Enantioselective conjugate addition of ketones to nitroalkenes catalyzed by pyrrolidine-sulfamides

Article abstract of DOI:10.1002/chir.21987

A series of chiral pyrrolidine-sulfamides were prepared and examined as the catalysts for conjugate addition of ketones to nitroalkenes. Benzoic acid was identified as the most efficient additives for the transformation. Excellent enantioselectivities, diastereoselectivities, and yields were achieved for the reaction of cyclohexanone with β-aryl nitroethylenes under solvent free conditions. β-Isopropyl nitroethylene is also applicable and the product could be obtained with excellent enantioselectivity after extended reaction time. A comparison of the catalytic behaviors of pyrrolidine-sulfamide organocatalysts with different side chains demonstrates that the enantioselectivity is mainly controlled by the chiral pyrrolidine unit and the additional chiral center at the side chain exerts neglectable effects. The H-bonding interaction between the sulfamide and the nitro group is proposed to be crucial for the activation of the nitroalkene and the constitution of well-organized transition state. Copyright

Full text of DOI:10.1002/chir.21987

CHIRALITY 24:232–238 (2012)
Enantioselective Conjugate Addition of Ketones to Nitroalkenes
Catalyzed by Pyrrolidine-Sulfamides
*
JINJIA WANG, JINHUA LAO, QUANSHENG DU, SHAOZHEN NIE, ZHIPENG HU, AND MING YAN
Institute of Drug Synthesis and Pharmaceutical Process, School of Pharmaceutical Sciences,
Sun Yat-Sen University, Guangzhou 510006, China
ABSTRACT
A series of chiral pyrrolidine-sulfamides were prepared and examined as the
catalysts for conjugate addition of ketones to nitroalkenes. Benzoic acid was identified as the
most efficient additives for the transformation. Excellent enantioselectivities, diastereoselectiv-
ities, and yields were achieved for the reaction of cyclohexanone with b-aryl nitroethylenes
under solvent free conditions. b-Isopropyl nitroethylene is also applicable and the product could
be obtained with excellent enantioselectivity after extended reaction time. A comparison of the
catalytic behaviors of pyrrolidine-sulfamide organocatalysts with different side chains demon-
strates that the enantioselectivity is mainly controlled by the chiral pyrrolidine unit and the addi-
tional chiral center at the side chain exerts neglectable effects. The H-bonding interaction
between the sulfamide and the nitro group is proposed to be crucial for the activation of the
nitroalkene and the constitution of well-organized transition state. Chirality 24:232–238,
C
VV
2012.
2012 Wiley Periodicals, Inc.
KEY WORDS: asymmetric conjugate addition; chiral pyrrolidine-sulfamide; organocatalysis;
nitroalkene; ketone
and 13C NMR spectra were recorded on Bruker AVANCE 400 spectrom-
INTRODUCTION
eter. Peaks are labeled as singlet (s), doublet (d), triplet (t), quartet (q),
and multiplet (m). Optical rotations were measured on a Perkin-Elmer
341 digital polarimeter. Melting points were measured on a WRS-2A
melting point apparatus and are uncorrected. The high resolution mass
spectroscopic data were obtained at Shimadazu LCMS-IT-TOF spectrom-
eter. Infrared (IR) spectra were recorded on a Bruker Tensor 37 spectro-
photometer. Enantiomeric excesses were determined by high perform-
ance liquid chromatography (HPLC) using a Daicel Chiralcel AS-H, AD-
H, or OD-H column and eluting with a hexane/2-propanol solution. Flash
chromatography was performed over silica gel (230–400 mesh), pur-
chased from Qingdao Haiyang Chemical Co.
In recent years, organocatalysis has evolved to be a power-
ful tool for asymmetric synthesis.1–5 The activation of carbonyl
compounds by chiral primary and secondary amines is the
most useful method.6–8 In these reactions, the combination of
concurrent H-bonding interactions (bifunctional catalysis)
proved to be important for achieving excellent stereoselectiv-
ities and yields.9–11 Ureas, thioureas, guandiniums, and amidi-
nium ions, which are capable of simultaneously forming two
hydrogen bonds, are privileged H-bond donors.12–15 Recently,
we found that readily available sulfamides are also efficient H-
bond donors for primary amine-based bifunctional organocata-
lysts.16–18 The stronger acidity of N-H bonds in sulfamides is
expected to provide more efficient H-bonding interaction than
the corresponding thioureas or ureas. Although the primary
amine-sulfamide catalysts provided excellent enantioselectiv-
ities for conjugate addition of aldehydes to nitroalkenes,16 they
are less efficient for the conjugate addition of ketones to nitro-
alkenes.17 A careful investigation of the reported results indi-
cated that pyrrolidine-based organocatalysts are extremely effi-
cient for the transformation.19,20 Pyrrolidine-based amides,21–24
thioureas (ureas),25–29 sulfonamides,30–34 and the others35–46
have been developed successfully. Considering the excellent
H-bond donation ability of sulfamides, we speculate that pyrrol-
idine-based sulfamides are also efficient catalysts for the conju-
gate addition of ketones to nitroalkenes (After we had submit-
ted this article for 5 months, a similar study from Chen et al.’s
group was submitted and published).47 In this article, we
report the synthesis and application of novel chiral pyrrolidine-
sulfamides in asymmetric conjugate addition of ketones to
nitroalkenes.
Typical Procedure for the Synthesis
of Pyrrolidine-Sulfamides 1a–1d
A 100-ml round bottomed flask was charged with catechol (4.40 g, 40
mmol), pyridine (6.40 g, 80 mmol), and hexane (40 ml). A solution of sul-
furyl chloride (5.40 g, 40 mmol) in hexane (10 ml) was then added drop-
wise over 1 h at 258C. The reaction mixture was stirred at 08C overnight
and at ambient temperature for another 12 h. The upper layer of the
reaction mixture was decanted. The lower layer was diluted with water
(100 ml) and extracted with ethyl ether (4 3 60 ml). The combined or-
ganic layer was washed with 2% NaOH (3 3 60 ml) and dried over so-
dium sulfate. After the evaporation of solvent under vacuum, catechol
sulfate was obtained as a colorless oil (2.60 g, 38% yield), which was
used in the next step without further purification.
To a solution of benzylamine (1.17 g, 10 mmol), triethylamine (1.20 g,
12 mmol), N,N-dimethylformamide (DMF) (20 ml), and anhydrous
dichloromethane (10 ml) under an ice-bath, a solution of catechol sulfate
Contract grant sponsor: National Natural Science Foundation of China;
Contract grant numbers: 20772160, 20972195.
Contract grant sponsor: Ministry of Health of China; Contract grant number:
2009ZX09501-017.
*Correspondence to: Ming Yan, School of Pharmaceutical Sciences, Sun Yat-
Sen University, Guangzhou 510006, China.
E-mail: yanming@mail.sysu.edu.cn
Received for publication 28 September 2010; Accepted 2 November 2011
DOI: 10.1002/chir.21987
Published online 25 January 2012 in Wiley Online Library
(wileyonlinelibrary.com).
EXPERIMENTAL SECTION
General Remarks
All solvents were used as commercial anhydrous grade without fur-
ther purification. All reactions were performed under open air. 1H NMR
C
VV
2012 Wiley Periodicals, Inc.

ADDITION OF KETONES TO NITROALKENES
233
(1.72 g, 10.0 mmol) in dichloromethane (20 ml) was added dropwise.
Typical Procedure for Asymmetric Conjugate
Addition of Ketones to Nitroalkenes
The reaction mixture was stirred for 24 h at room temperature and then
diluted with dichloromethane (30 ml). The reaction solution was washed
with 1 M hydrochloric acid (2 3 20 ml), brine (2 3 20 ml) and dried
over anhydrous Na2SO4. After the evaporation of solvent under vacuum,
the crude product was purified by flash chromatography over silica gel
(EtOAc/petroleum ether 5 1/1) to give 2-hydroxyphenyl benzylsulfa-
mate as a white solid (2.77 g, 99% yield).
A solution of 1b (11 mg, 0.04 mmol) and PhCO2H (5 mg, 0.04 mmol)
in cyclohexanone (0.5 ml) was stirred for 15 min at 08C, and then, b-
nitrostyrene (30 mg, 0.2 mmol) was added. The reaction mixture was
stirred at 08C until complete consumption of b-nitrostyrene (as moni-
tored by thin layer chromatography (TLC)). The mixture was concen-
trated under reduced pressure, and the residue was purified by flash
chromatography over silica gel (petroleum ether: EtOAc 5 8:1) to give
3a as a white solid (48 mg, 98% yield).
A solution of 2-hydroxyphenyl benzylsulfamate (837 mg, 3 mmol) and
(S)-N-Boc-2-aminomethyl-pyrrolidine (600 mg, 3.0 mmol) in dry dioxane
(50 ml) was refluxed for 2.5 h. After dioxane was removed under vac-
uum, the residue was dissolved in ethyl acetate (100 ml). The solution
was washed with water (40 ml), 2% NaOH (3 3 40 ml), brine (40 ml)
and dried over anhydrous Na2SO4. After the evaporation of the solvent
under vacuum, the crude product was purified by flash chromatography
over silica gel (MeOH/EtOAc 5 1/10) to give N-benzyl-N0-[(S)-(1-Boc-
pyrrolidin-2-yl)methyl]-sulfamide as a colorless oil (864 mg, 78% yield).
A solution of N-benzyl-N0-[(S)-(1-Boc-pyrrolidin-2-yl) methyl]-sulfamide
(738 mg, 2 mmol), trifluoroacetic acid (2.4 ml) in CH2Cl2 (4 ml) was
stirred at room temperature for 2 h. The mixture was basified with
aqueous NaOH (2 M) and extracted with CH2Cl2 (4 3 20 ml). After the
evaporation of the solvent under vacuum, the residue was purified
through flash column chromatography over silica gel (EtOAc/ metha-
nol/Et3N 5 70:10:1) to give 1b as a white solid (403 mg, 75% yield).
Pyrrolidine-sulfamides 1a, 1c, and 1d were prepared by similar proce-
dures.
Products 3a–3n, 4a–4f are known compounds.25,31 Their relative and
absolute configurations were determined by comparison with the
reported 1H NMR spectra, chiral HPLC chromatogram, and optical
rotations.
(S)-2-((R)-2-Nitro-1-phenylethyl)cyclohexanone (3a)
[a]D20 5 215.7 (c 0.24, CH2Cl2), 1H NMR (400 MHz, CDCl3): d 5
7.40–7.24 (m, 3H), 7.18–7.15 (m, 2H), 4.93 (dd, J 5 12.4, 4.4 Hz, 1H),
4.64 (dd, J 5 12.4, 9.6 Hz, 1H), 3.76 (td, J 5 10.0, 4.8 Hz, 1H), 2.72–2.65
(m, 1H), 2.51–2.34 (m, 2H), 2.12–2.04 (m, 1H), 1.81–1.52 (m, 4H), 1.29–
1.19 (m, 1H). The enantiometric excess was determined by HPLC with a
Chiralpak AS-H column (hexane:2-propanol 5 80:20, k 5 208 nm, 1.0
ml/min); tR (minor enantiomer) 5 8.86 min, tR (major enantiomer) 5
12.16 min, 96% ee.
(S)-2-((R)-2-Nitro-1-p-tolylethyl)cyclohexanone (3b)
N-(2-Phenyl)ethyl-N0-[(S)-(pyrrolidin-2-yl)methyl]-
1
[a]D20 5 215.3 (c 0.25, CH2Cl2), H NMR (400 MHz, CDCl3): d 5 7.12
(d, J 5 8.0 Hz, 2H), 7.04 (d, J 5 8.0 Hz, 2H), 4.91 (dd, J 5 12.4, 4.8 Hz,
1H), 4.61 (dd, J 5 12.4, 10.0 Hz, 1H), 3.72 (td, J 5 10.0, 4.8 Hz, 1H),
2.72–2.63 (m, 1H), 2.50–2.34 (m, 2H), 2.31 (s, 3H), 2.10–2.04 (m, 1H),
1.81–1.55 (m, 4H), 1.27–1.18 (m, 1H). The enantiometric excess was
determined by HPLC with a Chiralpak AS-H column (hexane:2-propanol
5 80:20, k 5 208 nm, 1.0 ml/min); tR (minor enantiomer) 5 8.35 min, tR
(major enantiomer) 5 13.74 min, 90% ee.
sulfamide (1a)
White solid, m.p. 109–1108C, [a]D20 5 29.2 (c 0.25, CH2Cl2). 1H NMR
(400 MHz, CD3OD): d 5 7.31–7.19 (m, 5H), 3.21–3.12 (m, 3H), 2.95–
2.89 (m, 1H), 2.86–2.80 (m, 5H), 1.92–1.72 (m, 3H), 1.46–1.38 (m, 1H);
13C NMR (100 MHz, CD3OD): d 5 140.5, 130.0, 129.6, 127.5, 59.3, 47.5,
46.8, 45.5, 37.1, 30.0, 25.9; HRMS (ESI) calcd for C13H20N3O2S (M 2
H)2: 282.1276, found: 282.1281; IR (KBr): 3326, 2952, 2852, 1604, 1496,
1456, 1144, 701 cm21
.
(S)-2-((R)-1-(4-Methoxyphenyl)-2-nitroethyl)
cyclohexanone (3c)
N-Benzyl-N0-[(S)-(pyrrolidin-2-yl)methyl]-sulfamide (1b)
[a]D20 5 2 12.1 (c 0.25, CH2Cl2), 1H NMR (400 MHz, CDCl3): d 5 7.08
(d, J 5 8.8 Hz, 2H), 6.85 (d, J 5 8.4 Hz, 2H), 4.91 (dd, J 5 12.4, 4.8 Hz,
1H), 4.58 (dd, J 5 12.4, 10.0 Hz, 1H), 3.78 (s, 3H), 3.71 (td, J 5 10.0, 4.8
Hz, 1H), 2.67–2.61 (m, 1H), 2.49–2.34 (m, 2H), 2.11–2.04 (m, 1H), 1.81–
1.52 (m, 4H), 1.28–1.19 (m, 1H). The enantiometric excess was deter-
mined by HPLC with a Chiralpak AS-H column (hexane:2-propanol 5
80:20, k 5 208 nm, 1.0 ml/min); tR (minor enantiomer) 5 16.26 min, tR
(major enantiomer) 5 23.67 min, 97% ee.
White solid, m.p. 96–978C, [a]D20 5 25.0 (c 0.28, CH2Cl2). 1H NMR
(400 MHz, CD3OD): d 5 7.28–7.14 (m, 5H), 4.04 (s, 2H), 3.14–3.08 (m,
1H), 2.87–2.81 (m, 3H), 2.78–2.72 (m, 1H), 1.84–1.75 (m, 1H), 1.72–1.63
(m, 2H), 1.40–1.31 (m, 1H); 13C NMR (100 MHz, CD3OD): d 5 139.4,
129.6, 129.1, 128.5, 59.5, 47.7, 47.3, 46.8, 29.8, 25.7; HRMS (ESI) calcd
for C12H18N3O2S (M 2 H)2: 268.1120, found: 268.1112; IR (KBr): 3285,
2966, 2867, 1496, 1456, 1147, 699 cm21
.
N-[(R)-1-Methyl]benzyl-N0-[(S)-(pyrrolidin-2-yl)methyl]-
(S)-2-((R)-1-(4-Florophenyl)-2-nitroethyl)
sulfamide (1c)
cyclohexanone (3d)
Colorless oil, [a]D20 5 47.6 (c 0.21, CH2Cl2). 1H NMR (400 MHz,
CD3OD): d 5 7.41–7.33 (m, 4H), 7.28–7.24 (m, 1H), 4.45 (q, J 5 6.8 Hz,
1H), 3.04–2.97 (m, 1H), 2.90–2.75 (m, 3H), 2.70 (dd, J 5 12.8, 5.6 Hz,
1H), 1.82–1.67 (m, 3H), 1.49 (d, J 5 6.8 Hz, 3H), 1.35–1.28 (m, 1H); 13C
NMR (100 MHz, CD3OD): d 5 144.1, 128.0, 126.7, 125.9, 57.6, 53.0, 46.0,
45.2, 28.3, 24.3, 22.9; HRMS (ESI) calcd for C13H20N3O2S (M 2 H)2:
282.1276, found: 282.1279; IR (KBr): 3289, 2972, 2874, 1634, 1541, 1493,
[a]D20 5 2 13.2 (c 0.28, CH2Cl2), 1H NMR (400 MHz, CDCl3): d 5
7.16–7.13 (m, 2H), 7.04–7.00 (m, 2H), 4.93 (dd, J 5 12.4, 4.4 Hz, 1H),
4.60 (dd, J 5 12.4, 10.0 Hz, 1H), 3.77 (td, J 5 10.0, 4.8 Hz, 1H), 2.69–2.62
(m, 1H), 2.50–2.32 (m, 2H), 2.12–2.06 (m, 1H), 1.87–1.56 (m, 4H), 1.27–
1.18 (m, 1H). The enantiometric excess was determined by HPLC with a
Chiralpak AS-H column (hexane:2-propanol 5 90:10, k 5 208 nm, 1.0
ml/min); tR (minor enantiomer) 5 16.92 min, tR (major enantiomer) 5
26.25 min, 91% ee.
1151, 701 cm21
.
N-[(S)-1-Methyl]benzyl-N0-[(S)-(pyrrolidin-2-yl)methyl]-
(S)-2-((R)-1-(4-Chlorophenyl)-2-nitroethyl)
sulfamide (1d)
cyclohexanone (3e)
Colorless oil, [a]D20 5 9.6 (c 0.25, CH2Cl2). 1H NMR (400 MHz,
CD3OD): d 5 7.40–7.32 (m, 4H), 7.27–7.23 (m, 1H), 4.45 (q, J 5 7.2 Hz,
1H), 3.14–3.11 (m, 1H), 2.91–2.81 (m, 3H), 2.71 (dd, J 5 13.6, 7.2 Hz,
1H), 1.85–1.74 (m, 3H), 1.42 (d, J 5 7.2 Hz, 3H), 1.42–1.37 (m, 1H); 13C
NMR (100 MHz, CD3OD): d 5 145.6, 129.6, 128.3, 127.4, 59.4, 54.5, 47.0,
46.7, 29.7, 25.7, 24.4; HRMS (ESI) calcd for C13H20N3O2S (M 2 H)2:
282.1276, found: 282.1270; IR (KBr): 3282, 2973, 2875, 1681, 1495, 1455,
[a]D20 5 2 15.7 (c 0.24, CH2Cl2), 1H NMR (400 MHz, CDCl3): d 5 7.30
(d, J 5 8.4 Hz, 2H), 7.12 (d, J 5 8.4 Hz, 2H), 4.93 (dd, J 5 12.6, 4.4 Hz,
1H), 4.61 (dd, J 5 12.6, 10.0 Hz, 1H), 3.76 (td, J 5 10.0, 4.8 Hz, 1H),
2.69–2.62 (m, 1H), 2.51–2.45 (m, 1H), 2.42–2.34 (m, 1H), 2.13–2.06 (m,
1H), 1.83–1.55 (m, 4H), 1.28–1.18 (m, 1H). The enantiometric excess
was determined by HPLC with a Chiralpak AS-H column (hexane:2-pro-
panol 5 80:20, k 5 208 nm, 1.0 ml/min); tR (minor enantiomer) 5 10.29
min, tR (major enantiomer) 5 16.83 min, 94% ee.
1151, 701 cm21
.
Chirality DOI 10.1002/chir

234
WANG ET AL.
(S)-2-((R)-1-(4-Bromophenyl)-2-nitroethyl)
(S)-2-((S)-1-(Furan-2-yl)-2-nitroethyl)cyclohexanone (3l)
[a]D20 5 2 7.5 (c 0.24, CH2Cl2), 1H NMR (400 MHz, CDCl3): d 5 7.34–
7.33 (m, 1H), 6.29–6.28 (m, 1H), 6.18 (d, J 5 3.2Hz, 1H), 4.79 (dd, J 5
12.4, 4.8 Hz, 1H), 4.67 (dd, J 5 12.4, 9.2 Hz, 1H), 3.97 (td, J 5 9.2, 4.8
Hz, 1H), 2.79–2.72 (m, 1H), 2.48–2.32 (m, 2H), 2.13–2.07 (m, 1H), 1.85–
1.83 (m, 1H), 1.79–1.73 (m, 1H), 1.68–1.62 (m, 2H), 1.34–1.23 (m, 1H).
The enantiometric excess was determined by HPLC with a Chiralpak
AS-H column (hexane:2-propanol 5 90:10, k 5 208 nm, 0.7 ml/min); tR
(major enantiomer) 5 13.24 min, tR (minor enantiomer) 5 15.81 min,
91% ee.
cyclohexanone (3f)
[a]D20 5 2 12.3 (c 0.24, CH2Cl2), 1H NMR (400 MHz, CDCl3): d 5 7.45
(d, J 5 8.4 Hz, 2H), 7.06 (d, J 5 8.4 Hz, 2H), 4.93 (dd, J 5 12.4, 4.4 Hz,
1H), 4.60 (dd, J 5 12.4, 10.0 Hz, 1H), 3.75 (td, J 5 10.0, 4.4 Hz, 1H),
2.68–2.61 (m, 1H), 2.51–2.49 (m, 1H), 2.38–2.33 (m, 1H), 2.13–2.06 (m,
1H), 1.83–1.52 (m, 4H), 1.28–1.18 (m, 1H). The enantiometric excess
was determined by HPLC with a Chiralpak AS-H column (hexane:2-pro-
panol 5 90:10, k 5 208 nm, 1.0 ml/min); tR (minor enantiomer) 5 16.34
min, tR (major enantiomer) 5 28.70 min, 93% ee.
(S)-2-((S)-2-Nitro-1-(thiophen-2-yl)ethyl)cyclohexanone
(S)-2-((R)-1-(3-Chlorophenyl)-2-nitroethyl)
(3m)
cyclohexanone (3g)
[a]D20 5 2 14.5 (c 0.25, CH2Cl2), 1H NMR (400 MHz, CDCl3): d 5
7.22–7.21 (m, 1H), 6.93 (dd, J 5 4.8, 3.2 Hz, 1H), 6.88–6.87 (m, 1H), 4.89
(dd, J 5 12.8, 4.8 Hz, 1H), 4.65 (dd, J 5 12.8, 9.2 Hz, 1H), 4.13 (td, J 5
9.2, 4.8 Hz, 1H), 2.72–2.65 (m, 1H), 2.49–2.33 (m, 2H), 2.13–2.08 (m, 1H),
1.93–1.82 (m, 2H), 1.71–1.57 (m, 2H), 1.38–1.28 (m, 1H). The enantiomet-
ric excess was determined by HPLC with a Chiralpak AD-H column
(hexane:2-propanol 5 95:5, k 5 208 nm, 1.0 ml/min); tR (minor enan-
tiomer) 5 15.49 min, tR (major enantiomer) 5 17.80 min, 89% ee.
[a]D20 5 2 13.1 (c 0.58, CH2Cl2), 1H NMR (400 MHz, CDCl3): d 5
7.27–7.25 (m, 2H), 7.18–7.17 (m, 1H), 7.09–7.06 (m, 1H), 4.94 (dd, J 5
12.8, 4.4 Hz, 1H), 4.61 (dd, J 5 12.8, 10.0 Hz, 1H), 3.76 (td, J 5 10.0, 4.4
Hz, 1H), 2.69–2.63 (m, 1H), 2.51–2.34 (m, 2H), 2.11–2.07 (m, 1H), 1.83–
1.68 (m, 2H), 1.67–1.60 (m, 2H), 1.29–1.19 (m, 1H). The enantiometric
excess was determined by HPLC with
a Chiralpak AS-H column
(hexane:2-propanol 5 80:20, k 5 208 nm, 1.0 ml/min); tR (minor enan-
tiomer) 5 10.34 min, tR (major enantiomer) 5 17.49 min, 91% ee.
(S)-2-((S)-3-Methyl-1-nitrobutan-2-yl)cyclohexanone (3n)
1
[a]D20 5 2 6.3 (c 0.25, CH2Cl2), H NMR (400 MHz, CDCl3): d 5 4.64
(S)-2-((R)-1-(2,4-Dichlorophenyl)-2-
(dd, J 5 13.6, 5.6 Hz, 1H), 4.36 (dd, J 5 13.6, 4.8 Hz, 1H), 2.66–2.61 (m,
1H), 2.42–2.29 (m, 3H), 2.14–2.06 (m, 2H), 1.97–1.89 (m, 2H), 1.74–1.58
(m, 3H), 0.94 (d, J 5 6.8 Hz, 3H), 0.90 (d, J 5 6.8 Hz, 3H). The enantio-
metric excess was determined by HPLC with a Chiralpak AD-H column
(hexane:2-propanol 5 90:10, k 5 208 nm, 1.0 ml/min); tR (minor enan-
tiomer) 5 5.93 min, tR (major enantiomer) 5 6.90 min, 95% ee.
nitroethyl)cyclohexanone (3h)
[a]D20 5 2 41.0 (c 0.26, CH2Cl2), 1H NMR (400 MHz, CDCl3) d 5 7.41
(d, J 5 2.1 Hz, 1H), 7.25–7.17 (m, 2H), 4.92–4.87 (m, 2H), 4.27–4.21 (m,
1H), 2.91–2.84 (m, 1H), 2.51–2.45 (m, 1H), 2.42–2.32 (m, 1H), 2.14–2.09
(m, 1H), 1.88–1.81 (m, 1H), 1.77–1.58 (m, 3H), 1.39–1.26 (m, 1H). The
enantiometric excess was determined by HPLC with a Chiralpak AD-H
column (hexane:2-propanol 5 90:10, k 5 208 nm, 1.0 ml/min); tR (minor
enantiomer) 5 8.31 min, tR (major enantiomer) 5 10.67 min, 93% ee.
(R)-Tetrahydro-3-((R)-2-nitro-1-phenylethyl)
pyran-4-one (4a)
[a]D20 5 2 24.2 (c 5 0.55, CH2Cl2), 1H NMR (400 MHz, CDCl3): d 5
7.36–7.28 (m, 3H), 7.20–7.18 (m, 2H), 4.93 (dd, J 5 12.8, 4.4 Hz, 1H), 4.65
(dd, J 5 12.8, 10.0 Hz, 1H), 4.17–4.11 (m, 1H), 3.86–3.74 (m, 2H), 3.70
(ddd, J 5 11.6, 5.6, 1.2 Hz, 1H), 3.27 (dd, J 5 11.6, 8.8 Hz, 1H), 2.91–2.85
(m, 1H), 2.70–2.63 (m, 1H), 2.59–2.54 (m, 1H).The enantiometric excess
was determined by HPLC with a Chiralpak AD-H column (hexane:2-pro-
panol 5 90:10, k 5 208 nm, 1.0 ml/min); tR (minor enantiomer) 5 11.49
min, tR (major enantiomer) 5 19.79 min, 70% ee.
(S)-2-((R)-1-(2-Bromophenyl)-2-nitroethyl)
cyclohexanone (3i)
[a]D20 5 2 12.1 (c 0.25, CH2Cl2), 1H NMR (400 MHz, CDCl3): d 57.58
(dd, J 5 8.0, 1.2 Hz, 1H), 7.32–7.28 (m, 1H), 7.22 (dd, J 5 7.6, 1.6 Hz,
1H), 7.13 (td, J 5 7.6, 1.6 Hz, 1H), 4.96–4.85 (m, 2H), 4.33–4.28 (m, 1H),
2.91 (s, 1H), 2.51–2.32 (m, 3H), 2.14–2.08 (m, 1H), 1.90–1.65 (m, 4H),
1.43–1.26 (m, 1H). The enantiometric excess was determined by HPLC
with a Chiralpak AS-H column (hexane:2-propanol 5 90:10, k 5 208 nm,
0.8 ml/min); tR (minor enantiomer) 5 17.95 min, tR (major enantiomer)
5 23.55 min, 95% ee.
(4S, 5R)-4-Methyl-6-nitro-5-phenylhexan-3-one (4b)
[a]D20 5 7.5 (c 5 0.12, CH2Cl2), 1H NMR (400 MHz, CDCl3): d 5 7.35–
7.28 (m, 3H), 7.17–7.15 (m, 2H), 4.67 (dd, J 5 12.4, 8.8 Hz, 1H), 4.60
(dd, J 5 12.4, 4.8 Hz, 1H), 3.70 (td, J 5 9.2, 4.8 Hz, 1H), 3.02–2.96 (m,
1H), 2.66–2.56 (m, 1H), 2.46–2.36 (m, 1H), 1.07 (t, J 5 7.2 Hz, 3H), 0.97
(d, J 5 7.2 Hz, 3H). The enantiometric excess was determined by HPLC
with a Chiralpak OD-H column (hexane:2-propanol 5 97:3, k 5 210 nm,
0.5 ml/min); tR (major enantiomer) 5 42.05 min, tR (minor enantiomer)
5 53.73 min, 92% ee.
(S)-2-((R)-2-Nitro-1-(2-nitrophenyl)ethyl)
cyclohexanone (3j)
[a]D20 5 2 54.2 (c 0.38, CH2Cl2), 1H NMR (400 MHz, CDCl3): d 5 7.84
(dd, J 5 8.0, 1.2 Hz, 1H), 7.59 (td, J 5 7.6, 1.2 Hz, 1H), 7.47–7.42 (m,
2H), 4.98–4.90 (m, 2H), 4.33 (td, J 5 8.8, 5.2 Hz, 1H), 2.98–2.91 (m, 1H),
2.50–2.35 (m, 2H), 2.15–2.09 (m, 1H), 1.87–1.79 (m, 2H), 1.72–1.43 (m,
3H). The enantiometric excess was determined by HPLC with a Chiral-
pak AD-H column (hexane:2-propanol 5 95:5, k 5 208 nm, 0.9 ml/min);
tR (minor enantiomer) 5 34.23 min, tR (major enantiomer) 5 47.31 min,
95% ee.
(R)-5-Nitro-4-phenylpentan-2-one (4c)
[a]D20 5 2 4.5 (c 0.24, CH2Cl2), 1H NMR (400 MHz, CDCl3): d 5 7.35–
7.02 (m, 5H), 4.69 (dd, J 5 12.4, 6.8 Hz, 1H), 4.60 (dd, J 5 12.4, 7.6 Hz,
1H), 4.04–3.97 (m, 1H), 2.92 (d, J 5 6.8 Hz, 2H), 2.11 (s, 3H). The enan-
tiometric excess was determined by HPLC with a Chiralpak AS-H col-
umn (hexane:2-propanol 5 80:20, k 5 208 nm, 1.0 ml/min); tR (minor
enantiomer) 5 13.28 min, tR (major enantiomer) 5 14.64 min, 48% ee.
(S)-2-((R)-1-(Naphthalen-1-yl)-2-nitroethyl)
cyclohexanone (3k)
(3S, 4R)-3-Hydroxy-5-nitro-4-phenylpentan-2-one (4d)
[a]D20 5 2 73.8 (c 0.26, CH2Cl2), 1H NMR (400 MHz, CDCl3): d 5 8.16
(s, 1H), 7.86 (d, J 5 8.0 Hz, 1H), 7.78 (d, J 5 8.0 Hz, 1H), 7.60–7.36 (m,
4H), 5.07 (dd, J 5 12.8, 4.4 Hz, 1H), 4.91 (dd, J 5 12.8, 9.6 Hz, 1H), 4.76
(s, 1H), 2.87 (s, 1H), 2.53–2.38 (m, 2H), 2.11–2.05 (m, 1H), 1.73–1.50 (m,
4H), 1.30–1.20 (m, 1H). The enantiometric excess was determined by
HPLC with a Chiralpak AS-H column (hexane:2-propanol 5 70:30, k 5
208 nm, 0.7 ml/min); tR (minor enantiomer) 5 14.64 min, tR (major
enantiomer) 5 20.58 min, 93% ee.
1H NMR (400 MHz, CDCl3): d 5 7.43–7.17 (m, 5H 1 3H*), 5.03 (dd, J
5 13.3, 8.0 Hz, 1H), 4.82 (dd, J 5 13.6, 6.4 Hz, 0.57H*), 4.73 (dd, J 5
13.6, 7.2 Hz, 1H), 4.65 (dd, J 5 13.6, 8.0 Hz, 0.57H*), 4.53–4.51 (m, 1H),
4.40–4.38 (m, 0.5H*), 4.03 (td, J 5 7.6, 2.8 Hz, 1H), 3.85–3.81 (m,
0.57H*), 3.72–3.71 (m, 1H 1 0.56H*), 2.18 (s, 3H), 2.07 (s, 1.6H*). The
enantiometric excess was determined by HPLC with a Chiralpak AD-H
column (hexane:2-propanol 5 90:10, k 5 220 nm, 1.0 ml/min); (major
Chirality DOI 10.1002/chir

ADDITION OF KETONES TO NITROALKENES
235
Scheme 1. Synthesis of pyrrolidine-sulfamides 1a–1d. Reaction conditions: (a) pyridine, hexane, ice-bath, 1 day; (b) Et3N, CH2Cl2; (c) dioxane, reflux, 2.5 h;
and (d) TFA, CH2Cl2.
isomer) tminor5 20.46 min, tmajor 5 43.00 min, 28% ee; (minor isomer)
tminor 5 21.04 min, tmajor 5 26.63 min, 10% ee.
(Table 2, entry 3). Toluene gave better yield, however with
moderate enantioselectivity (Table 2, entry 4). The reaction
did not occur in isopropanol (Table 2, entry 5). Interestingly
better yield and enantioselectivity were obtained in neat
cyclohexanone; in addition, the reaction became faster (Ta-
ble 2, entry 6). Furthermore, the effect of acid additives was
(R)-2,2-Dimethyl-4-nitro-3-phenylbutanal (4f)
1H NMR (400 MHz, CDCl3): d 5 7.35–7.29 (m, 3H), 7.21–7.19 (m,
2H), 4.85 (dd, J 5 12.8, 11.2 Hz, 1H), 4.69 (dd, J 5 12.8, 4.0 Hz, 1H),
3.78 (dd, J 5 11.2, 4.4 Hz, 1H), 1.14 (s, 3H), 1.01 (s, 3H). The enantio-
studied (Table 2, entries 7–9). PhCO2H significantly acceler-
metric excess was determined by HPLC with a Chiralpak OD-H column
ated the reaction and provided 3a in excellent yield and
(hexane:2-propanol 5 80:20, k 5 210 nm, 0.8 ml/min); tR (major enan-
enantioselectivity (Table 2, entry 7). CH3CO2H is less effi-
tiomer) 5 18.88 min, tR (minor enantiomer) 5 26.53 min, 72% ee.
cient than PhCOOH (Table 2, entry 8). On the other hand,
the reaction was inhibited completely while CF3CO2H was
RESULTS AND DISCUSSION
Pyrrolidine-sulfamides 1a–1d were prepared in good
yields via stepwise reactions of amines and (S)-N-Boc-2-ami-
nomethyl-pyrrolidine with catechol sulfate (Scheme 1).16,48,49
The conjugate addition of cyclohexanone to trans-b-nitrostyr-
ene (2a) was examined using 1a–1d as the catalysts, and
the results are summarized in Table 1. The catalyst 1a pro-
vided the expected product 3a in good yield and enantiose-
lectivity (Table 1, entry 1). Slightly better enantioselectivity
was achieved with the catalyst 1b (Table 1, entry 2). The
catalysts 1c and 1d, which are derived from (R)- and (S)-1-
phenylethylamine, respectively, afforded 3a in the same
absolute configurations, and with similar yields and enantio-
selectivities (Table 1, entries 3–4). The result suggests that
the enantioselectivity of the reaction is mainly controlled by
chiral pyrrolidine unit and the additional chiral center at the
side chain only exerts neglectable effects.
TABLE 1. Screening of pyrrolidine-sulfamides 1a–1da
Entry
Catalyst
Yield (%)b
Drc (syn:trans)
Ee (%)d,e syn
1
2
3
4
1a
1b
1c
1d
82
79
76
73
94:6
96:4
96:4
97:3
89
92
91
89
aThe reactions were performed with cyclohexanone (1.60 mmol), 2a (0.20
mmol), and 1a–1d (0.04 mmol) in CH2Cl2 (0.5 ml) at room temperature for
20 h.
bIsolated yields.
A number of reaction solvents were screened using 1b as
the catalyst and the results are listed in Table 2. CHCl3
provided similar result with CH2Cl2 (Table 2, entry 2). Hex-
ane afforded for slightly lower yield and enantioselectivity
cDetermined by 1H NMR analysis.
dDetermined by chiral HPLC analysis.
eThe absolute configuration of 3a was assigned as (10R, 2S) by comparing
the optical rotation with the reported data.25
Chirality DOI 10.1002/chir

236
WANG ET AL.
TABLE 2. Effect of reaction solvents, additives,
and temperaturea
TABLE 4. Reaction of ketones and isobutyraldehyde
with b-nitrostyrenea
Time Yield
Dr
Ee
Entry Solvent
Additive
(h)
(%)
(syn:trans) (%) syn
1
2
3
4
CH2Cl2
CHCl3
Hexane
–
–
–
–
–
20
20
20
20
20
11
6
79
78
74
88
trace
80
98
90
trace
98
91
96:4
96:4
95:5
93:7
–
95:5
96:4
94:6
–
92
93
90
84
–
94
94
91
–
Time Yield
(h)
Drc
(syn:trans)
Ee (%)d
syn
Toluene
i-PrOH
Entry
1
Product
(%)b
5
6b
7b
8b
9b
10b,c
11b,d
–
–
–
–
–
–
–
14
94
99:1
70
PhCO2H
CH3CO2H
CF3CO2H
PhCO2H
PhCO2H
6
20
12
22
4a
97:3
96:4
96
95
2
5d
34
99:1
92
aThe reactions were performed with cyclohexanone (1.60 mmol), 2a (0.20
mmol), 1b (0.04 mmol), and the additive (0.04 mmol) in solvent (0.5 ml) at
room temperature.
4b
4c
3
4
15
24
85
94
–
48
bCyclohexanone (0.5 ml) was used.
cThe reaction was performed at 08C.
d10 mol % 1b was used.
65:35
28/10
used as the additive (Table 2, entry 9). The decrease of reac-
tion temperature resulted in better enantioselectivity and dia-
stereoselectivity (Table 2, entry 10). The loading of 1b could
be reduced to 10 mol % without the erosion of enantioselec-
tivity, however lower yield was obtained (Table 2, entry 11).
The reaction of cyclohexanone with a variety of b-aryl-
nitroethylenes was examined, and the results are summar-
ized in Table 3. Excellent yields, enantioselectivities, and
diastereoselectivities were generally achieved for ortho-,
meta-, and para-substituted b-nitrostyrenes (Table 3, entries
1–10). Both electron-withdrawing groups and electron-donat-
4d
4e
5
120
144
–
–
–
–
6e
40
72
4f
aThe reactions were performed with ketones or isobutyraldehyde (0.5 mL),
2a (0.2 mmol), PhCO2H (0.04 mmol), and 1b (0.04 mmol) at 08C under sol-
vent free condition.
bIsolated yields.
cDetermined by 1H NMR analysis.
TABLE 3. Reaction of b-aryl-nitroethylenes with cyclohexa-
none catalyzed by 1ba
dDetermined by chiral HPLC analysis.
eThe reaction was performed at room temperature.
ing groups were tolerated very well. In addition, b-naphthyl-
nitroethylene and b-heteroaryl nitroethylenes also provided
the products in excellent yields and enantioselectivities
(Table 3, entries 11–13). b-Isopropyl nitroethylene showed
lower reactivity than b-aryl-nitroethylenes. After extended
reaction time, the corresponding product could be obtained in
excellent enantioselectivity and good yield (Table 3, entry 14).
Several other ketones and isobutyraldehyde were also
examined in the reaction with b-nitrostyrene, and the results
are summarized in Table 4. 4-Oxo-cyclohexanone provided
the product in good yield and excellent diastereoselectivity,
however with moderate enantioselectivity (Table 4, entry 1).
Good yield, diastereoselectivity, and enantioselectivity were
achieved for pentan-3-one (Table 4, entry 2). Acetone could
also be used in the reaction, but the enantioselectivity is low
(Table 4, entry 3). Even lower enantioselectivity was
observed for the reaction of 2-hydroxy acetone (Table 4,
entry 4). Acetophenone was found to be unreactive under
these conditions (Table 4, entry 5). The reaction of isobutyr-
aldehyde provided the product in low yield and with moder-
ate enantioselectivity (Table 4, entry 6).
Time
Yield
Drc
Ee (%)d
syn
Entry
R3
(h) Product (%)b (syn:trans)
1
2
3
4
5
6
7
8
Ph
12
12
14
12
12
11
12
11
12
11
13
12
12
108
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
98
99
99
99
96
97
92
98
99
99
95
96
98
78
97:3
96:4
98:2
95:5
97:3
95:5
93:7
98:2
97:3
99:1
99:1
92:8
89:11
99:1
96
90
97
91
94
93
91
93
95
95
93
91
89
95
4-Me-C6H4
4-MeO-C6H4
4-F-C6H4
4-Cl-C6H4
4-Br-C6H4
3-Cl-C6H4
2,4-diCl-C6H4
2-Br-C6H4
2-NO2-C6H4
1-Naphthyl
2-Furanyl
2-Thiophenyl
2-Propyl
9
10
11
12
13
14
aThe reactions were performed with cyclohexanone (0.5 ml), 2a (0.2 mmol),
PhCO2H (0.04 mmol), and 1b (0.04 mmol), at 08C under solvent free condi-
A reaction transition state is proposed (Scheme 2).25 The
enamine intermediate is generated from the reaction of
cyclohexanone and the catalyst 1b. The H-bonding interac-
tion.
bIsolated yields.
cDetermined by 1H NMR analysis.
dDetermined by chiral HPLC analysis.
Chirality DOI 10.1002/chir

ADDITION OF KETONES TO NITROALKENES
237
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Chirality DOI 10.1002/chir