Asymmetric Michael reaction of aldehydes with β-nitroalkenes catalyzed by pyrrolidine-camphor derived organocatalysts bearing hydrogen-bond donors

Article abstract of DOI:10.1002/chir.21991

Several pyrrolidine-camphor derived organocatalysts were designed and synthesized. These organocatalysts were used for direct Michael reaction of aldehydes with nitroalkenes to give the desired γ-nitrocarbonyl compounds in high yields (up to 99%), high di

Full text of DOI:10.1002/chir.21991

CHIRALITY 24:271–275 (2012)
Asymmetric Michael Reaction of Aldehydes with b-Nitroalkenes
Catalyzed by Pyrrolidine–Camphor Derived Organocatalysts
Bearing Hydrogen-Bond Donors
y
y
*
JIANG WENG, HUI-BING AI, REN-SHI LUO, AND GUI LU
Institute of Medicinal Chemistry, School of Pharmaceutical Sciences, Sun Yat-sen University,
Guangzhou, People’s Republic of China
ABSTRACT
Several pyrrolidine–camphor derived organocatalysts were designed and
synthesized. These organocatalysts were used for direct Michael reaction of aldehydes with
nitroalkenes to give the desired g-nitrocarbonyl compounds in high yields (up to 99%), high
diastereoselectivities (syn:anti up to 92:8), and good to excellent enantioselectivities (up to
94% ee). Possible transition-state model was also proposed for this asymmetric transformation,
which may involve hydrogen-bond interactions between the nucleophilic enamine formed in
C
VV
situ and the nitroalkenes. Chirality 24:271–275, 2012.
2012 Wiley Periodicals, Inc.
KEY WORDS: asymmetric catalysis; organocatalysis; camphor; sulfonamide; Michael reaction;
nitroalkene; aldehyde; hydrogen bond
INTRODUCTION
the camphorsulfonamide-based proline derivatives and their
impacts on the organocatalytic Michael reactions of alde-
hydes with nitroalkenes.
Chiral g-nitrocarbonyl compounds are important precur-
sors for many bioactive compounds such as oseltamivir,1
nakadomarin A,2 baclofen,3 rolipram,4 and esermethole.5
Considerable efforts have been paid on the development of
efficient synthetic methods for these versatile compounds.6
Among them, asymmetric Michael reaction of carbonyl com-
pounds to nitroalkenes is perhaps the most straightforward
and useful approach.7 On the other hand, organocatalytic
reactions have attracted much attention in recent years.8 In
2001, Betancort and Barbas9 reported the first organocata-
lytic asymmetric Michael reaction of unmodified aldehydes
to nitroolefins using chiral secondary amine as catalyst.
Afterward, numerous selective and efficient catalysts includ-
ing chiral proline derivatives and bifunctional primary amine-
thioureas were developed in this transformation.10–12
Recently, we have developed a series of new perhydroindole
derived organocatalysts, which readily facilitated the reaction of
a wide range of aldehydes and nitroalkenes, providing Michael
adducts in nearly optically pure form (99% ee), good yields, and
high diastereoselectivities (syn/anti up to 99:1).13 In continua-
tion of our interest in using rigid cyclic compounds, such as per-
hydroindole,14 binaphthalene,15 and camphor,16 as backbones
of catalysts or ligands, we decided to investigate the potential of
pyrrolidine–camphor derived organocatalysts 1–3 (Fig. 1),
whose bulky rigid camphor ring could exert stereocontrolling
influence, while the inherent secondary amine and sulfonamide
(or amide) moieties could activate both the nucleophilic and the
electrophilic substrates via the enamine formation process and
hydrogen-bond activation simultaneously.
EXPERIMENTAL
General Methods
Unless otherwise stated, all reagents were used as purchased from
commercial suppliers without additional purification. The solvents were
distilled from standard drying agents. Air and/or moisture sensitive
reactions were performed under the inert atmospheric conditions. Purifi-
cation of reaction products was carried out by flash column chromatogra-
phy with silica gel (200–300 mesh) purchased from Qingdao Haiyang
Chemical Co. Ltd. 1H NMR spectra were recorded on a Bruker AVANCE
400 spectrometer. Chemical shifts were reported as parts per million
(ppm) in the d scale downfield from tetramethylsilane. Peaks are labeled
as singlet (s), doublet (d), triplet (t), quartet (q), and multiplet (m). 13C
NMR spectra were recorded on Bruker spectrometer with complete pro-
ton decoupling, and chemical shifts were reported in ppm from TMS
with the solvent as the internal reference (CDCl3, d 5 77.0 ppm). High-
performance liquid chromatography (HPLC) analyses were conducted
on Agilent 1200 instrument using Chiralcel OD-H, Chiralpak AD-H or
AS-H columns (0.46 cm diameter 3 25 cm length). Optical rotations
were recorded on a Perkin Elmer polarimeter (Model 341). MS spectra
were recorded on an electrospray ionization (ESI)-ion trap Mass spec-
trometer (Shimadzu LCMS-IT-TOF). Key intermediate 7 and organocata-
lysts 1–3 were prepared using similar procedures with literatures.21–23
General Procedure for the Michael Addition Reaction
To a solution of nitrostyrene (74.5 mg, 0.5 mmol) and 2 (32 mg,
0.1 mmol) in toluene (0.8 mL), propanal (0.18 mL, 2.5 mmol) was added
at room temperature. The reaction mixture was stirred for 24 h. Then,
the solvent was removed, and the residue was purified by flash column
It should be noted that during our research, several pyrrol-
idine–camphor organocatalysts linked with amine, amide,
and sulfide functionalities (4–6) were developed and applied
in asymmetric Michael reactions with high diastereoselectiv-
ity and enantioselectivity.17–19 In contrast, sulfonamide-linked
catalysts 1–3 have never been used in similar reactions,
although 1–2 have already been used in direct a-amination
of aldehyde with dialkylazodicarboxylates and afforded the
desired a-aminated products in good chemical yields and
stereoselectivities.20 Herein, we wish to report our results on
yThese authors contributed equally to this paper.
Contract grant sponsor: European Commission funded project; Contract grant
number: FP7-201431(CATAFLU.OR).
Contract grant sponsor: Guangdong Recruitment Program of Creative
Research Groups.
*Correspondence to: Gui Lu, Institute of Medicinal Chemistry, School of
Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006,
People’s Republic of China. E-mail: lugui@mail.sysu.edu.cn
Received for publication 28 July 2011; Accepted 5 December 2011
DOI: 10.1002/chir.21991
Published online 25 January 2012 in Wiley Online Library
(wileyonlinelibrary.com).
C
VV
2012 Wiley Periodicals, Inc.

272
WENG ET AL.
1H). 13C NMR (100 MHz, CDCl3): d 5 11.4, 27.4, 47.8, 76.9, 121.4, 123.0,
124.2, 125.0, 125.8, 127.6, 128.3, 130.0, 132.3, 133.1, 201.5.
(2R,3R)-2-Methyl-4-nitro-3-(thiophen-2-yl)butanal (16f). Color-
less oil (75% yield), ee 5 87%.13 The enantiomeric excess was determined
by HPLC with a Daicel Chiralpak AD-H column (n-hexane/i-PrOH 5
99/1, 1.0 mL/min, k 5 238 nm), tR 5 29.8 min (major), tR 5 40.8 min
1
(minor). H NMR (400 MHz, CDCl3): d 5 1.14 (d, J 5 7.3 Hz, 3H), 2.79
(dd, J 5 1.2, 6.1 Hz, 1H), 4.25 (dt, J 5 6.1, 8.2 Hz, 1H), 4.69 (dd, J 5 8.8,
12.9 Hz, 1H), 4.79 (dd, J 5 5.8, 12.9 Hz, 1H), 6.88–6.90 (m, 2H), 7.17–
7.24 (m, 1H), 9.70 (d, J 5 1.2 Hz, 1H). 13C NMR (100 MHz, CDCl3): d 5
11.5, 39.4, 48.8, 78.4, 125.3, 126.7, 127.1, 138.8, 201.7.
Fig. 1. Various pyrrolidine–camphor organocatalysts.
(2R,3R)-3-Furyl-2-methyl-4-nitrobutanal (16g). Colorless oil (86%
yield), ee 5 80%.13 The enantiomeric excess was determined by HPLC
with a Daicel Chiralpak AD-H column (n-hexane/i-PrOH 5 99/1, 1.0
mL/min, k 5 210 nm), tR 5 24.4 min (major), tR 5 28.0 min (minor). 1H
NMR (400 MHz, CDCl3): d 5 1.30 (d, J 5 7.2 Hz, 3H), 2.97–3.11 (m,
1H), 4.31 (m, 1H), 4.88–5.02 (m, 2H), 6.37–6.45 (m, 1H), 6.51–6.56 (m,
1H), 7.58 (d, J 5 1.7 Hz, 1H), 9.93 (d, J 5 1.7 Hz, 1H). 13C NMR (100
MHz, CDCl3): d 5 11.0, 37.6, 47.0, 75.8, 108.8, 110.4, 142.7, 149.8, 201.6.
chromatography on silica gel using ethyl acetate/hexane (1:5) as the elu-
ent to afford the Michael adduct. Assignment of the stereoisomers was
performed by comparison with literature data. The value of syn/anti ratio
was determined by 1H NMR by comparing different integrations of
hydrogens of the aldehyde group. The enantiomeric excess was meas-
ured by HPLC with Chiralcel OD-H, Chiralpak AD-H or AS-H columns.
(2S,3R)-3-Cyclohexyl-2-methyl-4-nitrobutanal (16h). Colorless
oil (70% yield), ee 5 55%.13 The enantiomeric excess was determined by
HPLC with a Daicel Chiralpak AD-H column (n-hexane/i-PrOH 5 99/1,
1.0 mL/min, k 5 210 nm), tR 5 15.2 min (major), tR 5 19.1 min (minor).
1H NMR (400 MHz, CDCl3): d 5 0.81–0.93 (m, 3H), 0.96–1.00 (m, 2H),
1.13 (d, J 5 6.8 Hz, 3H), 1.34–1.70 (m, 6H), 2.48–2.67 (m, 2H), 4.29–4.36
(m, 1H), 4.50–4.55 (m, 1H), 9.61 (s, 1H). 13C NMR (100 MHz, CDCl3): d
5 9.7, 25.0, 25.2, 25.3, 28.9, 30.5, 36.9, 42.4, 45.6, 76.4, 202.2.
Characterization of Micheal Addition Products
(2R,3S)-2-Methyl-4-nitro-3-phenylbutanal (16a). Colorless oil
(91% yield), ee 5 94%.13 The enantiomeric excess was determined by
HPLC with a Daicel Chiralcel OD-H column (n-hexane/i-PrOH 5 85/15,
0.8 mL/min, k 5 208 nm), tR 5 18.0 min (minor), tR 5 24.0 min (major).
1H NMR (400 MHz, CDCl3): d 5 1.01 (d, J 5 7.3 Hz, 3H), 2.64–2.72 (m,
1H), 3.82 (td, J 5 5.5, 9.2 Hz, 1H), 4.69 (dd, J 5 9.3, 12.7 Hz, 1H), 4.81
(dd, J 5 5.5, 12.7 Hz, 1H), 7.16–7.18 (m, 2H), 7.26–7.28 (m, 3H), 9.72 (d,
J 5 1.7 Hz, 1H). 13C NMR (100 MHz, CDCl3): d 5 12.1, 44.0, 48.4, 78.1,
128.0, 128.1, 129.1, 136.5, 202.2.
(2R,3R)-2,5-Dimethyl-3-(nitromethyl)-hexanal (16i). Colorless
oil (99% yield), ee 5 49%.13 The enantiomeric excess was determined by
HPLC with a Daicel Chiralpak AD-H column (n-hexane/i-PrOH 5 99/1,
1.0 mL/min, k 5 210 nm), tR 5 8.2 min (major), tR 5 10.2 min (minor).
1H NMR (400 MHz, CDCl3): d 5 0.91 (d, J 5 7.6 Hz, 3H), 0.95 (d, J 5
7.6 Hz, 3H), 1.14 (d, J 5 7.1 Hz, 3H), 1.20–1.24 (m, 1H), 1.54–1.62 (m,
2H), 2.50–2.54 (m, 1H), 2.78–2.83 (m, 1H), 4.32–4.34 (m, 1H), 4.42–4.44
(m, 1H), 9.68 (s, 1H). 13C NMR (100 MHz, CDCl3): d 5 8.7, 21.8, 23.0,
25.3, 35.0, 37.4, 47.1, 77.1, 202.6.
(2R,3S)-2-Methyl-4-nitro-3-(2-methoxyphenyl)-butanal (16b).
Colorless oil (87% yield), ee 5 89%.13 The enantiomeric excess was deter-
mined by HPLC with a Daicel Chiralcel OD-H column (n-hexane/i-PrOH
5 99/1, 1.0 mL/min, k 5 208 nm), tR 5 36.6 min (major), tR 5 40.2 min
(minor). 1H NMR (400 MHz, CDCl3): d 5 1.12 (d, J 5 7.5 Hz, 3H),
3.18 (m, 1H), 4.02 (s, 3H), 4.21 (m, 1H), 4.92 (m, 1H), 5.04 (m, 1H),
7.06–7.46 (m, 4H), 9.90 (s, 1H). 13C NMR (100 MHz, CDCl3): d 5 12.1,
40.5, 47.1, 55.3, 111.1, 120.9, 124.4, 129.3, 130.3, 157.3, 202.8.
(2R,3S)-2-Ethyl-4-nitro-3-phenylbutanal (16j). Colorless oil
(91% yield), ee 5 72%.13 The enantiomeric excess was determined by
HPLC with a Daicel Chiralcel OD-H column (n-hexane/i-PrOH 5 85/15,
0.8 mL/min, k 5 208 nm), tR 5 18.6 min (major), tR 5 15.3 min (minor).
1H NMR (400 MHz, CDCl3): d 5 0.71 (t, J 5 7.5 Hz, 3H), 1.35–1.44 (m,
2H), 2.56–2.62 (m, 1H), 3.68–3.74 (m, 1H), 4.51–4.69 (m, 2H), 7.09–7.25
(m, 5H), 9.67 (d, J 5 2.5 Hz, 1H). 13C NMR (100 MHz, CDCl3): d 5 10.5,
20.2, 42.6, 54.9, 78.5, 128.0, 128.2, 129.0, 136.9, 203.3.
(2R,3S)-2-Methyl-4-nitro-3-(4-methoxyphenyl)-butanal (16c). Color-
less oil (77% yield), ee 5 90%.13 The enantiomeric excess was determined
by HPLC with a Daicel Chiralpak AS-H column (n-hexane/i-PrOH 5 85/
15, 1.0 mL/min, k 5 208 nm), tR 5 20.2 min (minor), tR 5 26.9 min
(major). 1H NMR (400 MHz, CDCl3): d 5 1.01 (d, J 5 7.3 Hz, 3H), 1.21
(d, J 5 7.2 Hz, 1H), 2.65–2.67 (m, 1H), 3.79 (s, 3H), 4.64 (dd, J 5 9.4,
12.5 Hz, 1H), 4.62–4.71 (m, 1H), 6.79–6.84 (m, 1H), 7.01–7.06 (m, 3H),
9.71 (d, J 5 1.7 Hz, 1H). 13C NMR (100 MHz, CDCl3): d 5 12.0, 43.3,
48.6, 55.2, 78.3, 114.4, 128.3, 129.1, 159.3, 202.4.
(2R,3S)-2-Propyl-4-nitro-3-phenylbutanal (16k). Colorless oil
(83% yield), ee 5 43%.13 The enantiomeric excess was determined by
HPLC with a Daicel Chiralcel OD-H column (n-hexane/i-PrOH 5 85/15,
0.8 mL/min, k 5 208 nm), tR 5 19.1 min (major), tR 5 14.7 min (minor).
1H NMR (400 MHz, CDCl3): d 5 0.69 (t, J 5 7.1 Hz, 3H), 1.06–1.42 (m,
4H), 2.59–2.66 (m, 1H), 3.67–3.73 (m, 1H), 4.53–4.65 (m, 2H), 7.08–7.27
(m, 5H), 9.60 (d, J 5 2.5 Hz, 1H). 13C NMR (100 MHz, CDCl3): d 5 12.9,
18.6, 28.3, 42.0, 52.7, 77.4, 127.0, 127.0, 128.0, 135.8, 202.4.
(2R,3S)-3-(4-Bromophenyl)-2-methyl-4-nitrobutanal (16d). White
solid (93% yield), ee 5 79%.18 The enantiomeric excess was determined
by HPLC with a Daicel Chiralcel OD-H column (n-hexane/i-PrOH 5
90/10, 1.0 mL/min, k 5 254 nm), tR 5 27.5 min (major), tR 5 29.6 min
(minor). 1H NMR (400 MHz, CDCl3): d 5 1.01 (d, J 5 7.3 Hz, 3H), 2.63–
2.92 (m, 1H), 3.51–3.67 (m, 1H), 4.65 (dd, J 5 9.6, 12.8 Hz, 1H), 4.80
(dd, J 5 5.2, 12.8 Hz, 1H), 7.13–7.23 (m, 2H), 7.52–7.55 (m, 2H), 9.70 (d,
J 5 1.5 Hz, 1H). 13C NMR (100 MHz, CDCl3): d 5 12.2, 43.5, 48.2, 122.2,
129.7, 129.8, 132.3, 135.6, 201.8.
(2R,3S)-2-Isopropyl-4-nitro-3-phenylbutanal (16l). Colorless oil
(92% yield), ee 5 59%.13 The enantiomeric excess was determined by
HPLC with a Daicel Chiralcel OD-H column (n-hexane/i-PrOH 5 85/15,
0.8 mL/min, k 5 208 nm), tR 5 22.1 min (major), tR 5 20.4 min (minor).
1H NMR (400 MHz, CDCl3): d 5 0.87 (d, J 5 7.0 Hz, 3H), 1.09 (d, J 5 7.2
Hz, 3H), 1.66–1.75 (m, 1H), 2.76–2.80 (m, 1H), 4.54–4.69 (m, 2H), 7.18–
7.36 (m, 5H), 9.91 (d, J 5 2.4 Hz, 1H). 13C NMR (100 MHz, CDCl3): d 5
16.9, 21.6, 27.9, 41.9, 58.6, 79.0, 127.9, 128.0, 129.1, 137.1, 204.4.
(2R,3S)-2-Methyl-3-(1-naphthalenyl)-4-nitrobutanal (16e). Color-
less oil (83% yield), ee 5 75%.13 The enantiomeric excess was determined
by HPLC with a Daicel Chiralcel OD-H column (n-hexane/i-PrOH 5
75/25, 0.8 mL/min, k 5 208 nm), tR 5 26.4 min (major), tR 5 19.5 min
(minor). 1H NMR (400 MHz, CDCl3): d 5 0.87 (d, J 5 7.3 Hz, 3H), 2.86–
2.91 (m, 1H), 4.67–4.85 (m, 3H), 7.25–7.50 (m, 4H), 7.71 (d, J 5 8.2 Hz,
1H), 7.78 (d, J 5 8.0 Hz, 1H), 8.01–8.03 (m, 1H), 9.65 (d, J 5 1.6 Hz,
(2R,3S)-2-Butyl-4-nitro-3-phenylbutanal (16m). Colorless oil
(95% yield), ee 5 51%.13 The enantiomeric excess was determined by
HPLC with a Daicel Chiralcel OD-H column (n-hexane/i-PrOH 5 85/15,
Chirality DOI 10.1002/chir

PYRROLIDINE–CAMPHOR DERIVED ORGANOCATALYSTS
273
Scheme 1. Preparation of organocatalysts 1–3.
0.8 mL/min, k 5 208 nm), tR 516.8 min (major), tR 513.5 min (minor).
1H NMR (400 MHz, CDCl3): d 5 0.78 (t, J 5 6.8 Hz, 3H), 1.12–1.30
(m, 4H), 1.42–1.45 (m, 1H), 1.40–1.44 (m, 1H), 2.62–2.67 (m, 1H), 3.78
(m, 1H), 4.64 (dd, J 5 9.9, 12.9 Hz, 1H), 4.71 (dd, J 5 5.1, 12.9 Hz, 1H),
7.08–7.16 (m, 2H), 7.35–7.26 (m, 3H), 9.69 (d, J 5 2.6 Hz, 1H). 13C NMR
(100 MHz, CDCl3): d 5 13.6, 22.5, 27.0, 28.5, 43.1, 53.8, 78.4, 128.0,
128.1, 129.1, 136.7, 203.3.
dicyclohexylcarbodiimide and 4-(dimethylamino) pyridine,
followed by TFA treatment to provide 3.
Screening of Organocatalysts and Optimization of
Reaction Conditions
With pyrrolidinylcamphor compounds 1–3 in hand, we
explored their catalytic activities in the Michael reaction of
aldehydes with nitroalkenes. Initially, propanal and (E)-(2-
nitrovinyl)-benzene were chosen as model substrates. The
reaction was carried out with 20 mol % catalyst at ambient
temperature (Table 1). Catalyst 2 bearing a sulfonamide link-
age and a hydroxy functionality provided the desired adduct
in good yield (91%) and high stereoselectivity (ee up to 94%,
syn:anti 88:12). We reasoned that the free hydroxyl group of
2 may play some role in determining the stereochemical out-
comes of the reaction through activating nitroalkenes by
(2R,3S)-2-Pentyl-4-nitro-3-phenylbutanal (16n). Colorless oil
(95% yield), ee 5 62%.13 The enantiomeric excess was determined by
HPLC with a Daicel Chiralcel OD-H column (n-hexane/i-PrOH 5 85/15,
0.8 mL/min, k 5 208 nm), tR 5 11.5 min (minor), tR 5 13.8 min (major).
1H NMR (400 MHz, CDCl3): d 5 0.72 (t, J 5 6.8 Hz, 3H), 1.01–1.42 (m,
8H), 2.59–2.65 (m, 1H), 3.67–3.73 (m, 1H), 4.53–4.65 (m, 2H), 7.09 (d,
J 5 7.2 Hz, 2H), 7.18–7.27 (m, 3H), 9.61 (d, J 5 2.6 Hz, 1H). 13C NMR
(100 MHz, CDCl3): d 5 13.8, 22.1, 26.0, 27.2, 31.5, 43.1, 53.8, 78.4, 128.0,
128.0, 129.0, 136.9, 203.3.
(R)-2,2-Dimethyl-4-nitro-3-phenylbutanal (16o). Colorless oil
(67% yield), ee 5 86%.13 The enantiomeric excess was determined by
HPLC with a Daicel Chiralcel OD-H column (n-hexane/i-PrOH 5 85/15,
0.8 mL/min, k 5 208 nm), tR 5 15.3 min (major), tR 5 20.7 min (minor).
1H NMR (400 MHz, CDCl3): d 5 0.86 (s, 3H), 0.99 (s, 3H), 3.67–3.71 (m,
1H), 4.59 (dd, J 5 4.2, 13.1 Hz, 1H), 4.73–4.79 (m, 1H), 7.09–7.21 (m,
5H), 9.39 (s, 1H). 13C NMR (100 MHz, CDCl3): d 5 18.7, 21.4, 48.2, 48.3,
77.5, 128.0, 128.6, 129.1, 135.5, 204.3.
TABLE 1. The effects of organocatalysts and solvents in the
Michael reaction of propanal and (E)-(2-nitrovinyl)-benzene
Entry Catalyst Solvent Time (h) Yield (%)a syn/antib ee (%)c
RESULTS AND DISCUSSION
Preparation of Organocatalysts
1
2
3
4
5
6
7
8
1
2
3
2
2
2
2
2
2
2
Toluene
Toluene
Toluene
Hexane
THF
25
23
18
23
23
23
23
23
23
36
87
91
88
56
86
96
96
93
76
83
80:20
88:12
56:44
90:10
85:15
88:12
78:22
67:33
91:9
66
94
87
94
77
90
48
52
81
94
The chiral pyrrolidine-camphorsulfonamide catalysts were
prepared as depicted in Scheme 1. Treatment of Boc-pro-
tected (S)-2-aminomethylpyrrolidine (7) with (1S)-camphor-
10-sulfonyl chloride (8) in pyridine at 08C gave the corre-
sponding sulfonamide 9 in 71% isolated yield. Then, removal
of the N-Boc protecting group using trifluoroacetic acid
(TFA) provided catalyst 1 in 96% yield. 9 can also be
reduced by sodium borohydride at 2208C to afford the corre-
sponding exo-alcohol 10 as a single diastereoisomer, which
was then treated with TFA to generate organocatalyst 2.
More acidic sulfonamide catalyst 3 was prepared by conven-
ient coupling between N-Boc-protected L-proline (11) and
(1S)-10-camphorsulfonamide (12) in the presence of N,N0-
DCM
MeCN
MeOH
H2O
9
10d
Toluene
86:14
aYield of isolated product.
bDetermined by 1H NMR spectroscopy (400 MHz).
cThe ee value was determined by HPLC analysis on a chiral phase (Chiralcel
OD-H).
dThe reaction was performed at 08C.
Chirality DOI 10.1002/chir

274
WENG ET AL.
TABLE 2. Catalytic asymmetric Michael reaction of propanal
reaction time, yield, and diastereoselectivity and enantiose-
lectivity (entry 2). Hexane gave comparable stereoselectivity
(ee up to 94%, syn:anti 90:10), but the yield was unsatisfactory
(entry 4). Although high yields were also achieved in polar
solvents such as MeCN, MeOH, and water, the correspond-
ing diastereoselectivities and enantioselectivities were only
moderate (entries 7–9), which can be attributed to the
adverse effect of polar solvent for the formation of hydrogen-
bond between the catalyst and the substrate. The Michael
reaction can also be performed at lower temperature (08C)
without compromising the enantioselectivity and diastereose-
lectivity, albeit the yield dropped slightly and a longer reac-
tion time as 36 h was needed (entry 10).
and nitroalkenes
Entry
1
Product
Yield (%)a
91
syn/antib
ee (%)c
Michael Addition of Various Aldehydes and Nitroalkenes
88:12
94
To explore the substrate generality of this asymmetric
reaction, we examined the reaction of propanal with various
TABLE 3. Catalytic asymmetric Michael reaction of
(E)-(2-nitrovinyl)-benzene with various aldehydes
2
3
4
5
6
7
8
9
87
77
93
83
75
86
77:23
84:16
73:27
91:9
89
90
79
75
87
80
Entry
1
Product
Yield (%)a
91
syn/antib
ee (%)c
88:12
94
86:14
84:16
2
3
4
5
6
7
91
83
92
95
95
67
70:30
82:18
92:8
81:19
82:18
–
72
43
59
51
62
86
70
99
91:9
55
49
90:10
aYield of isolated product.
bDetermined by 1H NMR spectroscopy (400 MHz).
cThe ee value was determined by HPLC analysis on a chiral phase (Chiralcel
OD-H, Chiralpak AD-H or AS-H).
hydrogen bonding (entries 1 vs. 2). Similar phenomenon has
also been observed in the literature.35 The reaction was also
sensitive to the structure of catalyst. A slight improvement in
the reaction rate was observed when more acidic organocata-
lyst 3 was used, albeit poor diastereoselectivity was also
obtained (entries 2 vs. 3).
Regarding the reactivity and stereoselectivity, 2 was cho-
sen for further optimization (Table 1, entries 1–3). It
appeared that toluene was a suitable solvent with respect to
aYield of isolated product.
bDetermined by 1H NMR spectroscopy (400 MHz).
cThe ee value was determined by HPLC analysis on a chiral phase (Chiralcel
OD-H, Chiralpak AD-H or AS-H).
Chirality DOI 10.1002/chir

PYRROLIDINE–CAMPHOR DERIVED ORGANOCATALYSTS
275
LITERATURE CITED
1. Ishikawa H, Suzuki T, Hayashi Y. High-yielding synthesis of the anti-
influenza neuramidase inhibitor (2)-oseltamivir by three ‘‘one-pot’’ opera-
tions. Angew Chem Int Ed 2009;48:1304–1307.
2. Jakubec P, Cockfield DM, Dixon DJ. Total synthesis of (2)-nakadomarin
A. J Am Chem Soc 2009;131:16632–16633.
Fig. 2. Proposed transition state model for the Michael reaction.
3. Zu LS, Xie HX, Li H, Wang J, Wang W. Highly enantioselective organoca-
talytic conjugate addition of nitromethane to a,b-unsaturated aldehydes:
three-step synthesis of optically active baclofen. Adv Synth Catal 2007;
349:2660–2664.
substituted b-nitroalkenes under optimal condition, and the
results were summarized in Table 2. The reaction proceeded
smoothly in toluene at room temperature in the presence of
2. High chemical yields, good diastereoselectivities, and
enantioselectivities (75–94% ee) were obtained when aromatic
nitroalkenes were used. Electron-rich aromatic nitroalkenes
performed better over the electron-deficient aromatic nitroal-
kenes (entries 2–5). Heteroaryl-substituted nitroalkenes,
such as 14f and 14g, also yielded the corresponding
adducts with good selectivities (87% and 80% ee respectively;
entries 6–7). The reaction with alkyl-substituted nitroalkenes
resulted lower enantioselectivities (entries 8–9), and longer
reaction time was needed for complete conversion.
A variety of aldehydes were also used in the asymmetric
Michael reaction of trans-b-nitrostyrene, affording the desired
g-nitro aldehyde products in good yields and diastereoselec-
tivities (Table 3). The enantioselectivities were influenced by
the length of the chains of aliphatic aldehydes (entries 1–3
and 5–6) and the steric hindrance around a-carbon of
aldehydes (entries 4 and 7). Best results were achieved for
propanal in 91% yield, 88:12 diastereoselectivity (syn:anti),
and 94% enantioselectivity. Branched aldehydes, such as
isobutylaldehyde and isovaleraldehyde, need longer reaction
time to ensure full conversions (entries 4 and 7).
4. Palomo C, Landa A, Mielgo A, Oiarbide M, Puente A, Vera S. Water-com-
patible iminium activation: organocatalytic Michael reactions of carbon-
centered nucleophiles with enals. Angew Chem Int Ed 2007;46:8431–8435.
5. Bui T, Syed S, Barbas CF III. Thiourea-catalyzed highly enantio- and
diastereoselective additions of oxindoles to nitroolefins: application to the for-
mal synthesis of (1)-physostigmine. J Am Chem Soc 2009;131;8758–8759.
6. Roca-Lopez D, Sadaba D, Delso I, Herrera RP, Tejero T, Merino P. Asymmet-
ric organocatalytic synthesis of g-nitrocarbonyl compounds through Michael
and domino reactions. Tetrahedron: Asymmetry 2010;21:2561–2601.
7. Berner OM, Tedeschi L, Enders D. Asymmetric Michael additions to
nitroalkenes. Eur J Org Chem 2002;1877–1894.
8. Dalko PI. Enantioselective organocatalysis. Weinheim: Wiley-VCH; 2007.
9. Betancort JM, Barbas CF III. Catalytic direct asymmetric Michael reac-
tions: taming naked aldehyde donors. Org Lett 2001;3:3737–3740.
10. Tsogoeva SB. Recent advances in asymmetric organocatalytic 1,4-conju-
gate additions. Eur J Org Chem 2007;1701–1716.
11. Almasi D, Alonso DA, Najera C. Organocatalytic asymmetric conjugate
additions. Tetrahedron: Asymmetry 2007;18:299–365.
12. Vicario JL, Badia D, Carrillo L. Organocatalytic enantioselective Michael
and hetero-Michael reactions. Synthesis 2007;2065–2092.
13. Luo RS, Weng J, Ai HB, Lu G, Chan ASC. Highly efficient asymmetric Mi-
chael reaction of aldehydes to nitroalkenes with diphenylperhydroindoli-
nol silyl ethers as organocatalysts. Adv Synth Catal 2009;351:2449–2459.
14. Lin N, Chen MM, Luo RS, Deng YQ, Lu G. Indolinylmethanol catalyzed
enantioselective Reformatsky reaction with ketones. Tetrahedron: Asym-
metry 2010;21:2816–2824.
Proposed Transition-State Model
15. Lu G, Kwong FY, Ruan JW, Li YM, Chan ASC. Highly enantioselective addi-
tion of in situ prepared arylzinc to aldehydes catalyzed by a series of atropiso-
meric binaphthyl-derived amino alcohols. Chem Eur J 2006; 12:4115–4120.
According to the general mechanism of enamine catalysis
and the stereochemical outcome in the current Michael reac-
tions, we propose that pyrrolidine-camphorsulfonamide 2
catalyze the reaction of aldehydes with nitroalkenes via the
transition state shown in Figure 2. The pyrrolidine reacts
with aldehyde to form an enamine intermediate. Meanwhile,
the nitroalkene could be activated through the formation of
hydrogen bond with NH and OH groups on the camphorsul-
fonamide moiety. The rigid camphor scaffold could selec-
tively shield the approach of the nitroalkene from the Re-face
of enamine to generate the major isomer.
16. Lu G, Li XS, Jia X, Chan WL, Chan ASC. Enantioselective alkynylation of
aromatic ketones catalyzed by chiral camphorsulfonamide ligands.
Angew Chem Int Ed 2003;42:5057–5058.
17. Chang C, Li SH, Reddy RJ, Chen KM. Pyrrolidine–camphor derivative as an
catalyst for asymmetric Michael additions of a,a-disubstituted aldehydes to
b-nitroalkenes: construction of quaternary carbon-bearing aldehydes under
solvent-free conditions. Adv Synth Catal 2009;351:1273–1278.
18. Reddy RJ, Kuan HH, Chou TY, Chen KM. Novel Prolinamide-camphor-
containing organocatalysts for direct asymmetric Michael addition of
unmodified aldehydes to nitroalkenes. Chem Eur J 2009;15:9294–9298.
19. Ting YF, Chang C, Reddy RJ, Magar DR, Chen KM. Pyrrolidinyl-
camphor derivatives as a new class of organocatalyst for direct asymmetric
Michael addition of aldehydes and ketones to b-nitroalkenes. Chem Eur J
2010;16:7030–7038.
CONCLUSIONS
In conclusion, we have used bifunctional pyrrolidine-cam-
phorsulfonamide organocatalysts in the reaction of a wide
range of aldehydes and nitroalkenes and obtained Michael
adducts in high yields (up to 99%), high diastereoselectivities
(syn:anti up to 92:8), and good to excellent enantioselectiv-
ities (up to 94%). Besides the pyrrolidine structural unit and
the camphor scaffold, the appropriate linker functionality as
well as the free hydroxyl group also contributed significantly
toward the diastereoselectivity and enantioselectivity of
the reaction. Further studies on the application of these
pyrrolidine-camphorsulfonamide catalysts in asymmetric
Michael reaction and other stereoselective synthesis are
now in progress.
20. Liu PM, Magar DR, Chen, KM. Highly efficient and practical
pyrrolidine–camphor-derived organocatalysts for the direct a-amination
of aldehydes. Eur J Org Chem 2010;5705–5713.
21. Morris DJ, Partridge AS, Manville CV, Racys DT, Woodward G, Doch-
erty G, Wills M. Asymmetric organocatalysis of the addition of acetone to
2-nitrostyrene using N-diphenylphosphinyl-1,2- diphenylethane-1,2-dia-
mine (PODPEN). Tetrahedron Lett 2009;51:209–212.
22. Liu PM, Chang C, Reddy RJ, Ting YF, Kuan HH, Chen KM. Remarkable
reaction rate and excellent enantioselective direct aa-amination of alde-
hydes with azodicarboxylates catalyzed by pyrrolidinylcamphor-derived
organocatalysts. Eur J Org Chem 2010;42–46.
23. Bellis E, Vasilatou K, Kokotos G. 4-Substituted prolyl sulfonamides as
enantioselective organocatalysts for aldol reactions. Synthesis 2005;2407–
2413.
Chirality DOI 10.1002/chir