mmol) was
added via syringe pump over 26 min to a stirred and cooled
(ꢀ78 °C) solution of 1-C (539 mg, 2.18 mmol) in CH2Cl2 (7 mL)
under an Ar atmosphere. After stirring for 6 h, 0.5 mL of MeOH
was added at the same temperature. The mixture was warmed
to room temperature and a solution of potassium sodium tar-
trate (2 M, 11 mL) was added and the resulting mixture was stir-
red vigorously for 0.5 h. The organic layer was separated and the
aqueous layer was extracted further with CH2Cl2. The combined
organic extracts were washed with brine, dried over Na2SO4,
concentrated, and purified by flash column chromatography to
yield 1-D as a light yellow solid. 421.1 mg, 54% yield; mp 57–
4.3. General Michael addition procedure
To a solution of 1-F (0.1 equiv) in ketone (5.0 equiv) was added
TFA (0.1 equiv) at room temperature. Next, nitroolefin 2 (1.0 equiv)
was added to the solution. The mixture was stirred at room tem-
perature until TLC showed complete conversion. The solvents were
removed in vacuo, and the products were purified by flash column
chromatography on silica gel.
59 °C; ½a 2D0
ꢁ
¼ ꢀ80:7 (c 1.0, CHCl3, 589 nm). 1H NMR (400 MHz,
CDCl3):
d 9.55 (s, 1H), 9.50 (t, J = 2.2 Hz, 1H), 5.17 (d,
J = 52.3 Hz, 1H), 4.19 (dd, J = 44.3, 9.4 Hz, 1H), 3.71–3.88 (m,
1H), 3.44–3.59 (m, 1H), 2.12–2.43 (m, 2H), 1.45 (s, 4H), 1.39
(s, 5H) ppm. 19F NMR (376 MHz, CDCl3): d ꢀ172.8 (m, 1F)
ppm. 13C NMR (100 MHz, CDCl3): d 202.0 (minor), 201.8 (major),
154.6 (minor), 153.7 (major), 92.2 (JC–F = 176.8 Hz, minor), 91.2
(JC–F = 176.8 Hz, major), 81.0 (major), 80.8 (minor), 63.4 (major),
63.2 (minor), 53.3 (JC–F = 23.2 Hz, minor), 53.0 (JC–F = 23.2 Hz,
major), 36.1 (JC–F = 21.2 Hz, major), 34.9 (JC–F = 21.2 Hz, minor),
28.2 (minor), 28.1 (major). HRMS (ESI) calcd for C10H16FNNaO3
(M+Na+) 240.1012, found 240.1006. IR (KBr, cmꢀ1): 2984, 2888,
2836, 2824, 1728, 1698, 1402, 1368, 1168.
4.3.1. (S)-2-[(R)-2-Nitro-1-phenylethyl]cyclohexanone 4a
A
white solid, 97% yield; 50:1 dr (syn/anti), 96% ee;
½ ꢁ
a 2D0
¼ ꢀ29:6 (c 1.0, CHCl3, 589 nm). 1H NMR (400 MHz, CDCl3): d
7.22–7.31 (m, 3H), 7.14–7.16 (m, 2H), 4.92 (dd, J = 12.5, 4.4 Hz,
1H), 4.60 (dd, J = 11.7, 10.9 Hz, 1H), 3.74 (td, J = 10.0, 4.4 Hz, 1H),
2.66–2.72 (m, 1H), 2.35–2.46 (m, 2H), 2.06–2.08 (m, 1H), 1.52–
1.76 (m, 4H), 1.19–1.22 (m, 1H) ppm. HPLC (Chiralpak PC column,
hexanes/i-PrOH = 95:5, flow rate = 0.6 mL/min, k = 214 nm): tR (syn
isomer) = 50.73 (minor), 59.13 (major) min.
4.2.4. (S,S)-2-((Pyrrolidin-1-yl)methyl)-4-fluoro-pyrrolidine-1-
carboxylic acid tert-butyl ester 1-E
4.3.2. (S)-2-[(R)-2-Nitro-1-p-methoxyphenylethyl]cyclohexanone
Powdered 4 Å molecular sieves (ca. 1.5 g) were added to a
solution of 1-D (1.5 g, 6.90 mmol) in MeOH (13 mL) under an
Ar atmosphere, and the resulting suspension was cooled to
ꢀ2 °C. Pyrrolidine was added dropwise (0.68 mL, 8.30 mmol),
and the mixture was stirred for 20 min. A solution of sodium
cyanoborohydride (291 mg, 4.60 mmol) in MeOH (9 mL) was
added via syringe pump over 3.6 h. The reaction mixture was
stirred for another 12 h at ꢀ2 °C before it was filtered through
a pad of Celite. The filter cake was washed with MeOH, and
the filtrate was concentrated under reduced pressure. The resi-
due was partitioned between ethyl acetate and water. The aque-
ous layer was washed with ethyl acetate. The combined organic
extract was dried over K2CO3, concentrated, and purified by flash
column chromatography to yield 1-E as a pale yellow oil. 1.0 g,
4b
A
white solid, 91% yield; 99:1 dr (syn/anti), 93% ee;
¼ ꢀ23:5 (c 1.1, CHCl3, 589 nm). 1H NMR (400 MHz, CDCl3): d
½ ꢁ
a 2D0
7.07 (d, J = 8.6 Hz, 2H), 6.84 (d, J = 8.5 Hz, 2H), 4.90 (dd, J = 12.3,
4.5 Hz, 1H), 4.57 (dd, J = 12.3, 10.1 Hz, 1H), 3.77 (s, 3H), 3.70 (td,
J = 10.1, 4.5 Hz, 1H), 2.59–2.64 (m, 1H), 2.36–2.45 (m, 2H), 2.03–
2.06 (m, 1H), 1.52–1.76 (m, 4H), 1.20–1.25 (m, 1H) ppm. HPLC
(Chiralpak
AD
column,
hexanes/i-PrOH = 80:20,
flow
rate = 0.5 mL/min, k = 214 nm): tR (syn isomer) = 17.18 (minor),
20.78 (major) min.
4.3.3. (S)-2-[(R)-2-Nitro-1-p-tert-butylphenylethyl]cyclohexanone
4c
53% yield.
(400 MHz, CDCl3):
½ ꢁ
a 2D0
¼ ꢀ50:1 (c 1.1, CHCl3, 589 nm). 1H NMR
A
colorless oil, 80% yield; 30:1 dr (syn/anti), 88% ee;
¼ ꢀ15:6 (c 1.0, CHCl3, 589 nm). 1H NMR (400 MHz, CDCl3): d
½ ꢁ
a 2D0
d
5.17 (d, J = 53.1 Hz, 1H), 3.91–4.02 (m,
7.31 (d, J = 8.4 Hz, 2H), 7.08 (d, J = 8.3 Hz, 2H), 4.91 (dd, J = 12.5,
4.6 Hz, 1H), 4.63 (dd, J = 12.5, 9.9 Hz, 1H), 3.74 (td, J = 9.9, 4.5 Hz,
1H), 2.59–2.80 (m, 1H), 2.26–2.53 (m, 2H), 2.05–2.09 (m, 1H),
1.58–1.75 (m, 5H), 1.29 (s, 9H) ppm. HPLC (Chiralpak PA-2 column,
hexanes/i-PrOH = 70:30, flow rate = 0.7 mL/min, k = 214 nm): tR
(syn isomer) = 10.58 (major), 16.58 (minor) min.
1H), 3.48–3.65 (m, 2H), 2.38–2.74 (m, 7H), 1.94–2.10 (m, 1H),
1.71 (s, 4H), 1.44 (s, 5H) ppm. 19F NMR (376 MHz, CDCl3): d
ꢀ169.9 (m, 1F) ppm. 13C NMR (100 MHz, CDCl3): d 153.8, 93.3
(JC–F = 177.8 Hz, minor), 92.5 (JC–F = 175.7 Hz, major), 79.2, 60.0,
59.2 (major), 58.5 (minor), 55.4 (minor), 54.0 (major), 53.1 (ma-
jor), 52.8 (minor), 35.5 (JC–F = 20.2 Hz, major), 34.7 (JC–F = 20.2 Hz,

Y. Wang et al. / Tetrahedron: Asymmetry 25 (2014) 212–218
217
4.3.4. (S)-2-[(R)-2-Nitro-1-p-chlorophenylethyl]cyclohexanone
min, k = 214 nm): tR (syn isomer) = 15.13 (major), 18.48 (minor)
4d
min.
A
white solid, 92% yield; 33:1 dr (syn/anti), 91% ee;
¼ ꢀ27:0 (c 1.5, CHCl3, 589 nm). 1H NMR (400 MHz, CDCl3): d
½
a 2D0
ꢁ
4.3.10. (S)-2-[(S)-2-Nitro-1-cyclohexylethyl]cyclohexanone 4j
Pale yellow oil, 16% yield; 15:1 dr (syn/anti), 84% ee;
7.27 (d, J = 8.2 Hz, 2H), 7.09 (d, J = 8.2 Hz, 2H), 4.91 (dd, J = 12.6,
4.4 Hz, 1H), 4.58 (dd, J = 12.6, 10.3 Hz, 1H), 3.74 (td, J = 10.3,
4.4 Hz, 1H), 2.60–2.65 (m, 1H), 2.34–2.46 (m, 2H), 2.05–2.08 (m,
1H), 1.24–1.79 (m, 4H), 1.19–1.22 (m, 1H) ppm. HPLC (Chiralpak
AD column, hexanes/i-PrOH = 90:10, flow rate = 0.7 mL/min,
k = 214 nm): tR (syn isomer) = 17.68 (minor), 26.73 (major) min.
½
a 2D0
ꢁ
¼ ꢀ25:0 (c 0.3, CHCl3, 589 nm). 1H NMR (400 MHz, CDCl3): d
4.69 (dd, J = 13.8, 5.8 Hz, 1H), 4.36 (dd, J = 13.8, 5.9 Hz, 1H), 2.65–
2.70 (m, 1H), 2.28–2.37 (m, 3H), 2.07–2.10 (m, 2H), 1.93–1.97
(m, 1H), 1.57–1.75 (m, 9H), 1.12–1.25 (m, 3H), 0.87–1.03 (m, 2H)
ppm. HPLC (Chiralpak AD column, hexanes/i-PrOH = 95:5, flow
rate = 0.5 mL/min, k = 214 nm): tR (syn isomer) = 13.98 (major),
15.33 (minor) min.
4.3.5. (S)-2-[(R)-2-Nitro-1-p-bromophenylethyl]cyclohexanone
4e
4.3.11. (S)-2-((S)-1-Nitrohexan-2-yl)cyclohexanone 4k
A
white solid, 86% yield; 49:1 dr (syn/anti), 98% ee;
¼ ꢀ25:7 (c 1.0, CHCl3, 589 nm). 1H NMR (400 MHz, CDCl3): d
Pale yellow oil, 43% yield; 20:1 dr (syn/anti), 96% ee;
½ ꢁ
a 2D0
½
a 2D0
ꢁ
¼ ꢀ20:1 (c 0.9, CHCl3, 589 nm). 1H NMR (400 MHz, CDCl3): d
7.44 (d, J = 8.4 Hz, 2H), 7.05 (d, J = 8.4 Hz, 2H), 4.92 (dd, J = 12.6,
4.5 Hz, 1H), 4.59 (dd, J = 12.6, 10.1 Hz, 1H), 3.74 (td, J = 10.1,
4.5 Hz, 1H), 2.61–2.68 (m, 1H), 2.33–2.49 (m, 2H), 2.07–2.11 (m,
1H), 1.54–1.82 (m, 4H), 1.20–1.27 (m, 1H) ppm. HPLC (Chiralpak
AS column, hexanes/i-PrOH = 90:10, flow rate = 1.0 mL/min,
k = 214 nm): tR (syn isomer) = 17.23 (minor), 29.78 (major) min.
4.55 (dd, J = 12.3, 6.0 Hz, 1H), 4.39 (dd, J = 12.3, 6.5 Hz, 1H), 2.54–
2.60 (m, 1H), 2.45–2.51 (m, 1H), 2.37–2.41 (m, 1H), 2.26–2.34
(m, 1H), 2.07–2.13 (m, 2H), 1.92–1.95 (m, 1H), 1.61–1.70 (m,
2H), 1.42–1.49 (m, 1H), 1.25–1.32 (m, 6H), 0.87–0.92 (m, 3H)
ppm. HPLC (Chiralpak AD-H column, hexanes/i-PrOH = 70:30, flow
rate = 0.7 mL/min, k = 214 nm): tR (syn isomer) = 10.70 (major),
12.57 (minor) min.
4.3.6. (S)-2-[(R)-2-Nitro-1-ortho-bromophenylethyl]cyclohexa-
none 4f
4.3.12. (R)-Tetrahydro-3-[(R)-2-nitro-1-phenylethyl]pyran-4-one
4l
A
white solid, 92% yield; 99:1 dr (syn/anti), 96% ee;
½ ꢁ
a 2D0
¼ ꢀ54:0 (c 1.0, CHCl3, 589 nm). 1H NMR (400 MHz, CDCl3): d
A
white solid, 92% yield; 39:1 dr (syn/anti), 95% ee;
¼ ꢀ36:2 (c 1.0, CHCl3, 589 nm). 1H NMR (400 MHz, CDCl3): d
7.57 (dd, J = 8.0, 1.2 Hz, 1H), 7.27–7.31 (m, 1H), 7.22 (dd, J = 7.8,
1.7 Hz, 1H), 7.11–7.15 (m, 1H), 4.88 (d, J = 6.0 Hz, 2H), 4.30–4.34
(m, 1H), 2.85–2.87 (m, 1H), 2.35–2.50 (m, 2H), 2.08–2.13 (m,
1H), 1.61–1.84 (m, 4H), 1.33–1.42 (m, 1H) ppm. HPLC (Chiralpak
AS column, hexanes/i-PrOH = 90:10, flow rate = 1.0 mL/min,
k = 214 nm): tR (syn isomer) = 14.83 (minor), 19.83 (major) min.
½ ꢁ
a 2D0
7.25–7.34 (m, 3H), 7.17–7.19 (m, 2H), 4.92 (dd, J = 12.8, 4.5 Hz,
1H), 4.62 (dd, J = 12.7, 10.2 Hz, 1H), 4.10–4.15 (m, 1H), 3.65–3.85
(m, 3H), 3.25 (dd, J = 11.5, 9.0 Hz, 1H), 2.84–2.90 (m, 1H), 2.61–
2.65 (m, 1H), 2.50–2.65 (m, 1H) ppm. HPLC (Chiralpak AD column,
hexanes/i-PrOH = 95:5, flow rate = 1.0 mL/min, k = 214 nm): tR (syn
isomer) = 28.83 (minor), 60.48 (major) min.
4.3.7. (S)-2-[(R)-2-Nitro-1-(2,4-dichlorophenyl)-ethyl]cyclohexa-
none 4g
4.3.13. 2-Nitro-1-phenylethyl cyclopentanone (syn and anti) 4m
A white solid, mixture, 84% yield; 2:1 dr (syn/anti), 88% ee (syn),
A
white solid, 94% yield; 99:1 dr (syn/anti), 99% ee;
½ ꢁ
a 2D0
¼ ꢀ59:6 (c 0.9, CHCl3, 589 nm). 1H NMR (400 MHz, CDCl3): d
86% ee (anti); ½a D20
ꢁ
¼ ꢀ44:2 (c 1.0, CHCl3, 589 nm). 1H NMR
7.38 (s, 1H), 7.15–7.25 (m, 2H), 4.85–4.87 (m, 2H), 4.24 (td,
J = 9.5, 7.1 Hz, 1H), 2.81–2.87 (m, 1H), 2.31–2.47 (m, 2H), 2.08–
2.10 (m, 1H), 1.62–1.82 (m, 4H), 1.30–1.36 (m, 1H) ppm. HPLC
(Chiralpak AS column, hexanes/i-PrOH = 95:5, flow rate = 0.7 mL/
min, k = 214 nm): tR (syn isomer) = 22.63 (minor), 44.63 (major)
min.
(400 MHz, CDCl3): d 7.25-7.33 (m, 4.5H), 7.15–7.19 (m, 3H), 5.32
(dd, J = 12.9, 5.5 Hz, 1.5H), 4.70 (dd, J = 12.9, 10.0 Hz, 1.5H), 3.80–
3.85 (m, 0.5H, anti-isomer), 3.69 (td, J = 9.6, 5.5 Hz, 1H, syn-iso-
mer), 2.30–2.42 (m, 3H), 2.06–2.18 (m, 1.5H), 1.85–1.92 (m, 3H),
1.66–1.71 (m, 3H) ppm. HPLC (Chiralpak AS column, hexanes/i-
PrOH = 80:20, flow rate = 0.5 mL/min, k = 214 nm): tR (syn iso-
mer) = 22.58 (minor), 36.38 (major) min; tR (anti isomer) = 23.93
(major), 29.38 (minor) min.
4.3.8. (S)-2-[(R)-1-(Naphthalene-1-yl)-2-nitroethyl]cyclohexa-
none 4h
A
white solid, 77% yield; 99:1 dr (syn/anti), 98% ee;
4.3.14. (S)-2-[(R)-2-Nitro-1-phenylethyl]cycloheptanone 4n
½ ꢁ
a 2D0
¼ ꢀ84:5 (c 0.5, CHCl3, 589 nm). 1H NMR (400 MHz, CDCl3): d
A
colorless oil, 69% yield; 17:1 dr (syn/anti), 80% ee;
½ ꢁ
a 2D0
¼ ꢀ14:6 (c 1.0, CHCl3, 589 nm). 1H NMR (400 MHz, CDCl3): d
8.17 (s, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.43–
7.56 (m, 3H), 7.36 (d, J = 7.0 Hz, 1H), 5.08 (dd, J = 12.4, 3.8 Hz,
1H), 4.87–4.93 (m, 1H), 4.77 (br, 1H), 2.85 (s, 1H), 2.47–2.50 (m,
1H), 2.37–2.43 (m, 1H), 2.05–2.06 (m, 1H), 1.44–1.67 (m, 4H),
1.19–1.27 (m, 1H) ppm. HPLC (Chiralpak AS column, hexanes/i-
PrOH = 50:50, flow rate = 0.7 mL/min, k = 214 nm): tR (syn iso-
mer) = 11.28 (minor), 15.23 (major) min.
7.25–7.33 (m, 3H), 7.15–7.17 (m, 2H), 4.64 (dd, J = 6.8, 2.6 Hz,
2H), 3.65–3.71 (m, 1H), 2.98 (td, J = 10.4, 3.4 Hz, 1H), 2.49–2.53
(m, 2H), 1.83–1.90 (m, 2H), 1.54–1.75 (m, 3H), 1.13–1.24 (m, 3H)
ppm. HPLC (Chiralpak AD column, hexanes/i-PrOH = 80:20, flow
rate = 0.5 mL/min, k = 214 nm): tR (syn isomer) = 12.23 (minor),
15.23 (major) min.
4.3.9. (S)-2-[(S)-1-(Furan-2-yl)-2-nitroethyl]cyclohexanone 4i
4.3.15. (S)-2-[(R)-1-(2,3-Dimethoxyphenyl)-2-nitroethyl]cyclo-
A
white solid, 90% yield; 21:1 dr (syn/anti), 98% ee;
hexanone 4o
½ ꢁ
a 2D0
¼ ꢀ13:2 (c 1.0, CHCl3, 589 nm). 1H NMR (400 MHz, CDCl3): d
A white solid, 56% yield; 49% ee; ½a D20
ꢁ
¼ ꢀ1:5 (c 0.6, CHCl3,
589 nm). 1H NMR (400 MHz, CDCl3, 589 nm): d 7.19–7.33 (m,
5H), 4.67 (dd, J = 12.3, 6.8 Hz, 1H), 4.58 (dd, J = 12.3, 7.8 Hz, 1H),
3.96–4.03 (m, 1H), 2.89 (d, J = 7.0 Hz, 2H), 2.10 (s, 3H) ppm. HPLC
7.32 (dd, J = 1.7, 0.5 Hz, 1H), 6.26 (dd, J = 3.2, 1.9 Hz, 1H), 6.14–
6.16 (m, 1H), 4.78 (dd, J = 12.5, 4.7 Hz, 1H), 4.64 (dd, J = 12.5,
9.5 Hz, 1H), 3.95 (td, J = 9.3, 4.7 Hz, 1H), 2.69–2.76 (m, 1H), 2.34–
2.45 (m, 2H), 2.04–2.08 (m, 1H), 1.80–1.83 (m, 1H), 1.70–1.75
(m, 1H), 1.59–1.65 (m, 2H), 1.21–1.31 (m, 1H) ppm. HPLC (Chir-
alpak AD column, hexanes/i-PrOH = 90:10, flow rate = 0.7 mL/
(Chiralpak
AS
column,
hexanes/i-PrOH = 80:20,
flow
rate = 0.5 mL/min, k = 214 nm): tR = 30.53 (minor), 40.88 (major)
min.

218
Y. Wang et al. / Tetrahedron: Asymmetry 25 (2014) 212–218
8. Wolfe, S. Acc. Chem. Res. 1972, 5, 102.
9. Gooseman, N. E. J.; O’Hagan, D.; Peach, M. J. G.; Slawin, A. M. Z.; Tozer, D. J.;
Young, R. J. Angew. Chem., Int. Ed. 2007, 46, 5904.
10. (a) Melling, R. C.; Marson, C. M. Chem. Commun. 1998, 1223; (b) Melling, R. C.;
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4.3.16. (E)-(S)-2-((S)-1-Nitro-4-phenylbut-3-en-2-yl)cyclohexa-
none 4q
A white solid, 84% yield, 14:1 dr (syn/anti), 99% ee; ½a D20
¼ ꢀ60:1
ꢁ
(c 1.1, CHCl3, 589 nm). 1H NMR (400 MHz, CDCl3): d 7.20–7.33 (m,
5H), 6.47 (d, J = 15.8 Hz, 1H), 6.00 (dd, J = 15.8, 9.6 Hz, 1H), 4.65
(dd, J = 11.9, 4.7 Hz, 1H), 4.54 (dd, J = 11.9, 8.5 Hz, 1H), 3.33 (qd,
J = 8.5, 4.8 Hz, 1H), 2.33–2.64 (m, 1H), 2.40–2.44 (m, 1H), 2.29–
2.37 (m, 1H), 2.12–2.17 (m, 1H), 2.05–2.09 (m, 1H), 1.86–1.90
(m, 1H), 1.62–1.68 (m, 2H), 1.38–1.48 (m, 1H) ppm. HPLC (Chir-
alpak PA column, hexanes/i-PrOH = 80:20, flow rate = 0.7 mL/min,
k = 214 nm): tR (syn isomer) = 16.28 (major), 19.41 (minor) min.
13. Quintard, A.; Langlois, J. B.; Emery, D.; Mareda, J.; Guénée, L.; Alexakis, A. Chem.
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Acknowledgments
Financial support from the National Natural Science Foundation
of China (No. 21172243) is gratefully acknowledged.
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